BE557985A - - Google Patents

Description

       

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   The invention relates to a. composition of matter: and a mode of use thereof.



   It concerns more. especially a composition which contains, as an essential element a derivative of biguanide and comprises improvements and correlative findings which have made it possible to produce a composition having the property of lowering blood sugar.



     For many years the appropriate treatment of hyperglycemia associated with diabetes mellitus has been the use of injectable insulin. This method has been very satisfactory and has in fact prolonged the life and maintained the good health of hundreds of thousands of diabetics, however the use of injectable insulin has certain restrictions.



   Since the diabetic condition is a chronic condition, it requires constant, and usually daily, injections of insulin. It has been customary to allow the patient to make his own injections and thus introduce the risks

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 incorrect dosages and non-septic injection techniques.



  Insulin as it is currently available is subject to deterioration over time and unless it is properly refrigerated or cooled, it loses strength. An additional risk associated with the use of insulin is that in the preparation of long-lasting insulins active insulin suspensions (NPH insulin) are frequently used, and incorrect resuspension of these insulins results in that more or less than the indicated dose is administered and measured as a volumetric dose of a variably suspended insulin.



   Also associated with the use of insulin is the factor that the physical and emotional strain or expense of everyday life necessitates additional amounts of insulin. This results in the need for an estimate by the doctor or the patient of the effort to come, or additional injections. Additional factors associated with the use of insulin are that it involves difficulties in relation to the economic, psychological and mental levels of the patient which make correct therapy difficult using the injection of insulin.

   It is associated with treatment with insulin by injection. also a great inconvenience for people who are not at home and are confronted with the problem of aseptic injections of a substance to be injected which requires constant refrigeration.



   These disadvantages could be overcome by oral treatment which would reduce blood sugar levels, and which would be administered in the form of tablets containing a given amount of a stable active ingredient.



   The main object of the invention is to provide a hypoglycenic composition which overcomes the disadvantages mentioned above involved in the use of insulin.



   It is an object of the invention to provide a composition which, upon oral ingestion, will rapidly and effectively reduce blood sugar levels in a lasting manner for sustained periods.
Another object of the invention is to provide a composition which can be easily, effectively and economically prepared, and measured with precision. and which can be administered

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 in adjusted buccal doses, providing a rapid and effective lowering of sugar and blood levels,
 EMI3.1
 In addition, the rigcaa: D ... rû compositions thus prepared have the property that their action hy, poglyc.émj, qt:

  1.e little 13 til ,. "ra,} j.a8.-. Ment reversed by the administration of glucose or other c <J.rbo.t1.Y '@ drate rapidly assimilable.'
 EMI3.2
 It is well known that a risk of 'Gn; ra1) el.l'Q.ue a leinsu-Liiie is that of overdose, which can * [, lead, to a dangerous edllc, - tion such levels of blood sugar that death ensues. The development of such a reaction or hy-
 EMI3.3
 poglycemic associated with overdose of insulin is C orrectl DLe by the administration of a carbohydrate; e ", It is equal.sT11Eil'G necessary in oral therapy to have a process
 EMI3.4
 of similar correction in the event of an overdose.



  A particular object of the invention is to provide hypoglycemic agents containing organic material which can be rapidly absorbed in effective amounts from the gastrointestinal tract, said organic material bi-.
 EMI3.5
 Nitrogen substituted guanide (NI SUQs'tHue.).



  Conformed 1? Inven-Iïiom comprises a compoaicion ae ma- -possessing the characteristics, properties and the relation
 EMI3.6
 constituents which will be explained in the composition described below.



   The Applicant has observed that compositions containing certain biguanide derivatives and their salts are effective as
 EMI3.7
 oral hypogiycemic agents.



   The substituted biguanides of the invention have the following general structure:
 EMI3.8
 

 <Desc / Clms Page number 4>

 
 EMI4.1
 in which R-. represents dej rafts I. yùroc: eE e -'- i.pnati # in aqe e RI represented by.3 ra; J.:!.: aux r, y '::. rY:; ç- -; sz, , 3 - '. PlH: simple and suostituès t'tques, having 0 4- onune car-oone content, in particular butytes¯t for example n-butyl and 2- # aéuliyi-Dn% 3ee j amyls, n-amyl and isu-amyl, and d * au! .res ,, ¯ and simple and substituted arJ groups, for example, penaxis,% Q.L5rJ, e and napntyl, and R2 is part of the group consisting of: Hydrogen, azy! es, for example methyl, ethyl, propyl and the like and.! enrlcs, ar example, ally.e ez suires.

   In preferred embodiments of the invention, the sum of the carbon atoms in R1 and Rp will be at. meiis
 EMI4.2
 equal to 5.
 EMI4.3
 



  According to the na: nen: the tuxc of the pnolicatiou "Chemical Abstracts" the substituted biguanides are rz.s? Éraes gobie suiz: starting with one of the nitrogen teftlna, in ze present exeiaùle, -The nitrogen si-uué du c8z-- 'left of the ifiaigaée structure is numbered 1, e> the remaining nitrogen atoms are numbered 2, 3,4 and 5 reading from left to right. The biguanides of the invention require that at least one of the terminal nitrogen, hereinafter designated Ni, Soil substituted 2n Rl, ev that the position remaining at this nitrogen can be substituted (R - alkYLe ai alzenyl or remains unsubstituted (R2 = H ).
 EMI4.4
 



  The biguanides of the invention are all relatively strong bases and form stable salts with inorganic and organic acids, and hence the invention provides for the bi-
 EMI4.5
 guanides in the form of their salts. These biguanides can be observed
 EMI4.6
 held and used as acid-addition salts. Acids
 EMI4.7
 which can be used to prepare acid-addition sois are .., avan% ageusema + 1i, those which, when combined with
 EMI4.8
 the liore box, give salts whose anions are sound; relatively
 EMI4.9
 harmless to animal organisms in therapeutic Lioses, so that the beneficial properties of the lore box inherent are not vitiated by side effects of the anion.

   Appropriate acid-addition salts
 EMI4.10
 pries are those derived from inorganic aciaes such as the acids
 EMI4.11
 hydric, brumnydnque, nitric, piiospnoric and sulfur1-
 EMI4.12
 that, organic acids such as acetic, citric,
 EMI4.13
 malic, tartaric, lactic, glycolic and bJta-ethoxy-propiQ-

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 EMI5.1
 nique, and acidic nitrogen compounds of the salt-forming type
 EMI5.2
 with biguanide bases, such as tfiophyJ.J.ne9 8 = cnJ.orotheophylline, saccharin, pntalimide, venzorazify .... 20,1.-OEio; ie, and the benzoxainem2 d4-diomes su.osti'cuees: () xazO.L1.dine2. 4-dion0y oxazolicLine-2.4 - diones StH) s'ti1j \ H> es 5g J. '"Bu'cyl -3- * P-'3'ylbenzenesuit'ooyiurea, succinimide, bcriu acid: .cue, barbituric acid suOStitU8 , ez analogues.



  The biguanides, as will be explained ulroëx aeur: car, can be prepared by appropriate metiiocts. Some
 EMI5.3
 compounds used as starting materials for the synthesis
 EMI5.4
 Some biguanides are known to occur commercially, although others can be prepared by known methods.



  Thus the fusion of ÇLuan1ii "JJés éqcd.valen '" G8s dfufie hydroenj-oramine and diayanaiamide during. 1/2 to 3 hours at 1 iw.Cr 'provides biguanide chlornyd.rate, and in cases where J.'ú;> rd.rOC! .1J.o! The amine is an alipnatic amine, it can be pulls fixed by the
 EMI5.5
 following general formula:
 EMI5.6
 
 EMI5.7
 0 HCl in which R 1 and E 2 have the mt! 1e 81gro ..: ÜoatJ.on that more liazo Usually, the C.tLLor.tlycira'te can be isolated from the melt mixture by recrystallization. When the cilorriyura-Ge only develops with difficulty or with a: ta1.tue yield, the treatment of an aqueous solution of the inéiange of the uusion with excess of aqueous scalum ntraze causes the precipitation of the salt. substituted oiguanide-acicla ni'crique less sO.Lubleg.ui peul ..

   S'cre puriI1é Al1ierna1iÍ van en 1i, lialcalinisatiofi ai, \,. Cooling a
 EMI5.8
 
 EMI5.9
 aqueous solution of the lusion mixture with strong sodium 111.1yaroxyae precipitates biguanide as free base -This can be separated and purified by recrystalssa't.o-¯r9fl and converted into the desired salt by reaction with stoeorâcuétriqtaes amounts
 EMI5.10
 acidic.

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 EMI6.1
 



  When the amine is of aroJllC: \ liHlUG nature, the desired biguanide ciiJ.ornydrate is advantageously prepared in uraila * .qu ixiamine in an equivalent amount: ze diacid c! L.Lor.1.ydriq, u 3: N, adding an equivalent of dicyailQaili1ae and heating to reflux
 EMI6.2
 for one to twelve neutrals. During reflux heating or at
 EMI6.3
 cooling, the biguanide enlornydrate precipitates from T Ol.'dnaJ..rE and can be separated and purified. Alternatively, the aruuiatiqtie amine O-Qiornydraie and -La dicyandiamide are refluxed in pyridine.

   More specifically biguarudes are
 EMI6.4
 represented by the following formulas!
 EMI6.5
 
 EMI6.6
 in which n is an integer, 1 or 2, R 1 represents hydrogen and an alkyl group airanT 1 - C coBime carbon content, and R 2 represents hydrogen, chlorine, ground and an aloxy group. and salts of eàk + ei, and,
 EMI6.7
 
 EMI6.8
 in which Ri represents alkyl and cyoloalkyl groups having 4 - '07 as carbon content, and R. represents hydrogen, alkyl and metnyiene attached to the terminal carbon of the sheath of R1 and in IGue1l.ela sowiae carbon αones in R1 and RZ is at least 5, and salts thereof.



  The following examples are illustrative of the compounds of the invention and of the process used for their preparation, and serve to demonstrate the compounds emitted by the formulas.
 EMI6.9
 general data above and their preparation, respectively,
 EMI6.10
 However, it should be noted that the use indicated for the various compounds comes from the elements of the general structure common to all.

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 EMI7.1
 



  SSâJL Hydrochloride da lÎÍ'ê .: 'p'b.âr.!. Tl1Yl biil (; mide 15.76 gr. Of. B = phenylé' hydrochloride; .hy19mi! '1e and 8 4, gr of dieyandiamide are ground et intieie, neiit mélng: é8 00) The. The mixture is heated in an oil bath, in a three-necked flask fitted with a thermometer and a stirrer, and the mixture begins to rise at a bath temperature of 12,500 and is completely heated to 13,000. Additional heating at 145-2.50 ° C initiates an exothermic reaction, and the temperature of the waste mixture (156 C) exceeds the temperature of the oil bath (15000) 6.

   The
 EMI7.2
 heating is continued for one hour at a temperature :, e. From 148-150 C $ bath. The reaction mixture is cooled, dissolved in approximately 100 co of methanol and filtered. The metha- filtrate
 EMI7.3
 nol is concentrated under pressure ed, with i'ùe, i; ei'noid, ௠and the product (hydrochloride of B-pl'1ényléth; yl biùtiar-ide) is filtered and recrystallized from 95% isopropanol
Analysis: Calculated for C10 H16 N5 c1
 EMI7.4
 0.49.7H.67; N. 2990 Found: 0.49.7;

   H. 67 N. 29j ,. xample 2 Chlor, mTdra te d! i> l ..!.! l, Y ': Llr:! hJ: l) oi,' 3, \. 1ani 3 = -8minopentane hydrochloride is prepared cn fai-. sant pass dry hydrogen chloride in an ethereal solution of the amine The insoluble hydrochloride is filtered and dried 4-3 <5 5 g of hydrochloride # aainopentane and 23.5 mgr of dicyandiamide are crushed and thoroughly mixed ;, The mixture is gradually heated with stirring in an oil bath.



   After one hour of heating to about 150 C, a vigorous exothermic reaction occurs while heating is continued for a further 20 minutes, after which the internal temperature rises to 190 C (170 C bath) The melting mixture is cooled)) dissolved in 1020 this hot ethanol treated '
 EMI7.5
 by carbon and filter. By cooled 8Ci: lEm. at room temperature, 29.2 g of product are obtained which is recrystallized from ethanol (1 g per 30 cc of solvent).

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 EMI8.1
 
<tb>
<tb> Analysis <SEP> * .- <SEP> Calculated <SEP> for <SEP> C8 <SEP> H18 <SEP> N5 <SEP> C1;
<tb> 0.40.5 <SEP>; <SEP> H, 8.7 <SEP> N.33.7
<tb> found <SEP>: <SEP> C.40.8;

   <SEP> H, 8.7 <SEP> N, 33.7
<tb>
 
Example 3 N1-hexemetjylene biguanide hydrochloride
Hexamethyl0ne-imine hydrochloride is prepared from the free base as described in Example 2.



   22 g of hexamethylene imine hydrochloride and 12.6 g of dicyandiamide are mixed and melted. The mixture begins to melt at 97 C (bath 127 C) and completely melts at 120 C (bath
132 C). The bath temperature is gradually raised over an hour to about 170 ° C. and heating is continued at a bath temperature of 170-179 ° C. for 50 minutes. The melt mixture is cooled and dissolved in 130 cc of hot ethanol, treated with carbon and filtered. The alcoholic filtrate is treated with 300 cc of dry ether and 18.9 g of a precipitate is obtained which is dissolved in 180 cc of hot isopropyl alcohol, treated with carbon and filtered. On cooling the product is obtained.
 EMI8.2
 
<tb>
<tb>



  Analysis <SEP>: <SEP> Calculated <SEP> For <SEP> 08 <SEP> H18 <SEP> N5 <SEP> Cl <SEP>: <SEP>
<tb> 0.43.8 <SEP>; <SEP> H.8.3 <SEP>; <SEP> N, 31.8
<tb> found <SEP> C.43.5; <SEP> H.7.9 <SEP>; <SEP> N.32.
<tb>
 



  Example 4 - N-p- chlorobenzylbiguanide (free base)
P-Chlorobenzylamine hydrochloride is prepared at. from the free base as described in example 2.



   17.1 g of p-chlorobenzylamine hydrochloride and 8.4 g of dicyandiamide are mixed and melted as indicated above.



  The mixture begins to melt and foams at 107 ° C. (130 ° C. bath).



   The temperature of the bath is gradually increased to about 170 C over a period of 30 minutes, after which an exothermic reaction is noted with an internal temperature rising to 17 C (bath 173 C). The dark brown reaction mixture is noted. heated for another 3 minutes. The melt mixture is cooled and dissolved in 110 cc of propanol, treated with carbon and filtered.



  On cooling, p-chlorobenzylbiguanide hydrochloride is obtained by filtration, which is dissolved in 75 cc of hot water treated with carbon and filtered.

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 EMI9.1
 



  The filtrate is cooled and stirred with 10 c:, ï of 4Oi socliulli hydroxide, which is dissolved in 60% free oase, which is allowed to crystallize at 500. The fJ.n'atol1 provides ja nase Íûl1.mre, which is dissolved in 60 this hot water, treated with coolant, ± ï.L1irea and rsfroiaie. The free base precipitate is pulled wire.
 EMI9.2
 



  Analysis: Calculated for 0 H N Cl s 0.48.0; H.5.4 LirOlve C-48.0; IL5.2
 EMI9.3
 Example 5 - Ch.Lornycira'be de 1, Ti éttip.l nll '0-oiyl j o., uarmd.e A solution of 50.8 gr of cniornydrate-e of 1-ethyl-0-toluicLinpet. 24.4 gr of dicyandiamicLe in 200 cc of pyridine are heated at reflux for 5y.L2 hours.Au- cooling with alilbian amerazide1:; e a copious precipitate is formed, which is fi-LTré, riïicé 'with J- ether to remove aireraliié and dried pyriciine. The product is recrystallized from {acetonii; ri ...! ... e.
 EMI9.4
 



  Analysis: Calculated for garlic H18 N5 01: oo51.6; H-7, i; N.27.4 Found 0.51.9; Ho "Î, 0 1 No? 'Î, 2
 EMI9.5
 Example 6 - ChjeJr1gygx = az篯¯ # q Np - am NI -mé [Digunlde The cnlornydrate of H-UJ.éfil1ya.! LY..LajlJ..a.e is prepared from
 EMI9.6
 free base as described in Example 2.
 EMI9.7
 



  36.9 gr of c.tllorl1ydra1e of N-illétn.YH1JJ1; Y '.. Law.ine and 20 gr of dicyanalaialue soiio méj-anggéa and: t "ond \ 4S coniue in exiupia 1. The mixture begins to melt at 8th the onû cOillp.Le1st: Jï; at s1.3 C (bath.). 18 0 The temperature of the bath is graaneliefflcrrt aLg: erée in .. The space of 1
 EMI9.8
 1 3/4 hours up to 17600-Cooled melt is dissolved
 EMI9.9
 in 150 cc of hot acetoninle., l; ra'jjé by carbon, filter and re-
 EMI9.10
 chilled, giving the desired product which is recrystallized from
 EMI9.11
 dtacétoni1: irll ..
 EMI9.12
 Analysis: Calculated for CH N Cl C <43) 3? 1H.9.0; N.31t5 -found 0.43.3; H.9eO; N.31.6
 EMI9.13
 Example 7 - Aceti9.Lle Acid Salt (.

   Ni-oelZy'J..NI - :. illë \ ïny: lbigua: nide The cilloriiyarale ne N-mè \ ïXl; Y-.L08nzY.LSmÍl is prepared from the free base as aëori in Example 2.



  62.8 gr of cniorayOEi'a% e ae N-IJ1é ', hy.L l) enz.y .La year ne etc 33.6gr of dieyariaiamiae are mixed and melted as in Example 1. The mixture begins to melt at 80C and cornp.eemwt melts at 126G (oain 1390C). The temperature of the sheep is gradually. raised to 160 C in

 <Desc / Clms Page number 10>

 
 EMI10.1
 within 25 itiliiutes. The cn8u! 'Faé', e dwarf 150-! 6 C j ept, continue an additional period of 2 1/4 neures. The rerroiài fusion product is dissolved dams 11eau, l, raJ.Lè by du. caroone eli: t'J..L1ire.

   On: 1: 'llùra1; aqueous is chalked by 80 cc of 40% soalum naroxyae with re: trodisseillen1; and agiationoUrill yellowish oil separates and freezes to a soft solid after standing 3. 5 C.
 EMI10.2
 Soft acid: the free base is separated and dissolved in 380 cc of acetonitrile, and filtered. The scetonitrile filtrate containing the free base is treated with 19 ml of glacial acetic acid with stirring. A white precipitate separates which is filtered off, rinsed with acetonitrile, filtered and dried, giving the product which is recrystallized from isopropyl alcohol.
 EMI10.3
 



  Analysis: Calculated for 12 H19 Ne CL:
 EMI10.4
 
<tb>
<tb> c.54.3 <SEP>; <SEP> H.7,2 <SEP>; <SEP> N. <SEP> 26.4
<tb> Found <SEP> C.54,!; <SEP> H.7.1; <SEP> N.26.
<tb>
 
 EMI10.5
 



  Example 8 - Salt of nitri acid, ue -i; -lli-bromobenzylbiguanide iD.-broQ1ooenzylamine is prepared by reacting abronobenzoyl m-bromobenzoylamide chloride and reduction with 1 ithium-aluminum hydride to 11-broillobenzylamine which is converted to hydrochloride. 12.7 g of m-bromobenzylamine hydrochloride and 4.8 g of dicy-andiamide are mixed and melted as indicated above. The mixture begins to melt at 125 C (13g bath vs # -t 1 a fusion is as you at 153 C. Heating is continued at the bath temperature of 150-160 C. for 1 hour. The cooled melt is dissolved in 250 cc of water,

  treated with carbon and filtered. The fiitrat is concentrated to about 50 cc by vacuum distillation and treated with a solution of 5 g of sodium nitrate in 5%. of water and after cooling to 5 ° C., the precipitate is collected and recrystallized from 90 cc of acetonitrile. By concentrating the acetonitrile solution to 55 cc and cooling to 5 ° C., the desired product is obtained.
 EMI10.6
 
<tb>
<tb> d. <SEP> Analysis <SEP>: <SEP> Calculated <SEP> for <SEP> C9H13N6BrO3;
<tb> 0.32.5 <SEP>; <SEP> H.4.0 <SEP>; <SEP> N. 25.2
<tb> found <SEP> C. <SEP> 32.4 <SEP>; <SEP> H, 3.9 <SEP>; <SEP> N.24,7.
<tb>
 
 EMI10.7
 



  Example 9-Ni- (3 4-3ichlorobenzyl) Nf-ethylbiguanide hydrochloride.



  N-ethyl-3.4-üichlorobenzy3¯omina (boiling point

 <Desc / Clms Page number 11>

 114-118 C at 2.75-4 mm) is prepared from 3,4-dichlorobenzyl chloride and ethylamine in aqueous acetonitrile alandine and converted to the hydrochloride in the usual manner.



   24 g of N-ethyl-3,4-dichlorobenzyl-amine hydrochloride and 8.4 g of dicyandiamide are mixed and melted as indicated above.



   The mixture begins to melt at 14200 (bath 156 C). Heating is continued with a gradual increase in temperature.
 EMI11.1
 bath for up to 16,700 for a period of 1 hour. The cooled melt is dissolved in 82 cc of hot ethanol, filtered and cooled with separation of the product.
 EMI11.2
 
<tb>
<tb> Analysis <SEP>: <SEP> Calculated <SEP> for <SEP> C11H16N5C13;
<tb> C.40.6; <SEP> H.5.0 <SEP>; <SEP> N.21.5
<tb>
 
 EMI11.3
 Found 0.41.2; H.51 TT.21.9.
 EMI11.4
 Example 10. N; -p-methoxybenzylbiguanide (free base)
P-methoxybenzylamine hydrochloride is prepared from the free base as indicated above.



     17.3 g of p-methoxybenzylamine hydrochloride and 8.4 g of dicyandiamide are mixed and melted as in Example '1.



  The mixture begins to melt at 143 ° C. (158 ° C. bath) and completely melts at 167 ° C., with an abrupt rise in internal temperature to 170 ° C. (164 ° C. bath). Heating (bath 164--169 0) is maintained for 1 hour 18 minutes. The cooled melt is dissolved in 200 ° C. of water, treated with carbon and filtered. The filtrate is concentrated to 125 cc by vacuum distillation; 10 cc of 40% sodium hydroxide are added with cooling and stirring, and the reaction mixture is kept or stored at 5 ° C. Filtration and drying give the product which is dissolved in 30 cc of acetonitrile. carbon treated, filtered and cooled.
 EMI11.5
 
<tb>
<tb>



  Analysis <SEP>: <SEP> Calculated <SEP> for <SEP> C10H15N5O;
<tb> C.54.3 <SEP> H.6.8 <SEP>; <SEP> N.31.7
<tb> found <SEP> C.54.2; <SEP> H.6.7 <SEP>; <SEP> N.32.0
<tb>
 
 EMI11.6
 Example 11 - NI-al1yl-N'-0-chlorobenzyl-biguanide hydrochloride N-allyl-2-ehlorobenzylemine (bp 68-700 under 0.04 mm) is prepared from o- chloride. chloro-

 <Desc / Clms Page number 12>

 benzyl and allylanine in aqueous alkaline acetonitrile and converted to the hydrochloride in the usual manner.



   33 g of N-allyl-2-chlorobenzyl-amine hydrochloride and 12.6 g of dicyandiamide are mixed and melted as indicated above.



   The mixture begins to melt at 81 C (bath 97 C) and the melting is complete at 124 C (bath 132 C). Heating is continued with a gradual rise in the temperature of the bath (132-167 C) over a period of 1 1/2 hours. The cooled melt is heated with 7 cc of acetonitrile and filtered. On refriodization the filtrate gives the product.
 EMI12.1
 
<tb>
<tb>



  Analysis <SEP>: <SEP> Calculated <SEP> for <SEP> C12H17N5C12;
<tb> C.47.8 <SEP>; <SEP> H.5.7 <SEP>; <SEP> N.23.2
<tb> found <SEP> C.48.2 <SEP>; <SEP> H.5.8 <SEP>; <SEP> N.22.8
<tb>
   Example 12 - N'-n-amyl-biguanide hydrochloride.



   N-Amylamine hydrochloride is prepared by passing dry hydrogen chloride through an ethereal solution of the amine. The insoluble hydrochloride is filtered off and dried.



   52.9 g of n-amylamine hydrochloride and 36.2 g of di cyandiamide are ground and thoroughly mixed. The mixture is brought gradually with stirring, on an oil bath, over the course of one hour, to 158 ° C., and maintained at this temperature for four hours. The fusion mixture is ref: oidi, dissolved in 229 ml of isopropanol, treated with carbon and filtered. On cooling, 24.1gr of product are obtained - melting point 174-176C.
 EMI12.2
 
<tb>
<tb>



  Analysis <SEP>: <SEP> Calculated <SEP> for <SEP> C7H18N5C1;
<tb> 0.40.5 <SEP>; <SEP> H.8.8 <SEP>; <SEP> N.33.7.
<tb> found <SEP> C.40,7 <SEP>; <SEP> H.8.8 <SEP>; <SEP> N.33.8.
<tb>
 



  Example 13 - Salt of N'-n-butyl-biguanide-nitric acid
105.6 gr of n-butylamine hydrochloride and 79.3 gr of dicyandiamide are crushed and thoroughly mixed.The mixture is heated using an oil bath, gradually, with stirring, and after thirty minutes, when the internal temperature has reached 150 C, an exothermic reaction takes place with the internal temperature rising to 178 C The reaction mixture is

 <Desc / Clms Page number 13>

 removed from the oil bath until the internal temperature has dropped to 150 C, and the heating is on. then resumed at 150 C for one hour. The cooled fusion mixture is. dissolved in 3 liters of acetonitrile, and on cooling, 51.3 g of, n-butyl-biguanide hydrochloride precipitated.

   They are dissolved in 70 ml of water. hot and 30 ml of a solution containing 26 gr of sodium nitrate, and the reaction mixture is stored or. stored at 10 C for 18 hours. The crystalline product is separated, dried and recrystallized from 55 ml of acetonitrile, obtaining 22.4 g of product - melting point 125-126 C.
 EMI13.1
 
<tb>
<tb>



  Analysis <SEP>.: <SEP> Calculated <SEP> for <SEP> C6H16N6O3 <SEP>; <SEP> N, 38.2
<tb> found <SEP> N, 38.0
<tb>
 Therapeutic composition. Although the compounds prepared as described are effective as hypoglycemic agents in small doses, the exact amount required will vary with the severity of the condition, the weight of the patient and his reaction to the compound.



   The new compounds are advantageously! incorporated or combined with an excipient or vehicle which may be a solid or a liquid, and must be non-toxic, edible, or potable, and chemically inert with respect to the substituted biguanide salt.



  The proportion of the excipient will be at least sufficient to separate the particles of the hypoglycemic agent from one another and to cause the rapid dissolution or dispersion of the hypoglycemic composition upon contact with the gastric juice of the stomach.



  When the excipient is a solid, its amount may range from 0.3 to about 4 parts per 1 part of the active ingredient.



   As solid excipients, use can be made of lactose, sucrose, starch, pregelatinized starch, acacia, tragacanth, or a mixture of these substances. Suitably, the solid excipient may also contain in admixture magnesium stearate, talc, wheat starch, or two or more of these additives to facilitate the separation of the composition from the mold and punch used for. conform the composition in tablets to be used orally.

 <Desc / Clms Page number 14>

 
 EMI14.1
 



  HYP091Y-Oiqllu-e tablet
 EMI14.2
 
<tb>
<tb> Weight <SEP> in <SEP> mgs <SEP> Percentage
<tb> ¯¯¯¯¯¯¯ <SEP> approximate.
<tb>



  B-Phenyl- <SEP> <SEP> hydrochloride <SEP> 100ex <SEP> 62.10
<tb>
 
 EMI14.3
 ethylbigaaniàe 100.0 62.0
 EMI14.4
 
<tb>
<tb> Sucrose <SEP> 25.9 <SEP> 16.0
<tb> Starch <SEP> 22.1 <SEP> 13.5
<tb> Acacia <SEP> 7.8 <SEP> 4.5
<tb> Talc <SEP> 3.1 <SEP> 2.0
<tb> magnesium <SEP> stearate <SEP> <SEP> 1.5 <SEP> 1.0
<tb> Stearic acid <SEP> <SEP> 1.6 <SEP> 1.0
<tb>
 
He must be heard. than the biguanide derivative mentioned in the composition above. can be replaced by any of the other derivatives described on an equal weight basis. It should also be considered that the biguanides can be employed alone or in compatible mixtures in the preparation of various formulations.



   In making the tablet, the biguanide is mixed with the sucrose and the acacia gum, and then with the starch previously put into a paste with a small amount of water. distilled. This mixture is dried with gentle heat and passed through a granulator which transforms it into a granular powder. This mixture is then mixed with talc, magnesium stearate and stearic acid which act as mold lubricants. The whole is then mixed in a mixer or. other equipment suitable for mixing powders, and is then ready for tableting in any type of tablet manufacturing machine, or else for filling hard gelatin capsules.



   As the liquid excipient, in particular for injection, use can be made of water containing a bacteriostat. Suitable bacteriostats which are illustrative are: benzyl alcohol at 1% concentration in physiological saline solution, mono-chlorobutanol at 0.5% concentration and ana-
 EMI14.5
 logues. The N 1-substituted biguanide salts are dissolved separately or mixed in a suitable proportion to make the concentration equal to about 5-10%. The resulting solutions are effective and stable for long periods of time. Higher concentrations

 <Desc / Clms Page number 15>

 biguanides are unnecessary, and lower concentrations require unnecessarily large volumes of solutions.



   Solutions of the biguanides suitable for injection are prepared by dissolving 5 g of the hydrochloride, or an equivalent salt, in physiological saline solution, and rendering the solutions sterile by Berkefeld filtration. The solutions are then placed in ampoules or in multiple dose vials and the inclusion of a bacteriostat of the kind described ensures sterility and stability during long periods of storage or storage before use.



   Solutions in water are prepared analogously.



  Further, solutions can be prepared in a sem- manner. blable from pure free bases, using calculated amounts of the bases and aqueous hydrochloric acid or other suitable acid.



   It should be understood that the invention encompasses all variations and modifications of the examples chosen for the purpose of illustration, and which do not depart from its spirit or its scope.



   Table i identifies and indicates the properties of a number of biguanides which have been prepared, evaluated and shown to have hypoglycemic action.



   Table 1
 EMI15.1
 R1 represents simple and substituted alkyl, cycloalkyl and aryl radicals having a carbon content of C4-C12 R2 represents hydrogen, alkyl and methylene attached to carbon. terminal of the chain of Ri, and X represents a mineral acid

 <Desc / Clms Page number 16>

 Ph = phenyl
 EMI16.1
 RRX Point Formula 1¯¯¯¯¯¯¯¯¯¯¯¯¯2¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ <: ) - CH3 C2H5 HOI 201-3 11HlSN501 Cl <f H HOI 199-201 OaHl.N50l2 3 01 - (") - H 144-170 9HIIF501.H20 'OH3!! H 187 C Il Hl 2 16 NH 322 / E Hel 217-8 7HlSN5ca cE3 HH 1 aH3 - cf - C¯ t H HOI 220-2 C7H1SN501 CH3 3 EH (1 CH3 - C - I C-! H HOI 231-3 7H1Sl'f5C1 H 2H5 H 1 CH3 -CH2- -CH2 OH2- If Hel 141-5 CSH20N501 CH3.

   H HC1 221-3 C SHU1N 501. 1} F1 220-2 Cl2H24N5CI (d bornyl)

 <Desc / Clms Page number 17>

 Table I (continued)
 EMI17.1
 Ri R2 X point of formula. fusion 0- H HN03 160-1 C9H201 \ f60) CH N - CH-CHZ-Cg2- H 2 ECI 70-3 7H2: ON601Z OH3 n C4H9 CH3 HOl 181-3 7H1SN501 4Hg CH3 HOl 182-4 7H18-N501 0 5H] -1 CH3 Hol 132--4 G8HZON5Cl H 1 CH 3 -C-CR 1 S Hal 133--5 C 8 H 20 N 5 Ol .CH - H - .. H. CFCOOH 169-72 H NQF -, :: ../ '3,169-72 C HgN512F3.



  -0- CH3 HOl 140-5 a 9H2j5 ci - (OHZ) 5- Hal 205-7 C7H16N5Cl from piperiâine -CH) 6-- Roi 203-7 8HlSN5Cl from hexametnylene imine h .- .. CH2-- II HNO 3 131-8 C9H14N60)

 <Desc / Clms Page number 18>

 Table I (continued)
 EMI18.1
 Rl R2 X Formula point Ri fasion C> -OH3-ph-OH2- H RNO 3 123-5 Cl, pH16N603 "2 CH3 HAC 173-5 C12H19N5 2 Ph-OH2- C2H5 HC1 193-5 ClZHl $ N5 ClPh-- CH2- no P7 iiCl 188-90 C12H20N5 CI Ph-OH2- iC3H7 Hel 119-21 C12H20N5Cl H Ph-OH2- OH2 = C-OH2- Hel 180-1 C12Hl8-'q5ol p-Cl-ph-CH2- H 118- 21 C9H12N5C1 p-Ol-Ph-OH2- CH3 HOI 223-5 Ci, Oh. 15N5C12 p-Ol -. Ph-GH - 2 nC3H7 HC1 189-91 C 12 H 19 N 3 C1 2 p-Cl-ph- CH2- iC3H7 OCI 187-89 C12H19N5C12 o-C1-pn-CH2¯ H HN03 119-31 C9H13N6p3 o-Cl-ph-CH2-.

   CH3 HC1 112-25 C10H15N5C12 o-Ol-pn-CH2- nC3H7 HOI 159-62 C12H19N5 C12 o-Cl-pn-CH2¯ iC3H7 HCl 174-8 C! 2H19N5C12 o-C1-ph-C132- OH2 = a-GH2 - Hoi 166-7 02H17N5C12

 <Desc / Clms Page number 19>

 
 EMI19.1
 .l; , 1, is., T. . l.m ..., uu H)
 EMI19.2
 i, i; j 1> v. i. n d3 Ji'w.,:,. i; 1,, a 1 'ndT; 0, ......



  384-a.-C1 ..,. Clw-CT3 'M iiiti Ù j 1 ,, &î>; is = ¯ <tlrs:,.' I ;, 3 s dx¯Cl¯pnCH- in H01 j.13 ± = 5 #, tÇiii ,, NjE 1 j 3,4i-.01-PCH 2 il <? 1. Ù4- .6 iy, r-¯L3I'I â $ ¯d..a-C1.-ph - CH- .. 3 7 * 5 & 7 lai 8 '5 "' 3 li 3,4- <n-Cl -i-OH2- <ii 1; j xa; xl "ïlj, <-HOi 1 there efi = .8 () ij i.H to 671 i 'lL 3, 7,;. ¯¯Q1.-an¯II¯ 3 7 HCl 192-4. à.2% 85 "'3 Here 2-di-.0, .NH- (: ii, # (1: = (lX =; FV) lE 1..tl i, 1..lJ 1; ,,, H ,, #.;.,.; L toj p-Cl-pn ... #) tv <. H 1101 2.1.6 = î tl. .. I #: g Cs.F .. 4 m-Br- pn-CH Fi UNO, 1 3 tà. - 't, i <tI, A I6 -13r-ph - CFi4. C 2 -115 Hul. ë06-8 L 1, 11 -tl' 5 B: o C l 9, -QCH3-ijn - CH2- II - ". 311" 4 l ']. 0l.5 5 o-002ll5-P-CH2- II HN0.3 1., 3 8-40 È j¯¯i, 1] 181 "60% 'OCI-1n- = CII. 11 3 8-26 C%": L8IV64 0-002H5 - iri-OH2- 0113; Ei.J.3 <,!, 5 4., =. b G .-, 'C164.



  "h-CF12-OEF12- II l'i L to ',' 14-" 5 .i Ô 'to.61'5'

 <Desc / Clms Page number 20>

 Table I (continued)
 EMI20.1
 Rl R2 X Formula point, - melting. --- - ---, -.



  P-Cl-ph-OHZ-OH2- H Hel 187-90 C1OH15N5C12 Ph-CH2-CH2- CH3 HC1 161-4 CIIH18N5Cl Ph-CH2-OH2- C2H5 HC1 166-8 C12H2oN5Cl Ph-CH2-CH2- nC3H Hal 125- 7 C13H22N5C1 Ph-OH2-CH2- iC3H7 H01 115-7 C13H22N501 H Ph-OH2-CH2- CH = -CH2- Hel 143-5 C13H20N5Cl Ph-nvH2-CH2 -CH2 H! Nû3 109-15 Cll Hl SN 603 H CH3 --CH2-C- OH2- H EN03 118-21 C22IiZ OH608 pH. CH3. 1 b - k- H HC1 198-202 C2 ° H18N5C1 co .... CH2-CH2- H H1T03 169-171 0 141'18 "603

 <Desc / Clms Page number 21>

 
 EMI21.1
 The specific examples below! 'OU.i.'rl2.ssen, (the c! Rmiées .1..1.u.S1iratJ.ves detiionrail-i, the nOIJ. \ Í' .-> 2 ... 1.es CÜJ! 1.;. J \ Js, t "J¯hl ::; l cositiie nypogiyamic agents by the sacai route.



  After é1i8oJ.J..ssemen: r; Ae laccivile n, yaoiycéru.Cue by the cane route, biguanides are evaluated by the oral route in terms of their ability to lower blood sugar levels in trained animals. The current procedure or. usual was to establish the minimum toxic dose.

     (DTK) in laboratory animals and then to assess hypoglycemic inactivity of the
 EMI21.2
 biguanide at a level of approximately one-third of that of the determined minimum toxic dose., As can be seen from the following data obtained on alloxane animals, the
 EMI21.3
 DTM as usually established does not reflect the true toxicity of the compounds, but rather the level at which they cause hypoglycemic death.



   The following results were obtained and are expressed as a function of time, in terms of percentage reduction in blood sugar from that found for the normal animal. Thus a normal level of 80 mg. % reduced to 20% is represented as a reduction of 75%.



   Guinea pigs were used as test animals and the findings are shown in Table 11. The table shows that some of the compounds do not elicit a hypoglycemic response at the dose employed. These compounds have a sign-
 EMI21.4
 Ficatjn in that, initially, by in1irapéri1ioneal filtration one had noted a good hypoglycaemic activity.



   The minimum toxic dose (MTD) had been established by intraperitoneal injection into mice. With these hypo-
 EMI21.5
 Glyoemic active agents, the toxic dose, as determined in the absence of supporting glucose is essentially a measure of toxic hypoglycemia, and animals given such dosage levels show blood sugar levels as low as 5 and 10 mg. %.



   In the case of control compounds, synthalin

 <Desc / Clms Page number 22>

   (d0camethylenediguanidine dihydrochloride) shows extreme toxicity and latency hypoglycaemia with an effect which is not evident until after 24 hours, whereas with Np-methylbenzenasulfonyl -N'-n-butyl urea, doses high levels are needed and its overall hypoglycemic action is such that blood sugar levels cannot be lowered to the point of hypoglycaemic death.
Table II Hypoglycemia in Indian cocoons by oral administration.
 EMI22.1
 



  Compound Dm Dose, reduction in RR mg / Xg oral glucose, in ... hours 2 5 24 ¯ 2-é-t.nyl-pH G2H5 50 20 0 0 0 2-CIi-5-Zh H 170 60 20 23 0 r¯T -: - f. ''. '1i2-CH2 - Î H-- H 100 35 0 0 0 OH3 cl13', 5 1 0-c- H 300 250 11 21 CH3 OH3 ri H 300 100 15 29 0 OH3-OH2-CH2-CH2- OH3 200 75 26 48 0 OH3 H / C-CE2- OH3 300 250 0 12 0 OH3 nC5H9- C13 100 75 16 14 0 Cli 3H 1 CH j '/ c-cx2 -cI12- cxj 200 70 OH3

 <Desc / Clms Page number 23>

 
Table 11 (continued) Phypoglycemia in guinea pigs by oral administration.
 EMI23.1
 



  Compound 7irl Dose. ô reduction in RI R2 mg / kg buccal glucose, in. hours 3 5 24 - (CH2) 5- 200 70 0 0 0 ¯UCH2) 6¯ 300 100 0 0 0 Ph-CH2- H 150 50 51 73 0 Ph-CIi2- CH3 500 150 20 44 0 p-C1 p12 CH2-- H 100 33 22 40 23 o-C1 Ph-C- CH3 200 65 10 26 0 o-cl-ph-cx2- H CHZ = C-CH 100 35 19 12 0 3 4-ài-Çl-Ph- Cù- cH3 100 35 11 21 0 3t4-di-01-ph - CH2- 02H5 150 50 10 22 11 m-Br-ph-CI2- H 200 70 19 43 0 p-OH30-Ph-CH2- H 150 50 15 34 15 .Ph-CH2-CH2-- H 100 33 69 70 0 p-Cl h-CH2-CH2- H 100 45 30 51 0 OH3 1 B-naphthyl- CH-- H 150 50 18 22 11 Control compounds Synthalin 10 20 0 0 41 Np-methylbcnzenesulfonyl-Nt-nbutyl urea 1000 150 35 38 0
It has been observed that the hypoglycemic action is reversible when the blood sugar level approaches normal glucose levels over time, usually within 24 hours.



   Animals receiving glucose during the test period were also observed to survive doses of the fatal hypoglycemia producing compound in control animals.

 <Desc / Clms Page number 24>

 



   The following series of experiments were performed to establish the ability of the compounds to reduce the blood sugar levels of diabetic animals by alloxan. Although alloxan diabetes is not completely parallel or similar to human diabetes mellitus, it serves as a convenient laboratory method for the study of diabetes in animals.
 EMI24.1
 Rats received 300-400 mg / kg of aloxane iniraperitoneally and their blood glucose level increased to 200-450 mg.%.



  Due to the severity of diabetes, the doses of the test compound needed to lower blood sugar to normal levels,
 EMI24.2
 varied considerably. Comparable values were, however, obtained by determining the dose necessary to lower blood glucose by 100 mg.%. These values are given in Table III as the means of four animals in each group.



   Table III
 EMI24.3
 Compound Oral dose mg / kg Ri R2 Dose determining a reduction of 100 ¯mgtfo of glucose H (CH32-, C - CHp- CH3 200 HH (CH 3) 2 - or- H 350 U "3 H CH- CH2- -CH- C - H 1000 CE.



  Ph-OH2-CH2- H 400 Bh-cX2- H 100 p-clph-cH2- H 70 - (cH25- 300 0-Tolyl 02H5 1200 Synthalin (a) 50 (non-reversible, death of animals) (a) A compound which has been used in the treatment of diabetes
 EMI24.4
 decamethyloneguanidine dihydrochloride. After cessation of treatment with the compounds,

 <Desc / Clms Page number 25>

 blood sugar levels rose again due to alloxanic diabetes. In particular, the results of this table demonstrate the absence of toxicity of the compounds of the invention when their ability to cause death by hypoglycemia is overcome by the use of animals having pathologically high sugar levels.

   In the case of the control compound, Synthalin, a dose of 50 mg / kg resulted in substantial drops in blood sugar, but at this level of Synthalin the result was a gradual drop in blood sugar and the animals eventually died.
 EMI25.1
 



  Recently, two urea derivatives, 1'-sulfanilyl-N n butyiurea and lT- ± -méthyInenzene sulfonjrl-Nr-n'butyl urea, have been offered as oral therapeutics in diabetes, and these drugs are said not to be. lowering blood sugar in diabetic animals by alloxan.



   Additional work with alloxan was carried out on rabbits with β-phenylethylbiguanide hydrochloride as compound. Rabbits . were made diabetic by intravenous injection of 200 mg / kg dalloxane. Three rabbits would form significantly high sugar levels of about 200 mg.% And one amounted to 400 mg.%. By oral administration of 80 mg / kg of the test compound, the blood sugar levels of the first three rabbits fell to normal levels and could be maintained as long as the treatment was continued. The rabbit with severe diabetes required 200 mg / kg of the test compound to halve the blood sugar level.

   After a period of 4 to 5 days with cessation of the irai, the glucose of the
 EMI25.2
 blood stirred again in you animals.



  General ineffectiveness of the compounds as oral hypoglycomic agents having been detuofiured, and with the mans- festation of their essential lack of toxicity separately from
 EMI25.3
 the hypoglycemic action which results a. Evidence from alloxan work remained to be shown that a dose level of approximately 1/25 to 1/50 of that proven in non-toxic e3senie L. Leillin, non-toxic, would effectively act as a hypoglycemic agent.

   For this work .LI :) macuque monkey i'Cz6 chosen coi.,.: Iie animal t1'esssi en

 <Desc / Clms Page number 26>

 
 EMI26.1
 Using B-pnenylétnyibiguanidej hydrochloride as the compound, the observations are recorded in Table IV
TaDleau IV
 EMI26.2
 
<tb>
<tb> <SEP> level of <SEP> Monkey <SEP> <SEP> level of <SEP> Glucose <SEP> of blood <SEP> -mg.%. hours
<tb> Concrete <SEP> dose <SEP> 2 <SEP> 5 <SEP> 24 <SEP> 48
<tb> mg / zg
<tb> 0 <SEP> A <SEP> 63.6
<tb> 2 <SEP> 60 <SEP> 56 <SEP> 59
<tb> 5 <SEP> 64 <SEP> 59 <SEP> 43 <SEP> 59
<tb> 10 <SEP> 43 <SEP> 43 <SEP> 48 <SEP> 71
<tb> 0 <SEP> B <SEP> 71
<tb> 2 <SEP> 68 <SEP> 65 <SEP> 53
<tb> 5 <SEP> 54 <SEP> 49 <SEP> 57 <SEP> 68
<tb> 10 <SEP> 43 <SEP> 43 <SEP> 43 <SEP> 60
<tb>
 
Definite hypoglycemic effects are evident at dose levels of 1/200 to 1/80

  of that easily tolerated by the diabetic rat by alloxan.



   Although the mode of action of the compounds of the invention has not yet been fully elucidated, and although the aim here is not to provide a mechanism, it is nonetheless instructive to provide additional data reflecting the fact that these compounds have an action similar to insulin.



   It is well known that insulin added to an "in vitro" preparation of rat diaphragm accelerates the uptake of glucose by the muscle. Rat nemidiauhragms are suspended in Warburg bottles in oxygen-saturated Ringer's solution containing 1 mg / ml glucose. After an hour, the muscle is removed and the glucose is determined in the surrounding solution.



  Taking into account the spontaneous oxidation of glucose, the quantity that has disappeared from the solution is assumed to have been absorbed by the muscle.The results are shown in Table V.

 <Desc / Clms Page number 27>

 Board. V
 EMI27.1
 i compound upright Mg of compound increased dt Ri R 2 u.'bilisë absorption of glu.cose -uglg. muscle / hour Ph-CH-CH2- H 1..6 12 2z, 6 24 self - (OR2) 5- 6 2e7 12 3w3 24 4,1 o-Tolyle 2H5 5 01> 6 15 1,6 25 lea 50 2j8 CH-CHs -cH 2 -J 5 O 5 3 15 1.0 2.5 16, O 2 n tr81, 1 Synthaline 6 oe8 20 2.0 'Np-methylbenzenesulfonyl Ne-n-butyi urea 10, 9,100 Or. > 9 Insulin 0.05 unit 1, .2 0..0'7 [mite 1.8 0.10 unit 2ù1
Nature analogous to. the insulin of the biguanides is thus manifested, by their increased capacity to provide a greater absorption of glucose by the muscle of the.

   rat with increasing dose of. compound.



     It can thus be seen that the objects defined above, among those which emerge from the foregoing description, are in fact achieved and, as certain modifications can be introduced into the above compositions of matter without departing from the spirit of invention, it should be understood that everything contained in this degrintion should be understood

 <Desc / Clms Page number 28>

 flabbergasted as illustrative and not interpreted in a limiting sense
Claims 1.- As a composition of matter, a hypoglycemic composition containing as the essential active ingredient a bigunide having the following formula:

   
 EMI28.1
 wherein R1 represents single and substituted aliphatic hydrocarbon radicals having a C4-C9 carbon content and single and substituted aryl groups, and R2 is a member of the hydrogen, alkyl and alkenyl group, together with a harmless and non-toxic substance which is chemically inert with respect to biguanide.


    

Claims (1)

2. - A composition of matter as defined in claim 1, wherein biguanide is present together with an excipient and a lubricant. 3.- As composition of matter, a hypoglycemic composition containing as the essential active ingredient a bigu-nide having the following formula: EMI28.2 wherein n is an integer 1 and 2, R1 represents hydrogen and an alkyl group having a carbon content of C, - 03, and R represents hydrogen, chlorine, bromine and an alkoxy group, and salts thereof, together with a harmless, non-toxic substance which is chemically inert to biguanide. 4. A composition of matter as defined in claim 3, in which the biguanide is present together with an excipient and a -Lubricant. 5.- A composition of matter as defined in claim 3, wherein the biguanide is hydrochloride. <Desc / Clms Page number 29> EMI29.1 tie? i'-n.àrh paénjri 7 ".L r; igùaniGe. de J.,: 1. IJ ¯: JU pnény- e'L". '3'. i "ît'C: di1¯. Ù'.3. 6. "A C O.1L.9 S1.1; Oll ae matter as defined in the reVeIlCi2C1'r.it2 ç" '-> r.:, <¯, a # 1. = e ¯.,. ., -, PV \ "'; 6 es'5 ia N-p' - 'c.hloro # ûll'û.3. P2.lU'sl14,1C: 7e'- A C01l1: pos ::: t; iorl de '' wYl .. ^: î? î: 'V such 2 d.' & f: '± 1l..0 :: ia: 1S.:. 9reve.'1. d, ice: ti or 3; in which the oigt18Uiû.e is in c! 2.or? n, yrve of H '-P- {H1J.orophé: ay1 C t.,.: "' a. '.. L ulgu.an'; ';: ;, 0 8.- A C01ll!: LOs: Ï. ",: Lorl ds raa'cisre as defined in claim 3! In.:. A '.:!, Uel. The biguanide is the nitro acid salt of S'-m-or <Mi.ob3H.syRt biguanid :, 9. A ccinposition of matter such as the gue defined in the r8-vendioation J, in l8Glle a biguanida is the diacid salt acatiqIJ¯6 of ïM '- # *. Iz ,,; ± ± µlÎ-i; iétiijrl biguanides 10. - A C o! .. lposi ':; - 1 Oil of matter' Gel. as defined in claim 3, 8S wherein the biguanide is the nitric acid salt of Rï¯b33Y.l iyaaW, eo 11. Sounne co.pod: .c due m.a "tiere9 a hypoglyeéaiqae composition containing cc,.: .. e essential active ingredient a biguanide EMI29.2 having the formula EMI29.3 EMI29.4 in which Rj¯ are alkyl and cycloalkyl groups having a carbon content of 04 - 1 and R2 is hydrogen EMI29.5 alkyl and methylene bonding to. terminal carbon of the EMI29.6 chain B,, and in which the sum of the carbon atoms in RI and H2 is at least equal to 5, and salts of this! this., eorijointement with sobsts'noe 1 .-? offenaiiire and nontoxic which is chemiql..1E :: 1len t inert = .5.i L, due to bigu-anide. EMI29.7 12.- A composition of this material as defined in EMI29.8 claim 11, 4 years if the biguanide is present together with an ex * 1:> i a:; n ± and tLz lubricant. 13 - '"* A coji'? '.' <7: -tio't ce m: 1tj.x'e such def-1-nie dsna la r e n d *. T n 11 u # .-- ##. #. <Desc / Clms Page number 30> EMI30.1 wherein the biguanide is Ni, N'-pentamethylene biguanide hydrochloride. 14. A composition of matter as defined in claim 11, wherein the biguanide is hydrochloride. EMI30.2 from NI, NI -: tlexamethylene biguanide. 15. A composition of matter as defined in claim 11, wherein the biguanide is hydrochloride. EMI30.3 of NI-i-butyl-NI-methyl biguanide. 16. - A composition of matter as defined in claim 11, wherein the biguanide is hydrochloride. EMI30.4 of NI-1-methyl-isobutyl biguanide. 17.- As a composition of matter, a hypoglycemic composition containing the following constituents: a biguanide as defined in claim 1, sucrose, starch, acacia, talc, magnesium stearate and stearic acid. 18.- As composition of matter, a hypoglycemic composition containing the constituents below in the relative percentages by weight indicated. EMI30.5 <tb> <tb> Approximate <SEP> percentage <tb> <SEP> beta-phenylethylbiguanide hydrochloride <SEP> <SEP> 62.0 <tb> sucrose <SEP> 16.0 <tb> starch <SEP> 13.5 <tb> acacia <SEP> 4.5 <tb> talc <SEP> 2 <SEP>, <SEP> 0 <SEP> <tb> magnesium <SEP> stearate <SEP> <SEP> 1.0 <tb> <SEP> stearic acid <SEP> 1.0 <tb> 19.- As a composition of matter, a biguanide having the EMI30.6 in which n is an integer 1 and 2, R1 represents hydrogen and an alkyl group having a carbon content <Desc / Clms Page number 31> EMI31.1 1. C and R2 represents hydrog3ne, chlorine, bromine 3 and an alkoxy group, and salts thereof. 20 .- As a composition of matter, a biguanide having the following formula EMI31.2 in which R1 represents alkyl and cycloalkyl groups EMI31.3 having a carbon content of 4 - C7 and R2 represents hydrogen, alkyl and methylene bonding to the terminal carbon of the R1 chain. 9 and in which the sum of the atoms of, car- EMI31.4 bjne in Ih .1. and R) .., .. 'g. at. minus equal to 5, and the salts of this! - 'the one