Hypoglycemic compositions containing benzhydryllactamimide derivatives
United States Patent [1 1 Grisar et al.  
 [ Apr. 29, 1975 [75] Inventors: Johann Martin Grisar; Thomas R.  
 Blohm, both of Cincinnati, Ohio [73] Assignee: Richardson-Merrell Inc., New York,  
 [22] Filed: June 1, 1973 [21] Appl. No.1 366,106  
  Related US. Application Data [62] Division of Ser. No. 180,118. Sept. 13, I971.  
 [52] US. Cl. 424/244 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/244 [56] References Cited OTHER PUBLICATIONS Chemical Abstracts 72:1325llp (1970). Chemical Abstracts 75:20l83p (1971).  
 [57] 7 ABSTRACT Pharmaceutical compositions with hypoglycemic and diuretic properties and methods for their use are disclosed herein. The active ingredients of the compositions are compounds of the formula CH R Q wherein R is hydrogen or lower alkoxy of from I to 6 carbon atoms, and when R represents lower alkoxy the substituent alkoxy radical may be attached at the ortho-, metaor para-position of the phenyl radical; R is hydrogen or lower alkyl of from 1 to 4 carbon atoms; n is a whole integer of from 3 to l l; or pharmaceutically acceptable acid addition salts of said compounds and individual optical isomers where applicable.  
 8 Claims, N0 Drawings HYPOGLYCEMIC COMPOSITIONS CONTAINING BENZI-IYDRYLLACTAMIMIDE DERIVATIVES This is a division of application Ser. No. 180,118, filed Sept. 13, 1971.  
 FIELD OF INVENTION This invention relates to pharmaceutical compositionswith hypoglycemic and diuretic properties containing benzyhydryllactamimide derivatives as the active ingredient, and to the use of such compositions.  
 SUMMARY OF INVENTION It has been found that compounds of the following formula, or pharmaceutically acceptable acid addition salts of said compounds and individual optical isomers where applicable, are useful as hypoglycemic and diuretic agents:  
 wherein R is hydrogen or lower alkoxy of from 1 to 6 carbon atoms; and when R represents lower alkoxy the substituent alkoxy radical may be attached at the ortho-, metaor para-positions of the phenyl ring; R is hydrogen or loweralkyl of from I to 4 carbon atoms; and n is a whole integer of from 3 to l 1.  
 DISCUSSION OF THE PRIOR ART Compounds of Formula I wherein R is hydrogen, R is lower alkyl and n is an integer from 3 to 5 and processes for the preparation thereof are disclosed in French Pat. No. l,576,l ll of McNeil Laboratories Inc., published on July 17, 1968, and Canadian Pat. No. 850,116 of McNeil Laboratories Inc., issued on Aug. 25, 1970. In the Canadian patent some of these compounds are stated to possess antiinflammatory activity and central nervous system depressant activity. There is no disclosure of these compounds being useful as hypoglycemic or diuretic agents.  
 DETAILED DESCRIPTION OF INVENTION For convenience and uniformity all of the compounds of this invention are named and represented by Formula I. It is known, however, that compounds of this type as acid addition salts may also be represented by the tautomeric form illustrated by the following Formula II:  
 This tautomerism has been discussed by R. Kwok and P. Pranc, J. Org. Chem. 32, 740 (1967). Structures of Formula I R anlon N Formula II anion- Formula III Preferred active ingredients of the compositions of this invention are compounds of the formula Formula IV wherein R has the meaning given hereinbefore and n is a whole integer of from 3 to 7. The more preferred active ingredients of the compositions of this invention are compounds of Formula IV wherein R is hydrogen and n is a whole integer of from 3 to 5.  
  As examples of lower alkyl radicals that R may represent in Formulas I, II and III there may be mentioned, for example, methyl, ethyl, propyl, isopropyl butyl, tertiary butyl and the like.  
  As examples of lower alkoxy radicals that R may represent in Formulas I, II, III and IV there may be mentioned, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy and the like.  
  Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acids. Suitable inorganic acids are for example, hydrochloric, hydrobromic, sulfuric or phosphoric acids and the like. Suitable organic acids are, for example, carboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, Z-phenoxybenzoic and the like, or sulfonic acids such as methane sulfonic, 2- hydroxyethane sulfonic acid and the like.  
  As examples of compounds of this invention there may be mentioned, for example,  
 Z-(diphenylmethylimino)hexahydroazepine hydrochloride, hexahydro-2-[(a-phenyl-p-methoxybenzyl)imino]azepine hydrochloride, 2-[(diphenylmethyl)imino]-l-methylpiperidine hydrochloride, 2-[(diphenylmethyl)imino]octahydroazocine hydrochloride,  
 2-[ diphenylmethyl )imino ]octahydroazonine hydrochloride,  
  3 2-[ (diphenylmethyl)imino]- l -methylpyrrolidine hydrochloride, 2-[(diphenylmethyl)imino]pyrrolidine hydrochloride,  
 2-[ (diphenylmethyl)imino]piperidine hydrochloride,  
 hexahydro-2-[(m-methoxy-a-phenylbenzyl- )imino]azepine hydrochloride, hexahydro-2-[(omethoxy-a-phenylbenzyl)imino]azepine hydrochloride 2-[(p-butoxy-a-phenylbenzyl)imino]hexahydroazepine hydrochloride,  
 2-[(p-methoxy-a-phenylbenzyl)imino]piperidine hydrochloride,  
 2-[(p-ethoxy-a-phenylbenzyl)imino]octahydroazonme,  
 2-[(diphenylmethyl)imino]-lpropyloctahydroazocine,  
 2-[(diphenylmethyl)imino]azacyclotridecane hydrochloride,  
 2-[ (diphenylmethyl)imino]- l -methylhexahydroazepine acid maleate, and the like.  
  It has been found that the compounds of this invention are useful as hypoglycemic and diuretic agents and can be used in the form of pharmaceutical preparations suitable for oral or parenteral administration. The quantity of compound in the unit dosage can vary over a wide range to provide from about 1.0 mg/kg to about 100 mg/kg of body weight of the patient per dose to achieve the desired effect. The desired effect can be obtained by consumption of 25 to 500 mg of the active ingredient taken 1 to 4 times daily. The compounds of this invention can be administered to warm blooded animals and particularly to mammals.  
 The novel compounds, together with conventional pharmaceutical carriers can be employed in unit dos- 5 age forms such as solids, for example, tablets or capsules or liquid solutions, suspensions or elixirs for oral administration and injections, or liquid solutions, suspensions, emulsions and the like-for parenteral use. The quantity of active ingredient in each dosage will generally differ depending on the type of unit dosage, the  
 type of animal and its weight. Thus, each dosage can contain from about 25 mg to over 500 mg of active ingredients in a significant quantity of pharmaceutical carrier.  
 As hypoglycemic agents, the compounds of this invention may be used to control hyperglycemic conditions such as occurs in diabetic patients. To illustrate the hypoglycemic activity&#39; of the compounds of this invention male rats of the Charles River C .D. strain each weighing from 120 to 140 grams were fasted for 15 hours then injected subcutaneously with 1 g/kg of body weight of glucose in 0.5 ml of 0.9% NaCl. Immediately following the glucose injection the animals were administered by oral intubation a compound of this invention in 0.5 ml of carboxymethyl cellulose. Two hours after the test compound was administered blood was withdrawn from the animals and a quantitative analysis of glucose in the plasma was performed by use of the ultramicro glucose oxidase procedure as described by L.  
  P. Cawley et al., Am. J. Clin. Path. 32, l200 (1959). Animals receiving carboxymethyl cellulose with no test compound served as a control. The results of this test are summarized in the following Table l.  
 hydroazonine hydrochloride HeXahydro-Z-[a-phenyl-p-methoxyl5 benzyl )imino1azepine hydrochloride Hexahydro-2-[ m-methoxy-a-phenyl- 100 l l benzyl )iminolazepine hydrochloride Hexahydro-2-l (o-methoxy-a-phenyl- 100 9 benzyl )imino lazepine hydrochloride 2-[ (p-Methoxy-a-phenylbenzyl iminolpiperidine hydrochloride 2-[(p-Butoxy-a-phenylbenzyl)- imino lhexahydroazepine hydrochloride lower alkyl-O-C 2)n Formula V with a primary amine of the following general formula H Formula VI in a manner similar to that reported by R. E. Benson and T. L. Cairns in J. Am. Chem. Soc. 70, 2ll58 (1948). The symbols n and R have the meanings defined hereinbefore and lower alkyl may be methyl, ethyl or the like. This reaction may be carried out with or without a solvent. When a solvent is used that preferred is a lower alcohol; however, other solvents such as benzene, toluene and the like may be used. A basic or acidic catalyst such as a tertiary amine or hydrogen chloride may be added to the reaction mixture. In general it is preferred that the hydrochloride salt of the amine be used in the reaction. The temperature of the reaction varies from 40 C to 180 C, and the preferred temperature is about l5-25 C. The reaction time varies from 1 hour to about 60 days being dependent upon the temperature of the reaction, the reactant primary amine, and more particularly on the degree of steric hindrance of the amine since highly sterically hindered amines react very slowly.  
  The compounds of this invention may also be prepared using a complex of an appropriate lactam of the formula wherein n and R have the meanings defined hereinbefore, with phosphorous oxychloride, phosgene, borontrifluoride etherate, dimethyl sulfate, hydrogen halide or a combination of two or more such reagents. Several attempts have been made to formulate the structure of these complexes, and one formulation includes the vinyl halide, that is, 2-chloro-4,5,6,7-tetrahydro-3I-lazepine. However, none of the formulations have been unambiguously established. This reaction has been studied by H. Bredereck in a series of articles in Chem.  
 Ben, 1953-1968, particularly in vol. 94, 2278 (1961) and vol. 97, 1403 (1964). The complex formed is reacted with an appropriate primary amine, described hereinabove in an aromatic hydrocarbon solvent such as benzene, toluene or xylene or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, dichloroethane, tetrachloroethylene or the like. The reaction temperature is limited by the boiling point of the solvent, however, in some cases it is advantageous to carry out the reaction at room temperature or with cooling at 0 to 40 C depending on the reactants.  
  Similarly the above reaction may be carried out by using known thiolactim ethers such as S-methylthiocaprolactim [I-I. Behringer and H. Meier, Ann. 607, 73-91 1957)], or by using thiolactams wherein the latter case it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [J Gauthier and J. Renault, CR. Acad. Sci. 234, (1952)].  
  Also by catalytic hydrogenation of an appropriate. amino-pyridine derivative as described by T. Grave, J. Am. Chem. Soc. 46, 1460 (1924), M. Friefelder et al., J. Org. Chem. 29, 3730 (1964) and L. Birkhofer, Ber. 75, 429 (1942), compounds of this invention containing a pentamethylenimine moiety may be obtained.  
  The lactim ethers which find use in this reaction may be prepared from commercially available corresponding lactams by methods known in the art. For example, by reaction of an appropriate lactam with dimethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent for 2-24 hours the corresponding O-methyl lactim ether is obtained.  
  The primary amines which find use in this invention are benzhydrylamines of the following structure:  
 dride. A number of methods are available to convert benzophenones (VIII) axe.  
 to benzhydrylamines either directly, for instance by the Leuckart reaction or a variation thereof, or indirectly by way of the oximes (IX) fl-OH C Formula IX formed from benzophenones and hydroxylamine, using a reducing agent such as lithium aluminum hydride, so-  
 Formula VII Formula VIII dium in alcohol or molecular hydrogen in the presence of a noble metal catalyst, preferably rhodium-oncharcoal. In the above Formulas VII, VIII and IX, R has the meaning defined hereinbefore.  
  The following specific examples are illustrative of this invention.  
 EXAMPLE 1 Z-(Diphenylmethylimino)hexahydroazepine chloride A slurry of 18.3 g (0.083 mole) of benzhydrylamine hydrochloride in 25 ml of O-methylcaprolactim was allowed to stand at room temperature for 3 days and was stirred occasionally with a glass rod. At first the mixture began to solidify and small amounts of anhydrous ethanol were added to keep the mixture in a stirrable slurry. The mixture was then cooled. The resulting solid was collected, washed with ether and recrystallized from methanol-acetone to give the desired compound, m.p. 264.5-265.5C.  
 EXAMPLE 2 Hexahydro-2-[(a-phenyl-p-methoxybenzyl)imino]azepine hydrochloride A. To p-methoxyphenylmagnesium bromide, prepared from 10.8 g of magnesium turnings and 80.3 g of p-bromoanisole in about 180 ml of anhydrous ether, was added dropwise a solution of 37.2 g of benzonitrile in 50 ml of anhydrous ether. The mixture was refluxed for 3 hours and allowed to stand overnight at room temperature. The resulting slurry of ketimine salt was added dropwise to 16.3 g of lithium aluminum hydride under 1500 ml of anhydrous ether, and the mixture was refluxed overnight. The mixture was decomposed by adding 16.3 ml of water followed by 16.3 ml of NaOH which was followed by 48.9 ml of water. The mixture was stirred about 5 hours at room temperature. The inorganic material was filtered off, and 250 ml of 2NI-IC1 was added to the filtrate which was washed with water. The resulting precipitate was collected and recrystallized from isopropanol/water to give a-phenyl-pmethoxybenzylamine hydrochloride.  
  B. By the procedure of Example 1, only substituting for benzhydrylamine hydrochloride, an appropriate amount of a-phenyl-p-methoxybenzylamine hydrochloride the desired product was obtained, m.p. 224-226.5 C.  
 hydro- EXAMPLE 3 Following the procedure of Example 2 A only substituting for p-methoxyphenylmagnesium bromide appropriate amounts of 0- or m-methoxyphenylmagnesium bromide or p-n-butoxyphenylmagnesium bromide the following compounds were prepared:  
 a-phenyl-o-metlioxybenzylamine hydrochloride,  
  m.p. 26026lC, a-phenyl-m-methoxybenzylamine hydrochloride,  
  m.p. 265-266C (dec), a-phenyl-p-butoxybenzylamine hydrochloride, m.p.  
 EXAMPLE 4 By the procedure of Example 1 only substituting for benzhydrylamine hydrochloride appropriate amounts of a-phenyl-o-methoxybenzylamine hydrochloride, a-phenyl-m-methoxybenzy1amine hydrochloride or a-phenyl-p-butoxybenzylamine hydrochloride the following compounds were prepared:  
 hexahydro-2-[(o-methoxy-a-phenylbenzyl- )imino]azepine hydrochloride, m.p. 235237C. hexahydro-2-](m-methoxy-a-phenylbenzyl- )iminolazepine hydrochloride, m.p. 235237 C, 2-[(p-butoxy-a-phenylbenzyl)imino]hexahydroazepine hydrochloride, m.p. l65168C.  
 EXAMPLE 5 2-[(p-Methoxy-a-phenylbenzyl)imino]piperidine drochloride By the procedure of Example 1 only substituting for benzhydrylamine hydrochloride and O- methylcaprolactim, appropriate amounts of a-phenyl-p-methoxybenzylamine hydrochloride and O-methylvalerolactim respectively, the title compound was obtained, m.p.l84-l86 C.  
 EXAMPLE 6 EXAMPLE 7 2-[(Diphenylmethyl)iminolpyrrolidine hydrochloride By the procedure of Example 1, only substituting for O-methylcaprolactim an appropriate amount of O-methyl-y-butyrolactim the title compound was obtained, m.p. 2l72l8.5 C.  
 EXAMPLE 8 2- Diphenylmethyl)imino]- 1 -methylpiperidine hydrochloride To 25.3 g (0.223 mole) of N-methylpiperid-Z-one in 250 ml of benzene was added 34.1 g (0.223 mole) of phosphorus oxychloride over 30 minutes. The mixture was stirred at room temperature for 4 hours after which 40.8 g (0.223 mole) of benzhydrylamine was added. The reaction mixture was stirred at room temperature for 1 hour and refluxed for 4 hours then allowed to stand overnight. The resulting precipitate was washed with benzene, and the benzene wash was extracted with aqueous 2N HCl and combined with the precipitate. The combined fractions were made alkaline with 2N NaOH, extracted into ether/methylene chloride, dried and recrystallized from isopropanol to give 2- [(diphenylmethyl)-imino]- 1 -methylpiperidine which was subsequently converted to the hydrochloride salt, m.p. 225-228C.  
 EXAMPLE 9 2-[(diphenylmethyl)iminoloctahydroazocine hydrochloride, m.p. 285286 C,  
  9 2[(diphenylmethyl)imino]octahydroazonine hydrochloride, m.p. 283285 C, 2-[(diphenylmethyl)imino]azacyclotridecane hydrochloride, m.p. l40-l65 C, 2- (diphenylmethyl)imino]- l -methylpyrrolidine hydrochloride, m.p. l94-l95 C.  
 EXAMPLE l 2-[ Diphenylmethyl )imino lhexahydrol methylazepine acid maleate By the procedure of Example 8 only substituting for N-methyl-piperid-Z-one an appropriate amount of N-methyl-e-caprolactam, 2- [(diphenylmethyl )imino ]hexahydrol -methylazepine hydrochloride was obtained and subsequently converted to the acid maleate salt, m.p. l47149 C.  
 EXAMPLE 1 l 2-[ a-phenyl-p-methoxybenzyl )imino]- l methylpyrrolidine hydrochloride By the procedure of Example 8 only substituting for benzhydrylamine and N-methylpiperid-Z-one appropriate amounts of a-phenyl-p-methoxybenzylamine hydrochloride and N-methylpyrrolid-Z-one the title compound is obtained.  
 EXAMPLE 12 An illustrative composition for tablets is as follows:  
 Per Tablet (a) 2[(diphenylmethyl)iminolpiperidine 100.0 mg  
  hydrochloride (b) wheat starch 15.0 mg (0) lactose 33.5 mg (d) magnesium stearate 1.5 mg  
 A granulation obtained upon mixing lactose with the starch and granulated starch paste is dried, screened and mixed with the active ingredient and magnesium stearate. The mixture is compressed in tablets weighing 150 mg each.  
 EXAMPLE 13 An illustrative composition for a parenteral injection is the following wherein the quantities are on a weight to volume basis.  
 (a) 2-[(Diphenylmethyl)imino]-l- 100 mg.  
 methylpiperidine hydrochloride (b) Sodium chloride q.s.  
 (c) Water for injection to make ml.  
 The composition is prepared by dissolving the active ingredient and sufficient sodium chloride in water for injection to render the solution isotonic. The composition may be dispensed in a single ampule containing 100 mg. of the active ingredient for multiple dosage or in 10 ampules for a single dosage.  
 EXAMPLE 14 An illustrative composition for hard gelatin capsules is as follows:  
  Per Capsule (a) hexahydro-2[(a-phenyl-p-methoxybenzyl- 200 mg.  
  )iminoI-azepine hydrochloride 6 35 mg.  
 The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into No. 0 hard gelatin capsules at a net fill of 235 mg. per capsule.  
 EXAMPLE 15 An illustrative composition for pills is as follows:  
 Per Fill (a) 2-[(Di henylmethyl)iminolpiperidine -l00 mg.  
 hydroc ride (b) Starch, corn 90 mg.  
 (c) Liquid glucose l0 mg.  
  compound having the formula wherein R is selected from hydrogen or lower alkoxy of from 1 to 6 carbon atoms; R is selected from hydrogen or lower alkyl of from 1 to 4 carbon atoms; n is a whole integer of from 5 to 11; or a pharmaceutically acceptable acid addition salt of said compound.  
  2. A method as claimed in claim 1 wherein the effective amount of compound administered is from 1 mg/kg to mg/kg of body weight of the patient.  
  3. A method as claimed in claim 2 wherein said compound is administered in dosage units containing from 25 mg to 500 mg of said compound in tablets which are taken from 1 to 4 times daily.  
  4. A method as claimed in claim 2 wherein said compound is administered orally.  
  5. A method as claimed in claim 2 wherein said compound is administered parenterally.  
  6. A method as claimed in claim 2 wherein the compound has the formula wherein R is selected from hydrogen or lower alkoxy of from 1 to 6 carbon atoms; n is a whole integer of from 5 to 7; or a pharmaceutically acceptable acid addition salt of said compound.  
  7. A method as claimed in claim 6 wherein R is hydrogen and n is a whole integer of from 5 to 7.  
  8. A method as claimed in claim 7 wherein the compound is 2-(diphenylmethylimino )hexahydroazepine.