US3567830A - Compositions and methods for producing a sedative and depressant effect in a mammal with an azaspiroalkyl-butyrophenone - Google Patents

Compositions and methods for producing a sedative and depressant effect in a mammal with an azaspiroalkyl-butyrophenone Download PDF

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US3567830A
US3567830A US768178A US76817868A US3567830A US 3567830 A US3567830 A US 3567830A US 768178 A US768178 A US 768178A US 76817868 A US76817868 A US 76817868A US 3567830 A US3567830 A US 3567830A
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azaspiro
dioxa
hydrochloride
butyrophenone
acid
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Rolf Denss
Hugo Ryf
Daniel Prins
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
    • C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/10—Spiro-condensed systems

Definitions

  • compositions containing an azaspiro-alkylbutyrophenone or a pharmaceutically acceptable acid addition salt thereof exhibit sedative and depressant actions on the central nervous system.
  • This invention relates to methods for therapeutic treatments and to compositions useful for this purpose. More particularly the invention pertains to methods for inducing sedative and depressant actions on the central nervous system in mammals involving the administration of a therapeutically effective amount of a substituted azaspiroalkyl-butyrophenone as hereinafter defined, or a pharmaceutically acceptable acid addition salt thereof. This invention relates also to therapeutic compositions consisting essentially of (a) a substituted 'azaspiro-alkyl-butyrophenone as hereinafter defined, or a pharmaceutically acceptable acid addition salt thereof, and (b) a pharmaceutical carrier.
  • R is a divalent hydrocarbon having from 2 to 11 carbon atoms, no more than four of which separate X and Y; and each of X and Y, independently of the other, is oxygen or sulfur; and
  • R is hydrogen, chloro or fluoro
  • the divalent hydrocarbon radical R represents,
  • the compounds of the present invention have sedative and depressant actions and are suitable, in particular, for the treatment of states of tension and agitation of various origin.
  • the new compounds have a favorable therapeutic index and are largely free from extrapyramidal and antenomic side effects; therefore, they are particularly useful as calmatives and psychoregulators, i.e. in the treatment of psychic disturbances and mental disorders.
  • R is fiuoro
  • X and Y are oxygen
  • R is a divalent hydrocarbon radical of from 2 to 11 carbon atoms, no more than four of which are straight-enchained between X and Y so as to form an aliphatic bridge between them
  • pharmaceutically acceptable addition salts of the bases of the invention are meant salts with those acids the anions of which are pharmacologically acceptable in the usual dosages, i.e. they have no toxic effects.
  • salts to be used crystallise well and are not or are only slightly hygroscopic.
  • pharmaceutically acceptable salts are the salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane-sulfom'c acid, fi-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.
  • substituted azaspiro-alkyl-butyrophenone derivatives according to the invention i.e. those of Formula I as well as their addition salts with inorganic or organic acids, are administered orally, rectally, or parenterally, preferably orally and parenterally.
  • the compounds possess valuable pharmacological properties, in particular sedative and depressant actions on the central nervous system and have, at the same time, a favorable therapeutic index.
  • Their pharmacological properties which are illustratively demonstrated further below render the compounds of Formula I well suited for the treatment of insomnia and various states of excitement in mammals.
  • the pharmacological action of the compounds of the invention can be illustratively demonstrated, for example, by means of standard harmacological tests.
  • depression of the central nervous system can be shown by reduction of motility in mice according to the method described by Theobald et al. in Arch. int. Pharmacodyn. 148, 561 if. (1964).
  • the dose is determined which affects the reduction of motility to a value which is half of that of the control valve (ED Illustrative results are shown in Table I.
  • the sedative activity can be determined according to the method described by W. Theobald et al. in Arzeiffenbachutz 9, 2856 (1959). In this test there is measured the potentiation of anesthesia induced by a standard amount of the anesthetic 2-methoxy-4 -allyl-phenoxyacetic acid diethylamide.
  • the test animals are mice weighing between 17 and 25 g.
  • the standard amount of anesthetic, 4O mg./kg. is administered subcutaneously. In normal animals, this dose induces shortlasting anesthesia in about half of the animals treated.
  • An esthetized mice remain in side position which is the criterion for anesthesia. The time during which the mice remain in this side position is recorded for each animal.
  • the toxicity of the compounds of the instant invention is low.
  • the LD of 4-(7,12-dioxa3-azaspiro l .6] dodec-3 -yl -4'-fiuorobutyrophenone hyd rochloride administered intravenously to mice is 51 mg./kg.
  • the LD of 4-(Z-methyl-1,5-dioxa-9-azaspiro[5.5]undec- 3-yl)-4-fluorobutyrophenone hydrochloride in mice is 25 mg./kg. iv.
  • the LD of 4-(3-phenyl-l,5-dioxa-9- yl)-4'-fluorobutyrophenone hydrochloride is 39 mg./kg. on intravenous administration to mice.
  • the compounds of the instant invention may be administered orally in the form of aqueous solutions, including appropriate pharmaceutically acceptable acid addition salts, parenterally or rectally, preferably orally.
  • aqueous solutions including appropriate pharmaceutically acceptable acid addition salts, parenterally or rectally, preferably orally.
  • the dosage used naturally depends on the species, age and weight of the subject under treatment, as well as on the particular condition being treated and, of course, the mode of administration.
  • the daily dosages of the compounds used in the present invention, or their pharmaceutically acceptable acid addition salts vary between about 0.1 and about 15 mg. per kg. of bodyweight of the mammal, preferably 0.2 mg. to 4 mg. per kg.
  • compositions consist essentially of a piperidine derivative according to the invention, or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutical carrier and, if desired, further additives. These compositions are presented for oral or parenteral administration in solid and liquid dosage units, respectively, such as tablets, dragees, capsules, ampoules, and the like. For rectal administration, they are presented in form of suppositories, rectal capsules, etc. Each dosage unit preferably contains between about 5 mg. to about 200 mg. of an inventive piperidine derivative or a pharmaceutically acceptable acid addition salt there of, as active ingredient.
  • Suitable dosage units for oral administration such as dragees, tablets or capsules generally contain 1% to of active ingredients.
  • Tablets and dragee cores are formed from mixtures containing the active substance in combination with solid pulverulent carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, maize starch or amylopectin, laminaria powder or citrus pulp powder; cellulose derivatives or gelatin; optionally with the addition of a lubricant such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights.
  • the dragee cores are coated, for example, with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/ or titanium dioxide, or With a lacquer dissolved in easily volatile organic solvents or mixtures of solvents.
  • Dyestuffs can be added to these coatings to distinguish between different dosages of active substance.
  • suitable oral dosage units such as hard gelatin capsules contain the active substance and the carrier, preferably as a granulate, in admixture with lubricants such as talcum or magnesium stearate and, optionally, appropriate stabilisers.
  • the active substance is preferably dissolved or suspended in suitable liquid carriers such as liquid polyethylene glycols; stabilizers can also be added.
  • Dosage units for rectal administration include suppositories which consist of a combination of a compound of Formula I, or a suitable salt thereof and a neutral fatty foundation as a carrier and gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycols (Carbowaxes) of suitable molecular weight as carriers.
  • suppositories which consist of a combination of a compound of Formula I, or a suitable salt thereof and a neutral fatty foundation as a carrier
  • gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycols (Carbowaxes) of suitable molecular weight as carriers.
  • Ampoules for parenteral, particularly intramuscular, administration preferably contain as active ingredient a Water soluble pharmaceutically acceptable acid addition salt of an inventive compound, the carrier being water.
  • concentration of the active ingredient is preferably between 0.5% and 10.0%. If necessary, suitable stabilising agents and/or buffer substances are added to the ampoule solutions.
  • EXAMPLE 1 (a) A mixture of 3 g. of 1,4-dioxa-8-azaspiro[4.5] decane and 6 g. of 4'-fiuoro-4-chlorobutyrophenone is refluxed for 20 hours with 5.5 g. of anhydrous potassium carbonate and mg. of potassium iodide in 50 ml. of anhydrous acetone. The mixture is filtered and washed with acetone. The solvent is evaporated, the residue taken up in ether and extracted three times with 10% acetic acid. The combined acetic acid extracts are made alkaline with sodium carbonate solution and extracted with ether. The ethereal solution is dried with anhydrous sodium sulfate and concentrated.
  • the 4-(1,4-dioxa-8-azaspiro[4.5] dec-8-yl)-4-fluorobutyrophenone remains as an oil and is converted into the hydrochloride with the equimolar amount of ethereal hydrochloric acid.
  • the hydrochloride is recrystallised from acetone, M.P. 167170.
  • azaspiro-alkanes used as starting materials are prepared according to the following procedure:
  • EXAMPLE 3 A granulate is produced from 250 g. of 4-(7,12-dioxa- 3 azaspiro[5.6]dodec-3-yl)-4'-fiuorobutyrophenone hydrochloride, 175.90 g. of lactose and the alcoholic solution of 10 g. of stearic acid. After drying, 56.60 g. of colloidal silicum dioxide, g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate are mixed in and the whole is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made from 502.28 g. of crystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestuff and 1.5 g. of titanium dioxide and dried. Each of the dragees obtained weighs 120 mg. and contains 25 mg. of active substance.
  • EXAMPLE 4 250 g. of 4-(1,5-dioxa 9 azaspiro[5.5]undec-9-yl)- 4'-fluorobutyrophenone hydrochloride are well mixed with 442.8 g. of potato starch and 295.2 g. of lactose, the mixture is moistened with an alcoholic solution of 30.0 g. of stearic acid and granulated through a sieve. After drying, this granulate is mixed with 96.0 g. of talcum, 80.0 g. of potato starch and 6.0 g. of magnesium stearate and the mixture obtained is again granulated through a sieve. This granulate serves as filling for 10,000 hard gelatine capsules each weighing 120 mg., and each of the capsules so obtained contains 25 mg. of active substance.
  • EXAMPLE 5 4 (3 phenyl 1,5 dioxa 9 azaspiro[5.5]undec- 9-yl)-4' fiuorobutyrophenone hydrochloride are introduced into a two-piece gelatine No. 1 capsule.
  • EXAMPLE 6 1.0 g. of 4-(2-methyl 1,5 dioxa 9-azaspiro[5.5]- undec 9 yl) 4' fiuorobutyrophenone hydrochloride and 0.10 g. of ascorbic acid are dissolved in distilled water and the solution is diluted up to 100 ml. The solution obtained is used to fill ampoules each containing 1 ml. which corresponds to a content of mg. of the active butyrophenone. The filled ampoules are then sterilized by heating in the usual way.
  • EXAMPLE 8 250 g. of 4-(3-phenyl 1,5 dioxa 9 azaspiro[5.5]- undec 9 yl) 4' fiuorobutyrophenone hydrochloride, 175.9 g. of lactose and 169.7 g. of potato starch are mixed and the mixture is moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch, 200 g. of talcum, 2.5 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed and the mixture is pressed into 10,000 tablets each weighing 100 mg. and containing mg. of the active butyrophenone. If desired, the tablets can be grooved to enable better adaptation of the dosage instructions.
  • EXAMPLE 9 10 mg. of 4-(7,12-dioxa 3 aZaspiro[5.6]dodec-3- yl)-4'-fluorobutyrophenone hydrochloride are introduced into a two-piece gelatine No. 1 capsule.
  • EXAMPLE 10 10 mg. of 4-(1,4-dioxa 8 azaspiro[4.5]dec-8-yl)-4- fiuorobutyrophenone hydrochloride are introduced into a two-piece gelatine No. 1 capsule.
  • EXAMPLE 1 1 10.0 g. of 4-(2-1nethyl 1,5 dioxa 9 azaspiro- [5.5]undec 9 yl) 4' fiuorobutyrophenone hydrochloride, 30.0 g. of lactose and 5.0 g. of highly dispersed silicic acid are mixed, the mixture is moistened with a solution of 5.0 g. of gelatine and 7.5 g. of glycerine in distilled water and granulated through a sieve. The granulate is dried, sieved and carefully mixed with 3.5 g. of potato starch, 3.5 g. of talcum and 0.5 g. of magnesium stearate. The mixture is pressed into 1,000 tablets each weighing 65 mg. and containing 10 mg. of active substance.
  • EXAMPLE 12 10.0 g. of 4-(3-phenyl 1,5 dioxa 9 azaspiro- [5.5]undec 9 yl)-butyrophenone hydrochloride, 15 g. of lactose and 20 g. of starch are mixed, the mixture is moistened with a solution of 5.0 g. of gelatine and 7.5 g. of glycerin in distilled water and granulated through a sieve. The granulate is dried, sieved and carefully mixed with 3.5 g. of potato starch, 3.5 g. of talcum and 0.5 g. of magnesium stearate. The mixture is pressed into 1,000 drage cores.
  • a therapeutic composition for producing a sedative and depressant effect comprising (a) an effective amount of a compound of the formula Olly-CH wherein R is a divalent hydrocarbon having 2 to 11 carbon atoms, no more than four of which separate X and Y;
  • each of X and Y, independent of the other, is oxygen or sulfur
  • R is hydrogen, chloro or fluoro or a pharmaceutically acceptable acid addition salt thereof and (b) a pharmaceutical carrier.
  • R is a divalent hydrocarbon of from 2 to 11 carbon atoms, no more than four of which separate X and Y, X and Y are oxygen and R is fluoro.
  • R is a divalent hydrocarbon having from 2 to 11 carbon atoms, no more than four of which separate X and Y;
  • each of X and Y, independent of the other, is oxygen or sulfur
  • R is hydrogen, chloro or fluoro or a pharmaceutically acceptable acid addition salt thereof.
  • R is a References Cited divalent hydrocarbon of from 2 to 11 carbon atoms, no UN T D TATE P EN more than four of which separate X and Y, X and Y I E S S AT TS are oxygen and R1 is fluoro.
  • a me hod as de ned in 0 mm W erem is e ta 5 3,209,006 9/1965 gg t a 2 '7 methylene, X and Y are oxygen and R is fluoro.

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Abstract

THERAPEUTIC COMPOSITIONS CONTAINING AN AZASPIRO-ALKYLBUTYROPHENONE OR A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, EXHIBIT SEDATIVE AND DEPRESSANT ACTIONS ON THE CENTRAL NERVOUS SYSTEM. ILLUSTRATIVE EMBODIMENTS AND TO COMPOSITIONS USEFUL FOR THIS PURPOSE. MORE FLUOROBUTYROPHENONE AND 4-(3-PHENYL-1,5-DIOXA-9-AZASPIRO)5.5)UNDEC-9-YL)-4''-FLUOROBUTYROPHENONE.

Description

United States Patent COMPOSITIONS AND METHODS FOR PRODUCING A SEDATIVE AND DEPRESSANT EFFECT IN A MAMMAL WITH AN AZASPIROALKYL-BUTYRO- PHENONE Rolf Denss and Hugo Ryf, Basel, and Daniel Prins, Oberwil, Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N.Y.
No Drawing. Continuation-impart of application Ser. No.
734,182, Mar. 11, 1968, which is a division of application Ser. No. 565,753, July 18, 1966, now Patent No. 3,424,755, which in turn is a continuation-in-part of application Ser. No. 438,047, Mar. 8, 1965. This application Oct. 16, 1968, Ser. No. 768,178
Claims priority, application Switzerland, Mar. 10, 1964, 2,994/64; July 26, 1965, 10,444/65; June 15, 1966,
Int. Cl. A61k 27/00 11.5. Cl. 424-267 8 Claims ABSTRACT OF THE DISCLOSURE Therapeutic compositions containing an azaspiro-alkylbutyrophenone or a pharmaceutically acceptable acid addition salt thereof, exhibit sedative and depressant actions on the central nervous system. Illustrative embodi ments and to compositions useful for this purpose. More fluorobutyrophenone and 4-(3-phenyl-1,5-dioxa-9-azaspiro [5.5] undec-9-yl) 4'-fluorobutyrophenone.
CROSS REFERENCE TO RELATED APPLICATIONS This is a continuation-in-part application of copending patent application Ser. No. 734,182, filed Mar. 11, 1968, now abandoned which is a divisional application of our copending application Ser. No. 565,753, filed July 18, 1966, now US. Pat. No. 3,424,755 which in turn is a continuation-in-part application of application Ser. No. 438,047, filed Mar. 8, 1965, now abandoned.
DETAILED DISCLOSURE This invention relates to methods for therapeutic treatments and to compositions useful for this purpose. More particularly the invention pertains to methods for inducing sedative and depressant actions on the central nervous system in mammals involving the administration of a therapeutically effective amount of a substituted azaspiroalkyl-butyrophenone as hereinafter defined, or a pharmaceutically acceptable acid addition salt thereof. This invention relates also to therapeutic compositions consisting essentially of (a) a substituted 'azaspiro-alkyl-butyrophenone as hereinafter defined, or a pharmaceutically acceptable acid addition salt thereof, and (b) a pharmaceutical carrier.
The substituted azaspiro-alkyl butyrophenone derivatives which are employed in this invention can be represented by the following Formula I wherein R is a divalent hydrocarbon having from 2 to 11 carbon atoms, no more than four of which separate X and Y; and each of X and Y, independently of the other, is oxygen or sulfur; and
R is hydrogen, chloro or fluoro;
and their addition salts with inorganic and organic acids.
In the compounds of the above-described formula I and in the starting materials used therefor which are mentioned below, the divalent hydrocarbon radical R represents,
ice
e.g. the ethylene, propylene, 1,2-dimethylethylene, trimethylene, l-methyl-trimethylene, Z-methyl-trimethylene, 1,3-dimethyl-trimethylene, 2,2-dimethyl-trimethylene, 2,2- diethyl-trimethylene, tetramethylene, 1,4-dimethyl-tetramethylene, 2-butylene, 2,2-ethylene-trimethylene, 2,2- pentamethylene-trimethylene, 1-benzyl-ethylene, 2-phenyltrimethylene, Z-methyl-2-phenyltrimethylene, 2-ethyl-2- phenyl-trimethylene, cis-1,2-cyclohexylene or o-xylylene radical.
As mentioned above, the compounds of the present invention have sedative and depressant actions and are suitable, in particular, for the treatment of states of tension and agitation of various origin. The new compounds have a favorable therapeutic index and are largely free from extrapyramidal and antenomic side effects; therefore, they are particularly useful as calmatives and psychoregulators, i.e. in the treatment of psychic disturbances and mental disorders.
Of particular importance are those compounds wherein R is fiuoro, X and Y are oxygen, and R is a divalent hydrocarbon radical of from 2 to 11 carbon atoms, no more than four of which are straight-enchained between X and Y so as to form an aliphatic bridge between them including the pharmaceutically acceptable addition salts thereof with inorganic or organic acids. By pharmaceutically acceptable addition salts of the bases of the invention are meant salts with those acids the anions of which are pharmacologically acceptable in the usual dosages, i.e. they have no toxic effects.
It is also of advantage if the salts to be used crystallise well and are not or are only slightly hygroscopic. Examples of pharmaceutically acceptable salts are the salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane-sulfom'c acid, fi-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.
The compounds employed in the present invention are prepared as described in copending application Ser. No. 565,753, filed July 18, 1966.
The substituted azaspiro-alkyl-butyrophenone derivatives according to the invention, i.e. those of Formula I as well as their addition salts with inorganic or organic acids, are administered orally, rectally, or parenterally, preferably orally and parenterally.
The compounds possess valuable pharmacological properties, in particular sedative and depressant actions on the central nervous system and have, at the same time, a favorable therapeutic index. Their pharmacological properties, which are illustratively demonstrated further below render the compounds of Formula I well suited for the treatment of insomnia and various states of excitement in mammals.
The pharmacological action of the compounds of the invention can be illustratively demonstrated, for example, by means of standard harmacological tests. For instance, depression of the central nervous system can be shown by reduction of motility in mice according to the method described by Theobald et al. in Arch. int. Pharmacodyn. 148, 561 if. (1964). In this test, the dose is determined which affects the reduction of motility to a value which is half of that of the control valve (ED Illustrative results are shown in Table I.
TABLE I Compound tested: ED mg./kg. i.p. 4 (7,12 dioxa-3-azaspiro[5,6]-dodec-3-yl)-4- fluorobutyrophenone hydrochloride 1.0 4 (3 phenyl-1,5-dioxa-9-azaspiro[5.5]undec- 9-yl)-4'-fluorobutyrophenone hydrochloride 1.3
3 A similar pharmacological activity can be shown in a test described by Theobald et al. in Arch. int. Pharmacodyn. 148, 563 and 564 (1964) in which the dose is dedetermined which depresses the fighting reaction of mice in 50% of the test animals (ED Illustrative results are shown in Table II.
TABLE II Compound tested: ED mg./kg., s.c. 4 (7,12 dioxa-3-azaspiro[5.6]dodec-3-yl)-4- fiuorobutyrophenone hydrochloride 1.5 4 (2 methyl-1,5-dioxa-9-azaspiro-[5.5]undec- 9-yl)-4-fluorobutyrophenone hydrochloride 1.1 4 (3 phenyl-1,5-dioxa-9-azaspiro[5.5]undec- 9-yl)-4-fluorobutyrophenone hydrochloride 1.3
Another test for the depressive activity on the central nervous system is described by Theobald et al. in Arch. int. Pharmacodyn. 148, 572 (1964). According to this method, the dosage is determined at which the frequency of vomiting (induced by 0.1 mg./ kg. of apomorphine hydrochloride administered subcutaneously) is reduced to 50% of its original value. Results are provided in Table III.
TABLE III Compound tested: ED mg./kg. s.c.
4 (7,12 dioxa-3-azaspiro[5.6]dodec-3-yl-4'- fiuorobutyrophenone hydrochloride 0.2 4 (2 methyl-1,5-dioxa-9-azaspiro[5.5]undec- 9-yl)-fluorobutyrophenone hydrochloride 0.1 4 (3 phenyl-l,5-dioxa-9-azaspiro[5.5]undec- 9-yl)-4-fiuorobutyrophenone hydrochloride 0.07
The sedative activity can be determined according to the method described by W. Theobald et al. in Arzeimittelforschung 9, 2856 (1959). In this test there is measured the potentiation of anesthesia induced by a standard amount of the anesthetic 2-methoxy-4 -allyl-phenoxyacetic acid diethylamide. The test animals are mice weighing between 17 and 25 g. The standard amount of anesthetic, 4O mg./kg. is administered subcutaneously. In normal animals, this dose induces shortlasting anesthesia in about half of the animals treated. An esthetized mice remain in side position which is the criterion for anesthesia. The time during which the mice remain in this side position is recorded for each animal. Thirty minutes prior to injection of the standard amount of anesthetic, the animals received the test compound in aqueous solution by subcutaneous injection. The change in duration of the anesthetic effect is calculated in percent of the effect observed with a control group. The change is expressed in percent. Representative results are shown in Table IV.
The toxicity of the compounds of the instant invention is low. For instances, the LD of 4-(7,12-dioxa3-azaspiro l .6] dodec-3 -yl -4'-fiuorobutyrophenone hyd rochloride administered intravenously to mice is 51 mg./kg., the LD of 4-(Z-methyl-1,5-dioxa-9-azaspiro[5.5]undec- 3-yl)-4-fluorobutyrophenone hydrochloride in mice is 25 mg./kg. iv. and the LD of 4-(3-phenyl-l,5-dioxa-9- yl)-4'-fluorobutyrophenone hydrochloride is 39 mg./kg. on intravenous administration to mice.
For their intended uses the compounds of the instant invention may be administered orally in the form of aqueous solutions, including appropriate pharmaceutically acceptable acid addition salts, parenterally or rectally, preferably orally. The dosage used naturally depends on the species, age and weight of the subject under treatment, as well as on the particular condition being treated and, of course, the mode of administration. In general, the daily dosages of the compounds used in the present invention, or their pharmaceutically acceptable acid addition salts, vary between about 0.1 and about 15 mg. per kg. of bodyweight of the mammal, preferably 0.2 mg. to 4 mg. per kg.
Therapeutic compositions consist essentially of a piperidine derivative according to the invention, or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutical carrier and, if desired, further additives. These compositions are presented for oral or parenteral administration in solid and liquid dosage units, respectively, such as tablets, dragees, capsules, ampoules, and the like. For rectal administration, they are presented in form of suppositories, rectal capsules, etc. Each dosage unit preferably contains between about 5 mg. to about 200 mg. of an inventive piperidine derivative or a pharmaceutically acceptable acid addition salt there of, as active ingredient.
Suitable dosage units for oral administration such as dragees, tablets or capsules generally contain 1% to of active ingredients.
Tablets and dragee cores are formed from mixtures containing the active substance in combination with solid pulverulent carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, maize starch or amylopectin, laminaria powder or citrus pulp powder; cellulose derivatives or gelatin; optionally with the addition of a lubricant such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights. The dragee cores are coated, for example, with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/ or titanium dioxide, or With a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings to distinguish between different dosages of active substance. Other suitable oral dosage units such as hard gelatin capsules contain the active substance and the carrier, preferably as a granulate, in admixture with lubricants such as talcum or magnesium stearate and, optionally, appropriate stabilisers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquid carriers such as liquid polyethylene glycols; stabilizers can also be added.
Dosage units for rectal administration include suppositories which consist of a combination of a compound of Formula I, or a suitable salt thereof and a neutral fatty foundation as a carrier and gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycols (Carbowaxes) of suitable molecular weight as carriers.
Ampoules for parenteral, particularly intramuscular, administration preferably contain as active ingredient a Water soluble pharmaceutically acceptable acid addition salt of an inventive compound, the carrier being water. The concentration of the active ingredient is preferably between 0.5% and 10.0%. If necessary, suitable stabilising agents and/or buffer substances are added to the ampoule solutions.
The following examples will serve to further typify the nature of the present invention but should not be construed as a limitation on the scope thereof.
EXAMPLE 1 (a) A mixture of 3 g. of 1,4-dioxa-8-azaspiro[4.5] decane and 6 g. of 4'-fiuoro-4-chlorobutyrophenone is refluxed for 20 hours with 5.5 g. of anhydrous potassium carbonate and mg. of potassium iodide in 50 ml. of anhydrous acetone. The mixture is filtered and washed with acetone. The solvent is evaporated, the residue taken up in ether and extracted three times with 10% acetic acid. The combined acetic acid extracts are made alkaline with sodium carbonate solution and extracted with ether. The ethereal solution is dried with anhydrous sodium sulfate and concentrated. The 4-(1,4-dioxa-8-azaspiro[4.5] dec-8-yl)-4-fluorobutyrophenone remains as an oil and is converted into the hydrochloride with the equimolar amount of ethereal hydrochloric acid. The hydrochloride is recrystallised from acetone, M.P. 167170.
The following compounds are produced in an analogous manner via the corresponding free bases:
(b) 4-(7,12-dioxa 3 azaspiro[5.6]dodec-3yl)4'- fluorobutyrophenone hydrochloride, M.P. 207-208;
(c) 4-(2-methyl-l,5-dioxa 9 aZaspiro[5.5]undec-9- yl)-4fluorobutyrophenone hydrochloride, M.P. 201- 203.
(d) 4-(3-phenyl-1,5-dioxa 9 aZaspiro[5.5]undec-9- yl)-4-fiuorobutyrophenone hydrochloride, M.P. 231- 233.
(e) 4-(3,3-diethyl-1,5-dioxa 9 azaspiro[5.5]undec-9 yl)-4'-fiuorobutyrophenone hydrochloride, M.P. 215.
(f) 4-(7,16-dioxa 3 azadispiro[5.2.5.21hexadec-3- yl)-4'fiuorobutyrophenone hydrochloride, M.P. 229- 236, of the formula (g) 4-(1,4-dithia 8 azaspiro[4.5]dec-8-yl)-4-fluorobutyrophenone hydrochloride; M.P. 232-237";
-(h) 4-(1,5-dithia 9 azaspiro[5.5]undec-9-yl)-4'- fiuorobutyrophenone;
(i) 4-(2-methyl-1,4-dioxa-8-azaspiro [4.5]dec 8 yl)- 4'-fluorobutyrophenone, M.P. 174-176.
(j) 4-(2-methyl-1,4-dithia 8 azaspiro[4.5]dec-8-yl)- 4'-fluorobutyrophenone hydrochloride; M.P. 235-240".
(k) 4-(3-methyl-3-phenyl-1,5-dioxa 9 aZaspiro[ 5] undec-9-yl)-4'-fiuorobutyrophenone hydrochloride, M.P'. 194-195 (l) 4-(5,12-dioxa 9 azadispiro[2.2.5.2]tridec-9-yl)- 4'-fluorobutyrophenone hydrochloride, M.P. 220221, which is of the formula 0 i j 4112011201124 o-Q-r H01 (m) 4 (1,5 dihydro-spiro[2,4-benzodioxepin-3,4'- piperidine] 1 -yl) -4fluorobutyrophenone hydrochloride, M.P. 250-251.
(n) 4 (1,4 dioxa-8-azaspiro[4.5]dec-8-yl)-butyrophenone hydrochloride, M.P. 187-189".
(0) 4 1,5 dioxa-9-azaspiro[5.5]undec-9-yl)-butyrophenone hydrochloride;
(p) 4 (2 methyl-1,5-dioxa-9-azaspiro[5.5]undec-9- yl) -butyrophenone hydrochloride;
(q) 4 (3 phenyl-1,5-dioxa-9-azaspiro[5.51undeC-9- yl)-4-chlorobutyrophenone hydrochloride;
(r) 4 (3 methyl-3-phenyl-1,5-dioxa-9-azaspiro[5.5] undec-9-yl)-butyrophenone hydrochloride;
(s) 4 (3,3 diethyl-1,5-dioxa-9-azaspiro[5.5]undec 9-yl)-butyrophenone hydrochloride;
(t) 4 (7,12 dioxa-3-azaspiro[5.6]dodec-9-en-3-yl)- butyrophenone hydrochloride;
(u) 4 (5,12 dioxa-9-azadispiro[2.2.5.2]tridec-9-yl butyrophenone hydrochloride;
(v) 4 (7,16 dioxa-3-azadispiro[5.2.5.21hexadec-3- yl) -butyrophenone hydrochloride;
(w) 4 (cis hexahydro-spiro[1,3-benzodioxole-2,4'- piperidine]-1'-yl)-butyrophenone hydrochloride;
(x) 4 (1,5 dihydro-spiro[2,4-benzodioxepin-3,4'- piperidine]-1'-yl)-butyrophenone hydrochloride;
(y) 4 (3 ethyl-3-phenyl-1,5-dioxa-9-azaspiro[5.5] undec-9-yl) -butyrophenone hydrochloride.
(2) 4 (1 oxa 4-thia-8-azaspiro[4.5]dec-8-yl)-4'- chlorobutyrophenone hydrochloride.
The azaspiro-alkanes used as starting materials are prepared according to the following procedure:
A mixture of 30 g. of 4,4-dihydroxy-piperidine hydro chloride, 17 g. of 1,2-dihydroxypropane and 1 g. of ptoluenesulfonic acid and 500 ml. of benzene is stirred and refluxed under a water separator. When the azeotropic distillation of water is finished, the benzene is decanted and 100 ml. of 50% potassium carbonate solution and 200 ml. of chloroform is added to the stirred residue. The chloroform phase is removed and the aqueous phase is extracted several times with chloroform. The combined chloroform phases are washed with Water, dried and concentrated to give Z-methyl-1,4-dioxa-9-azaspiro [4.5]decane which is distilled at 12 torr. (Starting material for (i).)
The following starting materials are obtained analogously by reacting the 4,4-dihydroxy-piperidine hydrochloride with the pertinent dihydroxy, hydroxy-mercapto or dimercapto compounds:
1,4-dioxa-8-azaspiro[4.5]decane (starting material for and 7,12-dioxa-3-azaspiro[5.6]dodecane, B.P. 113-115 11 torr (starting material for (b) Z-methyl- 1,5 -dioxa-9-azaspiro [5 .5 undecane, B .P.
107/ 10 torr (starting material for (c) and (p) 3-phenyl-1,5-dioxa-9-azaspiro[5 .5 Jundecane, B.P.
137/0.01 torr (starting material for (d) and (q) 3,3-diethyl-1 ,5-dioxa-9-azaspiro [5 .5 undecane, B.P.
145-149/ 12 torr (starting material for (e) and (s) 7,16-dioxa-3-azadispiro[5.2.5.21hexadecane, B.P.
1l0/0.001 torr (starting material for (f) and 1,4-dithia-8-azaspiro [4.5 decane (starting material for 1,5-dithia-9-azaspiro[5.5]undecane (starting material for Z-methyl-1,4-dithia-8-azaspiro [4.5] decane (starting material for (1'));
3-methyl-3-pheny1- 1,5 -dioxa-9-azaspiro [5 .5 1 undecane, B.P. 150/0.001 torr (starting material for and 5,12-dioxa=9-azadispiro[2.2.5.2] tridecane, B.P. 131- 144/11 torr (starting material for (l) and (u));
1,5-dihydrospiro(2,4-benzodioxepin-3,4'-piperidine) (starting material for (m) 1,5-dioxa-9-azaspiro [5.51undecane (starting material for 7,12-dioxa-3-azaspiro[5.6]dodec-9-ene, B.P. 128/ 12 torr (starting material for (t) cis-hexahydrospiro[ 1,3-benzodioxole-2,4'-piperidine] B.P. 128-130/ 10 torr (produced using cis-l,2 cyclohexanediol, it is the starting material for (w) 1,5-dihydro-spiro [2,4-benzodioxepin-3,4'apiperadine] M.P. 120-12l (produced using o-xylene-a,ot-diol; it is the starting material for (x) 3-ethy1-3-phenyl- 1,5-dioxa-9-azaspiro [5 .5 undecane (starting material for (y) 1-oxa-4-thia-8-azaspiro [4.5 ]decane (starting material for (z) EXAMPLE 2 250 g. of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4'-fiuorobutyrophenone hydrochloride, are mixed with 175.80 g. of lactose and 169.70 g. of potato starch, the mixture is moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, g. of potato starch, 200 g. of talcum, 250 g. of magnesium stearate and 32 g. of colloidal silicum dioxide are mixed in and the mixture is pressed into 10,000 tablets each Weighing 100 mg. and containing 25 mg. of active substance. If desired, the tablets can be grooved to attain better adaptation of the dosage.
EXAMPLE 3 A granulate is produced from 250 g. of 4-(7,12-dioxa- 3 azaspiro[5.6]dodec-3-yl)-4'-fiuorobutyrophenone hydrochloride, 175.90 g. of lactose and the alcoholic solution of 10 g. of stearic acid. After drying, 56.60 g. of colloidal silicum dioxide, g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate are mixed in and the whole is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made from 502.28 g. of crystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestuff and 1.5 g. of titanium dioxide and dried. Each of the dragees obtained weighs 120 mg. and contains 25 mg. of active substance.
EXAMPLE 4 250 g. of 4-(1,5-dioxa 9 azaspiro[5.5]undec-9-yl)- 4'-fluorobutyrophenone hydrochloride are well mixed with 442.8 g. of potato starch and 295.2 g. of lactose, the mixture is moistened with an alcoholic solution of 30.0 g. of stearic acid and granulated through a sieve. After drying, this granulate is mixed with 96.0 g. of talcum, 80.0 g. of potato starch and 6.0 g. of magnesium stearate and the mixture obtained is again granulated through a sieve. This granulate serves as filling for 10,000 hard gelatine capsules each weighing 120 mg., and each of the capsules so obtained contains 25 mg. of active substance.
EXAMPLE 5 4 (3 phenyl 1,5 dioxa 9 azaspiro[5.5]undec- 9-yl)-4' fiuorobutyrophenone hydrochloride are introduced into a two-piece gelatine No. 1 capsule.
EXAMPLE 6 1.0 g. of 4-(2-methyl 1,5 dioxa 9-azaspiro[5.5]- undec 9 yl) 4' fiuorobutyrophenone hydrochloride and 0.10 g. of ascorbic acid are dissolved in distilled water and the solution is diluted up to 100 ml. The solution obtained is used to fill ampoules each containing 1 ml. which corresponds to a content of mg. of the active butyrophenone. The filled ampoules are then sterilized by heating in the usual way.
EXAMPLE 7 mg. of 4 (1 oxa 4 thia 8 azaspiro[4.5]- dec-8-yl 4' chlorobutyrophenone hydrochloride are introduced into a two-piece gelatin No. 1 capsule.
EXAMPLE 8 250 g. of 4-(3-phenyl 1,5 dioxa 9 azaspiro[5.5]- undec 9 yl) 4' fiuorobutyrophenone hydrochloride, 175.9 g. of lactose and 169.7 g. of potato starch are mixed and the mixture is moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, 160 g. of potato starch, 200 g. of talcum, 2.5 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed and the mixture is pressed into 10,000 tablets each weighing 100 mg. and containing mg. of the active butyrophenone. If desired, the tablets can be grooved to enable better adaptation of the dosage instructions.
EXAMPLE 9 10 mg. of 4-(7,12-dioxa 3 aZaspiro[5.6]dodec-3- yl)-4'-fluorobutyrophenone hydrochloride are introduced into a two-piece gelatine No. 1 capsule.
EXAMPLE 10 10 mg. of 4-(1,4-dioxa 8 azaspiro[4.5]dec-8-yl)-4- fiuorobutyrophenone hydrochloride are introduced into a two-piece gelatine No. 1 capsule.
EXAMPLE 1 1 10.0 g. of 4-(2-1nethyl 1,5 dioxa 9 azaspiro- [5.5]undec 9 yl) 4' fiuorobutyrophenone hydrochloride, 30.0 g. of lactose and 5.0 g. of highly dispersed silicic acid are mixed, the mixture is moistened with a solution of 5.0 g. of gelatine and 7.5 g. of glycerine in distilled water and granulated through a sieve. The granulate is dried, sieved and carefully mixed with 3.5 g. of potato starch, 3.5 g. of talcum and 0.5 g. of magnesium stearate. The mixture is pressed into 1,000 tablets each weighing 65 mg. and containing 10 mg. of active substance.
EXAMPLE 12 10.0 g. of 4-(3-phenyl 1,5 dioxa 9 azaspiro- [5.5]undec 9 yl)-butyrophenone hydrochloride, 15 g. of lactose and 20 g. of starch are mixed, the mixture is moistened with a solution of 5.0 g. of gelatine and 7.5 g. of glycerin in distilled water and granulated through a sieve. The granulate is dried, sieved and carefully mixed with 3.5 g. of potato starch, 3.5 g. of talcum and 0.5 g. of magnesium stearate. The mixture is pressed into 1,000 drage cores. These are then coated with a concentrated syrup of 26.660 g. of crystallised saccharose, 17.500 g. of talcum, 1.000 g. of shellac, 3.750 g. of gum arabic, 1.000 g. of highly dispersed silicic acid and 0.090 g. of of dyestulf and dried. The drages obtained each weigh mg. and contain 10 mg. of active substance.
Percentages in the preceding specification and in these examples are given by weight; the temperatures are given in degrees centigrade; torr means mm. Hg.
What is claimed is:
1. A therapeutic composition for producing a sedative and depressant effect comprising (a) an effective amount of a compound of the formula Olly-CH wherein R is a divalent hydrocarbon having 2 to 11 carbon atoms, no more than four of which separate X and Y;
each of X and Y, independent of the other, is oxygen or sulfur; and
R is hydrogen, chloro or fluoro or a pharmaceutically acceptable acid addition salt thereof and (b) a pharmaceutical carrier.
2. A therapeutic composition as defined in claim 1 wherein R is a divalent hydrocarbon of from 2 to 11 carbon atoms, no more than four of which separate X and Y, X and Y are oxygen and R is fluoro.
3. A therapeutic composition as defined in claim 1 wherein R is tetramethylene, X and Y are oxygen and R is fluoro.
4. A therapeutic composition as defined in claim 1 wherein R is 2-phenyltrimethylene, X and Y are oxygen and R is fluoro.
5. A method of producing a sedative and depressant effect in a mammal which comprises administering to said mammal an effective amount of a compound of the formula:
CIh-CH wherein R is a divalent hydrocarbon having from 2 to 11 carbon atoms, no more than four of which separate X and Y;
each of X and Y, independent of the other, is oxygen or sulfur; and
R is hydrogen, chloro or fluoro or a pharmaceutically acceptable acid addition salt thereof.
9 10 6. A method as defined in claim 5 wherein R is a References Cited divalent hydrocarbon of from 2 to 11 carbon atoms, no UN T D TATE P EN more than four of which separate X and Y, X and Y I E S S AT TS are oxygen and R1 is fluoro. 3,074,952 1/1963 Casy et a1. 260-29475 t fi 5 h tt 3,080,372 3/1963 Vanssen 260294.75 7 A me hod as de ned in 0 mm W erem is e ta 5 3,209,006 9/1965 gg t a 2 '7 methylene, X and Y are oxygen and R is fluoro.
8. A method as defined in claim 5 wherein R is 2 phenyltrimethylene, X and Y are oxygen and R is ALBERT MEYERS Pnmary Exammer fluoro. S. J. FRIEDMAN, Assistant Examiner
US768178A 1964-03-09 1968-10-16 Compositions and methods for producing a sedative and depressant effect in a mammal with an azaspiroalkyl-butyrophenone Expired - Lifetime US3567830A (en)

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US4070473A (en) * 1973-01-26 1978-01-24 Ab Ferrosan Piperidino-butyrophenones
US4863918A (en) * 1987-02-06 1989-09-05 Boc, Inc. Enamine quaternary compounds, methods of making and their use as muscle relaxants
US4963557A (en) * 1987-09-28 1990-10-16 Smithkline Beecham Corporation Immunomodulatory azaspiranes
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