US3743732A

US3743732A - Process for suppressing the tremor of parkinson's syndrome

Info

Publication number: US3743732A
Application number: US00226238A
Authority: US
Inventors: R Rodriguez
Original assignee: Miles Laboratories Inc
Current assignee: Bayer Corp
Priority date: 1972-02-14
Filing date: 1972-02-14
Publication date: 1973-07-03
Anticipated expiration: 1990-07-03

Abstract

THE TREMOR OF PARKINSONS''S SYNDROME IN MAMMALS IS SUPPRESSED BY THE ADMINSTRATION OF A COMPIUND OF THE FORMULA:

2-(4-R-PIPERAZIN-1-YL)-QUINOLINE

IN WHICH R IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF H AND CH3, AND NONTOXIC PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. THESE COMPOUNDS MAY BE UTILIZED IN CONJUNCTION WITH PHARMACEUTICALLY ACCEPTABLE VEHICLES THEREFOR.

Description

United States Patent 3,743,732 PROCESS FOR SUPPRESSING THE TREMOR OF PARKINSONS SYNDROME Rodolfo Rodriguez, Mexico City, Mexico, assignor to Miles Laboratories, Inc., Elkhart, Ind. No Drawing. Filed Feb. 14, 1972, Ser. No. 226,238 Int. Cl. A61k 27/00 US. Cl. 424-250 3 Claims ABSTRACT OF THE DISCLOSURE The tremor of Parkinsons syndrome in mammals is suppressed by the administration of a compound of the formula:

N N-R in which R is a member selected from the group consisting of H and CH and nontoxic pharmacologically acceptable acid addition salts thereof. These compounds may be utilized in conjunction with pharmaceutically acceptable vehicles therefor.

This invention relates to a process for suppressing Parkinson-like syndrome of a mammal by the administration to such mammal of a tremor suppressing amount of a compound of the formula:

wherein R is selected from the group consisting of H and CH and nontoxic pharmacologically acceptable acid addition salts thereof.

The management of Parkinsons disease is a complex problem in which drug therapy plays a major role. For many years the most widely used therapeutic agents were belladonna alkaloids such as atropine and scopolamine, and although some neurologists still regard these products as useful agents, they have been largely replaced by synthetic anticholinergic compounds such as trihexyphenidyl, benztropine, cycrimine, procyclidine and biperiden. Certain drugs that are classified primarily as antihistaminics such as diphenhydramine, orphenadrine and chlorphenoxamine are also used in Parkinsons disease, but since these also exhibit significant anticholinergic actions, it is probable that the underlying attribute responsible for their therapeutic activity is related to this effect.

Recently, the dopamine precursor, levodopa, has been shown to be effective in controlling Parkinsonism when administered in adequate doses over extended periods of time. Although both anticholinergic agents and levodopa are beneficial in alleviating the primary symptoms of Parkinsonism, their clinical use is limited by the frequency with which they elicit untoward side elfects. Thus, anticholinergic drugs may produce dry mouth, blurred vision, photophobia, constipation, urinary retention and tachychardia, while nausea, anorexia, vomiting, attempted suicide, agitation, confusion, restlessness, hallucinations, delirium, choreiform movements, palpitations, postural hypotension, flushing and phlebitis may occur with levodopa.

An object of this invention is to provide a new process for controlling extrapyramidal symptoms. This effect is desirable in patients suffering from either ideopathic or postencephalitic Parkinsonism.

3,743,732 Patented July 3, 1973 "ice The active ingredient of the medication used for the novel process of the present invention has the following structural formula:

(lisp- N N NH CHOOCH CHOOOH Although 2-bromoquinoline has been utilized in this general equation, other 2-haloquinolines, such as 2-chloroquinoline, may be similarly used with equally desirable results.

The active ingredient used in the novel process of this invention may be in the form of the free base and is preferably in the form of a nontoxic pharmacologically acceptable acid addition salt thereof. These acid addition salts may be prepared from mineral acids such as halogen acids or sulfuric acid, or organic acids such as citric acid, maleic acid, oxalic acid and other similar acids. Additional examples of the preparation of these acids will be presented in the subsequent detailed examples.

Medications may be prepared for use in the novel process of this invention including, as an active ingredient, at least one of the compounds of Formula I. These medications may be conveniently prepared by combining the active ingredient with a pharmaceutical vehicle having components selected from the fillers, carriers, extenders, excipients and the like, generally used in pharmaceutical formulations. Medications may be prepared in the solid state as tablets or capsules or in the liquid state as suspensions or solutions. Similar dosage forms suitable for oral, parenteral, intramuscular, subcutaneous, intravenous or other convenient routes of administration may also be provided. The pharmaceutical vehicle may also include common diluents or tableting adjuncts such as cellulose powder, cornstarch, magnesium sterate, calcium sulfate, talc and such, used according to accepted pharmaceutical manufacturing practices. Unit dosages (a specific weight, such as mg. or g.) of active ingredient in a medication may be varied so that an adequate amount is present to provide the desired therapeutic dose which produces a particular therapeutic effect without untoward side eifects. Unit dosages of between about 1 and 30 mg. per tablet, capsule and so forth, are beneficially used for oral administration of the medication.

The therapeuitic dose, administered using the unit dosages described above, will depend upon the condition of the patient. Beneficially, daily doses ranging between about and 90 mg./kg. per day are considered safe and readily indicative of a required therapeutic dose.

The inveniton will be further understood by reference to the following examples which are provided as illustrations and are not intended to be construed as limitations upon the invention which is properly set forth in claims appended hereto.

EXAMPLE -1 Preparation of 1-(2-quinolyl)piperaz.ine

A mixture of 2-chloroquinoline (477 g., 2.92 moles), piperazine (503 g., 5.83 moles) and 750 ml. of toluene was stirred and heated under reflux for 6 hours. The mixture was cooled in an ice bath and 750 ml. of water was added with stirring. Then the mixture was acidified with concentrated hydrochloric acid. The insoluble 1,4-bis(2- quinolyl)piperazine was removed by filtering the slightly warm mixture through infusorial earth. The filtrate was diluted with 2 liters of water which dissolved most of the solid which had separated out. The toluene layer was separated and the aqueous portion was extracted with a little ether. Then the aqueous mixture was treated with decolorizing charcoal and filtered through infusorial earth. The solution was made alkaline with sodium hydroxide. The solid free base was collected on a filter and washed with water. The crude material was dissolved in about 1 liter of hot ethanol and the solution was clarified with charcoal. Then the mixture was diluted with 2 liters of water. The white crystals which separated on cooling were collected, washed with water and dried in an oven at 150 F. The l-(2-quinolyl)piperazine (437 g., 70.2 percent) melted at 81 83 C.

Analysis.Calcd. for C H N (percent): N (basic), 13.14; N (total), 19.70. Found (percent): N (basic), 12.93; N (total), 19.72.

EXAMPLE 2 Preparation of 1-(2-quinolyl)piperazine maleate The free base was dissolved in 4200 ml. of hot 2-propanol and a solution of maleic acid (239 g., 2.06 moles) in 1500 ml. of hot 2-propanol was added in one portion with stirring. The stirring was continued, while the mixture was cooled in an ice bath. Then the salt was collected, washed with 2-propanol and dried in the oven at 150 F. The 1-(2- quinolyl)piperazine maleate amounted to 650 g. (95.8 percent based on the free base) and melted at 174175 C.

Analysis.Calcd. for C H N O (percent): N (basic), 8.51; N (total) 12.75; N.E., 164.7. Found (percent): N (basic), 8.50; N (total), 12.70; N.E. 165.3.

EXAMPLE 3 Preparation of 1-(2-quinolyl)-4-methylpiperazine A mixture of 2-chloroquinoline (81.8 g., 0.5 mole), l-methylpiperazine (100.2 g., 1 mole) and 100 ml. of toluene was heated to boiling. An exothermic reaction set in, but it was necessary to apply additional heat to maintain a vigorous boiling. After about 30 minutes the spontaneous reaction was over, and the mixture was heated under reflux for 2 hours longer. A dark syrupy material separated out.

The mixture was stirred and cooled, during which 300 ml. of water containing 100 ml. of concentrated hydrochloric acid was added. A small amount of insoluble solid material was removed by filtration and washed with ether and water. The aqueous portion of the filtrate and washings was separated and clarified with charcoal. An excess of a saturated aqueous solution of sodium hydroxide was added to the filtrate. The free base was collected, washed with Water and dried at 50 C. The crude product (104.5 g., melted at 111 C.

The crude free base was dissolved in hot ethanol, and the solution was clarified with charcoal. The filtrate and washings were concentrated by evaporation and diluted with hot water to incipient cloudiness. The crystals which formed on cooling and scratching were collected, washed with water and dried at 100 C. The cream-colored free base (102 g., 90%) melted at 111-112 C.

Analysis.Calcd. for C H N (percent): N (basic), 6.16. Found (percent): N (basic), 6.08.

EXAMPLE 4 Preparation of 1-(2-quinolyl)-4-methylpiperazine maleate 1-(2-quinolyl)-4-methylpiperazine (101.0 g., 0.445 mole) in 300 ml. of hot 2-propanol was treated with a solution of maleic acid (53.6 g., 0.46 mole) in 200 ml. of hot 2-propanol. Crystals began to form immediately. After cooling in an ice bath the crystals were collected, washed with ethyl acetate and dried at 100 C. The crude salt (146.0 g., M.P. 161 C.) was dissolved in about 2 liters of boiling 2-propanol. The solution was concentrated by evaporation until crystals began to form. The mixture was cooled and the salt was collected. The crystals were washed with ethyl acetate and dried at 100 C. The product amounted to 141.5 g. (93%).

Analysis.-Calcd. for C I-I N .C H O (percent): N (basic), 8.16; N (total), 12.24; N.E., 171.7. Found (percent): N (basic), 8.14; N (total), 12.32; N.E., 173.3.

EXAMPLE 5 Pharmacological activity of 1-(2-quino1yl)piperazine and 1-(2-quinolyl)-4-methylpiperazine The anti-Parkinson activity of 1-(2-quinolyl)piperazine and 1-(2-quinolyl)-4-methylpiperazine was assessed by its ability to antagonize tremorine-induced tremor in mice and was compared with that of the reference compounds atropine sulfate, trihexyphenidyl hydrochloride and levodopa. For this test, graded doses of test drugs were given orally to groups of 10 mice 15 minutes before the intraperatoneal injection of tremorine (20 mg./kg.). This dose causes severe tremor, together with profuse salivation, lachrymation and diarrhea. The presence of tremor was determined 30 minutes after administration of tremorine by an observer who was unaware of the treatment the animals had received. Animals which did not show tremor of the head during a 1 minute observation period were considered protected. The proportion of mice protected at each dose level was used to estimate ED s. The results observed in this experiment are presented in the table which follows, wherein Compound A is 1-(2- quinolyl)piperazine maleate and Compound B is 1-(2- quinolyl) -'4-methylpiperazine.

Mg./kg., p.o.

Drugs ED 50 L as N Compound A 5.0 3. 3-7. 5 40 Compound B 15. 5 9. 425. 6 5O Atropine 8. 4 5. 6-12. 6 b0 Trihexyphenidyl. 7. 0 4. 211. 5 50 Levodopa 375. 0 279. 8-502. 5 50 evaluation of tremor was carried out 15 minutes after injection of the tremorigenic substance. The active ingredients of these compositions antagonized oxotremorine-induced tremor in a dose-response fashion. The ED and 95% confidence limits for Compounds A and B were 8.0 (3.8-l6.8) mg./kg. and 18.5 (10243.7) mg./kg., respectively.

What is claimed is:

1 A process of suppressing the tremor of Parkinsons syndrome in a mammal comprising administering to said mammal a tremor suppressing amount of a compound selected from the group consisting of 1-(2-quinolyl)piperazine, 1-(2 quinolyl)-4-piperazine, and a pharmacologi- 6 cally acceptable acid addition salt of said compound.

2. The process of claim 1 in which said compound is 1-(2-quinolyl)piperazine.

3. The process of claim 1 in which said compound is 5 l- (2- quinolyl) -4-methylpiperazine.

References Cited UNITED STATES PATENTS STANLEY J. FRIEDMAN, Primary Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 732 Dated ug 10 1973 Inventor(s) Rodolfo Rodriguez It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, line 13, Qjlaim l:

l-(Z-quinOlYl)-4-piperazine. should reed 1-(2-quinolyl)-4 'methylpiperazine-.

Signed end sealed this 20th day of Novem ber' 1973.

(SEAL) Atte st EDWARD M.FLETCHER,JR. V RENE D. 'I'EGTMEYER Acting Commissioner of Patents Attesting Officer USCOMM-DC 60376-P69 U,S GOVERNMENT PRINTING OFFICE I I969 O366'33l FORM PO-105O (10-69)