US2925363A - Vinyl ethinyl tertiary carbinols - Google Patents
Vinyl ethinyl tertiary carbinols Download PDFInfo
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- US2925363A US2925363A US580718A US58071856A US2925363A US 2925363 A US2925363 A US 2925363A US 580718 A US580718 A US 580718A US 58071856 A US58071856 A US 58071856A US 2925363 A US2925363 A US 2925363A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
Description
V asj followsz kers, 4N.Y., assignors to- ChasiPfizer 8: Co., Inc.', New
- 'York, N;Y.', a corporation of Delaware lNo Drawing. A ucafionLA rn 25,1955
. Serial No. 580,718' 7 fie'claims. (Cl. 167-52 "This invention concerned with new and useful 'organi'cmedicinal agents. :In particulanitis concerned with compounds that are effective as hypnotic and/or lanticonvulsant agents. This application is a continua itiori in-ipart 'ofronr :now abandoned' but formerly copending applications Serial No. 296,745, fi1ed July l, 1952, and Serial No. 286,012; filed' May 3, 1952.
1i propane ketone, i.e ethyl vinyl'ketone qr n-propylvinjyl -ketone, in the presence of an alkaline cpndensati "A number of compounds have beenproposed from time to time as hypnotic agents for inducing sleep or sedation and for combattingconvulsive reactions. some of these compounds have undesirable :side efiects, others are slow to act or act in Ia very 'inefieetive :rnanner. A
compound which may prepared without great alifficulty and which displays :azlow' toxicity and appreciable hypoticand/or anticonvulsant :activity .is 'a valuable addition to ?this class 'of :medicinal agents. a f v One object 'of this inventio'nais' :making available novel compounds'which are .higlilyrefiective in inducing hypnosis :and suppressing excitability in animals and in protecting them: against zcoi'nuil'siwe '-.seiz1.f1res. Another object of this invention is .the preparation-10f dosage wherein Ris an ethyl propylgroupb Morespe'ciiioal- 1y, 'the'cornpounds "with "which"*this invention-is :con-
35 ifoi'ms'iof such compounds which mayiradily rhesadmin- V 'isteredbyim'outh orbyi-iniecti'on'andnvhichiarmeffective V within-asshott:time'efor.;thej pui7poses':describedlr ;Further objects will be apparent ironi the description "of this-tin ventiongivenebelow; i v x r Ithas now been found that these objects are accomplished by vinylethinyl tertiary carbinols having the fol L 7 'lc wving-fo rmula:- r 7 g cemed are 3-ethylpent-1-ene-4-yne-3-ol or ethyl; vinyl 1 n piopyl vinyl ethinyl cafbinol; o
Ethyl vinyl ethinyl carbinol is a colorlessgmobile' liquiclfhavingfa distinctjodm, similar to ca mphor It is "solublein Waterito {thefextent -of -'appro rimately '0I25 grainlniilliliter nilit ismiscible 'withimostforganicsol;
nol,' ethen hloroform;iac'etone and-'so "vents'such as'e forth. 7 The product-has a boiling point of 284486" 'Cg a't 98 mm, iof :merea-r j pressure. I Its chemical struc tu 're' is matic ihydrocarbdn's, gl eenaad as -forth'. anan Pl'bpyl Vinyl e "in 1-'eaibinolv'is acolorless {liquid havieg adistin'c't' butndt unpleasant io'dor; 'f lt issoli'lble 'in' water to' iheextent-(i492:"and is m'iscible'w V L offthe "common organi'c solvents,esuch' as' lower ahpliatic v alcohols-ethersfiketones, halogenatedihydrocarbonsfaro-.l
5 7 tion awas addedaa -..sol-utio'n of 42-;5-grarns most a 5 it; v v
r quantities can, be. used without any serious fsidere'a cp ditionsandmhen. quid am' 1 a p ball d e thelfimigitnre shaman mod'fi a i ns ndequival ntsasf lthinthe" utes. The addition,of -acetylenefyvas =co a ffl ae ied eb- 26 terial has a boiling point of ture is as follows:
agent; such asfan: alkali or,all a1ine ,ea rth metal or dioxide; Thereaction is Y 'refe fably conducted inert solvent which will dissolve the various, reactants, 7
but which does not itself enter into undesirable sidere actions} Liquid ammoniajhas been, found to bepartic: ularly suitable but other usefiul solvents, such as ethers or mixtures of liquid ammonia andw'ethers, Qmay also be use h s a ate ma b m a the orm i a e acetylide, such as lithium, "potassium or calciumcompounds, in which case; no metallic catalyst need be used; However, the condensation may be conducted by passing acetylene gas into a solution of the ketone in the presence of a suitable alkaline'condensing agent. We haVe found that lithium dissolved in liquid ammonia is a particularly valuable material for conducting the reaction in question. -.They proportion of the agent jneed generally Thereaction iscond t d under s b fventpraslone ot-the, qwered so; that the,
volfv'apaaizl (194 I tollow ng exampl s a g v nb 5f i usttav .t -h consid e s helscle eta: i bodiments of the inv ntion Resort. may b wh d am only and are n v.
the'inventinnlan th scope qfltheiappendedyla v EXAMPLE 'niilliliters'iof liquid ammonia over a three-minutefperiod,
clear solution= was obtained; took about 1 'nute rgr l g l l 9.8 1" war lia afpt s r Ci 'of' 102 'mm.--of mercury. The'p-ro duc' zt has a gdejisity of r 0.8733 lgram, pe'r'milliliter arzo l tschemipill stin ithiuin ribbon vveighing 4.66 gr s was added td 350;
tilled .ethyl yinyl ketone in 150 milliliters ofabsolute ether. The addition was made during a period of ten minutes. The stirred mixture was allowed to reflux for two -to three hours, then i) milliliters of' absolute ether was added. The mixture was agitated overnight at room temperature with a water-cooled condenser substituted for the Dry-Ice cooled condenser. In the morning, all of the ammonia had evaporated. The mixture in the flask was added to 800 milliliters of ice containing acetic acid. Suflicient acetic acid, was added so that the pH was adjusted to 4.0. The aqueous phase was separated and this was extracted twice with l00milliliter portions of ether. The original ether layer, together with the two extracts, were washed with dilute sodium carbonate solution and then with water. 'After drying the ether solution over anhydrous magnesium sulfate, the solvent was distilled and the product was fractionated. The material boiled at 8083' C. under a pressure of 101 mm.of mercury. It weighed 66.8 grams. Part of'this material was redistilled through a Vigreauxcolumn, and a fraction boiling at 8489 C. under 98 mm. of mercury pressure was selected. The colorless liquid was analyzed:
Analysis.-Calcd. for (su o: C, 76.32; H, 9.15. Found: C, 76.19; H, 9.04.
A test with ammoniacal silver solution showed the presence of the acetylenic grouping.
Instead of using lithium metal in the above condensation, calcium was used and the desired ethyl vinyl ethinyl carbinol was again recovered.
EXAMPLE II A three-neck, two-liter, round-bottom, glass flask was equipped with a stirrer, a Dry Ice condenser, a gas inlet tube, and a plug for the addition of various materials. In the flask was placed 500 milliliters of liquid ammonia and to the liquid was added 6.94 grams of lithium ribbon. Acetone-free acetylene was bubbled through the mixture at' a' rate of 3,5..liters per minute for 6 minutes. The blue" color changed and a gray precipitate, which had formed, dissolved. Acetylene was then bubbled through the mixture at a rate of one liter per minute for 8 minutes. Suflicient liquid ammonia was added to the reaction mixture to replacethat which hadbeen lost. A solution of 101.5 grams of n-propyl vinyl ketone in 200 milliliters of ether was added just above the surface of the reaction mixture over a period of 7 minutes. Throughout this addition, a slow stream of acetylene was bubbled through the mixture. throughout these steps and for an additional two hours. In addition, throughout these operations the temperature of'thc mixture was kept at about that of the boiling point of ammonia. To the mixture was added 250 milli- The reaction mixture was stirred rapidly 4- proportion of acetylenic groups by means of the method of Siggia. It was found to be 95.5% pure.
As indicated above, the compounds of this invention are colorless liquids which are readily adapted to therapeutic use. Marked hypnosis was observed in animals to which they had been administered. 'Furthermore, the compounds were found to protect such animals effectively against convulsive seizures. The compounds are therefore suitable for use in thetreatment of veterinary animals, such as cats, dogs, monkeys, and even mice. They permit certain treatment of animalswhich would not be possible without theuse of a hypnotic agent. For example, the compounds ofthisinvention may be employed to induce hypnosis in mice'and thereby facilitate implantation of tumoroustissue which is so vital to the study of cancer. The toxicity of the compounds was found to be quite low whenthey were administered to mice in amounts sufficient toachieve the desired results, and no harmful. pharmacological efiects were observed as a result of such administration.
The activity of the tertiary carbinols of this invention is Well illustrated by the tests hereinafter described, in
which Rockland Farm Swiss mice weighing 18 to 22 gramswere used as the experimental animals. The compounds were given subcutaneously in aqueous solution and the onset and duration of sleep in each animal was recorded. Sleep is defined as the period during which the animal failed to assume a normal position when placed on its back. Hypnotic activity is defined as-the, dose of the compound in mg. per kg. of body weight which caused sleepin 50% of the animals tested. To determine anticonvulsant activity, each mouse was given subcutane'- ously a convulsant dose of'Metrazol (pentylenetetrazole), i.e. 85 mg./kg., ten minutes after the subcutaneous injection of the compound under test. Anticonvulsant effeet was recorded in terms of the amount of the compound which protected .5Q%-of the mice from Metrazol- Tab'le 1 Hypnotic Anticon- Compound Activity, ant
mgJkg. Activity,
s-I e- 3-ethylpent-1-ene-4-yne-3-ol 180 58 S-n-propylpent 1 ene-4-yne-3-ol.-..- 400 400 liters of ether. .The Dry'Ice condenser wasremoved I and replaced with a water-cooled condenser. The mixture was stirred for an hour and a half and then allowed to stand at room temperature overnight. An additional 500 milliliters of ether was added and the mixture was then stirred for one and -a half hours. It was poured into 500 milliliters of ice containing 99 milliliters of glacial acetic acid. The mixturehad a pH of 4.3. The organic phase was separated and the aqueous phase was extracted twice with 400-milliliter portions of ether. The combined other phases were extracted with aqueous sodium carbonate solution until apH of 6.2 in the aqueous phase was reached. The organic phase wasthen washed with water 7 and dried'over anhydrous magnesium sulfate;. The prod-' uct was distilled. 55.5 grams of crudernaterial boiling at ,96- to 104 C. at 103 mm. pressure was obtained.
This was redistilled and 37.8 grams of a product boiling at, 98- to 99 C. at 102 mm. pressure was obtained. This material was analyzed. e
: Analysis-Calm. for C H O; C, 77.37; H, 9.74. FoundzC, 76.76; H, 9.66.
I kilogram of body weight is usually adequate.
The compound was also assayed by determiningthe m From the foregoing tests, it is apparent that both of the 'to be treated, and its individual responsefto the drug,
amongother factors. A single eifective dosa'ge may range from about 10 to 500 mg. per kilogram of body weight, which is generally sufiicient to achieve the desired results. However, for'some species and when only a mild sedative or soporific effect is desired, from aboutl to 10 mg. per
in exceptional cases, larger doses may be administered without harmful pharmacological effect if the subject is less sensitive to the drug and is of sufiicient weight so that the drug'is well tolerated at this level. The compounds may be administered in single or divided dosages,'using capsules, tablets or other dosage forms providing aunit dosage of theactive ingredient in anamount of pref 1"; ".5 115- i i "fl- M .t' erably-at least l'0jm'g.j,1althouh asihtghas about 100 to 500-mg'.-'per' unit dosage may' be"employed -toiadvanf tage. Capsules containing 500 mg. of the active'ingredi- Ethyl vinyl ethinyl carbinol 500 ent have been' found to befafparticularlyjusefiil dosage Potato starch 100 form. When larger doses-of theptertiary carbinols are 8 Magnesium stearate' 10 desired, it is preferable toadminister twdfor; more-jcapi 4 t f sules or'tablets, -etc., if necessary; adjusting' theiohtent v -'-EXAMPLE of-the tertiary 'carbinol in the dosage rom accordingly. t... It 1 [I It should be apparent from the foregoing that theabove n-Propylvinyl ethinyl carbinol-= ..;.;;;L--..;;;;i."- 250 described compounds may be employed in a'variety of 10 Sucrose. 100 V medicinal dosage forms, that is, they may be incorporated Potato starch V V 20 a with various inert pharmaceutical carriers such as solid Magnesium stearate 5* diluents, oils, etc. or with other biologically active matea I rials, in the form of capsules, elixirs injectable solu- EXAMPLE VHL-ORAL SUSPENSION tions and the like. Materials for oral administration may r I be sweetened and flavored with various agents of the V Grams yp commonly mpl y r that pu pose. Ethyl vinyl ethinyl carbinol 10 For example, in the preparation of tablets various carsucrose 40 riers or diluents, such as lactose, sucroseand calcium Methylparahydmxybenzoicacid 0,13 carbonate. may be p y a ng with distint s'ra ts, Propyl parahydroxybenzoic acid' 0.02 such as starch, preferably potato or tapioca starch, alginic Fl i d color as de 'irei acid and certain complex silicates; binding agents, such as W t to makg 100 gelatin, acacia, and lubricating agents such as magnesium I stearate, steanc acid and talc are also usetul for tablet- Each ,t f I 5 dosagc f the resulting suspen. mg p p y oomrosmonsl of a similar yp may SiOll will provide 500 mg. of the tertiary carbinol. also be employed in gelatin capsules, particularly the hard gelatin type of capsule. In those cases wherethe EXAMPLE R SUSPENSION tertiary carbinol is normally liquid it has been found I t especially advantageous to encapsulate the compounds v Gr in softgelatin capsules. For this type of dosage form n.P 1 i l thi l bi l 10 the'active therapeutic agent may first be -combined with Sucrose I such agents as p y y s y .-p p g yc or Methyl 'parahydroxybenz'oic acid 0.18'
gly r n which f tion no nly as il nts but l o Propyl parahydroxybenzoic acid 0.02 exert a plasticizing action on the gelatin capsule to pro- Ethyl hb 10 tect it from becoming denatured by the tertiary car- Fl i d 51 s d i d, y binol which may result in leakage from the capsule. water to k 100 When elixirs or,suspensions for oral administration are" v l I v V a desired, the compounds of this-'invention'may be com- EXAMPLE N O N bined with sugar syrup, flavoring agents and dyes, and if V t 1 desired, emulsifyingand/or suspending agents- In such Ethyl vinyl ethinyl carbinol 5 dosage forms the diluents which may be employed in- Sterile, distilled water to make 100 cc. clude water, glycerine, propylene glycol, alcohol, various 7 combinations thereof, and the like. Dry powders. may What is claimed is: v 7 also be prepared which are suitable for reconstitution '1. A therapeutic compositionin dosageunit form com with water-prior to use. In like manner, parenteral soluprising a significant amount of a pharmaceutical carrier tions or suspensions in sterile distilled water mayalso and at least 10 mg. per dosage unit of a compound se be emploeyd, containing say 5% of the tertiary'carbinol. lected from the group consistingof 3-ethylpent-l-ene-4- When incorporated in such medicinal dosage forms as yne-B-ol and 3-n-propylpent-1-ene-4-yne-3-ol, said comthose previously mentioned, the compounds of this invenposition being 1 e'fiective for inducing hypnosis in veterition maybe present in concentrationsranging from about nary animals and for protecting the'same'against 'con- 0.5% by weight to about 90% by weight of the comvulsive seizures; S position, i.e. in an amount suflicient to providethe de- .2.' The composition ofclaim l'in which said composisired unit dosage as previously described. Lower con-- tion' is in-tablet dosage unit 'form. r centrations are generally not advisable, since the volume V 3; The composition of claim 1 in which said pharof material which must be administered becomes excesmaceuticalcarrierisaliquid. I sive. The invention is further illustrated by the follow I 4.-A therapeutic composition in dosage unit form com-5 ingexamples of typical dosage; formulations'whichmay prising a significant amount of a, pharmaceutical carbe employed for administration of the tertiary carbinols rier and from about 1 mg. to 500 mg. per dosage unit of previously described. V a compound selectedfrom thegroup consisting of 3-ethyl- .60 pent-1 ene-4-yne-3-ol and j3-n-propylpent-l ene-4-yne-3- EXAMPLE H GE C p S', I 7 ol, said composition being elfectivefor inducing hypnosisj V 4 in veterinary animals andfor protecting the same against Ethyl vinyl ethinyl carbinol t 500 oonvulslvo z o Polyethylene glycol (average? molecular weight v P P P HY FQ hypnfmc .cpmplsltlon i; I 175 dosage unit formcompnslng a gelatin capsulelcontaina in per capsule at least about 10 mg. of a compound:
EXAMPLE I --SQ GELATIN S L selected from the group consisting of 3-ethylpent-l-enen-Propyl vinyl ethinyl carbinol 250; -ynola p y t- -=n said com; Polyethylene glycol (average molecular weight posltlonfifimg efiectlveofof yp i v t r 400) I 1 "37,5 nary an mals and for protecting the same against con- ELATIN vulsive seizures. f
E G I o 1 '6.'A therapeutically eflective hypnotic" composition n-Propyl vinyl ethinyl carbinol 100, "comprising not less than about 0.5 of-a compound sea Polyethylene glycol (average molecular weight a lected from the'group consisting of :3-ethylpent 1-ene-4 azcma '7 ma mi l rr iemhageior, aid, w pns ml b n #3- tive'fbr induc'inghyphd'sis in vter'inary animals.
References Cited in the' file-of this patefit UNITED STATES PATENTS 1,963,074 Caxothegsqt a1. Iune 19, 1934 2,425,201 Orishnik Aug. 5, 1947 2,451,739 Islet V. Oct. 1 9., 1 948 as-sh n 1,: S mme; 1.1 9&4.- 12 195-1, pp-
Papa at =al.: fiiochem, and Biophysics, vol. 33', 5 NQ.13,, (pm, 1951;, pp. 432-483.
C m A rn \YOL; 019 3) PP 53699 37-0- Chc Abs n 3m- Ind 7- 6) .P- 7
Olgg. Chem. in Phax macy, 1,949.,
Claims (1)
1. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FROM COMPRISING A SIGNIFICANT AMOUNT OF A PHARAMACEUTICAL CARRIER AND AT LEAST 10 MG. PER DOSAGE UNIT OF A COMPOUND SESELECTED FROM THE GROUP CONSISTING OF 3-ETHYLENE-1-ENE-4YNE-3-OL AND 3-N-PROPYPENT-1-ENE-4-YNE-3-OL, SAID COMPOSITION BEING EFFECTIVE INCLUDING HYPNOSIS IN VETERINARY ANIMALS AND FOR PROTECTING THE SAME AGANIST CONVULSIVE SEIZURES.
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US580718A US2925363A (en) | 1956-04-26 | 1956-04-26 | Vinyl ethinyl tertiary carbinols |
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US580718A US2925363A (en) | 1956-04-26 | 1956-04-26 | Vinyl ethinyl tertiary carbinols |
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US2925363A true US2925363A (en) | 1960-02-16 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3496240A (en) * | 1966-09-20 | 1970-02-17 | Hoffmann La Roche | Acetylenic carbinol production and recovery by thin film,superatmospheric pressure evaporation with condenser pressure control by venting |
US4011271A (en) * | 1974-04-15 | 1977-03-08 | Hoffmann-La Roche Inc. | Preparation and use of magnesium acetylene complex |
US4371461A (en) * | 1980-10-02 | 1983-02-01 | The Procter & Gamble Company | Liquid detergent compositions with tertiary alcohol skin feel additives |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1963074A (en) * | 1931-11-11 | 1934-06-19 | Du Pont | Vinylethinyl carbinol polymers and processes for preparing same |
US2425201A (en) * | 1945-09-11 | 1947-08-05 | Ortho Pharma Corp | Method for producing ethynyl carbinols |
US2451739A (en) * | 1945-10-18 | 1948-10-19 | Hoffmann La Roche | Process for the manufacture of pentaenes |
-
1956
- 1956-04-26 US US580718A patent/US2925363A/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1963074A (en) * | 1931-11-11 | 1934-06-19 | Du Pont | Vinylethinyl carbinol polymers and processes for preparing same |
US2425201A (en) * | 1945-09-11 | 1947-08-05 | Ortho Pharma Corp | Method for producing ethynyl carbinols |
US2451739A (en) * | 1945-10-18 | 1948-10-19 | Hoffmann La Roche | Process for the manufacture of pentaenes |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3496240A (en) * | 1966-09-20 | 1970-02-17 | Hoffmann La Roche | Acetylenic carbinol production and recovery by thin film,superatmospheric pressure evaporation with condenser pressure control by venting |
US4011271A (en) * | 1974-04-15 | 1977-03-08 | Hoffmann-La Roche Inc. | Preparation and use of magnesium acetylene complex |
US4371461A (en) * | 1980-10-02 | 1983-02-01 | The Procter & Gamble Company | Liquid detergent compositions with tertiary alcohol skin feel additives |
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