EP0675892A1 - Neue phosphor-enthaltende radikalfänger-zusammensetzungen - Google Patents
Neue phosphor-enthaltende radikalfänger-zusammensetzungenInfo
- Publication number
- EP0675892A1 EP0675892A1 EP94931432A EP94931432A EP0675892A1 EP 0675892 A1 EP0675892 A1 EP 0675892A1 EP 94931432 A EP94931432 A EP 94931432A EP 94931432 A EP94931432 A EP 94931432A EP 0675892 A1 EP0675892 A1 EP 0675892A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- group
- aryl
- spin
- dmpo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title 1
- 229910052698 phosphorus Inorganic materials 0.000 title 1
- 239000011574 phosphorus Substances 0.000 title 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims abstract description 6
- VCUVETGKTILCLC-UHFFFAOYSA-N 5,5-dimethyl-1-pyrroline N-oxide Chemical compound CC1(C)CCC=[N+]1[O-] VCUVETGKTILCLC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910021645 metal ion Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 150000002739 metals Chemical class 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 claims 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- 150000003254 radicals Chemical class 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- -1 tert-butoxyl Chemical group 0.000 description 5
- 239000002775 capsule Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000001362 electron spin resonance spectrum Methods 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
- 238000002360 preparation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000000804 electron spin resonance spectroscopy Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000013319 spin trapping Methods 0.000 description 3
- XACANKVITMWNOO-UHFFFAOYSA-N 5-diethylphosphoryl-2,2-dimethyl-1-oxido-3,4-dihydropyrrol-1-ium Chemical compound CCP(=O)(CC)C1=[N+]([O-])C(C)(C)CC1 XACANKVITMWNOO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- LUQZKEZPFQRRRK-UHFFFAOYSA-N 2-methyl-2-nitrosopropane Chemical compound CC(C)(C)N=O LUQZKEZPFQRRRK-UHFFFAOYSA-N 0.000 description 1
- GRFXXWWBAWFSRF-UHFFFAOYSA-N 2-nitrosobutane Chemical compound CCC(C)N=O GRFXXWWBAWFSRF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061218 Inflammation 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
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- RNRMWTCECDHNQU-XYOKQWHBSA-N N-tert-butyl-1-(1-oxidopyridin-1-ium-4-yl)methanimine oxide Chemical compound CC(C)(C)[N+](\[O-])=C/C1=CC=[N+]([O-])C=C1 RNRMWTCECDHNQU-XYOKQWHBSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- HXEQSCUBDIKNLN-UHFFFAOYSA-N ditert-butyl ethanediperoxoate Chemical compound CC(C)(C)OOC(=O)C(=O)OOC(C)(C)C HXEQSCUBDIKNLN-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical group ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IYSYLWYGCWTJSG-UHFFFAOYSA-N n-tert-butyl-1-phenylmethanimine oxide Chemical compound CC(C)(C)[N+]([O-])=CC1=CC=CC=C1 IYSYLWYGCWTJSG-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical class [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 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
- C07F9/4003—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
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Definitions
- This invention relates to the field of spin-trap molecules useful for trapping free radicals in biological systems and methods for preparation thereof.
- spin-traps free radical trapping compounds
- Ischemia and inflammation are two examples of biological events in which free radicals have been implicated.
- Spin traps are important for diagnostic and therapeutic purposes .
- Known spin-traps include ⁇ -phenyl N-tert-butyl (-) nitrone (PBN) , - (4-pyridyl-1-oxide) -N-tert-butyl nitrone (POBN) , 2- methyl-2-nitrosopropane (MNP) , and 5, 5-dimethyl-l- pyrroline N-oxide (DMPO) .
- a new family of spin trap molecules comprising dialklphosphoryl nitrones (“DAP-DMPO”) substituted in the ⁇ -position (or 2-position) is disclosed.
- DAP-DMPO dialklphosphoryl nitrones
- a new spin trap molecule, 5, 5-dimethyl-2- diethylphosphoryl-1-pyrroline N-oxide (“2- diethylphosphoryl-DMPO" 2-"DEP-DMPO") has been synthesized and characterized.
- the synthetic method for making the compound is also new and is expected to be useful for making the family of ⁇ -dialkylphosphoryl nitrones .
- PBN type phosphoryl derivatives and a method for making the same are disclosed.
- FIG. 1 demonstrates the synthetic route for preparation of 3-diethylphosphonanyl-DMPO.
- FIG. 2 demonstrates the synthetic scheme for PBN- type 2-phosphoryl nitrones.
- FIG. 3 demonstrates the synthetic scheme for DMPO- type 2-phosphoryl nitrones.
- DMPO 5, 5-dimethyl-1- pyrroline N-oxide
- DAP-DMPO dialkylphosphoryl-DMPO
- R an alkyl group having 1-18 carbons, preferably,
- the novel spin trap is effective in trapping free radicals, as shown in Table 1.
- DAP-DMPO can be used as a spin trap in cell membrane regions to trap free radicals which are formed in these areas.
- Another related utility is believed to be site- specific defense against reactive free radicals created in the polar interface and outer aqueous layers of membranes.
- Prophylactic treatment of free-radical disorders is expected.
- the utility of the compounds of the present invention in preventing or treating diseases is believed to be initiated or mediated by free-radical generation in the body.
- Exemplary doses range from 25 to 125 mg/kg of body weight in rats.
- the effective range of dosage in humans and other mammals is expected to be between about 25 to about 125 mg/kg, and preferably between about 25 to about 35 mg/kg of body weight. Particular dosage may vary depending on the particular derivative selected.
- the compounds of the present invention are preferably administered systemically.
- the compounds can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of times.
- the compounds may be administered orally or by other methods including intravenous, subcutaneous, topical and intraperitoneal administration.
- a method of administration of the compounds of the present invention is oral delivery.
- the compounds may be enclosed in capsules, compressed into tablets, microencapsulated, entrapped in liposomes, in solution or suspension, alone or in combination with a substrate immobilizing material such as starch or poorly absorbable salts.
- Pharmaceutically compatible binding agents and/or adjuvant materials can be used as part of a composition.
- Tablets or capsules can contain any of the following ingredients, or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; and excipient such as starch or lactose, an integrating agent such as alginic acid, corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and sweetening and flavoring agents.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- excipient such as starch or lactose, an integrating agent such as alginic acid, corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and sweetening and flavoring agents.
- a capsule form the liquid carrier such as a fatty oil may be used.
- Capsules and tablets can be coated with sugar, shellac and other enteric agents as is known.
- 2-DEP-DMPO was synthesized and tested. Characterization of 2-DEP-DMPO using Electron Paramagnetic Resonance Spectroscopy (EPR) revealed distinctive spin trapping chemistry which provides an optimum condition for this type of analysis. All spin adducts give a large phosphorous hyperfine splitting which varies in magnitude with the kind of free radical trapped.
- EPR Electron Paramagnetic Resonance Spectroscopy
- EPR HFSC's of 2-DEP-DMPO ADDUCTS about 20 free radicals have been tested. Of this eighteen (18) successfully give EPR spectra .due to the spin adducts .
- the solvent can be either benzene (selected as typical of lipophilic environments) or water. Only the bulky radicals such as tert-butoxyl or trichloromethyl are not apparently trapped by 2-DEP-DMPO.
- the lifetime characteristic is an important feature of the spin adduct. As can be seen with a hydrocarbon adduct like phenyl (Ph-) the Lifetime of the spin adduct is very long even in water (no decay within 16.5 hours) .
- hv ultraviolet radiation for seconds, mercury arc
- t 1/2 the time required for 50% of the adduct to decay
- G - gauss butyl
- DMSO dimethylsulfoxide
- Ph phenyl
- Me methyl
- Et ethyl
- Pr n-propyl
- i-Pr isopropyl.
- the synthetic scheme is given in FIG. 3.
- the molecular compatibility should be good because phospholipid bilayers have very similar ester structures in their make-up.
- X H N R spectrum was recorded on a Varian XL-300 NMR spectrometer using tetramethylsilane (T S) as an initial standard. EPR spectra were measured on a Bruker ESP-300E spectrometer. Chemicals are purchased from Aldrich Chemical Company, Inc. DMPO was prepared in our laboratory by known methods. The procedure for the addition reaction of dimethylphosphoryl anion to DMPO was adapted from R. Huber, A. Knierzinger, J.P. Obrechy, and A. Vasella, Helvetica Chimica Acta, 68: 1730-1747 (1985) .
- lithium diisopropylamide (LDA, lOmL, 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene, 20 mmoL) was added dropwise to a solution of diethylphosphite (5.0 g, 36.2 mmoL) in dichloromethane (40mL) which had been precooled to -20°C. The mixture was stirred for 15 min. at -20°C and then further cooled to -60°C. A solution of DMPO (2.0 g, 17.7 mmoL) in dichloromethane (4 mL) was added. The reaction solution was allowed to warm slowly to -20°C over a period of 3.5 h.
- LDA lithium diisopropylamide
- the phosphorous derivatives of DMPO or PBN spin traps will be administered to an animal either orally or intraperitoneally in amounts of about 25-250 mg/kg. An effective amount of spin traps will be administered to trap the anticipated concentration of free radicals generated in the particular disease state of the patient.
- a method for in-vivo spin trapping is conducted according to Lai, et al Arch . Biochem. Biophys . 244:156- 160 (1986) which is hereby incorporated by reference.
- the phosphorous-containing spin traps are tested for effectiveness in treating various diseases.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Detergent Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14123193A | 1993-10-25 | 1993-10-25 | |
| US141231 | 1993-10-25 | ||
| PCT/US1994/012109 WO1995011908A1 (en) | 1993-10-25 | 1994-10-20 | Novel phosphorus-containing spin-trap compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0675892A1 true EP0675892A1 (de) | 1995-10-11 |
Family
ID=22494771
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP94931432A Withdrawn EP0675892A1 (de) | 1993-10-25 | 1994-10-20 | Neue phosphor-enthaltende radikalfänger-zusammensetzungen |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0675892A1 (de) |
| JP (1) | JPH08505406A (de) |
| AU (1) | AU8051894A (de) |
| CA (1) | CA2152363A1 (de) |
| WO (1) | WO1995011908A1 (de) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2731428B1 (fr) * | 1995-03-06 | 1997-06-06 | Centre Nat Rech Scient | Derives phosphoryles de nitrones, leur procede de preparation et compositions les contenant |
| NZ316288A (en) * | 1995-09-11 | 2000-01-28 | Hoechst Marion Roussel Inc | 3,4-dihydro-isoquinoline, 4,5-3H-benzo[c]azepin-7-ol and 1H-isoindole derivatives and pharmaceutical compositions containing them |
| JP2011098910A (ja) * | 2009-11-06 | 2011-05-19 | Mikuni Seiyaku Kogyo Kk | 新規ピロリジン化合物又はその塩、その製造法及びそれを用いるピロリン環を有するニトロン化合物の製造法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2639350B1 (fr) * | 1988-11-21 | 1990-12-21 | Commissariat Energie Atomique | Radical nitroxyde, son procede de fabrication et son application en magnetometrie |
| DE69012138T2 (de) * | 1989-10-17 | 1995-04-06 | Oklahoma Med Res Found | Verfahren und zubereitungen zur hemmung von mit oxidativer schädigung assoziierten krankheiten. |
| FR2707990B1 (fr) * | 1993-07-20 | 1995-10-20 | Centre Nat Rech Scient | Nouvelles nitrones utilisables pour le piégeage des radicaux libres. |
-
1994
- 1994-10-20 AU AU80518/94A patent/AU8051894A/en not_active Abandoned
- 1994-10-20 JP JP7512737A patent/JPH08505406A/ja active Pending
- 1994-10-20 EP EP94931432A patent/EP0675892A1/de not_active Withdrawn
- 1994-10-20 CA CA002152363A patent/CA2152363A1/en not_active Abandoned
- 1994-10-20 WO PCT/US1994/012109 patent/WO1995011908A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9511908A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2152363A1 (en) | 1995-05-04 |
| WO1995011908A1 (en) | 1995-05-04 |
| AU8051894A (en) | 1995-05-22 |
| JPH08505406A (ja) | 1996-06-11 |
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