US3252989A - Pyrazole-1-carboxamidines - Google Patents

Pyrazole-1-carboxamidines Download PDF

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US3252989A
US3252989A US256115A US25611563A US3252989A US 3252989 A US3252989 A US 3252989A US 256115 A US256115 A US 256115A US 25611563 A US25611563 A US 25611563A US 3252989 A US3252989 A US 3252989A
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carboxamidine
nitrate
sodium
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III Horace FLETCHER
Harvey E Alburn
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Wyeth LLC
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    • 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
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

Definitions

  • This invention relates to new carhoxamidine compounds having valuable pharmacological properties. More particularly this invention relates to new substituted carboxamidines and to the methods by which such compounds are prepared.
  • the new compounds of the present invention may be represented by the Formula I t RCNA where R is a to 6 membered nitrogen containing heterocycle and tetrahydroisoquinolino, R is selected from the group consisting of hydrogen, and
  • R is an .alkyl radical and A is selected from the group consisting of hydrogen
  • the heterocyclic R group includes pyrrolidino, morpholino, pyrazolino, pyrazolo and piperidino, all of which may be substituted with lower .alkyl, di-lower alkyl and tri-lower alkyl radicals.
  • R-CNA H (II) wherein R represents a member of the group consisting of piperidino, morpholino, pyrrolidino and pyrazolo together with the lower alkyl and di-lower alkyl homologs of each of these and tetrahydroisoquinolino; R represents 46-011 or hydrogen; A is selected from the group consisting of hydrogen,
  • R is an alkyl radical having not more than 7 carbon atoms and in which R is selected from the group consisting of aryl and alkaryl; together with their ph-aImacolo-gical'ly acceptable acid salts.
  • the new compounds of the present invention possess valuable pharmacological properties. More specifically, the new compounds of the present invention are useful as hypoglycemic agents.
  • the new compounds are administered in dosage amounts of from 10 to 100 UL/kg. either orally or parenterally in liquid or solid dosage 'ice forms.
  • the compound When used with such carriers, the compound will be present in the carrier in an amount of from 0.1 to about percent by weight.
  • Dosage forms include injectables, elixirs, capsules, lozenges and tablets together with appropriate liquid or solid vehicles, excipients or carriers according to conventional pharmaceutical practice.
  • the new compounds of the present invention are prepared by reacting a carboxamidine salt such as for example 3,5-dimethylpyrazole-l-carboxamidine nitrate, with excess acetic anhydride and excess triethyla mine or trimelthylamine or an equivalent tertiary base having a higher ionization constant than that of the pyrazole base starting material, in an alcohol solution.
  • the alcohol used is preferably a low molecular weight alcohol such as methanol, ethanol or the like.
  • the reaction mixture is allowed to stand for a period of time such as from minutes to 24 hours at room temperature or lower. Temperatures higher than room temperature are not preferred.
  • the alcohol is then removed, as by distillation, and the oil product chssolved in water and extracted in low molecular weight, water immiscible, ether or ester solvent such as diethyl ether or ethyl acetate.
  • the ethereal or ester solution is dried, filtered and evaporated.
  • the residue containing the desired compound can then be recrystallized from other or if desired the salt can be prepared, such as for example the hydrochloride, by passing HCl through the ethereal solution of the product.
  • the resulting crystalline hydrochloride is then recovered by filtration.
  • the monoacetyl compounds of the present invention may ⁇ be prepared by first reacting a selected carboxa-midine salt with one equivalent of an anhydrous alcohol solution of sodium. The sodium salt resulting is filtered off and the filtrate evaporated to dryness. The solid residue obtained is then suspended in excess ethyl acetate and refluxed with stirring for a period of from 10 to 30 hours. The reaction mixture is then filtered and the filtrate evaporated to dry ne'ss. The residue is washed, preferably with ether, and the ether insoluble portion dissolved in hot ethyl acetate from which the desired monacetyl derivative is obtained on cooling.
  • the selected carboxarnidine salt such as for example the 3,5-dimethylpyrazole-l-carboxamidine nitrate referred to above, is prepared according to the method of Theile, Annalen der Chemie, 302, 275-311 (1898). In this method, 1 mole of aminoguanidine nitrate is added, over a period of 1 /2 hours to 1 mole of 2,4-pentanedione in ethanol. After refluxing for 2 /2 hours, the nitrate salt is obtained on cooling to 0 C.
  • the salt of 3,5-dimethylpyrazole carboxamidine is reacted with the free base, such as for example pyrrolidine, piperidine or the like, in a low molecular Weight alcohol solution for a period of from 1 to 3 hours.
  • suitable alcohols for this purpose include methanol, ethanol and the like.
  • An .amidine shift occurs in which the pyrrolidine replaces the dimethyl pyrazole, yielding the desired pyrrolidino carboxamidine salt.
  • This product, in the form of the nitrate salt may then be converted to the sulfate form if desired by treating with sulfuric acid in ethanol.
  • the other starting compounds identified in the examples which follow are prepared. It has been found that nitrate and sulfate salts are most satisfactory for purposes of the present invention.
  • R is the selected carboxamidine salt, such as for example piperidine-l-carboxamidine sulfate
  • R is the selected carboxamidine salt
  • Sodium sulfate is filtered off and the filtrate evaporated to dryness.
  • the residue is dissolved in ether and acetic anhydride added.
  • a precipitate of the acetate salt of the guanidine starting material is obtained by filtration.
  • the desired product is then recoverable as the salt, such as the hydrochloride, by passing HCl gas into the filtrate and recovering the crystalline product which separates out on cooling.
  • Example I 50 gms. (0.25 mol) of 3,5-dimethylpyrazole-l-carboxamidine nitrate and 290 gms. (2.0 moles) of triethylamine are dissolved in 1 liter of dry methanol, cooled in an ice bath, 108 gms. (1.5 moles) of acetic anhydride is added in one portion and the reaction mixture allowed to stand for two hours at room temperature. The methanol is then removed in vacuo and the oil dissolved in 800 ml. of water. This solution is extracted with three 100 ml. portions of ether. The ether extracts are dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. 100 ml.
  • Example II To 8.85 gms. (.05 mole) of pyrrolidine-l-carboxamidine nitrate, a solution of 1.15 gms. (.05 mole) of sodium in 100 ml. of anhydrous ethanol is added and stirred for thirty minutes while protected with a sodalime tube. The suspension is filtered and the filtrate evaporated in vacuo. The solid residue is suspended in 200 ml. of ethyl acetate and refluxed with stirring for 20 hours.
  • N-acetyl-morpholine-l-carboxamidine is prepared by reacting morpholine-4-carboxamidine nitrate with an alcoholic solution of sodium followed by refluxing with ethyl acetate.
  • N-acetylpiperidine-l-carboxamidine is prepared by reacting piperidinel-carhoxamidine nitrate with an alcoholic solution of sodium followed by refluxing with ethyl acetate.
  • Example V According to the method of Example I, pyr-azole-lcarboxamidine nitrate in the presence of triethylamine is reacted with acetic anhydride to produce N-acetylpyrazole-l-carboxamidine.
  • N-acetyl-1,2,3,4- tetrahydroisoquinoline-l-carboxamidine is prepared by reacting 1,2,3,4-tetrahydroisoquinoline 1 carboxamidine nitrate in an alcoholic solution of sodium followed by refluxing with ethyl acetate.
  • Example VII at 7. The solid material is filtered, washed with water and.
  • N-p-tolylsulfonyl-3,S-dimethylpyrazole-l carboxamldine is obtained, M.P. 140141 C. corr.
  • N-phenylsulfonylpyrrolidine-l-carboxamidine is prepared by reacting pyrrolidine-l-carboxamidine nitrate with benzene sulfonyl chloride.
  • Example IX 15.0 gms. (.04 mole) of piperidine-I-carboxamidine sulfate is stirred in ml. of absolute ethanol containing 1.81 gms. (.08 mole) of sodium for 1 hour. The sodium sulfate is filtered off and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 200 ml. of dry ether and 8.15 gms. (.08 mole) of acetic anhydride is added. A precipitate forms immediately and afterstirring :for 1 hour and filtering 6 gms. (20%) of the acetate salt of the starting material is obtained.
  • HCl gas is passed into the filtrate and a yellow oil separates which crystallizes on scratching andcooling to 0 C.
  • a yellow oil separates which crystallizes on scratching andcooling to 0 C.
  • One recrystallization from 30 ml. of ethanol and 200 ml. of dry ether give 5.0 gms. or 60% yield of N,N'-diacetyl-piperidine-l-carboxamidine hydrochloride, M.P. 166-168 C. corr.
  • Example X Following the method of Example II, N-acetyl-2,6-dimethylmorpholine-4-carboxamidine is prepared by reacting 2,6-dimethylmorpholine-4-carboxamidine sulfate with an alcoholic solution of sodium followed by refluxing with ethyl acetate.
  • Example XI Following the method of Example m, pyrrolidine-lcarboxamidine sulfate is reacted with an ethanolic solution of sodium. After filtration of sodium sulfate the filtrate is evaporated to dryness and the residue dissolved in ether to which solution acetic anhydride is added. A precipitate forms, the acetate salt of the starting material, which is removed by filtration. Passing HCl gas into the filtrate will precipitate N,N'-diacetyl-pyrrolidine-l-carboxamidine hydrochloride.
  • Example XII overnight. 5.8 gms. (60%) of N-octanoyl-pyrrolidine-1- carboxamidine is obtained. After one recrystallization from pet-ether, 4.4 gms. (46% yield) of pure material is obtained, M .P. 7071 C. corr.
  • N-acetyl- 2,4-dimethylpiperidine-l-carboxamidine is prepared by reacting 2,4-dimethylpiperidine-1 carboxamidine nitrate with an ethanolic solution of sodium followed by refluxing with ethyl acetate.
  • Example XIV N,N-diacetyl-Z,4-dimethylpyrrolidine-1-carboxamidine is prepared according to the method of Example IX by reacting 2,4-dimethylpyrrolidine-1 carboxamidine sulfate with analcohol solution of sodium :followed by refluxing with acetic anhydride.
  • Example XV Following the method of Example VII, 2,6-diethylmorpholine-4-carboxamidine nitrate is reacted with p-toluene sulfonyl chloride to produce N-p-tolylsulfonyl-Z,6-diethylmorpholinet-carboxarnidine.
  • Example XVI N-acetyl-3,5-diethyl-2-pyrazoline-l-carboxamidine is prepared by reacting 3,5-diethyl-2-pyrazoline-l-carboxamidine nitrate with acetic anhydride according to the method described in Example 1.
  • Example XVII Following the method of Example XII, N-heptanoylpiperidine-l-carboxamidine is obtained by reacting piperidine-l-carboxamidine nitrate With an ethanol solution of sodium followed by heating the sodium containing carhoxamidine with methyl heptanoate following removal of the alcohol.

Description

United States Patent This invention relates to new carhoxamidine compounds having valuable pharmacological properties. More particularly this invention relates to new substituted carboxamidines and to the methods by which such compounds are prepared.
The new compounds of the present invention may be represented by the Formula I t RCNA where R is a to 6 membered nitrogen containing heterocycle and tetrahydroisoquinolino, R is selected from the group consisting of hydrogen, and
wherein R is an .alkyl radical and A is selected from the group consisting of hydrogen,
. (fi --R3 in which R is an alkyl group having not more than 7 carbon atoms, and -S(O) R in which R is aryl or alk'aryl; together with their acid salts. In the foregoing structure, the heterocyclic R group includes pyrrolidino, morpholino, pyrazolino, pyrazolo and piperidino, all of which may be substituted with lower .alkyl, di-lower alkyl and tri-lower alkyl radicals.
A preferred group of compounds Within the class represented by Formula I above constitutes those represented by the following structural Formula II:
i R-CNA H (II) wherein R represents a member of the group consisting of piperidino, morpholino, pyrrolidino and pyrazolo together with the lower alkyl and di-lower alkyl homologs of each of these and tetrahydroisoquinolino; R represents 46-011 or hydrogen; A is selected from the group consisting of hydrogen,
in which R is an alkyl radical having not more than 7 carbon atoms and in which R is selected from the group consisting of aryl and alkaryl; together with their ph-aImacolo-gical'ly acceptable acid salts.
As has been suggested, the new compounds of the present invention possess valuable pharmacological properties. More specifically, the new compounds of the present invention are useful as hypoglycemic agents. When used for the foregoing purposes, the new compounds are administered in dosage amounts of from 10 to 100 UL/kg. either orally or parenterally in liquid or solid dosage 'ice forms. When used with such carriers, the compound will be present in the carrier in an amount of from 0.1 to about percent by weight. Dosage forms include injectables, elixirs, capsules, lozenges and tablets together with appropriate liquid or solid vehicles, excipients or carriers according to conventional pharmaceutical practice.
According to one method of preparation, the new compounds of the present invention are prepared by reacting a carboxamidine salt such as for example 3,5-dimethylpyrazole-l-carboxamidine nitrate, with excess acetic anhydride and excess triethyla mine or trimelthylamine or an equivalent tertiary base having a higher ionization constant than that of the pyrazole base starting material, in an alcohol solution. The alcohol used is preferably a low molecular weight alcohol such as methanol, ethanol or the like. The reaction mixture is allowed to stand for a period of time such as from minutes to 24 hours at room temperature or lower. Temperatures higher than room temperature are not preferred. The alcohol is then removed, as by distillation, and the oil product chssolved in water and extracted in low molecular weight, water immiscible, ether or ester solvent such as diethyl ether or ethyl acetate. The ethereal or ester solution is dried, filtered and evaporated. The residue containing the desired compound, can then be recrystallized from other or if desired the salt can be prepared, such as for example the hydrochloride, by passing HCl through the ethereal solution of the product. The resulting crystalline hydrochloride is then recovered by filtration.
The monoacetyl compounds of the present invention, other than the pyrazole derivatives, may \be prepared by first reacting a selected carboxa-midine salt with one equivalent of an anhydrous alcohol solution of sodium. The sodium salt resulting is filtered off and the filtrate evaporated to dryness. The solid residue obtained is then suspended in excess ethyl acetate and refluxed with stirring for a period of from 10 to 30 hours. The reaction mixture is then filtered and the filtrate evaporated to dry ne'ss. The residue is washed, preferably with ether, and the ether insoluble portion dissolved in hot ethyl acetate from which the desired monacetyl derivative is obtained on cooling.
In the foregoing methods of preparation, the selected carboxarnidine salt, such as for example the 3,5-dimethylpyrazole-l-carboxamidine nitrate referred to above, is prepared according to the method of Theile, Annalen der Chemie, 302, 275-311 (1898). In this method, 1 mole of aminoguanidine nitrate is added, over a period of 1 /2 hours to 1 mole of 2,4-pentanedione in ethanol. After refluxing for 2 /2 hours, the nitrate salt is obtained on cooling to 0 C. To prepare other suitable heterocyclic carboxamidines, the salt of 3,5-dimethylpyrazole carboxamidine is reacted with the free base, such as for example pyrrolidine, piperidine or the like, in a low molecular Weight alcohol solution for a period of from 1 to 3 hours. Suitable alcohols for this purpose include methanol, ethanol and the like. An .amidine shift occurs in which the pyrrolidine replaces the dimethyl pyrazole, yielding the desired pyrrolidino carboxamidine salt. This product, in the form of the nitrate salt, may then be converted to the sulfate form if desired by treating with sulfuric acid in ethanol. In a similar manner, the other starting compounds identified in the examples which follow are prepared. It has been found that nitrate and sulfate salts are most satisfactory for purposes of the present invention.
In preparing compounds of the present invention encompassed within those included in Formula I in which the di-acetyl structure is desired, that is wherein R is the selected carboxamidine salt, such as for example piperidine-l-carboxamidine sulfate, is first reacted with one equivalent of an ethanolic solution of sodium. Sodium sulfate is filtered off and the filtrate evaporated to dryness. The residue is dissolved in ether and acetic anhydride added. A precipitate of the acetate salt of the guanidine starting material is obtained by filtration. The desired product is then recoverable as the salt, such as the hydrochloride, by passing HCl gas into the filtrate and recovering the crystalline product which separates out on cooling.
Reference now to the specific examples which follow will provide a better understanding of the new compounds of the present invention and the manner in which the same are prepared:
Example I 50 gms. (0.25 mol) of 3,5-dimethylpyrazole-l-carboxamidine nitrate and 290 gms. (2.0 moles) of triethylamine are dissolved in 1 liter of dry methanol, cooled in an ice bath, 108 gms. (1.5 moles) of acetic anhydride is added in one portion and the reaction mixture allowed to stand for two hours at room temperature. The methanol is then removed in vacuo and the oil dissolved in 800 ml. of water. This solution is extracted with three 100 ml. portions of ether. The ether extracts are dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. 100 ml. of benzene is added and re-evaporated. The residue is dissolved in 600 ml. of dry ether and hydrogen chloride added until the solution indicates a pH of 2. The crystalline hydrochloride is filtered, washed with ether, and dried in vacuo over P Yield of N-acetyl-3,S-dimethylpyrazole-l-carboxamidine hydrochloride is 44.8 gms. or 69%, MP. 146147 C. corr.
Example II To 8.85 gms. (.05 mole) of pyrrolidine-l-carboxamidine nitrate, a solution of 1.15 gms. (.05 mole) of sodium in 100 ml. of anhydrous ethanol is added and stirred for thirty minutes while protected with a sodalime tube. The suspension is filtered and the filtrate evaporated in vacuo. The solid residue is suspended in 200 ml. of ethyl acetate and refluxed with stirring for 20 hours. The reaction mixture is filtered and the filtrate Following the method of Example II, N-acetyl-morpholine-l-carboxamidine is prepared by reacting morpholine-4-carboxamidine nitrate with an alcoholic solution of sodium followed by refluxing with ethyl acetate.
Example IV Following the method of Example II, N-acetylpiperidine-l-carboxamidine is prepared by reacting piperidinel-carhoxamidine nitrate with an alcoholic solution of sodium followed by refluxing with ethyl acetate.
Example V According to the method of Example I, pyr-azole-lcarboxamidine nitrate in the presence of triethylamine is reacted with acetic anhydride to produce N-acetylpyrazole-l-carboxamidine.
Example VI Following the method of Example II, N-acetyl-1,2,3,4- tetrahydroisoquinoline-l-carboxamidine is prepared by reacting 1,2,3,4-tetrahydroisoquinoline 1 carboxamidine nitrate in an alcoholic solution of sodium followed by refluxing with ethyl acetate.
Example VII at 7. The solid material is filtered, washed with water and.
crystallized from 200ml. of hot aqueous ethanol. N-p-tolylsulfonyl-3,S-dimethylpyrazole-l carboxamldine is obtained, M.P. 140141 C. corr.
Example VIII Following the method of the previous example, N-phenylsulfonylpyrrolidine-l-carboxamidine is prepared by reacting pyrrolidine-l-carboxamidine nitrate with benzene sulfonyl chloride.
Example IX 15.0 gms. (.04 mole) of piperidine-I-carboxamidine sulfate is stirred in ml. of absolute ethanol containing 1.81 gms. (.08 mole) of sodium for 1 hour. The sodium sulfate is filtered off and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 200 ml. of dry ether and 8.15 gms. (.08 mole) of acetic anhydride is added. A precipitate forms immediately and afterstirring :for 1 hour and filtering 6 gms. (20%) of the acetate salt of the starting material is obtained. HCl gas is passed into the filtrate and a yellow oil separates which crystallizes on scratching andcooling to 0 C. One recrystallization from 30 ml. of ethanol and 200 ml. of dry ether give 5.0 gms. or 60% yield of N,N'-diacetyl-piperidine-l-carboxamidine hydrochloride, M.P. 166-168 C. corr.
Example X Following the method of Example II, N-acetyl-2,6-dimethylmorpholine-4-carboxamidine is prepared by reacting 2,6-dimethylmorpholine-4-carboxamidine sulfate with an alcoholic solution of sodium followed by refluxing with ethyl acetate.
Example XI Following the method of Example m, pyrrolidine-lcarboxamidine sulfate is reacted with an ethanolic solution of sodium. After filtration of sodium sulfate the filtrate is evaporated to dryness and the residue dissolved in ether to which solution acetic anhydride is added. A precipitate forms, the acetate salt of the starting material, which is removed by filtration. Passing HCl gas into the filtrate will precipitate N,N'-diacetyl-pyrrolidine-l-carboxamidine hydrochloride.
Example XII overnight. 5.8 gms. (60%) of N-octanoyl-pyrrolidine-1- carboxamidine is obtained. After one recrystallization from pet-ether, 4.4 gms. (46% yield) of pure material is obtained, M .P. 7071 C. corr.
Example XIII According to the method previously described, N-acetyl- 2,4-dimethylpiperidine-l-carboxamidine is prepared by reacting 2,4-dimethylpiperidine-1 carboxamidine nitrate with an ethanolic solution of sodium followed by refluxing with ethyl acetate.
Example XIV N,N-diacetyl-Z,4-dimethylpyrrolidine-1-carboxamidine is prepared according to the method of Example IX by reacting 2,4-dimethylpyrrolidine-1 carboxamidine sulfate with analcohol solution of sodium :followed by refluxing with acetic anhydride.
Example XV Following the method of Example VII, 2,6-diethylmorpholine-4-carboxamidine nitrate is reacted with p-toluene sulfonyl chloride to produce N-p-tolylsulfonyl-Z,6-diethylmorpholinet-carboxarnidine.
Example XVI N-acetyl-3,5-diethyl-2-pyrazoline-l-carboxamidine is prepared by reacting 3,5-diethyl-2-pyrazoline-l-carboxamidine nitrate with acetic anhydride according to the method described in Example 1.
Example XVII Following the method of Example XII, N-heptanoylpiperidine-l-carboxamidine is obtained by reacting piperidine-l-carboxamidine nitrate With an ethanol solution of sodium followed by heating the sodium containing carhoxamidine with methyl heptanoate following removal of the alcohol.
Various modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these modifications are within the purview of the attached claims, they are to be considered as part of this invention.
The invention claimed is:
1. A member of the group consisting of a compound of the formula:
References Cited by the Examiner UNITED STATES PATENTS 2,408,694 10/1946 Simons et al 260561 2,926,172 2/1960 Boehme et a1. 260247.2 2,951,843 9/1960 Haack et a1 260288 2,993,062 7/1961 Moyle et a1 260561 3,693,632 6/1963 Mull 260288 OTHER REFERENCES Brewer, Organic Chemistry, 2nd ed., page 211 (1948).
Scott, Jour. of Org. Chem, vol. 22, pages 1568- (1957).
Scott et al., Jour. Amer. Chem. Soc., vol. 74, pages 4562-66 (1952).
WALTER A. MODANCE, Primary Examiner.
NICHOLAS S. RIZZO, JOHN D. RANDOLPH,
Examiners.
DON M. KERR, NATALIE TROUSOF,
Assistant Examiners.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2174710A1 (en) * 1972-03-08 1973-10-19 Fuveau Sa Pyrazole carboxamidines - as analgesics and anti inflammatory agents

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2408694A (en) * 1942-05-29 1946-10-01 Libbey Owens Ford Glass Co Method of preparing acyl guanidines
US2926172A (en) * 1957-10-24 1960-02-23 Ethicon Inc New series of organic compounds
US2951843A (en) * 1958-08-06 1960-09-06 Boehringer & Soehne Gmbh Tetrahydrosoquinoline biguanides
US2993062A (en) * 1959-10-22 1961-07-18 Dow Chemical Co Carboxamides of nu-pentachlorophenylethylenediamine
US3093632A (en) * 1961-02-02 1963-06-11 Ciba Geigy Corp Dibenzpolymethylenimino-alkylene-guanidines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2408694A (en) * 1942-05-29 1946-10-01 Libbey Owens Ford Glass Co Method of preparing acyl guanidines
US2926172A (en) * 1957-10-24 1960-02-23 Ethicon Inc New series of organic compounds
US2951843A (en) * 1958-08-06 1960-09-06 Boehringer & Soehne Gmbh Tetrahydrosoquinoline biguanides
US2993062A (en) * 1959-10-22 1961-07-18 Dow Chemical Co Carboxamides of nu-pentachlorophenylethylenediamine
US3093632A (en) * 1961-02-02 1963-06-11 Ciba Geigy Corp Dibenzpolymethylenimino-alkylene-guanidines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2174710A1 (en) * 1972-03-08 1973-10-19 Fuveau Sa Pyrazole carboxamidines - as analgesics and anti inflammatory agents

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