US2887481A - Heterocyclic amides - Google Patents

Heterocyclic amides Download PDF

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US2887481A
US2887481A US655539A US65553957A US2887481A US 2887481 A US2887481 A US 2887481A US 655539 A US655539 A US 655539A US 65553957 A US65553957 A US 65553957A US 2887481 A US2887481 A US 2887481A
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methylisonipecotoyl
hydrochloride
phenothiazine
compounds
water
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US655539A
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Margaret H Sherlock
Sperber Nathan
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Merck Sharp and Dohme Corp
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Schering Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • our new compounds possess significant physiological properties useful in the treatment of bronchospasm and Parkinsons disease. Furthermore, the compounds of this invention show remarkable selectivity in blocking pilocarpine-induced bronchospasm without causing-undesirable side effects such as mydriasis andxerostemia. Moreover, our compounds, in doses sufficient to block the invitro spasmodic eflfects of acetylcholine on the tracheal chain and perfused lung, are equally active in blocking the spasmodic effects of histamine. Thus, our compounds appear to possess a combination of anticholinergic and antihistaminic activities, which are unique in their specificity for treatment of bronchospasm.
  • the ability to block pilocarpine-induced bronchospasm appears to be a property of both the isonipecotoylphenothiazines of our invention and their L l-isomers, the nipecotoylphenothiazines.
  • our compounds are significantly more potent and have a more favorabletherapeutic ratio than their isomers.
  • 10-(N-methylisonipecotoyl)-phenothiazine is 33 times'as potent as atropine and 11 times as potent as its 3-isomer, IO-(N-methylnipecotoyl)-phenothiazine in relieving bronchospasm.
  • the isonipecotoyl derivative has greater specificity of action with minimal side effects.
  • the isonipecotoyl derivatives are distinct from, and preferred to, their position isomers.
  • the present treatment of Parkinsonism has been limited by the appearance of undesirable side eifects produced by the medicament employed.
  • the unique specificity of the compounds of our invention in overcoming the effects panied by a similar specificity of cholinergic blockade within the central nervous system without untoward side efiects.
  • the compounds of our invention are readily prepared via a conventional amide synthesis. Reacting a phenothiazine or its 2-X substitution products, wherein X is as above defined, with an N-lower alkyl isonipecotoyl halide yields the amides of our invention.
  • an acid salt of an isonipecotoylchloride such as N-methylisonipecotoylchloride hydrochloride and effect the reaction in an inert solvent such as benzene, toluene, xylene and the like.
  • an inert solvent such as benzene, toluene, xylene and the like.
  • heat the mixture generally at reflux.
  • the acid salts are usually prepared from the free base and a non-toxic acid preferably in an inert solvent such as ether, benzene, ethyl acetate and the like, whereby the salt precipitates in a relatively pure state.
  • non-toxic salts which may be prepared in this manner are the hydrochloride, phosphate, maleate, citrate, tartrate, salicylate and the like.
  • the hydrochloride is prepared from the free base with ethanolic hydrogen chloride.
  • the salt is obtained as the monohydrate, and melts at 241-242 C., after several recrystallizations from ethanol-ether.
  • EXAMPLE 3 10- (N-methylisonipecotoyl)-2-br0mophen0thiazine scribed in Example 2.
  • the hydrochloride salt so obtained is further treated as in Example 2, the free base is isolated as a light tan solid which is crystallized from ethanol-water.
  • EXAMPLE 4 10-(N-isopropylisonipecotoyl) -phenothiazine
  • the requisite intermediate, methyl N-isopropylisonipecotate, B.P. 127-l30 C./3 mm. Hg, is prepared by the alkylation of methyl isonipecotate with potassium carbonate and isopropyl iodide in benzene.
  • a solution of 17.5 g. of methyl N-isopropylisonipecotate and 100 ml. of concentrated hydrochloric acid is heated on a steam bath for 16 hours, concentrated to dryness, then refluxed for two hours with 50 ml. of thionyl chloride. After the excess thionyl chloride is removed in vacuo, the residual solid is suspended in 400 ml. of anhydrous benzene, and 20 g. of phenothiazine is added portionwise. The reaction mixture is stirred and refluxed for 12 hours. One liter of water is then added, the aqueous layer separated, and the basic layer extracted several times with dilute hydrochloric acid.
  • the acid extracts combined with the original aqueous layer are made basic with dilute sodim hydroxide solution and are then extracted with ether.
  • the ether solution is cooled to --30 C. in an acetone Dry Ice bath and the green solid which precipitates is filtered. Extraction of the solid in a Soxhlet extractor with hexane yields 10-(N- isopropylisonipecotoyl)-phenothiazine as a yellow crystalline solid.
  • This crystalline amide is converted to the maleatesalt in ethyl acetate with an equimolar amount of maleic acid in ethyl acetate.
  • EXAMPLE 5 1 0- (N -methylisonipec0toyl -2-acetylphen0thiazine Z-acetylphenothiazine g.) is reacted with a suspension of N-methylisonipecotoylchloride hydrochloride (from 10.7 g. of N-methylisonipecotic acid hydrochloride) in 200 ml. of anhydrous benzene, in the manner described in Example 2, to yield the hydrochloric acid salt of 10 (N-methylisonipecotoyl) 2 acetylphenothiazine which is crystallized from methanol.
  • the hydrochloride salt M.P. 225226 C. (monohydrate) so obtained is further treated as in Example 2, the ,free base is isolated as a light tan solid which is crystallized from ethanol-water.
  • EXAMPLE 6 10-(N-methylisonipecotoyl) -2-trifluoromethylphenothi- .azine
  • 2-trifiuoromethylphenothiazine 21 g.
  • 2-trifiuoromethylphenothiazine 21 g.
  • crude N-methylisonipecotoylchloride hydrochloride from 18 g. of N-methylisonipecotic acid hydrochloride.
  • the reaction miXture is stirred and refluxed for 18 hours, then 500 ml. of water is added.
  • the aqueous layer is sepa rated and made basic with sodium hydroxide.
  • the hydrochloride salt of the above compound is prepared by adding an ethanolsolution of hydrogen chloride to a solutoin of the free base in methyl ethyl ketone until the solution is faintly acidic. With the addition of dry ether, the hydrochloride precipitates as a colorless solid which melts at 235-236 C. after recrystallization from methyl ethyl ketone.
  • the compounds .ofpur invention can be incorporated into various oral pharmaceutical preparations such as tablets, capsules, elixirs, syrups, nasal sprays, suppositories, and the like, by mixing the same alone, or in conjunction with other active ingredients with various proportions of pharmaceutical carriers suitable for the preparation being made.
  • Active ingredients which may be used with the compounds of our invention are: aminophylline, prednisone, ephedrine sulfate, potassium iodide, codein sulfate or phosphate, phenobarbital, perphenazine, calcium phosphate, chlorpheniramine maleate, and the like.
  • the recommended optimum dose .range for oral administration of the claimed compounds is from 0.5 to 2 mg. t.i.d.
  • the compounds of our invention can also be administered intravenously, preferably in the form of aqueous solutions of their non-toxic amine salts (such as the hydrochloride), in the presence of preservatives such as methyl paraben, propyl paraben, and the like.
  • Other active ingredients such as those used in the oral preparations may also be used in these parenteral compositions. From 0.1 to 0.4 mg. of the phenothiazine compound per parental dose is the optimum range recommended.
  • compositions can be varied over a substantial range, subject to the practical limitation that a sufficient proportion of active ingredient be present to provide a suitable dosage. Obviously, the practice of administering several unit dosage forms at about the same time can be followed. The dosage of these compounds may be varied, depending on the requirements of the patient.
  • formulations are intended as illustrative only, and are not to be construed as limiting the scope of the invention.
  • the 10-(N-methylisonipecotoyl) -phenothiazine hydrochloride is mixed with the lactose and the starch.
  • a 10 percent starch paste is prepared and the-mixed powders granulated therewith. This wet granulation is passed through a No. 12 screen and then dried at 50 C. for twelve hours, or until the moisture content is less than 0.5 percent.
  • the dry granules are passed through aNo. 16 screen, incorporated with the remainder of the starch and-magnesium 'stearate, and then pressed into tablets.
  • the 10 (N methylisonipecotoyl) PbmQFh aZinehydrochloride and prednisone are mixed thoroughly with the lactose. Magnesium stearateisthen added and mixed until the composition is uniform; No. 1 hard shell capsules are then filled with this uniform mixture.
  • Soft gela tirt capsule Mg. 10-(N-methylisonipecotoyl)#phenothiazine hydrochloride 1.00 Ephedrine sulfate 25.00 Lactose 10.00 Beeswax 2.00 Corn oil 5 172.00
  • EXAMPLE 12 Syrup 10- (N-methylisonipecotoyl)-pheno Quantity/l. 10 (N methylisonipecotoyl)-phenothiazine hydrochloride gm 0.2 Potassium iodide, U.S.P. XV -..gm 13.0 Compound sarsaparilla syrup, N.F. X, 1.0 1.
  • the 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride and potassium iodide are dissolved in a quantity .of compound sarsaparilla syrup sufficient to make the total volume measure one liter. The solution is filtered, if necessary, until clear.
  • EXAMPLE 13 I Suppository Gm. 10 (N methylisonipecotoyl) -phenothiazine hydrochloride 0.1 Aminophylline, U.S.P. XV 30.0 Theobroma oil, U.S.P. XV-A sufiicient quantity to make 100 suppositories.
  • the ingredients are mixed intimately and prepared according to the process of cold compression to form 100 rectal suppositories, each of which weighs approximately 2 gm.
  • the 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride and chlorpheniramine maleate are dissolved in a suitable quantity of water.
  • the sorbitol and benzalkonium chloride solutions are added, then sufiicient purified water to make the total volume of one liter.
  • the solution is filtered until clear.
  • the ingredients are dissolved in the water for injection, filtered, filled into ampules or vials, and sterilized by autoclaviug.
  • the 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride is dissolved in about 50 ml. of water for injection.
  • the other ingredients are dissolved in the propylene glycol.
  • the solutions are mixed, bringing the volume to one liter with water'for injection, filtered, filled into ampules or'vialsi and sterilized by autocl'avingj l
  • the ingredients are dissolved in the water for injection, filtered, filled into ampules or vials, and sterilized by autoclaving.
  • JWGI alkyl wherein X is a member of the group consisting of hy- 7 8 drogen, lower alkanoyl;ttifiuoromethyl, and a halogen sf'l' heuo'thiazines having the formula: atom having anatomioweight between 30 and 80, and the non-toxic acid addition salts thereof. 4 l I s .1
  • Phenothiazines having the formula:
  • N E o If, lower'alkyl N my] wherein X is lower alkanoyl.

Description

United States Patent HETEROCYCLIC AMIDES Margaret H. Sherlock, Bloomfield, and Nathan Sperher,
North Caldwell, N.J.,assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Application April 29, 1957 Serial No. 655,539
9 Claims. I (Cl. 260-443) wherein X is a member of the group consisting of hydrogen, chlorine, fluorine, bromine, lower alkanoyl, and trifluoromethyl, and R is a lower alkyl group.
We have found that our new compounds possess significant physiological properties useful in the treatment of bronchospasm and Parkinsons disease. Furthermore, the compounds of this invention show remarkable selectivity in blocking pilocarpine-induced bronchospasm without causing-undesirable side effects such as mydriasis andxerostemia. Moreover, our compounds, in doses sufficient to block the invitro spasmodic eflfects of acetylcholine on the tracheal chain and perfused lung, are equally active in blocking the spasmodic effects of histamine. Thus, our compounds appear to possess a combination of anticholinergic and antihistaminic activities, which are unique in their specificity for treatment of bronchospasm.
The ability to block pilocarpine-induced bronchospasm appears to be a property of both the isonipecotoylphenothiazines of our invention and their L l-isomers, the nipecotoylphenothiazines. We have found, however, that our compounds are significantly more potent and have a more favorabletherapeutic ratio than their isomers. For example, via intravenous administration in dogs, we have found that 10-(N-methylisonipecotoyl)-phenothiazine is 33 times'as potent as atropine and 11 times as potent as its 3-isomer, IO-(N-methylnipecotoyl)-phenothiazine in relieving bronchospasm. Furthermore, the isonipecotoyl derivative has greater specificity of action with minimal side effects. In view of the advantageous therapeutic ratio, the isonipecotoyl derivatives are distinct from, and preferred to, their position isomers.
The present treatment of Parkinsonism has been limited by the appearance of undesirable side eifects produced by the medicament employed. The unique specificity of the compounds of our invention in overcoming the effects panied by a similar specificity of cholinergic blockade within the central nervous system without untoward side efiects. These advantageous properties make our compounds more effective than agents currently employed in Parkinsonism and provide for favorable control of symptons without concomitant side effects.
The compounds of our invention are readily prepared via a conventional amide synthesis. Reacting a phenothiazine or its 2-X substitution products, wherein X is as above defined, with an N-lower alkyl isonipecotoyl halide yields the amides of our invention. We prefer to use an acid salt of an isonipecotoylchloride such as N-methylisonipecotoylchloride hydrochloride and effect the reaction in an inert solvent such as benzene, toluene, xylene and the like. To hasten the reaction we prefer to heat the mixture, generally at reflux.
The acid salts are usually prepared from the free base and a non-toxic acid preferably in an inert solvent such as ether, benzene, ethyl acetate and the like, whereby the salt precipitates in a relatively pure state. Examples of non-toxic salts which may be prepared in this manner are the hydrochloride, phosphate, maleate, citrate, tartrate, salicylate and the like.
The following examples are intended merely to illustrate the invention and are not to be construed as limiting the 'scope thereof:
EXAMPLE 1 l0-(N-methylisanipecotoyl)-phenothiazine Phenothiazine (40 g.) is added portionwise to a suspension of N-methylisonipecotoylchloride hydrochloride (from 36 g. of N-methylisonipecotic acid hydrochloride) in 800 ml. anhydrous benzene. The reaction mixture is stirred and refluxed for 12 hours, then one liter of water is added. The aqueous layer is separated and the henzene layer extracted several times with dilute hydrochloric acid. The acid extracts combined with the original aqueous layer are basified with dilute sodium hydroxide solution, and a gummy material separates which slowly crystallizes. Several recrystallizations from benzene-petroleum ether yields 10-(N-methylisonipecotoyl)- phenothiazine as a yellow solid, M.P. 179l80 C.
The hydrochloride is prepared from the free base with ethanolic hydrogen chloride. The salt is obtained as the monohydrate, and melts at 241-242 C., after several recrystallizations from ethanol-ether.
EXAMPLE 2 10- (N-methylisonipecotoyl) -2-chlorophen0thiazz'ne crude product is filtered from the benzene solution andrecrystallized from ethanol to yield the hydrochloride salt of 10-(N-methylisonipecotoyl) 2 chlorophenothiazine, M.P. 2635-2645 C.
When the hydrochloride salt so obtained is dissolved in hot water and the resulting solution made basic with of aoetyl-choline in bronchial smooth muscle is accomsodium hydroxide solution, the free base, IO-(N-methylisonipecotoyl)-2-chlorophenothiazine is precipitated, filtered, and recrystallized from ethanol-water, M.P.
EXAMPLE 3 10- (N-methylisonipecotoyl)-2-br0mophen0thiazine scribed in Example 2. The hydrochloric acid salt of 10- (N-methylisonipecotoyl)-2-bromophen0thiazine which is formed, crystallizes from methanol as colorless crystals. When the hydrochloride salt so obtained is further treated as in Example 2, the free base is isolated as a light tan solid which is crystallized from ethanol-water.
EXAMPLE 4 10-(N-isopropylisonipecotoyl) -phenothiazine The requisite intermediate, methyl N-isopropylisonipecotate, B.P. 127-l30 C./3 mm. Hg, is prepared by the alkylation of methyl isonipecotate with potassium carbonate and isopropyl iodide in benzene.
A solution of 17.5 g. of methyl N-isopropylisonipecotate and 100 ml. of concentrated hydrochloric acid is heated on a steam bath for 16 hours, concentrated to dryness, then refluxed for two hours with 50 ml. of thionyl chloride. After the excess thionyl chloride is removed in vacuo, the residual solid is suspended in 400 ml. of anhydrous benzene, and 20 g. of phenothiazine is added portionwise. The reaction mixture is stirred and refluxed for 12 hours. One liter of water is then added, the aqueous layer separated, and the basic layer extracted several times with dilute hydrochloric acid. The acid extracts combined with the original aqueous layer are made basic with dilute sodim hydroxide solution and are then extracted with ether. The ether solution is cooled to --30 C. in an acetone Dry Ice bath and the green solid which precipitates is filtered. Extraction of the solid in a Soxhlet extractor with hexane yields 10-(N- isopropylisonipecotoyl)-phenothiazine as a yellow crystalline solid.
This crystalline amide is converted to the maleatesalt in ethyl acetate with an equimolar amount of maleic acid in ethyl acetate.
EXAMPLE 5 1 0- (N -methylisonipec0toyl -2-acetylphen0thiazine Z-acetylphenothiazine g.) is reacted with a suspension of N-methylisonipecotoylchloride hydrochloride (from 10.7 g. of N-methylisonipecotic acid hydrochloride) in 200 ml. of anhydrous benzene, in the manner described in Example 2, to yield the hydrochloric acid salt of 10 (N-methylisonipecotoyl) 2 acetylphenothiazine which is crystallized from methanol. When the hydrochloride salt M.P. 225226 C. (monohydrate) so obtained is further treated as in Example 2, the ,free base is isolated as a light tan solid which is crystallized from ethanol-water.
EXAMPLE 6 10-(N-methylisonipecotoyl) -2-trifluoromethylphenothi- .azine To a stirred solution of 2-trifiuoromethylphenothiazine (21 g.) in 200 ml. of dry benzene, there is added crude N-methylisonipecotoylchloride hydrochloride (from 18 g. of N-methylisonipecotic acid hydrochloride). The reaction miXture is stirred and refluxed for 18 hours, then 500 ml. of water is added. The aqueous layer is sepa rated and made basic with sodium hydroxide. The oil which separates is extracted with benzene, and these extracts, in turn, are concentrated in vacuo .to an oily residue. This residue is dissolved in 200 ml. of hexane treated with charcoal, filtered and cooled. The product of our invention, .10-(N-methylisonipecotoyl)e2etrifiuoromethylphenothiazine, precipitates as a tan solid (3.12 g.) M.P. 136-137.-5 .C.
The hydrochloride salt of the above compound is prepared by adding an ethanolsolution of hydrogen chloride to a solutoin of the free base in methyl ethyl ketone until the solution is faintly acidic. With the addition of dry ether, the hydrochloride precipitates as a colorless solid which melts at 235-236 C. after recrystallization from methyl ethyl ketone.
The compounds .ofpur invention can be incorporated into various oral pharmaceutical preparations such as tablets, capsules, elixirs, syrups, nasal sprays, suppositories, and the like, by mixing the same alone, or in conjunction with other active ingredients with various proportions of pharmaceutical carriers suitable for the preparation being made. Active ingredients which may be used with the compounds of our invention are: aminophylline, prednisone, ephedrine sulfate, potassium iodide, codein sulfate or phosphate, phenobarbital, perphenazine, calcium phosphate, chlorpheniramine maleate, and the like. The recommended optimum dose .range for oral administration of the claimed compounds, is from 0.5 to 2 mg. t.i.d.
The compounds of our invention can also be administered intravenously, preferably in the form of aqueous solutions of their non-toxic amine salts (such as the hydrochloride), in the presence of preservatives such as methyl paraben, propyl paraben, and the like. Other active ingredients such as those used in the oral preparations may also be used in these parenteral compositions. From 0.1 to 0.4 mg. of the phenothiazine compound per parental dose is the optimum range recommended.
The proportions of active ingredients in our compositions can be varied over a substantial range, subject to the practical limitation that a sufficient proportion of active ingredient be present to provide a suitable dosage. Obviously, the practice of administering several unit dosage forms at about the same time can be followed. The dosage of these compounds may be varied, depending on the requirements of the patient. The following formulations are intended as illustrative only, and are not to be construed as limiting the scope of the invention.
EXAMPLE 7 Table 10- N-methylisonipecotoyl) -phenothiazine hydrochloride 1.00 Lactose 48.05 Starch 20.60 Starch paste Gs Magnesium stearate 0.35
The 10-(N-methylisonipecotoyl) -phenothiazine hydrochloride is mixed with the lactose and the starch. A 10 percent starch paste is prepared and the-mixed powders granulated therewith. This wet granulation is passed through a No. 12 screen and then dried at 50 C. for twelve hours, or until the moisture content is less than 0.5 percent. The dry granules are passed through aNo. 16 screen, incorporated with the remainder of the starch and-magnesium 'stearate, and then pressed into tablets.
The 1'0-(N-methylisonipecotoyl) phenothiazine hydrochloride aminophylline, and calcium phosphate 'are' made int'o'tablets'by theprocedure described in Example'7.
.EXAMPLE 9 .Hard, gelatin capsule 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride 1.00 Prednisone ,-5.0.0 Lactose l 432.00 Magnesium :stearate M,.... 2.00
The 10 (N methylisonipecotoyl) PbmQFh aZinehydrochloride and prednisone are mixed thoroughly with the lactose. Magnesium stearateisthen added and mixed until the composition is uniform; No. 1 hard shell capsules are then filled with this uniform mixture.
EXAMPLE 10 Soft gela tirt capsule Mg. 10-(N-methylisonipecotoyl)#phenothiazine hydrochloride 1.00 Ephedrine sulfate 25.00 Lactose 10.00 Beeswax 2.00 Corn oil 5 172.00
One milligram of -(N-methylisonipecotoyl)-phenothiazine hydrochlorideiand 25 milligramsaof ephedrine sulfate are mixed with the lactose, then passed throughla No. 180 meshscreen. --This mixture is added to the 90m small opening size; The beeswax, whichhad been melted at 60 C., is poured into this milled suspensionjwith constant stirring. Stirring is continued until there is a homogeneous suspension which is filled into so'ft gelatin capsules. Seal capsules.
EXAMPLE 11 1A;
Elixir chloride Aminophylline, U.S.P. XV' Amaranth, U.S.P. XV.. Syrup, U.S.P. XV Glycerin, U.S.P. XV Orangeoil, U.S.P. XV Alcohol, U.S.P. XV Purified water, U.S.P. XV., q.s. 1:01.
EXAMPLE 12 Syrup 10- (N-methylisonipecotoyl)-pheno Quantity/l. 10 (N methylisonipecotoyl)-phenothiazine hydrochloride gm 0.2 Potassium iodide, U.S.P. XV -..gm 13.0 Compound sarsaparilla syrup, N.F. X, 1.0 1.
The 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride and potassium iodide are dissolved in a quantity .of compound sarsaparilla syrup sufficient to make the total volume measure one liter. The solution is filtered, if necessary, until clear.
EXAMPLE 13 I Suppository Gm. 10 (N methylisonipecotoyl) -phenothiazine hydrochloride 0.1 Aminophylline, U.S.P. XV 30.0 Theobroma oil, U.S.P. XV-A sufiicient quantity to make 100 suppositories.
The ingredients are mixed intimately and prepared according to the process of cold compression to form 100 rectal suppositories, each of which weighs approximately 2 gm.
oil and put through a rotor and atator type mill setiat a 6 .;=;EXAMPLE:14- 1- a Nasaldrop and/or spray r r Quantity/l. 1Q-(N-methylisonipecotoyl) -phenothiazine hydro 1 chloride g 1.0 Chlorpheniramine maleate, U.S.P. XV gm.. 3.0 Sorbitol solution, N.F. X gm 70.0 Benzalkonium chloride solution, 12.8% ml 1.95
Purified water, q.s. 1.01.
The 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride and chlorpheniramine maleate are dissolved in a suitable quantity of water. The sorbitol and benzalkonium chloride solutions are added, then sufiicient purified water to make the total volume of one liter. The solution is filtered until clear.
v ,EXAMPLE 15 Parenteral solution Gm./ liter 10 (N methylisonipecotoyl) -phenothiazine hydrochloride 1 0.10 Methyl Paraben 1.80 Propl Paraben 0.20
Water for injection, q.s. ad. 1.00 liter.
The ingredients are dissolved in the water for injection, filtered, filled into ampules or vials, and sterilized by autoclaviug.
EXAMPLE 16 Parenteral solution 10 (N-methylisonipecotoyl)-phenothiazine hydrochloride gm lliter..- 0.20 Phenobarbital gm./liter 15.00
I Propylene glycol 900 Methyl Paraben gm./liter 1.8 Propyl Paraben gm./liter 0.2
Water for injection, q.s. ad. 1.00 liter.
The 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride is dissolved in about 50 ml. of water for injection. The other ingredients are dissolved in the propylene glycol. The solutions are mixed, bringing the volume to one liter with water'for injection, filtered, filled into ampules or'vialsi and sterilized by autocl'avingj l EXAMPLE 17 Parenteral solution Gm./liter 10 (N methylisonipecotoyl)-phenothiazine hydrochloride 0.20 1 (2 hydroxyethyl) 4[3 (2 chloro 10-phenothiazinyl)-propyl] piperazine 0.10 Sodium biphosphate 20.0 Sodium phosphate 1.5 Methyl Paraben 1.8 Propyl Paraben 0.2
Water for injection, q.s. ad. 1.00 liter.
The ingredients are dissolved in the water for injection, filtered, filled into ampules or vials, and sterilized by autoclaving.
We claim:
1. Compounds having the formula:
It JWGI alkyl wherein X is a member of the group consisting of hy- 7 8 drogen, lower alkanoyl;ttifiuoromethyl, and a halogen sf'l' heuo'thiazines having the formula: atom having anatomioweight between 30 and 80, and the non-toxic acid addition salts thereof. 4 l I s .1
2. Phenothiazines having the formula:
N E=o If, lower'alkyl N my] wherein X is lower alkanoyl. v 6. 10-(N-methylisonipecotoyl)-phenothiazine. 3. Phenothlazmes having the formula: 7;; trifiuommethylr .10 (N-methylisonipecotoyl)- 's phenothiazine.
8. 2 acetyl- 10 (N-methylisonipecotoyl) pheno- 7 thiazineo 'Q 9. '2 chloro 1O (N-methylisonipecotoyl) pheno- =0 thiazine.
References Cited in the file of this patent UNITED STATES PATENTS N 2,587,660 Smith Mar. 4, 1952 2,591,679 Cusic Apr. 8, 1952 alkyl 2,690,441 Burtner Sept. 28, 1954 4. Phenothiazines'having the formula: 2,712914 Suter June 28, 1955 2,753,352 Bernstein July 3, 1956 ..2,768,202 Goldberg Oct. 23, 1956 m FOREIGN PATENTS 829,297 Germany Jan. 24, 1952 662,903 Great Britain Dec. 12, 1951 129,371 Sweden Dec. 12, 1950 40 OTHER REFERENCES Dahlborn: Acta Pharmcol et toxicoL, vol. 9, pp. 168- r I I 1 n 178 (1953).
alkyl Dahlbom: Acta Chem. Scand., vol. 5, pp. 102-114 wherein Hal. is a halogen having anatomic weighttbe- (1951), tween 30 and 80. Massie: Chem. Reviews, vol. 54, pp. 798-833 (1954).

Claims (1)

1. COMPOUNDS HAVING THE FORMULA: WHEREIN X IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN, LOWER ALKANOYL, TRIFLUOROMETHYL, AND A HALOGEN ATOM HAVING AN ATOMIC WEIGHT BETWEEN 30 AND 80, AND THE NON-TOXIC ACID ADDITION SALTS THEREOF.
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Cited By (7)

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Publication number Priority date Publication date Assignee Title
US3043839A (en) * 1959-06-15 1962-07-10 Smith Kline French Lab Substituted phenoselenazine compounds
US3130194A (en) * 1958-04-24 1964-04-21 Rhone Poulenc Sa Phenthiazine derivatives
US3212970A (en) * 1960-02-04 1965-10-19 Glasser Joseph Treatment of psoriasis
US4097596A (en) * 1976-11-02 1978-06-27 American Home Products Corporation Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine
US4183912A (en) * 1978-01-16 1980-01-15 American Home Products Corporation Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine
US20090325904A1 (en) * 2007-01-17 2009-12-31 Lg Life Sciences Ltd. Maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof

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GB662903A (en) * 1948-08-13 1951-12-12 Astra Apotekarnes Kem Fab Process of preparing phenothiazine derivatives
US2587660A (en) * 1952-03-04 Trifluoromethyl phenothiazine
US2591679A (en) * 1952-04-08 Aminoalkanoyl phenothiazine deriv
US2690441A (en) * 1953-06-11 1954-09-28 Searle & Co 3-carboline derivatives
US2712014A (en) * 1955-06-28 Derivatives of nicotinic acid amides
US2753352A (en) * 1953-01-14 1956-07-03 Olin Mathieson Derivatives of isonicotinic acid hydrazide
US2768202A (en) * 1955-04-12 1956-10-23 Hoffmann La Roche Glycinamide derivatives

Patent Citations (7)

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Publication number Priority date Publication date Assignee Title
US2587660A (en) * 1952-03-04 Trifluoromethyl phenothiazine
US2591679A (en) * 1952-04-08 Aminoalkanoyl phenothiazine deriv
US2712014A (en) * 1955-06-28 Derivatives of nicotinic acid amides
GB662903A (en) * 1948-08-13 1951-12-12 Astra Apotekarnes Kem Fab Process of preparing phenothiazine derivatives
US2753352A (en) * 1953-01-14 1956-07-03 Olin Mathieson Derivatives of isonicotinic acid hydrazide
US2690441A (en) * 1953-06-11 1954-09-28 Searle & Co 3-carboline derivatives
US2768202A (en) * 1955-04-12 1956-10-23 Hoffmann La Roche Glycinamide derivatives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3130194A (en) * 1958-04-24 1964-04-21 Rhone Poulenc Sa Phenthiazine derivatives
US3043839A (en) * 1959-06-15 1962-07-10 Smith Kline French Lab Substituted phenoselenazine compounds
US3212970A (en) * 1960-02-04 1965-10-19 Glasser Joseph Treatment of psoriasis
US4097596A (en) * 1976-11-02 1978-06-27 American Home Products Corporation Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine
US4183912A (en) * 1978-01-16 1980-01-15 American Home Products Corporation Inhalation therapy for relieving bronchial spasm using quaternary salts of promethazine
US20090325904A1 (en) * 2007-01-17 2009-12-31 Lg Life Sciences Ltd. Maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof

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