US2961377A - Oral anti-diabetic compositions and methods - Google Patents
Oral anti-diabetic compositions and methods Download PDFInfo
- Publication number
- US2961377A US2961377A US676386A US67638657A US2961377A US 2961377 A US2961377 A US 2961377A US 676386 A US676386 A US 676386A US 67638657 A US67638657 A US 67638657A US 2961377 A US2961377 A US 2961377A
- Authority
- US
- United States
- Prior art keywords
- hydrochloride
- biguanide
- filtered
- composition
- insulin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
Definitions
- This invention relates to a composition of matter and a manner for utilization thereof. More particularly it pertains to a composition which contains as the essential constituent a biguanide derivative and includes correlated improvements and discoveries whereby a composition is provided which has the property of lowering blood sugar in diabetic humans.
- compositions containing certain biguanide derivatives and their salts are effective as oral hypoglycemic agents in diabetic humans.
- Anadditional hazard associated with the use of insulin is that in the achievement of desirably long-acting insulins, suspensions of active insulin (NPH insulin) are frequently utilized, and improper resuspension of these insulins results in more or less than the indicated dosage being administered and measured as a volumetric dose of a varying sus pended insulin.
- NPH insulin active insulin
- insulin there is also associated with the use of insulin the factor thatthe physical and emotional stress of day to day existence will require additional quantities of insulin. This entails an estimate by the physician or the patient of his forthcoming stress, or additional injections. Additional factors associated with the, use of insulin are that it involves difiiculties concerned with the patients economic, psychologic and mental levels which make proper therapy difiicult using insulin injection. Insulintherapy by injection is also associated with great inconvenience for those individuals who-are'not'at home and are confronted with the problem of aseptic injections of an injectable requiring constant refrigeration.
- hypoglycemic agents containing an organic material which is rapidly adsorbed in effective amounts from the gastrointestinal tract, said organic material being an N substituted biguanide.
- the biguanide compositions so prepared have the property that their hypoglycemic effect can be rapidly reversedby the administration of glucose or other rapidly assimilable carbohydrate.
- the invention accordingly comprises a composition of matter possessing the characteristics, properties, and the relation of constituents which will be exemplified in the composition hereinafter described, and the scope of the invention will be-indicated in the claims.
- the substituted biguanides of the invention have the following general structure example, the nitrogen on the left side of the depicted.
- N the terminal nitrogens
- the biguanides of this invention are all relatively strong bases and form stable salts with inorganic-and organic acids and hence the invention suitably uses the addition salts.
- The'acids which can be used to prepare acid-addition salts are suitably those which produce, when combined with the free base, salts whose anions are rela- Lively innocuous to animal organisms in therapeutic doses thereof so that the beneficial physiological properties inherent in the free base are not vitiated by side effects ascribable to the anions.
- Appropriate acid-addition salts are those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, phosphoric and sulfuric acids; from organic acids such as acetic, citric, malic, tartaric, lactic, glycolic, beta-ethoxypropionic, amino, and sulfonic acids; from acidic nitrogen compounds of the type which can form salts with the biguanide bases such as theophylline, substituted theophyllines and similar purines, saccharin, phthalimide, brizoxazihe-ZA-dione and substituted benzoxazine-2,4-diones, oxazolidine-2,4- dione and substituted oxazolidone-2,4-diones, N-p-methylbenzenesulfonyl-N-n-butyl urea, barbituric acid and substituted barbituric acids, mercaptobenzothiazole, and the like.
- the biguanide base When used in the form of its salt the biguanide base is the active portion of the molecule which produces the hypoglycemic efiect but the salt component used can afford therapeutic properties, for example, causing superior absorption, slower or more rapid absorption, and the like, and the selection of the salt also aifords practical advantages such as increased or decreased solubility in physiological environment, as well as formulatory factors of lessened sensitivity to hydroscopicity.
- the biguanides may be prepared by suitable methods. Some of the compounds used as starting materials for the synthesis of the biguanides are known and commercially available, whereas others can be prepared by known methods. Thus the fusion of equivalent quantities of an amine hydrochloride and dicyandiamide for 0.5-3.0 hours at 120-200 C. affords the hydrochloride of biguanide and in those instances where the amine hydrochloride is an aliphatic amine it may be illustrated by the following general formula:
- R and K have the same meaning as hereinabove.
- the hydrochloride can be isolated from the fusion mixture by recrystallization.
- the treatment of an aqueous solution of the fusion mixture with an excess of aqueous sodium nitrate causes precipitation of the less soluble substituted biguanide-nitric acid salt, which can be purified.
- alkalinization and cooling of an aqueous solution of the fusion mixture with sodium hydroxide precipitates the biguanide as the free base which can be separated and purified by recrystallization, and converted to the salt desired by reaction with stoichiometric amounts of acid.
- n is a whole number 1 and 2
- R is hydrogen
- Y is a member of the group consisting ofhydrogen, halogen and methoxy, and salts thereof, and other simple aryl groups such as furyl, thienyl, and pyridyl may replace the phenyl to give aralkyl structures
- R NE NH and which is one of the group consisting of: (l) the compound wherein R is a C -C alkyl, and R is hydrogen; and (2) the compound wherein R is benzyl and R is methyl.
- N -B-phenylethyl biguanide hydrochloride 15.76 g. of B-phenylethylamine hydrochloride and 8.4 g. of dicyandiamide were ground and intimately mixed. The mixture was heated in an oil bath in a 3-neck flask fitted with a thermometer and stirrer, and the mixture began to melt at a bath temperature of C. and was completely fluid at C. Further heating at -150 C. initiated an exothermic reaction and the temperature of the fusion mixture (156 C.) exceeded the oil bath temperature C.) by 6. Heating was continued for one hour at bath temperature of 148-150 C. The reaction mixture was cooled, dissolved in about 100 cc. of methanol and filtered. The methanol filtrate was concentrated under reduced pressure, cooled and the product (B-phenylethyl biguanide hydrochloride) filtered off and recrystallized from 95% isopropanol.
- Example 1 62.8 g. of N-methylbenzylamine hydrochloride and 33.6 g. of dicyandiamide were mixed and fused as in Example 1. The mixture begins to melt at 80 C. and fuses completely at 126 C. (bath 139 C.). The bath temperature was gradually raised to 160 C. over a minute period. Heating (bath 160168 C.) was continued for an additional 2.25 hours. The cooled fusion product was dissolved in water, treated with carbon and filtered. The aqueous filtrate was treated with 80 cc. of 40% sodium hydroxide with cooling and stirring. A yellowish oil separated and congealed to a soft solid after standing at 5 C. The soft solid of the free base was separated and dissolved in 380 cc.
- m-Bromobenzylamine was prepared by reaction of m-bromobenzoylchloridem-bromobenzoylamide and reduction with lithium-aluminum hydride to m-bromobenzylamine which was converted to the hydrochloride.
- Example 1 17.3 g. of p-methoxybenzylamine hydrochloride and 8.4 of dicyandiamide were mixed and fused as in Example 1. The mixture begins to melt at 143 C. (bath 158 C.) and fuses completely at 167 C. with abrupt rise of internal temperature to 170 C. (bath 164 C. Heat- .iug (bath 164169 C.) was maintained for 1.3 hours.
- N-n-batyl-biguanide nitric acid salt 105.6 g. of n-butylamine hydrochloride and 79.3 g. of dicyandiamide were ground intimately and mixed. The mixture was heated by means of an oil bath, gradually with stirring, and after thirty minutes when the internal temperature had reached 150 C., an exothermic reaction ensued with internal temperature rising to 178 C. The reaction mixture was removed from the oil bath imtil the internal temperature had fallen to 150 C. and then heating was resumed at 150 C. for one hour. The cooled fusion mixture was dissolved in 3 liters of acetonitrile, and on cooling n-butyl-biguanide hydrochloride precipitated.
- N-n-amylbiguanide nitric acid salt 2.5 g. of N-n-amylbiguanide hydrochloride were dissolved in 12 ml. of water and 1.7 g. of sodium nitrate added. After standing, the nitrate which had formed was separated and recrystallized from 29 ml. of acetonitrile. The product had a M.P. 133-134 C.
- N-B-phenethylbiguanide-8-chlorotheophylline salt 6.0 g. of beta-phenethylbiguanide hydrochloride was dissolved in ml. of methanol, and 5.6 ml. of 23% NaOMe in methanol added. The formed sodium chloride was filtered. At room temperature there were added to the filtrate, with stirring, 5.4 g. of solid-8-chlorotheophylline. On standing about 20 minutes a crystalline precipitate formed. After 24 hours, the precipitate was filtered and dried. The product was dissolved in 105 ml. of hot isopropanol; treated with carbon; filtered, and allowed to stand. The formed crystals were filtered, yielding a product having a M.P. 117 C. (decomp.).
- composition to, the phrase treating diabetes mellitus is intended to mean obtaining the desired controlled reduction of the sugar levels in theblood and urine of the diabetic patient; comparable to that generally achieved by the injection of insulin.
- the new compounds suitably are compounded with excipient, which is non-toxic, edible or potable, and chemically inert to the substituted biguanide salt.
- the proportion of the excipient should be at least sufiicient to separate the particles of the hypoglycemic agent from each other, and to cause quick solution or dispersion of the hypoglycemic composition when contacted with the gastric juice of the stomach.
- the excipient is a solid, the amount thereof may be from about 0.3 to about 4 parts for 1 part of the active ingredient.
- solid excipients utilization may be made of lactose, sucrose, starch, pre-gelatinized starch, gum arabic, gum tragacanth and mixtures of these.
- the solid excipient may contain also admixed magnesium stearate, talc, cornstarch, or two or more of these additives to promote separation of the composition from the plunger and mold using in shaping the composition into tablets for use orally.
- hypoglycemia tablet It will be understood that the biguanide derivative mentioned in the above composition may be substituted by any of the other derivatives described and claimed herein on an equal weight basis. It is also to be considered that the biguanides may be employed alone and in compatible admixtures when preparing various formulations.
- the biguanide is mixed with the sucrose and gum acacia, and then with the starch made previously into a paste with a small amount of distilled water. This mixture is dried at low heat and put through a granulator which converts it into a granular powder. This mix is then blended with the talc, magnesium stearate and the stearic acid which act as mold lubricants. The whole is now mixed in a pony mixer or other suitable powder mixing equipment, and then is ready for tabletting on any type of tabletting machine or for filling into hard gelatin capsules.
- Table I gives the identity and properties of a number of the biguanides which we prepared, evaluated and demonstrated to have desirable hypoglycemic action when orally administered.
- the biguanides were evaluated by the oral route in terms of their capacity to lower blood sugar levels of test animals.
- the routine procedure was to establish the minimum lethal dose (MLD) in the laboratory animals and then to assess the hypoglycemic activity of the biguanide at a level approximately one third of that of the established MLD.
- MLD minimum lethal dose
- Guinea pigs were used as the test animal and the findings are indicated in Table II.
- Ph CH The minimum lethal dose (MLD) was established by intraperitoneal injection in mice. With these active hypoglycemic agents the lethal dose as established in the absence of supportive glucose is essentially a measure of toxic hypoglycemia and animals receiving such dosage levels show blood sugar levels as low as 5 and 10 mg. percent.
- Synthalin decamethylenediguanidinedihydrochloride
- Synthalin shows extreme toxicity and latent hypoglycemia with the effect being noted only after 24 hours; whereas with N-p-methylbenzenesulfonyl-N'-n-butyl urea high dosages are required and its overall hypoglycemic effect is such that blood sugar levels cannot be depressed to the point of death.
- hypoglycemic efiect is reversible.
- Rat hemidiaphragms were suspended in Warburg flasks in oxygen-saturated Ringer solution containing 1 mg./rnl. of glucose. After one hour the muscle was removed and the glucose determined in the surrounding solution. Taking into account the spontaneous oxidation of glucose, the amount which disappeared from the solution was assumed to be taken up by the muscle. The results are contained in Table V.
- the insulin-like character of the biguanides is thus manifest by the increasing capacity to afiord increased glucose uptake by the rat muscle with increasing dose of the compound.
- composition of matter adapted for treating diabetes mellit'us by oral administration containing as an essential active ingredient a biguanide having the following formula:
- composition of matter as defined in claim 1 in which the biguanide is N'-n-amyl biguanide hydrochloride.
- starch starch, acacia, talc, magnesium stearate and stearic acid.
- composition of matter adapted for treating diabetes mellitus by oral administration, and being in dosage unit form, said composition containing the following constituents in the following relative percentages by weight:
- Approximate percentage 9 The method for treating diabetes mellitus which comprises orally administering to a diabetic human a composition containing as an essential active ingredient a compound selected from the group consisting of a biguanide and substantially non-toxic salts thereof having hypoglycemic activity, said biguanide having the following formula:
Description
nice
ORAL ANTI-DIABETIC COMPOSITIONS AND METHODS Seymour L. Shapiro, Hastings-on-Hudson, and Louis Freedman, Bronxville, N.Y., assignors to US. Vitamin & Pharmaceutical Corporation, a corporation of Delaware No Drawing. Filed Aug. 5, 1957, Ser. No. 676,386
13 Claims. (Cl. 167-65) This invention relates to a composition of matter and a manner for utilization thereof. More particularly it pertains to a composition which contains as the essential constituent a biguanide derivative and includes correlated improvements and discoveries whereby a composition is provided which has the property of lowering blood sugar in diabetic humans.
We have found that compositions containing certain biguanide derivatives and their salts are effective as oral hypoglycemic agents in diabetic humans.
For many years the appropriate treatment of the hyperglycemia associated with diabetes mellitus has been through the use of injectable insulin. This method has been most satisfactory and has indeedprolonged the lives and sustained the good health of hundreds of thousands of diabetics. The use of injectable insulin has associated with it, however, certain reservations. betic condition is a chronic one, it requires constant and, ordinarily, daily injections of insulin. It has been the practice to permit the patient to make his own injections and thus introduce the hazards of improper measurements and non septic injection techniques. Insulin as now available is subject to deterioration on standing. and unless properly refrigerated, will lose its potency. Anadditional hazard associated with the use of insulin is that in the achievement of desirably long-acting insulins, suspensions of active insulin (NPH insulin) are frequently utilized, and improper resuspension of these insulins results in more or less than the indicated dosage being administered and measured as a volumetric dose of a varying sus pended insulin.
There is also associated with the use of insulin the factor thatthe physical and emotional stress of day to day existence will require additional quantities of insulin. This entails an estimate by the physician or the patient of his forthcoming stress, or additional injections. Additional factors associated with the, use of insulin are that it involves difiiculties concerned with the patients economic, psychologic and mental levels which make proper therapy difiicult using insulin injection. Insulintherapy by injection is also associated with great inconvenience for those individuals who-are'not'at home and are confronted with the problem of aseptic injections of an injectable requiring constant refrigeration.
Now theseobjections can be, overcome by oral therapy using our invention in the form of tablets containing a stated quantity of the active, stable ingredient.
It is, therefore the'principal object of the invention to Since the dia- I biguanides in the form of their salts. These biguanides can also be obtained and utilizedin' the form of acid- 2 provide a hypoglycemic composition which obviates the above-mentioned disadvantages that attend the use of insulin, and which upon oral ingestion will rapidly and effectively lower blood sugar levels of the diabetics for sustained periods.
It is a further object of the invention to provide a composition which can be readily, effectively and economically prepared and accurately measured, and which can be administered in regulated oral doses affording rapid and eifective lowering of blood sugar levels of the diabetics.
It is well known that a hazard of insulin therapy is that of overdo-sage, which can lead to such a dangerous lowering of blood sugar levels that death results. The development of such a response associated with insulin overdosage is correctableby administration of aca-rbohydrate. It is necessary also in oraltherapy to have a similarly correctable pattern in theevent of overdosage.
It is a particular object of the invention to provide hypoglycemic agents containing an organic material which is rapidly adsorbed in effective amounts from the gastrointestinal tract, said organic material being an N substituted biguanide. The biguanide compositions so prepared have the property that their hypoglycemic effect can be rapidly reversedby the administration of glucose or other rapidly assimilable carbohydrate.
The invention accordingly comprises a composition of matter possessing the characteristics, properties, and the relation of constituents which will be exemplified in the composition hereinafter described, and the scope of the invention will be-indicated in the claims.
The substituted biguanides of the invention have the following general structure example, the nitrogen on the left side of the depicted.
structure is numbered as l, and the remaining nitrogen atoms are numbered, reading from left to right, 2, 3, 4 and 5. The biguanides of this invention require that at least one of the terminal nitrogens, e.g. N hereinafter designated as N be substituted as R and'that the remaining position on this: nitrogen may. be; substituted (R =methyl), or remain unsubstituted (R =H).
The biguanides of this invention are all relatively strong bases and form stable salts with inorganic-and organic acids and hence the invention suitably uses the addition salts. The'acids which can be used to prepare acid-addition salts are suitably those which produce, when combined with the free base, salts whose anions are rela- Lively innocuous to animal organisms in therapeutic doses thereof so that the beneficial physiological properties inherent in the free base are not vitiated by side effects ascribable to the anions. Appropriate acid-addition salts are those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, phosphoric and sulfuric acids; from organic acids such as acetic, citric, malic, tartaric, lactic, glycolic, beta-ethoxypropionic, amino, and sulfonic acids; from acidic nitrogen compounds of the type which can form salts with the biguanide bases such as theophylline, substituted theophyllines and similar purines, saccharin, phthalimide, brizoxazihe-ZA-dione and substituted benzoxazine-2,4-diones, oxazolidine-2,4- dione and substituted oxazolidone-2,4-diones, N-p-methylbenzenesulfonyl-N-n-butyl urea, barbituric acid and substituted barbituric acids, mercaptobenzothiazole, and the like. When used in the form of its salt the biguanide base is the active portion of the molecule which produces the hypoglycemic efiect but the salt component used can afford therapeutic properties, for example, causing superior absorption, slower or more rapid absorption, and the like, and the selection of the salt also aifords practical advantages such as increased or decreased solubility in physiological environment, as well as formulatory factors of lessened sensitivity to hydroscopicity.
The biguanides, and as will subsequently be exemplified, may be prepared by suitable methods. Some of the compounds used as starting materials for the synthesis of the biguanides are known and commercially available, whereas others can be prepared by known methods. Thus the fusion of equivalent quantities of an amine hydrochloride and dicyandiamide for 0.5-3.0 hours at 120-200 C. affords the hydrochloride of biguanide and in those instances where the amine hydrochloride is an aliphatic amine it may be illustrated by the following general formula:
wherein R and K; have the same meaning as hereinabove.
Usually, the hydrochloride can be isolated from the fusion mixture by recrystallization. Where the hydrochloride is obtainable only with difficulty or in poor yield, the treatment of an aqueous solution of the fusion mixture with an excess of aqueous sodium nitrate causes precipitation of the less soluble substituted biguanide-nitric acid salt, which can be purified. Alternatively, alkalinization and cooling of an aqueous solution of the fusion mixture with sodium hydroxide precipitates the biguanide as the free base which can be separated and purified by recrystallization, and converted to the salt desired by reaction with stoichiometric amounts of acid.
More particularly, the biguanides are represented by the following formulas:
in which n is a whole number 1 and 2, R is hydrogen, and Y is a member of the group consisting ofhydrogen, halogen and methoxy, and salts thereof, and other simple aryl groups such as furyl, thienyl, and pyridyl may replace the phenyl to give aralkyl structures, and
R: NE NH and which is one of the group consisting of: (l) the compound wherein R is a C -C alkyl, and R is hydrogen; and (2) the compound wherein R is benzyl and R is methyl.
The following examples will be illustrative of the compounds of the invention and of the procedure for their preparation, and will, it is believed, serve to make apparent the compounds embraced by the general formulas given above and the preparation thereof respectively, it being noted that the utility indicated for the several compounds flows from the elements of the general structure common to all of them.
EXAMPLE 1 N -B-phenylethyl biguanide hydrochloride 15.76 g. of B-phenylethylamine hydrochloride and 8.4 g. of dicyandiamide were ground and intimately mixed. The mixture was heated in an oil bath in a 3-neck flask fitted with a thermometer and stirrer, and the mixture began to melt at a bath temperature of C. and was completely fluid at C. Further heating at -150 C. initiated an exothermic reaction and the temperature of the fusion mixture (156 C.) exceeded the oil bath temperature C.) by 6. Heating was continued for one hour at bath temperature of 148-150 C. The reaction mixture was cooled, dissolved in about 100 cc. of methanol and filtered. The methanol filtrate was concentrated under reduced pressure, cooled and the product (B-phenylethyl biguanide hydrochloride) filtered off and recrystallized from 95% isopropanol.
Analysis calculated for C H N Clz C, 49.7; H, 6.7; N, 29.0.
Found: C, 49.7; H, 6.7; N, 29.4.
EXAMPLE 2 N '-(diethylmethyl biguanide hydrochloride The hydrochloride of 3-aminopentane was prepared by passing dry hydrogen chloride into an ethereal solution of the amine. The insoluble hydrochloride was filtered and dried.
43.5 g. of 3-aminopentane hydrochloride and 23.5 g. of dicyandiamide were ground and intimately mixed. The mixture was heated gradually with stirring in an oil bath. After one hour at about 150 C. a vigorous exothermic reaction occurred, with heating continued for an additional 20 minutes, whereupon the internal temperature rose to 190 C. (bath C.). The fusion mixture was cooled, dissolved in 1020 cc. of hot ethanol, treated with carbon and filtered. Upon cooling to room temperature, 29.2 g. of product was obtained which was recrystallized from ethanol (1 g. to 30 cc. of solvent).
Analysis calculated for C H N Cl: C, 40.5; H, 8.7; N, 33.7.
Found: C, 40.8; H, 8.7; N, 33.7.
EXAMPLE 3 N -p-chl0robenzylbiguanide (free base) The hydrochloride of p-chlorobenzylamine was prepared from the free base as described in Example 2.
17.1. g. of p-chlorobenzylamiue hydrochloride and 8.4
'g. of dicyandiamide were mixed and fused as above. The mixture begins to melt and froth at 107 C. (bath 130 C.). The bath temperature was raised gradually to about 1 70 C. over a period of 30 minutes, whereupon an exothermic reaction was noted with internal temperature rising to 176 C. (bath 173 C.). The dark brown reaction mixture Was heated for an additional 3 minutes. The fusion mixture was cooled and dissolved in 110 cc. of propanol, treated with carbon and filtered. On cooling, pchlorobenzylbiguanide hydrochloride is obtained on filtration, which was dissolved in 75 cc. of warm water, treated with carbon and filtered. The filtrate was cooled and stirred with cc. of 40% sodium hydroxide, precipitating the free base which was permitted to crystallize at 5 C. Fltration afforded the impure base, which was dissolved in 60 cc. of warm water, treated with carbon, filtered and cooled. The precipitate of free base was filtered.
Analysis calculated for C H N Cl: C, 48.0; H,
Found: C, 48.0; H, 5.2.
EXAMPLE 4 N -benzyl,N'-methylbiguanide acetic acid salt The hydrochloride of N-methylbenzylamine was prepared from the free base as described in Example 2.
62.8 g. of N-methylbenzylamine hydrochloride and 33.6 g. of dicyandiamide were mixed and fused as in Example 1. The mixture begins to melt at 80 C. and fuses completely at 126 C. (bath 139 C.). The bath temperature was gradually raised to 160 C. over a minute period. Heating (bath 160168 C.) was continued for an additional 2.25 hours. The cooled fusion product was dissolved in water, treated with carbon and filtered. The aqueous filtrate was treated with 80 cc. of 40% sodium hydroxide with cooling and stirring. A yellowish oil separated and congealed to a soft solid after standing at 5 C. The soft solid of the free base was separated and dissolved in 380 cc. of acetonitrile and filtered. The acetonitrile filtrate containing the free base was treated with 19 ml. of glacial acetic acid with stirring. A white precipitate separated which was filtered, rinsed with acetonitrile, filtered and dried yieldingthe product which was recrystallized from isopropyl alcohol.
Analysis calculated for C H N O C, 54.3; H, 7.2; N, 26.4. Found: C, 54.1; H, 7.1; N, 26.0.
EXAMPLE 5 N'-m-br0m0benzylbigaanide nitric acid salt.
m-Bromobenzylamine was prepared by reaction of m-bromobenzoylchloridem-bromobenzoylamide and reduction with lithium-aluminum hydride to m-bromobenzylamine which was converted to the hydrochloride.
12.7 g. of m-bromobenzylamine hydrochloride and 4.8 g. of dicyandiamide were mixed and fused as above. The mixture begins to melt at 125 C. (bath 139 C.) and fusion is complete at 153 C. Heating was continued at bath temperature of ISO-160 C. for one hour. The cooled fusion product was dissolved in 250 cc. of water, treated with carbon and filtered. The filtrate was concentrated to about 50 cc. by vacuum distillation and treated with a solution of 5 g. of sodium nitrate in 5 cc. of water, and after chilling at 5 C. the precipitate was collected and recrystallized from 90 cc. of acetonitrile. On concentrating the acetonitrile solution to 55 cc. and chilling at 5 C. the desired product was obtained.
Analysis calculated for: C H N BrO C, 32.5; H, 4.0; N, 25.2. Found: C, 32.4; H, 3.9; N, 24.7.
7 temperature for four hours. cooled, dissolved in 229 ml. of isopropanol, treated with 6 EXAMPLE 6 N-p-methoxybenzylbiguanide free base The hydrochloride of p-methoxybenzylamine was prepared from the free base as above.
17.3 g. of p-methoxybenzylamine hydrochloride and 8.4 of dicyandiamide were mixed and fused as in Example 1. The mixture begins to melt at 143 C. (bath 158 C.) and fuses completely at 167 C. with abrupt rise of internal temperature to 170 C. (bath 164 C. Heat- .iug (bath 164169 C.) was maintained for 1.3 hours.
EXAMPLE 7 N'-n-amyl-bigaanide hydrochloride The hydrochloride 'of n-amylamine was prepared by passing dry hydrogen chloride into an ethereal solution of the amine. The insoluble hydrochloride was filtered and dried.
529g. of n-amylamine hydrochloride and 36.2 g. of dicyandiamide were ground and intimately mixed. The
mixture was heated gradually with stirring on an oil bath over a one-hour period to 158 C. and maintained at this The fusion mixture was carbon and filtered. Upon cooling the product was obtained having a M.P. 174-176 C. I
Analysis calculated for C H N Cl: C, 40.5; H, 8.7; N, 33.7. Found: C, 40.7; H, 8.8; N, 33.8.
EXAMPLE 8 N-n-batyl-biguanide nitric acid salt 105.6 g. of n-butylamine hydrochloride and 79.3 g. of dicyandiamide were ground intimately and mixed. The mixture was heated by means of an oil bath, gradually with stirring, and after thirty minutes when the internal temperature had reached 150 C., an exothermic reaction ensued with internal temperature rising to 178 C. The reaction mixture was removed from the oil bath imtil the internal temperature had fallen to 150 C. and then heating was resumed at 150 C. for one hour. The cooled fusion mixture was dissolved in 3 liters of acetonitrile, and on cooling n-butyl-biguanide hydrochloride precipitated. This was dissolved in ml. of hot water and 30 ml. of a solution containing 26 g. of sodium nitrate added. The reaction mixture was stored at 10 C. for 18 hours. The crystalline product was separated, dried and recrystallized from 55 m1. of acetonitrile, M.P. 126 C.
Analysis calculated for C H N O N, 38.2. Found: N, 38.0.
EXAMPLE 9 N'-(2-methylbatyl)biguanide hydrochloride Thev hydrochloride of 2-methylbutylamine was prepared by passing dry hydrogen chloride into an ethereal solution of the amine. The insoluble hydrochloride was filtered and dried. 4
24.3 g. of 2-methylbutylamine hydrochloride and 15.9
g. of dicyandiamide were ground and intimatelymi xed,
7 The mixture was heated gradually with stirring in an oil bath. After about 20 minutes (bath temperature 165 C.) a rapid rise in internal temperature occurred (to 190 C.). The oil bath was removed and after the reaction mixture had cooled to 120 C., heating was resumed for one hour (bath 159 C.).
On cooling, the reaction mass was leached with 470 ml. of acetonitrile, and the insoluble product filtered off and dried. There was obtained the product, having a M.P. 204-207 C.
Analysis calculated for C-,H N Cl: C, 40.5; H, 8.7; N, 33.7.
Found: C, 40.2; H, 8.3; N, 33.3.
EXAMPLE 10 N -furfurylbiguanide hydrochloride NH NH The hydrochloride of furfurylamine was prepared by passing dry hydrogen chloride into an ethereal solution of the amine. The insoluble hydrochloride was filtered and dried.
12.8 g. of furfurylamine hydrochloride and 7.98 g. of dicyandiamide were ground and intimately mixed. The mixture was heated gradually with stirring on an oil bath over a one-hour period to 150 C. The internal temperature rose to 160 C. The amber solid which formed upon cooling the fusion mixture was dissolved in 95 ml. of isopropyl alcohol; treated with carbon and filtered. Upon cooling, the crystalline product which formed was separated, rinsed with 40 ml. of acetonitrile and filtered. The product had a M.P. 161-164 C.
Analysis calculated for C7H12N5OC1: C, 38.6; H, 5.6; N, 32.1.
Found: C, 38.9; H, 5.7; N, 32.2.
EXAMPLE 11 N-n-amylbiguanide nitric acid salt 2.5 g. of N-n-amylbiguanide hydrochloride were dissolved in 12 ml. of water and 1.7 g. of sodium nitrate added. After standing, the nitrate which had formed was separated and recrystallized from 29 ml. of acetonitrile. The product had a M.P. 133-134 C.
Analysis calculated for C7H13N503Z C, 36.0; H, 7.7; N, 36.0.
Found: C, 36.5; H, 7.7; N, 36.5.
EXAMPLE 12 N-B-phenethylbiguanide-8-chlorotheophylline salt 6.0 g. of beta-phenethylbiguanide hydrochloride was dissolved in ml. of methanol, and 5.6 ml. of 23% NaOMe in methanol added. The formed sodium chloride was filtered. At room temperature there were added to the filtrate, with stirring, 5.4 g. of solid-8-chlorotheophylline. On standing about 20 minutes a crystalline precipitate formed. After 24 hours, the precipitate was filtered and dried. The product was dissolved in 105 ml. of hot isopropanol; treated with carbon; filtered, and allowed to stand. The formed crystals were filtered, yielding a product having a M.P. 117 C. (decomp.).
Analysis calculated for C I-I N O Cl: C, 48.6; H, 5.3; N, 30.0.
Found: c, 48.6; H, 6.1; N, 29.7.
Therapeutic composition to, the phrase treating diabetes mellitus is intended to mean obtaining the desired controlled reduction of the sugar levels in theblood and urine of the diabetic patient; comparable to that generally achieved by the injection of insulin.
The new compounds suitably are compounded with excipient, which is non-toxic, edible or potable, and chemically inert to the substituted biguanide salt. The proportion of the excipient should be at least sufiicient to separate the particles of the hypoglycemic agent from each other, and to cause quick solution or dispersion of the hypoglycemic composition when contacted with the gastric juice of the stomach. When the excipient is a solid, the amount thereof may be from about 0.3 to about 4 parts for 1 part of the active ingredient.
As solid excipients utilization may be made of lactose, sucrose, starch, pre-gelatinized starch, gum arabic, gum tragacanth and mixtures of these. Suitably, the solid excipient may contain also admixed magnesium stearate, talc, cornstarch, or two or more of these additives to promote separation of the composition from the plunger and mold using in shaping the composition into tablets for use orally.
Hypoglycemia tablet It will be understood that the biguanide derivative mentioned in the above composition may be substituted by any of the other derivatives described and claimed herein on an equal weight basis. It is also to be considered that the biguanides may be employed alone and in compatible admixtures when preparing various formulations.
In making the tablet the biguanide is mixed with the sucrose and gum acacia, and then with the starch made previously into a paste with a small amount of distilled water. This mixture is dried at low heat and put through a granulator which converts it into a granular powder. This mix is then blended with the talc, magnesium stearate and the stearic acid which act as mold lubricants. The whole is now mixed in a pony mixer or other suitable powder mixing equipment, and then is ready for tabletting on any type of tabletting machine or for filling into hard gelatin capsules.
It will be understood that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.
Table I gives the identity and properties of a number of the biguanides which we prepared, evaluated and demonstrated to have desirable hypoglycemic action when orally administered.
SALTS OF N-AMYLBI GUANIDE Acid Forming Salts 12169., Formula Remarks C7H1BN603 nHzz o 2-- C12H25N7 2- uHztNoOzCl SALTS OF N-METHYL-N-BENZYLBIGUANIDE HHwNaOz onHzuNaOaS Saceharin The following specific examples Present illustrative data demonstrating the efiectiveness of the novel compositions as oral hypoglycemic agents.
After hypoglycemic activity had been established by subcutaneous route the biguanides were evaluated by the oral route in terms of their capacity to lower blood sugar levels of test animals. The routine procedure was to establish the minimum lethal dose (MLD) in the laboratory animals and then to assess the hypoglycemic activity of the biguanide at a level approximately one third of that of the established MLD. As will be seen from data that follow onalloxan animals, the MLD as routinely established here does not reflect the true toxicity of the compounds but rather the level at which they cause death.
The following results were obtained and are expressed as a function of time in terms of the percentage reduction in blood sugar from that found for the normal animal. Thus a normal level of 80 mg. percent reduced to 20% is represented as a 75% reduction.
Guinea pigs were used as the test animal and the findings are indicated in Table II.
Table II HYPOGLYCEMIA EFFECT IN GUINEA PIGS ON ORAL ADMINISTRATION Compound Percent Reduction in DOral Glfioosein mg. g. osa e ours R1 R; g
CHr-CH:-+CHr- H 200 50 18 49 0 (CHs)sC-CH: H 300 100 14 7 0 CHr-CHr- Control Compounds:
Synthalm 10 0 0 11 N-p-msthylbenzenesulfonyl-N- 1,000 150 35 38 U n-butyl urea.
Ph CH The minimum lethal dose (MLD) was established by intraperitoneal injection in mice. With these active hypoglycemic agents the lethal dose as established in the absence of supportive glucose is essentially a measure of toxic hypoglycemia and animals receiving such dosage levels show blood sugar levels as low as 5 and 10 mg. percent.
In the instance of the control compounds, Synthalin (decamethylenediguanidinedihydrochloride) shows extreme toxicity and latent hypoglycemia with the effect being noted only after 24 hours; whereas with N-p-methylbenzenesulfonyl-N'-n-butyl urea high dosages are required and its overall hypoglycemic effect is such that blood sugar levels cannot be depressed to the point of death.
It was noted that the hypoglycemic efiect is reversible.
with the level of blood sugar approaching the normal glucose levels with time, generally in 24 hours. It was also observed that animals receiving glucose during the test period survived doses of the compound which produced fatal hypoglycemia in control animals.
Our next series of experiments was to establish the capacity of the compounds to reduce the blood sugar 'levels of alloxan diabetic animals. While alloxan diabetes does not completely parallel human diabetes mellitus, it serves as a convenient laboratory method for the study of diabetes in animals.
Rats were given 300400 mg./kg. of alloxan intraperitoneally and their blood glucose level rose to 200-450 mg. percent. Owing to the severity of the diabetes, the doses of the test compound required to depress the blood sugar to normal levels varied considerably. Consistent values were, however obtained when the dose necessary to lower blood glucose by mg. percent was deter mined. These values are given in Table III as averages of four animals in each group.
Oral Dosage, rag/kg. Dose Causing Reduetlon of 100 mg. Percent Glucose Compound lIt | (CHah-C- H 350.
I CHa H CHr-CHrCHr-WB- H Pll-CHg-CHrp-G1phGHa-. Synthalin animals died 50 (not reversible,
l A compound which has been used in diabetes, decamethylene dlgu anidine dihydrochloride.
After cessation of treatment with the compounds, the blood sugar levels rose again due to the alloxan diabetes. In particular, the results of this table demonstrate the essential lack of toxicity of the compounds of this invention when their capacity to induce death by hypoglycemia is overcome, by the use of animals having pathologically high sugar levels. In the case of the control compound, Synthalin, dosage of 50 mg./kg. resulted in substantial falls of blood sugar but at this level of Synthalin a progressive fall in the blood sugar ensued and the animals ultimately died.
Additional work with alloxan was conducted in rabbits with the compound B-phenylethylbiguanide hydrochloride. Rabbits were rendered diabetic by intravenous injection of 200 mg./kg. of alloxan. Three rabbits developed substantially elevated blood sugar levels of about 200 mg. percent and one rose to 400 mg. percent. Upon 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 so maintained as long as the treatment was continued. The rabbit with severe diabetes required 200 mg./kg. of'the test'compound to reduce the blood sugar level by half. After-a period of 4 to 5 days with cessation of treatment the blood glucose rose again in all the animals.
The overall effectiveness as oral hypoglycemic agents having been demonstrated, and with the manifestation of their essential lack of toxicity divorced from the hypoglycemic effect being evident from the alloxan work, it remained to demonstrate that a dosage level approximately 3 to of that proven essentially nontoxic would operate eifectively as a hypoglycemic agent. For this work the Rhesus monkey was selected as the test animal using the compound B-phenylethylbiguanide hydrochloride and the observations are given in Table IV.
Table IV EVALUATION OF B-PHENETHYL BIGUANIDE IN MONKEYS Blood Glucose-mg. Mon- Percent Hours Dose Level, mgJkg.
key
Definite hypoglycemic effects are manifest at dosage levels of ,4 to ,4 of that readily tolerated by the alloxan diabetic rat.
While the mode of action of the compounds of this invention is not as yet completely understood, and although it is not our purpose to offer a mechanism, nevertheless it is instructive to offer additional data reflecting the fact that these compounds have an insulin-like action.
It is well known that insulin added to an in vitro preparation of rat diaphragm will accelerate the uptake of glucose by the muscle. Rat hemidiaphragms were suspended in Warburg flasks in oxygen-saturated Ringer solution containing 1 mg./rnl. of glucose. After one hour the muscle was removed and the glucose determined in the surrounding solution. Taking into account the spontaneous oxidation of glucose, the amount which disappeared from the solution was assumed to be taken up by the muscle. The results are contained in Table V.
Table 'V GLUCOSE UPTAKE BY RAT DIAPHRAGM Increase Control Compounds:
Synthalin 2:3 N-p-methylbenzenesulfonyl-N-n- 3 butyl urea. 2 Insulin 1. 6 0.10 units..." 2.1
The insulin-like character of the biguanides is thus manifest by the increasing capacity to afiord increased glucose uptake by the rat muscle with increasing dose of the compound.
This application is a continuation in part of our copending application Serial No. 588,264, filed May 31, '1956, now abandoned.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efiiciently attained and, since certain changes may be made in the above composition of matter without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
Having described our invention, what we claim as new and desire to secure by Letters Patent is:
l. A composition of matter adapted for treating diabetes mellit'us by oral administration, containing as an essential active ingredient a biguanide having the following formula:
In is it;
and which is one of the group consisting of: (a) the compound wherein R is a C -C alkyl, and R is hydrogen; (b) the compound wherein R is aryl-(CH where n is an integer in the range 1 to 2, the total number of carbon atoms in R being 6 to 8, and R is hydrogen; and (c) the compound wherein R is benzyl, and R is methyl; and substantially non-toxic salts thereof; said active ingredient being present in conjunction with an innocuous and non-toxic solid substance that is chemically inert with respect to the said active ingredient, and being in dosage unit form.
2. A composition of matter as defined in claim 1, in which the biguanide is N'-beta phenyl ethyl biguanide hydrochloride.
3. A composition of matter as defined in claim 1, in which the biguanide is N'-p-chlorobenzyl biguanide.
4. A composition of matter as defined in claim 1 in which the biguanide is N'-n-amyl biguanide hydrochloride.
5. A composition of matter as defined in claim 1, in which the biguanide is N'-benzyl-N-methyl biguanide hydrochloride.
a 15 6. A composition of matter as defined in claim 1, in which the biguanide is 'N'-n-butyl biguanide nitric acid salt.
.7. A composition of matter as defined in claim 1, and in which the said solid substance comprises sucrose,
starch, acacia, talc, magnesium stearate and stearic acid.
8. A composition of matter adapted for treating diabetes mellitus by oral administration, and being in dosage unit form, said composition containing the following constituents in the following relative percentages by weight:
Approximate percentage 9. The method for treating diabetes mellitus which comprises orally administering to a diabetic human a composition containing as an essential active ingredient a compound selected from the group consisting of a biguanide and substantially non-toxic salts thereof having hypoglycemic activity, said biguanide having the following formula:
and which is one of the group consisting of (a) the compound wherein R is a C -C alkyl, and R is hydrogen; (b) the compound wherein R is aryl(CH where n is an integer in the range 1 to 2, the total number of'carbon atoms in R being 6 to 8, and R is hydrogen; and (c) the compound wherein R is benzyl, and R is methyl; said oral administration being in amount sufficient to control the sugar level of the blood and urine of the diabetic patient.
10. A method as defined in claim 9, in which the active ingredient is N-beta phenyl ethyl biguanide hydrochloride.
11. A method as defined in claim 9, in which the active ingredient is N'-benzyl-N'-rnethyl biguanide hydrochloride. 1
12. A method as defined in claim 9, in which the active ingredient is N'-n-amyl biguanide hydrochloride.
' 13. A method as defined in claim 9, in which the active ingredient is N-n-butyl biguanide nitric acid salt.
References Cited in the file of this patent UNITED STATES PATENTS 2,149,709 Rein Mar. 7, 1939 2,221,333 Sibley Nov. 12, 1940 2,455,896 Nagy Dec. 7, 1948 FOREIGN PATENTS 581,346 Great Britain -5.-- Oct. 9, 1946 649,692 Great Britain Ian. 31, 1951 OTHER REFERENCES Chem. Abstracts, 1950, 44:6032e, f, g; 1947, 4121628 1929, 23:4930 4932; 1930, 24:2181 2182; 1951, 45:4348D.
Claims (1)
1. A COMPOSITION OF MATTER ADAPTED FOR TREATING DIABETES MELLITUS BY ORAL ADMINISTRATION, CONTAINING AS AN ESSENTIAL ACTIVE INGREDIENT A BIGUANIDE HAVING THE FOLLOWING FORMULA:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US676386A US2961377A (en) | 1957-08-05 | 1957-08-05 | Oral anti-diabetic compositions and methods |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US676386A US2961377A (en) | 1957-08-05 | 1957-08-05 | Oral anti-diabetic compositions and methods |
Publications (1)
Publication Number | Publication Date |
---|---|
US2961377A true US2961377A (en) | 1960-11-22 |
Family
ID=24714288
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US676386A Expired - Lifetime US2961377A (en) | 1957-08-05 | 1957-08-05 | Oral anti-diabetic compositions and methods |
Country Status (1)
Country | Link |
---|---|
US (1) | US2961377A (en) |
Cited By (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3098008A (en) * | 1960-10-05 | 1963-07-16 | Us Vitamin Pharm Corp | Method for treatment of dermatological disorders |
US3183230A (en) * | 1961-01-13 | 1965-05-11 | Us Vitamin Pharm Corp | Haloaralkyl biguanides |
US3247203A (en) * | 1962-02-22 | 1966-04-19 | Aec Chim Organ Biolog | Caffeine acetyl tryptophanate |
US3251737A (en) * | 1962-11-05 | 1966-05-17 | Horner Frank W Ltd | Methods for inhibiting gastric secretions with substituted biurets |
US3277164A (en) * | 1962-03-21 | 1966-10-04 | Boehringer & Soehne Gmbh | Salicylic acid derivatives |
US3366650A (en) * | 1965-10-07 | 1968-01-30 | Squibb & Sons Inc | Tetra-and penta-fluoro-phenyl- and phenylalkyl-biguanides and salts thereof |
US3456059A (en) * | 1965-07-09 | 1969-07-15 | San Diego State College Founda | N1-(2 - (p-hydroxyphenyl)ethyl)biguanide as a hypoglycemic agent and as a weight reducing agent |
US3800043A (en) * | 1971-10-14 | 1974-03-26 | Rorer Inc William H | 1-substituted biguanides as gastrointestinal spasmolytic agents |
US3879541A (en) * | 1970-03-03 | 1975-04-22 | Bayer Ag | Antihyperglycemic methods and compositions |
DE3129309A1 (en) * | 1980-07-28 | 1982-03-18 | Pfizer Inc., 10017 New York, N.Y. | HYPOGLYKAEMIC 5-SUBSTITUTED OXAZOLIDIN-2,4-DIONE |
US4430337A (en) | 1982-06-23 | 1984-02-07 | Pfizer Inc. | Alicyclic substituted oxazolidine-2,4-diones having hypoglycemic activity |
US4753956A (en) * | 1981-01-02 | 1988-06-28 | Pfizer Inc. | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
FR2773560A1 (en) * | 1998-01-14 | 1999-07-16 | Lipha | 2,4-Diamino triazepinones having an inhibiting action on sugar - amine reactions |
US5981594A (en) * | 1997-03-11 | 1999-11-09 | Toray Industries, Inc. | Method of treatment for diabetic neuropathy |
WO2000032580A2 (en) * | 1998-12-01 | 2000-06-08 | Nihon Bayer Agrochem K.K. | Substituted 1,3,5-triazines as herbicides |
US20010020006A1 (en) * | 1998-06-24 | 2001-09-06 | Hans-Ulrich Demuth | Compounds of unstable DP IV-inhibitors |
US6303661B1 (en) | 1996-04-25 | 2001-10-16 | Probiodrug | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
US6319893B1 (en) | 1998-07-31 | 2001-11-20 | Probiodrug | Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV |
US20020006899A1 (en) * | 1998-10-06 | 2002-01-17 | Pospisilik Andrew J. | Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals |
US6348435B1 (en) | 1997-10-07 | 2002-02-19 | Bayer Aktiengesellschaft | Substituted 2,4-diamino-1,3,5-triazine and their use as herbicides |
JP2002531443A (en) * | 1999-05-27 | 2002-09-24 | 日本バイエルアグロケム株式会社 | Substituted 1,3,5-triazines |
US20020165164A1 (en) * | 1999-08-24 | 2002-11-07 | Hans-Ulrich Demuth | New effectors of dipeptidyl peptidase IV for topical use |
US6500804B2 (en) | 2000-03-31 | 2002-12-31 | Probiodrug Ag | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US6548481B1 (en) | 1998-05-28 | 2003-04-15 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV |
US6559314B2 (en) | 1999-06-10 | 2003-05-06 | Probiodrug Ag | Method for the production of thiazolidin |
US20030119738A1 (en) * | 2001-09-06 | 2003-06-26 | Andre Niestroj | Novel inhibitors of dipeptidyl peptidase I |
US20030130199A1 (en) * | 2001-06-27 | 2003-07-10 | Von Hoersten Stephan | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US20030148961A1 (en) * | 2001-10-12 | 2003-08-07 | Ulrich Heiser | Peptidyl ketones as inhibitors of DPIV |
US20030162820A1 (en) * | 2002-02-28 | 2003-08-28 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
US20030176357A1 (en) * | 1998-10-06 | 2003-09-18 | Pospisilik Andrew J. | Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels |
WO2003086563A2 (en) * | 2002-04-11 | 2003-10-23 | Carbomer, Inc. | Diabetes imaging probes |
US20030232761A1 (en) * | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
US20040033051A1 (en) * | 2002-08-16 | 2004-02-19 | Ip Kiril Kun Wan | Method and system for producing and displaying visual presentations which inhibit off-screen duplication |
US20040043919A1 (en) * | 2000-10-27 | 2004-03-04 | Stephan Von Horsten | Method for the treatment of neurological and neuropsychological disorders |
US20040058876A1 (en) * | 2002-09-18 | 2004-03-25 | Torsten Hoffmann | Secondary binding site of dipeptidyl peptidase IV (DP IV) |
US20040063780A1 (en) * | 2002-10-01 | 2004-04-01 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical preparations for treatment of type II diabetes and methods for treatment of type II diabetes |
US20040171555A1 (en) * | 1998-06-24 | 2004-09-02 | Hans-Ulrich Demuth | Prodrugs of DP IV-inhibitors |
US20040214762A1 (en) * | 2001-08-16 | 2004-10-28 | Hans-Ulrich Demuth | Use of inhibitors of proline endopeptidase to modulate inositol (1,4,5) triphosphate concentration dependent on intracellular signal cascades |
US20040224875A1 (en) * | 2003-05-05 | 2004-11-11 | Stephan Schilling | Inhibitors of glutaminyl cyclase |
EP1500656A1 (en) * | 2002-04-26 | 2005-01-26 | Chugai Seiyaku Kabushiki Kaisha | Biguanide derivative and therapeutic agent for diabetes containing the same |
US20050058635A1 (en) * | 2003-05-05 | 2005-03-17 | Hans-Ulrich Demuth | Use of effectors of glutaminyl and glutamate cyclases |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
US20050171112A1 (en) * | 2003-11-03 | 2005-08-04 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
US20050176622A1 (en) * | 2002-09-18 | 2005-08-11 | Kerstin Kuhn-Wache | Secondary binding site of dipeptidyl peptidase IV (DPIV) |
US20050272641A1 (en) * | 2003-02-07 | 2005-12-08 | Ajinomoto Co., Inc. | Therapeutic agents for diabetes |
US20060189523A1 (en) * | 2003-10-15 | 2006-08-24 | Stephan Schilling | Use of effectors of glutaminyl and glutamate cyclases |
US7132104B1 (en) | 2000-10-27 | 2006-11-07 | Probiodrug Ag | Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders |
US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7199159B2 (en) | 2000-05-26 | 2007-04-03 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of biguanide derivatives for making a medicine having a wound healing effect |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7687638B2 (en) | 2004-06-04 | 2010-03-30 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
US20100099721A1 (en) * | 2003-11-03 | 2010-04-22 | Probiodrug Ag | Novel compounds for the treatment of neurological disorders |
US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7825242B2 (en) | 2004-07-16 | 2010-11-02 | Takeda Pharmaceutical Company Limted | Dipeptidyl peptidase inhibitors |
US7872124B2 (en) | 2004-12-21 | 2011-01-18 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
WO2011018742A1 (en) | 2009-08-13 | 2011-02-17 | Csir | Triazine derivates for use in the treatment of malaria |
US7897633B2 (en) | 2004-02-05 | 2011-03-01 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US20110196015A1 (en) * | 2008-10-13 | 2011-08-11 | Hanall Biopharma Co., Ltd. | N 1-2-thiophene-2-ylethyl-n2-substituted biguanide derivate, preparation method thereof, and pharmaceutical composition containing the same as active ingredients |
CN106458868A (en) * | 2014-04-17 | 2017-02-22 | 伊谬诺米特医疗有限公司 | Guanidine compounds and use thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2149709A (en) * | 1935-05-09 | 1939-03-07 | Ig Farbenindustrie Ag | Textile assistants |
US2221333A (en) * | 1936-09-24 | 1940-11-12 | Monsanto Chemicals | Stabilized soap |
GB581346A (en) * | 1943-09-29 | 1946-10-09 | Francis Henry Swinden Curd | New pyrimidine compounds |
US2455896A (en) * | 1945-10-12 | 1948-12-07 | American Cyanamid Co | 1-aryl, 5-alkyl, biguanides |
GB649692A (en) * | 1948-10-20 | 1951-01-31 | Albert Frederick Crowther | Manufacture of biguanide derivatives |
-
1957
- 1957-08-05 US US676386A patent/US2961377A/en not_active Expired - Lifetime
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2149709A (en) * | 1935-05-09 | 1939-03-07 | Ig Farbenindustrie Ag | Textile assistants |
US2221333A (en) * | 1936-09-24 | 1940-11-12 | Monsanto Chemicals | Stabilized soap |
GB581346A (en) * | 1943-09-29 | 1946-10-09 | Francis Henry Swinden Curd | New pyrimidine compounds |
US2455896A (en) * | 1945-10-12 | 1948-12-07 | American Cyanamid Co | 1-aryl, 5-alkyl, biguanides |
GB649692A (en) * | 1948-10-20 | 1951-01-31 | Albert Frederick Crowther | Manufacture of biguanide derivatives |
Cited By (108)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3098008A (en) * | 1960-10-05 | 1963-07-16 | Us Vitamin Pharm Corp | Method for treatment of dermatological disorders |
US3183230A (en) * | 1961-01-13 | 1965-05-11 | Us Vitamin Pharm Corp | Haloaralkyl biguanides |
US3247203A (en) * | 1962-02-22 | 1966-04-19 | Aec Chim Organ Biolog | Caffeine acetyl tryptophanate |
US3277164A (en) * | 1962-03-21 | 1966-10-04 | Boehringer & Soehne Gmbh | Salicylic acid derivatives |
US3251737A (en) * | 1962-11-05 | 1966-05-17 | Horner Frank W Ltd | Methods for inhibiting gastric secretions with substituted biurets |
US3456059A (en) * | 1965-07-09 | 1969-07-15 | San Diego State College Founda | N1-(2 - (p-hydroxyphenyl)ethyl)biguanide as a hypoglycemic agent and as a weight reducing agent |
US3366650A (en) * | 1965-10-07 | 1968-01-30 | Squibb & Sons Inc | Tetra-and penta-fluoro-phenyl- and phenylalkyl-biguanides and salts thereof |
US3879541A (en) * | 1970-03-03 | 1975-04-22 | Bayer Ag | Antihyperglycemic methods and compositions |
US3800043A (en) * | 1971-10-14 | 1974-03-26 | Rorer Inc William H | 1-substituted biguanides as gastrointestinal spasmolytic agents |
DE3129309A1 (en) * | 1980-07-28 | 1982-03-18 | Pfizer Inc., 10017 New York, N.Y. | HYPOGLYKAEMIC 5-SUBSTITUTED OXAZOLIDIN-2,4-DIONE |
US4753956A (en) * | 1981-01-02 | 1988-06-28 | Pfizer Inc. | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
US4430337A (en) | 1982-06-23 | 1984-02-07 | Pfizer Inc. | Alicyclic substituted oxazolidine-2,4-diones having hypoglycemic activity |
US6303661B1 (en) | 1996-04-25 | 2001-10-16 | Probiodrug | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
US20050107309A1 (en) * | 1996-04-25 | 2005-05-19 | Hans-Ulrich Demuth | Use of dipeptidyl peptidase IV effectors for normalizing the blood glucose level in mammals |
US5981594A (en) * | 1997-03-11 | 1999-11-09 | Toray Industries, Inc. | Method of treatment for diabetic neuropathy |
US6348435B1 (en) | 1997-10-07 | 2002-02-19 | Bayer Aktiengesellschaft | Substituted 2,4-diamino-1,3,5-triazine and their use as herbicides |
FR2773560A1 (en) * | 1998-01-14 | 1999-07-16 | Lipha | 2,4-Diamino triazepinones having an inhibiting action on sugar - amine reactions |
US6258804B1 (en) | 1998-01-14 | 2001-07-10 | Merck Patent Gmbh | Triazepinones, process for their preparation and their therapeutic application |
CZ297276B6 (en) * | 1998-01-14 | 2006-10-11 | Merck Patent Gmbh | Triazepinone derivative, process for its preparation and pharmaceutical composition in which the derivative is comprised |
WO1999036396A1 (en) * | 1998-01-14 | 1999-07-22 | Merck Patent Gmbh | Triazepinones, process for their preparation and their therapeutic application |
JP2002509134A (en) * | 1998-01-14 | 2002-03-26 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Triazepinone, its production method and therapeutic use |
US6548481B1 (en) | 1998-05-28 | 2003-04-15 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV |
US20050203030A1 (en) * | 1998-05-28 | 2005-09-15 | Hans-Ulrich Demuth | Novel effectors of dipeptidyl peptidase IV |
US20030134802A1 (en) * | 1998-05-28 | 2003-07-17 | Hans-Ulrich Demuth | Novel effectors of dipepetidyl peptidase IV |
US20080182798A1 (en) * | 1998-05-28 | 2008-07-31 | Hans-Ulrich Demuth | Novel effectors of dipeptidyl peptidase IV |
US7084120B2 (en) | 1998-06-24 | 2006-08-01 | Probiodrug Ag | Prodrugs of DP IV-inhibitors |
US20010020006A1 (en) * | 1998-06-24 | 2001-09-06 | Hans-Ulrich Demuth | Compounds of unstable DP IV-inhibitors |
US20040171555A1 (en) * | 1998-06-24 | 2004-09-02 | Hans-Ulrich Demuth | Prodrugs of DP IV-inhibitors |
US7053055B2 (en) | 1998-06-24 | 2006-05-30 | Prosidion Ltd. | Compounds of unstable DP IV-inhibitors |
US7166579B2 (en) | 1998-06-24 | 2007-01-23 | Prosidion Limited | Prodrugs of DP IV-inhibitors |
US6319893B1 (en) | 1998-07-31 | 2001-11-20 | Probiodrug | Raising blood sugar level in hypoglycemic mammals by administering inhibitors of dipeptidyl peptidase IV |
US20020006899A1 (en) * | 1998-10-06 | 2002-01-17 | Pospisilik Andrew J. | Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals |
US20030176357A1 (en) * | 1998-10-06 | 2003-09-18 | Pospisilik Andrew J. | Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels |
US20020110560A1 (en) * | 1998-10-06 | 2002-08-15 | Hans-Ulrich Demuth | Use of dipeptidyl peptidase IV effectors for normalizing the blood glucose level in mammals |
WO2000032580A3 (en) * | 1998-12-01 | 2000-08-17 | Bayer Agrochem Kk | Substituted 1,3,5-triazines as herbicides |
WO2000032580A2 (en) * | 1998-12-01 | 2000-06-08 | Nihon Bayer Agrochem K.K. | Substituted 1,3,5-triazines as herbicides |
US6645915B1 (en) | 1998-12-01 | 2003-11-11 | Nihon Bayer Agrochem K. K. | Substituted 1,3,5- triazines |
JP4911820B2 (en) * | 1999-05-27 | 2012-04-04 | バイエルクロップサイエンス株式会社 | Substituted 1,3,5-triazines |
JP2002531443A (en) * | 1999-05-27 | 2002-09-24 | 日本バイエルアグロケム株式会社 | Substituted 1,3,5-triazines |
US6559314B2 (en) | 1999-06-10 | 2003-05-06 | Probiodrug Ag | Method for the production of thiazolidin |
US20020165164A1 (en) * | 1999-08-24 | 2002-11-07 | Hans-Ulrich Demuth | New effectors of dipeptidyl peptidase IV for topical use |
US7335645B2 (en) | 1999-08-24 | 2008-02-26 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US20030092630A2 (en) * | 1999-08-24 | 2003-05-15 | Probiodrug Ag | New effectors of dipeptidyl peptidase iv for topical use |
US6949515B2 (en) | 1999-08-24 | 2005-09-27 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US20050209159A1 (en) * | 1999-08-24 | 2005-09-22 | Hans-Ulrich Demuth | Effectors of dipeptidyl peptidase IV for topical use |
US20050222221A1 (en) * | 2000-03-31 | 2005-10-06 | Hans-Ulrich Demuth | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US20030008905A1 (en) * | 2000-03-31 | 2003-01-09 | Hans-Ulrich Demuth | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US6500804B2 (en) | 2000-03-31 | 2002-12-31 | Probiodrug Ag | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US20050014703A1 (en) * | 2000-03-31 | 2005-01-20 | Hans-Ulrich Demuth | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US7199159B2 (en) | 2000-05-26 | 2007-04-03 | Centre National De La Recherche Scientifique (C.N.R.S.) | Use of biguanide derivatives for making a medicine having a wound healing effect |
US7435420B2 (en) | 2000-10-27 | 2008-10-14 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors for the treatment of anxiety |
US7132104B1 (en) | 2000-10-27 | 2006-11-07 | Probiodrug Ag | Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders |
US20040043919A1 (en) * | 2000-10-27 | 2004-03-04 | Stephan Von Horsten | Method for the treatment of neurological and neuropsychological disorders |
US20060252701A1 (en) * | 2000-10-27 | 2006-11-09 | Probiodrug | Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV)-like activity for the treatment of neurological and neuropsychological disorders |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
US20030130199A1 (en) * | 2001-06-27 | 2003-07-10 | Von Hoersten Stephan | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US20060293248A1 (en) * | 2001-06-27 | 2006-12-28 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
US20050171025A1 (en) * | 2001-06-27 | 2005-08-04 | Von Hoersten Stephan | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7368576B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7109347B2 (en) | 2001-06-27 | 2006-09-19 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US20040214762A1 (en) * | 2001-08-16 | 2004-10-28 | Hans-Ulrich Demuth | Use of inhibitors of proline endopeptidase to modulate inositol (1,4,5) triphosphate concentration dependent on intracellular signal cascades |
US20050107308A1 (en) * | 2001-08-17 | 2005-05-19 | Pospisilik Andrew J. | Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels |
US6844316B2 (en) | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US7144856B2 (en) | 2001-09-06 | 2006-12-05 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US20050233978A1 (en) * | 2001-09-06 | 2005-10-20 | Andre Niestroj | Novel inhibitors of dipeptidyl peptidase I |
US20030119738A1 (en) * | 2001-09-06 | 2003-06-26 | Andre Niestroj | Novel inhibitors of dipeptidyl peptidase I |
US7608577B2 (en) | 2001-10-12 | 2009-10-27 | Osi Pharmaceuticals, Inc. | Peptidyl ketones as inhibitors of DPIV |
US20030148961A1 (en) * | 2001-10-12 | 2003-08-07 | Ulrich Heiser | Peptidyl ketones as inhibitors of DPIV |
US6946480B2 (en) | 2002-02-28 | 2005-09-20 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
US20030162820A1 (en) * | 2002-02-28 | 2003-08-28 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
US20030232761A1 (en) * | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
US6911457B2 (en) | 2002-04-11 | 2005-06-28 | Carbomer, Inc. | Diabetes imaging probes |
WO2003086563A3 (en) * | 2002-04-11 | 2004-03-18 | Carbomer Inc | Diabetes imaging probes |
WO2003086563A2 (en) * | 2002-04-11 | 2003-10-23 | Carbomer, Inc. | Diabetes imaging probes |
EP1500656A4 (en) * | 2002-04-26 | 2006-09-06 | Chugai Pharmaceutical Co Ltd | Biguanide derivative and therapeutic agent for diabetes containing the same |
US7396858B2 (en) | 2002-04-26 | 2008-07-08 | Chugai Seiyaku Kabushiki Kaisha | Biguanide derivative and therapeutic agent for diabetes containing the same |
US20050124693A1 (en) * | 2002-04-26 | 2005-06-09 | Naoki Taka | Biguanide derivative and therapeutic agent for diabetes containing the same |
EP1500656A1 (en) * | 2002-04-26 | 2005-01-26 | Chugai Seiyaku Kabushiki Kaisha | Biguanide derivative and therapeutic agent for diabetes containing the same |
US20040033051A1 (en) * | 2002-08-16 | 2004-02-19 | Ip Kiril Kun Wan | Method and system for producing and displaying visual presentations which inhibit off-screen duplication |
US20040058876A1 (en) * | 2002-09-18 | 2004-03-25 | Torsten Hoffmann | Secondary binding site of dipeptidyl peptidase IV (DP IV) |
US20050176622A1 (en) * | 2002-09-18 | 2005-08-11 | Kerstin Kuhn-Wache | Secondary binding site of dipeptidyl peptidase IV (DPIV) |
US20040063780A1 (en) * | 2002-10-01 | 2004-04-01 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical preparations for treatment of type II diabetes and methods for treatment of type II diabetes |
US20050272641A1 (en) * | 2003-02-07 | 2005-12-08 | Ajinomoto Co., Inc. | Therapeutic agents for diabetes |
US7807663B2 (en) * | 2003-02-07 | 2010-10-05 | Ajinomoto Co., Inc. | Therapeutic agents for diabetes |
US7371871B2 (en) | 2003-05-05 | 2008-05-13 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US7381537B2 (en) | 2003-05-05 | 2008-06-03 | Probiodrug Ag | Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease |
US20050058635A1 (en) * | 2003-05-05 | 2005-03-17 | Hans-Ulrich Demuth | Use of effectors of glutaminyl and glutamate cyclases |
US20040224875A1 (en) * | 2003-05-05 | 2004-11-11 | Stephan Schilling | Inhibitors of glutaminyl cyclase |
US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US20060189523A1 (en) * | 2003-10-15 | 2006-08-24 | Stephan Schilling | Use of effectors of glutaminyl and glutamate cyclases |
US7462599B2 (en) | 2003-10-15 | 2008-12-09 | Probiodrug Ag | Use of effectors of glutaminyl and glutamate cyclases |
US20100099721A1 (en) * | 2003-11-03 | 2010-04-22 | Probiodrug Ag | Novel compounds for the treatment of neurological disorders |
US20100159032A1 (en) * | 2003-11-03 | 2010-06-24 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
US20050171112A1 (en) * | 2003-11-03 | 2005-08-04 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
US7897633B2 (en) | 2004-02-05 | 2011-03-01 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7687638B2 (en) | 2004-06-04 | 2010-03-30 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
US7825242B2 (en) | 2004-07-16 | 2010-11-02 | Takeda Pharmaceutical Company Limted | Dipeptidyl peptidase inhibitors |
US7872124B2 (en) | 2004-12-21 | 2011-01-18 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US20110196015A1 (en) * | 2008-10-13 | 2011-08-11 | Hanall Biopharma Co., Ltd. | N 1-2-thiophene-2-ylethyl-n2-substituted biguanide derivate, preparation method thereof, and pharmaceutical composition containing the same as active ingredients |
US8648111B2 (en) * | 2008-10-13 | 2014-02-11 | Hanall Biopharma Co., Ltd. | N1-2-thiophene-2-ylethyl-N2-substituted biguanide derivate, preparation method thereof, and pharmaceutical composition containing the same as active ingredients |
WO2011018742A1 (en) | 2009-08-13 | 2011-02-17 | Csir | Triazine derivates for use in the treatment of malaria |
CN106458868A (en) * | 2014-04-17 | 2017-02-22 | 伊谬诺米特医疗有限公司 | Guanidine compounds and use thereof |
JP2017513948A (en) * | 2014-04-17 | 2017-06-01 | イミューノメット セラピューティクス インコーポレイテッド | Guanidine compounds and uses thereof |
JP2019077703A (en) * | 2014-04-17 | 2019-05-23 | イミューノメット セラピューティクス インコーポレイテッド | Guanidine compounds and use thereof |
US11465989B2 (en) | 2014-04-17 | 2022-10-11 | ImmunoMet Therapeutics, Inc. | Guanidine compounds and use thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US2961377A (en) | Oral anti-diabetic compositions and methods | |
NO127359B (en) | ||
US2878264A (en) | Substituted amino alcohols | |
JPS5953895B2 (en) | Substituted anilino-acetamidoxime derivatives | |
NZ206945A (en) | Pyridazines and pharmaceutical compositions | |
PL128791B1 (en) | Process for manufacturing novel substituted bis-hydrazones-9,10-anthracene | |
US4267339A (en) | Imidazo(2,1-B)thiazoles | |
JPS6259264A (en) | 5-pyrimidinecarboxamides, manufacture and medicinal composition | |
US2918406A (en) | Anti-spasmodics specific for peptic ulcer | |
JPS6043351B2 (en) | Manufacturing method for geriatric drugs | |
US2918407A (en) | Anti-spasmodics specific for upper gastrointestinal pain and spasm | |
US3210247A (en) | Anti-epileptic i-cyclohexyl-z-methyl- aiviino propane salt of phenyl ethyl barbituric acid | |
US3161565A (en) | Lysine orotate | |
US3456059A (en) | N1-(2 - (p-hydroxyphenyl)ethyl)biguanide as a hypoglycemic agent and as a weight reducing agent | |
US2889351A (en) | Therapeutic agents | |
US4137320A (en) | Pharmaceutical compositions containing imidazo(2,1-b)thiazoles and process for reducing blood sugar levels therewith | |
US2943022A (en) | Substituted 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds and process of making same | |
US3041331A (en) | N-alkanoylbenzenesulfonyl | |
US2928768A (en) | Use of substituted amino-formoguanamines in diuretic therapy | |
US2776993A (en) | 1-paramethoxyphenyl-2-cyclopentylamino-1-propanol compounds | |
US2419230A (en) | Therapeutic compositions and method of preparing same | |
US3098008A (en) | Method for treatment of dermatological disorders | |
US4183934A (en) | 4-Hydroxy-7-(substituted)phenylpteridines | |
US3005818A (en) | 1-phenyl-2, 3-dimethyl-4-morpholino methyl pyrazolone-(5) compounds | |
US3590039A (en) | N - (alpha,alpha,alpha,alpha',alpha',alpha' -hexafluoro - 3,5 - xylyl) anthranilic acid and salts thereof |