US3352878A - Certain pyridylmethyl guanidine derivatives - Google Patents

Certain pyridylmethyl guanidine derivatives Download PDF

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US3352878A
US3352878A US440948A US44094865A US3352878A US 3352878 A US3352878 A US 3352878A US 440948 A US440948 A US 440948A US 44094865 A US44094865 A US 44094865A US 3352878 A US3352878 A US 3352878A
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methyl
alkyl
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pyridylmethyl
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William F Minor
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Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/12—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from polycarboxylic acids and polyhydroxy compounds
    • C08G63/52—Polycarboxylic acids or polyhydroxy compounds in which at least one of the two components contains aliphatic unsaturation
    • C08G63/56—Polyesters derived from ester-forming derivatives of polycarboxylic acids or of polyhydroxy compounds other than from esters thereof
    • C08G63/58—Cyclic ethers; Cyclic carbonates; Cyclic sulfites ; Cyclic orthoesters

Definitions

  • R is hydrogen or methyl
  • R is (lower)a1kyi 1 and preferably methyl
  • R R and R each represent ABSTRACT OF THE DISCLOSURE hydrogen or (lower)alkyl
  • N'alkylated derivatives and the corresponding Compounds A preferred embodiment of the present invention concontaining a methyl group at the 6-position of the pyri i sists of the salt and free base forms of the compounds ring are anti-depressant agents Which counteract psychic of the formula depression without stimulating motor activity or appearing to stimulate the central nervous system.
  • the 1'(1?Wr) jalkyl'1"(2"Pyndy1mefl ⁇ y1)guamdmes of The compounds of the present invention are best pm the Present mvennon are compounds havmg the formula 'pared from commercially available 2-picolylmethylamine R3 (also named 2-methylaminomethylpyridine) or 6-methyl- 2-picolylmethylamine (also named 6-methyl-2-methyln aminomethylpyridine) (Aldrich Chemical Co.) or a 2- R OH-NCN (lower) alkylaminomethylpyridine or a 6-methyl-2-(low- N er) alkylaminomethylpyridine by reacting such amine with 40 a Z-methyl-Z-thiopseudourea or a cyanamide or a 3,5-diin which R is a member selected from the group conmethyl-l-guanylpyrazole (also called a 3,5-dimethylpyrasisting of hydrogen and methyl, R represents (lower)
  • R1 R 1 1 Rt s R ll H R1 CH2N-H or salt thereof plus CHaS-C- -HI or AHgSO; R1 N CH -ll ICN ⁇ N R2 ⁇ R5 R2 R5 from the group consisting of hydrogen and (lower) alkyl; 4 and the nontoxic pharmaceutically acceptable acid addi- 4 tion salts thereof.
  • This invention relates to a novel series of nontoxic Rr-K CHBN(N antidepressant agents which counteract psychic depression I N without stimulating motor activity or appearing to stimulate the central nervous system and, more particularly HQC NH to 1-(lower)-alkyl-1a(2' ridylmethyl)guanidines and NH their N-alkylated derivatives and the corresponding com- P N NH2-HOl I pounds containing a methyl group at the 6-position of the H1 pyridine ring and their non-toxic, pharmaceutically ac- CH8 2 ceptable acid addition salts.
  • R R R R and R have the meanings set out novel nontoxic antidepressant agents whose use would not above.
  • the products are recovered as the free base or acid be restricted by their exhibition of other pharmacological addition salt depending upon the procedure used for their activity, e.g. hypotensive action, inhibition of monoamine isolation.
  • method A includes the corresponding substiquently exhibited by previously investigated guanidines is -tuted 2-methyl-2-thiopseudoureas (also called S-methylhighly undesirable in an antidepressant agent. isothioureas) prepared by the reaction of a (lower)alkyl
  • the object of the present invention has been achieved iodide or a di(lower)alky1 sulfate with, for example, N-
  • methylthiourea N-n-butylthiourea, N,N-diethylthiourea, N,N,N'-trimethylthiourea.
  • equimolar amounts of the amine and 2-methyl-2-thiopseudourea sulfate or hydriodide in water or ethanol are heated under reflux for several hours or allowed to stand at room temperature overnight. The higher temperatures are preferred.
  • the product is recovered by removal of the solvent in vacuo.
  • the necessary thiopseudoureas also called isothioureas
  • R are each hydrogen or (lower)alky1.
  • method B includes substituted cyanamides which are prepared as reported in the literature and especially by the reaction in equivalent amounts in a solvent such as diethyl ether of cyanogen chloride or cyanogen bromide with an amine of the formula R N R N CN [lithium aluminum hydride R omNrn II 1) RGCl 2) lithium aluminum hydride R1 CH NH HQR wherein R represents hydrogen or methyl and R represents hydrogen or (lower)alkyl.
  • (lower)alkyl refers to straight and branched chainsaturated monovalent aliphatic hydrocarbon radicals having from one to ten carbon atoms inclusive, e.g.- methyl, ethyl,-propyl, isopropyl, butyl, -normal-and secondary and tertiary butyl, 'arnyl, decyl, etc.
  • Includedwithin the present invention are the acid addition salts prepared by reactionof these basic compounds with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid, sulfamic acid, glycolic acid, succinic acid, ascorbic acid and the like. Monoor poly-salts may be formed.
  • organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid, sulfamic acid, glycolic acid, succinic acid, ascorbic acid and the like.
  • Monoor poly-salts may be formed.
  • the new guanidine compounds may be obtained in the form of the free compounds, or as the salts thereof.
  • a salt may be converted into the free compound in the customary way, for example, by treatment with a strong alkaline reagent, such as-aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or a strong quaternary ammonium anion (hydroxy ion) exchange resin and the like.
  • a strong alkaline reagent such as-aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or a strong quaternary ammonium anion (hydroxy ion) exchange resin and the like.
  • a free base may be transformed into-its therapeutically useful acid addition salts by reacting the latter with an appropriate inorganic or organic acid, such as one of those outlined hereinabove; such reaction may be carried out advantageously in a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, an ether, e.g. diethylether, p-dioxane and the like, a lower alkyl lower alkanoate, e.g. ethyl acetate and the like, or a mixture of such solvents, and isolating the desired salt.
  • a solvent such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, an ether, e.g. diethylether, p-dioxane and the like, a lower alkyl lower al
  • Salts of the polybasic compounds of this invention may be obtained, in which not all of the salt-forming basic groups participate in the salt formation. Such salts may be treated with an acid in order to form compounds in which all or a greater number of the basic groups take part inthe salt formation.
  • these compounds are associated with a significant amount of a pharmaceutically acceptable carrier which may be either a solid material or a liquid.
  • a pharmaceutically acceptable carrier which may be either a solid material or a liquid.
  • the compositions may take the form. of tablets, etr'ervescent tablets, powder, granules, capsules (both hard and soft shell. capsules), or suspensions inedible oils, or other dosage forms which are particularly useful for oral ingestion.
  • Liquid diluents are employed .in sterile conditions for parenteral use, that is by intramuscular, intravenous and intraperitoneal injection.
  • Such a medium may be a sterile solvent or suspending agent such as water or an injectable oil.
  • compositions may take the form of active material admixed with solid diluents and/or tabletting adjuvants such as corn starch, lactose, talc, stearic acid, magnesium stearate, gums or the like. Any of the encapsulatingor tabletting materials used in pharmaceutical practice may be employed where there is no incompatibility with the compounds.
  • the materials may be tabletted with or without adjuvants.
  • the compounds may be placed in the usual capsule or resorbable material such as the usual gelatin capsule and administered in that form.
  • the compounds may be put up as a powder and so employed, as by nasal inhalation, or the compounds may be prepared in the form of a palatable suspension in which the compounds are not soluble.
  • Suspensions may be given orally as made or may be encapsulated. Ointments and lotions are useful topically; use for topical therapy is made of nose drops, troches and suppositories.
  • the compounds of the present invention are particularly useful when given by the oral, intramuscular, or intravenous routes; a useful dosage range in man is about 10-1000 mgms. per dose. Dosages are given about one to six timesper day, depending on the patient, the infection, the route of administration and the like.
  • the percentage of the active ingredients in these compositlons may be varied. It is necessary that the. active ingredients constitute a proportion such that a suitable dosage will be obtained. Obviously, several unit dosage forms may be administered at about the same time. Althoughit is found, particularly on intravenous injection, that a percentage of less than 0.10 percent of the compound -is effective, it is preferable to use not less than 0.10 percent of the compounds. Activity increases with the concentrationof the compound. The percentage of active agent may be 10 percent, or 25 percent, or even ahigher proportion of the substance administered. For
  • tablets may be prepared with a minor proportion of diluent and a major proportion of active material. Tablets containing from about to 1000 mgms. of the compound are particularly useful.
  • the solid pharmaceutical carrier used may be an envelope enclosing pure compound in a gelatin capsule.
  • This compound exhibited an oral LD in mice of about 700 mgm./kg. and at doses of 10 mgm./kg. (and even as low as 2 mgm./kg.) p.o. in the mouse given prior to treatment with 5 mgn1./kg. reserpine caused the mice to behave normally and prevented the usual sedative effect of reserpine. This is a marked contrast to the results of pretreatment with monoamine oxidase inhibitors before reserpine dosage as in that instance the mice exhibit great motor stimulation and indeed become so hyperactive that death usually results. Thus this compound exhibits marked antidepressant activity without the undesirable motor stimulation of the usual monoamine oxidase inhibitors.
  • This compound at doses of 20 mgm./kg. (and even as low as mgm./kg.) p.0. in the mouse given prior to treatment with 5 mgm./kg. reserpine caused the mice to behave normally and prevented the usual sedative effect of reserpine. This is a marked contrast to the results of pretreatment with monoamine oxidase inhibitors before reserpine dosage as in that instance the mice exhibit great motor stimulation and indeed become so hyperactive that death usually results. Thus this compound, exhibits marked antidepressant activity without the undesirable motor stimulation of the usual monoamine oxidase inhibitors.
  • the new guanidine compounds of the present invention also form quaternary ammonium compounds, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, di-lower alkyl-sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower :alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate, or lower alkyl monocyclic carbocyclic aryl sulfonates, e.g.
  • lower alkyl halides e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like
  • di-lower alkyl-sulfates e.g
  • the quaternary ammonium compounds may be obtained by reacting a free .base with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl. chloride, bromide or iodide and the like, a di-lower alkyl-sulfate, e.g. dimethyl sulfatehdiethylsulfate and the like, a lower alkyl lower alkane sulfonate, e.g. methyl or ethyl methane or ethane sulfonate and the like, or a lower alkyl monocyclic carbocyclic aryl sulfonate, e.g.
  • a lower alkyl halide e.g. methyl, ethyl, n-propyl, isopropyl. chloride, bromide or iodide and the like
  • the quaternizing reaction may be performed in the presence of a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, methyl ethyl ketone and the like, or an organic acid amide, e.g. formamide, N,N-dimethylformamide and the like.
  • a solvent such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, methyl ethyl ketone and the like, or an organic acid amide, e.g. formamide, N,N-dimethylformamide and the like.
  • the resulting quaternary ammonium compounds are
  • R, R and R each represent (lower)alky1.

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  • Health & Medical Sciences (AREA)
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Description

' 3,352,878 Ice Patented Nov. 14, 1967 United States Patent I O by the provision, according to the present invention, of 3,352,878 bases of the formula CERTAIN PYRIDYLMETHYL GUANIDINE DERIVATIVES R William F. Minor, Fayetteville, N.Y., assignor to Bristoll Myers Company, New York, N.Y., a corporation of 5 I I Delaware R1 QHZN (JJ N No Drawing. Filed Mar. 18, 1965, Ser. No. 440,948 N/ I v 12 Claims. Cl. 260-296) in which R is hydrogen or methyl, R is (lower)a1kyi 1 and preferably methyl and R R and R each represent ABSTRACT OF THE DISCLOSURE hydrogen or (lower)alkyl; and the nontoxic, pharmaceuti- 1 (lower)-alkyl-l-(2'-pyridylmethyl)guanidines, their cally acceptable acid addition salts thereof.
N'alkylated derivatives and the corresponding Compounds A preferred embodiment of the present invention concontaining a methyl group at the 6-position of the pyri i sists of the salt and free base forms of the compounds ring are anti-depressant agents Which counteract psychic of the formula depression without stimulating motor activity or appearing to stimulate the central nervous system.
I NH
I Background of the invention 4 CHPIIFAJIH (1) Fzeld of the znventz0n.-Th1s invention relates to chemical compounds acting as antidepressants which are wherein R represents (lower) alkyl. useful in the treatment of psychic depression in man. Another preferred series of compounds of the present (2) Description of the prior art.--The compounds of invention is that of'the compounds of the formula the present invention represent a new family of antidepressant agents. Heretofore compounds of this general chemical structure have only been associated with anti- I F hypertensive activity. H3 OHPN-(l-NH:
Summary of the invention wherein R represents (lower)alkyl.
The 1'(1?Wr) jalkyl'1"(2"Pyndy1mefl}y1)guamdmes of The compounds of the present invention are best pm the Present mvennon are compounds havmg the formula 'pared from commercially available 2-picolylmethylamine R3 (also named 2-methylaminomethylpyridine) or 6-methyl- 2-picolylmethylamine (also named 6-methyl-2-methyln aminomethylpyridine) (Aldrich Chemical Co.) or a 2- R OH-NCN (lower) alkylaminomethylpyridine or a 6-methyl-2-(low- N er) alkylaminomethylpyridine by reacting such amine with 40 a Z-methyl-Z-thiopseudourea or a cyanamide or a 3,5-diin which R is a member selected from the group conmethyl-l-guanylpyrazole (also called a 3,5-dimethylpyrasisting of hydrogen and methyl, R represents (lower) zole-l-carboxamidine) as illustrated by the following alkyl and R R and R each represent a member selected equations:
R1 R: 1 1 Rt s R ll H R1 CH2N-H or salt thereof plus CHaS-C- -HI or AHgSO; R1 N CH -ll ICN\ N R2 \R5 R2 R5 from the group consisting of hydrogen and (lower) alkyl; 4 and the nontoxic pharmaceutically acceptable acid addi- 4 tion salts thereof. p us N -N I This invention relates to a novel series of nontoxic Rr-K CHBN(N antidepressant agents which counteract psychic depression I N without stimulating motor activity or appearing to stimulate the central nervous system and, more particularly HQC NH to 1-(lower)-alkyl-1a(2' ridylmethyl)guanidines and NH their N-alkylated derivatives and the corresponding com- P N NH2-HOl I pounds containing a methyl group at the 6-position of the H1 pyridine ring and their non-toxic, pharmaceutically ac- CH8 2 ceptable acid addition salts.
It was the object of the present invention to provide wherein R R R R and R have the meanings set out novel nontoxic antidepressant agents whose use would not above. The products are recovered as the free base or acid be restricted by their exhibition of other pharmacological addition salt depending upon the procedure used for their activity, e.g. hypotensive action, inhibition of monoamine isolation.
oxidase. Thus, the hypotensive or the diuretic action fre- The use of method A includes the corresponding substiquently exhibited by previously investigated guanidines is -tuted 2-methyl-2-thiopseudoureas (also called S-methylhighly undesirable in an antidepressant agent. isothioureas) prepared by the reaction of a (lower)alkyl The object of the present invention has been achieved iodide or a di(lower)alky1 sulfate with, for example, N-
methylthiourea, N-n-butylthiourea, N,N-diethylthiourea, N,N,N'-trimethylthiourea. In -a useful procedure equimolar amounts of the amine and 2-methyl-2-thiopseudourea sulfate or hydriodide in water or ethanol are heated under reflux for several hours or allowed to stand at room temperature overnight. The higher temperatures are preferred. The product is recovered by removal of the solvent in vacuo. The necessary thiopseudoureas (also called isothioureas) can be made as follows R wherein R R and R are each hydrogen or (lower)alky1. (See Organic Syntheses III, 363 and British Patent 973,- 882.) These S-methylpseudothioureas may be replaced by O-methylpseudoureas.
The use of method B includes substituted cyanamides which are prepared as reported in the literature and especially by the reaction in equivalent amounts in a solvent such as diethyl ether of cyanogen chloride or cyanogen bromide with an amine of the formula R N R N CN [lithium aluminum hydride R omNrn II 1) RGCl 2) lithium aluminum hydride R1 CH NH HQR wherein R represents hydrogen or methyl and R represents hydrogen or (lower)alkyl.
The term (lower)alkyl as used herein refers to straight and branched chainsaturated monovalent aliphatic hydrocarbon radicals having from one to ten carbon atoms inclusive, e.g.- methyl, ethyl,-propyl, isopropyl, butyl, -normal-and secondary and tertiary butyl, 'arnyl, decyl, etc.
Includedwithin the present invention are the acid addition salts prepared by reactionof these basic compounds with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid, sulfamic acid, glycolic acid, succinic acid, ascorbic acid and the like. Monoor poly-salts may be formed.
The new guanidine compounds may be obtained in the form of the free compounds, or as the salts thereof. A salt may be converted into the free compound in the customary way, for example, by treatment with a strong alkaline reagent, such as-aqueous alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or a strong quaternary ammonium anion (hydroxy ion) exchange resin and the like. A free base may be transformed into-its therapeutically useful acid addition salts by reacting the latter with an appropriate inorganic or organic acid, such as one of those outlined hereinabove; such reaction may be carried out advantageously in a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, an ether, e.g. diethylether, p-dioxane and the like, a lower alkyl lower alkanoate, e.g. ethyl acetate and the like, or a mixture of such solvents, and isolating the desired salt. Salts of the polybasic compounds of this invention may be obtained, in which not all of the salt-forming basic groups participate in the salt formation. Such salts may be treated with an acid in order to form compounds in which all or a greater number of the basic groups take part inthe salt formation.
For use as antidepressant'agents, these compounds are associated with a significant amount of a pharmaceutically acceptable carrier which may be either a solid material or a liquid. The compositions may take the form. of tablets, etr'ervescent tablets, powder, granules, capsules (both hard and soft shell. capsules), or suspensions inedible oils, or other dosage forms which are particularly useful for oral ingestion. Liquid diluents are employed .in sterile conditions for parenteral use, that is by intramuscular, intravenous and intraperitoneal injection. Such a medium may be a sterile solvent or suspending agent such as water or an injectable oil. The compositions may take the form of active material admixed with solid diluents and/or tabletting adjuvants such as corn starch, lactose, talc, stearic acid, magnesium stearate, gums or the like. Any of the encapsulatingor tabletting materials used in pharmaceutical practice may be employed where there is no incompatibility with the compounds. The materials may be tabletted with or without adjuvants. Alternatively, the compounds may be placed in the usual capsule or resorbable material such as the usual gelatin capsule and administered in that form. In yet another embodiment, the compounds may be put up as a powder and so employed, as by nasal inhalation, or the compounds may be prepared in the form of a palatable suspension in which the compounds are not soluble. Suspensions may be given orally as made or may be encapsulated. Ointments and lotions are useful topically; use for topical therapy is made of nose drops, troches and suppositories. The compounds of the present invention are particularly useful when given by the oral, intramuscular, or intravenous routes; a useful dosage range in man is about 10-1000 mgms. per dose. Dosages are given about one to six timesper day, depending on the patient, the infection, the route of administration and the like.
The percentage of the active ingredients in these compositlons may be varied. It is necessary that the. active ingredients constitute a proportion such that a suitable dosage will be obtained. Obviously, several unit dosage forms may be administered at about the same time. Althoughit is found, particularly on intravenous injection, that a percentage of less than 0.10 percent of the compound -is effective, it is preferable to use not less than 0.10 percent of the compounds. Activity increases with the concentrationof the compound. The percentage of active agent may be 10 percent, or 25 percent, or even ahigher proportion of the substance administered. For
example, tablets may be prepared with a minor proportion of diluent and a major proportion of active material. Tablets containing from about to 1000 mgms. of the compound are particularly useful. The solid pharmaceutical carrier used may be an envelope enclosing pure compound in a gelatin capsule.
The following examples will illustrate the present invention without limiting it thereto.
EXAMPLE I I-methyl-I-(2'-pyridylethyl)guanidine sulfate.To a warm solution of 13.9 g. (0.05 mole) of 2-rnethyl-2- thiopseudourea sulfate in 40 mil. water was added 12.2 g. (0.10 mole) of 2-picolylmethylamine (Aldrich Chemical Co.). Brief warming caused a vigorous reaction with evolution of methyl mercaptan. After being heated for three hours on the steam bath the solution was cooled and the crystalline product, l-methyl-l-(Z-pyridylmethyl) guanidine sulfate, was collected and recrystallized from 50% ethanol; yield 4.3 g., M.P. 267.5268 C. (dec.).
Analysis.Calcd for (C H N -H SO -H O: C, 43.23; H, 6.35; N, 25.21. Found: C, 43.45; H, 6.32; N, 25.50.
This compound exhibited an oral LD in mice of about 700 mgm./kg. and at doses of 10 mgm./kg. (and even as low as 2 mgm./kg.) p.o. in the mouse given prior to treatment with 5 mgn1./kg. reserpine caused the mice to behave normally and prevented the usual sedative effect of reserpine. This is a marked contrast to the results of pretreatment with monoamine oxidase inhibitors before reserpine dosage as in that instance the mice exhibit great motor stimulation and indeed become so hyperactive that death usually results. Thus this compound exhibits marked antidepressant activity without the undesirable motor stimulation of the usual monoamine oxidase inhibitors.
EXAMPLE 2 respectively, produces the products of the formulae II CHr-N-C-NHCH;
CHHOHQ N N/ CHr-N -N(CH (1H3 respectively, as their sulfate salts.
EXAMPLE 3 Substitution in the procedure of Example 1 for the 2- picolylmethylamine used therein of an equimolar weight of 2-ethylaminomethylpyridine and 2-n-propylaminomethylpyridine, respectively, produces the compounds of the formulae I OH;
and
Repetition of the procedures of Example 2 with the replacement of the 2-picolylmethylamine used therein with an equimolar weight of 6-methyl-2-picolylmethylamine produces the compounds of the following formulae:
respectively, as their sulfate salts.
1 -methyl-1 (6 methyl 2' pyria'ylmethyl)guanidine hemisulfate mn0hydrate.-To a solution of 13.6 g. (0.10 mole) of 6-methyl-2-picolylmethylamine (Aldrich) in 40 ml. water there was added 14.0 g. (0.05 mole) of 2- methyl-Z-thiopseudourea sulfate (Eastman Kodak C0,). The mixture was heated to reflux and then refluxed for 6.5 hours. The evolution of methyl mercaptan became vigorous at about 80 C. The mixture was then allowed to stand overnight at 25 C. Upon cooling in ice crystalline l-methyl 1 (6-methyl-2-pyridylmethyl)guanidine hemisulfate separated and was collected by filtration, recrystallized from aqueous acetone dried in vacuo over P 0 at 25 C. and found to weigh 3.4 g., MP. 243-- 244.5 C. (dec.).
Analysis.-Calcd for C H N O S-H O: C, 45.75; H, 6.83; N, 23.71. Found: C, 45.75; H, 6.68; N, 23.50.
This compound at doses of 20 mgm./kg. (and even as low as mgm./kg.) p.0. in the mouse given prior to treatment with 5 mgm./kg. reserpine caused the mice to behave normally and prevented the usual sedative effect of reserpine. This is a marked contrast to the results of pretreatment with monoamine oxidase inhibitors before reserpine dosage as in that instance the mice exhibit great motor stimulation and indeed become so hyperactive that death usually results. Thus this compound, exhibits marked antidepressant activity without the undesirable motor stimulation of the usual monoamine oxidase inhibitors.
The new guanidine compounds of the present invention also form quaternary ammonium compounds, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, di-lower alkyl-sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower :alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate, or lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl P-toluenesulfonate, and thelike, as well as thecorresponding quaternary ammonium hydroxides and the salts, which may be formed from the quaternary ammonium hydroxides by the reaction with inorganic acids other than the hydrohalic acids or with organic acids such as those outlined above for the preparation of the acid addition salts.
The quaternary ammonium compounds may be obtained by reacting a free .base with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl. chloride, bromide or iodide and the like, a di-lower alkyl-sulfate, e.g. dimethyl sulfatehdiethylsulfate and the like, a lower alkyl lower alkane sulfonate, e.g. methyl or ethyl methane or ethane sulfonate and the like, or a lower alkyl monocyclic carbocyclic aryl sulfonate, e.g. methyl p-toluene sulfonate and the like. The quaternizing reaction may be performed in the presence of a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, methyl ethyl ketone and the like, or an organic acid amide, e.g. formamide, N,N-dimethylformamide and the like. The resulting quaternary ammonium compounds, are efiectiveantiseptic and germicidal a ents.
While in the foregoing specification various embodiments of this invention have been set forth in specific detail and elaborated for the purpose of illustration, it will be apparent to those skilled in the art that this invention is susceptible to other embodiments and that many of the details can be varied widely without departing from the basic concept andthe spirit and scope of the invention.
I claim:
1. A member selected from the groupconsisting of bases of the formula wherein .R represents (lower).alkyl.
3. The compounds of the formula wherein R represents (lower)alkyl.
4. The compounds of the formula N/ CH Af-PP-NH- li in which each ofR and R is (lower) alkyl.
5. The compounds of the formula,
in which R, R and R each represent (lower)alky1.
6. The compounds of the formula IIIH a CHg-N-C-NHR N ll wherein R and'll each represent (lower)alkyl.
7. The compound of the formula 8. The compound of the formula.
IIITH N CHr-N- C-NH1 9. The compound of the formula 9 10. The compound of the formula I N-CH:
N CHrI| T -N( Ha): CH; 12. The compound of the formula References Cited UNITED STATES PATENTS 3/1960 Mull. 5/1962 Mull. 7/1963 Mull. 4/ 1965 Mull.
FOREIGN PATENTS 3/1962 Great Britain. 10/ 1964 Great Britain.
OTHER REFERENCES Chemical Abstracts 42, 8957e (1948). 15 Short eta1.: J. Med. Chem. 6, 275-283 (1963).
Mull et 211.: J. Org. Chem. 25, 1953-1956 (1960).
WALTER A. MODANCE, Primary Examiner. 20 A. L. ROTMAN, Assistant Examiner.

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3933836A (en) * 1974-09-26 1976-01-20 E. R. Squibb & Sons, Inc. Pyridinylidene guanidines
EP0009362A1 (en) * 1978-09-18 1980-04-02 McNeilab, Inc. Heterocyclic derivatives of guanidine, their preparation and pharmaceutical formulations comprising them
US20110105797A1 (en) * 2009-11-02 2011-05-05 Tianjin Tiancheng Pharmaceutical Co., Ltd. Creatinol sulfate and synthesis method thereof

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Publication number Priority date Publication date Assignee Title
US2928829A (en) * 1959-08-31 1960-03-15 Ciba Pharm Prod Inc Alkyleneimino-lower alkyl-guanidines
GB890602A (en) * 1959-05-15 1962-03-07 Ciba Ltd New pyridine compounds and process for their manufacture
US3098066A (en) * 1960-03-04 1963-07-16 Ciba Geigy Corp Diaza-heterocyclic guanidine compounds
GB973882A (en) * 1959-12-23 1964-10-28 Wellcome Found Benzyl-guanidines,their preparation and pharmaceutical compositions containing them
US3178443A (en) * 1963-04-01 1965-04-13 Ciba Geigy Corp N-(2-guandinoethyl)-n-(picolyl)-amines

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB890602A (en) * 1959-05-15 1962-03-07 Ciba Ltd New pyridine compounds and process for their manufacture
US3036083A (en) * 1959-05-15 1962-05-22 Ciba Geigy Corp Certain 2-pyridyl lower alkyl guanidines
US2928829A (en) * 1959-08-31 1960-03-15 Ciba Pharm Prod Inc Alkyleneimino-lower alkyl-guanidines
GB973882A (en) * 1959-12-23 1964-10-28 Wellcome Found Benzyl-guanidines,their preparation and pharmaceutical compositions containing them
US3098066A (en) * 1960-03-04 1963-07-16 Ciba Geigy Corp Diaza-heterocyclic guanidine compounds
US3178443A (en) * 1963-04-01 1965-04-13 Ciba Geigy Corp N-(2-guandinoethyl)-n-(picolyl)-amines

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3933836A (en) * 1974-09-26 1976-01-20 E. R. Squibb & Sons, Inc. Pyridinylidene guanidines
EP0009362A1 (en) * 1978-09-18 1980-04-02 McNeilab, Inc. Heterocyclic derivatives of guanidine, their preparation and pharmaceutical formulations comprising them
US20110105797A1 (en) * 2009-11-02 2011-05-05 Tianjin Tiancheng Pharmaceutical Co., Ltd. Creatinol sulfate and synthesis method thereof

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