WO1992019627A2 - Phosphonates and phosphinates as anti-cancer, -inflammatory, -allergy and -myocarditis agents - Google Patents
Phosphonates and phosphinates as anti-cancer, -inflammatory, -allergy and -myocarditis agents Download PDFInfo
- Publication number
- WO1992019627A2 WO1992019627A2 PCT/CA1992/000165 CA9200165W WO9219627A2 WO 1992019627 A2 WO1992019627 A2 WO 1992019627A2 CA 9200165 W CA9200165 W CA 9200165W WO 9219627 A2 WO9219627 A2 WO 9219627A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- group
- administered
- phosphonate
- treatment
- Prior art date
Links
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 8
- 230000003266 anti-allergic effect Effects 0.000 title abstract description 7
- 230000001093 anti-cancer Effects 0.000 title abstract description 7
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title description 30
- 208000009525 Myocarditis Diseases 0.000 title description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 25
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 23
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical group NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims abstract description 17
- CDAISMWEOUEBRE-UHFFFAOYSA-N inositol Chemical group OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 12
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 12
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims abstract description 7
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims abstract description 7
- 229960000367 inositol Drugs 0.000 claims abstract description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims abstract description 5
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960001231 choline Drugs 0.000 claims abstract description 5
- 229940031098 ethanolamine Drugs 0.000 claims abstract description 5
- 229960005150 glycerol Drugs 0.000 claims abstract description 5
- 229960001153 serine Drugs 0.000 claims abstract description 5
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims abstract description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 47
- 239000003937 drug carrier Substances 0.000 claims description 22
- 241000124008 Mammalia Species 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims description 18
- -1 phosphonate compound Chemical class 0.000 claims description 17
- 208000006673 asthma Diseases 0.000 claims description 13
- 201000011510 cancer Diseases 0.000 claims description 13
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 12
- 208000010201 Exanthema Diseases 0.000 claims description 12
- 230000000172 allergic effect Effects 0.000 claims description 12
- 208000010668 atopic eczema Diseases 0.000 claims description 12
- 201000005884 exanthem Diseases 0.000 claims description 12
- 206010037844 rash Diseases 0.000 claims description 12
- 231100000046 skin rash Toxicity 0.000 claims description 12
- 208000026935 allergic disease Diseases 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 208000027866 inflammatory disease Diseases 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 206010020751 Hypersensitivity Diseases 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 230000007815 allergy Effects 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 230000010261 cell growth Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 125000001931 aliphatic group Chemical group 0.000 abstract description 4
- 125000004437 phosphorous atom Chemical group 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 3
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 17
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 14
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 14
- 229940104230 thymidine Drugs 0.000 description 14
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 13
- 108010003541 Platelet Activating Factor Proteins 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YHHSONZFOIEMCP-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethyl hydrogen phosphate Chemical compound C[N+](C)(C)CCOP(O)([O-])=O YHHSONZFOIEMCP-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 210000000440 neutrophil Anatomy 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- BSQJJBWZWJTFEO-UHFFFAOYSA-N trimethyl(2-phosphanyloxyethyl)azanium Chemical compound C[N+](C)(C)CCOP BSQJJBWZWJTFEO-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000010348 incorporation Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- NAFSTSRULRIERK-UHFFFAOYSA-M monosodium urate Chemical compound [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108010008211 N-Formylmethionine Leucyl-Phenylalanine Proteins 0.000 description 4
- 108010067372 Pancreatic elastase Proteins 0.000 description 4
- 102000016387 Pancreatic elastase Human genes 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N glycerol 1-phosphate Chemical class OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000016942 Elastin Human genes 0.000 description 3
- 108010014258 Elastin Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- PRQROPMIIGLWRP-UHFFFAOYSA-N N-formyl-methionyl-leucyl-phenylalanin Chemical compound CSCCC(NC=O)C(=O)NC(CC(C)C)C(=O)NC(C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-UHFFFAOYSA-N 0.000 description 3
- SUHOOTKUPISOBE-UHFFFAOYSA-N O-phosphoethanolamine Chemical compound NCCOP(O)(O)=O SUHOOTKUPISOBE-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229920002549 elastin Polymers 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- LXAWQKKSNNYYEK-NRFANRHFSA-N methyl (2s)-3-hydroxy-2-(tritylamino)propanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N[C@@H](CO)C(=O)OC)C1=CC=CC=C1 LXAWQKKSNNYYEK-NRFANRHFSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- PYTMBSDYMPHFOQ-UHFFFAOYSA-N 2,2,2-trichloro-n-[4-(trifluoromethyl)phenyl]acetamide Chemical compound FC(F)(F)C1=CC=C(NC(=O)C(Cl)(Cl)Cl)C=C1 PYTMBSDYMPHFOQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 230000002959 anti-hypotensive effect Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940124572 antihypotensive agent Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000005792 cardiovascular activity Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000036543 hypotension Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical compound C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000024719 uterine cervix neoplasm Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ODYBCPSCYHAGHA-UHFFFAOYSA-N 1,2-bis(2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol Chemical compound O1C(C)(C)OCC1C(O)C(O)C1OC(C)(C)OC1 ODYBCPSCYHAGHA-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- ODTQUKVFOLFLIQ-UHFFFAOYSA-N 2-[di(propan-2-yloxy)phosphorylmethyl-propan-2-yloxyphosphoryl]oxypropane Chemical compound CC(C)OP(=O)(OC(C)C)CP(=O)(OC(C)C)OC(C)C ODTQUKVFOLFLIQ-UHFFFAOYSA-N 0.000 description 1
- 238000010600 3H thymidine incorporation assay Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- NJLHHACGWKAWKL-UHFFFAOYSA-N ClP(Cl)=O Chemical compound ClP(Cl)=O NJLHHACGWKAWKL-UHFFFAOYSA-N 0.000 description 1
- 108010075031 Cytochromes c Proteins 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 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 1
- 208000006552 Lewis Lung Carcinoma Diseases 0.000 description 1
- 238000007014 Michaelis-Becker reaction Methods 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ASVZZKJRKMAZRU-UHFFFAOYSA-N OCCP(O)=O Chemical compound OCCP(O)=O ASVZZKJRKMAZRU-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010048908 Seasonal allergy Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 206010007625 cardiogenic shock Diseases 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000006642 detritylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- OLSDWRNWUGHKSY-UHFFFAOYSA-J dicalcium;phosphonato phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O OLSDWRNWUGHKSY-UHFFFAOYSA-J 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- HGVHMIAKUYLQLL-UHFFFAOYSA-N ethene;propane-1,2,3-triol Chemical compound C=C.OCC(O)CO HGVHMIAKUYLQLL-UHFFFAOYSA-N 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000005090 tracheal smooth muscle Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- VMZOBROUFBEGAR-UHFFFAOYSA-N tris(trimethylsilyl) phosphite Chemical compound C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C VMZOBROUFBEGAR-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 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
- C07F9/28—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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- 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
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/303—Cycloaliphatic 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
-
- 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
- C07F9/4075—Esters with hydroxyalkyl compounds
Definitions
- This invention pertains to the synthesis and use as therapeutic agents of a group of substances with a glycerol backbone or aliphatic chain structure linked to phosphonocholine, phosphinocholine, phosphonoinositol, phosphinoinositol, or other phosphorus-containing head groups.
- the substance has anti-cancer, anti-inflammatory, anti-allergy, or anti-cardiovascular disease properties.
- West German Patent No. P 0230575A2 dated April 12, 1986, discloses a group of glycerophosphohpids compounds having an alkyl chain of C2-C22 and a methoxy group at the sn-2 position and a phosphocholine at the sn-3 position. These compounds are stated to be useful as anticancer agents.
- None of these patents discloses a substance with a glycerol backbone linked to a phosphorus atom with a polar head group used as an anti-cancer, anti-inflammatory, anti-allergy, or anti-cardiovascular disease treating agents.
- the present invention provides anti-leukemic phospholipids of the general formula:
- T is an oxygen atom
- U is an oxygen atom
- NH is an aliphatic chain such as hexadecyl or octadecyl
- R 2 is a methyl group when U is oxygen or when U is NH
- X is a methylene group
- n is 0 to 14
- R 3 is either an oxygen atom or a methylene group
- m is 2, 3, 4, 5,
- R 4 , R 5 and R 6 represent alkyl groups containing 1 to 3 carbon atoms.
- Phosphonolipids of the general formula R-P(O)(O-)OR' wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
- n 0 or 1
- R 1 and R 2 are as defined in claim 1
- R 4 is an alkyl group such as methyl, ethyl, n-propyl, or isopropyl.
- the phosphonate or phosphinate compounds as claimed in described include either of the opposite stereochemical configurations [( R) or ( S)], or a mixture thereof.
- a phosphinate for treatment of leukemic cells having the formula:
- R 1 is a long-chain alkyl group
- R 2 is a methyl group
- n 0 or
- R 3 is N + (CH 3 ) 3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
- the compound as identified in the second paragraph of this summary can be used as an agent in inhibiting cancer cell growth when the compound is administered at a concentration in the range of 5 mg/l to 50 mg/l, and pharmaceutically acceptable acid or salts thereof; and a pharmaceutically acceptable carrier.
- the compound as identified in the third paragraph of this summary can be used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
- the compounds identithis summary can be used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
- the phosphonates or phosphinates as identified in the second, third, fourth, fifth, and sixth paragraphs of this summary can be used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
- a method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a compound of the formula:
- a method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphonolipid of the general formula: R-P(O)(O-)(OR), wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
- a method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate of the general formula:
- n 0 or 1
- R 1 and R 2 are as defined in claim 1
- R 4 is an alkyl group such as methyl, ethyl, n- propyl, or isopropyl.
- the phosphonate or phosphinate compound can includes either of the opposite stereochemical configurations [(R ) or (S)], or a mixture thereof.
- a method of treating leukemic cells in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate having the formula:
- R 1 is a long-chain alkyl group
- R 2 is a methyl group
- n 0 or
- R 3 is N + (CH 3 ) 3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
- the present invention also provides phospholipids with the following structures:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined above.
- the present invention provides phospholipids with an inositol group for use as anti-inflammatory agents:
- R 1 is as defined herein above.
- phosphonates and phosphinates are useful as anti-cancer agents since they inhibit growth of leukemic and tumor cells, as anti-inflammatory and anti-allergic agents, and as anti-cardiovascular agents.
- the invention also involves the use of one or several of the above-mentioned phosphonates and phosphinates for treatment of cardiovascular diseases, such as septic shock (cardiogenic shock, thrombosis and others) when given at 5-50 mg/l in a pharmaceutically acceptable acid or salt thereof, and carrier.
- septic shock cardiac shock, thrombosis and others
- the invention is also directed to the use of phosphonates and phosphinates in the treatment of malignant cells, solid tumors of any type, leukemia and in bone marrow transplantation.
- the invention also pertains to the use of phosphonates in the treatment of inflammatory diseases of any form, for example, arthritis, inflammatory bowel diseases, colitis, and pulmonary inflammation.
- the invention relates to the use of phosphonates in the treatment of allergic diseases of any form, such as asthma, allergic rhenitis, hay fever, skin rashes and seasonal allergies.
- the phosphonocholines and phosphonoglycerols can be synthesized according to the following reaction sequence:
- Diethyl phosphite is treated with hexadecyl (or octadecyl) bromide in a Michaelis-Becker reaction, giving the corresponding diethyl ester.
- the alkyl phosphonic acid is formed in situ from the ester , then treated with 2.1 equivalents of pyridine at 0°C in tetrahydrofuran, followed by 2.1 equivalents of oxaloyl chloride at -78°C under nitrogen.
- the phosphonic acid dichloride thus obtained is treated with either (R )-2-O -benzylglycerol (for conversion to phosphonoglycerol) or with ethylene glycerol to give the phospholane intermediate, which is reacted with triethylamine in acetonitrile at 75°C in a pressure bottle to give phosphonocholine.
- the intermediates and products are purified by chromatography on silica gel G or by high-pressure liquid chromatography.
- the structures are established by nuclear magnetic resonance spectroscopy, mass spectrometry, and by elemental analysis.
- the phosphonoinositol is prepared by the following reaction sequence:
- the phosphonoinositol is produced by reacting hexadecyl (or octadecyl) bromide with tris(trimethylsilyl)phosphite under argon at 135°C to form the alkyl phosphonic acid. After the excess phosphite is removed by distillation, the residue is purified and coupled to pentabenzylinositol in the presence of trichloroacetonitrile in pyridine at 60°C to form pentabenzylinositol phosphonate.
- the phosphonoethanolamine is prepared by the following reaction sequence:
- the phosphonoserine is prepared by the following reaction
- N-tritylserine methyl ester is added to a solution of the alkyl phosphonic acid dichloride in tetrahydrofuran and diisopropylethylamine in tetrahydrofuran.
- the intermediate N-tritylserine methyl ester is purified by silica gel chromatography, then subjected to detritylation with 0.1 M hydrochloric acid and alkaline hydrolysis of the methyl ester.
- the product is purified by Dowex 50W-X8 (H + form) followed by silica gel chromatography.
- Phosphonocholines are prepared by the following reaction sequence:
- the r ⁇ c-phosphonic acid shown above is prepared by proceeding according to the following sequence of reactions.
- a n-alkyl allyl ether is reacted with methanol in the presence of zinc oxide and iodine; alkyl groups other than methyl can be conveniently introduced by this method (reference: Rosenthal, A.F.; Kosolapoff, G.M.; Geyer, R.P. Recl. Trav. Chim. Pays-Bas 1964, 83, 1273).
- the 1 - O-alkyl-2-O -methyliodopropane is treated with triethyl phosphite, affording the corresponding diethyl phosphonate ester, which is hydrolyzed to give the phosphonic acid.
- Phosphonocholine is obtained by reaction with dry choline tosylate (9 equivalents) in the presence of trichloroacetonitrile in pyridine at 50°C for 2 days.
- the corresponding glycerol-linked phosphonoethanolamine is prepared by reaction of the phosphonic acid with N-(tert-butoxycarbonyl)- ethanolamine (N-t-Boc-ethanolamine) in the presence of trichloroacetonitrile or 1H -tetrazole; after purification of the coupling product by silica gel chromatography, the Boc protecting group is removed under standard conditions (50% trifluoroacetic acid in dichloromethane at 0°C).
- the corresponding glycerol-linked phosphonoserine is prepared in a similar fashion, using N-tritylserine methyl ester for coupling with the phosphonic acid.
- the acid-labile trityl group is removed by treatment with 0.1 M hydrochloric acid in tetrahydrofuran-water (1:1), and then the methyl ester is hydrolyzed by using 0.2 M sodium hydroxide. Purification is by silica gel chromatography.
- Isosteric phosphonates are prepared according to the following reaction sequences:
- Isosteric phosphonocholine and isosteric phosphonoinositol are prepared from 1 ,2,5,6-diisopropylidene-D-mannitol as outlined above.
- O-benzylation is carried out at the 3 and 4 positions, then the isopropylidene groups are removed and the primary alcohols are alkylated with long-chain alkyl groups via the mesylates or similar alkylati ⁇ g agents. Methylation is carried out at the 2 and 5 positions.
- Phosphonoglycerols are available by a similar route.
- octadecyl glycidol gives the enantiomeric phosphonolipid.
- the nonisosteric phosphinocholines are prepared according to the following reaction sequence:
- 1-O-alkyl-2-O-methyliodopropane gives isopropyl 2-methoxy-3- O-alkylpropyl(allyl)phosphinate, which is cleaved with osmate-periodate, and reduced with sodium borohydride in ethanol to the hydroxyethylphosphinate. The latter is converted to the mesylate and allowed to react with aqueous dimethylamine, followed by quaternization to give the phosphinate compound.
- Isosteric phosphinocholines and phosphinoinositols are prepared according to the following reaction sequences:
- Isosteric phosphinocholine is prepared as outlined by the reaction sequence shown above. Wittig reaction of the aldehyde followed by hydroboration gives the alcohol, which is then converted into the desired phosphinate. Hydroboration gives an alcohol (not shown) that can be coupled to a protected inositol to yield the corresponding phosphinoinositol. Mesylation of the alcohol gives the phosphinate compound, which is aminated, then treated with methyl iodide, and the phosphonate ester is hydrolyzed to give the isosteric phosphinocholine.
- the distance between the phosphorus and nitrogen atoms in the phosphonolipids is varied by using procedures known in the corresponding phosphate-containing compounds (references: All, S.;
- Table I shows the effect of various concentrations of the phosphonate of the following formula on the growth of WEHI-3B cells:
- Table II shows results of thymidine uptake by WEHI-3B and HL-60 cells during 48 hours of incubation.
- Thymidine uptake during 48 hours phosphonate thymidine uptake (% of control) concentration ( ⁇ M) WEHI-3B cells HL-60 cells
- Table III shows the results of thymidine uptake by WEHI-3B and
- Thymidine uptake during 72 hours phosphonate thymidine uptake (% of control)
- Table V demonstrates the effect of phosphonate of the above structure on the incorporation of thymidine into DNA of the C-41 cell line (a human cervical tumor cell) Table V
- Table VI shows the effect of the above phosphonate on tumor growth in mice.
- BALB/C mice were injected with 3-Lewis lung carcinoma under the skin at the back. Three days after injection of tumor cells the treatment was initiated with 50 mg/day orally once a day. In the control group the mice received only the carrier mucilage of tragacanth. As seen in Table VI, in control animals the first sign of a detectable tumor was observed after the seventh day of post cell injection. In the phosphonate-treated animals, the tumor growth was retarded by approximately 6 days. The tumor size in the
- Example 1 Effect of the phosphonate of the following formula on the activation of human neutrophils
- Example 2 Effect of phosphonate on neutrophil degranulation and lysosomal enzyme release (elastase)
- Petri dishes were coated with [ 3 H]elastin and were used to assess the release of elastase.
- Neutrophils (10 6 ) in 500 ⁇ l of medium were added to each Petri dish well. Addition of 1 ⁇ M FMLP for 1 hour at 37°C
- CPPD calcium pyrophosphate dihydrate
- MSU monosodium urate
- Asthma is an allergic disease caused by the contraction of airway
- Thrombosis is the result of activation of platelets by agents such as
- PAF platelet activating factor
- Phosphonates also inhibited serotonin release from platelets activated with thrombin or PAF. As seen in Table XIII, phosphonate at 10 ⁇ M blocked serotonin release entirely.
- Phosphonates were shown' to block PAF-induced hypotension in rats. When given at 5 mg/kg, phosphonates inhibited the hypotensive activity of PAF dramatically. As seen in Table XTV, normal rat blood pressure was about 150 mm Hg, and this dropped to about 40 mm Hg after administration of PAF (10 ⁇ g/kg). Animals given phosphonates (5 mg/kg) had only slightly reduced blood pressure after the injection of PAF, suggesting that phosphonates are anti-hypotensive agents.
- An effective concentration of phosphonate (normally 5-50 mg/l) can be given orally, intravenously (i.v.), intramuscularly (i.m.) or subcutaneously (s.c.), in the form of tablets (orally), capsules (orally), or injection ampules (i.v., i.m., s.c).
- the drug can be applied in the form of a rubbing cream.
- Tablets can be prepared via compression of 50 mg of phosphonates, 200 mg of lactose, and 50 mg Avicel (TM) .
- Capsules are made by making bilayers of liposomal phosphonates in the concentrations of 5-50 mg with lecithin.
- Injection solutions are made either in water or propylene glycol with an upwardly adjusted pH in phosphate buffer.
- the drag solution is sterilized through a filter of 0.22 mm.
- Solutions can be made in 20% propylene glycol with about 0.5% of a preservative such as ascorbic acid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention pertains to the synthesis and use as therapeutic agents of a group of substances with a glycerol backbone or aliphatic chain structure linked to a phosphorus atom and a polar head group. Depending on the polar head group, the substance has anti-cancer, anti-inflammatory, anti-allergy or anti-cardiovascular disease properties. Compounds of formulas (I) and (II), wherein n is O to 14 and R1 is an alkyl group of C12-C20, R2 is a methyl group, and wherein R3 is an inositol analog head group, a (CH2)mN+(CH3)3 group with m = 2 to 10, a serine head group, or an ethanolamine head group, or of formula (III), wherein R1 and R2 are as described above, n = 0 or 1, and R3 is (CH2)mN+(CH3)3 (m=2-10) are claimed. This invention also pertains to the synthesis and use as therapeutic agents of a group of substances that have no glycerol backbone but have an aliphatic chain structure linked directly to a phosphorus atom of the general formula R-P(0)(0-)OR' wherein R is a long-chain alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
Description
PHOSPHONATES AND PHOSPHINATES AS ANTI-CANCER, -INFLAMMATORY, -ALLERGY AND -MYOCARDITIS AGENTS
FIELD OF THE INVENTION
This invention pertains to the synthesis and use as therapeutic agents of a group of substances with a glycerol backbone or aliphatic chain structure linked to phosphonocholine, phosphinocholine, phosphonoinositol, phosphinoinositol, or other phosphorus-containing head groups. Depending on the polar head group, the substance has anti-cancer, anti-inflammatory, anti-allergy, or anti-cardiovascular disease properties.
B ACKGOUND OF THE INVENTION
West German Patent No. P 0230575A2, dated April 12, 1986, discloses a group of glycerophosphohpids compounds having an alkyl chain of C2-C22 and a methoxy group at the sn-2 position and a phosphocholine at the sn-3 position. These compounds are stated to be useful as anticancer agents.
U.S. Patent No. 4,408,052, dated February 25, 1981, assigned to Takeda Chemical Industries, Osaka, Japan, claims a group of phospholipid carbamates as useful as antitumor agents.
Canadian Patent No. 1,248,534, dated January 10, 1989, granted to Takeda Chemical Industries of Japan, protects a group of ketolyso phospholipids, which purportedly are useful as antitumor agents.
U.S. Patent No.4,515,722, dated May 7, 1985, granted to Merck Sharp & Dohme, protects a group of phosphatidylinositol analogs which are evidently effective in inhibiting phospholipase C and thereby have utility as anti-inflammatory and analgestic agents.
None of these patents discloses a substance with a glycerol backbone linked to a phosphorus atom with a polar head group used as an anti-cancer, anti-inflammatory, anti-allergy, or anti-cardiovascular disease treating agents.
SUMMARY OF THE INVENTION
The present invention provides anti-leukemic phospholipids of the general formula:
6, 7, 8, or 9, and R4, R5 and R6 represent alkyl groups containing 1 to 3 carbon atoms.
A compound of the formula:
wherein n is 0 to 14 and R1 is an alkyl group of C1 2-C20 ; wherein R 2 is a methyl group; and wherein R3 is an inositol analog head group, a (CH2)mN + (CH3)3 group with m = 2 to 10, a serine head group, or an ethanolamine head group.
A phosphonate compound of the formula:
Phosphonolipids of the general formula R-P(O)(O-)OR' wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
Phosphinates of the general formula:
The phosphonate or phosphinate compounds as claimed in described
include either of the opposite stereochemical configurations [( R) or ( S)], or a mixture thereof.
A phosphinate for treatment of leukemic cells having the formula:
1, m = 2 or 3, and R3 is N+(CH3)3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
The compound as identified in the second paragraph of this summary can be used as an agent in inhibiting cancer cell growth when the compound is administered at a concentration in the range of 5 mg/l to 50 mg/l, and pharmaceutically acceptable acid or salts thereof; and a pharmaceutically acceptable carrier. The compound used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
The compound as identified in the third paragraph of this summary can be used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
The compounds identithis summary can be used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
The phosphonates or phosphinates as identified in the second, third, fourth, fifth, and sixth paragraphs of this summary can be used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
A method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a compound of the formula:
wherein n is 0 to 14 and R1 is an alkyl group of C12-C20 ; wherein R2 is a methyl group; and wherein R3 is an inositol analog head group, a (CH2)mN+(CH3)3 group with m = 2 to 10, a serine head group, or an ethanolamine head group.
A method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a compound of the formula:
wherein R is an alkyl group such as hexadecyl or octadecyl, m = 0 or 1, n = 2 - 10, or the enantiomer thereof, or a mixture of stereoisomers.
A method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphonolipid of the general formula: R-P(O)(O-)(OR), wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
A method of treating cancer, inflammation, allergy or cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate of the general formula:
The phosphonate or phosphinate compound can includes either of the opposite stereochemical configurations [(R ) or (S)], or a mixture thereof.
A method of treating leukemic cells in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate having the formula:
wherein R1 is a long-chain alkyl group, R2 is a methyl group, n = 0 or
1, m = 2 or 3, and R3 is N+(CH3)3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
The present invention also provides phospholipids with the following structures:
and
wherein R1, R2, R3, R4, R5, R6 and n are as defined above.
The present invention provides phospholipids with an inositol group for use as anti-inflammatory agents:
wherein R1 is as defined herein above.
These phosphonates and phosphinates are useful as anti-cancer agents since they inhibit growth of leukemic and tumor cells, as anti-inflammatory and anti-allergic agents, and as anti-cardiovascular agents.
The invention also involves the use of one or several of the above-mentioned phosphonates and phosphinates for treatment of cardiovascular diseases, such as septic shock (cardiogenic shock, thrombosis and others) when given at 5-50 mg/l in a pharmaceutically acceptable acid or salt thereof, and carrier.
The invention is also directed to the use of phosphonates and phosphinates in the treatment of malignant cells, solid tumors of any type, leukemia and in bone marrow transplantation.
The invention also pertains to the use of phosphonates in the treatment of inflammatory diseases of any form, for example, arthritis, inflammatory bowel diseases, colitis, and pulmonary inflammation.
Further, the invention relates to the use of phosphonates in the treatment of allergic diseases of any form, such as asthma, allergic rhenitis, hay fever, skin rashes and seasonal allergies.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
Production of the Phospholipids of the Invention
(a) Synthesis of Phosphonocholines and Phosphonoglycerols
The phosphonocholines and phosphonoglycerols can be synthesized according to the following reaction sequence:
Diethyl phosphite is treated with hexadecyl (or octadecyl) bromide in a Michaelis-Becker reaction, giving the corresponding diethyl ester. The alkyl phosphonic acid is formed in situ from the ester , then treated with 2.1 equivalents of pyridine at 0°C in tetrahydrofuran, followed by 2.1 equivalents of oxaloyl chloride at -78°C under nitrogen. The phosphonic acid dichloride thus obtained is treated with either (R )-2-O -benzylglycerol (for conversion to phosphonoglycerol) or with ethylene glycerol to give the
phospholane intermediate, which is reacted with triethylamine in acetonitrile at 75°C in a pressure bottle to give phosphonocholine. The intermediates and products are purified by chromatography on silica gel G or by high-pressure liquid chromatography. The structures are established by nuclear magnetic resonance spectroscopy, mass spectrometry, and by elemental analysis.
(b) Synthesis of phosphonoinositol
The phosphonoinositol is prepared by the following reaction sequence:
The phosphonoinositol is produced by reacting hexadecyl (or octadecyl) bromide with tris(trimethylsilyl)phosphite under argon at 135°C to form the alkyl phosphonic acid. After the excess phosphite is removed by distillation, the residue is purified and coupled to pentabenzylinositol in the presence of trichloroacetonitrile in pyridine at 60°C to form pentabenzylinositol phosphonate. The coupling product is purified by chromatography on silica gel, the benzyl groups are removed by catalytic hydrogenolysis, and the product phosphonoinositol is purified by cation exchange and silica gel chromatography.
(c) Synthesis of phosphonoethanolamine
The phosphonoethanolamine is prepared by the following reaction sequence:
To a solution of the alkyl phosphonic acid dichloride and triethylamine in tetrahydrofuran is added a solution of 2-aminoethanol in tetrahydrofuran. Evaporation of the solvent under reduced pressure gives the intermediate phospholane, which is purified by column chromatography, dissolved in 2-propanol, and then hydrolyzed by using a mixture of glacial acetic acid in water (1:4 by volume).
(d) Synthesis of phosphonoserine
The phosphonoserine is prepared by the following reaction
To a solution of the alkyl phosphonic acid dichloride in tetrahydrofuran and diisopropylethylamine in tetrahydrofuran is added a solution of N-tritylserine methyl ester in tetrahydrofuran.
The intermediate N-tritylserine methyl ester is purified by silica gel chromatography, then subjected to detritylation with 0.1 M hydrochloric acid and alkaline hydrolysis of the methyl ester. The product is purified by Dowex 50W-X8 (H+ form) followed by silica gel chromatography.
(e) Production of glycerol-linked phosphonolipids
Phosphonocholines are prepared by the following reaction sequence:
The rαc-phosphonic acid shown above is prepared by proceeding according to the following sequence of reactions. First, a n-alkyl allyl ether is reacted with methanol in the presence of zinc oxide and iodine; alkyl groups other than methyl can be conveniently introduced by this method (reference: Rosenthal, A.F.; Kosolapoff, G.M.; Geyer, R.P. Recl. Trav. Chim. Pays-Bas 1964, 83, 1273). The 1 - O-alkyl-2-O -methyliodopropane is treated with triethyl phosphite, affording the corresponding diethyl phosphonate ester, which is hydrolyzed to give the phosphonic acid. Phosphonocholine is obtained by reaction with dry choline tosylate (9 equivalents) in the presence of trichloroacetonitrile in pyridine at 50°C for 2 days.
The corresponding glycerol-linked phosphonoethanolamine is prepared by reaction of the phosphonic acid with
N-(tert-butoxycarbonyl)- ethanolamine (N-t-Boc-ethanolamine) in the presence of trichloroacetonitrile or 1H -tetrazole; after purification of the coupling product by silica gel chromatography, the Boc protecting group is removed under standard conditions (50% trifluoroacetic acid in dichloromethane at 0°C).
The corresponding glycerol-linked phosphonoserine is prepared in a similar fashion, using N-tritylserine methyl ester for coupling with the phosphonic acid. The acid-labile trityl group is removed by treatment with 0.1 M hydrochloric acid in tetrahydrofuran-water (1:1), and then the methyl ester is hydrolyzed by using 0.2 M sodium hydroxide. Purification is by silica gel chromatography.
(f) Production of glycerol-linked isosteric phosphonates
Isosteric phosphonates are prepared according to the following reaction sequences:
Isosteric phosphonocholine and isosteric phosphonoinositol are prepared from 1 ,2,5,6-diisopropylidene-D-mannitol as outlined above. First, the O-benzylation is carried out at the 3 and 4 positions, then the isopropylidene groups are removed and the primary alcohols are alkylated with long-chain alkyl groups via the mesylates or similar alkylatiπg agents. Methylation is carried out at the 2 and 5 positions.
After catalytic hydrogenolysis, periodic acid cleavage gives the
aldehyde. Reaction of the aldehyde with tetraisopropyl methylenebisphosphonate and n-butyllithium in hexane at 0°C gives the phosphonic ester, which is hydrolyzed to the corresponding phosphonic acid by using trimethylsilyl bromide followed by aqueous workup. The vinyl group is reduced, and the phosphonic acid is coupled to choline tosylate to give the desired
phosphonocholine compound or to suitably protected inositol, followed by deprotection, to give the desired phosphonoinositol compound. The products are purified by ion-exchange
chromatography followed by silica gel chromatography.
Phosphonoglycerols are available by a similar route.
An alternative procedure for making phosphonoinositols and phosphonocholines is illustrated below.
The above reaction sequence shows the use of (R)- O-hexadecyl or
-octadecyl glycidol as the starting material. Use of (S)-hexadecyl or
octadecyl glycidol gives the enantiomeric phosphonolipid.
(g) Production of glycerol-linked phosphinocholines .
The nonisosteric phosphinocholines are prepared according to the following reaction sequence:
Reaction of diisopropylallylphosphinate with
1-O-alkyl-2-O-methyliodopropane gives isopropyl
2-methoxy-3- O-alkylpropyl(allyl)phosphinate, which is cleaved with osmate-periodate, and reduced with sodium borohydride in ethanol to the hydroxyethylphosphinate. The latter is converted to the mesylate and allowed to react with aqueous dimethylamine, followed by quaternization to give the phosphinate compound.
(h) Production of glycerol-linked isosteric phosphinates
Isosteric phosphinocholines and phosphinoinositols are prepared according to the following reaction sequences:
Isosteric phosphinocholine is prepared as outlined by the reaction sequence shown above. Wittig reaction of the aldehyde followed by hydroboration gives the alcohol, which is then converted into the desired phosphinate.
Hydroboration gives an alcohol (not shown) that can be coupled to a protected inositol to yield the corresponding phosphinoinositol. Mesylation of the alcohol gives the phosphinate compound, which is aminated, then treated with methyl iodide, and the phosphonate ester is hydrolyzed to give the isosteric phosphinocholine.
(i) Production of agents with modified distances between the
phosphorus and nitrogen atoms
The distance between the phosphorus and nitrogen atoms in the phosphonolipids is varied by using procedures known in the corresponding phosphate-containing compounds (references: All, S.;
Bittman, R. Chem. Phys. Lipids 1989, 50, 11-21 ; Isaacson, Y.A.; Deroo,
P.W.; Rosenthal, A.F.; Bittman, R.; McIntyre, J.O.; Bock, H-G.; Gazzotti,
P.; Fleischer, S. J. Biol. Chem. 1979, 254, 117-126; Ukawa, K.;
Imamiya, E.; Yamamoto, H., et al. Chem. Pharm. Bull. 1989, 37,
1249-1255). One method for conversion of the glycerol derivative to the phosphonocholine analog with a variable number of methylene groups between the phosphorus and nitrogen atoms is shown below.
1. Anti-cancer activity
Several laboratory tests have been conducted to establish that phosphonates kill cancer cells.
It has been discovered that a phosphonate of the following structure:
inhibits thymidine incorporation into DNA of several cancer cell lines. This behavior is indicative of anti-cancer activity.
Example 1
Experiments were performed with three different cell lines: (1) with a mouse myelomonocytic leukemic cell line (WEHI-3B cells), (2) a human myeloleukemic cell line (HL-60 and a human cervical tumor cell line (C-41)). Cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, mercaptoethanol (5 μg/ml), penicillin (50 units/ml), streptomycin (50 μg/ml), in an atmosphere of 5% CO2. The cells were passaged weekly by serial
1/10 to 1/10000 dilutions. The cell viability and growth were constantly monitored by staining with trypan blue exclusion dye or the incorporation of tritiated thymidine.
3H-Thymidine incorporation
Cells were placed in 96-well plates at 2 × 104 cells/ well in 200 μl of medium and another 5 μl of medium containing the drugs was added. Control cultures were incubated without drugs. Cells in 96-well plates were incubated in a CO2 incubator for 24 hours. The cells were then pulsed with 0.1 μCi of [3H]thymidine for 24 hours prior to the harvesting. The cells were harvested using a Brandel cell harvester model M-12, and collected on Whatman glass microfilters. The radioactivity associated with the filters was counted in a liquid scintillation counter and plotted as percent survival versus concentration of phosphonate, and the data were compared with
[3H]thymidine incorporation into the untreated cells.
Table I shows the effect of various concentrations of the phosphonate of the following formula on the growth of WEHI-3B cells:
Table I
Thymidine uptake during 24 hours phosphonate thymidine uptake(% of control) concentration (μM) mean ± s.d.
0 100
0.62 137 ±6
1.25 93 ± 7
2.5 91±4
5 88 ±11
10 76±6
20 48 ±4 0 43 ± 15
Table II shows results of thymidine uptake by WEHI-3B and HL-60 cells during 48 hours of incubation.
Table II
Thymidine uptake during 48 hours phosphonate thymidine uptake (% of control) concentration (μM) WEHI-3B cells HL-60 cells
Mean ± s.d. n=8
0 100 100
0.62 93 ± 6 84 ± 5
1.25 90 ± 5 76 ± 4
2.5 86 ± 8 63 ± 4
5 61 ± 6 24 ± 3
10 23 ± 2 3 ± 2
20 18 ± 8 1 ± 0
Table III shows the results of thymidine uptake by WEHI-3B and
HL-60 cells during 72 hours of incubation.
Table III
Thymidine uptake during 72 hours phosphonate thymidine uptake (% of control)
concentration (μM) WEHI-3B HL-60
Mean ± s.d., n=8
0 100 100
0.62 85 ± 3 93 ± 4
1.25 86 ± 4 81 ± 4
2.5 82 ± 6 66 ± 3
5 60 ± 4 16 ± 4
10 26 ± 3 5 ± 1
20 10 ± 3 1 ± 0.9
40 7 ± 3 3 ± 1
Effect of phosphonate of the following structure on thymidine
incorporation into DNA of WEHI-3B cells.
Table IV
Thymidine uptake after various days (% of control) phosphonate day 1 day 2 day 3 concentration (μM) Mean, n =5
0 100 100 100
1.25 95 84 77
2.5 72 67 54
5 34 22 12
10 18 13 10
20 8 2 1
40 3 2 2
Table V demonstrates the effect of phosphonate of the above structure on the incorporation of thymidine into DNA of the C-41 cell line (a human cervical tumor cell)
Table V
Thymidine uptake into DNA of C-41 cell line phosphonate thymidine uptake (% of control) concentration (μM) Mean, n=3
0 100
2.5 88
5 63
10 42
20 41
40 16
Table VI shows the effect of the above phosphonate on tumor growth in mice. BALB/C mice were injected with 3-Lewis lung carcinoma under the skin at the back. Three days after injection of tumor cells the treatment was initiated with 50 mg/day orally once a day. In the control group the mice received only the carrier mucilage of tragacanth. As seen in Table VI, in control animals the first sign of a detectable tumor was observed after the seventh day of post cell injection. In the phosphonate-treated animals, the tumor growth was retarded by approximately 6 days. The tumor size in the
phosphonate-treated animals remained below that in the control animals throughout the experiments.
Table VI
Days after tumor implant Tumor volume (mm3)
control + phosphonate
0 0 0
7 30 0
10 120 0
17 250 100
18 432 175
20 670 252
22 810 500
2. Anti-inflammatory activity
Example 1: Effect of the phosphonate of the following formula on the activation of human neutrophils
Superoxide anion generation in neutrophils has been used as an index of cell activation. The continuous spectrophotometric measurement of a superoxide dismutase inhibitable reduction of ferricytochrome C at 549 nm was used to demonstrate superoxide anion generation.
Human neutrophils were stimulated with 1 μM FMLP
(N-formylmethionyl-leucyl-phenylalanine). A rapid generation of
superoxide was observed. Table VII shows the inhibition of
superoxide anion generation by 10 μM phosphonate after various
times.
Table VII
Time (min) absorbance at 549 nm
control FMLP FMLP + phosphonate
0 0 0 0
1 0.001 0.1 0.03
2 0.002 0.14 0.04
3 0.01 0.16 0.04
4 0.015 0.16 0.04
Example 2: Effect of phosphonate on neutrophil degranulation and lysosomal enzyme release (elastase)
Petri dishes were coated with [3H]elastin and were used to assess the release of elastase. Neutrophils (106) in 500 μl of medium were added to each Petri dish well. Addition of 1 μM FMLP for 1 hour at 37°C
stimulated elastase release as determined by the breakdown of
elastin. Phosphonate inhibited the neutrophil degranulation and the
release of elastase (Table VIII).
Table VIIl phosphonate μg elastin degraded/106 cells/hr concentration (μM) Mean, n = 3
0 17
2.5 16
5 8
10 6
25 4
50 3
3. Anti-arthritis activity of phosphonates
In the synovial fluids of patients with arthritis there is an
accumulation of two types of crystals, calcium pyrophosphate dihydrate (CPPD) and monosodium urate (MSU). These two crystals types are the major contributors to the development of arthritis by causing rapid leukocyte activation. Table IX shows that phosphonates (50 μM) inhibited leukocyte activation in response to CPPD. Table X shows the inhibition in response to MSU.
Table IX
Time (min) chemiluminescence (mV)
CPPD CPPD + phosphonate
0 0 0
1 25 0
2 175 0
3 500 100
4 750 275
5 900 300
6 800 250
7 500 150
Table X
Time (min) chemiluminescence (mV)
MSU MSU+ phosphonate
0 0 0
1 200 10
2 500 50
3 600 75 4 675 80 5 550 50 6 400 20
4. Anti-allergic activity of phosphonates
Asthma is an allergic disease caused by the contraction of airway
smooth muscles in response to activation with contractile agonists such as leukotriene D4 (LTD4). As seen in Table XI, phosphonates at 5 μM inhibited LTD4-induced contraction of trachea from guinea pigs.
Table XI
LTD4 dose (μM) contraction (% of max carbachol) no phosphonate with phosphonate
0 0 0
0.01 7 0
0.1 21 0
1 45 0
10 50 8
Inhibition of tracheal smooth muscle contraction by phosphonates
supports the anti-allergic and asthmatic properties of these agents.
5. Anti-thrombolytic and cardiovascular activity
Thrombosis is the result of activation of platelets by agents such as
platelet activating factor (PAF). Platelet activation is associated with aggregation and release of vasoactive compounds such as serotonin
that have profound effects on heart and vascular tissues.
The effects of phosphonate on aggregation of platelets caused by PAF or thrombin are shown in Table XII. As seen in Table XII, PAF at 1 μM or thrombin at 1 unit/ml caused 60-70% aggregation of platelets. In the presence of various concentrations of phosphonate a
dose-dependent inhibition of platelet aggregation is obtained. At 10 μM of phosphonate, a complete inhibition of platelet aggregation is seen.
Table XII phosphonate dose (μM) platelet aggregation (% of control)
thrombin (1 unit) PAF (1 μM)
0 100 100 0.5 58 74
1 29 48
5 7.5 26
10 0 0
Phosphonates also inhibited serotonin release from platelets activated with thrombin or PAF. As seen in Table XIII, phosphonate at 10 μM blocked serotonin release entirely.
Table XIII
phosphonate dose (mM) serotonin release (% of control)
thrombin (1 unit) PAF (1 μM)
0 100 100 1 76 80
5 36 48
10 16 28
The data in Table XIII support the anti-cardiovascular disease activity of phosphonates.
6. Anti-hypotensive activity
Administration of PAF intravenously causes severe hypotension.
Phosphonates were shown' to block PAF-induced hypotension in rats. When given at 5 mg/kg, phosphonates inhibited the hypotensive activity of PAF dramatically. As seen in Table XTV, normal rat blood pressure was about 150 mm Hg, and this dropped to about 40 mm Hg after administration of PAF (10 μg/kg). Animals given phosphonates (5 mg/kg) had only slightly reduced blood pressure after the injection of PAF, suggesting that phosphonates are anti-hypotensive agents.
Table XIV
PAF dose (μg/kg) blood pressure (mm Hg)
no phosphonate with phosphonate
0 150 148
0.5 135 145
1 120 145
2.5 100 140
5 60 140
10 40 130
These data strongly support the anti-hypotensive and cardiovascular activity of phosphonates.
Usage and Dosage
An effective concentration of phosphonate (normally 5-50 mg/l) can be given orally, intravenously (i.v.), intramuscularly (i.m.) or subcutaneously (s.c.), in the form of tablets (orally), capsules (orally), or injection ampules (i.v., i.m., s.c). The drug can be applied in the form of a rubbing cream. Tablets can be prepared via compression of 50 mg of phosphonates, 200 mg of lactose, and 50 mg Avicel(TM). Capsules are made by making bilayers of liposomal phosphonates in the concentrations of 5-50 mg with lecithin. Injection solutions are made either in water or propylene glycol with an upwardly adjusted pH in phosphate buffer. The drag solution is sterilized through a filter of 0.22 mm. Solutions can be made in 20% propylene glycol with about 0.5% of a preservative such as ascorbic acid.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof.
Claims
1. A compound of the formula:
wherein n is 0 to 14 and R1 is an alkyl group of C12-C20 ; wherein R2 is a methyl group; and wherein R3 is an inositol analog head group, a (C H2)mN+(CH3)3 group with m = 2 to 10, a serine head group, or an ethanolamine head group.
2. A phosphonate compound of the formula:
3. Phosphonolipids of the general formula R-P(O)(O-)OR' wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
4. Phosphinates of the general formula:
5. A phosphonate compound as claimed in claims 1 and 2 including either of the opposite stereochemical configurations [(R) or (S)], or the mixture thereof.
6. A phosphinate for treatment of leukemic cells having the formula:
wherein R1 is a long-chain alkyl group, R2 is a methyl group, n = 0 or 1, m = 2 or 3, and R3 is N+(CH3)3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
7. A compound as claimed in claim 1 used as an agent in inhibiting cancer cell growth when the compound is administered at a concentration in the range of 5 mg/l to 50 mg/l, and pharmaceutically acceptable acid or salts thereof; and a pharmaceutically acceptable carrier.
8. A compound as claimed in claim 1 used in the treatment of an inflammatory disease administered at 5-50 mg/l in a
pharmaceutically acceptable carrier.
9. A compound as claimed in claim 2 used in the treatment of an inflammatory disease administered at 5-50 mg/l in a
pharmaceutically acceptable carrier.
10. A compound as claimed in claim 3 used in the treatment of an inflammatory disease administered at 5-50 mg/l in a
pharmaceutically acceptable carrier.
11. A compound as claimed in claim 4 used in the treatment of an inflammatory disease administered at 5-50 mg/l in a
pharmaceutically acceptable carrier.
12. A phosphonate or phosphinate as defined in claim 1 or 4 used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
13. A phosphonate or phosphinate as defined in claim 2 or 4 used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
14. A phosphonate or phosphinate as defined in claim 3 or 4 used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
15. A phosphonate or phosphinate as defined in claim 1 or 4 used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular diseasewhen admimstered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
16. A phosphonate as defined in claim 5 used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
17. A method of treating; cancer, inflammation, allergy or
cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a compound of the formula: 
wherein n is 0 to 14 and R1 is an alkyl group of C12-C20 ; wherein R2 is a methyl group; and wherein R3 is an inositol analog head group, a (CH2)mN+(CH3)3 group with m = 2 to 10, a serine head group, or an ethanolamine head group.
18. A method of treating cancer, inflammation, allergy or
cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a compound of the formula:
19. A method of treating cancer, inflammation, allergy or
cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphonolipid of the general formula: R-P(O)(O-)(OR), wherein R is an alkyl group such as hexadecyl or octadecyl and R' is a head group such as choline, glycerol, inositol, ethanolamine, or serine.
20. A method of treating cancer, inflammation, allergy or
cardiovascular disease in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate of the general formula:
21. A method as claimed in claim 17 or 18 wherein the phosphonate or phosphinate compound includes either of the opposite
stereochemical configurations [(R) or (S)], or the mixture thereof.
22. A method of treating leukemic cells in a mammal comprising treating the mammal with a therapeutic amount of a phosphinate having the formula: 
wherein R1 is a long-chain alkyl group, R2 is a methyl group, n = 0 or
1, m = 2 or 3, and R3 is N+(CH3)3 , and pharmaceutically acceptable salts thereof, administered at a dosage of about 5 to 50 mg/l, with or without a carrier.
23. A method as claimed in claim 17 wherein the compound is used as an agent in inhibiting cancer cell growth when the compound is administered at a concentration in the range of 5 mg/l to 50 mg/l, and pharmaceutically acceptable acid or salts thereof; and a
pharmaceutically acceptable carrier.
24. A method as claimed in claim 17 wherein the compound is used in the treatment of an inflammatory disease administered at 5-50 mg/l in a pharmaceutically acceptable carrier.
25. A method as claimed in claim 17 wherein the phosphonate or phosphinate is used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a
pharmaceutically acceptable carrier.
26. A method as claimed in claim 20 wherein the phosphonate or phosphinate is used in the treatment of allergic skin rashes, hayfever, and asthma or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
27. A phosphonate or phosphinate as defined in claim 3 used in the treatment of allergic skin rashes, hayfever, and asthma or
cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
28. A phosphonate or phosphinate as defined in claim 4 used in the treatment of allergic skin rashes, hayfever, and asthma or
cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
29. A phosphonate or phosphinate as defined in claim 5 used in the treatment of allergic skin rashes, hayfever, and asthma, or cardiovascular disease when administered to the patient at a dosage of about 5-50 mg/l in association with a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69245291A | 1991-04-25 | 1991-04-25 | |
| US692,452 | 1991-04-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1992019627A2 true WO1992019627A2 (en) | 1992-11-12 |
| WO1992019627A3 WO1992019627A3 (en) | 1993-05-13 |
Family
ID=24780645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1992/000165 WO1992019627A2 (en) | 1991-04-25 | 1992-04-21 | Phosphonates and phosphinates as anti-cancer, -inflammatory, -allergy and -myocarditis agents |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0581793A1 (en) |
| WO (1) | WO1992019627A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997026266A1 (en) * | 1996-01-19 | 1997-07-24 | Perstorp Ab | A new chemical compound |
| EP1387847A2 (en) * | 2001-02-21 | 2004-02-11 | The Research Foundation Of the City university of New York | Enantiomers of unsaturated alkyllysophosphonocholines and use as anti-neoplastics |
| EP1587518A2 (en) * | 2003-01-09 | 2005-10-26 | Zeneus Pharma Limited | Antineoplastic ether lipid compounds with modifications at the sn-3 carbon |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2619686A1 (en) * | 1976-05-04 | 1977-11-24 | Max Planck Gesellschaft | ANTI-TUMOR AGENTS |
| EP0092190A2 (en) * | 1982-04-19 | 1983-10-26 | Fujisawa Pharmaceutical Co., Ltd. | Phospholipid derivatives, process for preparation thereof and pharmaceutical composition of the same |
| EP0108565A2 (en) * | 1982-11-08 | 1984-05-16 | Takeda Chemical Industries, Ltd. | Phospholipids, their production and use thereof |
| US4515722A (en) * | 1982-03-30 | 1985-05-07 | Merck & Co., Inc. | Phosphatidyl inositol analogs useful as anti-inflammatory/analgesic agents |
| US4640913A (en) * | 1983-01-10 | 1987-02-03 | American Cyanamid Company | Phosphocholine derivatives having antihypertensive action |
| EP0338407A1 (en) * | 1988-04-19 | 1989-10-25 | Hafslund Nycomed Pharma Aktiengesellschaft | New alkylphosphonoserines, methods for preparing them, and pharmaceutical substances containing them |
| JPH0669088A (en) * | 1992-03-26 | 1994-03-11 | Nec Kyushu Ltd | Air-conditioning system |
-
1992
- 1992-04-21 WO PCT/CA1992/000165 patent/WO1992019627A2/en not_active Application Discontinuation
- 1992-04-21 EP EP19920908170 patent/EP0581793A1/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2619686A1 (en) * | 1976-05-04 | 1977-11-24 | Max Planck Gesellschaft | ANTI-TUMOR AGENTS |
| US4515722A (en) * | 1982-03-30 | 1985-05-07 | Merck & Co., Inc. | Phosphatidyl inositol analogs useful as anti-inflammatory/analgesic agents |
| EP0092190A2 (en) * | 1982-04-19 | 1983-10-26 | Fujisawa Pharmaceutical Co., Ltd. | Phospholipid derivatives, process for preparation thereof and pharmaceutical composition of the same |
| EP0108565A2 (en) * | 1982-11-08 | 1984-05-16 | Takeda Chemical Industries, Ltd. | Phospholipids, their production and use thereof |
| US4640913A (en) * | 1983-01-10 | 1987-02-03 | American Cyanamid Company | Phosphocholine derivatives having antihypertensive action |
| EP0338407A1 (en) * | 1988-04-19 | 1989-10-25 | Hafslund Nycomed Pharma Aktiengesellschaft | New alkylphosphonoserines, methods for preparing them, and pharmaceutical substances containing them |
| JPH0669088A (en) * | 1992-03-26 | 1994-03-11 | Nec Kyushu Ltd | Air-conditioning system |
Non-Patent Citations (5)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 114, 1991, Columbus, Ohio, US; abstract no. 82129h, BRACHWITZ, H. ET AL. page 767 ; * |
| CHEMICAL ABSTRACTS, vol. 117, 1992, Columbus, Ohio, US; abstract no. 90393s, RIES, U.J. ET AL. page 794 ; * |
| JOURNAL OF MEDICINAL CHEMISTRY vol. 34, no. 4, 1 April 1991, pages 1377 - 1383 MEYER, K.L. ET AL. * |
| JOURNAL OF MEDICINAL CHEMISTRY vol. 34, no. 4, 1 April 1991, pages 1408 - 1414 PIANTADOSI, C. ET AL. * |
| JOURNAL OF THE AMERICAN CHEMICAL SOCIETY vol. 110, 1988, pages 2665 - 2666 YUAN, W. ET AL. * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997026266A1 (en) * | 1996-01-19 | 1997-07-24 | Perstorp Ab | A new chemical compound |
| EP1387847A2 (en) * | 2001-02-21 | 2004-02-11 | The Research Foundation Of the City university of New York | Enantiomers of unsaturated alkyllysophosphonocholines and use as anti-neoplastics |
| EP1387847A4 (en) * | 2001-02-21 | 2005-06-29 | Univ City | Enantiomers of unsaturated alkyllysophosphonocholines and use as anti-neoplastics |
| EP1587518A2 (en) * | 2003-01-09 | 2005-10-26 | Zeneus Pharma Limited | Antineoplastic ether lipid compounds with modifications at the sn-3 carbon |
| EP1587518A4 (en) * | 2003-01-09 | 2008-08-20 | Zeneus Pharma Ltd | Antineoplastic ether lipid compounds with modifications at the sn-3 carbon |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992019627A3 (en) | 1993-05-13 |
| EP0581793A1 (en) | 1994-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5369097A (en) | Phosphonates as anti-cancer agents | |
| US5260288A (en) | Method for inhibition of cell motility by sphingosine-1-phosphate and derivatives | |
| Starrett et al. | Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy) ethyl] adenine (PMEA) | |
| CA1338627C (en) | Pharmaceuticals based on phosphoric acid esters for use in tumor therapy, and process for their preparation | |
| AU651835B2 (en) | Phosphorous prodrugs | |
| KR100874392B1 (en) | LPA agonists and antagonists, and methods of use | |
| EP0050460B1 (en) | Tridecyloxy- or tetradecyloxy-propane derivatives, and their use | |
| EP0070433B1 (en) | Phospholipid derivatives, processes for preparation thereof and pharmaceutical composition of the same | |
| CA1227792A (en) | Phosphinylalkanoyl substituted imino acids | |
| US4804789A (en) | D-mannite derivatives as starting products for the synthesis of phospholipids | |
| JP3218313B2 (en) | Elsyl-, brassyl- and nerbonyl derivatives, methods for their preparation, medicaments for combating diseases caused by tumors and protozoa and fungi containing them, medicaments for the treatment of autoimmune diseases and bone marrow disorders, and methods for producing the medicaments | |
| US20140171394A1 (en) | Cyclitols and their derivatives and their therapeutic applications | |
| US5219845A (en) | Phosphonates as anti-inflammation agents | |
| JPH041759B2 (en) | ||
| Rosenthal | [48] Chemical synthesis of phospholipids and analogues of phospholipids containing carbon-phosphorus bonds | |
| CA2415214C (en) | Phosphotetrahydropyran compounds | |
| WO1998009668A2 (en) | Use of amphiphiles as phosphatidyl choline synthesis inhibitors | |
| WO1992019627A2 (en) | Phosphonates and phosphinates as anti-cancer, -inflammatory, -allergy and -myocarditis agents | |
| US6903080B2 (en) | Disease treatment with novel phospholipid derivatives | |
| CA2100228C (en) | Phospholipid derivatives | |
| US5506217A (en) | Phosphonates as anti-cancer agents | |
| US5916884A (en) | Compositions containing a mixture of phosphorus compounds and alkylglycerols | |
| US20070123492A1 (en) | Analogs of lysophosphatidic acid and methods of making and using thereof | |
| EP1019418B1 (en) | Inositol derivatives and pharmaceutical compositions comprising them | |
| US20020173489A1 (en) | Compositions containing a mixture of phosphorous compounds and alkylglycerols |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): CA JP |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): CA JP |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 1992908170 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 1992908170 Country of ref document: EP |
|
| NENP | Non-entry into the national phase in: |
Ref country code: CA |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1992908170 Country of ref document: EP |