Classifications

• • 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
• • 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
• • 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
• • 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
• • 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 I 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, toluene, and the like; haloaromatic hydrocarbons, e.g., chlorobenzene, 1,2-dichlorobenzene, and the like; haloaliphatic hydrocarbons, e.g., chloroform, methylene dichloride, 1,2-dichlorethane and the like; lower alkanols, e.g., methanol, isopropanol, t-butanol and the like, ethers, e.g., diethyl ether, dioxane and the like, and ketones, e.g., acetone, 2-butanone and the like. 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 solvent
• Suitable acids may be inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric and the like 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 , p-aminosalicylic and the like 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, isoamyl and the like; 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 1 , 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 (III) may be performed utilizing approximately equimolar amounts in wnich case up to an equimolar amount of a suitable tertiary amine, such as, for example, triethylamine, tripropylamine and the like, is preferably added in order to enhance the rate of reaction.
• a suitable tertiary amine such as, for example, triethylamine, tripropylamine and the like
• the precursors of Formula (II) are obtainable by methodologies reported in the literature.
• the compound wherein Y, Z and R 1 all equal hydrogen may be prepared according to S. 0. Winthrop et al., 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 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 isothio- cyanates 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.
• DCC dicyclohexylcarbodiimide
• 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 1 NH 2 , wherein Ri is a substituent as previously defined, preferably in an ethereal solvent such as, for example, diethyl ether, tetrahydrofuran (THF),.dioxane, 1,2-dimethoxyethane and the like at about 0°C to ambient temperature.
• an ethereal solvent such as, for example, diethyl ether, tetrahydrofuran (THF),.dioxane, 1,2-dimethoxyethane and the like at about 0°C to ambient temperature.
• N-benzhydrylthiourea which may be isolated from the reaction mixture and purified by conventional techniques, is then subjected to S-methylation according to methodologies reported in the literature for the conversion of thioureae 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, methyl fluorosulfonate and the like.
• the preferred methylating agent is methyl iodide.
• the S-methylated product (II) is obtained in the form of an acid addition salt (HX).
• Typical benzhydryl guanidine derivatives of Formula (I) which may be prepared according to the synthetic procedures described herein by using appropriate precursors are:
• 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.
• 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 Z N SO 4 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.
• 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-l-pyrrolidinecarboximidamide or N-benzhydryl-4-morpholine- carboximidamide, at 1-10 mg./kg. body weight p.o. provides a marked lowering of blood sugar in test animals.
• this invention provides valuable pharmaceutical compositions comprising the said compounds as the active hypoglycemic ingredient in admixture with a pharmaceutical carrier.
• a benzhydryl guanidine of Formula (I) 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.
• a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
• any of the usual pharmaceutical media may be employed.
• suitable carriers and additives include water, glycols,oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. 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.
• 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, suspending agents and the like may be employed.
• the pharmaceuctical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 10 to about 500 mg. of the active ingredient, and, preferably, from about 10 to about 250 mg.
• 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 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.
• 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.

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• Chemical & Material Sciences (AREA)
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• 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/xx unknown
  • 1978-08-28 JP JP10396778A patent/JPS5446754A/ja active Pending
  • 1978-08-28 EP EP78100774A patent/EP0000952B1/fr not_active Expired
  • 1978-08-28 DE DE7878100774T patent/DE2860474D1/de not_active Expired

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