EP0000952B1 - Benzhydryl guanidine derivatives and pharmaceutical compositions - Google Patents
Benzhydryl guanidine derivatives and pharmaceutical compositions Download PDFInfo
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- EP0000952B1 EP0000952B1 EP78100774A EP78100774A EP0000952B1 EP 0000952 B1 EP0000952 B1 EP 0000952B1 EP 78100774 A EP78100774 A EP 78100774A EP 78100774 A EP78100774 A EP 78100774A EP 0000952 B1 EP0000952 B1 EP 0000952B1
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/18—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms
- C07C331/22—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C331/24—Isothiocyanates having isothiocyanate groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
- C07C335/10—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C335/12—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- This invention relates to benzhydryl guanidine derivatives having the formula wherein:
- novel benzhydryl guanidine derivatives of Formula (I) as free bases are generally soluble in many common polar and non-polar organic solvents such as aromatic hydrocarbons, e.g., benzene or toluene; haloaromatic hydrocarbons, e.g., chlorobenzene or 1,2-dichlorobenzene; haloaliphatic hydrocarbons, e.g., chloroform, methylene dichloride or 1,2-dichloroethane; lower alkanols, e.g., methanol, isopropanol or t-butanol; ethers, e.g., diethyl ether or dioxane; and ketones, e.g., acetone or 2-butanone. They are preferably obtained and employed in the form of their acid addition salts which are generally white crystalline solids soluble in water and polar solvents such as the lower alkanols or ketones.
- Suitable acids may be inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric and nitric acids, or organic acids such as acetic, propionic, glycolic, pamoic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic and p-aminosalicylic acids.
- the preferred acid addition salts are the hydrohalic addition salts.
- loweralkyl refers to a straight or branch chained hydrocarbon radical having from 1 to 5 carbons, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl or isoamyl; and the term "halo" represents a halogen of atomic weight less than 127, i.e., chloro, bromo, fluoro and iodo.
- the compounds of Formula (I) are conveniently prepared by reacting a methylthio compound of Formula (II), wherein R,, Y and Z are as previously defined, in acid addition salt (HX) form with an appropriate amine of Formula (III), wherein R 2 , R 3 and -NR 2 R 3 are as previously defined, preferably utilizing a stoichiometric excess of (III), in a lower alkanol solvent such as isopropanol and t-butanol and generally at reflux temperatures to yield the benzhydryl guanidine compounds of Formula (I) in acid addition salt form which are readily transformed into the corresponding base form by conventional treatment with suitable alkali.
- reaction of (II) with (111) may be performed utilizing approximately equimolar amounts in which case up to an equimolar amount of a suitable tertiary amine, such as, for example, triethylamine or tripropylamine, is preferably added in order to enhance the rate of reaction.
- a suitable tertiary amine such as, for example, triethylamine or tripropylamine
- the precursors of Formula (II) are obtainable by methods reported in the literature.
- the compound wherein Y, Z and R, all equal hydrogen may be prepared according to S. O. Winthrop et a/., J. Am. Chem. Soc., 79, 3496 (1957), which describes the reaction of benzhydryl amine, preferably as the hydrochloride salt, with ammonium thiocyanate to yield N-benzhydryl thiourea which is then methylated by standard S-methylation techniques to yield methyl N-benzhydrylcarbamimidothioate as an acid addition salt.
- the compounds represented by Formula (I) and the acid addition salts thereof are useful as hypoglycemic agents suitable for lowering blood sugar. This property may be demonstrated by the rat glucose tolerance test, an extremely sensitive standard procedure used in the diagnosis of diabetes and hypoglycemic disease states.
- the mean glucose values of the controls are compared statistically by the Student's t-Test to the means of the experimental group at each of the corresponding time points. If the compound lowers the blood glucose significantly at any time at a 95% confidence limit, the compound is considered to have hypoglycemic activity.
- the blood glucose lowering expressed as percent lowering, is obtained by dividing the difference between the mean blood glucose values for test and control animals by the mean glucose value for the control animal.
- the cloudy oil is treated with 500 ml of pentane which dissolves the product and precipitates more insoluble impurities. Filtration through filter aid (diatomaceous earth) and solvent removal in vacuo gives p-chlorobenzhydryl isothiocyanate as an oil; IR (neat) 2140 cm -1.
Description
- In U.S. Patent No. 3,961,056, certain benzyl derivatives of guanidine are described as having anti- arrhythmic and diuretic uses. However, no benzhydryl derivatives of guanidine are described.
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- R, is a member selected from the group consisting of hydrogen and loweralkyl, preferably methyl and ethyl;
- R2 is a member selected from the group consisting of hydrogen and loweralkyl, preferably methyl and ethyl;
- R3 is a member selected from the group consisting of hydrogen, loweralkyl, preferably methyl and ethyl, and cycloalkyl, preferably cyclopentyl and cyclohexyl;
- The novel benzhydryl guanidine derivatives of Formula (I) as free bases are generally soluble in many common polar and non-polar organic solvents such as aromatic hydrocarbons, e.g., benzene or toluene; haloaromatic hydrocarbons, e.g., chlorobenzene or 1,2-dichlorobenzene; haloaliphatic hydrocarbons, e.g., chloroform, methylene dichloride or 1,2-dichloroethane; lower alkanols, e.g., methanol, isopropanol or t-butanol; ethers, e.g., diethyl ether or dioxane; and ketones, e.g., acetone or 2-butanone. They are preferably obtained and employed in the form of their acid addition salts which are generally white crystalline solids soluble in water and polar solvents such as the lower alkanols or ketones.
- The non-toxic, therapeutically acceptable acid addition salts of the Formula (I) compounds are also embraced within the scope of this invention. Suitable acids may be inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric and nitric acids, or organic acids such as acetic, propionic, glycolic, pamoic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic and p-aminosalicylic acids. The preferred acid addition salts are the hydrohalic addition salts.
- As used herein, the term "loweralkyl" refers to a straight or branch chained hydrocarbon radical having from 1 to 5 carbons, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl or isoamyl; and the term "halo" represents a halogen of atomic weight less than 127, i.e., chloro, bromo, fluoro and iodo.
- The compounds of Formula (I) are conveniently prepared by reacting a methylthio compound of Formula (II), wherein R,, Y and Z are as previously defined, in acid addition salt (HX) form with an appropriate amine of Formula (III), wherein R2, R3 and -NR2R3 are as previously defined, preferably utilizing a stoichiometric excess of (III), in a lower alkanol solvent such as isopropanol and t-butanol and generally at reflux temperatures to yield the benzhydryl guanidine compounds of Formula (I) in acid addition salt form which are readily transformed into the corresponding base form by conventional treatment with suitable alkali. Alternatively, the reaction of (II) with (111) may be performed utilizing approximately equimolar amounts in which case up to an equimolar amount of a suitable tertiary amine, such as, for example, triethylamine or tripropylamine, is preferably added in order to enhance the rate of reaction. The foregoing reaction may be illustrated as follows:
- The precursors of Formula (II) are obtainable by methods reported in the literature. For example, the compound wherein Y, Z and R, all equal hydrogen may be prepared according to S. O. Winthrop et a/., J. Am. Chem. Soc., 79, 3496 (1957), which describes the reaction of benzhydryl amine, preferably as the hydrochloride salt, with ammonium thiocyanate to yield N-benzhydryl thiourea which is then methylated by standard S-methylation techniques to yield methyl N-benzhydrylcarbamimidothioate as an acid addition salt.
- Alternatively, the precursors of Formula (II) may be prepared by the following synthetic sequence. The benzhydrylamines of Formula (IV), which compounds and methods of preparing same are known in the literature, are transformed into the corresponding benzhydryl isothiocyanates of Formula (V) according to the method described by J. C. Jochims et al., Angew. Chem. Internat. Ed., 6 (2), 174 (1967), which method involves the interaction of (IV) with excess carbon disulfide in the presence of an equimolar amount of dicyclohexylcarbodiimide (DCC) at initial temperatures preferably below 0°C in anhydrous ether.
- The resultant benzhydryl isothiocyanate (V), which may be isolated from the reaction mixture and purified by conventional means, is then converted to the corresponding N-benzhydrylthiourea of Formula (VI) by the reactions of (V) with ammonia or a primary amine of the formula, R,NH2, wherein R, is a substituent as previously defined, preferably in an ethereal solvent such as, for example, diethyl ether, tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane at about 0°C to ambient temperature.
- The thus-obtained N-benzhydrylthiourea (VI), which may be isolated from the reaction mixture and purified by conventional techniques, is then subjected to S-methylation according to methods reported in the literature for the conversion of thioureas to S-methyl-pseudothioureas, e.g., see Winthrop et al., loc. cit., which utilize methyl iodide and methyl chloride as the methylating agent. Other methylating agents which may be employed include methyl mesylate, methyl tosylate and methyl fluorosulfonate. The preferred methylating agent is methyl iodide. In general, the S-methylated product (II) is obtained in the form of an acid addition salt (HX).
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- Typical benzhydryl guanidine derivatives of Formula (I) which may be prepared according to the synthetic procedures described herein by using appropriate precursors are:
- N-(4,4'-dichlorobenzhydryl)-4-thiamorpholinecarboximidamide;
- N-(4,4'-dichlorobenzhydryl)-N',N'-diethylguanidine;
- N-(4-chlorobenzhydryl)-N'-cyclohexyl-N'-methylguanidine;
- N-(4-chlorobenzhydryl)-N'-ethyl-N',N"-dimethylguanidine;
- N-(4,4'-diethoxybenzhydryl)-N'-ethyl-1-piperidinecarboximidamide;
- N-(4,4'-diethoxybenzhydryi)-N'-ethyt-1-pyrroiidinecarboximidamide;
- N-(4,4'-dimethoxybenzhydryl)-N'-cyclopentyl-N'-methylguanidine;
- N-(4,4'-dimethoxybenzhydryl)-4-morpholinecarboximidamide;
- N-(4,4'-dimethoxybenzhydryl)-1-(4-phenylpiperazine) carboximidamide;
- N-(4,4'-dibromobenzhydryl)-1-piperidinecarboximidamide;
- N-(3-bromobenzhydryl)-4-thiamorpholinecarboximidamide;
- N-(3-bromobenzhydryl)-N'-methyl-4-thiamorpholinecarboximidamide;
- N-(4-chlorobenzhydryl)-1-(4-methylpiperazine)carboximidamide;
- N-(4-chlorobenzhydryl)-N'-cyclohexyl-N'-methylguanidine;
- N-(4,4'-diethoxybenzhydryl)-N',N'-diethylguanidine;
- N-(4,4'-diethoxybenzhydryl)-1-pyrrolidinecarboximidamide;
- N-(4,4'-dimethylbenzhydryl)-4-morpholinecarboximidamide;
- N-(4,4'-dimethylbenzhydryl)-N',N'-diethylguanidine;
- N-(4-methylbenzhydryl)-N'-cyclohexyl-N'-methylguanidine;
- N-(4-methylbenzhydryl)-N'-ethyl-N'-methylguanidine;
- N-(4-methoxybenzhydryl)-N'-cyclopentyl-N'-methylguanidine;
- N-(4-methoxybenzhydryl)-1-pyrrolidinecarboximidamide; and
- N-(4-methoxybenzhydryl)-4-morpholinecarboximidamide.
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- Furthermore, when the benzhydryl substituents Y and Z are non-identical or in different positions on their respective phenyl rings, it is evident that optical isomeric forms (d- and I-) of the Formula (I) products are possible. For example, by utilizing an appropriate resolved (d- or I-) benzhydrylamine of Formula (IV) as a precursor in the synthetic sequence previously described, the final Formula (I) product thus-obtained will similarly be a d- or I-optical isomer.
- In the following examples, the terms "benzhydryl" and "diphenylmethyl" are equivalent. Furthermore, the terms "guanidine" and "N-carboximidamide" are utilized as dictated for purposes of clarity according to the structure of the particular compound of Formula (I) under consideration.
- The compounds represented by Formula (I) and the acid addition salts thereof are useful as hypoglycemic agents suitable for lowering blood sugar. This property may be demonstrated by the rat glucose tolerance test, an extremely sensitive standard procedure used in the diagnosis of diabetes and hypoglycemic disease states.
- In this test, male Sprague-Dawley rats (Charles River 184-250 grams) are given water ad libitum and fasted 24 hours prior to the experiment. Two to five rats are used for each test and control group. Test compounds, 0.5-100 mg/kg., are administered (s.c., i.p. or orally) suspended in 0.5 or 1.0 milliliter, but preferably the former, of 0.5-1.0% methylcellulose vehicle. Control animals are given an equal amount of vehicle. Serial blood samples (0.1 milliliter) are obtained from the tail without anesthesia prior to and at 30, 60, 90, 120, 150 and 180 minutes after administration of 0.8 to 1.0 gram of glucose per kilogram of body weight in 1 milliliter of water. (The glucose is given orally if the test compound has been given parenterally, and subcutaneously if the test compound has been given orally.) Specimens of blood are immediately deproteinized with aqueous solutions of Ba(OH)2 and ZnS04 and glucose levels are determined using the glucose oxidase assay described by L. P. Cawley et al., "Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase", Amer. J. Clin. Path., 32, 195 (1959). The blood glucose values at each time point are expressed in terms of milligram percent (mg. glucose/100 ml. of blood). The mean glucose values of the controls are compared statistically by the Student's t-Test to the means of the experimental group at each of the corresponding time points. If the compound lowers the blood glucose significantly at any time at a 95% confidence limit, the compound is considered to have hypoglycemic activity. The blood glucose lowering, expressed as percent lowering, is obtained by dividing the difference between the mean blood glucose values for test and control animals by the mean glucose value for the control animal.
- For reducing blood glucose, the compounds of Formula (I) may be employed at a dosage range of about 0.5-100 mg./kg. body weight. It has been found, for example, that administration of the most preferred compounds, the acid addition salts of N-benzhydryl-1-pyrrolidinecarboximidamide or N-benzhydryl-4-morpholinecarboximidamide, at 1-10 mg./kg. body weight p.o. provides a marked lowering of blood sugar in test animals.
- In view of the aforementioned hypoglycemic activity of the Formula (I) compounds and salts thereof, this invention provides valuable pharmaceutical compositions comprising the said compounds as the active hypoglycemic ingredient in admixture with a pharmaceutical carrier.
- To prepare the pharmaceutical compositions of this invention, a benzhydryl guanidine of Formula (1) or acid addition salt thereof, as the active hypoglycemic ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed: Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders and disintegrating agents. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers and suspending agents may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection or teaspoonful, from about 10 to about 500 mg. of the active ingredient, and, preferably, from about 10 to about 250 mg.
- Following are specific examples of compounds of Formula (I) which can be compounded into pharmaceutical compositions and used within the scope of this invention. These examples are not intended to be limitations upon the broad scope of the invention but merely illustrative.
- To 76.86 g (0.2 mole) of methyl N-(diphenylmethyl)-carbamidothioate hydroiodide in t-BuOH (120 ml) is added 28.44 g (0.4 mole) of pyrrolidine. The resulting mixture is heated under reflux on the steam bath for 3-1/2 hours. The reaction mixture is cooled to room temperature affording crystals of crude HI salt, mp. 200-203°C. Recrystallization from tert.-BuOH gives pure N-diphenylmethyl-1-pyrrolidinecarboximidamide hydroiodide; mp. 205-206°C.
- Conversion of the HI salt of Example IA to the free base in CH2CI* 2 by treatment with cold 20% NaOH; drying the organic layer over KZC03, filtration, and solvent removal in vacuo gives the free base.
- Treatment of the free base in moist isopropanol with HCI gas furnishes the crude hydrochloride hemihydrate. The crystals are recrystallized from i-PrOH to give the pure salt; N-diphenylmethyl-1-pyrrolidinecarboximidamide hydrochloride hemihydrate; m.p. 230-233°C.
- 1-(Diphenylmethyl)-2-methyl-2-thiopseudourea hydroiodide (19.2 g, 0.05 mole) in 75 ml tert- butanol is heated at reflux for 24 hours with morpholine (8.7 g, 0.1 mole) under a slow stream of nitrogen. The effluent gas is passed through sodium hypochlorite and sodium hydroxide traps to remove the methyl mercaptan formed in the reaction. The mixture was taken to dryness in vacuo and the residue was treated with 3N sodium hydroxide. Extraction with methylene chloride, washing the combined extracts with water, drying over potassium carbonate, filtration and solvent removal under reduced pressure furnishes an oil which solidifies on standing. Recrystallization several times from acetone-ether gives N-(diphenylmethyl)-4-morpholinecarboximidamide as a white solid; mp. 122-1240C.
- To a suspension of 9.61 g (0.025 mole) of methyl N-(diphenylmethyl)-carbamimidothioate hydroiodide in 20 ml of t-BuOH is added 3.66 g (0.05 mole) of diethylamine. The mixture is heated under reflux for twenty hours (trapping the methyl mercaptan formed in the reaction with NaOH and NaOCI sol'n). About two additional mls of dimethyl amine is added and refluxing is resumed for another 4 hours. The resulting white solid is filtered from the cooled reaction mixture and washed with t-BuOH and ether to yield crude product mp. 187-189°C. The pure product, N,N-diethyl-N'- diphenylmethylguanidine hydroiodide, is isolated after one recrystallization from 1:1:1 MeOH/i-PrOH/t-BuOH as a white crystalline solid, mp. 187-189°C.
- To a suspension of 9.61 g (0.025 mole) of methyl N-(diphenylmethyl)-carbamimidothioate hydroiodide in 20 ml of t-BuOH is added 4.26 g (0.05 mole) of piperidine. The mixture is heated under reflux overnight. The resulting crystals after cooling in ice, are filtered; mp. 200-213°C. One crystallization from methanol-t-BuOH yields the pure product, N-(diphenylmethyl)-1-piperidinecarboximidamide monohydroiodide as a white crystalline solid; mp. 207-2100C.
- To 8.84 g (0.023 mole) of methyl N-diphenylmethylcarbamidothioate hydroiodide in t-BuOH is added 4.71 g (0.047 mole) of N-methylpiperazine. The resultant mixture is allowed to heat under reflux overnight. The mixture is evaporated to dryness in vacuo then diluted with i-PrOH to give crystals; mp. 200-204°C. The crystals are recrystallized from 2-propanol affording pure product, N-(diphenylmethyl)-1-(4-methylpiperazine)carboximidamide monohydroiodide hydrate; mp. 202-204°C.
- A mixture of 80 ml of carbon disulfide and 39.82 g (0.193 mole) of dicyclohexylcarbodiimide in 100 ml of anhydrous ether, under dry N2, is cooled with stirring to -35°C. Then 42.23 g (0.194 mole) of p-chlorobenzhydrylamine in 500 ml of dry ether is added over about 5 min such that the temperature within the reaction vessel does not rise above -20°C. The temperature is allowed to rise slowly over 3 hrs. to ca. 25°C and stirring is continued overnight. Dicyclohexylthiourea was removed by filtration and the filtrate is taken to dryness in vacuo. The cloudy oil is treated with 500 ml of pentane which dissolves the product and precipitates more insoluble impurities. Filtration through filter aid (diatomaceous earth) and solvent removal in vacuo gives p-chlorobenzhydryl isothiocyanate as an oil; IR (neat) 2140 cm-1.
- A solution of 4-chlorobenzhydryl isothiocyanate (5.2 g, 0.02M) in 50 ml of dry ether at 0°C is treated with NH3 (anhyd.) for 1/2 hour while maintaining a temperature of 0.2 with stirring. Stirring is continued an additional 1.5 hours at 9 to 10°C during which time a white solid appears. The crude thiourea is filtered and washed thoroughly with ether; mp. 173-175°C. The filtrate is concentrated in vacuo to yield additional product. The combined crops of N-(4-chlorobenzhydryl)thiourea are used in the next step without further purification.
- A solution of 5.3 g (0.019 mole) of N-(4-chlorobenzhydryl)thiourea in 25 ml of methanol is treated with 2.64 g (0.019 mole) of methyl iodide and allowed to stir at room temperature overnight. The methanol is removed in vacuo to yield the crude pseudothiourea as an oil. The oily methyl N-(4-chlorobenzhydryl)-carbamimidothioate hydroiodide is used in the next step without further purification.
- A mixture of 7.0 g (0.017 mole) of methyl N-(4-chlorobenzhydryl)carbamimidothioate hydroiodide and 2.85 g (0.04 mole) of pyrrolidine in 20 ml of t-BuOH is heated at reflux overnight. The t-BuOH is removed in vacuo and the crude guanidine hydroiodide is crystallized from methanol-ether. The crude product is recrystallized from methanol-t-butanol to yield pure N-(4-chlorobenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp. 218-220°C (dec.).
- To a suspension of 9.61 g (0.025 mole) of methyl N-(diphenylmethyl)carbamimidothioate hydroiodide in 20 ml of t-BuOH is added 3.5 g (0.035 mole) of N-methylcyclopentylamine and 4 ml of triethylamine. The mixture is then heated under reflux overnight. Upon cooling, the crude guanidine hydroiodide forms as an oil that does not crystallize under various conditions. The free base is liberated with 10% NaOH and extracted with CH2CI2. The methylene chloride sol'n is dried (K2CO3) and concentrated to dryness in vacuo to yield 8.0 g of an oil. The free base crystallizes from ether to give N-cyclopentyl-N-methyl-N'-(diphenylmethyl)guanidine; mp. 102-104°C.
- A mixture of 6.38 g (0.017 mole) of N-benzhydryl-S-methyl-pseudothiourea monohydroiodide and 5.81 g (0.034 mole) of N-phenylpiperazine in t-BuOH is heated under reflux overnight. About 50 ml of moist 2-propanol is added and the mixture is then allowed to crystallize. The crude guanidine melts at 119-128'C. Recrystallization from 1:2 MeOH/t-BuOH and then from 2-prqpanol gives pure N-diphenylmethyl-4-phenyl-1-piperazinecarboximidamide monohydroiodide hemihydrate; mp. (113-117) 208-210°C.
- A solution of 13.50 g (0.06 mole) of benzhydrylisothiocyanate in ether is saturated with anhydrous methylamine in an ice bath. The crystals are filtered to yield the product, N-benzhydryl-N'- methylthiourea; mp. 152-154°C, which is sufficiently pure for the next step.
- A suspension of 14.64 g (0.057 mole) of N-benzyl-N'-methylthiourea in methanol is treated with 8.09 g (0.057 mole) of methyl iodide and stirred overnight. The solvent is removed in vacuo and the residue dissolved in t-BuOH and 2-propanol. Cooling and scratching yields methyl N-diphenylmethyl-N'-methylcarbamimidothioate hydroiodide; mp. 170-173°C.
- A mixture of 20.81 g (0.052 mole) of the compound of Example IX B and 7.4 g (0.104 mole) of pyrrolidine in t-BuOH is heated at reflux overnight. Crystals started forming after about two hours of heating. The mixture is filtered to yield crude guanidine; mp. 200-205°C. Recrystallization from t-BuOH yields N-(diphenylmethyl)-N'-methyl-1-pyrrolidinecarboximidamide hydroiodide hydrate; mp. 211.5-213.5°C.
- A solution of 20.42 g (0.099 mole) of N,N-dicyclohexylcarbodiimide and 40 ml of carbon disulfide in 50 ml of dry Et2O at -40°C under N2 is treated dropwise with stirring over a 5 min period (so that temperature does not exceed -30°C) with a solution of 19.7 g (0.1 mole) of 4-methylbenzhydrylamine. The temperature is allowed to rise slowly over 3 hours to ca. 25°C and stirring is continued overnight. The insoluble dicyclohexylthiourea formed is filtered off and the filtrate concentrated in vacuo to an oil. A second crop of the thiourea is obtained via trituration of the crude isothiocyanate with hexane. 4-methylbenzhydrylisothiocyanate is obtained as an oil; IR (neat) 2080 cm-1.The material is of sufficient purity to use in the next step.
- A solution of 22 g (0.092 mole) of 4-methylbenzhydrylisothiocyanate in 250 ml of dry ether at 0°C is treated with anhydrous NH3 for 3 hours while stirring. The mixture is stirred an additional 1.5 hours at 0 to 10°C during which time the crude product precipitates as a white solid. Filtration and washing with Et20 affords the product; mp. 167-168°C.
- A suspension of 16.5 g (0.064 mole) of N-(4-methylbenzhydryl)thiourea in 75 ml of MeOH is treated with 9.08 g (0.064 mole) of methyl iodide and allowed to stir overnight at room temperature. The reaction mixture is concentrated in vacuo to yield 26.5 g (100%) of the crude product, which crystallizes. Recrystallization from t-BuOH affords pure methyl N-(4-methylbenzhydryl)-carbamimidothioate hydroiodide; mp. 145-147°C.
- The free base of the product is obtained by treatment of the salt with ammonium hydroxide. Recrystallization of the free base from ether-hexane furnishes pure methyl N-(4-methylbenzhydryl)-carbamimidothioate; mp. 130-132°C.
- A mixture of 13.3 g (0.0334 mole) of methyl N-(4-methylbenzhydryl)carbamimidothioate hydroiodide and 5.0 g (0.07 mole) of pyrrolidine in 40 ml of t-BuOH is heated under reflux for 24 hrs. The crude product crystallizes out of the reaction mixture while refluxing. The mixture is allowed to cool overnight at room temperature and filtered to yield crude product; mp. 227-230°C. Recrystallization from MeOH/t-BuOH yields the pure N-(4-methylbenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp. 229-230°C, as a white solid.
- By repeating the amine-to-isothiocyanate procedure of Example VI-A or X-A, except that an equivalent amount of an appropriate benzhydrylamine is employed, the following benzhydryl- isothiocyanates of Formula (V) are:
- 4,4'-dichlorobenzhydrylisothiocyanate;
- 4,4'-diethoxybenzhydrylisothiocyanate;
- 4-methoxybenzhydrylisothiocyanate;
- 4,4'-dimethoxybenzhydrylisothiocyanate;
- 4,4'-dibromobenzhydrylisothiocyanate;
- 3-bromobenzhydrylisothiocyanate; and
- 4,4'-dimethylbenzhydrylisothiocyanate.
-
-
- By heating an appropriate methyl N-benzhydryl-N'-R1-carbamimidothioate salt of Formula (II) with an appropriate R2R3NH amine of Formula (III) in the indicated molar ratios at reflux temperature in either isopropanol or t-butanol according to the procedures previously described, the following benzhydryl guanidine derivatives of Formula (I) are obtained in the form of the indicated acid addition (HX) salt:
Claims (12)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US828694 | 1977-08-29 | ||
US05/828,694 US4101659A (en) | 1977-08-29 | 1977-08-29 | Benzhydryl guanidines |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000952A1 EP0000952A1 (en) | 1979-03-07 |
EP0000952B1 true EP0000952B1 (en) | 1981-02-11 |
Family
ID=25252495
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100774A Expired EP0000952B1 (en) | 1977-08-29 | 1978-08-28 | Benzhydryl guanidine derivatives and pharmaceutical compositions |
Country Status (7)
Country | Link |
---|---|
US (2) | US4101659A (en) |
EP (1) | EP0000952B1 (en) |
JP (1) | JPS5446754A (en) |
AU (1) | AU519174B2 (en) |
DE (1) | DE2860474D1 (en) |
NZ (1) | NZ188178A (en) |
ZA (1) | ZA784885B (en) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0034002A3 (en) * | 1980-01-22 | 1981-09-23 | Beecham Group Plc | Carboxamidine derivatives |
US4281004A (en) * | 1980-03-31 | 1981-07-28 | Pfizer Inc. | Phenylguanidine therapeutic agents |
US5612332A (en) * | 1984-03-19 | 1997-03-18 | Alteon Inc. | Di- and triaminoguanidines, and methods of use |
US5852009A (en) * | 1984-03-19 | 1998-12-22 | The Rockefeller University | Compositions, including pharmaceutical compositions, for inhibiting the advanced glycosylation of proteins, and therapeutic methods based thereon |
ES2181668T3 (en) | 1990-03-02 | 2003-03-01 | Oregon State | TRI- AND TETRA-SUBSTITUTED GUANIDINS AND ITS USE AS EXCITING AMINO ACID ANTAGONISTS. |
US5262568A (en) * | 1990-03-02 | 1993-11-16 | State Of Oregon | Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists |
IN172842B (en) * | 1990-05-17 | 1993-12-11 | Boots Pharmaceuticals Limited | |
US5741661A (en) * | 1991-02-08 | 1998-04-21 | Cambridge Neuroscience, Inc. | Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers |
AU670232B2 (en) * | 1991-02-08 | 1996-07-11 | Cambridge Neuroscience, Inc. | Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers |
US5847006A (en) * | 1991-02-08 | 1998-12-08 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
DE69432984T2 (en) * | 1993-05-27 | 2004-05-27 | Cenes Ltd. | THERAPEUTIC SUBSTITUTED GUANIDINE |
WO1995014461A1 (en) * | 1993-11-23 | 1995-06-01 | Cambridge Neuroscience, Inc. | Therapeutic substituted guanidines |
US5441984A (en) * | 1994-01-06 | 1995-08-15 | Eli Lilly And Company | Urea, thiourea and guanidine derivatives |
KR100423272B1 (en) | 1994-02-03 | 2004-09-01 | 캠브리지 뉴로사이언스, 인코포레이티드 | Compounds regulating the release of neurotransmitters, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising them |
US6143791A (en) * | 1994-02-03 | 2000-11-07 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
US6787569B1 (en) | 1994-02-03 | 2004-09-07 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
US7351743B1 (en) | 1994-02-03 | 2008-04-01 | Wyeth | Therapeutic guanidines |
US5850840A (en) * | 1995-11-15 | 1998-12-22 | Alteon Inc. | Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
US5877217A (en) * | 1995-12-26 | 1999-03-02 | Alteon Inc. | N-acylaminoalkyl-hydrazinecarboximidamides |
US6110968A (en) * | 1995-12-26 | 2000-08-29 | The Picower Institute For Medical Research | Methods for treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts |
US6025355A (en) * | 1997-05-19 | 2000-02-15 | Cambridge Neuroscience, Inc. | Pharmaceutically active compounds and methods of use |
US6242198B1 (en) | 1996-07-25 | 2001-06-05 | Cambridge Neuroscience, Inc. | Methods of treatment of eye trauma and disorders |
US6756389B2 (en) * | 1996-08-09 | 2004-06-29 | Cambridge Neuroscience, Inc. | Pharmaceutically active compounds and methods of use |
SE0104326D0 (en) * | 2001-12-19 | 2001-12-19 | Astrazeneca Ab | Therapeutic heterocycles |
US9145530B2 (en) * | 2012-12-10 | 2015-09-29 | Infineum International Limited | Lubricating oil compositions containing sterically hindered amines as ashless TBN sources |
JP6711512B2 (en) * | 2016-02-24 | 2020-06-17 | 出光興産株式会社 | Lubricating oil composition and method for producing the lubricating oil composition |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1805889A (en) * | 1925-01-07 | 1931-05-19 | Firm Shering Kahlbaum Ag | Substituted guanidine alcohols |
US3117994A (en) * | 1959-12-03 | 1964-01-14 | Monsanto Canada Ltd | Nu, nu', nu'-trisubstituted guanidines |
CA940537A (en) * | 1959-12-23 | 1974-01-22 | Wellcome Foundation Limited (The) | Benzyl guanidines, and a process of production |
US3274230A (en) * | 1962-09-18 | 1966-09-20 | Du Pont | Pentasubstituted guanidines containing cyano groups |
US3252982A (en) * | 1963-10-16 | 1966-05-24 | Ciba Geigy Corp | Benzhydryl compounds |
US3968243A (en) * | 1970-06-05 | 1976-07-06 | Burroughs Wellcome Co. | Substituted guanidine compounds in the treating of arrythmias |
US3961056A (en) * | 1974-02-11 | 1976-06-01 | The Upjohn Company | Substituted morpholine guanidines for the treatment of arrhythmic conditions |
NZ183570A (en) * | 1976-03-19 | 1979-06-08 | Mcneilab Inc | Heterocyclic guanidine derivatives, having anti-secretory and hypogliycaemic activity |
-
1977
- 1977-08-29 US US05/828,694 patent/US4101659A/en not_active Expired - Lifetime
-
1978
- 1978-02-27 US US05/881,208 patent/US4161541A/en not_active Expired - Lifetime
- 1978-08-18 NZ NZ188178A patent/NZ188178A/en unknown
- 1978-08-22 AU AU39158/78A patent/AU519174B2/en not_active Expired
- 1978-08-28 ZA ZA784885A patent/ZA784885B/en unknown
- 1978-08-28 EP EP78100774A patent/EP0000952B1/en not_active Expired
- 1978-08-28 JP JP10396778A patent/JPS5446754A/en active Pending
- 1978-08-28 DE DE7878100774T patent/DE2860474D1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
ZA784885B (en) | 1980-04-30 |
JPS5446754A (en) | 1979-04-12 |
NZ188178A (en) | 1984-05-31 |
DE2860474D1 (en) | 1981-03-26 |
EP0000952A1 (en) | 1979-03-07 |
AU3915878A (en) | 1980-02-28 |
US4161541A (en) | 1979-07-17 |
AU519174B2 (en) | 1981-11-12 |
US4101659A (en) | 1978-07-18 |
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