US3689644A - 2-imino-5-phenyl-4-oxazolidinone and a potentiating agent to treat parkinson{40 s disease - Google Patents
2-imino-5-phenyl-4-oxazolidinone and a potentiating agent to treat parkinson{40 s disease Download PDFInfo
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- US3689644A US3689644A US110255A US3689644DA US3689644A US 3689644 A US3689644 A US 3689644A US 110255 A US110255 A US 110255A US 3689644D A US3689644D A US 3689644DA US 3689644 A US3689644 A US 3689644A
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- oxazolidinone
- phenyl
- imino
- disease
- potentiating agent
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- 230000003389 potentiating effect Effects 0.000 title claims abstract description 12
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 201000010099 disease Diseases 0.000 title abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 6
- 239000000203 mixture Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical group [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 10
- 239000000347 magnesium hydroxide Substances 0.000 claims description 10
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 10
- 239000002552 dosage form Substances 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 15
- -1 alkaline earth metal salt Chemical class 0.000 abstract description 10
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 9
- 229910052782 aluminium Inorganic materials 0.000 abstract description 7
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002585 base Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 8
- 208000018737 Parkinson disease Diseases 0.000 description 7
- 208000027089 Parkinsonian disease Diseases 0.000 description 7
- 206010034010 Parkinsonism Diseases 0.000 description 7
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 2
- CVBMAZKKCSYWQR-BPJCFPRXSA-N Deserpidine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cccc3 CVBMAZKKCSYWQR-BPJCFPRXSA-N 0.000 description 2
- 208000012661 Dyskinesia Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000648 anti-parkinson Effects 0.000 description 2
- 239000000939 antiparkinson agent Substances 0.000 description 2
- 230000000035 biogenic effect Effects 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- ISMCNVNDWFIXLM-WCGOZPBSSA-N deserpidine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ISMCNVNDWFIXLM-WCGOZPBSSA-N 0.000 description 2
- 229960001993 deserpidine Drugs 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 229960005333 tetrabenazine Drugs 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 206010001541 Akinesia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 235000010210 aluminium Nutrition 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical class O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000008921 facial expression Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000011160 magnesium carbonates Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004764 thiosulfuric acid derivatives Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/08—Oxides; Hydroxides
Definitions
- ABSTRACT Covers the use of the combination of 2-imino-5-phenyl-4-oxazolidinone or a salt thereof and a potentiating agent comprising an aluminum or alkaline earth metal salt or base in treating Parkinsons disease.
- Parkinsonism is generally characterized by involuntary tremors, diminished motor power and rigidity.
- the onset of the disease is insidious, with increasing rigidity or tremor or both.
- the patients facial expression may be fixed or less mobile than normal; smiling spreads and slowly disappears. Body movements generally become slower. There may be gradually increased rigidity with diminished swaying of the arms during walking, Generally, the patients legs may begin to feel stiff and excessive effort may be required to lift them from the ground while walking. Patients often assume a stooping posture and shuffle rather than walk. As the disease progresses, movements such as adjusting a tie, buttoning a coat, etc. become impossible.
- l-dopa was the first effective single agent in the treatment of the disease.
- L-dopa has been reported to be effective against the akinesia and rigidity of Parkinsonism, particularly in extremely severe cases. An increase in mental alertness and wakefulness, relief from depression and an increase in intellect has also been observed.
- a specific method of the invention is to provide a method of treating Parkinsonism with a drug exhibiting a low level of side effects, if any, and which does not become tolerated over extended usage.
- the invention here is concerned with a method of treating Parkinsons disease with a composition comprising in combination 2-imino-5-phenyl-2-oxazolidinone or a salt thereof and a potentiating agent comprising an aluminum or alkaline earth metal salt or base.
- compositions found useful here in treating Parkinsonism comprise the combination of 2- imino-S-phenyl-4-oxazolidinone and a wide variety of aluminum or alkaline earth metal salts or bases. While the oxazolidinone compound itself is known to have some activity against Parkinsons disease it has been discovered here that its activity in this area may be substantially increased by combining said oxazolidinone with an aluminum or alkaline earth metal base or salt. Such potentiation of the effect of the oxazolidinone is accomplished by combination with a salt or base, despite the fact that the salt or base alone, even in rela tively large dosages is substantially ineffective in this treatment area.
- Typical potentiating agents include aluminum, magnesium and calcium carbonates, hydroxides, sulfates, chlorides, bicarbonates, phosphates, citrates, thiosulfates, iodides, bromides, carbonate-hydroxides, acetates, propionates, lactates, benzoates, tartrates, etc.
- magnesium salts and bases such as magnesium hydroxide, magnesium sulfate, magnesium chloride.
- One particularly useful composition comprises a combination of percent by weight of oxazolidinone and 25 percent by weight of magnesium hydroxide, wherein approximately equimolar amounts of each are present.
- compositions employed here which exhibit anti-Parkinsonism activity are formed by combining one or more of the just described salts or bases with the oxazolidinone in a ratio of at least 0.05 mole of base or salt to 1 mole of oxazolidinone. While no upper limit of said ratio is to be construed, yet as a practical matter, up to about 50 or more moles of bases per mole of oxazolidinone may be combined to form useful treatment compositions.
- the active compounds may be provided in granulation, tablet, capsule, elixir and other dosage forms. Oral administration is preferred and is the most convenient. Other means of administration may be employed such as, for example, by intraperitioneal or intramuscular injection.
- the active ingredients can also be incorporated in an oil or wax base and administered in the form of a suppository.
- the compounds of the invention are found to be effective in humans at a dosage range of from about 0.1
- EXAMPLE I One basic approach for evaluation of anti-Parkinson activity is estimating reversal of the extrapyramidal effects of reserpine which depletes biogenic amines in animals and in man, which test was employed here.
- a composition comprising a mixture of 2-imino-5- phenyl-4-oxazolidinone with magnesium hydroxide (75.3 percent and 24.7 percent by weight, respectively) was prepared in a liquid form and administered to mice.
- the composition was found to reverse the effects of deserpidine in mice with a dosage range of 25-100 mg./kg., i.p.
- the effects of deserpidine were reversed in an oral dose range of -20 mg./kg. orally.
- EXAMPLE II The above composition was also studied for its anti- Parkinson activity in additional tests. Specifically, it was studied with respect to its activity in reversing the motor activity effects of tetrabenazine (a reserpine-like drug) in mice. As is shown below, the composition demonstrated marked activity in reversing the sedative effects of tetrabenazine, which depletes brain biogenic amines.
- composition was made up in the form of a capsule and administered orally.
- the capsule mixture was composed as follows:
- composition 1 Ingredients Grams 2-imine5-phenyl-4-oxazolidinone 3.76 magnesium hydroxide 1.24 lactose l 5 .00
- salts of the oxazolidinone compound may also be employed here.
- This particular oxazolidinone is a relatively weak acid, and therefore salts may be formed via combination with a strong base.
- alkali metal salts may be formed such as the sodium, lithium, etc. salts.
- alkaline earth metal salts such as the calcium salt may also be formed.
- these salts are formed by reacting the oxazolidinone with a strong alkali metal or alkaline earth metal base-or anhydride such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc., or sodium hydride, calcium hydride.
- a strong alkali metal or alkaline earth metal base-or anhydride such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc., or sodium hydride, calcium hydride.
- a method of treating a patient suffering from Parkinsons disease comprising the step of administering to said patient at least an effective dosage of a composition comprising in combination Z-i r inO-S-phen l-4-oxazolldlnone or a pharmaceutic ly accepta le salt thereof and a potentiating agent comprising a base or salt selected from the group consisting of an aluminum base, an aluminum salt, an alkaline earth metal salt and an alkaline earth metal bases said potentiating agent being combined in a ratio of at least 0.05 mole of potentiating agent to 1 mole of 2-imino-5-phenyl-4-oxazolidinone.
- composition is administered in a unit dosage form in a pharmaceutically acceptable carrier, said carrier comprising a major portion of said dosage form.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Covers the use of the combination of 2-imino-5-phenyl-4oxazolidinone or a salt thereof and a potentiating agent comprising an aluminum or alkaline earth metal salt or base in treating Parkinson''s disease.
Description
United States Patent Plotnikoff [451 Sept. 5, 1972 [54] 2-IMINO-5-PHENYL-4- OXAZOLIDINONE AND A POTENTIATING AGENT TO TREAT PARKINSON'S DISEASE [72] Inventor: Nicholas Peter Plotnikoff, Lake Bluff, Ill.
[73] Assignee: Abbott Laboratories,
Chicago, Ill.
[52] US. Cl. ..424/157, 424/153, 424/154, 424/272 North [51] Int. Cl. A611: 27/00 [58] Field of Search ..424/272, 154, 157, 153
[56] References Cited UNITED STATES PATENTS 3,348,999 10/ 1967 Woroch ..424/272 Primary Examiner-Stanley J. Friedman Att0rney-Robert L. Niblack [57] ABSTRACT Covers the use of the combination of 2-imino-5-phenyl-4-oxazolidinone or a salt thereof and a potentiating agent comprising an aluminum or alkaline earth metal salt or base in treating Parkinsons disease.
6 Claims, No Drawings Z-IMINO-5-PI-IENYL-4-OXAZOLIDINONE AND A POTENTIATING AGENT TO TREAT PARKINSON'S DISEASE CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of copending application U.S. Ser. No. 80,760, filed Oct. 14, 1970 now abandoned.
BACKGROUND OF THE INVENTION Parkinsonism is generally characterized by involuntary tremors, diminished motor power and rigidity. The onset of the disease is insidious, with increasing rigidity or tremor or both. The patients facial expression may be fixed or less mobile than normal; smiling spreads and slowly disappears. Body movements generally become slower. There may be gradually increased rigidity with diminished swaying of the arms during walking, Generally, the patients legs may begin to feel stiff and excessive effort may be required to lift them from the ground while walking. Patients often assume a stooping posture and shuffle rather than walk. As the disease progresses, movements such as adjusting a tie, buttoning a coat, etc. become impossible.
The disease is usually slowly progressive and patients may live for many years. However, with increased disability, patients often become depressed, anxious, and emotionally disturbed. While treatment with various drugs such as anti-spasmodics, central nervous system stimulants and the like have been used alone or in combination to produce temporary amelioration of complaints, l-dopa was the first effective single agent in the treatment of the disease.
L-dopa has been reported to be effective against the akinesia and rigidity of Parkinsonism, particularly in extremely severe cases. An increase in mental alertness and wakefulness, relief from depression and an increase in intellect has also been observed.
While l-dopa has produced some rather promising results in experimental therapy, unfortunately it is not well tolerated by a number of patients. The most frequent side effects are nausea, vomiting, hypotension, and abnormal involuntary movements, as well as mental changes. The abnormal involuntary movements particularly pose severe problems to its continued use of approximately in 50 percent of its patients. Thus, it is evident that drugs having a minimum of unwanted complications are needed to treat patients suffering from Parkinsonism.
SUMMARY OF THE INVENTION It, therefore, becomes an object of the invention to provide a method of treating Parkinsonism. A specific method of the invention is to provide a method of treating Parkinsonism with a drug exhibiting a low level of side effects, if any, and which does not become tolerated over extended usage. Essentially the invention here is concerned with a method of treating Parkinsons disease with a composition comprising in combination 2-imino-5-phenyl-2-oxazolidinone or a salt thereof and a potentiating agent comprising an aluminum or alkaline earth metal salt or base.
DETAILED DESCRIPTION OF THE INVENTION In more detail, compositions found useful here in treating Parkinsonism comprise the combination of 2- imino-S-phenyl-4-oxazolidinone and a wide variety of aluminum or alkaline earth metal salts or bases. While the oxazolidinone compound itself is known to have some activity against Parkinsons disease it has been discovered here that its activity in this area may be substantially increased by combining said oxazolidinone with an aluminum or alkaline earth metal base or salt. Such potentiation of the effect of the oxazolidinone is accomplished by combination with a salt or base, despite the fact that the salt or base alone, even in rela tively large dosages is substantially ineffective in this treatment area.
Typical potentiating agents include aluminum, magnesium and calcium carbonates, hydroxides, sulfates, chlorides, bicarbonates, phosphates, citrates, thiosulfates, iodides, bromides, carbonate-hydroxides, acetates, propionates, lactates, benzoates, tartrates, etc. Most preferred are magnesium salts and bases such as magnesium hydroxide, magnesium sulfate, magnesium chloride. One particularly useful composition comprises a combination of percent by weight of oxazolidinone and 25 percent by weight of magnesium hydroxide, wherein approximately equimolar amounts of each are present.
In the typical situation the compositions employed here which exhibit anti-Parkinsonism activity are formed by combining one or more of the just described salts or bases with the oxazolidinone in a ratio of at least 0.05 mole of base or salt to 1 mole of oxazolidinone. While no upper limit of said ratio is to be construed, yet as a practical matter, up to about 50 or more moles of bases per mole of oxazolidinone may be combined to form useful treatment compositions.
For use in treating Parkinsons disease it may be administered in either liquid or solid form. Thus, the active compounds may be provided in granulation, tablet, capsule, elixir and other dosage forms. Oral administration is preferred and is the most convenient. Other means of administration may be employed such as, for example, by intraperitioneal or intramuscular injection. The active ingredients can also be incorporated in an oil or wax base and administered in the form of a suppository.
The compounds of the invention are found to be effective in humans at a dosage range of from about 0.1
to about 200 mg./kg. of body weight daily. More often the dose is 0.1- mg./kg. and most often is 1-100 mg./kg.
EXAMPLE I One basic approach for evaluation of anti-Parkinson activity is estimating reversal of the extrapyramidal effects of reserpine which depletes biogenic amines in animals and in man, which test was employed here.
A composition comprising a mixture of 2-imino-5- phenyl-4-oxazolidinone with magnesium hydroxide (75.3 percent and 24.7 percent by weight, respectively) was prepared in a liquid form and administered to mice. The composition was found to reverse the effects of deserpidine in mice with a dosage range of 25-100 mg./kg., i.p. In another series of tests involving six Rhesus monkeys the effects of deserpidine were reversed in an oral dose range of -20 mg./kg. orally.
EXAMPLE II The above composition was also studied for its anti- Parkinson activity in additional tests. Specifically, it was studied with respect to its activity in reversing the motor activity effects of tetrabenazine (a reserpine-like drug) in mice. As is shown below, the composition demonstrated marked activity in reversing the sedative effects of tetrabenazine, which depletes brain biogenic amines.
Here the composition was made up in the form of a capsule and administered orally. The capsule mixture was composed as follows:
' Composition 1 Ingredients Grams 2-imine5-phenyl-4-oxazolidinone 3.76 magnesium hydroxide 1.24 lactose l 5 .00
Total The activity of the above composition is as follows:
In analyzing data from the above the table, it should be noted that in each instance the t test p value was significantly different from the controls.
It is understood, of course, that in addition to use of the above salts or bases in combination with 2-irnino-5- phenyl-4-oxazolidinone itself, salts of the oxazolidinone compound may also be employed here. This particular oxazolidinone is a relatively weak acid, and therefore salts may be formed via combination with a strong base. For example, alkali metal salts may be formed such as the sodium, lithium, etc. salts. In addition alkaline earth metal salts such as the calcium salt may also be formed. Normally, these salts are formed by reacting the oxazolidinone with a strong alkali metal or alkaline earth metal base-or anhydride such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide etc., or sodium hydride, calcium hydride.
What is claimed is: y
l. A method of treating a patient suffering from Parkinsons disease comprising the step of administering to said patient at least an effective dosage of a composition comprising in combination Z-i r inO-S-phen l-4-oxazolldlnone or a pharmaceutic ly accepta le salt thereof and a potentiating agent comprising a base or salt selected from the group consisting of an aluminum base, an aluminum salt, an alkaline earth metal salt and an alkaline earth metal bases said potentiating agent being combined in a ratio of at least 0.05 mole of potentiating agent to 1 mole of 2-imino-5-phenyl-4-oxazolidinone.
2. The method of claim 1 wherein said potentiating agent is magnesium hydroxide.
3. The method of claim 2 wherein said magnesium hydroxide is combined in a ratio of about 1 mole of magnesium hydroxide to 1 mole of 2-imino-5-phenyl-4- oxazolidinone.
4. The method of claim 1 wherein said dosage range is from about O.l to about 200 mg./kg. of body weight daily.
5. The method of claim 4 wherein said dosage range is 0. 1-100 mg./kg.
6. The method of claim 1 wherein said composition is administered in a unit dosage form in a pharmaceutically acceptable carrier, said carrier comprising a major portion of said dosage form.
Claims (5)
- 2. The method of claim 1 wherein said potentiating agent is magnesium hydroxide.
- 3. The method of claim 2 wherein said magnesium hydroxide is combined in a ratio of about 1 mole of magnesium hydroxide to 1 mole of 2-imino-5-phenyl-4-oxazolidinone.
- 4. The method of claim 1 wherein said dosage range is from about 0.1 to about 200 mg./kg. of body weight daily.
- 5. The method of claim 4 wherein said dosage range is 0.1- 100 mg./kg.
- 6. The method of claim 1 wherein said composition is administered in a unit dosage form in a pharmaceutically acceptable carrier, said carrier comprising a major portion of said dosage form.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11025571A | 1971-01-27 | 1971-01-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3689644A true US3689644A (en) | 1972-09-05 |
Family
ID=22332029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US110255A Expired - Lifetime US3689644A (en) | 1971-01-27 | 1971-01-27 | 2-imino-5-phenyl-4-oxazolidinone and a potentiating agent to treat parkinson{40 s disease |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3689644A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4217340A (en) * | 1979-03-21 | 1980-08-12 | Merck & Co., Inc. | Rapid acting combination of phenyl benzoic acid compounds and magnesium hydroxide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3348999A (en) * | 1966-02-10 | 1967-10-24 | Abbott Lab | Compositions to enhance the learning rate and retention level in animals comprising 2-imino-5-phenyl-4-oxazolidinone and a relatively insoluble base |
-
1971
- 1971-01-27 US US110255A patent/US3689644A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3348999A (en) * | 1966-02-10 | 1967-10-24 | Abbott Lab | Compositions to enhance the learning rate and retention level in animals comprising 2-imino-5-phenyl-4-oxazolidinone and a relatively insoluble base |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4217340A (en) * | 1979-03-21 | 1980-08-12 | Merck & Co., Inc. | Rapid acting combination of phenyl benzoic acid compounds and magnesium hydroxide |
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