US2830995A - X-tert - Google Patents

X-tert Download PDF

Info

Publication number
US2830995A
US2830995A US2830995DA US2830995A US 2830995 A US2830995 A US 2830995A US 2830995D A US2830995D A US 2830995DA US 2830995 A US2830995 A US 2830995A
Authority
US
United States
Prior art keywords
dioxo
diphenyl
pyrazolidine
tert
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
Publication date
Application granted granted Critical
Publication of US2830995A publication Critical patent/US2830995A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms

Definitions

  • dioxo-pyrazolidines which are. substituted by a primary or secondary alkyl group is known.
  • 4-n-butyl-l,Z-diphenyl-Ia,S-dioxo-pyrazolidine,v more particularly, has been able to achieve great significance and to. find a Wide-therapeutic employment.
  • The-resultant l,2-diphenyl-3,5-dioxo-pyrazolidine derivatives are distinguished by an essentially lower toxicity and by an enhanced antiphlogistic action while maintaining a comparable anti-pyretic and analgetic action, so that the therapeutic breadth of the new compounds of the present invention is significantly greater and more favorable that that of the known compounds of similar constitution.
  • This effect is particularly realized, by the combination of the sodium salts of thenew pyrazolidine derivatives with 1-phenyl-2,3-dimethyl-4-dimethylamino pyrazolone, for which the new compounds of the present invention are excellent solvents.
  • the preferred 1,2-diphenyl-3,5-dioxo-4-tert. alkylpyrazolidines correspond to the formula laHs wherein each of R R and R stands for a lower (saturated) alkyl group or R and R together with the central tertiary carbon atom form a cyclohexyl group and R is a lower alkyl group, and wherein the sum of the carbon atoms in R +R +R is at least 3 and at most 8.
  • each of R R and R may be a methyl group; or each of R R and R may be an ethyl group; or R and R may each be a methyl group while R is a propyl group; or one of R R and R may be methyl while the other two are ethyl; or R may be methyl, R ethyl and R propyl; or R and R may each be a propyl group while R is a methyl or ethyl group; or R and R together with the central tertiary C atom form a cylohexyl group and R is methyl, ethyl or propyl; etc.
  • the phenyl groups in the 1- and 2-p0sition may be substituted but such substituents do not appear to add to the pharmacological activity of the compounds.
  • 1,2-diphenyl-3,5-dioxo-4-tertl alkylpyrazolidines and l,2-diphenyl-3,S-dioxo-4-(1'-alkylcyclohexyl)-pyrazolidines form Well-defined salts with a wide variety of organic and inorganic bases, which bases and salts are therapeutically valuable because of their analgetic, antipyretic, antiphlogistic and sedative action;
  • Preferred among the aforesaid salts are the sodium and magnesium salts and those of ethylenediamine, triethanolamine and trimethylamine.
  • the new 1,2-diphenyl-3,5-dioxo-4-tert. alkylor -4-(-1' alkylcyclohexyl)-pyrazolidines are preferably prepared
  • the synthesis in this way of the aforesaid diphenyldioxo-pyrazoiidines which contain a tertiary substituent in the 4-position is new in pyrazolidine chemistry.
  • Such synthesis has to be regarded as unobvious and unexpected since there was a real reason to expect that the Grignard compounds would react primarily with the pyrazolidinenitrogen and the two oxo groups, and that'- the balance of the concurrent-reactions would therefore be in favor of those reaction products which are not here desired.
  • alkyl-pyrazolidines are obtained by the action of alkylmagnesium halides on the" diphenyl-dioxo-alkylideneor -cyclohexylidene-pyrazolidines, and by the splitting (hydrolysis) of the thus-obtained intermediates.
  • Example 1 To a conventionally prepared solution of 18.2 parts of methylmagnesium iodide in parts by volume of ether, there are slowly added dropwise 29.2 parts of 1,2-dipheny1-3,S-dioxo 4 isopropylidene-pyrazolidine (prepared by boiling 1,2-dipheny1-3,S-dioxo-pyrazolidine in acetone) in solution in -200 parts by volume of ether. The mixture is then heated to boiling for /2 hour. Upon cooling, water is added and the mixture is acidified with 10% hydrochloric acid. The resultant directly precipitated 1,2-diphenyl-3,5-dioxo-4-tert.
  • 1,2-dipheny1-3,S-dioxo 4 isopropylidene-pyrazolidine prepared by boiling 1,2-dipheny1-3,S-dioxo-pyrazolidine in acetone
  • butyl-pyrazolidine as well as that isolated from the ether solution, is recrystallized from alcohol. It is in the form of fine colorless 2,830,995 Patented Apr. 15, 1958
  • Example 2 A Grignard solution is preparedfrom 4.8 parts of magnesium and 21.8 parts of ethyl bromide in 100 parts by volume of diethyl ether. To this solution, there is added, dropwise and while stirring, a solution of 14.6 parts of 1,2-diphenyl-3,5-dioxo-4-isopropylidene-pyrazolidine in 300 parts by volume of diethyl ether. Upon completion of the ensuing reaction, the obtained organometallic intermediate compound settles out. The ether is removed by decantation, after which ice-water is added to the residue. After acidification with normal hydrochloric. acid, the crude 1,2-diphenyl-3,5-dioxo-4-tert.
  • amyl-pyrazolidine which is produced is isolated and dried. By recrystallization from toluene and then from methanol, this product is obtained as fine colorless needles which .melt at.140.5 C. The yield amounts to about 60% of the theoretical yield.
  • Example 3 Cl x-C 2 C 2 C CCHCO CHr-CH: C O NCeHs N-COH5 is in the form of fine colorless needles which melt at 181. The yield is about 60% of the theoretical.
  • hydrolyzing agent such as dilute sulfuric acid
  • hydrochloric acid any other suitable hydrolyzing agent such, for example as dilute sulfuric acid, may be substituted for the hydrochloric acid, used by way of illustration, in the foregoing examples.
  • a process for the preparation of a 1,2-diphenyl-3,5- dioxo-pyrazolidine containing a tertiary substituent in the 4-position which comprises subjecting a member selected from the group consisting of a 1,2-diphenyl-3,5-dioxo- 4-alkylidene-pyrazolidine and a 1,2-diphenyl-3,5-dioxo- 4-cyclohexylidene-pyrazolidine'to the action of an alkylmagnesium halide and then subjecting the resultant product to the action of hydrolyzing agent whereby the corresponding 4-tert. alkyl-substituted or 4-(1'-alkyl-cylohexyl) substituted 1,2 diphenyl-3,S-dioxd-pyrazolidine results.
  • a process for the preparation of 1,2-diphenyl-3,5- dioxo-4-tert. butyl-pyrazolidine which comprises subjecting 1,2-diphenyl-3,5-dioxo-4-isopropylidene-pyrazolidine to the action of methylmagnesium iodide, and then subjecting the resultant productto the action of dilute hydrochloric acid whereby hydrolytic splitting takes place with formation of the 1,2-diphenyl-3,5-dioxo-4-tert. butyl-pyrazolidine.
  • a process for the preparation of 1,2-diphenyl-3,5- dioxo-4-tert. amyl-pyrazolidine which comprises subjecting 1,2-diphenyl-3,5-dioXo-4-isopropylidene-pyrazolidine to the action of ethylmagnesium bromide, and then subjecting the resultant product to the action of dilute hydrochloric acid whereby hydrolytic splitting takes place with formation of the 1,2-diphenyl-3,5-dioxo- 4-tert. amyl-pyrazolidine.
  • a process for the preparation of l,2-diphenyl-3,5- dioxo-4-(lf-methylcyclohexyl)-pyrazolidine which comprises subjecting 1,2-diphenyl-3,5-dioXo-4-cyclohexylidene-pyrazolidine to the action of methylmagnesium iodide, and then subjecting the resultant product to the action of dilute hydrochloric acid whereby hydrolytic splitting takes place with formation of the 1,2-diphenyl- 3-5-dioxo-4-( 1-methylcyclohexyl) -pyrazolidine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

4-TERT.-HYDR( )CARBON-1,2-DIPHENYL-3,5- DIOXO-PYRAZOLIDINES AND PROCESS Albrecht Heymons, Berlin-Nikolassee, Hans Volk, Berlin- Tempelhof, and Helmut Gansau, Berlin-Siemensstadt, Germany, assignors to Firma Riedel-De Haen Aktiengesellschaft, Seelze, near Hannover, Germany, a firm of Germany No Drawing. Application December 14, 1954 Serial No. 475,296
Claimspriority, application Germany January 8, 1954 9 Claims. Cl. 260-610) The anti-pyretic and analgetic action-of 1,2-diaryl-3,5-
dioxo-pyrazolidines which are. substituted by a primary or secondary alkyl group is known. Of these alkylatedderivatives, 4-n-butyl-l,Z-diphenyl-Ia,S-dioxo-pyrazolidine,v more particularly, has been able to achieve great significance and to. find a Wide-therapeutic employment.-
It has now surprisingly been found that compounds with even more favorable therapeutic properties thansthe" aforementioned 4-n-butyl derivative are obtained if, in stead of. a primary or secondary alkyl group, a tertiary alkyl group, and more particularly the tertiary butyl group, is introduced into the 4-position of the 1,2'-diphenyl-3,S-dioxo-pyrazolidines. It has further been found that like results are also obtained if the group in the 4-position is a l-alkylcyclohexyl group. The-resultant l,2-diphenyl-3,5-dioxo-pyrazolidine derivatives, and particularly that substituted bythe tertiary butyl group, are distinguished by an essentially lower toxicity and by an enhanced antiphlogistic action while maintaining a comparable anti-pyretic and analgetic action, so that the therapeutic breadth of the new compounds of the present invention is significantly greater and more favorable that that of the known compounds of similar constitution. This effect is particularly realized, by the combination of the sodium salts of thenew pyrazolidine derivatives with 1-phenyl-2,3-dimethyl-4-dimethylamino pyrazolone, for which the new compounds of the present invention are excellent solvents.
The preferred 1,2-diphenyl-3,5-dioxo-4-tert. alkylpyrazolidines according to the'present' invention correspond to the formula laHs wherein each of R R and R stands for a lower (saturated) alkyl group or R and R together with the central tertiary carbon atom form a cyclohexyl group and R is a lower alkyl group, and wherein the sum of the carbon atoms in R +R +R is at least 3 and at most 8. Thus, each of R R and R may be a methyl group; or each of R R and R may be an ethyl group; or R and R may each be a methyl group while R is a propyl group; or one of R R and R may be methyl while the other two are ethyl; or R may be methyl, R ethyl and R propyl; or R and R may each be a propyl group while R is a methyl or ethyl group; or R and R together with the central tertiary C atom form a cylohexyl group and R is methyl, ethyl or propyl; etc.
The phenyl groups in the 1- and 2-p0sition may be substituted but such substituents do not appear to add to the pharmacological activity of the compounds.
The aforesaid 1,2-diphenyl-3,5-dioxo-4-tertl alkylpyrazolidines and l,2-diphenyl-3,S-dioxo-4-(1'-alkylcyclohexyl)-pyrazolidines form Well-defined salts with a wide variety of organic and inorganic bases, which bases and salts are therapeutically valuable because of their analgetic, antipyretic, antiphlogistic and sedative action;
Thus, administered orally, e. g. in tablet form, they; are useful in the treatment of arthritic conditions, gouty conditions, and the like.
Preferred among the aforesaid salts are the sodium and magnesium salts and those of ethylenediamine, triethanolamine and trimethylamine.
(lines of the above-indicated formula I by treating with an equimolecular' quantity of an appropriate base, e. g.-
with aqueous caustic soda, ethylenediamine, aqueous caustic potash, aqueous sodium carbonate solution, sodi-' um ethylate, etc.
The excellent therapeutic effect of the hitherto-unknown compounds of the present invention could not be foreseen since the literature describes only the primary and secondary 4-alkyl-1,2-diaryl-3,S-dioxopyrazolidines and of these only a very few have been found to be suitable for therapeutic purposes.
The new 1,2-diphenyl-3,5-dioxo-4-tert. alkylor -4-(-1' alkylcyclohexyl)-pyrazolidines are preferably prepared The synthesis in this way of the aforesaid diphenyldioxo-pyrazoiidines which contain a tertiary substituent in the 4-position is new in pyrazolidine chemistry. Such synthesis has to be regarded as unobvious and unexpected since there was a real reason to expect that the Grignard compounds would react primarily with the pyrazolidinenitrogen and the two oxo groups, and that'- the balance of the concurrent-reactions would therefore be in favor of those reaction products which are not here desired.
1,2-diphenyl-3,5-dioxo-4-te1't. alkyl-pyrazolidines are obtained by the action of alkylmagnesium halides on the" diphenyl-dioxo-alkylideneor -cyclohexylidene-pyrazolidines, and by the splitting (hydrolysis) of the thus-obtained intermediates.
The following examples set forth typical embodiments of the invention. In the said examples the parts and percentages, unless otherwise indicated, are by Weight and the temperatures are in degrees centigrade. Parts by volume bear the same relationship to parts by weight as do milliliters to grams.
Example 1 To a conventionally prepared solution of 18.2 parts of methylmagnesium iodide in parts by volume of ether, there are slowly added dropwise 29.2 parts of 1,2-dipheny1-3,S-dioxo 4 isopropylidene-pyrazolidine (prepared by boiling 1,2-dipheny1-3,S-dioxo-pyrazolidine in acetone) in solution in -200 parts by volume of ether. The mixture is then heated to boiling for /2 hour. Upon cooling, water is added and the mixture is acidified with 10% hydrochloric acid. The resultant directly precipitated 1,2-diphenyl-3,5-dioxo-4-tert. butyl-pyrazolidine, as well as that isolated from the ether solution, is recrystallized from alcohol. It is in the form of fine colorless 2,830,995 Patented Apr. 15, 1958 The salts are ad vantageously prepared from the corresponding pyrazoli=* It is therefore surprising that the desired needles and has a melting point of 175". By reacting with an equivalent quantity of an alcoholic sodium-ethylate solution, evaporating off the greater portion of the alcohol, and precipitating with'ether, there is obtained the corresponding sodium salt which is readily soluble'in water.
Example 2 A Grignard solution is preparedfrom 4.8 parts of magnesium and 21.8 parts of ethyl bromide in 100 parts by volume of diethyl ether. To this solution, there is added, dropwise and while stirring, a solution of 14.6 parts of 1,2-diphenyl-3,5-dioxo-4-isopropylidene-pyrazolidine in 300 parts by volume of diethyl ether. Upon completion of the ensuing reaction, the obtained organometallic intermediate compound settles out. The ether is removed by decantation, after which ice-water is added to the residue. After acidification with normal hydrochloric. acid, the crude 1,2-diphenyl-3,5-dioxo-4-tert. amyl-pyrazolidine which is produced is isolated and dried. By recrystallization from toluene and then from methanol, this product is obtained as fine colorless needles which .melt at.140.5 C. The yield amounts to about 60% of the theoretical yield.
2 In lieu of ethyl bromide, a corresponding quantity of ethyl iodide or of ethyl chloride may be used.
Example 3 Cl x-C 2 C 2: C CCHCO CHr-CH: C O NCeHs N-COH5 is in the form of fine colorless needles which melt at 181. The yield is about 60% of the theoretical.
Any other suitable hydrolyzing agent such, for example as dilute sulfuric acid, may be substituted for the hydrochloric acid, used by way of illustration, in the foregoing examples.
Having thus disclosed the invention, what is claimed is:
1. A compound selected from the group consisting of compounds corresponding to the formula wherein each of R R, and R stands for a lower alkyl group and wherein R and R may together with the adjacent C-atom represent a cyclohexyl group, the sum of the carbon atoms in R +R +R being at least 3 and not more than 8, and the salts of such compounds with bases.
2. 1,2-diphenyl-3,5-dioxo-4-tert. butyl-pyrazolidine.
3. The sodium salt of 1,2-diphenyl-3,5-dioXo-4-tert. butyl-pyrazolidine. I
4. 1,2-diphenyl-3,5-dioXo-4-tert. amyl-pyrazolidine.
5. 1,2-diphenyl-3,5-dioxo 4 (1'-methylcyclohexyl)- pyrazolidine.
6. A process for the preparation of a 1,2-diphenyl-3,5- dioxo-pyrazolidine containing a tertiary substituent in the 4-position, which comprises subjecting a member selected from the group consisting of a 1,2-diphenyl-3,5-dioxo- 4-alkylidene-pyrazolidine and a 1,2-diphenyl-3,5-dioxo- 4-cyclohexylidene-pyrazolidine'to the action of an alkylmagnesium halide and then subjecting the resultant product to the action of hydrolyzing agent whereby the corresponding 4-tert. alkyl-substituted or 4-(1'-alkyl-cylohexyl) substituted 1,2 diphenyl-3,S-dioxd-pyrazolidine results.
7. A process for the preparation of 1,2-diphenyl-3,5- dioxo-4-tert. butyl-pyrazolidine, which comprises subjecting 1,2-diphenyl-3,5-dioxo-4-isopropylidene-pyrazolidine to the action of methylmagnesium iodide, and then subjecting the resultant productto the action of dilute hydrochloric acid whereby hydrolytic splitting takes place with formation of the 1,2-diphenyl-3,5-dioxo-4-tert. butyl-pyrazolidine.
8. A process for the preparation of 1,2-diphenyl-3,5- dioxo-4-tert. amyl-pyrazolidine, which comprises subjecting 1,2-diphenyl-3,5-dioXo-4-isopropylidene-pyrazolidine to the action of ethylmagnesium bromide, and then subjecting the resultant product to the action of dilute hydrochloric acid whereby hydrolytic splitting takes place with formation of the 1,2-diphenyl-3,5-dioxo- 4-tert. amyl-pyrazolidine.
9. A process for the preparation of l,2-diphenyl-3,5- dioxo-4-(lf-methylcyclohexyl)-pyrazolidine, which comprises subjecting 1,2-diphenyl-3,5-dioXo-4-cyclohexylidene-pyrazolidine to the action of methylmagnesium iodide, and then subjecting the resultant product to the action of dilute hydrochloric acid whereby hydrolytic splitting takes place with formation of the 1,2-diphenyl- 3-5-dioxo-4-( 1-methylcyclohexyl) -pyrazolidine.
References-Cited in the file of this patent UNITED STATES PATENTS 2,562,830 Stenzl July 31, 1951 FOREIGN PATENTS 646,597 Great Britain Nov. 22, 1950 293,925 Switzerland Mar. 1, 1954

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS CORRESPONDING TO THE FORMULA
US2830995D X-tert Expired - Lifetime US2830995A (en)

Publications (1)

Publication Number Publication Date
US2830995A true US2830995A (en) 1958-04-15

Family

ID=3446968

Family Applications (1)

Application Number Title Priority Date Filing Date
US2830995D Expired - Lifetime US2830995A (en) X-tert

Country Status (1)

Country Link
US (1) US2830995A (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB646597A (en) * 1948-04-10 1950-11-22 Geigy Ag J R Improvements in or relating to the manufacture of derivatives of 3:5-dioxo-pyrazolidine
US2562830A (en) * 1951-07-31 Derivatives
CH293925A (en) * 1948-03-22 1953-10-15 Ag J R Geigy Process for the preparation of a derivative of 3,5-dioxo-pyrazolidine.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2562830A (en) * 1951-07-31 Derivatives
CH293925A (en) * 1948-03-22 1953-10-15 Ag J R Geigy Process for the preparation of a derivative of 3,5-dioxo-pyrazolidine.
GB646597A (en) * 1948-04-10 1950-11-22 Geigy Ag J R Improvements in or relating to the manufacture of derivatives of 3:5-dioxo-pyrazolidine

Similar Documents

Publication Publication Date Title
US2562830A (en) Derivatives
US4053474A (en) Pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine
US2905694A (en) Certain esters of i
US2830995A (en) X-tert
US3041342A (en) Amino-pyrazoles
US3669950A (en) DIPYRAZOLO{8 3,4-b:3,4d{9 -PYRIDIN-3-ONES
JPS6092275A (en) Substituted 4-alkyl-2(1h)quinazolinone-1-alkanoic derivative
US4053621A (en) 1-[2-(βNaphthyloxy)ethyl]-3-methylpyrazolone-(5) and antithrombotic and antithrombolytic compositions and methods utilizing them
DE1695702C3 (en) Process for the preparation of 1-acyl-2-carboxy-3-indolylacetic acids
DE69314413T2 (en) Piperidino-3,4-dihydrocarbostyryl compounds for the treatment of ischemic disorders
US2905693A (en) Methyl-pyrazolidine
US3344168A (en) N, n-diethyl-2-aminoethyl 2-substituted oxyisobutyrate
DE2461039A1 (en) Antiinflammatory, antithrombotic phenyl-ketone - oxime derivs - prepd. from corresp. ketone and hydroxylamine
US4560785A (en) Phenylacetic ester derivatives and process for preparing the same
US2835677A (en) 4-substituted 1.2-diaryl-3.5-dioxopyrazolidines
US2921071A (en) Halogeno-pyridazines and their
US3629279A (en) 4-aryl-2-imidazolone compounds
US2873278A (en) Certain 4-acyl-1, 2-diphenyl-3, 5-dioxopyrazolidines
US3068266A (en) 2-(substituted-benzyl)-1, 3-propanedisulfonates
US3153655A (en) 4-(gamma-oxobutyl)-1, 2-diphenyl-3, 5-dioxo-pyrazolidine derivatives
US2864824A (en) Alkoxy derivatives of 3:5-dioxo-pyrazolidene and process for their manufacture
US4147806A (en) Anti-inflammatory and analgesic medicaments
US3036065A (en) Dioxo-azetidines
US3703513A (en) Novel 3,5-dioxopyrazolidine derivatives
US3055912A (en) New substituted indole-(2)-aldehydes and process for their manufacture