US3391157A - 2, 4, 5-triloweralkyl-pyrrol-3-yl-hydroxymethyl ketones and ethers and carbamates thereof - Google Patents

2, 4, 5-triloweralkyl-pyrrol-3-yl-hydroxymethyl ketones and ethers and carbamates thereof Download PDF

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US3391157A
US3391157A US450520A US45052065A US3391157A US 3391157 A US3391157 A US 3391157A US 450520 A US450520 A US 450520A US 45052065 A US45052065 A US 45052065A US 3391157 A US3391157 A US 3391157A
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ketone
trimethylpyrrol
pyrrol
triloweralkyl
carbamates
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US450520A
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Irwin J Pachter
Schoen Karl
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EIDP Inc
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ENDO LAB
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Assigned to E.I. DU PONT DE NEMOURS AND COMPANY reassignment E.I. DU PONT DE NEMOURS AND COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ENDO LABORATORIES, INC., A CORP. OF DEL.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

Definitions

  • R is hydrogen, a lower alkyl group of not more than six carbon atoms, carbamyl, a monoor dihydroxy lower alkyl group of not more than four carbon atoms, a
  • Most of the compounds of this invention are prepared through the action of alkali metal alkoxides, hydroxides or phenoxides on 2, 4, 5 lower alkyl chloromethyl pyrrol- 3-yl ketones.
  • the chloromethyl ketones result either from reaction of appropriate pyrroles with chloroacetonitrile and hydrogen chloride, followed by hydrolysis of the intermediate imino compounds, or through reaction of chloracetyl chloride with Grignard derivatives of appropriate pyrroles.
  • the products of this invention may be prepared more directly through reaction of alkoxyor phenoxy-acetyl chlorides with Grignard derivatives of appropriate pyrroles.
  • a third method consists in reacting the alkoxyor phenoxyacetyl chlorides with the appropriate pyrrole and anhydrous aluminum chloride in a Friedel-Crafts reaction.
  • the useful carbamyl compounds are derived from the corresponding alcohols through standard procedures.
  • One preferred method involves reacting the alcohol with an alkali metal cyanate under acidic conditions.
  • the compounds of this invention possess muscle relaxing properties and mild tranquilizing effects on the central nervous system. They are effective as skeletal relaxants and are useful in the management of anxiety and tension states with a ,minimal incidence of undesirable side effects.
  • Unit dosage forms should generally contain a concentration of 1.0% to 50% by weight of one of the active compounds provided by this invention. In general, such unit dosage forms can contain about 10 to 400 mg. of active substance.
  • EXAMPLE 3 Ethoxyrnethyl 2,4,5-trimethylpyrrol-3-yl ketone This product was prepared by the method of Example 2 using ethanol in place of methanol, M.P. 111.
  • EXAMPLE 6 Ethoxymethyl 2,4-dimethyl--propylpyrrol-3-y1 ketone This product was prepared by the method of Example 5 from 2,4-dirnethyl-S-propylpyrrole and ethoxyacetyl chloride. Crystallized from heptane; MP. Ill-113.
  • EXAM PLE 8 Ethoxymethyl 2,5-dimethyl-4-propylpyrrol-3-yl ketone This product was prepared by the method of Example 5 from 2,5-dimethyl-4-propylpyrrole and ethoxyacetyl chloride. Crystallized from aqueous ethanol and heptane; M.P. lC-3105.
  • EXAMPLE 13 4-butyl-2,5-dimethylpyrrol-3-yl methoxymethyl ketone This product was prepared by the method of Example 5 from 4-buty1-2,5-dimethy1pyrrole and methoxyacetyl chloride. It was purified by crystallization from heptane; M.P. 114-116".
  • EXAMPLE 14 Ingredient: Mg./tablet Mcthoxymethyl 2,4-dimethyl-5-propylpyrrol-3-yl ketone 20 Lactose USP (spray dried) 170 Starch USP Magnesium stearate USP 1 Stearic and USP 5 Flavor Q.s.
  • EXAMPLE 16 Ingredient: Mg./tablet Carbamyloxymethyl 2,4,5-trimethylpyrrol-3-yl ketone Lactose USP (spray-dried) Magnesium stearate 1 Cab-O-Sil (amorphous silicon dioxide) 5 These ingredients were combined, blended and passed through a No. 1 screen of a Fitzpatrick comminutor machine before encapsulating into a two-piece hard gelatin No. 3 capsule on a standard capsulating machine at a net weight of 131 mg.
  • EXAMPLE 17 Ingredient: Mg./ tablet Methoxymethyl 2,4,5-trimethylpyrrol-3-y1 ketone 250 Lactose USP (spray-dried) 200 Magnesium stearate 1 Cab-O-Sil (amorphous silicon dioxide) 5 These ingredients were combined, blended and passed through a No. 1 screen of a Fitzpatrick comminutor machine before encapsulating with two-piece hard gelation No. 0 capsules on a standard capsulating machine at 465 mg.
  • NICHOLAS S RIZZO Primary Examiner 4. Carbamyloxymethyl 2,4,S-trimethylpyrrol-B-yl ketonfl JULIAN s. LEVITT, ALEX MAZEL, JOSE TOVAR,

Description

United States Patent 3,391,157 2,4,5 TRILOWERALKYL PYRROL 3 YL HY- DROXYMETHYL KETONES AND ETHERS AND CARBAMATES THEREOF Irwin J. Pachter, Woodbury, and Karl Schoen, Kew Gardens, N.Y., assignors to Endo Laboratories, Inc., Garden City, N.Y., a corporation of New York No Drawing. Filed Apr. 23, 1965, Ser. No. 450,520 Claims. (Cl. 260-4263) i? lower alkyl- ,C CH O R lower alkyl\iN3lower alkyl wherein:
the lower alkyl groups in positions 2, 4 and 5 have a maximum of six carbon atoms; and
R is hydrogen, a lower alkyl group of not more than six carbon atoms, carbamyl, a monoor dihydroxy lower alkyl group of not more than four carbon atoms, a
monoor di'carbamyloxy lower alkyl group of not more than four carbon atoms, phenyl and nuclear-substituted phenyl, benzyl or phenethyl.
Most of the compounds of this invention are prepared through the action of alkali metal alkoxides, hydroxides or phenoxides on 2, 4, 5 lower alkyl chloromethyl pyrrol- 3-yl ketones. The chloromethyl ketones result either from reaction of appropriate pyrroles with chloroacetonitrile and hydrogen chloride, followed by hydrolysis of the intermediate imino compounds, or through reaction of chloracetyl chloride with Grignard derivatives of appropriate pyrroles.
Alternatively, the products of this invention may be prepared more directly through reaction of alkoxyor phenoxy-acetyl chlorides with Grignard derivatives of appropriate pyrroles.
A third method consists in reacting the alkoxyor phenoxyacetyl chlorides with the appropriate pyrrole and anhydrous aluminum chloride in a Friedel-Crafts reaction.
The useful carbamyl compounds are derived from the corresponding alcohols through standard procedures. One preferred method involves reacting the alcohol with an alkali metal cyanate under acidic conditions.
The compounds of this invention possess muscle relaxing properties and mild tranquilizing effects on the central nervous system. They are effective as skeletal relaxants and are useful in the management of anxiety and tension states with a ,minimal incidence of undesirable side effects.
They are active when administered to animals and humans orally, parenterally or rectally. The oral route is 'ice preferred. Although they may be administered as pure compounds, their limited solubility in water makes it advantageous to combine them with pharmaceutical carriers such as starch, sugar, talc and the like to form powders which can be used directly or inserted into gelatin capsules or converted into tablets. Suitable lubricants like magnesium stearate, binders such as gelatin and disintegrating agents like sodium carbonate in combination with citric acid can be used to form tablets.
Unit dosage forms should generally contain a concentration of 1.0% to 50% by weight of one of the active compounds provided by this invention. In general, such unit dosage forms can contain about 10 to 400 mg. of active substance.
The following are examples in accordance with the invention. The temperatures are centigrade.
EXAMPLE 1 Hydroxymethyl 2,4,5-trimethylpyrrol-3-yl ketone 2,3,5-trimeth-ylpyrrole was converted. into chloromethyl 2,4,5 trimethylpyrrol-Ii-yl ketone by the method of Fischer, Schneller and Zerweck, Ber., 55, 2399 (1922).
To 20 g. of potassium hydroxide in 300 ml. of water was added 16 g. of chloromethyl 2,4,5-trimethylpyrro1-3- yl ketone and the mixture was heated under reflux for two hours, cooled and filtered. The solid product, upon recrystallization from methanol, melted at 188.
EXAMPLE 2 Methoxymethyl 2,4,5-trimethylpyrrol-3-yl ketone To a solution of 5 g. of sodium in 250 ml. of methanol was added 50 g. of chloromethyl 2,4,5-trimethylpyrrol-3- yl ketone. After six hours of heating under reflux, sodium chloride was filtered out and methanol was removed under reduced pressure. The residue was diluted with water and the product was collected and recrystallized from methanol. Yield 38 g., M.P. 138.
EXAMPLE 3 Ethoxyrnethyl 2,4,5-trimethylpyrrol-3-yl ketone This product was prepared by the method of Example 2 using ethanol in place of methanol, M.P. 111.
EXAMPLE 4 Isopropoxymethyl 2,4,5-trimethylpyrrol-3-yl ketone This product was prepared by the method of Example 2 using isopropanol in place of methanol, M.P.
EXAMPLE 5 Methoxymethyl 2,4-dimethyl5-propylpyrrol-3-yl ketone A Grignard solution was prepared from 7.3 g. magnesium filings and 33 g. ethyl bromide in 600 ml. anhydrous ether. To this solution 21 g. 2,4-dimethyl-5-propylpyrrole was added dropwise with stirring. Stirring was continued for two hours and the mixture allowed to stand overnight at room temperature. Methoxyacetyl chloride 22 g. was then added dropwise with stirring and cooling. After stirring three hours the mixture was decomposed with 150 ml. of 15% ammonium chloride solution. The ether solution was separated, washed with aqueous sodium bicarbonate solution, then with water and dried over MgSO The solvent was removed and the residue crystallized repeatedly from heptane; M.P. l24.
3 EXAMPLE 6 Ethoxymethyl 2,4-dimethyl--propylpyrrol-3-y1 ketone This product was prepared by the method of Example 5 from 2,4-dirnethyl-S-propylpyrrole and ethoxyacetyl chloride. Crystallized from heptane; MP. Ill-113.
EXAMPLE 7 Methoxymethyl 2,5-dimethyl-4-propylpyrrol-3-y1 ketone This product was prepared by the method of Example 5 from 2,5-dimethyl-4-propylpyrrole (b. 13 mm 90-93 11 25 1.4982) and methoxyacetyl chloride. crystallized from heptane; M.P. 132-134".
EXAM PLE 8 Ethoxymethyl 2,5-dimethyl-4-propylpyrrol-3-yl ketone This product was prepared by the method of Example 5 from 2,5-dimethyl-4-propylpyrrole and ethoxyacetyl chloride. Crystallized from aqueous ethanol and heptane; M.P. lC-3105.
EXAMPLE 9 Z-hydroxyethoxymethyl 2,4,5-trimethylpyrrol-3-yl ketone This product was obtained by the method of Example 2 through use of ethylene glycol in place of methanol and heating on a steam bath rather than under reflux; M.P. 130.
In similar fashion, the use of glycerol in place of ethylene glycol results in the synthesis of 2,3-dihydroxyproxymethyl 2,4,S-trimethylpyrrol-3-yl ketone.
EXAMPLE 1O Carbamyloxymethyl 2,4,S-trimethylpyrrol-Ii-yl ketone Phenoxymethyl 2,4,5-trimethylpyrrol-3-yl ketone 9 g. of chloromethyl 2,4,5-trimethylpyrrol-3-yl ketone in ethanol was added to an ethanolic solution of 7 g. of phenol and 4 g. of potassium hydroxide in ethanol. The resulting solution was heated under reflux four hours, concentrated and diluted with water. The solid product was recrystallized from ethanol; M.P. 132.
EXAMPLE 12 2-methoxyphenoxymethyl 2,4,5-trimethylpyrrol-3-yl ketone By the procedure of Example 10, using guaiacol in place of phenol, this Z-methoxy product was obtained; and purified by recrystallization from methanol; M.P. 128.
EXAMPLE 13 4-butyl-2,5-dimethylpyrrol-3-yl methoxymethyl ketone This product was prepared by the method of Example 5 from 4-buty1-2,5-dimethy1pyrrole and methoxyacetyl chloride. It was purified by crystallization from heptane; M.P. 114-116".
4 EXAMPLE 14 Ingredient: Mg./tablet Mcthoxymethyl 2,4-dimethyl-5-propylpyrrol-3-yl ketone 20 Lactose USP (spray dried) 170 Starch USP Magnesium stearate USP 1 Stearic and USP 5 Flavor Q.s.
All above ingredients were passed through a GO-mesh sieve, blended for 30 minutes and compressed directly into tablets on a suitable tablet press at a weigh-t of 206 mg,
using a 4 biconeave scored punch.
EXAMPLE Ingredient: M g./ tablet Hydroxymethyl 2,4,5-trimethylpyrrol-3-yl ketone 250 Lactose USP (impalpable) 6O Starch USP 140 Magnesium stearate USP 3 Stearic acid USP 10 Flavor (2.5.
These tablets were granulated with starch paste in conventional fashion. They were dried, passed through a No. mesh sieve and compressed on a suitable tablet press, using a biconcave punch at a weight of 463 mg.
EXAMPLE 16 Ingredient: Mg./tablet Carbamyloxymethyl 2,4,5-trimethylpyrrol-3-yl ketone Lactose USP (spray-dried) Magnesium stearate 1 Cab-O-Sil (amorphous silicon dioxide) 5 These ingredients were combined, blended and passed through a No. 1 screen of a Fitzpatrick comminutor machine before encapsulating into a two-piece hard gelatin No. 3 capsule on a standard capsulating machine at a net weight of 131 mg.
EXAMPLE 17 Ingredient: Mg./ tablet Methoxymethyl 2,4,5-trimethylpyrrol-3-y1 ketone 250 Lactose USP (spray-dried) 200 Magnesium stearate 1 Cab-O-Sil (amorphous silicon dioxide) 5 These ingredients were combined, blended and passed through a No. 1 screen of a Fitzpatrick comminutor machine before encapsulating with two-piece hard gelation No. 0 capsules on a standard capsulating machine at 465 mg.
It will be understood that the foregoing description of the invention and the examples set forth are merely illustrative of the principles thereof. Accordingly, the appended claims are to be construed as defining the invention within the full spirit and scope thereof.
We claim:
1. A compound having the formula:
l lower 21111311 U OI-IZO R 5 |i: v '1 lower alk yl \N/ loueiallql l H wherein? the lower alkyl groups have a maximum of six carbon atoms; and R designates a member of the group consisting of:
hydrogen, lower alkyl having a maximum of six carbon atoms, carbamyl, .hydroxy alkyl having a maximum of four carbon atoms and a max- 5 6 imum of two hydroxy groups; car-bamyloxy alkyl References Cited having a maximum of four carbon atoms and :1 UNITED STATES PATENTS maximum of two carbamyloxy groups, phenyl ,benzyl and phenethyL 1,915,334 6/1933 Salzberg et a1. 260-243 2. Hydroxymethyl 2,4,5-trimethylpyrro1-3-y1 ketone. 5 2075359 3/1937 salzberg et a1 167 22 3. Methoxymethyl 2,4,5-t1'i-I1lv3thf/1PYI'I'OL3-y1 ketone. NICHOLAS S RIZZO Primary Examiner 4. Carbamyloxymethyl 2,4,S-trimethylpyrrol-B-yl ketonfl JULIAN s. LEVITT, ALEX MAZEL, JOSE TOVAR,
5. Ethoxymethyl 2,4-dimethyl-5-propy1pyrro1-3-yl ketone. 10 S. J. FRIEDMAN, Assistant Examiner.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,391,157 July 2, 1968 Irwin J. Pachter et al.
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 1, line 15, "havinge" should read having lines 21 to 28, the formula should appear as shown below:
0 lower alk l..- A
Y 3 CH 0R lower alk l... 5 2 lower alk 1 Column 3, line 33, "proxymethyl" should read propoxymethyl Column 4, line 8, "and" should read Acid Signed and sealed this 16th day of September 1969.
(SEAL) Attest:
EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents

Claims (2)

1. A COMPOUND HAVING THE FORMULA:
4. CARBAMYLOXYMETHYL 2,4,5-TRIMETHYLPYRROL-3-YL KETONE.
US450520A 1965-04-23 1965-04-23 2, 4, 5-triloweralkyl-pyrrol-3-yl-hydroxymethyl ketones and ethers and carbamates thereof Expired - Lifetime US3391157A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090036421A1 (en) * 2006-02-20 2009-02-05 Astellas Pharma Inc Pyrrole Derivative or Salt Thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090036421A1 (en) * 2006-02-20 2009-02-05 Astellas Pharma Inc Pyrrole Derivative or Salt Thereof
US8222274B2 (en) * 2006-02-20 2012-07-17 Astellas Pharma Inc. Pyrrole derivative or salt thereof

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