US3029189A - S-aryl-z-mno-x-qxazolibinones - Google Patents

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US3029189A
US3029189A US3029189DA US3029189A US 3029189 A US3029189 A US 3029189A US 3029189D A US3029189D A US 3029189DA US 3029189 A US3029189 A US 3029189A
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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  • This invention relates to new organic compounds and more particularly is concerned with novel S-aryl-Z-imino- 4'oxazolidinones which may be represented by the following general formula:
  • the new compounds of this invention are highly useful central nervous system stimulants. They show a mild stimulant action and excellent anorexic action over a wide range of doses and possess distinct advantages over other stimulant drugs such as the amphetamines and pipradrol.
  • Amphetamine and closely related compounds such as methamphetamine have been used as central nervous system stimulants for many years, but numerous undesirable side reactions accompany their administration. For in stance, they cause more or less pronounced rise in blood pressure and there is a tendency toward developing tolerance upon continual use.
  • the compounds of the present invention do not have these serious side-effects and thus are markedly superior to the amphetamines.
  • the compounds of this invention also, even at high doses, are free of the undesirable adrenergic and cardiovascular actions characteristic of the amphetamines. As increasing doses of the amphetamines are given, convulsions are usually observed. The compounds of this invention do not cause convulsions as the doses are increased.
  • the new compounds possess a low order of toxicity and a desirably large spread between effective and lethal doses, i.e., a
  • the compounds of this invention have a much greater margin of safety than pipradrol which shows a rather narrow range between efiective and toxic doses. Furthermore, the new compounds of this invention are more active than 5-phenyl-2-imino-4-oxo oxazolidine disclosed in United States Patent No. 2,892,- 753.
  • 5-(o-fluorophenyl)-2-imino-4-oxazolidinone of this invention is approximately 7 times as effective in causing a 50% increase in motor activity at a nontoxic dose. This type of test is well recognized as a useful method for the determination of stimulant activity and is described by P. B. Dews, British Journal of Pharmacology, vol. 8, page 46 (1953) and by G. Chen, et al. Journal of Pharmacology and Experimental Therapeutics, vol. 127, page 241 (1959).
  • the compounds of this invention are, in general, white, crystalline solids, only slightly soluble in water. They are basic substances, soluble in aqueous mineral acids at room temperature, and in some cases form isolable acid addition salts. They also dissolve in alkaline solutions.
  • the compounds of this invention may be used in the form of their free bases 01 as the non-toxic acid addition salts such as the hydrochloride, sulfate, phosphate, citrate, etc.
  • the compounds may be administered orally or parenterally and when so administered are central nervous system stimulants at individual dosages ranging from about 1 to milligrams.
  • the dosage regimen can be adjusted to provide the optimum therapeutic response. For example, several doses may be administered daily, or the dose may be proportionately reduced. as indicated by the exigencies of the therapeutic situation.
  • a particular advantage of the compounds of the present invention is their low toxicity.
  • the LD of S-(o-chlorophenyl)-2-imino-4-oxazolidinone, for example, is greater than 4000 mg./kg. on oral administration.
  • the therapeutic index of this compound is about 10.
  • the new compounds may be incorporated with pharmaceutical excipients and used, for instance, in the form of tablets, dragees, capsules, suppositories, liquids to be administered in drops, emulsions, suspensions, sirups, chocolate, candy, chewing gum, and the like.
  • Such compositions and preparations should contain at least 0.1% of the active ingredient.
  • the percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 2% and about 60% or more of the weight of the unit.
  • the amount of active ingredient in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared in such a manner that a dosage unit form contains between 1 and milligrams of the novel compounds.
  • Tablets, pills, dragees, and the like usually contain the following: (A binder such as gum tragacanth, acacia, corn starch, or gelatin. 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 sucaryl or saccharin may be added, as well as a flavoring such as peppermint, oil of Wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin.
  • 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 sucaryl or saccharin may be added, as well as a flavoring such as peppermint, oil of Wintergreen,
  • the new oxazolidinones may be prepared by several different routes which also form a part of the present invention.
  • o-halo-substituted mandelic acid esters may be reacted with guanidine:
  • This reaction is generally carried out in a solvent such as a lower alkanol. Ethanol is conveniently used and refluxing temperature is maintained to bring about reaction, particularly the ring closure, in a reasonable period or" time, usually several hours.
  • a solvent such as a lower alkanol.
  • Ethanol is conveniently used and refluxing temperature is maintained to bring about reaction, particularly the ring closure, in a reasonable period or" time, usually several hours.
  • guanidine salts such as the hydrochloride and carbonate which are commercially available can be used and these are generally neutralized with alkali to allow effective reaction of guanidine with the ester.
  • the open chain structure (111) may be considered an intermediate which loses ammonia to give the desired products. However, isolation of such intermediates, formed in situ, is not necessary and is generally tedious and undesirable.
  • guanidine there may be substituted thiourea in a lower alkanol solvent such as ethanol containing one equivalent of an alkali metal alcoholate.
  • a lower alkanol solvent such as ethanol containing one equivalent of an alkali metal alcoholate.
  • cyanamide in the form of an alkali metal salt such as sodium or potassium cyanamide may be used in place of guanidine.
  • X is halogen and R is hydrogen or lower alkyl.
  • the conditions of this reaction are somewhat critical and, in general, the temperature may range from about 20 to about 50 C. Additionally, when R is hydrogen the reaction mixture is allowed to stand for an extended period of time, for example from about 8 hours to several days. It is usually desirable to employ an excess of ammonia to insure a reasonably complete reaction. It is also sometimes desirable, but by no means 'necoussey, to carry out the reaction in an autoclave or other pressure vessel to prevent loss of ammonia at the reaction temperature. The reaction may be carried out without a solvent or in the presence of a solvent such as water, a lower alkanol and the like.
  • X is halogen
  • Y is a reactive halogen such as chlorine and bromine, or a reactive arylsulfonyloxy group such as p-toluenesulfonyloxy
  • Z is a group which is displacable by urea such as a reactive halogen including chlorine and bromine, a lower alkoxy radical and the like.
  • Suitable starting materials are 2-(o-chlorophenyl)- Z-chloroacetyl chloride, 2-(o-fiuorophenyl)-2-bromoacetyl bromide, ethyl 2-(0- romophenyl)-2-bromoacetate, 2- (o-fluorophenyl)-2-(p-toluenesulfonyloxy) acetyl chloride, and the like.
  • the reaction is generally run in a solvent.
  • An inert solvent such as benzene, toluene and the like is commonly used when it is desirable to isolate the intermediate acyl urea (IV). In some cases, particularly When simultaneous ring closure is desired, an aqueous solvent is useful.
  • the intermediate acyl ureas- (IV) are conveniently cyclized with aqueous or alcoholic bases.- The temperature range is usually 25150 C.
  • EXAMPLE 3 Ethyl o-Fluoromandelate Known substituted mandelic acids are converted to the corresponding esters by a procedure described by S. L. Shapiro, et a1. [1. Am. Chem. Soc. 81, 5646 (1959)]. in which a one molar solution of the acid in absolute ethanol is heated at the refluxing temperature for several hours With 2.5 milli-equivalents of p-toluenesulfonic acid monohydrate. The aqueous ethanol is removed by distillation and the residual oil is dissolved in sufiicient ether to give an approximately one molar solution of the ester.
  • the ether solution is Washed with sodium carbonate solution, a small amount of water and then dried over magnesium sulfate. After removal of the solvent and distillation of the residue under reduced pressure the esters are obtained in a substantially pure state. Ethyl o-fluoromandelate, when prepared by this procedure, distills at 7l-72 C. (0.2 mm.).
  • EXAMPLE 5 5 o-Bromophenyl -2-Thi0-2,4-Oxaz0lidinone
  • a stirred solution of 5.5 grams of sodium cyanide and 10.4 grams of potassium thiocyanate in 11 milliliters of Water is treated with grams of o-bromobenzaldehyde while the temperature is maintained at 0-10 C.
  • Concentrated hydrochloric acid 27 milliliters is added during 20 minutes followed by 100 milliliters of water.
  • the reaction mixture is allowed to stand at room temperature for several days and 100 milliliters of chloroform is added.
  • the chloroform layer is separated, Washed with wator and then shaken with 500 milliliters of 0.5 molar sodium bicarbonate solution.
  • the mixture is lubricated with 1% magnesium stearate and compressed into
  • the active ingredient, lactose and corn starch (for mix) are blended together.
  • the corn starch (for paste) is suspended in 800 milliliters of water and heated, with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary.
  • the wet granules are passed through a #8 hand screen and dried at 120 F.
  • the dry granules are then passed through a #16 screen.
  • the mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
  • a process of stimulating the central nervous system of mammals which comprises administering internally to a mammal a compound selected from the group consisting of 5-aryl-2-irnino-4-oxazolidinones of the formula:
  • a process of stimulating the central nervous system 7 S of mammals which comprises administering internally to OTHER REFERENCES a mammal 5 (o-chlorophenyl)-2-imin0'4-oxazolidinone.
  • Lienert et aL Chem. Abstracts, v01. 51, col. 15805 References Cited in the file of this patent 19 57 V FOREIGN PATENTS 666,778 Great Britain- Oct. 13, 1947 10

Description

United States Patent Ofifice 3,029,189 Patented Apr. 10, 1962 3,029,189 S-ARYL-Z-lli/lll IO-d-OXAZOLEDWGNES Robert A. Hardy, Jr., Ridgewood, NJ., and Charles F.
Howell, New City, and Nicanor Q. Quinories, New York, N.Y., assignors to American Cyanarnid Company, New York, N.Y., a corporation of Maine No Drawing. Filed June 10, 196i), fies. No. 35,116 6 Claims. (Cl. 167-65) This invention relates to new organic compounds and more particularly is concerned with novel S-aryl-Z-imino- 4'oxazolidinones which may be represented by the following general formula:
wherein X is halogen.
Due to the mobility of the hydrogen atoms it is quite likely that the novel compounds may also exist in several additional tautomeric forms, one of which is shown below: wherein X has the meaning hereinbefore given.
It is to be understood that the present invention includes within its scope all spch tautomeric forms. For ease of description, however, the novel compounds herein are named as S-(o-halo-phenyl)-2-imino-4-oxazolidinones which is descriptive of the tautomeric form in which they are usually named and written.
The new compounds of this invention are highly useful central nervous system stimulants. They show a mild stimulant action and excellent anorexic action over a wide range of doses and possess distinct advantages over other stimulant drugs such as the amphetamines and pipradrol.
Amphetamine and closely related compounds such as methamphetamine have been used as central nervous system stimulants for many years, but numerous undesirable side reactions accompany their administration. For in stance, they cause more or less pronounced rise in blood pressure and there is a tendency toward developing tolerance upon continual use. The compounds of the present invention do not have these serious side-effects and thus are markedly superior to the amphetamines. The compounds of this invention also, even at high doses, are free of the undesirable adrenergic and cardiovascular actions characteristic of the amphetamines. As increasing doses of the amphetamines are given, convulsions are usually observed. The compounds of this invention do not cause convulsions as the doses are increased. The new compounds possess a low order of toxicity and a desirably large spread between effective and lethal doses, i.e., a
high therapeutic index. The compounds of this invention have a much greater margin of safety than pipradrol which shows a rather narrow range between efiective and toxic doses. Furthermore, the new compounds of this invention are more active than 5-phenyl-2-imino-4-oxo oxazolidine disclosed in United States Patent No. 2,892,- 753. For example, 5-(o-fluorophenyl)-2-imino-4-oxazolidinone of this invention is approximately 7 times as effective in causing a 50% increase in motor activity at a nontoxic dose. This type of test is well recognized as a useful method for the determination of stimulant activity and is described by P. B. Dews, British Journal of Pharmacology, vol. 8, page 46 (1953) and by G. Chen, et al. Journal of Pharmacology and Experimental Therapeutics, vol. 127, page 241 (1959).
The compounds of this invention are, in general, white, crystalline solids, only slightly soluble in water. They are basic substances, soluble in aqueous mineral acids at room temperature, and in some cases form isolable acid addition salts. They also dissolve in alkaline solutions.
The compounds of this invention may be used in the form of their free bases 01 as the non-toxic acid addition salts such as the hydrochloride, sulfate, phosphate, citrate, etc. The compounds may be administered orally or parenterally and when so administered are central nervous system stimulants at individual dosages ranging from about 1 to milligrams. The dosage regimen can be adjusted to provide the optimum therapeutic response. For example, several doses may be administered daily, or the dose may be proportionately reduced. as indicated by the exigencies of the therapeutic situation.
A particular advantage of the compounds of the present invention is their low toxicity. The LD of S-(o-chlorophenyl)-2-imino-4-oxazolidinone, for example, is greater than 4000 mg./kg. on oral administration. Thus, with a dose of about 400 mg./ kg. as the eifective dose, the therapeutic index of this compound is about 10.
For therapeutic administration the new compounds may be incorporated with pharmaceutical excipients and used, for instance, in the form of tablets, dragees, capsules, suppositories, liquids to be administered in drops, emulsions, suspensions, sirups, chocolate, candy, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of the active ingredient. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 2% and about 60% or more of the weight of the unit. The amount of active ingredient in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared in such a manner that a dosage unit form contains between 1 and milligrams of the novel compounds.
Tablets, pills, dragees, and the like usually contain the following: (A binder such as gum tragacanth, acacia, corn starch, or gelatin. 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 sucaryl or saccharin may be added, as well as a flavoring such as peppermint, oil of Wintergreen, or cherry flavoring.
The new oxazolidinones may be prepared by several different routes which also form a part of the present invention. Thus, for example, o-halo-substituted mandelic acid esters may be reacted with guanidine:
wherein X is halogen.
This reaction is generally carried out in a solvent such as a lower alkanol. Ethanol is conveniently used and refluxing temperature is maintained to bring about reaction, particularly the ring closure, in a reasonable period or" time, usually several hours. Various guanidine salts such as the hydrochloride and carbonate which are commercially available can be used and these are generally neutralized with alkali to allow effective reaction of guanidine with the ester. The open chain structure (111) may be considered an intermediate which loses ammonia to give the desired products. However, isolation of such intermediates, formed in situ, is not necessary and is generally tedious and undesirable.
In place of guanidine there may be substituted thiourea in a lower alkanol solvent such as ethanol containing one equivalent of an alkali metal alcoholate. Alternatively, cyanamide in the form of an alkali metal salt such as sodium or potassium cyanamide may be used in place of guanidine.
Another general procedure for the preparation of our novel compounds is illustrated schematically as follows:
where X is halogen and R is hydrogen or lower alkyl.
The conditions of this reaction are somewhat critical and, in general, the temperature may range from about 20 to about 50 C. Additionally, when R is hydrogen the reaction mixture is allowed to stand for an extended period of time, for example from about 8 hours to several days. It is usually desirable to employ an excess of ammonia to insure a reasonably complete reaction. It is also sometimes desirable, but by no means 'necessaiy, to carry out the reaction in an autoclave or other pressure vessel to prevent loss of ammonia at the reaction temperature. The reaction may be carried out without a solvent or in the presence of a solvent such as water, a lower alkanol and the like.
Still another general procedure for the preparation of the novel compounds is illustrated schematically below:
x I -ooooNno0NHi law X Qua-= NH it.
Where X is halogen, Y is a reactive halogen such as chlorine and bromine, or a reactive arylsulfonyloxy group such as p-toluenesulfonyloxy and Z is a group which is displacable by urea such as a reactive halogen including chlorine and bromine, a lower alkoxy radical and the like. The above reaction scheme is feasible under a variety of conditions using several different a-(o-halo-phenyD- acetic acid derivatives for reaction with urea. The conditions and starting materials are chosen with the aim of obtaining the best possible conversion to the open chain intermediate (IV) followed by subsequent (or simultaneous) ring closure to give the desired new products. Suitable starting materials are 2-(o-chlorophenyl)- Z-chloroacetyl chloride, 2-(o-fiuorophenyl)-2-bromoacetyl bromide, ethyl 2-(0- romophenyl)-2-bromoacetate, 2- (o-fluorophenyl)-2-(p-toluenesulfonyloxy) acetyl chloride, and the like. The reaction is generally run in a solvent. An inert solvent such as benzene, toluene and the like is commonly used when it is desirable to isolate the intermediate acyl urea (IV). In some cases, particularly When simultaneous ring closure is desired, an aqueous solvent is useful. The intermediate acyl ureas- (IV) are conveniently cyclized with aqueous or alcoholic bases.- The temperature range is usually 25150 C.
The invention will be described in greater detail in conjunction with the following sp ecific examples.
EXAMPLE 1 Preparation of 5-(0-Chl0r0phenyl) -2-Im'in0-4- Oxazolidinone A mixture of 21.5 grams of ethyl o-chloromandelate, 9.6 grams of guanidine hydrochloride and 5.6 grams of potassium hydroxide pellets in milliliters of absolute ethanol is refluxed for about one hour and cooled. The
mixture is diluted with about 350 milliliters of water and composition) EXAMPLE 2.
Preparation of 5-(0-Flu0rophenyl)-2-lmino-4. Oxazolidinone A solution of 4.9 grants of ethyl o-fluoromandelate in 12 milliliters of absolute ethanol is heated to the refluxing temperature with 12.2 milliliters of 2.05 molar ethanolic guanidine (prepared by treating guanidine hydrochloride with an equivalent amount of sodium ethylate in ethanol and filtering the precipitated sodium chloride) for about 2 hours. The ethanol is removed by distillation and the residue is stirred for 15 minutes with 25 milliliters of 1 molar sodium hydroxide. The suspension is filtered and the filtrate is treated with 30 milliliters of 2 molar acetic acid. The precipitate is filtered and recrystallized from ethanol giving -(o-fluorophenyl)-2-imino-4-oxazolidinone, M.P. 235-237 C. (with decomposition).
EXAMPLE 3 Ethyl o-Fluoromandelate Known substituted mandelic acids are converted to the corresponding esters by a procedure described by S. L. Shapiro, et a1. [1. Am. Chem. Soc. 81, 5646 (1959)]. in which a one molar solution of the acid in absolute ethanol is heated at the refluxing temperature for several hours With 2.5 milli-equivalents of p-toluenesulfonic acid monohydrate. The aqueous ethanol is removed by distillation and the residual oil is dissolved in sufiicient ether to give an approximately one molar solution of the ester. The ether solution is Washed with sodium carbonate solution, a small amount of water and then dried over magnesium sulfate. After removal of the solvent and distillation of the residue under reduced pressure the esters are obtained in a substantially pure state. Ethyl o-fluoromandelate, when prepared by this procedure, distills at 7l-72 C. (0.2 mm.).
EXAMPLE 4 Preparation of 5-(o-Br0m0phenyl) -2-Imin0-4- Oxazolidinone A mixture of 2.7 grams of 5-(o-bromophenyl)-2-thio- 2,4-oxazolidindione in 5 milliliters of 28% ammonium hydroxide is allowed to react at room temperature for an extended period. From time to time the crude product, which is insoluble in the reaction medium, is collected. The various fractions of crude product are combined and recrystallized from aqueous dimethylformamide and purified 5-(o-bromophenyl)-2-imino-4-oxazolidinone, Ml.
262264 C. (with decomposition) is thereby obtained.
EXAMPLE 5 5 o-Bromophenyl -2-Thi0-2,4-Oxaz0lidinone A stirred solution of 5.5 grams of sodium cyanide and 10.4 grams of potassium thiocyanate in 11 milliliters of Water is treated with grams of o-bromobenzaldehyde while the temperature is maintained at 0-10 C. Concentrated hydrochloric acid (27 milliliters) is added during 20 minutes followed by 100 milliliters of water. The reaction mixture is allowed to stand at room temperature for several days and 100 milliliters of chloroform is added. The chloroform layer is separated, Washed with wator and then shaken with 500 milliliters of 0.5 molar sodium bicarbonate solution. The aqueous bicarbonate layer is separated and acidified (to Congo red) with contrated hydrochloric acid. The crude product separates as a precipitate, is collected and purified by recrystallization from carbon tetrachloride and benzene. When prepared -by this procedure S-(o-bromophenyl)-2-thio-2,4- oxazolidinedione melts at l44-146 C.
EXAMPLE 6 Per For tablet, 10,000
g. tablets,
0.0025 Active ingredient: 5-(o-fiuorophenyDQdmino- 4-oxazolidinone.
0. 0800 Lactose 800 0.0100 Corn starch (for nux) 100 0. 0075 Corn starch (for paste) 75 0.1000 1,000 0. 0010 Magnesium stearate (1%) 10 The active ingredient, lactose and cornstarch (for mix) are blended together. The corn starch (for paste) is suspended in 600 milliliters of water and heated, with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional Water is used, if necessary. The wet granules are passed through a #8 hand screen and dried at F. The dry granules are then passed through a #16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 800 milliliters of water and heated, with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a #8 hand screen and dried at 120 F. The dry granules are then passed through a #16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
We claim:
1. A compound selected from the group consisting of 5-aryl-2-imino-4-oxazolidinones of the formula:
II NH wherein X is halogen, and the non-toxic acid addition salts thereof.
2. 5-(o-chlorophenyl)-2-imino-4-oxazolidinone.
3. S-(o-fluorophenyl)-2-imino-4-oxazolidinone.
4. A process of stimulating the central nervous system of mammals which comprises administering internally to a mammal a compound selected from the group consisting of 5-aryl-2-irnino-4-oxazolidinones of the formula:
wherein X is halogen, and the non-toxic aeid'addition salts thereof.
5. A process of stimulating the central nervous system 7 S of mammals which comprises administering internally to OTHER REFERENCES a mammal 5 (o-chlorophenyl)-2-imin0'4-oxazolidinone.
6. A process of stimulating the central nervous system ASPehmdI Abstracts, 2416 of mammals which comprises administering internally to Russell 6 3L3 chfim- 306-, PP- 2279-82 a mammal 5 (o-fluorophenyl)-2-imino-4-oxazolidinone. 5 (1949).
Lienert et aL: Chem. Abstracts, v01. 51, col. 15805 References Cited in the file of this patent 19 57 V FOREIGN PATENTS 666,778 Great Britain- Oct. 13, 1947 10

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 5-ARYL-2-IMINO-4-OXAZOLIDINONES OF THE FORMULA:
4. A PROCESS OF STIMULATING THE CENTRAL NERVOUS SYSTEM OF MAMMALS WHICH COMPRISES ADMININTERING INTERNALLY TO A MAMMAL A COMPOUND SELECTED FROM TEH GROUP CONSISTING OF 5-ARYL-2-IMINO-4-OXAZOLIDINONES OF THE FORMULA:
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US3313688A (en) * 1964-03-20 1967-04-11 American Cyanamid Co Method of producing central nervous system stimulation and anorexia
US3609159A (en) * 1967-07-21 1971-09-28 Dausse Lab 5-phenyl-2-cyclopropylamino-4-oxazolinone, and process for making the same
US5708182A (en) * 1995-05-30 1998-01-13 Skw Trostberg Aktiengesellschaft Method for preparation of 2-imino 4-oxo-5-phenyloxazolidine
WO1998022450A1 (en) * 1996-11-20 1998-05-28 Abbott Laboratories Process for the preparation of 2-imino-5-phenyl-4-oxazolidinone and its intermediates
US6290985B2 (en) 1999-04-06 2001-09-18 Wm. Wrigley, Jr. Company Over-coated chewing gum formulations including tableted center
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US20020159956A1 (en) * 1999-04-06 2002-10-31 Ream Ronald L. Over-coated chewing gum formulations
US20020164398A1 (en) * 1998-12-15 2002-11-07 Johnson Sonya S. Method and product for accelerating absorption of medicaments through oral mucosa
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US6586023B1 (en) 1998-12-15 2003-07-01 Wm. Wrigley Jr. Company Process for controlling release of active agents from a chewing gum coating and product thereof
US6627234B1 (en) 1998-12-15 2003-09-30 Wm. Wrigley Jr. Company Method of producing active agent coated chewing gum products
US6645535B2 (en) 1999-09-02 2003-11-11 Wm. Wrigley Jr. Company Method of making coated chewing gum products containing various antacids
US6663849B1 (en) 2000-09-01 2003-12-16 Wm. Wrigley Jr. Company Antacid chewing gum products coated with high viscosity materials
US6773716B2 (en) 1999-04-06 2004-08-10 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US20040185144A1 (en) * 2000-06-09 2004-09-23 Witkewitz David L. Method for making coated chewing gum products with a coating including an aldehyde flavor and a dipeptide sweetener
US6949264B1 (en) 1996-11-27 2005-09-27 Wm. Wrigley Jr. Company Nutraceuticals or nutritional supplements and method of making
US20060141008A1 (en) * 1999-04-06 2006-06-29 Ream Ronald L Over-coated product including consumable center and medicament
US20080317902A1 (en) * 1999-09-20 2008-12-25 Jack Barreca Chewing Gum
US20100104620A1 (en) * 1999-04-06 2010-04-29 Wm. Wrigley Jr. Company Over-coated product including tableted center and medicament
US9253991B2 (en) 1999-09-20 2016-02-09 Jack Barreca Chewing gum with B vitamins
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GB666778A (en) * 1947-10-13 1952-02-20 Schering Corp Pyridyldialkylaminoalkyl acetonitriles and their piperidino and morpholino-analogues

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US3313688A (en) * 1964-03-20 1967-04-11 American Cyanamid Co Method of producing central nervous system stimulation and anorexia
US3609159A (en) * 1967-07-21 1971-09-28 Dausse Lab 5-phenyl-2-cyclopropylamino-4-oxazolinone, and process for making the same
US5708182A (en) * 1995-05-30 1998-01-13 Skw Trostberg Aktiengesellschaft Method for preparation of 2-imino 4-oxo-5-phenyloxazolidine
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US6949264B1 (en) 1996-11-27 2005-09-27 Wm. Wrigley Jr. Company Nutraceuticals or nutritional supplements and method of making
US20020164398A1 (en) * 1998-12-15 2002-11-07 Johnson Sonya S. Method and product for accelerating absorption of medicaments through oral mucosa
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US6586023B1 (en) 1998-12-15 2003-07-01 Wm. Wrigley Jr. Company Process for controlling release of active agents from a chewing gum coating and product thereof
US6465003B2 (en) 1999-04-06 2002-10-15 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6322806B1 (en) 1999-04-06 2001-11-27 Wm. Wrigley Jr. Company Over-coated chewing gum formulations including tableted center
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US20020159956A1 (en) * 1999-04-06 2002-10-31 Ream Ronald L. Over-coated chewing gum formulations
US20060141008A1 (en) * 1999-04-06 2006-06-29 Ream Ronald L Over-coated product including consumable center and medicament
US6355265B1 (en) 1999-04-06 2002-03-12 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6531114B1 (en) 1999-04-06 2003-03-11 Wm. Wrigley Jr. Company Sildenafil citrate chewing gum formulations and methods of using the same
US6773716B2 (en) 1999-04-06 2004-08-10 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6541048B2 (en) 1999-09-02 2003-04-01 Wm. Wrigley Jr. Company Coated chewing gum products containing an acid blocker and process of preparing
US6645535B2 (en) 1999-09-02 2003-11-11 Wm. Wrigley Jr. Company Method of making coated chewing gum products containing various antacids
US9253991B2 (en) 1999-09-20 2016-02-09 Jack Barreca Chewing gum with B vitamins
US8679522B2 (en) 1999-09-20 2014-03-25 Jack Barreca Chewing gum
US20080317902A1 (en) * 1999-09-20 2008-12-25 Jack Barreca Chewing Gum
US9387168B2 (en) 1999-09-20 2016-07-12 Jack Barreca Chewing gum with tomatidine
US20040185144A1 (en) * 2000-06-09 2004-09-23 Witkewitz David L. Method for making coated chewing gum products with a coating including an aldehyde flavor and a dipeptide sweetener
US7115288B2 (en) 2000-06-09 2006-10-03 Wm. Wrigley Jr. Company Method for making coated chewing gum products with a coating including an aldehyde flavor and a dipeptide sweetener
US6572900B1 (en) 2000-06-09 2003-06-03 Wm. Wrigley, Jr. Company Method for making coated chewing gum products including a high-intensity sweetener
US6444241B1 (en) 2000-08-30 2002-09-03 Wm. Wrigley Jr. Company Caffeine coated chewing gum product and process of making
US6663849B1 (en) 2000-09-01 2003-12-16 Wm. Wrigley Jr. Company Antacid chewing gum products coated with high viscosity materials
US6569472B1 (en) 2000-09-01 2003-05-27 Wm. Wrigley Jr. Company Coated chewing gum products containing antacid and method of making
US6579545B2 (en) 2000-12-22 2003-06-17 Wm. Wrigley Jr. Company Coated chewing gum products containing an antigas agent

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