DE1941697A1 - Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect - Google Patents

Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect

Info

Publication number
DE1941697A1
DE1941697A1 DE19691941697 DE1941697A DE1941697A1 DE 1941697 A1 DE1941697 A1 DE 1941697A1 DE 19691941697 DE19691941697 DE 19691941697 DE 1941697 A DE1941697 A DE 1941697A DE 1941697 A1 DE1941697 A1 DE 1941697A1
Authority
DE
Germany
Prior art keywords
naphthalene
disulfonate
biguanide
water
blood sugar
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.)
Pending
Application number
DE19691941697
Other languages
German (de)
Inventor
Harald Dr Horstmann
Hans-Joachim Dr Kabbe
Hans Dr Pluempe
Walter Dr Puls
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to BE754880D priority Critical patent/BE754880A/en
Application filed by Bayer AG filed Critical Bayer AG
Priority to DE19691941697 priority patent/DE1941697A1/en
Priority to BR215290/69A priority patent/BR6915290D0/en
Priority to IL34919A priority patent/IL34919A0/en
Priority to ZA705469A priority patent/ZA705469B/en
Priority to NL7011914A priority patent/NL7011914A/xx
Priority to FR7030099A priority patent/FR2068503A1/en
Publication of DE1941697A1 publication Critical patent/DE1941697A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

L EVE RK U S EN-Beyerwerk 14. August 19Ö9 Patent-Abteilung Si/RBgL EVE RK U S EN-Beyerwerk 14 August 19Ö9 Patent department Si / RBg

Biguanid-naphthalin-1,5-disulfonate mit antihyperglykämischerBiguanide-naphthalene-1,5-disulfonate with antihyperglycemic

Wirkung . Effect .

Es ist bekannt, daß durch Derivate des Biguanids ein erhöhter Blutzuckerspiegel, etwa bei Diabeteskranken, gesenkt wird. So sind z. B-. das 1-Butyl-biguanid-hydrochlorid (Buformin-hydrochlorid) und das 1-(ß-Phenäthyl)-biguanid-hydrochlorid (Phenformin-hydrochlorid) als Mittel zur Behandlung des Diabetes im Handel. Diese beiden Verbindungen lassen jedoch hinsichtlich ihrer Verträglichkeit, vor allem seitens des Magen-Darm-Traktes, noch zu wünschen übrig /vgl. W. Creutzfeldt und H.-D. Söling in "Ergebnisse der inneren Medizin und Kinderheilkunde", Neue Folge, I5. Band, Seiten 195 bis 198, Springer Verlag, Heidelberg (196O}7.It is known that by derivatives of biguanide an increased Blood sugar level, for example in people with diabetes, is lowered. So are z. B-. 1-butyl biguanide hydrochloride (Buformin hydrochloride) and 1- (ß-phenethyl) biguanide hydrochloride (phenformin hydrochloride) as an agent for treating the Diabetes in the trade. However, these two compounds are not tolerable, especially on the part of the Gastrointestinal tract, still to be desired / cf. W. Creutzfeldt and H.-D. Söling in "Results of Internal Medicine and Pediatrics ", New Series, Volume I5, pages 195 bis 198, Springer Verlag, Heidelberg (196O} 7.

Es wurde nun gefunden, daß Salze von Biguanid-Derivaten mit Naphthalin-1,5-disulfonsäure, die im Gegensatz zu den Hydrochloriden nur eine geringe Wasserlöslichkeit besitzen, wesentlich weniger toxisch sind als entsprechende Hydrochloride, daß aber die Senkung eines erhöhten Blutzuckers nach oraler Glucoseapplikation mit gleichen Dosen dieser neuen Salze - bezogen auf Biguanid-Base - erfolgt.It has now been found that salts of biguanide derivatives with Naphthalene-1,5-disulfonic acid, in contrast to the hydrochlorides have only a low solubility in water, are significantly less toxic than corresponding hydrochlorides, but that the lowering of increased blood sugar after oral glucose administration with the same doses of this new salts - based on biguanide base - takes place.

Diese Wirkung läßt sich in folgendem Versuch nachweisen: Nüchterne Ratten erhalten nach mehrmaliger oraler Applikation des Wirkstoffes in physiologischer Kochsalzlösung gelösteThis effect can be demonstrated in the following experiment: Fasting rats receive after repeated oral administration of the active ingredient dissolved in physiological saline solution

Le A 12Le A 12

109809/219?109809/219?

der be-the loading

Glucose per os verabreicht. Der BluVglucosespiegel handelten Tiere steigt dosisabhängig weniger stark an als bei unbehandelten Versuchstieren. Die Messung erfolgt 30 Minuten nach de. ,lucosegabe. Bei der angegebenen Dosis handelt es sich um die jeweils verabreichte Einzeldosis,Glucose administered orally. The BluVglucose level treated animals increases less strongly than dose-dependently in untreated test animals. The measurement takes place 30 Minutes after de. , lucosegabe. At the indicated dose it is the single dose administered in each case,

I = 1-Butylbiguanid-hydrochlorldI = 1-butyl biguanide hydrochloride

II = 1-Butylbiguanid-naphthalin-i,5-disulfonatII = 1-butyl biguanide naphthalene-1,5-disulfonate

III = 1-(ß-Phenäthyl)-biguanid-hydFOchloridIII = 1- (ß-phenethyl) -biguanid-hydrofchloride

IV = 1-(ß-Phenäthyl)-biguanid-naphthalin-1,5-disulfonatIV = 1- (β-phenethyl) -biguanid-naphthalene-1,5-disulfonate

V = 1-(4-Chlor-ß-phenäthyl)-biguanid-hydrochloridV = 1- (4-chloro-β-phenethyl) biguanide hydrochloride

VI = 1-(4-Chlor-ß-phenäthyl)-biguanid-naphthalin-VI = 1- (4-chloro-ß-phenethyl) -biguanid-naphthalene-

1,5-disulfonat.1,5-disulfonate.

Durchschnittswerte desAverage values of the )) 55 Blutzuckers in mg % Blood sugar in mg % 1010 - 1 S (+ - 1 S (+ 2020th unbehandelte Ratte (Kochsalzkontrolle)untreated rat (saline control) 7.1 *7.1 * 1212th unbehandelte, glucosebelastete Ratteuntreated, glucose-stressed rat 160 ί160 ί 1414th 25 mg/kg I25 mg / kg I. 132 - 132 - 1818th 40 mg/kg I40 mg / kg I 125 -125 - 1414th 63 mg/kg I63 mg / kg I. 95 ±95 ± 1111 25 mg/kg II25 mg / kg II 141 ί141 ί 55 40 mg/'kg' II40 mg / 'kg' II 124 ί124 ί 2222nd . 63 mg/kg II. 63 mg / kg II 98 i98 i 99 unbehandelte Ratte (Kochsalzkontrolle)untreated rat (saline control) 57 -57 - 1111 unbehandelte, glucosebelastete Ratteuntreated, glucose-stressed rat 175 -175 - 88th 25 mg/kg- III25 mg / kg- III 151 -151 - 63 mg/kg III63 mg / kg III 134 ί134 ί 160 mg/kg III160 mg / kg III 107 -107 -

Le A 12 414Le A 12 414

1 0 980 9/219 71 0 980 9/219 7

BAO ORIGINALBAO ORIGINAL

19416871941687

Durchschnittswerte desAverage values of the Blutzuckers in mg % Blood sugar in mg % - 1 s (+)- 1 s (+) 25 mg/kg IV25 mg / kg IV 163 - ΐ6163 - ΐ6 63 mg/ kg IV ,63 mg / kg IV, 146 ί 20146 ί 20 16O mg, kg IV16O mg, kg IV 112 ί 10112 ί 10 unbehandelte Ratte (Kochsalzkontrolle)untreated rat (saline control) 70 ί 970 ί 9 unbehandelto," glucosebelastete Ratteuntreated o, "glucose-contaminated rat 152 ί 5152 ί 5 10 me, kg V10 me, kg V 1J0 ί 241J0 ί 24 25 rar* kg V25 rar * kg V 119 - 13119-13 fr? mg/kg Vfr? mg / kg V 109 - ίο109 - ίο 10 sr,'kg VI10 sr, 'kg VI 139-10139-10 2S rap/kg· VI2S rap / kg · VI 125 - 12125 - 12 63 mr/kg VI63 mr / kg VI 116 ± δ '116 ± δ '

(+) ό = Mittlerer Fehler der Einzelwerte.(+) ό = mean error of the individual values.

Zahl der Versuchstiere pro Dosis η = 6,Number of test animals per dose η = 6,

Pei gleicher antihyperglykämischer Wirksamkeit besitzen die
neuer. Eiguar.id-naj hthalin-1, 5-disulfonate Jedoch eine geringere akute Toxizitiit als die vergleichbaren Hydrochloride.They have the same antihyperglycemic effectiveness
news. Eiguar.id-naj hthalin-1, 5-disulfonate However, a lower acute toxicity than the comparable hydrochloride.

Le A 12 414Le A 12 414

! 09809/2197 BAD QRIätNAL! 09809/2197 BAD QRIätNAL

in "1S Base / kg per os wit 95 % Vertrauensbereich in " 1 S base / kg per os wit 95 % confidence interval

α> c? coα> c? co

TierspeziesAnimal species Substanzsubstance 408408 (339-469)(339-469) Substanzsubstance 893893 (774-1041)(774-1041) Substanzsubstance Substanzsubstance ]] 350350 (329-373)(329-373) IIII 804804 (605-1006)(605-1006) IIIIII IVIV gefütterte Mausfed mouse 220220 (150-331)(150-331) 847847 (645-1204)(645-1204) 475-500475-500 1300 (1084-1556)1300 (1084-1556) nüchterne Maus sober mouse 148148 (128-174)(128-174) 348348 (281-423)(281-423) 353 (336-375)353 (336-375) 1546 (1309-1770)1546 (1309-1770) gefütterte Rattefed rat 1642 (1373-2172)1642 (1373-2172) >3000> 3000 nüchterne Rattesober rat 661 (553-788)661 (553-788) >3000> 3000

Die Herstellung der neuen Salze geschieht zweckmäßig durch doppelten Umsatz von gut wasserlöslichen Salzen eines Biguanid-Derivates und der Naphthalin-disulfonsäure, beispielsweise in Wasser, wo das gewünschte Produkt dann infolge seiner Schwerlöslichkeit ausfällt. Man kann natürlich auch das Biguanid als Base und die freie Naphthalin-1,5-disulfonsäure, jeweils gelöst in Wasser, Alkoholen oder sonstigen geeigneten organischen Lösungsmitteln, zusammengeben und das ausgefallene Salz isolieren.The new salts are expediently prepared double conversion of readily water-soluble salts of a biguanide derivative and naphthalene-disulfonic acid, for example in water, where the desired product then as a result of it Difficulty solubility fails. You can of course also use the biguanide as a base and the free naphthalene-1,5-disulfonic acid, each dissolved in water, alcohol or other suitable organic solvents, combine and the precipitated Isolate salt.

Beispiel 1example 1

9*7 S (0,05 Mol) .1-Butylbiguanid-hydrochlorid, gelöst in 50 ml Wasser, gibt man unter Rühren zu einer Lösung von 8,2 g (0,025 Mol) Dinatriumsalz der Naphthalin-1,5-disulfonsäure in 100 ml Wasser. Nach mehrstündigem Stehenlassen vfird das ausgefallene Produkt abgesaugt, mit Wasser gewaschen und getrocknet. Man erhält ein 1-Butylbiguanid-naphthalin-1,5-disulfonat der Zusammensetzung9 * 7 S (0.05 mol) .1-butyl biguanide hydrochloride, dissolved in 50 ml of water are added to a solution of while stirring 8.2 g (0.025 mol) of the disodium salt of naphthalene-1,5-disulfonic acid in 100 ml of water. After standing for several hours, the precipitated product is filtered off with suction, washed with water and dried. A 1-butyl biguanide naphthalene-1,5-disulfonate is obtained the composition

als farbloses feinkristallines Pulver (F. 231°C) in nahezu quantitativer Ausbeute.as a colorless, finely crystalline powder (m.p. 231 ° C) in almost quantitative yield.

Beispiel 2Example 2

14,5 g (0,06 Mol) 1-(ß-Phenäthyl)-biguanid-hydrochlorid, gelöst in 60 ml Wasser, gibt man unter Rühren zu einer Lösung von 10,0 g (0,03 Mol) Dinatriumsalz der Naphthalin-1,5-disulfonsäure in 120 ml Wasser. Nach mehrstündigem Stehenlassen wird das ausgefallene Produkt abgesaugt, mit Wasser gewaschen und getrocknet. Man erhält ein 1-(ß-Phen-14.5 g (0.06 mol) 1- (ß-phenethyl) biguanide hydrochloride, dissolved in 60 ml of water, it is added with stirring to a solution of 10.0 g (0.03 mol) of the disodium salt of naphthalene-1,5-disulfonic acid in 120 ml of water. After standing for several hours, the precipitated product is filtered off with suction, with Water washed and dried. A 1- (ß-phen-

Le A 12 414 - 5 - Le A 12 414 - 5 -

10980 97 2Ί9 710980 97 2Ί9 7

äthyl)-biguanid-naphthalin-1,5-disuironat der Zusammensetzungethyl) -biguanid-naphthalene-1,5-disuironate of the composition

als farbloses feinkristallines Pulver (P. 2380C) in nahezu quantitativer Ausbeute.as a colorless, finely crystalline powder (P. 238 0 C) in almost quantitative yield.

Beispiel 3Example 3

Analog Beispiel 2 erhält man aus 1~/i3-(p-Chlorphenyl)-äthyi7 biguanid-hydrochlorid und dem Dinatriumsalz der Naphthalin-1,5-disulfonsäure das 1-^ß-(p-Chlorphenyl)-äthyl7-biguanLdnaphthalin-1,5-disulfonat der ZusammensetzungAnalogously to Example 2, 1 ~ / i3- (p-chlorophenyl) -ethyi7 is obtained biguanide hydrochloride and the disodium salt of naphthalene-1,5-disulfonic acid 1- ^ ß- (p-chlorophenyl) -ethyl7-biguanLdnaphthalin-1,5-disulfonate the composition

2 C10H14ClN5XC10H6 (SO3H)2 2 C 10 H 14 ClN 5 XC 10 H 6 (SO 3 H) 2

als farbloses feinkristallines Pulver (F. 235 bis 237°C).as a colorless, finely crystalline powder (m.p. 235 to 237 ° C).

Le A 12 414 - 6 -Le A 12 414 - 6 -

10 9809/219?10 9809/219?

Claims (1)

2. Alkylbiguanid-naphthalin-1,5-disulfonate, in denen der Alkylrest 1,bis 6 Kohlenstoffatome enthält.2. Alkylbiguanid-naphthalene-1,5-disulfonate, in which the Alkyl radical 1, contains up to 6 carbon atoms. 3. Aralkylbiguanid-naphthaliri-ijS-disulfonate, in denen der Aralkylrest 7 bis P Kohlenstoffatome enthält.3. Aralkylbiguanid-naphthaliri-ijS-disulfonate, in which the aralkyl radical contains 7 to P carbon atoms. H. Arzneimittel, gekennzeichnet durch einen Gfhalt an einer Verbindung gemäß Anspruch 1 bis 3· H. Medicaments, characterized by a content of a compound according to Claims 1 to 3 I. Mittel Tiit blutsuckersenkender Wirkung, gekennzeichnet durch einen behalt an einer Verbindung gemäß Anspruch 1 bis 3· I. Means with blood sugar lowering effect, characterized by a retention of a compound according to claims 1 to 3 · 6. Oral applizierbare Mittel mit blutzuckersenkender Wirkung, gekennzeichnet durch einen Gehalt an einer Verbindung rerrJiZ Anspruch 1 bis 3·6. Orally applicable agents with blood sugar lowering effect, characterized by a content of a compound rerrJiZ claim 1 to 3 · LeA 12 414 - 7 -LeA 12 414 - 7 - 109809/2197 BAD109809/2197 BATH
DE19691941697 1969-08-16 1969-08-16 Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect Pending DE1941697A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
BE754880D BE754880A (en) 1969-08-16 BIGUANIDE NAPHTHALENE-1,5-DISULFONATES WITH ANTI-HYPERGLYCEMIA ACTION
DE19691941697 DE1941697A1 (en) 1969-08-16 1969-08-16 Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect
BR215290/69A BR6915290D0 (en) 1969-08-16 1969-12-17 PROCESS FOR THE PREPARATION OF BIGUANIDE-NAFTALENE 1,5-DISSULPHONATES
IL34919A IL34919A0 (en) 1969-08-16 1970-07-14 Biguanide-naphthalene-1,5-disulphonates and blood sugar level depressing compositions containing them
ZA705469A ZA705469B (en) 1969-08-16 1970-08-07 Biguanide-naphthalene-1,5 disulphonates and blood suggardepressing compositions thereof
NL7011914A NL7011914A (en) 1969-08-16 1970-08-12
FR7030099A FR2068503A1 (en) 1969-08-16 1970-08-14 Biguanide 1,5-naphthalene disulphonates

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19691941697 DE1941697A1 (en) 1969-08-16 1969-08-16 Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect

Publications (1)

Publication Number Publication Date
DE1941697A1 true DE1941697A1 (en) 1971-02-25

Family

ID=5742953

Family Applications (1)

Application Number Title Priority Date Filing Date
DE19691941697 Pending DE1941697A1 (en) 1969-08-16 1969-08-16 Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect

Country Status (7)

Country Link
BE (1) BE754880A (en)
BR (1) BR6915290D0 (en)
DE (1) DE1941697A1 (en)
FR (1) FR2068503A1 (en)
IL (1) IL34919A0 (en)
NL (1) NL7011914A (en)
ZA (1) ZA705469B (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2473112A (en) * 1946-04-03 1949-06-14 Boots Pure Drug Co Ltd Preparation of sulfonic acid salts of diguanides
DE1093349B (en) * 1958-08-20 1960-11-24 Gruenenthal Chemie Process for the preparation of monoalkyl biguanides

Also Published As

Publication number Publication date
IL34919A0 (en) 1970-09-17
BE754880A (en) 1971-02-15
BR6915290D0 (en) 1973-04-12
FR2068503A1 (en) 1971-08-27
NL7011914A (en) 1971-02-18
ZA705469B (en) 1971-04-28

Similar Documents

Publication Publication Date Title
DE2043933C3 (en) N- (ß-Naphthylaminomethyl) -aminocarboxylic acids and drugs containing them
DE3137125C2 (en)
DE2462367A1 (en) 7-(Oxo-alkyl)-1,3-dialkyl-xanthines - as agents for increasing blood flow in skeletal muscles
DE2403122C2 (en)
DE2460929C2 (en)
DE2823346A1 (en) ANTIVIRIAL AGENT AND METHOD OF USING THE SAME IN VIRUS INFECTION
DE3234537A1 (en) MEDICINES FOR TREATING CARDIOVASCULAR DISEASES
DE2108237C3 (en) Salt of pyridoxine a-ketoglutarate with 5-hydroxytryptophan and process for its preparation
DE1941697A1 (en) Biguanide-naphthalene-1,5-disulfonate with antihyperglycaemic effect
DE1900772C3 (en) Salt of N, N-dimethylbiguanide and p-chlorophenoxyacetic acid and medicinal products containing this
DE1910283C3 (en) Medicinal product effective against certain forms of cancer
DE1445446A1 (en) Benzylpenicillin derivative and method of production
DE2416339C3 (en) Arginine pyroglutanate, process for its preparation and pharmaceuticals
DE1965343A1 (en) Medicines, in particular for reducing the viscosity of the mucus and use as a cough suppressant, and process for its production
DE1695220C3 (en) 2-Guanidino-3r3-diphenyl-5-methylAl -pyrroline, process for its preparation and pharmaceuticals
DE1793769C2 (en) Process for the preparation of bis (thiosemicarbazones). Eliminated from: 151205
EP0152860B1 (en) Use of cephalosporin compounds for the manufacture of a medicament for the modulation of the immunologic system
DE1443386C3 (en) Process for the preparation of 3-cyanguanidine derivatives
DE2419317C3 (en) Lysine [2- (4-isobutylphenyl) propionate], process for its preparation and pharmaceuticals containing it
DE2428039B2 (en) Medicines with choleretic effects, containing 2,6-dihydroxycineol
DE2043330C3 (en) Polymeric substances from l-methyl-5- (5-OXO-4 ethyl-tetrahydrofuryl- (3) methyO-imidazole and cellulose glycolic acid, processes for their production and pharmaceuticals containing these substances
DE1915795C3 (en) N- (3,4,5-trimethoxycinnamoyl) -N'- (carbonylmethyl) -piperazine derivatives and their acid addition salts, processes for their preparation and medicaments containing these compounds
DE2417638C3 (en) 2-methyl-3-carbethoxy-4-chloro-5hydroxy-6-dimethylaminomethylbenzofuran and its pharmacologically acceptable salts, as well as drugs containing these compounds
DE2605182A1 (en) MEDICINE AGAINST TUMOR
DE2447444A1 (en) Gamma-Hydroxypropyl-substd. xanthines compositions - for improving peripheral blood flow