US3274054A - Antiviral compositions and method of administration - Google Patents

Antiviral compositions and method of administration Download PDF

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Publication number
US3274054A
US3274054A US291282A US29128263A US3274054A US 3274054 A US3274054 A US 3274054A US 291282 A US291282 A US 291282A US 29128263 A US29128263 A US 29128263A US 3274054 A US3274054 A US 3274054A
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US
United States
Prior art keywords
methylpiperazine
carboxylate
diethylaminoethyl
acid
sodium
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
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US291282A
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English (en)
Inventor
Tomcufcik Andrew Stephen
Angier Robert Bruce
Forbes Martin
Lindh Howard Frederick
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Wyeth Holdings LLC
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American Cyanamid Co
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Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US291282A priority Critical patent/US3274054A/en
Priority to US301194A priority patent/US3213097A/en
Priority to BE647594D priority patent/BE647594A/xx
Priority to NL6405988A priority patent/NL6405988A/xx
Priority to ES301524A priority patent/ES301524A1/es
Application granted granted Critical
Publication of US3274054A publication Critical patent/US3274054A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms

Definitions

  • compositions containing as an active ingredient a compound of the following formula are useful in treating viral infections in warm blooded animals:
  • R is hydrogen or lower alkyl
  • R and R are hydrogen or lower alkyl
  • R and R are lower alkyl
  • X is lower alkylene
  • Z is oxygen or sulfur and acid addition and quaternary salts thereof.
  • the free bases of the compounds of this invention are, in general, oily liquids or low melting solids. They are, in general, soluble in water and in the usual organic solvents, such as lower alkanols, acetone, lower alkyl esters of lower alkanols, benzene, toluene, ethers and the like.
  • the free bases of the compounds of this invention form acid addition salts with acids such as hydrochloric, hydrobromic, sulfuric, acetic, citric, tartaric, lactic, succinic, maleic, phosphoric, malic, gluconic, ascorbic, 1,1- methylene-bis-(2-naphthol-3-carboxylic acid), butanel,2,3,4-tetracarboxylic acid and the like.
  • acids such as hydrochloric, hydrobromic, sulfuric, acetic, citric, tartaric, lactic, succinic, maleic, phosphoric, malic, gluconic, ascorbic, 1,1- methylene-bis-(2-naphthol-3-carboxylic acid), butanel,2,3,4-tetracarboxylic acid and the like.
  • Such acid addition salts are in general soluble in water, but not soluble in non-polar organic solvents such as ethers and petroleum ethers; and they may be prepared, in general, by adding an anhydrous acid to an anhydrous solution of the basic compound in ether or alcohol and thereafter isolating the precipitated salt by filtration.
  • the compounds of the present invention can be prepared by methods described hereinafter in the examples and in the prior art.
  • the most general method for preparing the present compounds is the reaction of l-carbethoxy-4-lower alkylpiperazine with a di-loweralkylamino lower fatty acid alcohol. Other methods are shown hereinafter in the examples.
  • Treatment 15 Controls (0.85% NaOl) 5 1o0 1 Animals: Taconic male white mice; 16-20 grams body weight. Inigztion: Intranasal; 0.05 ml. of a 10' broth dilution of virus stock 0. Treatment: Single dose directly after infection; oral doses by tubing of 0 1.0 ml. volume of aqueous solution; subcutaneous doses by injection of 0.5 ml. volume of aqueous solutions; all solutions adjusted to pH 7.0.
  • Table I summarizes the results with a single dose as treatment directly after infection.
  • Table II summarizes results with three dose oral treatment.
  • Treatment Oral tubing of 1.0 ml. volume of aqueous solutions at 0, 24 and 48 hours after infection.
  • Controls (0.85% NaCl) 5/105 Animals: Taconie Farms male white mice; 19-25 grams body weight Infection: Intranasal; 0.05 ml. of a lCldilution in brain heart infusion broth of stock PR-8 virus. Treatment: Compounds dissolved in water, pH adjusted to 7.0. Indicated dose imected subcutaneously immediately after infection. Controls received 0.85% NaCl solution.
  • compositions comprising the active ingredient and excipients including a carrier. While the amount of active ingredient to be given daily will depend on many factors such as the size, weight, age, kind, and severity of infection, etc. of the warm blooded animal, a daily intake ranging from 5 to 500 milligrams per kilogram of body weight will produce good results.
  • the dosage unit may vary from 0.05 to 2 g. and may 'be in a form to be administered one or more times per day, or in smaller forms for multiple daily, or other more frequent administration. Any of the usual dosage unit forms of pharmaceutical compositions can be useful, for example, tablets, Oblets, hard or soft shell capsules, parenteral solutions or suspensions, oral solutions or syrups,
  • Tablets or Oblets may include, in addition to active ingredient, any of the following excipients.
  • a binder such as acacia, corn starch, gelatin, or the like.
  • a disintegrating agent such as corn starch, potato starch, alginic acid, or the like.
  • a lubricant such as stearic acid, magnesium stearate, talc or the like.
  • a sweetening agent such as saccharin or sucaryl, and/ or a flavoring such as peppermint oil, oil of Wintergreen, or orange or cherry flavoring can be used.
  • Capsules may include, in addition to active ingredient, a lubricant and also an inert filler such as lactose, sucrose, corn starch or the like.
  • Solutions usually include an acid such as hydrochloric, citric, tartaric, succinic, maleic, ascorbic, phosphoric or the like, or a suitable bufler thereof.
  • Suspensions include a surfactant such as polyoxyethylene sorbitan monooleate (a complex mixture of polyoxyethylene ethers of mixed partial oleic esters of sorbitol anhydrides); oxyethylated tertiary octylphenol formaldehyde polymer; p-isooctylpolyoxyethylenephenol polymers or the like; a suspending agent such as polyethylene glycol 4000 USP (a condensation polymer of ethylene oxide and water, represented by the formula: HOCH (CH OCH ),,CH OH, wherein n varies from about 70 to 85, the molecular weight being about 4000), carboxy methylcellulose (sodium carboxymethylcellulose USP, the sodium salt of carboxymethyl ether of cellulose having a closely controlled number of sodium carb
  • Both solutions and suspensions may include a stabilizer such as disodium salt of ethylenediaminetetraacetic acid, sodium sulfite, monothioglycerol, or the like; and a perservative such as benzyl alcohol, parabens (methyl and propyl esters of phydroxybenzoic acid), or the like.
  • a stabilizer such as disodium salt of ethylenediaminetetraacetic acid, sodium sulfite, monothioglycerol, or the like
  • a perservative such as benzyl alcohol, parabens (methyl and propyl esters of phydroxybenzoic acid), or the like.
  • Oral solutions may include a suspending agent or viscosity control such as magnesium aluminum silicate, carboxymethylcellulose or the like as Well as a buffer, preservative, etc. Solutions and suspensions may be of the aqueous sugar or sorbitol type. It is also known in pharmaceutical practice to employ a propyleneglycol type solvent for use with drugs.
  • a suspending agent or viscosity control such as magnesium aluminum silicate, carboxymethylcellulose or the like as Well as a buffer, preservative, etc.
  • Solutions and suspensions may be of the aqueous sugar or sorbitol type. It is also known in pharmaceutical practice to employ a propyleneglycol type solvent for use with drugs.
  • Example I.Preparati0n of Z-dimelhylaminoethylpiperazine-I-carboxylate In a flask connected to a condenser and receiver is placed 817 g. of Z-dimethylaminoethanol, which contains 8 g. of dissolved sodium, and 474 g. of l-carbethoxypiperazine. The mixture is heated first between 6070 C. for 7 hours at 32-38 mm. pressure and then at 140 C. for 7 hours at atmospheric pressure. The resultant solution is carefully fractionated at reduced pressure to remove excess 2-dimethylaminoethanol and unreacted l-carbeth- 4 oxypiperazine. A crude fraction, boiling point 140-160 C. at 1525 mm. is collected and redistilled to yield 2- dimethylaminoethyl piperazine-l-carboxylate, a colorless oil, boiling point 114-117 C./0.51 mm., 21 1.4823.
  • Example lI.-Preparation of Z-diethylaminoethylpi perazine-I -carboxy late Four g. of sodium are dissolved in 928 g. of 2-diethylaminoethanol and 474 g. of l-carbethoxypiperazine are added to the solution. The mixture is then heated in a manner similar to that described in Example I, first at reduced pressure, in this case at 40 mm. for 7 hours at 88 C., and then at the boiling point of Z-diethylaminoethanol for 7 hours at atmospheric pressure.
  • the Z-diethylaminoethyl piperazine-l-carboxylate is a colorless oil, boiling point l44.5-147 C./4 mm., n 1.4803.
  • Example IlI.Preparati0n of Z-diethylaminoelhyl 4-methylpiperazine-1-earb0xylate A mixture of 468 g. of Z-diethylaminoethanol containing 4 g. of dissolved sodium and 172 g. of 1-carbethoxy-4- methylpiperazine is heated under reduced pressure and at atmospheric pressure in a manner similar to that described in Example 11.
  • Purified material consists of 2-diethylaminoethyl 4-methylpiperazine-l-carboxylate, a colorless oil, boiling point l27-128 C./ 1 mm., 11 1.4700.
  • Example I Preparati0n of Z-diethylaminoethyl 4-methylpiperazine-I-carb0xylate dihydrochloride A salt is prepared by passing hydrogen chloride gas into an ethereal solution of 2-diethylaminoethyl 4- methylpiperazine-l-carboxylate of Example III.
  • the product, 2- diethylaminoethyl 4-methylpiperazine l-carboxylate dihydrochloride is obtained as a white solid which melts after recrystallization from alcohol-ether at 196.3- 198.3 C. with effervescence.
  • Example V Preparation of 3-diethylam-in0propyl 4-methylpiperazine-1-carb0xylate
  • Metallic sodium 0.4 g.
  • 17.2 g. (0.10 mole) of 1-carbethoxy-4-methylpiperazine The solution is heated in an oil bath at 90 C. for seven hours under reduced pressure (25-50 mm. of Hg) and then refluxed for ten hours at atmospheric pressure.
  • the excess aminoalcohol is removed on a steam bath at 20 mm. of mercury and the residue is distilled through a small Vigreux column.
  • Metallic sodium (0.4 g.) is dissolved in 41.3 g. (0.4 mole) of l-dimethylamino-2-propanol.
  • To this solution is added 17.2 g. (0.1 mole) of 1-carbethoxy-4-methylpiperazine and then heated for six hours at 80-90 C.
  • a stream of dry air is passed through the reaction mixture at the beginning of the heating period. This causes 15 ml. of the aminoalcohol to distill over which is added back to the reaction.
  • At the end of the six hours several ml. of distillate are collected before refluxing for an additional eight hours.
  • the mixture is filtered and the filtrate is distilled through a Nester-Faust spinning band column, yield 2.4 g., boiling point 84-88 C. (10.4 mm. of Hg), n 1.4662.
  • 4.6 g. (0.2 mole) of sodium followed by brief refluxing to complete solution.
  • the solution is then cooled to room temperature, diluted with 50 ml. of diglyme and 22.5 g.
  • Example 1X Preparation 0f Z-diethylaminoethyl 2,4,5- trimethy lpiperazz'lze-I -carb0xylale
  • Metallic sodium 0.4 g.
  • 2- diethylaminoethanol followed by the addition of 20.0 g. of 1-carbethoxy-2,4,S-trimethylpiperazine.
  • This is treated in a manner similar to Example V.
  • the product obtained is 2-diethylaminoethyl-2,4,S-trimethylpiperazine-l-carboxylate.
  • Example X Parenteral solutions of the compounds of the present invention can be used as a method of administration.
  • An illustrative formulation is the following.
  • Example XI The compounds of this invention may be administered in oral syrup preparations such as the following.
  • the above syrup has a pH of about 4.5-5 .5.
  • a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, methylcellulose, carbopol 934 (carboxy vinyl polymer of high molecular weight), etc.
  • the phosphates used above as buffers can be replaced with citrates or tartrates.
  • the parabens can be replaced with alkali metal benzoates, sorbic acid or the like.
  • the sugar and sorbitol could be replaced in Whole or in part with corn syrup, glycerol, other sugars, etc. And alternate dyes and flavors could replace those indicated above.
  • Example XII The compounds of this invention may be dispensed in hard or soft shell capsules.
  • a useful formulation for preparing such capsules is as follows.
  • Example XIII The com-pounds of this invention may be dispensed as pharmaceutical tablets or Oblets.
  • a useful formulation for preparing tablets or Oblets is as follows.
  • each containing 0.5 g. of active ingredient may be considered to provide an entire single daily dose. Such a tablet might be scored so as to provide fractional daily doses. Alternatively, tablets containing smaller amounts of active ingredient might be prepared for fractional daily or smaller doses.
  • a method of treating virus infections in warm blooded animals which comprises administering to said animals an antiviral composition comprising an edible carrier and from 5 to about 500 mg. per kg. based on body weight of said animal, of a substituted piperazine of the formula:
  • R is selected from the group consisting of hydrogen and lower alkyl
  • R and R are selected from the group consisting of hydrogen and lower alkyl
  • R and R are lower alkyl
  • X is lower alkylene
  • Z is selected from the group consisting of oxygen and sulfur and acid addition and quaternary salts thereof.
  • substituted piperazine is Z-dimethylaminoisopropyl 4-methylpiperazine-1- ca-rb-oxylate.
  • composition of matter having antiviral activity in dosage unit form, comprising a pharmaceutical carrier and from about 0.05 to 2 g. of a substituted piperazine of the formula:
  • R is selected from the group consisting of hydrogen and lower alkyl
  • R and R are selected from the group consisting of hydrogen and lower alkyl
  • R and R are lower alkyl
  • X is lower alkylene
  • Z is selected from the group consisting of oxygen and sulfur and acid addition and quaternary salts thereof.
  • composition of matter in accordance with claim 7 characterized in that the substituted piperazine is 2- diethyla-minoethyl 4-methylpi perazine-l-carboxylate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US291282A 1963-06-28 1963-06-28 Antiviral compositions and method of administration Expired - Lifetime US3274054A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US291282A US3274054A (en) 1963-06-28 1963-06-28 Antiviral compositions and method of administration
US301194A US3213097A (en) 1963-06-28 1963-08-09 4-(3'-dimethylaminopropyl)-1-carbalkoxy piperazine derivatives
BE647594D BE647594A (https=) 1963-06-28 1964-05-06
NL6405988A NL6405988A (https=) 1963-06-28 1964-05-28
ES301524A ES301524A1 (es) 1963-06-28 1964-06-27 Procedimiento de preparación de composiciones antivirus en forma unitaria de dosificación

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Application Number Priority Date Filing Date Title
US291282A US3274054A (en) 1963-06-28 1963-06-28 Antiviral compositions and method of administration
US301194A US3213097A (en) 1963-06-28 1963-08-09 4-(3'-dimethylaminopropyl)-1-carbalkoxy piperazine derivatives

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US301194A Expired - Lifetime US3213097A (en) 1963-06-28 1963-08-09 4-(3'-dimethylaminopropyl)-1-carbalkoxy piperazine derivatives

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BE (1) BE647594A (https=)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3458515A (en) * 1966-07-21 1969-07-29 American Home Prod Piperazine substituted pyrroles
US4977156A (en) * 1988-07-26 1990-12-11 The Dow Chemical Company Amino piperazine esters showing biocidal activity

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR150M (fr) * 1963-07-24 1961-01-20 Corbiere Et Pansements Brevete Nouveau produit a action anesthésique locale.
FR2081564A1 (en) * 1970-03-05 1971-12-10 Delalande Sa N-amino carbonyl-piperazines analgesics - antiinflammatories ,hypotensives and spasmolytics

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA547981A (en) * 1957-10-29 L. Bach Frederick Substituted piperazines and method of preparing the same
US2541584A (en) * 1947-06-11 1951-02-13 Nat Aluminate Corp N-acylated piperazines
US2753350A (en) * 1951-11-01 1956-07-03 Hasselstrom Torsten Pungent-tasting pentavalent piperazine diacid salts
US2710823A (en) * 1952-09-17 1955-06-14 Schenley Ind Inc Fungicidal compounds
US2710824A (en) * 1952-09-17 1955-06-14 Schenley Ind Inc Fungicidal compounds
US2794804A (en) * 1955-03-24 1957-06-04 American Cyanamid Co Substituted piperazines and method of preparing the same
US3015657A (en) * 1959-05-28 1962-01-02 Charles F Geschickter 1-carbalkoxy-4-(aminoalkanol) piperazines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3458515A (en) * 1966-07-21 1969-07-29 American Home Prod Piperazine substituted pyrroles
US4977156A (en) * 1988-07-26 1990-12-11 The Dow Chemical Company Amino piperazine esters showing biocidal activity

Also Published As

Publication number Publication date
US3213097A (en) 1965-10-19
NL6405988A (https=) 1964-12-29
ES301524A1 (es) 1962-12-16
BE647594A (https=) 1964-11-06

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