US3497596A - Method of treating parkinsonism with morphanthridine derivatives - Google Patents
Method of treating parkinsonism with morphanthridine derivatives Download PDFInfo
- Publication number
- US3497596A US3497596A US660912A US3497596DA US3497596A US 3497596 A US3497596 A US 3497596A US 660912 A US660912 A US 660912A US 3497596D A US3497596D A US 3497596DA US 3497596 A US3497596 A US 3497596A
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- United States
- Prior art keywords
- methyl
- dihydromorphanthridine
- lower alkyl
- tremorine
- carbon atoms
- 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.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title description 12
- IDWNSAXOQLJYOF-UHFFFAOYSA-N 11h-benzo[c][1]benzazepine Chemical class C1=NC2=CC=CC=C2CC2=CC=CC=C21 IDWNSAXOQLJYOF-UHFFFAOYSA-N 0.000 title description 4
- 208000027089 Parkinsonian disease Diseases 0.000 title description 3
- 206010034010 Parkinsonism Diseases 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 description 14
- 208000018737 Parkinson disease Diseases 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 206010044565 Tremor Diseases 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- JSUAJTLKVREZHV-UHFFFAOYSA-N 1-[4-(1-pyrrolidinyl)but-2-ynyl]pyrrolidine Chemical compound C1CCCN1CC#CCN1CCCC1 JSUAJTLKVREZHV-UHFFFAOYSA-N 0.000 description 6
- 208000018300 basal ganglia disease Diseases 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- -1 3-(l-pyridyl)-1-phenylcyclohexyl-1- propanol hydrochloride Chemical compound 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 208000027776 Extrapyramidal disease Diseases 0.000 description 4
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 208000012661 Dyskinesia Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000001431 Psychomotor Agitation Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- CLJWYXVAGLXDQW-UHFFFAOYSA-N dicyclohexylsulfamic acid Chemical compound C1CCCCC1N(S(=O)(=O)O)C1CCCCC1 CLJWYXVAGLXDQW-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001540 Akathisia Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000015592 Involuntary movements Diseases 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- XDXFALYQLCMAQN-WLHGVMLRSA-N butanedioic acid;(e)-but-2-enedioic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)\C=C\C(O)=O XDXFALYQLCMAQN-WLHGVMLRSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000001499 parasympathomimetic effect Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 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
- 229940068196 placebo Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Definitions
- the inventive method comprises administering a safe and effective amount of a selected morphanthridine derivative to an animal, especially a human being, afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder to control the symptoms of the disease.
- Specific morphanthridine derivatives disclosed are S-methyl-l l-(3- piperidino)propyl-S,6-dihydromorphanthridine, S-benzyl- 11 [4-(N-methylpiperidylene]-S,6-dihydromorphanthridine and S-methyl-l 1-( 3-dimethylamino) propylidene-5,6- dihydromorphanthridine.
- the patient exhibits one or more of the following symptoms: tremor, rigidity, increased salivation, akathisia, manifested by extreme restlessness, and dyskinesias, characterized by spastic contractions and involuntary movements.
- X and X are selected from hydrogen, a halogen such as chloro or bromo, a lower alkoxy such as methoxy or ethoxy, a lower alkyl thio such as thiomethyl or thioethyl and trifluo'romethyl
- R is hydrogen, a lower alkyl of l to 4 carbon atoms or a phenyl-lower alkyl of 7 to 13 carbon atoms such as benzyl, phenethyl, phenylisopropyl, and the like
- A is a straight or branched chain lower alkylene of 2 to 6 carbon atoms
- R and R are selected from hydrogen, a lower alkyl of 1 to 4 carbon atoms and phenyl-lower alkyl of 7 to 10 carbon atoms represent groups in which R and R are joined together to form a cyclic group selected from morpholino, pyrrolidino, piperid
- compositions containing a major amount of a pharmaceutical diluent and one or more of the described morphanthridine derivatives are administered orally or parenterally to patients afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder in doses ranging from 2 mg. per day to mg. or more a day depending upon the severity of the condition and the response of the patient to the active ingredients.
- compositions which may be employed are oral dosage forms such as tablets, coated or uncoated, of the immediate or sustained release type, capsules, syrups, elixirs or dosage forms adapted for other routes of administration such as suppositories, and sterile parenteral solutions and the like.
- the active ingredients may be incorporated into the pharmaceutical compositions as the free bases; however, it is usually preferred to employ them in the form of a pharmaceutically acceptable salt.
- Representative of the acid addition salts which, may be employed are the hydrochloride, sulfate, phosphate, acetate, fumarate succinate, maleate, sulfamate, and dicyclohexylsulfamate.
- Each of the above compounds blocked tremorine-inluced tremors when administered to mice prior to chalenge in doses of less than 10 mg./kg. intraperitoneally.
- Each of the above compounds blocked tremorine-inluced tremors when administered to mice prior to chalenge in doses of less than 20 mg./kg. intraperitoneally.
- Suitable pharmaceutical composiions which may be prepared are the following:
- the powders, other than magnesium stearate, are granilated with water, passed through a No. 16 mesh screen .nd dried at 50 C. Magnesium stearate is mixed in and -0 mg. tablets are pressed.
- EXAMPLE Sixteen human patients suifering from Parkinsons disase were administered tablets containing 2 mg. each of he compound -methyl-l1-(3-dimethylamino)propyliene-5,6-dihydromorphanthridine. The following is a ummary of the results of the study. The patients received oses ranging from '6 mg. per day to 50 mg. per day. All ixteen of the pat ents had tremor. Eleven of the patients responded favorably to the medication with reduced tremor. Of the eight patients that had rigidity, in addition to tremor, six improved on the medication. As part of the controlled study, placebos were administered in six cases, however, no placebo response was observed.
- the method of the present invention appears to possess a significant advantage over previous treatments of Parkinsons disease in that the beneficial effects of the method are not accompanied by the same degree of undesirable peripheral anticholinergic activity as previous methods.
- a method of controlling the tremor and rigidity of Parkinsons disease or a drug-induced extra-pyramidal disorder in an animal which is afiiicted with said disease or disorder which comprises administering to said animal a daily dose of 2 to mg. of a compound of the formulae:
- X and X are hydrogen, halogen, lower alkoxy, lower alkyl thio or trifluoromethyl
- R is hydrogen, lower alkyl of 1 to 4 carbon atoms or a phenyl-lower alkyl of 7 to 10 carbon atoms
- A is an alkylene of 2 to 6 carbon atoms
- R and R are hydrogen, lower alkyl of 1 to 4 carbon atoms, a phenyl-lower alkyl of 7 to 10 carbon atoms and when taken with the attached N are morpholino, pyrrolidino, piperidino, piperazino or 4-lower alkyl piperazino.
Description
United States Patent U.S. Cl. 424244 4 Claims ABSTRACT OF THE DISCLOSURE The inventive method comprises administering a safe and effective amount of a selected morphanthridine derivative to an animal, especially a human being, afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder to control the symptoms of the disease. Specific morphanthridine derivatives disclosed are S-methyl-l l-(3- piperidino)propyl-S,6-dihydromorphanthridine, S-benzyl- 11 [4-(N-methylpiperidylene]-S,6-dihydromorphanthridine and S-methyl-l 1-( 3-dimethylamino) propylidene-5,6- dihydromorphanthridine.
BACKGROUND OF THE INVENTION In both Parkinsons disease and drug-induced extrapyramidal disorders, the patient exhibits one or more of the following symptoms: tremor, rigidity, increased salivation, akathisia, manifested by extreme restlessness, and dyskinesias, characterized by spastic contractions and involuntary movements.
The drug most widely prescribed for use in the treatment of Parkinsons disease and the drug-induced extrapyramidal disorders is 3-(l-pyridyl)-1-phenylcyclohexyl-1- propanol hydrochloride. Unfortunately, this agent and SUMMARY OF THE INVENTION In the practice of the invention, an animal, especially a person afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder, is administered a safe and effective amount of a compound or a nontoxic salt of a compound selected from compounds of the formulae:
3,497,596 Patented Feb. 24, 1970 in which X and X are selected from hydrogen, a halogen such as chloro or bromo, a lower alkoxy such as methoxy or ethoxy, a lower alkyl thio such as thiomethyl or thioethyl and trifluo'romethyl, R is hydrogen, a lower alkyl of l to 4 carbon atoms or a phenyl-lower alkyl of 7 to 13 carbon atoms such as benzyl, phenethyl, phenylisopropyl, and the like, A is a straight or branched chain lower alkylene of 2 to 6 carbon atoms, and R and R are selected from hydrogen, a lower alkyl of 1 to 4 carbon atoms and phenyl-lower alkyl of 7 to 10 carbon atoms represent groups in which R and R are joined together to form a cyclic group selected from morpholino, pyrrolidino, piperidino, piperazino and 4-lower alkyl piperazino.
DETAILED DESCRIPTION In the preferred practice of the present invention, pharmaceutical compositions containing a major amount of a pharmaceutical diluent and one or more of the described morphanthridine derivatives are administered orally or parenterally to patients afflicted with Parkinsons disease or a drug-induced extrapyramidal disorder in doses ranging from 2 mg. per day to mg. or more a day depending upon the severity of the condition and the response of the patient to the active ingredients.
The pharmaceutical compositions which may be employed are oral dosage forms such as tablets, coated or uncoated, of the immediate or sustained release type, capsules, syrups, elixirs or dosage forms adapted for other routes of administration such as suppositories, and sterile parenteral solutions and the like.
The active ingredients may be incorporated into the pharmaceutical compositions as the free bases; however, it is usually preferred to employ them in the form of a pharmaceutically acceptable salt. Representative of the acid addition salts which, may be employed are the hydrochloride, sulfate, phosphate, acetate, fumarate succinate, maleate, sulfamate, and dicyclohexylsulfamate.
Among the compounds of Formula I which may be employed in the method of the invention are the followmg:
5 -methyl-1 l- 3-dimethylamino propylidene-S ,6-
dihydromorphanthridine,
5 -methyl-1 1- 3-dirnethylamino-2-methylpropylidene 5,6-dihydromorphanthridine,
S-methyl-l 1- 3-methylamino propylidene-5,6-
dihydromorphanthridine,
3-chloro-5-methyl-l 1- 3-dimethylamino propylidene- 5,6-dihydromorphanthridine, and
5 -rnethy1-1 1- 3- (4-methylpiperazino -propylidene] -5,6-
dihydromorphanthridine.
Each of the above compounds, when administered to mice in doses of 20 mg./kg. intraperitoneally, prior to challenge with either tremorine or oxotremorine, blocked the tremors normally induced when tremorine or x0- tremorine are administered to nonpretreated mice intraperitoneally. This is considered a significant indication of anti-Parkinsonism activity, for both tremorine and 0x0- tremorine induce a Parkinson disease-like behavior characterized by tremor, rigidity and parasympathomimetic stimulation in mice, rats, rabbits, dogs and monkeys. The similarity of tremorine and oxotremorine-induced behavior in animals to that seen in Parkinsons disease in man, and the fact that all agents found to be useful in treating Parkinsons disease also block the etfects of tremorine and oxotremorine in animals, has led to the general use of tremorine and oxotremorine in the screening of drugs for anti-Parkinsonism activity (Everett, et al., Science, 124, 79 (1956) and Cho, et a1. Biochem. biophys. Res. Communs. 5, 276 (1961)).
Compounds of Formula II which may be employed in the method of the invention are the following:
S-benzyl-l 1-[4-(N-methyl-4-piperidylene) ]-5,6-
dihydromorphanthridine, and
S-methyl-l l-(N-methyl-4-piperidylene) -5,6-
dihydromorphanthridine.
Each of the above compounds blocked tremorine-inluced tremors when administered to mice prior to chalenge in doses of less than 10 mg./kg. intraperitoneally.
Compounds of Formula III which may be employed in he method of the invention are the following:
i-methyl-l1-(3-piperidino)propyl-5,6-
dihydromorphanthridine,
i-methyl-l l- 3- (N'-methyl piperazine] propyl-5,6-
dihydromorphanthridine,
i-methyl-l 1-( 3 -methylamino propyl-S, 6-
dihydromorphanthridine,
i-methyl-11-(1-dimethylamino-3-butyl)-5,6-
dihydromorphanthridine,
l-chloro-S -methyl-1 1- 3-N-methyl-N-benzylamino) propyl-5,6-dihydromorphanthridine, and
I-chloro-S -methyl-1 1- 3-methylamino propyl-5,6-
dihydromorphanthridine.
Each of the above compounds blocked tremorine-inluced tremors when administered to mice prior to chalenge in doses of less than 20 mg./kg. intraperitoneally.
Representative of suitable pharmaceutical composiions which may be prepared are the following:
TABLETS -methyl-l 1- 3 -dimcthylamino propylidene-5,6-dihydromorphanthridine dicyclohexylsulfamate 25 /Iethyl cellulose, 400 cps. 4 .actose 9 llagnesium stearate 0.4 tarch 1.6
The powders, other than magnesium stearate, are granilated with water, passed through a No. 16 mesh screen .nd dried at 50 C. Magnesium stearate is mixed in and -0 mg. tablets are pressed.
The practice of the invention is further illustrated by be following example:
EXAMPLE Sixteen human patients suifering from Parkinsons disase were administered tablets containing 2 mg. each of he compound -methyl-l1-(3-dimethylamino)propyliene-5,6-dihydromorphanthridine. The following is a ummary of the results of the study. The patients received oses ranging from '6 mg. per day to 50 mg. per day. All ixteen of the pat ents had tremor. Eleven of the patients responded favorably to the medication with reduced tremor. Of the eight patients that had rigidity, in addition to tremor, six improved on the medication. As part of the controlled study, placebos were administered in six cases, however, no placebo response was observed.
The method of the present invention appears to possess a significant advantage over previous treatments of Parkinsons disease in that the beneficial effects of the method are not accompanied by the same degree of undesirable peripheral anticholinergic activity as previous methods.
I claim:
1. A method of controlling the tremor and rigidity of Parkinsons disease or a drug-induced extra-pyramidal disorder in an animal which is afiiicted with said disease or disorder which comprises administering to said animal a daily dose of 2 to mg. of a compound of the formulae:
X X1, X X
I II
III
in which X and X are hydrogen, halogen, lower alkoxy, lower alkyl thio or trifluoromethyl, R is hydrogen, lower alkyl of 1 to 4 carbon atoms or a phenyl-lower alkyl of 7 to 10 carbon atoms, A is an alkylene of 2 to 6 carbon atoms, R and R are hydrogen, lower alkyl of 1 to 4 carbon atoms, a phenyl-lower alkyl of 7 to 10 carbon atoms and when taken with the attached N are morpholino, pyrrolidino, piperidino, piperazino or 4-lower alkyl piperazino.
2. The method of claim 1 in which the compound administered is a compound of Formula 1 in which R is methyl, A is ethylene, X and X are hydrogen and R and R are methyl.
3. The method of claim 1 in which the compound administered is one in which X and X are hydrogen or chloro.
4. The method of claim 1 in which the animal is a human being.
References Cited UNITED STATES PATENTS 3,153,652 10/1964 Drukker et a1. 424-267 3,267,094 8/1966 Drukker et a1.
OTHER REFERENCES Current Therapy, Conn. (1966), pp. 603-608.
ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assistant Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,497,596
- February 24, 1970 Richard Ursillo It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:
Column 4, lines 25 to 30,
that portion of the formula reading I should read Signed and sealed this 15th day of September 1970.
( Attcst:
Edward M. Fletcher, Jr. Attcsting Officer WILLIAM E. SCHUYLER, JR.
Commissioner of Patents
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66091267A | 1967-08-16 | 1967-08-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3497596A true US3497596A (en) | 1970-02-24 |
Family
ID=24651459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US660912A Expired - Lifetime US3497596A (en) | 1967-08-16 | 1967-08-16 | Method of treating parkinsonism with morphanthridine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3497596A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0019172A1 (en) * | 1979-05-10 | 1980-11-26 | BASF Aktiengesellschaft | 6-Substituted 11-alkylene-morphantridines, process for preparing them and pharmaceutical compositions containing them |
| EP0409406A2 (en) * | 1989-06-19 | 1991-01-23 | The Wellcome Foundation Limited | Aryl-substituted amine derivatives useful in cancer therapy |
| US5208238A (en) * | 1989-06-19 | 1993-05-04 | Burroughs Wellcome Company | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| US5300282A (en) * | 1989-06-19 | 1994-04-05 | Burroughs-Wellcome Company | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| US5346897A (en) * | 1989-06-19 | 1994-09-13 | Burroughs Wellcome Co. | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| US5364843A (en) * | 1989-06-19 | 1994-11-15 | Burroughs Wellcome Co. | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3153652A (en) * | 1964-10-20 | Certificate of correction | ||
| US3267094A (en) * | 1962-09-12 | 1966-08-16 | Colgate Palmolive Co | Morphanthridine derivatives |
-
1967
- 1967-08-16 US US660912A patent/US3497596A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3153652A (en) * | 1964-10-20 | Certificate of correction | ||
| US3267094A (en) * | 1962-09-12 | 1966-08-16 | Colgate Palmolive Co | Morphanthridine derivatives |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0019172A1 (en) * | 1979-05-10 | 1980-11-26 | BASF Aktiengesellschaft | 6-Substituted 11-alkylene-morphantridines, process for preparing them and pharmaceutical compositions containing them |
| EP0409406A2 (en) * | 1989-06-19 | 1991-01-23 | The Wellcome Foundation Limited | Aryl-substituted amine derivatives useful in cancer therapy |
| EP0409406A3 (en) * | 1989-06-19 | 1991-04-03 | The Wellcome Foundation Limited | Aryl-substituted amine derivatives useful in cancer therapy |
| EP0487502A2 (en) * | 1989-06-19 | 1992-05-27 | The Wellcome Foundation Limited | Pharmaceutically active aryl-substituted amine derivatives |
| EP0487502A3 (en) * | 1989-06-19 | 1992-06-24 | The Wellcome Foundation Limited | Pharmaceutically active aryl-substituted amine derivatives |
| US5208238A (en) * | 1989-06-19 | 1993-05-04 | Burroughs Wellcome Company | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| US5300282A (en) * | 1989-06-19 | 1994-04-05 | Burroughs-Wellcome Company | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| AU650421B2 (en) * | 1989-06-19 | 1994-06-23 | Wellcome Foundation Limited, The | Medicaments useful in cancer therapy and having antihistaminic properties |
| US5346897A (en) * | 1989-06-19 | 1994-09-13 | Burroughs Wellcome Co. | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| US5364843A (en) * | 1989-06-19 | 1994-11-15 | Burroughs Wellcome Co. | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
| US5395610A (en) * | 1989-06-19 | 1995-03-07 | Burroughs-Wellcome Co. | Agents for potentiating the effects of antitumor agents and combating multiple drug resistance |
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