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US3005818A - 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds - Google Patents

1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds Download PDF

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US3005818A
US3005818A US803384A US80338459A US3005818A US 3005818 A US3005818 A US 3005818A US 803384 A US803384 A US 803384A US 80338459 A US80338459 A US 80338459A US 3005818 A US3005818 A US 3005818A
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phenyl
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pyrazolone
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Siemer Harm
Doppstadt Adolph
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Ravensberg GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • the present invention relates to valuable analgesic agents and more particularly to substituted l-phenyl-2,3- dimethyl-4-morpholino methyl pyrazolone-( compounds and to a process of making same. 1
  • Another object of the present invention is to provide a new and simple process of producing such valuable analgesic 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds. 7
  • a further object of the present invention is to provide valuable analgesic preparations such as tablets or injectable solutions containing, as active analgesic ingredient, said l-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds.
  • the new analgesic substituted 1-phenyl-2,3-dimethyl- 4-morpholine methyl pyrazolone-(5) compounds according to the present invention are compounds of the following formula In said formula:
  • R indicates a lower alkyl radical with 1 to 5 carbon atoms arranged in a straight or branched chain
  • R indicates hydrogen or a lower alkyl radical with 1 to 5 carbon atoms in a straight or branched chain.
  • Such new and valuable analgesic 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone compounds are produced in a surprisingly simple manner and in a good yield by adding to an alcoholic solution of the corresponding.
  • substituted morpholine compounds .for instance, to 2- phenyl-3-methyl morpholine or to 2-phenyl-3,6 -dimethyl.
  • optically active substituted morpholine compounds When using optically active substituted morpholine compounds as the one reaction component, the corresponding optically active 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone compounds are obtained which cause rotation of the plane of polarized light in the same direction.
  • the new compounds have a high analgesic activity.
  • the following table shows the results obtained on pharmacologically testing the new compound in comparison with well-known analgesic agents.
  • the dose given is the mean therapeutic dose (AD II) determined according to the method of Wolff-Hardy by focusing rays of a strong-light source on the blackened forehead of a test individual.
  • the compounds which contain the 2-phenyl-3,6-di- (lower) alkyl morpholino methyl group have the same analgesic and antiphlogistic elfect as the substances which contain the 2-phenyl-3-(lower) alkyl morpholin'o methyl group, but have the further advantage that their toxicity is only about half that of said 3-alkyl compounds.
  • 3,6-di- (lower) alkyl morpholino methyl group have the same analgesic and antiphlogistic elfect as the substances which contain the 2-phenyl-3-(lower) alkyl morpholin'o methyl group, but have the further advantage that their toxicity is only about half that of said 3-alkyl compounds.
  • dialkylated compounds a better hypnotic eflec-t is obtained 7 than with the 3-alkylated compounds.
  • the substituted 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds according to the present invention thus, possess a surprisingly high analgesic activity which coulld not be expected from their composition. Therefore, they represent new and valuable phannaceutical compounds, especially in the form of their pharmaceutically acceptable acid addition salts. Solutions of the salts, especially solutions of salts with organic acids, are suitable for injection because they are well tolerated by the human body.
  • the analgesic compounds accord-ing to the present in- Vention can be used in the form of their readily soluble salts with gentisic acid or ascorbic acid for preparing highly concentrated injectable solutions thereof; Su'ch solutions are prepared, for instance, by dissolving the indistilled water to form a solution of the desired concentration.
  • Example I 35.4 g. of 2-phenyl-3-methyl morpholine are dissolved in 50 cc. of methanol. 20 cc. of an aqueous 40% formaldehyde solution are added thereto while cooling. A solution of 37.6 g. of 1-phenyl-2,3-dimethyl pyrazolone- (5) in a mixture of 35 cc. of water and 20 cc. of concentrated hydrochloric acid is added at once to said reaction mixture. The pH-value of the resulting mixture is adjusted to a pH between about 2.0 and about 3.0 and the acid reaction mixture is then stirred on the Water bath at a temperature of 25-30 C. for two hours. The precipitated hydrochloride is recrystallized from a mixture of methanol and acetone (1:1).
  • the melting point of the recrystallized hydrocholride of 1phenyl-2,3-dimethyl-4-(2'-phenyl-3-methyl morpholino methyl) pyrazolone-() is 171-172 C. with decomposition). Yield: 81.6%.
  • the corresponding base is obtained by rendering alkaline the solution of said hydrochloride by the addition of sodium hydroxide solution, extraction by means of chloroform and evaporation of the extracting solvent. It has a melting point of 149-150" C.
  • Example 2 38.2 g. of 2-phenyl-3-ethyl morpholine are reacted with 37.6 g. of l-phenyl-2,3-dimethyl pyrazolone-(5) by following the procedure described hereinabove in Example 1.
  • the yield of l-phenyl-2,3-dimethyl-4-(2'-phenyl-3'- ethyl morpholino methyl) pyrazolone-(5) hydrochloride is 82.2%.
  • the melting point of the hydrochloride is 174-175 C. (with decomposition) after recrystallization from a mixture of acetone and methanol (1:1).
  • Example 3 37.7 g. of the free base of l-phenyl-Z,3-dimethyl-4-(2- phenyl-3-methyl morpholino methyl) pyrazolone(5) obtained according to Example 1 are dissolved in 50 cc. of methanol. 15.4 g. of gentisic acid are added thereto and the mixture is heated under reflux for one hour. 50 cc. of acetone are added to the reaction mixture, whereupon the addition salt with gentisic acid crystallizes. It melts at l69-170 C. (with decomposition).
  • Example 4 37.7 g. of 1-phenyl-2,3-dimethyl-4-(2'-phenyl-3-methyl morpholino methyl) pyrazolone-(5) are reacted by following the procedure described in Example 3, with 19.5 g. of salicylamide-O-acetic acid. After cooling, the reaction solution is stirred with ether until it remains turbid and crystals precipitate on standing. The crystalline salt of the pyrazolone compound with salicylamide- O-acetic acid melts at a temperature between 112-113 C. (with decomposition). This salt is suitable for making tablets.
  • Example 6 38.2 g. of 2-phenyl-3,6-dimethyl morpholino are dissolved in 50 cc. of methanol. 20 cc. of an aqueous 40% formaldehyde solution are added thereto while cooling. 37.6 g. of 1-phenyl-2,3-dimethyl pyrazolone-(5) dissolved in a mixture of 35 cc. of water and 20 cc. of concentrated hydrochloric acid are added at once to said reaction mixture. The pH-value of the reaction mixture is then adjusted to a pH between about 2 and 3. Stirring of the reaction mixture on a water bath is continued at 25-30 C. for two hours. The precipitated hydrochloride is recrystallized from a mixture of methanol and acetone.
  • the corresponding base which is obtained by rendering alkaline the aqueous solution of the hydrochloride, extracting the-alkaline solution with an organic solvent, such as chloroform, and evaporating the solvent from the extract, has a melting point of 132-133 C.
  • 2-phenyl-3-methyl morpholine or the 2-phenyl-3,6-dimethyl morpholine compounds used in the preceding examples there may be employed equimolecular amounts of other substituted 2-pheny1 compounds substituted in 3-position or in 3- and 6-positions by lower alkyl radicals having a straight or branched chain, such as 2-phenyl-3-n-propyl morpholine, 2-phenyl-3,6-di-npropyl morpholine, 2-phenyl-3-isopropyl morpholine, 2- phenyl-3,6 -diisopropyl morpholine, and the like, while otherwise the procedure is the same as given in said examples.
  • hydrochloride and the gentisic acid salt described in the preceding examples there may be prepared other acid addition salts such as salts with inorganic acids, for instance, with sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, or with other organic acids, such as with tartaric acid, citric acid, malic acid, acetic acid, benzoic acid, salicylic acid, nicotinic acid, and others.
  • inorganic acids for instance, with sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, or with other organic acids, such as with tartaric acid, citric acid, malic acid, acetic acid, benzoic acid, salicylic acid, nicotinic acid, and others.
  • the new 1-pheny1 2,3 dimethyl 4-(2' phenyl-3-lower alkyl morpholino methyl) pyrazolone-(5) compounds or 1-phenyl-2,3-dimethyl 4 (2'-phenyl-3',6'-di(lower) alkyl morpholino methyl) pyrazolone-(5) compounds or their acid addition salts and preferably their salts with gentisic acid or ascorbic acid are incorporated into pharmaceutical excipients and are used, for instance, in the form of tablets, dragees, capsules, pills, suppositories, sirups, and the like preparations. Such tablets and other preparations contain at least 15% of the active ingredient.
  • preparations may be varied and is preferably between about 15% andiabout 60% of the weight of the tablet or preparation. It is, of course, also possible to use greater amounts of the active ingredient although with such greater amounts administration of a suitable dosage becomes more difficult.
  • Preferred preparations according to the present invention are prepared in such a manner that a dosage unit form of tablet and the like preparation contains between about 50 mg. and about 250 mg.
  • diluting agents such as sugar, dextrose, lactose, starch, methyl cellulose, yeast. elitrat t,v
  • agar tragacanth, and as lubricants stearic acid, magnesium stearate, and others.
  • the effective daily dose for an adult person is between about 100 mg. and about 800 mg.
  • the preferred daily dose is about 4000 mg.
  • the dose is preferably given subdivided in 4 doses in intervals of 2 hours to 3 hours. Of course, larger or smaller doses may also be given if they are required.
  • novel compounds are characterized by a very low toxicity as was proven by the pharmacological tests carried outwith male mice in accordance with the method of Litchfield and Wilcoxon.
  • the testing substances were dissolved in a physiological solution of sodium chloride and the mice injected therewith subcutaneously. Each dose was dispensed in 0.5 cc. of
  • the lethal dose LD was determined in a testing period of 24 hours.
  • R and R indicate lower alkyl radicals with l to 5 carbon atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Unitd 3,005,818 Patented Get. 24, 1961 The present invention relates to valuable analgesic agents and more particularly to substituted l-phenyl-2,3- dimethyl-4-morpholino methyl pyrazolone-( compounds and to a process of making same. 1
The present application is a continuation-in-part of co-pending application Serial No. 717,332, now Patent No. 2,943,022, filed February 25, 1958, and being entitled Substituted 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds and process of making the same.
It is one object of the present invention to provide new and valuable analgesic agents which are far superior in their analgesic activity than any of the commonly used analgesic'agents such as l-phenyl-2,3-dimethyl-4-dimethylamino pyrazolone-(5), salicylic acid amide, aceto phenetidine, and others.
Another object of the present invention is to provide a new and simple process of producing such valuable analgesic 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds. 7
A further object of the present invention is to provide valuable analgesic preparations such as tablets or injectable solutions containing, as active analgesic ingredient, said l-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds.
Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.
The new analgesic substituted 1-phenyl-2,3-dimethyl- 4-morpholine methyl pyrazolone-(5) compounds according to the present invention are compounds of the following formula In said formula:
R indicates a lower alkyl radical with 1 to 5 carbon atoms arranged in a straight or branched chain, and
R indicates hydrogen or a lower alkyl radical with 1 to 5 carbon atoms in a straight or branched chain.
Such new and valuable analgesic 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone compounds are produced in a surprisingly simple manner and in a good yield by adding to an alcoholic solution of the corresponding.
substituted morpholine compounds, .for instance, to 2- phenyl-3-methyl morpholine or to 2-phenyl-3,6 -dimethyl.
morpholine, formaldehyde and an aqueous hydrochloric acid solution of l-phenyl-2,3-dimethyl pyrazolone-(5) l 2 methyl) pyrazolone (5) or the hydrochloride 'of l phenyl- 2,3 dimethyl 4 -(2' phenyl 3',6' dimethyl -morpholino methyl) pyrazolone-(5) precipitate from the reaction solution and can be recrystallized from a mixture of alcohol and acetone, if required. Addition of alkali hydroxide solution to the aqueous solution of the hydrochlorides yields the corresponding bases which are obtained in solid form.
When using optically active substituted morpholine compounds as the one reaction component, the corresponding optically active 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone compounds are obtained which cause rotation of the plane of polarized light in the same direction.
The new compounds have a high analgesic activity. The following table shows the results obtained on pharmacologically testing the new compound in comparison with well-known analgesic agents. The dose given is the mean therapeutic dose (AD II) determined according to the method of Wolff-Hardy by focusing rays of a strong-light source on the blackened forehead of a test individual.
TABLE Compound tested: A lI It is evident that the new compounds have an analgestic activity which is twice as strong as that of the known pyrazolone derivative and about ten times as strong as that of salicyclic acid amide or aceto phen'etidine. When taking into consideration that the analge'sic activity-of 1'-phenyl-2,3-dimethyl pyrazolone amounts to only one third of the activity of the tested compound l-phenyl-2,3-dimethyl-4-dimethylamino pyrazolone, it follows that the analgesic activity of the first mentioned l-phenyl-2,3-dimethyl pyrazolone is increased by about six times by introducing into its molecule the 2-phen'yl- 3 methyl morpholino methyl group or the 2-phenyl-3,6- dimethyl m'orhpolino methyl group. I
The compounds which contain the 2-phenyl-3,6-di- (lower) alkyl morpholino methyl group have the same analgesic and antiphlogistic elfect as the substances which contain the 2-phenyl-3-(lower) alkyl morpholin'o methyl group, but have the further advantage that their toxicity is only about half that of said 3-alkyl compounds. In addition thereto it has been found that byusing the 3,6-
dialkylated compounds a better hypnotic eflec-t is obtained 7 than with the 3-alkylated compounds.
The substituted 1-phenyl-2,3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds according to the present invention, thus, possess a surprisingly high analgesic activity which coulld not be expected from their composition. Therefore, they represent new and valuable phannaceutical compounds, especially in the form of their pharmaceutically acceptable acid addition salts. Solutions of the salts, especially solutions of salts with organic acids, are suitable for injection because they are well tolerated by the human body.
The analgesic compounds accord-ing to the present in- Vention can be used in the form of their readily soluble salts with gentisic acid or ascorbic acid for preparing highly concentrated injectable solutions thereof; Su'ch solutions are prepared, for instance, by dissolving the indistilled water to form a solution of the desired concentration.
The following examples serve to illustrate the present invention without, however, limiting the same thereto.
Example I 35.4 g. of 2-phenyl-3-methyl morpholine are dissolved in 50 cc. of methanol. 20 cc. of an aqueous 40% formaldehyde solution are added thereto while cooling. A solution of 37.6 g. of 1-phenyl-2,3-dimethyl pyrazolone- (5) in a mixture of 35 cc. of water and 20 cc. of concentrated hydrochloric acid is added at once to said reaction mixture. The pH-value of the resulting mixture is adjusted to a pH between about 2.0 and about 3.0 and the acid reaction mixture is then stirred on the Water bath at a temperature of 25-30 C. for two hours. The precipitated hydrochloride is recrystallized from a mixture of methanol and acetone (1:1).
The melting point of the recrystallized hydrocholride of 1phenyl-2,3-dimethyl-4-(2'-phenyl-3-methyl morpholino methyl) pyrazolone-() is 171-172 C. with decomposition). Yield: 81.6%. The corresponding base is obtained by rendering alkaline the solution of said hydrochloride by the addition of sodium hydroxide solution, extraction by means of chloroform and evaporation of the extracting solvent. It has a melting point of 149-150" C.
Example 2 38.2 g. of 2-phenyl-3-ethyl morpholine are reacted with 37.6 g. of l-phenyl-2,3-dimethyl pyrazolone-(5) by following the procedure described hereinabove in Example 1. The yield of l-phenyl-2,3-dimethyl-4-(2'-phenyl-3'- ethyl morpholino methyl) pyrazolone-(5) hydrochloride is 82.2%. The melting point of the hydrochloride is 174-175 C. (with decomposition) after recrystallization from a mixture of acetone and methanol (1:1).
Example 3 37.7 g. of the free base of l-phenyl-Z,3-dimethyl-4-(2- phenyl-3-methyl morpholino methyl) pyrazolone(5) obtained according to Example 1 are dissolved in 50 cc. of methanol. 15.4 g. of gentisic acid are added thereto and the mixture is heated under reflux for one hour. 50 cc. of acetone are added to the reaction mixture, whereupon the addition salt with gentisic acid crystallizes. It melts at l69-170 C. (with decomposition).
Example 4 Example 5 37.7 g. of 1-phenyl-2,3-dimethyl-4-(2'-phenyl-3-methyl morpholino methyl) pyrazolone-(5) are reacted by following the procedure described in Example 3, with 19.5 g. of salicylamide-O-acetic acid. After cooling, the reaction solution is stirred with ether until it remains turbid and crystals precipitate on standing. The crystalline salt of the pyrazolone compound with salicylamide- O-acetic acid melts at a temperature between 112-113 C. (with decomposition). This salt is suitable for making tablets.
Example 6 38.2 g. of 2-phenyl-3,6-dimethyl morpholino are dissolved in 50 cc. of methanol. 20 cc. of an aqueous 40% formaldehyde solution are added thereto while cooling. 37.6 g. of 1-phenyl-2,3-dimethyl pyrazolone-(5) dissolved in a mixture of 35 cc. of water and 20 cc. of concentrated hydrochloric acid are added at once to said reaction mixture. The pH-value of the reaction mixture is then adjusted to a pH between about 2 and 3. Stirring of the reaction mixture on a water bath is continued at 25-30 C. for two hours. The precipitated hydrochloride is recrystallized from a mixture of methanol and acetone.
Melting point of 1-phenyl-2,3-dimethyl-4-(2'-phenyl-3', 6-dimethyl morpholino methyl) pyrazolone-(5) hydrochloride: -137 C. (with decomposition). Yield 83.5%.
The corresponding base which is obtained by rendering alkaline the aqueous solution of the hydrochloride, extracting the-alkaline solution with an organic solvent, such as chloroform, and evaporating the solvent from the extract, has a melting point of 132-133 C.
In place of the 2-phenyl-3-methyl morpholine or the 2-phenyl-3,6-dimethyl morpholine compounds used in the preceding examples, there may be employed equimolecular amounts of other substituted 2-pheny1 compounds substituted in 3-position or in 3- and 6-positions by lower alkyl radicals having a straight or branched chain, such as 2-phenyl-3-n-propyl morpholine, 2-phenyl-3,6-di-npropyl morpholine, 2-phenyl-3-isopropyl morpholine, 2- phenyl-3,6 -diisopropyl morpholine, and the like, while otherwise the procedure is the same as given in said examples.
In place of the hydrochloride and the gentisic acid salt described in the preceding examples, there may be prepared other acid addition salts such as salts with inorganic acids, for instance, with sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, or with other organic acids, such as with tartaric acid, citric acid, malic acid, acetic acid, benzoic acid, salicylic acid, nicotinic acid, and others.
For therapeutic administration the new 1-pheny1 2,3 dimethyl 4-(2' phenyl-3-lower alkyl morpholino methyl) pyrazolone-(5) compounds or 1-phenyl-2,3-dimethyl 4 (2'-phenyl-3',6'-di(lower) alkyl morpholino methyl) pyrazolone-(5) compounds or their acid addition salts and preferably their salts with gentisic acid or ascorbic acid are incorporated into pharmaceutical excipients and are used, for instance, in the form of tablets, dragees, capsules, pills, suppositories, sirups, and the like preparations. Such tablets and other preparations contain at least 15% of the active ingredient. Its percentage in the preparation may be varied and is preferably between about 15% andiabout 60% of the weight of the tablet or preparation. It is, of course, also possible to use greater amounts of the active ingredient although with such greater amounts administration of a suitable dosage becomes more difficult. Preferred preparations according to the present invention are prepared in such a manner that a dosage unit form of tablet and the like preparation contains between about 50 mg. and about 250 mg. of an acid addition salt of 1-phenyl-2,3-dimethyl-4-(2'-phenyl-3- loweralkyl morpholino methyl) pyrazolone-(5) or 1- phenyl 2,3 dimethyl-4-(2'-phenyl-3,6'-di-(lower) alkyl morpholino methyl) pyrazolone-(5 When preparing tablets, pills, dragees, and the like shaped solid preparations for oral administration, the
commonly used diluting agents, binders, lubricants, and other tableting adjuvants are employed such as sugar, dextrose, lactose, starch, methyl cellulose, yeast. elitrat t,v
agar, tragacanth, and as lubricants stearic acid, magnesium stearate, and others.
Injectable solutions of the new analgesic compounds according to the present invention are prepared as described hereinabove in Example 3.
The effective daily dose for an adult person is between about 100 mg. and about 800 mg. The preferred daily dose is about 4000 mg. The dose is preferably given subdivided in 4 doses in intervals of 2 hours to 3 hours. Of course, larger or smaller doses may also be given if they are required.
With respect to the Wolif-Hardy method for determining the therapeutic dose as mentioned in column 2, it may be mentioned that the prolongation of the reaction time in seconds subsequent to administration (30 to 45 minutes) was taken as the criterion concerning the analgesic activity of the substances tested. In this connection a prolongation of the reaction time by 8 seconds represents the analgesic stage II. In carrying out the tests, the preparations were injected in mice weighing from 20 g. to 25 g.
Clinical tests with the new compounds have confirmed the above given pharmacological tests and have shown that they have not only a surprisingly high analgesic effect but also a remarkable antiphlogistic-antiedematous effect. They produce complete freedom from pain within a few days of administration. They eliminate inflammation within a short period of time. They permit considerable reduction of the amounts of opiates to be administered. No toxic effects nor any disagreeable sideefiects have been observed on administration of these compounds. They are well tolerated, especially by patients with a high sensitivity of the gastro-intestinal tract to drugs. No drug addiction has been observed.
The novel compounds are characterized by a very low toxicity as was proven by the pharmacological tests carried outwith male mice in accordance with the method of Litchfield and Wilcoxon. In carrying out said tests, the testing substances were dissolved in a physiological solution of sodium chloride and the mice injected therewith subcutaneously. Each dose was dispensed in 0.5 cc. of
the solvent per 20 g. of mouse weight. The lethal dose LD was determined in a testing period of 24 hours.
TABLE so Compound tested: nag/kg. 1 phenyl-2,3-dimethy1--4-(2'-phenyl-3'-methyl morpholino methyl) pyrazolone-(5).HC1.. 95.4 1 phenyl 2,3-dimethyl-4-(2-phenyl-3,6'-dimethyl morpholino methyl) pyrazolone- (5).HC1
R and R indicate lower alkyl radicals with l to 5 carbon atoms,
and its non-toxic pharmaceutically acceptable acid add tion salts.
References Cited in the file of this patent UNITED STATES PATENTS 2,943,022 Siemer et al June 28, 1960 Patent No. a oos sla October 2 19a Harm Sieme-r et al0 n the above numbered patthat error appears 1 nt should read as It is hereby certified that the said Letters Pate ent requiring correction and corrected below.
Column 2,, line 4L8 for "mcrhpolihc" read w mclrpholic'o "-3 llne 61 for "coulld". read could -;3 column 53 lineS for "pyrczolone" read pyrazolone line :29 for "hydrocholride" read hydrochloride Signed and sealed this 3rd day of April 1962 (SEAL) Attest:
ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents

Claims (1)

  1. 3. THE 1-PHENYL-2,3-DIMETHYL-4-MORPHOLINO METHYL PYRAZOLONE COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE 1-PHENYL-2,3-DIMETHYL-4-MORPHOLINO METHYL PYRAZOLONE COMPOUND OF THE FORMULA
US803384A 1958-04-03 1959-04-01 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds Expired - Lifetime US3005818A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
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US5512570A (en) * 1994-03-04 1996-04-30 Merck & Co., Inc. Treatment of emesis with morpholine tachykinin receptor antagonists
US5637699A (en) * 1992-06-29 1997-06-10 Merck & Co., Inc. Process for preparing morpholine tachykinin receptor antagonists
US5719147A (en) * 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US6048859A (en) * 1992-06-29 2000-04-11 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists

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US2943022A (en) * 1958-02-25 1960-06-28 Ravensberg G M B H Substituted 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds and process of making same

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DE955146C (en) * 1953-12-25 1956-12-27 Knoll Ag Process for the production of basic substituted pyrazolone capsules

Patent Citations (1)

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US2943022A (en) * 1958-02-25 1960-06-28 Ravensberg G M B H Substituted 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds and process of making same

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5637699A (en) * 1992-06-29 1997-06-10 Merck & Co., Inc. Process for preparing morpholine tachykinin receptor antagonists
US5719147A (en) * 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US5872116A (en) * 1992-06-29 1999-02-16 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US5922706A (en) * 1992-06-29 1999-07-13 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US6048859A (en) * 1992-06-29 2000-04-11 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US6235735B1 (en) 1992-06-29 2001-05-22 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US6638930B2 (en) 1992-06-29 2003-10-28 Merck & Co. Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US5512570A (en) * 1994-03-04 1996-04-30 Merck & Co., Inc. Treatment of emesis with morpholine tachykinin receptor antagonists
US5691336A (en) * 1994-03-04 1997-11-25 Merck & Co., Inc. Morpholine compounds are prodrugs useful as tachykinin receptor antagonists
US5716942A (en) * 1994-03-04 1998-02-10 Merck & Co., Inc. Treatment of migraine with morpholine tachykinin receptor antagonists
US5780467A (en) * 1994-03-04 1998-07-14 Merck & Co., Inc. Morpholine compounds are prodrugs useful as tachykinin receptor antagonists

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