WO1992011248A1 - Novel aliphatic amides, process for producing them and medicaments containing these compounds - Google Patents
Novel aliphatic amides, process for producing them and medicaments containing these compounds Download PDFInfo
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- WO1992011248A1 WO1992011248A1 PCT/EP1991/002390 EP9102390W WO9211248A1 WO 1992011248 A1 WO1992011248 A1 WO 1992011248A1 EP 9102390 W EP9102390 W EP 9102390W WO 9211248 A1 WO9211248 A1 WO 9211248A1
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- compounds
- general formula
- tetrazol
- acceptable salts
- physiologically acceptable
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Definitions
- New aliphatic amides processes for their preparation and medicaments containing these compounds
- A is fluorine or hydrogen, n is an integer between 1 and 10 and
- B represents a saturated or unsaturated, straight-chain or branched alkylene group having 1 to 12 carbon atoms, and their physiologically acceptable salts
- the substances have a pronounced lipid-lowering effect and are therefore also suitable for the treatment of fat metabolism disorders.
- Alkylene groups B are to be understood in particular as follows:
- -CH 2 -CH CH-CH 2 -
- -CH 2 -C CH-CH 2 -
- -CH 2 -C C-CH 2 -.
- Suitable physiologically acceptable salts are, in particular, alkali, alkaline earth or ammonium salts (and, if appropriate, salts with blood sugar-lowering biguanides).
- 1H-tetrazol-5-yl used in this application should therefore also include the tautomeric form 2H-tetrazol-5-yl.
- the invention furthermore relates to processes for the preparation of compounds of the general formula I by using an A in the general formula II in a manner known per se
- Examples of reactive derivatives of carboxylic acids III include Halides, azides or reactive esters in question, especially the acid chlorides.
- the reaction of carboxylic acid chlorides from carboxylic acids of the general formula III with compounds of the general formula II is advantageously carried out with the addition of acid-binding agents, such as e.g. Alkali acetate, sodium hydrogen carbonate, sodium carbonate or potassium carbonate.
- acid-binding agents such as e.g. Alkali acetate, sodium hydrogen carbonate, sodium carbonate or potassium carbonate.
- This function can also be used by organic bases such as Pyridine or triethylamine are taken over, the inert solvent being e.g. Ether, methylene chloride, dioxane or an excess of the tertiary amine is used.
- the reaction medium used is e.g. Ethanol, butanone-2, dimethylformamide or aqueous mixtures thereof.
- reaction of compounds of general formula IV with sodium azide is carried out in a high-boiling polar solvent such as e.g. N-methylpyrrolidone, carried out at higher temperatures, preferably at 100-200 ° C.
- a high-boiling polar solvent such as e.g. N-methylpyrrolidone
- the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carrier substances, aroma, flavor and colorants and shaped, for example, as tablets or dragees or with addition. speaking auxiliary substances suspended or dissolved in water or oil, such as olive oil.
- the substances of the general formula I can be administered orally and parenterally in liquid or solid form.
- Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions.
- Such additives are e.g. Tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
- Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acid, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular polymers (such as polyethylene glycols).
- Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
- the dose administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired.
- the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications per day in order to obtain the desired results. example 1
- mice Male C57BL / 6J ob / ob mice were obtained from Harlan Olac Ltd. at the age of 6-8 weeks. , Blackthorn, England. Animals with an age of 12-14 weeks were used for the study; five of the animals were housed in a cage under standard conditions. At the beginning of the experiment, the animals were weighed and 5 / ul of blood were obtained by docking the tip of the tail. The blood obtained was immediately diluted 1:51 with hemolysis reagent from Boehringer Mannheim GmbH Germany (digitonin 0.04 M, maleimide> 1.0 M, dissolved in agua dest.).
- the blood glucose was then measured using the test combination Gluco-guant glucose from Boehringer Mannheim GmbH Germany (UV test, hexokinase method according to FH Schmidt, Klin. Wschr. .39., 1244, 1961) with an EPOS Analyzer 5060, Eppendorf Adjustbau, Hamburg. Animals with a blood glucose concentration of at least 250 mg / dl were included in the study. 10 animals in the control group received only the solubilizer methyl cellulose (1% w / v), 10 animals in the substance group a dose of 100 mg / kg. On the 5th day of the substance application, the animals were weighed again and blood was obtained for the blood glucose determination as described above.
- a corresponding blood volume was obtained for the insulin determination after decapitation and separation of the carotids. After the blood obtained has been left to rest for at least 10 minutes, it is centrifuged at room temperature, 10 minutes and 9,000 ⁇ g. The serum is stored until the insulin concentration is determined by means of a commercially available insulin radioimmunoassay from Pharmacia-Diagnostiks AB, Uppsala, Sweden (Pharacia-Insulin-RIA 100) at -20 ° C.
- the ob / ob mice which received only 1% methyl cellulose showed almost no changes in the blood glucose concentrations on the 5th day of application, whereas the blood glucose concentration showed that with 100 mg / kg Substantive group were reduced to about 110 mg / dl.
- the insulin concentrations of the substance group were reduced to normoinsulinemic values.
Abstract
Compounds of formula (I) in which: A is fluorine or hydrogen, n is an integer between 1 and 10; and B is a saturated or unsaturated, straight or branched chain alkylene group with 1 to 12 carbon atoms; and the physiologically acceptable salts, process for producing them and their use as a medicament in the treatment of diabetes, prediabetes and maturity diabetes.
Description
Neue aliphatische Amide, Verfahren zu ihrer Herstellung sowie Arzneimittel, die diese Verbindungen enthaltenNew aliphatic amides, processes for their preparation and medicaments containing these compounds
In der Patentanmeldung US 4764-623-A sind Anilide von Per- fluoralkansäuren beschrieben, die antidiabetische Eigen¬ schaften besitzen und insbesondere an genetisch diabetischen Tiermodellen für den insulinresistenten Typ-I -Diabetes sowohl anti-hyperglykämisch als auch anti-hyperinsulinämisch wirksam sind.The patent application US 4764-623-A describes anilides of perfluoroalkanoic acids which have anti-diabetic properties and which are both anti-hyperglycemic and anti-hyperinsulinemic effective for genetically diabetic animal models for insulin-resistant type I diabetes.
Überraschend wurde nun gefunden, daß bestimmte aliphatische Amide von Perfluoralkansäuren eine erheblich höhere anti- hyperglykämische und anti-hyperinsulinämische Wirksamkeit besitzen und somit vorteilhaft in wesentlich geringerer Dosis verabreicht werden können. Die geringere Belastung des Organismus durch pharmakologisch wirksame Substanzen bei gleicher Wirksamkeit stellt für die Dauertherapie, wie sie bei Diabetes mellitus erforderlich ist, eine wesentliche Verbesserung des Standes der Technik dar. Gegenstand der Anmeldung sind daher neue aliphatische Amide von Perfluor¬ alkansäuren der allgemeinen Formel ISurprisingly, it has now been found that certain aliphatic amides of perfluoroalkanoic acids have a considerably higher anti-hyperglycemic and anti-hyperinsulinemic activity and can therefore advantageously be administered in a substantially lower dose. The lower burden on the organism by pharmacologically active substances with the same effectiveness represents a significant improvement in the prior art for the long-term therapy required for diabetes mellitus. The application therefore relates to new aliphatic amides of perfluoroalkanoic acids of the general formula I
(_. ^ 
in welcher ( _ . ^ in which
A Fluor oder Wasserstoff, n eine ganze Zahl zwischen 1 und 10 undA is fluorine or hydrogen, n is an integer between 1 and 10 and
B eine gesättigte oder ungesättigte, geradkettige oder verzweigte Alkylengruppe mit 1 bis 12 Kohlenstoffatome bedeutet, sowie deren physiologisch unbedenklichen Salze,B represents a saturated or unsaturated, straight-chain or branched alkylene group having 1 to 12 carbon atoms, and their physiologically acceptable salts,
ihre Verwendung als Arzneimittel zur Behandlung von Diabetes, Prädiabetes und insbesondere zur Behandlung von Alters- diabetes. Zusätzlich zeigen die Substanzen eine ausgeprägte lipidsenkende Wirkung und eignen sich daher auch zur Behand¬ lung von FettstoffWechselerkrankungen.their use as medicines for the treatment of diabetes, prediabetes and in particular for the treatment of adult diabetes. In addition, the substances have a pronounced lipid-lowering effect and are therefore also suitable for the treatment of fat metabolism disorders.
Unter Alkylengruppen B sind insbesondere die folgenden zu verstehen:Alkylene groups B are to be understood in particular as follows:
a) als gesättigte, unverzweigte Reste:a) as saturated, unbranched residues:
-(CH2)m- mit m = 1-12,- (CH 2 ) m - with m = 1-12,
b) als gesättigte, verzweigte Reste:b) as saturated, branched residues:
CH3 CH 3
I -(CH2)o-CH-(CH2)p- und -(CH2)0-C-(CH2)p-, CH3 CH3 I - (CH 2 ) o-CH- (CH 2 ) p- and - (CH 2 ) 0 -C- (CH 2 ) p-, CH 3 CH 3
wobei o und p ganze Zahlen bedeuten, deren Summe zwischen 0 und 11 beträgt.
c) als ungesättigte, verzweigte oder unverzweigte Reste:where o and p are integers, the sum of which is between 0 and 11. c) as unsaturated, branched or unbranched residues:
-CH2-CH=CH-CH2-, -CH2-C=CH-CH2- und -CH2-C=C-CH2-.-CH 2 -CH = CH-CH 2 -, -CH 2 -C = CH-CH 2 - and -CH 2 -C = C-CH 2 -.
CH3 CH 3
Als physiologisch unbedenkliche Salze kommen insbesondere Alkali-, Erdalkali- oder Ammoniumsalze (sowie gegebenenfalls Salze mit blutzuckersenkenden Biguaniden) infrage.Suitable physiologically acceptable salts are, in particular, alkali, alkaline earth or ammonium salts (and, if appropriate, salts with blood sugar-lowering biguanides).
Es ist bekannt, daß der lH-Tetrazol-5-yl-Rest leicht zum 2H- Tetrazol-5-yl-Rest tautomerisieren kann:It is known that the 1H-tetrazol-5-yl residue can easily tautomerize to the 2H-tetrazol-5-yl residue:
HH
Der in dieser Anmeldung verwendete Begriff lH-Tetrazol-5-yl soll daher auch die tautomere Form 2H-Tetrazol-5-yl mit umfassen.The term 1H-tetrazol-5-yl used in this application should therefore also include the tautomeric form 2H-tetrazol-5-yl.
Gegenstand der Erfindung sind weiterhin Verfahren zur Her¬ stellung von Verbindungen der allgemeinen Formel I, indem man in an sich bekannter Weise ein A in der allgemeinen Formel IIThe invention furthermore relates to processes for the preparation of compounds of the general formula I by using an A in the general formula II in a manner known per se
H2N-B-CN (II) ,H 2 NB-CN (II),
in welcher B die oben angegebene Bedeutung besitzt,in which B has the meaning given above,
zunächst mit reaktiven Derivaten von Carbonsäuren der all¬ gemeinen Formel III
A- ( CF2 ) n-COOH ( III ) ,initially with reactive derivatives of carboxylic acids of the general formula III A- (CF 2 ) n -COOH (III),
in welcher A und n die oben angegebenen Bedeutungen besitzen, zu Verbindungen der allgemeine Formel IVin which A and n have the meanings given above, to compounds of the general formula IV
A-(CF2)n-CONH-B-CN (IV) ,A- (CF 2 ) n -CONH-B-CN (IV),
umsetzt und diese dann durch Erhitzen mit Natriumazid in die gewünschten Verbindungen der allgemeinen Formel I überführt.implemented and then converted into the desired compounds of general formula I by heating with sodium azide.
Als reaktive Derivate der Carbonsäuren III kommen z.B. Halogenide, Azide oder reaktive Ester infrage, insbesondere die Säurechloride. Die Umsetzung von Carbonsäurechloriden aus Carbonsäuren der allgemeinen Formel III mit Verbindungen der allgemeinen Formel II erfolgen zweckmäßig unter Zusatz säure¬ bindender Mittel, wie z.B. Alkaliacetat, Natriumhydrogen- carbonat, Natriumcarbonat oder Kaliumcarbonat. Diese Funktion kann aber auch von organischen Basen wie z.B. Pyridin oder Triethylamin übernommen werden, wobei als inertes Lösungs¬ mittel z.B. Ether, Methylenchlorid, Dioxan oder ein Überschuß des tertiären Amins dient. Bei Einsatz anorganischer Säure¬ binder verwendet man als Reaktionsmedium z.B. Ethanol, Butanon-2, Dimethylformamid oder wässrige Gemische daraus.Examples of reactive derivatives of carboxylic acids III include Halides, azides or reactive esters in question, especially the acid chlorides. The reaction of carboxylic acid chlorides from carboxylic acids of the general formula III with compounds of the general formula II is advantageously carried out with the addition of acid-binding agents, such as e.g. Alkali acetate, sodium hydrogen carbonate, sodium carbonate or potassium carbonate. This function can also be used by organic bases such as Pyridine or triethylamine are taken over, the inert solvent being e.g. Ether, methylene chloride, dioxane or an excess of the tertiary amine is used. When using inorganic acid binders, the reaction medium used is e.g. Ethanol, butanone-2, dimethylformamide or aqueous mixtures thereof.
Die Umsetzung von Verbindungen der allgemeinen Formel IV mit Natriumazid wird in einem hochsiedenden polaren Lösungsmittel wie z.B. N-Methylpyrrolidon, bei höheren Temperaturen vor¬ zugsweise bei 100-200 ' C, durchgeführt.The reaction of compounds of general formula IV with sodium azide is carried out in a high-boiling polar solvent such as e.g. N-methylpyrrolidone, carried out at higher temperatures, preferably at 100-200 ° C.
Zur Herstellung von Arzneimittel werden die Verbindungen der allgemeinen Formel I in an sich bekannter Weise mit ge¬ eigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe ent-
sprechender Hilfsstoffe in Wasser oder öl, wie z.B. Olivenöl, suspendiert oder gelöst.For the production of pharmaceuticals, the compounds of general formula I are mixed in a manner known per se with suitable pharmaceutical carrier substances, aroma, flavor and colorants and shaped, for example, as tablets or dragees or with addition. speaking auxiliary substances suspended or dissolved in water or oil, such as olive oil.
Die Substanzen der allgemeinen Formel I können in flüssiger oder fester Form oral und parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Stabilisierungs¬ mittel, Lösungsvermittler und/oder Puffer enthält. Derartige Zusätze sind z.B. Tartrat- oder Borat-Puffer, Ethanol, Di- methylsulfoxid, Komplexbildner (wie Ethylendiamintetraessig- säure) , hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregulierung oder Polyethylen- Derivate von Sorbitanhydriden.The substances of the general formula I can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions. Such additives are e.g. Tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
Feste Trägerstoffe sind z.B. Stärke, Lactose, Mannit, Methyl- cellulose, Talkum, hochdisperse Kieselsäure, höhermolekulare Fettsäuren (wie Stearinsäure) , Gelatine, Agar-Agar, Calciu - phosphat, Magnesiumstearat, tierische und pflanzliche Fette oder feste hochmolekulare Polymere (wie Polyethylenglykole) . Für die orale Applikation geeignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe enthalten.Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicic acid, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
Die verabreichte Dosierung hängt vom Alter, der Gesundheit und dem Gewicht des Empfängers, dem Ausmaß der Krankheit, der Art gleichzeitiger gegebenenfalls durchgeführter weiterer Behandlungen, der Häufigkeit der Behandlungen und der Art der gewünschten Wirkung ab. üblicherweise beträgt die tägliche Dosis der aktiven Verbindung 0.1 bis 50 mg/kg Körpergewicht. Normalerweise sind 0.5 bis 40 und vorzugsweise 1.0 bis 20 mg/kg/Tag in einer oder mehreren Anwendungen pro Tag wirk¬ sam, um die gewünschten Resultate zu erhalten.
Beispiel 1The dose administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired. The daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications per day in order to obtain the desired results. example 1
2,2,3,3,4,4,5,5,6,6,7,7,8,8 ,8-pentadecafluoro-N-[4-(1H- tetrazol-5-yl)butyl1octanamid2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [4- (1H-tetrazol-5-yl) butyl-octanamide
Ein Gemisch von 21.0 g (0.05 mol) Perfluoroctansäure, 7.8 g (0.08 mol) 5-Aminovaleriansäurenitril, 8.5 ml (0.61 mol) Triethylamin und 100 ml Toluol werden unter Rühren tropfen¬ weise mit 6.5 ml (0.71 mol) Phosphoroxychlorid so versetzt, daß die Innentemperatur nicht über 60βC ansteigt. Dann er¬ hitzt man noch 2 h auf Rückflußtemperatur, dampft das Toluol ab und schüttelt den Rückstand mit einem Gemisch von Essig¬ ester und 1 N Salzsäure. Die organische Phase wird abge¬ trennt, getrocknet und eingedampft. Der Rückstand wird mit Isohexan verrieben. Man erhält 19.2 g (76 % d.Th.) 5- (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadcafluorooctan- amido)valeriansäurenitril, Fp. 60-63βC.A mixture of 21.0 g (0.05 mol) perfluorooctanoic acid, 7.8 g (0.08 mol) 5-aminovaleric acid nitrile, 8.5 ml (0.61 mol) triethylamine and 100 ml toluene are added dropwise with stirring with 6.5 ml (0.71 mol) phosphorus oxychloride so that the internal temperature does not rise above 60 C β. The mixture is then heated to the reflux temperature for a further 2 hours, the toluene is evaporated off and the residue is shaken with a mixture of ethyl acetate and 1 N hydrochloric acid. The organic phase is separated off, dried and evaporated. The residue is triturated with isohexane. 19.2 g (76% of theory) of 5- (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadcafluorooctane amido) valeric acid nitrile are obtained , Mp 60-63 β C.
18.5 g (37.4 m ol) dieses Nitrils werden in 250 ml 1-Methyl- pyrrolidon gelöst und unter Rühren mit 7.3 g (112.2 mmol) Natriumazid und 7.7 g (56 mmol) Triethylammoniumchlorid ver¬ setzt. Dann erhitzt man 5 Stunden auf 150βC. Anschließend wird das Gemisch im Hochvakuum eingedampft und der Rückstand in 1 N Natronlauge gelöst. Die alkalische Lösung wird mit Ether gewaschen und angesäuert. Der abgeschiedene Nieder¬ schlag wird abgetrennt, getrocknet und aus einem Gemisch von Essigsäureethylester und Isohexan umkristallisiert. Man erhält 12.9 g (64 % d.Th.) der Titelverbindung, Fp. 144- 146βC.18.5 g (37.4 mol) of this nitrile are dissolved in 250 ml of 1-methylpyrrolidone and mixed with stirring with 7.3 g (112.2 mmol) of sodium azide and 7.7 g (56 mmol) of triethylammonium chloride. The mixture is then heated to 150 ° C. for 5 hours. The mixture is then evaporated in a high vacuum and the residue is dissolved in 1 N sodium hydroxide solution. The alkaline solution is washed with ether and acidified. The deposited precipitate is separated off, dried and recrystallized from a mixture of ethyl acetate and isohexane. 12.9 g (64% of theory) of the title compound, mp. 144- 146 C. β
In analoger Weise werden die folgenden Verbindungen herge¬ stellt:
1. 2,2,2-Trifluoro-N-[10-(lH-tetrazol-5-yl)decyl] cetamidThe following connections are made in an analogous manner: 1. 2,2,2-trifluoro-N- [10- (1H-tetrazol-5-yl) decyl] cetamide
2. 2,2,3,3,4,4,4-Heptafluoro-N-[10-(lH-tetrazol-5-yl)- decyl]-butanamid2. 2,2,3,3,4,4,4-heptafluoro-N- [10- (1H-tetrazol-5-yl) decyl] butanamide
3. 2,2,3,3,4,4,5,5,5-Nonafluoro-N-[4-(lH-tetrazol-5-yl)- buty1]pentanamid3. 2,2,3,3,4,4,5,5,5-nonafluoro-N- [4- (1H-tetrazol-5-yl) buty1] pentanamide
4. 2,2,3,3,4,4,5,5,5-Nonafluoro-N-[8-(lH-tetrazol-5-yl)- octyl]pentanamid4. 2,2,3,3,4,4,5,5,5-nonafluoro-N- [8- (1H-tetrazol-5-yl) octyl] pentanamide
5. 2,2,3,3,4,4,5,5,6,6,7,7,7-Tridecafluoro-N-[4-(lH-tetra- zol- 5-yl)butyl]heptanamid5. 2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-N- [4- (1H-tetrazol-5-yl) butyl] heptanamide
6. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-Heptadecafluoro-N-[4- (lH-tetrazol-5-yl) utyl]nonanamid6. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-N- [4- (1H-tetrazole-5- yl) utyl] nonanamide
7. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Eicosa- fluoro-N-[2-(lH-tetrazol-5-yl)ethyl] ndecanamid7. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-eicosa-fluoro-N- [2- (1H-tetrazol-5-yl) ethyl] decanamide
8. 2,2,3,3,4,4,5,5,6,6,7,7,8,8-Tetradecafluoro-N-[4-(1H- tetrazol-5-yl)butyl]octanamid8. 2,2,3,3,4,4,5,5,6,6,7,7,8,8-tetradecafluoro-N- [4- (1H-tetrazol-5-yl) butyl] octanamide
9. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-(1H- tetrazol-5-ylmethyl)ocatanamid9. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- (1H-tetrazol-5-ylmethyl) ocatanamide
10. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentaecaflouro-N-[2-(1H- tetrazol-5-yl)ethyl]octanamid; Fp = 183-184° C10. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentaecaflouro-N- [2- (1H-tetrazol-5-yl) ethyl] octanamide; Mp = 183-184 ° C
11. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[3-(1H- tetrazol-5-yl)propyl]octanamid; Fp = 168° C11. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [3- (1H-tetrazol-5-yl) propyl] octanamide; Mp = 168 ° C
12. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[6-(1H- tetrazol-5-yl) exyl]octanamid
13. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[10-(1H- tetrazol-5-yl)decyl]octanamid12. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [6- (1H-tetrazol-5-yl) exyl] octanamide 13. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [10- (1H-tetrazol-5-yl) decyl] octanamide
14. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[2-(1H- tetrazol-5-yl)-2-methylethyl]octanamid14. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [2- (1H-tetrazol-5-yl) -2 -methylethyl] octanamide
15. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[4-(1H- tetrazol-5-yl)-4-methylbutyl]octanamid15. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [4- (1H-tetrazol-5-yl) -4 -methylbutyl] octanamide
16. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[4-(1H- tetrazol-5-yl)-4,4-dimethylbutyl]octanamid16. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [4- (1H-tetrazol-5-yl) -4 , 4-dimethylbutyl] octanamide
17. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[4-(1H- tetrazol-5-yl)-2-butenyl]octanamid17. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [4- (1H-tetrazol-5-yl) -2 -butenyl] octanamide
18. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Pentadecafluoro-N-[4-(1H- tetrazol-5-yl)-2-butinyl]octanmaid18. 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-N- [4- (1H-tetrazol-5-yl) -2 -butinyl] octane maiden
Versuchsbericht:Test report:
Die Wirksamkeit der beschriebenen Substanz(en) bezüglich Blutglukose- und Insulin-Konzentrationssenkung im Blut wurde mit folgendem Modell, ob/ob-Maus, nachgewiesen.The effectiveness of the described substance (s) in reducing blood glucose and insulin concentrations in the blood was demonstrated using the following model, whether / whether mouse.
Männliche C57BL/6J ob/ob-Mäuse wurden im Alter von 6-8 Wochen von Harlan Olac Ltd. , Blackthorn, England bezogen. Für die Untersuchung wurden Tiere mit einem Alter von 12-14 Wochen verwendet; die Unterbringung der Tiere erfolgte zu fünft in einem Käfig unter Standardbedingungen. Zu Versuchsbeginn wurden die Tiere gewogen und 5 /ul Blut via kupieren der Schwanzspitze gewonnen. Das gewonnene Blut wurde sofort 1:51 mit Hämolyse-Reagenz von Boehringer Mannheim GmbH Deutschland (Digitonin 0.04 M, Maleinimid > 1.0 M, gelöst in agua dest.) verdünnt. Anschließend wurde die Blutglukose mit Hilfe der Testkombination Gluko-guant Glukose von Boehringer Mannheim
GmbH Deutschland (UV-Test, Hexokinase-Methode nach F. H. Schmidt, Klin. Wschr. .39., 1244, 1961) mit einem EPOS Analyzer 5060, Eppendorf Gerätebau, Hamburg, bestimmt. In die Unter¬ suchung wurden Tiere mit einer Blutglukose-Konzentration von mindestens 250 mg/dl einbezogen. 10 Tiere der Kontrollgruppe erhielten nur den Lösungsvermittler Methylcellulose (1 % w/v) , 10 Tiere der Substanzgruppe eine Dosis von 100 mg/kg. Am 5. Tag der Substanzapplikation wurden die Tiere nochmals gewogen und Blut für die Blutglukose-Bestimmung, wie oben beschrieben, gewonnen. Für die Insulin-Bestimmung wurde ein entsprechendes Blutvolumen nach Dekapitation und Durch¬ trennung der Karotiden erhalten. Nach mindestens lOminütigem Ruhen des erhaltenen Blutes wird es bei Raumtemperatur, 10 min und 9.000 x g zentrifugiert. Das Serum wird bis zur Bestimmung der Insulin-Konzentration mittels eines kommer¬ ziell erhältlichen Insulinradioimmunoassays der Firma Pharmacia-Diagnostiks AB, Uppsala, Schweden (Phar acia- Insulin-RIA 100) bei -20° C aufbewahrt.Male C57BL / 6J ob / ob mice were obtained from Harlan Olac Ltd. at the age of 6-8 weeks. , Blackthorn, England. Animals with an age of 12-14 weeks were used for the study; five of the animals were housed in a cage under standard conditions. At the beginning of the experiment, the animals were weighed and 5 / ul of blood were obtained by docking the tip of the tail. The blood obtained was immediately diluted 1:51 with hemolysis reagent from Boehringer Mannheim GmbH Germany (digitonin 0.04 M, maleimide> 1.0 M, dissolved in agua dest.). The blood glucose was then measured using the test combination Gluco-guant glucose from Boehringer Mannheim GmbH Germany (UV test, hexokinase method according to FH Schmidt, Klin. Wschr. .39., 1244, 1961) with an EPOS Analyzer 5060, Eppendorf Gerätebau, Hamburg. Animals with a blood glucose concentration of at least 250 mg / dl were included in the study. 10 animals in the control group received only the solubilizer methyl cellulose (1% w / v), 10 animals in the substance group a dose of 100 mg / kg. On the 5th day of the substance application, the animals were weighed again and blood was obtained for the blood glucose determination as described above. A corresponding blood volume was obtained for the insulin determination after decapitation and separation of the carotids. After the blood obtained has been left to rest for at least 10 minutes, it is centrifuged at room temperature, 10 minutes and 9,000 × g. The serum is stored until the insulin concentration is determined by means of a commercially available insulin radioimmunoassay from Pharmacia-Diagnostiks AB, Uppsala, Sweden (Pharacia-Insulin-RIA 100) at -20 ° C.
Wie der Tabelle zu entnehmen ist, zeigten die ob/ob-Mäuse, die nur 1 %ige Methylcellulose erhielten, nahezu keine Ver¬ änderungen der Blutglukose-Konzentrationen am 5. Tag der Applikation, wohingegen die Blutglukose-Konzentration der mit 100 mg/kg Substanz versehenen Gruppe auf etwa 110 mg/dl gesenkt wurden. Die Insulin-Konzentrationen der Substanz¬ gruppe wurden auf normoinsulinämische Werte gesenkt.
As can be seen from the table, the ob / ob mice which received only 1% methyl cellulose showed almost no changes in the blood glucose concentrations on the 5th day of application, whereas the blood glucose concentration showed that with 100 mg / kg Substantive group were reduced to about 110 mg / dl. The insulin concentrations of the substance group were reduced to normoinsulinemic values.
Wirkung von Substanz A und einem Perfluoranilid auf die Blutglukose und Insulinkonzentrationen bei ob/ob-Mäusen, x +/- SEM. n=10Effect of substance A and a perfluoroanilide on blood glucose and insulin concentrations in ob / ob mice, x +/- SE M. n = 10
o Io I
A = Verbindung des Beispiels 1A = connection of example 1
B = Perfluoranilid (Beispiel 2 aus US-A-4,764,623B = perfluoroanilide (Example 2 from US-A-4,764,623
Claims
1. Verbindungen der allgemeinen Formel I1. Compounds of the general formula I
ι- 
ι-
in welcherin which
A Fluor oder Wasserstoff,A fluorine or hydrogen,
n eine ganze Zahl zwischen 1 und 10 undn is an integer between 1 and 10 and
B eine gesättigte oder ungesättigte, geradkettige oder verzweigte Alkylengruppe mit 1 bis 12 Kohlenstoffatome bedeutet,B represents a saturated or unsaturated, straight-chain or branched alkylene group having 1 to 12 carbon atoms,
sowie deren physiologisch unbedenkliche Salze.and their physiologically acceptable salts.
2. Verfahren zur Herstellung von Verbindungen der allge¬ meinen Formel I,2. Process for the preparation of compounds of general formula I,
E in welcherE in which
A Fluor oder Wasserstoff,A fluorine or hydrogen,
n eine ganze Zahl zwischen 1 und 10 undn is an integer between 1 and 10 and
B eine gesättigte oder ungesättigte, geradkettige oder verzweigte Alkylengruppe mit 1 bis 12 Kohlenstoffatome bedeutet,B represents a saturated or unsaturated, straight-chain or branched alkylene group having 1 to 12 carbon atoms,
sowie deren physiologisch unbedenkliche Salze,as well as their physiologically acceptable salts,
dadurch gekennzeichnet, daß man in an sich bekannter Weise ein Amin der Formel IIcharacterized in that an amine of the formula II
H2N-B-CN (II) ,H 2 NB-CN (II),
in welcher B die oben angegebene Bedeutung besitzt,in which B has the meaning given above,
zunächst mit reaktiven Derivaten von Carbonsäuren der allgemeinen Formel IIIfirst with reactive derivatives of carboxylic acids of the general formula III
A-(CF2)n-C00H (III),A- (CF 2 ) n -C00H (III),
in welcher A und n die oben angegebenen Bedeutungen besitzen, zu Verbindungen der allgemeine Formel IVin which A and n have the meanings given above, to compounds of the general formula IV
A-(CF2)n-CONH-B-CN (IV) ,A- (CF 2 ) n -CONH-B-CN (IV),
umsetzt und diese dann durch Erhitzen mit Natriumazid in die gewünschten Verbindungen der allgemeinen Formel I überführt, und anschließend gewunschtenfalls die erhaltenen Ver¬ bindungen in physiologisch unbedenkliche Salze um¬ wandelt.reacted and then converted into the desired compounds of general formula I by heating with sodium azide, and then, if desired, converts the compounds obtained into physiologically acceptable salts.
3. Arzneimittel, enthaltend mindestens eine Verbindung gemäß Anspruch 1, neben üblichen Träger- und Hilfs¬ stoffen.3. Medicament containing at least one compound according to claim 1, in addition to conventional carriers and auxiliary substances.
4. Verwendung von Verbindungen gemäß Anspruch 1 als Anti- diabetica. 4. Use of compounds according to claim 1 as anti-diabetic.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19904040619 DE4040619A1 (en) | 1990-12-19 | 1990-12-19 | NEW ALIPHATIC AMIDES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DEP4040619.9 | 1990-12-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992011248A1 true WO1992011248A1 (en) | 1992-07-09 |
Family
ID=6420706
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1991/002390 WO1992011248A1 (en) | 1990-12-19 | 1991-12-12 | Novel aliphatic amides, process for producing them and medicaments containing these compounds |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU9051091A (en) |
| DE (1) | DE4040619A1 (en) |
| WO (1) | WO1992011248A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2383535A (en) * | 2001-02-16 | 2003-07-02 | Cxr Biosciences Ltd | Medical use of fluorinated acids |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5366987A (en) * | 1991-08-22 | 1994-11-22 | Warner-Lambert Company | Isoxazolyl-substituted alkyl amide ACAT inhibitors |
| DE19605700A1 (en) * | 1996-02-16 | 1997-08-21 | Boehringer Mannheim Gmbh | 2,2-difluoroalkane carboxylic acids, process for their preparation and medicaments containing them |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4764623A (en) * | 1987-06-15 | 1988-08-16 | American Home Products Corporation | N-(1H-tetrazol-5-yl-alkylphenyl)polyfluoroalkanamides |
| EP0356989A2 (en) * | 1988-08-31 | 1990-03-07 | Roche Diagnostics GmbH | Sulfon amides with a tetrazolyl rest, process for their preparation an therapeutic agents |
-
1990
- 1990-12-19 DE DE19904040619 patent/DE4040619A1/en not_active Withdrawn
-
1991
- 1991-12-12 WO PCT/EP1991/002390 patent/WO1992011248A1/en active Application Filing
- 1991-12-12 AU AU90510/91A patent/AU9051091A/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4764623A (en) * | 1987-06-15 | 1988-08-16 | American Home Products Corporation | N-(1H-tetrazol-5-yl-alkylphenyl)polyfluoroalkanamides |
| EP0356989A2 (en) * | 1988-08-31 | 1990-03-07 | Roche Diagnostics GmbH | Sulfon amides with a tetrazolyl rest, process for their preparation an therapeutic agents |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2383535A (en) * | 2001-02-16 | 2003-07-02 | Cxr Biosciences Ltd | Medical use of fluorinated acids |
| JP2004531482A (en) * | 2001-02-16 | 2004-10-14 | シーエックスアール バイオサイエンス リミテッド | Method |
| GB2383535B (en) * | 2001-02-16 | 2005-09-21 | Cxr Biosciences Ltd | Pharmaceutical compositions containing fluorinated or perfluorinated carboxylic acids |
| JP4652665B2 (en) * | 2001-02-16 | 2011-03-16 | シーエックスアール バイオサイエンス リミテッド | Method |
| US8487003B2 (en) | 2001-02-16 | 2013-07-16 | Cxr Biosciences Limited | Treatment of cancer by administration of perfluorooctanoic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4040619A1 (en) | 1992-06-25 |
| AU9051091A (en) | 1992-07-22 |
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