DE10064402A1 - New diphenyl-azetidinone derivatives useful for the treatment of hyperlipidemia, arteriosclerosis and hypercholesterolemia - Google Patents
New diphenyl-azetidinone derivatives useful for the treatment of hyperlipidemia, arteriosclerosis and hypercholesterolemiaInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Die Erfindung betrifft Verbindungen der Formel I, DOLLAR F1 worin R1, R2, R3, R4, R5 und R6 die angegebenen Bedeutungen haben, sowie deren physiologisch verträglichen Salze. Die Verbindungen eignen sich z. B. als Hypolipidämika.The invention relates to compounds of the formula I, DOLLAR F1 in which R1, R2, R3, R4, R5 and R6 have the meanings indicated, and to their physiologically tolerable salts. The compounds are suitable for. B. as hypolipidemics.
Description
Die Erfindung betrifft substituierte Diphenylazetidinone, deren physiologisch verträgliche Salze sowie physiologisch funktionelle Derivate.The invention relates to substituted diphenylazetidinones, their physiological compatible salts and physiologically functional derivatives.
Es sind bereits Diphenylazetidinone sowie deren Verwendung zur Behandlung von Hyperlipidämie sowie Arteriosklerose und Hypercholesterinämie beschrieben worden [vgl. US 5,756,470].There are already diphenylazetidinones and their use for the treatment of Hyperlipidemia as well as arteriosclerosis and hypercholesterolaemia are described been [cf. US 5,756,470].
Der Erfindung lag die Aufgabe zugrunde, weitere Verbindungen zur Verfügung zu stellen, die eine therapeutisch verwertbare hypolipidämische Wirkung entfalten. Insbesondere bestand die Aufgabe darin, neue Verbindungen zu finden, die gegenüber den im Stand der Technik beschriebenen Verbindungen, sehr gering resorbierbar sind. Unter sehr gering resorbierbar wird eine intestinale Resorption kleiner 10%, bevorzugt kleiner oder gleich 5% verstanden.The object of the invention was to provide further connections places that have a therapeutically exploitable hypolipidemic effect. In particular, the task was to find new connections that compared to the compounds described in the prior art, very low are absorbable. Intestinal absorption becomes less absorbable understood less than 10%, preferably less than or equal to 5%.
Die Erfindung betrifft daher Verbindungen der Formel I,
The invention therefore relates to compounds of the formula I
worin bedeuten
R1, R2, R3, R4, R5, R6 unabhängig voneinander (C0-C15)-Alkylen-L,
wobei ein oder mehrere C-Atome des Alkylenrests, durch eine der
Gruppen -O-, -(C=O)-, -CH=CH, -C∼C-, -N((C1-C6)Alkyl)- oder -NH-
ersetzt sein können,
H, F, Cl, Br, J, CF3, NO2, CN, COOH, COO(C1-C6)Alkyl, CONH2,
CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl,
(C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, wobei in den Alkylresten ein, mehrere,
oder alle Wasserstoff(e) durch Fluor ersetzt sein können;
SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl,
S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n-Phenyl, SO2-(C1-C6)-
Alkyl, SO2-(CH2)n-Phenyl, wobei n = 0-6 sein kann und der Phenylrest
bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl,
(C1-C6)-Alkyl, NH2 substituiert sein kann;
NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C1-C7)-Acyl, Phenyl, O-
(CH2)n-Phenyl, wobei n = 0-6 sein kann, wobei der Phenylring ein bis
3-fach substituiert sein kann mit F, Cl, Br, J, OH, CF3, NO2, CN, OCF3,
O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2,
SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
in what mean
R1, R2, R3, R4, R5, R6 independently of one another (C 0 -C 15 ) alkylene-L, where one or more C atoms of the alkylene radical, by one of the groups -O-, - (C = O) - , -CH = CH, -C∼C-, -N ((C 1 -C 6 ) alkyl) - or -NH- can be replaced,
H, F, Cl, Br, J, CF 3 , NO 2 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) alkyl, wherein in the alkyl radicals may have one, more or all of the hydrogen (s) replaced by fluorine;
SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S- (C 1 -C 6 ) alkyl, S- ( CH 2 ) n -phenyl, SO- (C 1 -C 6 ) alkyl, SO- (CH 2 ) n -phenyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -Phenyl, where n = 0-6 and the phenyl radical can be substituted up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, ( C 1 -C 6 ) alkyl, NH 2 may be substituted;
NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 1 -C 7 ) acyl, phenyl, O- (CH 2 ) n - Phenyl, where n = 0-6, where the phenyl ring can be substituted one to three times with F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 - C 6 ) alkyl, (C 1 -C 6 ) alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) alkyl, CONH 2 ;
oder
or
R7 Methyl, Ethyl, Propyl, Butyl;
R8 H, OH, NH2, NH-(C1-C6)-Alkyl;
R9 Methyl, Ethyl, Propyl, Butyl;
R10 Methyl, Ethyl, Propyl, Butyl;
Rx, Ry, Rz unabhängig voneinander H, F, Cl, Br, J, CF3, NO2, CN,
COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-
C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-
Alkyl, wobei in den Alkylresten ein, mehrere, oder alle Wasserstoff(e)
durch Fluor ersetzt sein können;
SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl,
S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n-Phenyl, SO2-(C1-C6)-
Alkyl, SO2-(CH2)n-Phenyl, wobei n = 0-6 sein kann und der Phenylrest
bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl,
(C1-C6)-Alkyl, NH2 substituiert sein kann;
NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C1-C7)-Acyl, Phenyl, O-
(CH2)n-Phenyl, wobei n = 0-6 sein kann, wobei der Phenylring ein bis
3-fach substituiert sein kann mit F, Cl, Br, J, OH, CF3, NO2, CN, OCF3,
O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2,
SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
wobei immer mindestens einer der Reste R1 bis R6 die Bedeutung
(C0-C15)-Alkylen-L, wobei ein oder mehrere C-Atome des Alkylenrests, durch eine
der Gruppen -O-, -(C=O)-, -CH=CH-, -C∼C-, -N((C1-C6)-Alkyl)- oder -NH- ersetzt
sein können, besitzen muß,
sowie deren pharmazeutisch verträglichen Salze.R7 is methyl, ethyl, propyl, butyl;
R8 is H, OH, NH 2 , NH- (C 1 -C 6 ) alkyl;
R9 is methyl, ethyl, propyl, butyl;
R10 is methyl, ethyl, propyl, butyl;
Rx, Ry, Rz independently of one another H, F, Cl, Br, J, CF 3 , NO 2 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) - alkyl, where one, more or all of the hydrogen (s) in the alkyl radicals can be replaced by fluorine;
SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S- (C 1 -C 6 ) alkyl, S- ( CH 2 ) n -phenyl, SO- (C 1 -C 6 ) alkyl, SO- (CH 2 ) n -phenyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -Phenyl, where n = 0-6 and the phenyl radical can be substituted up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, ( C 1 -C 6 ) alkyl, NH 2 may be substituted;
NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 1 -C 7 ) acyl, phenyl, O- (CH 2 ) n - Phenyl, where n = 0-6, where the phenyl ring can be substituted one to three times with F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 - C 6 ) alkyl, (C 1 -C 6 ) alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) alkyl, CONH 2 ;
where at least one of the radicals R1 to R6 always has the meaning (C 0 -C 15 ) alkylene-L, where one or more C atoms of the alkylene radical are replaced by one of the groups -O-, - (C = O) -, - CH = CH-, -C∼C-, -N ((C 1 -C 6 ) alkyl) - or -NH- may have to be replaced,
and their pharmaceutically acceptable salts.
Bevorzugt sind Verbindungen der Formel I, worin mindestens einer der Reste R1 bis R6 die Bedeutung -NH-(C0-C6)-Alkylen-L, -C(=O)-NH-(C0-C6)-Alkylen-L oder -(C0- C6)-Alkylen-O-L besitzt.Preferred compounds of the formula I are those in which at least one of the radicals R1 to R6 is -NH- (C 0 -C 6 ) alkylene-L, -C (= O) -NH- (C 0 -C 6 ) alkylene -L or - (C 0 - C 6 ) alkylene-OL has.
Pharmazeutisch verträgliche Salze sind aufgrund ihrer höheren Wasserlöslichkeit gegenüber den Ausgangs- bzw. Basisverbindungen besonders geeignet für medizinische Anwendungen. Diese Salze müssen ein pharmazeutisch verträgliches Anion oder Kation aufweisen. Geeignete pharmazeutisch verträgliche Säureadditionssalze der erfindungsgemäßen Verbindungen sind Salze anorganischer Säuren, wie Salzsäure, Bromwasserstoff-, Phosphor-, Metaphosphor-, Salpeter-, Sulfon- und Schwefelsäure sowie organischer Säuren, wie z. B. Essigsäure, Benzolsulfon-, Benzoe-, Zitronen-, Ethansulfon-, Fumar-, Glucon-, Glykol-, Isothion-, Milch-, Lactobion-, Malein-, Apfel-, Methansulfon-, Bernstein-, p- Toluolsulfon-, Wein- und Trifluoressigsäure. Für medizinische Zwecke wird in besonders bevorzugter Weise das Chlorsalz verwendet. Geeignete pharmazeutisch verträgliche basische Salze sind Ammoniumsalze, Alkalimetallsalze (wie Natrium- und Kaliumsalze) und Erdalkalisalze (wie Magnesium- und Calciumsalze).Pharmaceutically acceptable salts are due to their higher water solubility compared to the original or basic connections, particularly suitable for medical applications. These salts must be pharmaceutically acceptable Have anion or cation. Suitable pharmaceutically acceptable Acid addition salts of the compounds according to the invention are salts inorganic acids, such as hydrochloric acid, hydrogen bromide, phosphorus, metaphosphorus, Nitric, sulfonic and sulfuric acid and organic acids, such as. B. Acetic acid, benzenesulfone, benzoin, lemon, ethanesulfone, fumarate, gluconium, Glycol, isothione, milk, lactobione, maleic, apple, methanesulfone, amber, p Toluene sulfonic, tartaric and trifluoroacetic acid. For medical purposes, in particularly preferably uses the chlorine salt. Suitable pharmaceutical compatible basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).
Salze mit einem nicht pharmazeutisch verträglichen Anion gehören ebenfalls in den Rahmen der Erfindung als nützliche Zwischenprodukte für die Herstellung oder Reinigung pharmazeutisch verträglicher Salze und/oder für die Verwendung in nicht- therapeutischen, zum Beispiel in-vitro-Anwendungen.Salts with a non-pharmaceutically acceptable anion also belong in the Framework of the invention as useful intermediates for the manufacture or Purification of pharmaceutically acceptable salts and / or for use in non- therapeutic, for example in vitro applications.
Der hier verwendete Begriff "physiologisch funktionelles Derivat" bezeichnet jedes physiologisch verträgliche Derivat einer erfindungsgemäßen Verbindung, z. B. ein Ester, das bei Verabreichung an einen Säuger, wie z. B. den Menschen, in der Lage ist, (direkt oder indirekt) eine solche Verbindung oder einen aktiven Metaboliten hiervon zu bilden.The term "physiologically functional derivative" as used herein means any physiologically acceptable derivative of a compound according to the invention, e.g. B. a Esters which, when administered to a mammal, e.g. B. humans, able is (directly or indirectly) such a compound or an active metabolite to form from this.
Ein weiterer Aspekt dieser Erfindung sind Prodrugs der erfindungsgemäßen Verbindungen. Solche Prodrugs können in vivo zu einer erfindungsgemäßen Verbindung metabolisiert werden. Diese Prodrugs können selbst wirksam sein oder nicht.Another aspect of this invention are prodrugs of the invention Links. Such prodrugs can be used in vivo to produce an invention Compound to be metabolized. These prodrugs can themselves be effective or Not.
Die erfindungsgemäßen Verbindungen können auch in verschiedenen polymorphen Formen vorliegen, z. B. als amorphe und kristalline polymorphe Formen. Alle polymorphen Formen der erfindungsgemäßen Verbindungen gehören in den Rahmen der Erfindung und sind ein weiterer Aspekt der Erfindung.The compounds according to the invention can also be in various polymorphic Shapes exist, e.g. B. as amorphous and crystalline polymorphic forms. All Polymorphic forms of the compounds according to the invention belong in the The scope of the invention and are a further aspect of the invention.
Nachfolgend beziehen sich alle Verweise auf "Verbindung(en) gemäß Formel (I)" auf Verbindung(en) der Formel (I) wie vorstehend beschrieben, sowie ihre Salze, Solvate und physiologisch funktionellen Derivate wie hierin beschrieben.In the following, all references refer to "compound (s) according to formula (I)" Compound (s) of the formula (I) as described above, and their salts, Solvates and physiologically functional derivatives as described herein.
Die Menge einer Verbindung gemäß Formel (I), die erforderlich ist, um den gewünschten biologischen Effekt zu erreichen, ist abhängig von einer Reihe von Faktoren, z. B. der gewählten spezifischen Verbindung, der beabsichtigten Verwendung, der Art der Verabreichung und dem klinischen Zustand des Patienten. Im allgemeinen liegt die Tagesdosis im Bereich von 0,1 mg bis 100 mg (typischerweise von 0,1 mg und 50 mg) pro Tag pro Kilogramm Körpergewicht, z. B. 0,1-10 mg/kg/Tag. Tabletten oder Kapseln, können beispielsweise von 0,01 bis 100 mg, typischerweise von 0,02 bis 50 mg enthalten. Im Falle pharmazeutisch verträgli cher Salze beziehen sich die vorgenannten Gewichtsangaben auf das Gewicht des vom Salz abgeleiteten Benzothiepin-Ions. Zur Prophylaxe oder Therapie der oben genannten Zustände können die Verbindungen gemäß Formel (I) selbst als Verbindung verwendet werden, vorzugsweise liegen sie jedoch mit einem verträglichen Träger in Form einer pharmazeutischen Zusammensetzung vor. Der Träger muß natürlich verträglich sein, in dem Sinne, daß er mit den anderen Bestandteilen der Zusammensetzung kompatibel ist und nicht gesundheitsschädlich für den Patienten ist. Der Träger kann ein Feststoff oder eine Flüssigkeit oder beides sein und wird vorzugsweise mit der Verbindung als Einzeldosis formuliert, beispielsweise als Tablette, die von 0,05% bis 95 Gew.-% des Wirkstoffs enthalten kann. Weitere pharmazeutisch aktive Substanzen können ebenfalls vorhanden sein, einschließlich weiterer Verbindungen gemäß Formel (I). Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können nach einer der bekannten pharmazeutischen Methoden hergestellt werden, die im wesentlichen darin bestehen, daß die Bestandteile mit pharmakologisch verträglichen Träger- und/oder Hilfsstoffen gemischt werden.The amount of a compound of formula (I) required to obtain the Achieving the desired biological effect depends on a number of Factors, e.g. B. the specific compound chosen, the intended one Use, route of administration and clinical condition of the patient. The daily dose is generally in the range from 0.1 mg to 100 mg (typically 0.1 mg and 50 mg) per day per kilogram of body weight, e.g. B. 0.1-10 mg / kg / day. Tablets or capsules, for example from 0.01 to 100 mg, typically contain from 0.02 to 50 mg. In the case of pharmaceutically acceptable The above-mentioned weights refer to the weight of the salts Benzothiepin ions derived from salt. For prophylaxis or therapy of the above States mentioned can the compounds according to formula (I) itself as Compound are used, but preferably they are with a compatible carrier in the form of a pharmaceutical composition. The Carrier must of course be compatible, in the sense that he with the others Components of the composition is compatible and not harmful to health is for the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet containing from 0.05% to 95% by weight of the active ingredient can. Other pharmaceutically active substances can also be present, including other compounds according to formula (I). The invention Pharmaceutical compositions can be prepared according to one of the known Pharmaceutical methods are essentially manufactured in it exist that the ingredients with pharmacologically acceptable carrier and / or Auxiliaries are mixed.
Erfindungsgemäße pharmazeutische Zusammensetzungen sind solche, die für orale und perorale (z. B. sublinguale) Verabreichung geeignet sind, wenngleich die geeignetste Verabreichungsweise in jedem Einzelfall von der Art und Schwere des zu behandelnden Zustandes und von der Art der jeweils verwendeten Verbindung gemäß Formel (I) abhängig ist. Auch dragierte Formulierungen und dragierte Retardformulierungen gehören in den Rahmen der Erfindung. Bevorzugt sind säure- und magensaftresistente Formulierungen. Geeignete magensaftresistente Beschichtungen umfassen Celluloseacetatphthalat, Polyvinalacetatphthalat, Hydroxypropylmethylcellulosephthalat und anionische Polymere von Methacrylsäure und Methacrylsäuremethylester.Pharmaceutical compositions according to the invention are those for oral and oral (e.g. sublingual) administration are suitable, although the most suitable method of administration in each individual case on the type and severity of the condition to be treated and the type of compound used in each case according to formula (I). Also coated formulations and coated Slow release formulations are within the scope of the invention. Acidic and enteric formulations. Suitable enteric-coated Coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, Hydroxypropyl methyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
Geeignete pharmazeutische Verbindungen für die orale Verabreichung können in separaten Einheiten vorliegen, wie zum Beispiel Kapseln, Oblatenkapseln, Lutschtabletten oder Tabletten, die jeweils eine bestimmte Menge der Verbindung gemäß Formel (I) enthalten; als Pulver oder Granulate; als Lösung oder Suspension in einer wäßrigen oder nicht-wäßrigen Flüssigkeit; oder als eine Öl-in-Wasser- oder Wasser-in Öl-Emulsion. Diese Zusammensetzungen können, wie bereits erwähnt, nach jeder geeigneten pharmazeutischen Methode zubereitet werden, die einen Schritt umfaßt, bei dem der Wirkstoff und der Träger (der aus einem oder mehreren zusätzlichen Bestandteilen bestehen kann) in Kontakt gebracht werden. Im allge meinen werden die Zusammensetzungen durch gleichmäßiges und homogenes Vermischen des Wirkstoffs mit einem flüssigen und/oder feinverteilten festen Träger hergestellt, wonach das Produkt, falls erforderlich, geformt wird. So kann beispielsweise eine Tablette hergestellt werden, indem ein Pulver oder Granulat der Verbindung verpreßt oder geformt wird, gegebenenfalls mit einem oder mehreren zusätzlichen Bestandteilen. Gepreßte Tabletten können durch Tablettieren der Verbindung in frei fließender Form, wie beispielsweise einem Pulver oder Granulat, gegebenenfalls gemischt mit einem Bindemittel, Gleitmittel, inertem Verdünner und/oder einem (mehreren) oberflächenaktiven/dispergierenden Mittel in einer geeigneten Maschine hergestellt werden. Geformte Tabletten können durch Formen der pulverförmigen, mit einem inerten flüssigen Verdünnungsmittel befeuchteten Verbindung in einer geeigneten Maschine hergestellt werden.Suitable pharmaceutical compounds for oral administration can be found in separate units, such as capsules, wafer capsules, Lozenges or tablets, each containing a certain amount of the compound contain according to formula (I); as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or Water-in-oil emulsion. As already mentioned, these compositions can be prepared by any suitable pharmaceutical method that Comprises step in which the active ingredient and the carrier (which consists of one or more additional components can be brought into contact. Generally the compositions are meant by uniform and homogeneous Mixing the active ingredient with a liquid and / or finely divided solid carrier manufactured, after which the product is molded if necessary. So can For example, a tablet can be made by using a powder or granulate Connection is pressed or molded, optionally with one or more additional components. Pressed tablets can be made by tabletting the Compound in free flowing form, such as a powder or granulate, optionally mixed with a binder, lubricant, inert thinner and / or one (more) surfactant / dispersant in one suitable machine. Shaped tablets can be shaped the powdered, moistened with an inert liquid diluent Connection to be made in a suitable machine.
Pharmazeutische Zusammensetzungen, die für eine perorale (sublinguale) Verabreichung geeignet sind, umfassen Lutschtabletten, die eine Verbindung gemäß Formel (I) mit einem Geschmacksstoff enthalten, üblicherweise Saccharose und Gummi arabicum oder Tragant, und Pastillen, die die Verbindung in einer inerten Basis wie Gelatine und Glycerin oder Saccharose und Gummi arabicum umfassen.Pharmaceutical compositions for oral (sublingual) Administration suitable include lozenges that are a compound according to formula (I) with a flavoring, usually sucrose and gum arabic or tragacanth, and lozenges that combine in one inert bases such as gelatin and glycerin or sucrose and gum arabic include.
Gegenstand der Erfindung sind weiterhin sowohl Stereoisomerengemische der Formel I, als auch die reinen Stereoisomere der Formel I, sowie Diastereomerengemische der Formel I als auch die reinen Diastereomere. Die Trennung der Gemische erfolgt auf chromatographischem Weg.The invention further relates to both stereoisomer mixtures Formula I, as well as the pure stereoisomers of formula I, as well Diastereomer mixtures of formula I as well as the pure diastereomers. The The mixtures are separated by chromatographic means.
Bevorzugt sind racemische als auch enantiomerenreine Verbindungen der Formel I
mit folgender Struktur:
Racemic and enantiomerically pure compounds of the formula I having the following structure are preferred:
Weiterhin bevorzugt sind Verbindungen der Formel I, worin die L Reste folgende
Bedeutung haben:
Also preferred are compounds of the formula I in which the L radicals have the following meaning:
Gegenstand der Erfindung ist weiterhin ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I, dadurch gekennzeichnet, daß man die Verbindungen der Formel I so gewinnt, daß analog dem folgenden Reaktionsschema vorgegangen wird.The invention further relates to a method for producing the Compounds of the general formula I, characterized in that the Compounds of formula I so that analogously to the following Reaction scheme is proceeded.
R4" bedeutet (C0-C15)-Alkylen, wobei ein oder mehrere C-Atome des Alkylenrests, durch eine der Gruppen -O-, -(C=O)-, -CH=CH-, -C∼C-, -N((C1-C6)-Alkyl)- oder -NH- ersetzt sein können.R4 "means (C 0 -C 15 ) alkylene, one or more C atoms of the alkylene radical being replaced by one of the groups -O-, - (C = O) -, -CH = CH-, -C∼C- , -N ((C 1 -C 6 ) alkyl) - or -NH- can be replaced.
Alternativ erfolgt die Verknüpfung zur L-Gruppe über Ring A oder Ring C. Alternatively, the link to the L group is via ring A or ring C.
Die nachfolgenden Beispiele dienen zur näheren Erläuterung der Erfindung, ohne dieselbe auf in den Beispielen beschriebene Produkte und Ausführungsformen einzuschränken.The following examples serve to explain the invention in more detail, without the same on products and embodiments described in the examples limit.
5-{4-[3-(3-Hydroxy-3-phenyl-propyl)-2-(4-methoxy-phenyl)-4-oxo-azetid in-1-yl]- benzylamino}-pentnsäure-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo- 2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-amid5- {4- [3- (3-Hydroxy-3-phenylpropyl) -2- (4-methoxyphenyl) -4-oxoacetide in-1-yl] - benzylamino} -pentnsäure- [3- (3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo- 2,3,4,5-tetrahydro-1H-benzo [b] thiepin-5-yl) -phenyl] -amide
100 mg 5-Brom-pentansäure-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1- dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-amid und 70 mg 1-(4- Aminomethyl-phenyl)-3-(3-hydroxy-3-phenyl-propyl)-4-(4-methoxy-phenyl)-azetidin- 2-on werden in 5 ml Dimethylormamid gelöst und ca. 2 bis 3 Std. unter Rühren auf 80°C erwärmt. Nach beendeter Reaktion (Kontrolle durch Dünnschichtchromatogramm oder HPLC-MS) wird das Lösemittel im Vakuum entfernt und der Rückstand durch Chromatographie gereinigt. Man erhält so das Produkt mit dem Molekulargewicht 929.24 (C55H68N4O7S); MS (FAB): 929 (M + H+). 100 mg 5-bromo-pentanoic acid- [3- (3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] thiepin-5-yl) -phenyl] -amide and 70 mg of 1- (4-aminomethyl-phenyl) -3- (3-hydroxy-3-phenyl-propyl) -4- (4-methoxy-phenyl) -azetidine- 2-one are dissolved in 5 ml of dimethylormamide and heated to 80 ° C. with stirring for about 2 to 3 hours. After the reaction has ended (control by thin layer chromatogram or HPLC-MS), the solvent is removed in vacuo and the residue is purified by chromatography. The product is thus obtained with the molecular weight 929.24 (C 55 H 68 N 4 O 7 S); MS (FAB): 929 (M + H + ).
Die Verbindungen der Formel I und deren pharmazeutisch verträgliche Salze und physiologisch funktionelle Derivate stellen ideale Arzneimittel zur Behandlung von Lipidstoffwechselstörungen, insbesondere von Hyperlipidämie dar. Die Verbindungen der Formel I eignen sich ebenfalls zur Beeinflussung des Serumcholesterinspiegels sowie zur Prävention und Behandlung arteriosklerotischer Erscheinungen. Die Verbindungen können gegebenenfalls auch in Kombination mit Statinen, wie z. B. Simvastatatin, Fluvastatin, Pravastatin, Cerivastatin, Lovastatin oder Atorvastin verabreicht werden.The compounds of formula I and their pharmaceutically acceptable salts and Physiologically functional derivatives represent ideal drugs for the treatment of Lipid metabolism disorders, especially hyperlipidemia Compounds of the formula I are also suitable for influencing the Serum cholesterol and for prevention and treatment arteriosclerotic phenomena. The compounds can optionally also in combination with statins, e.g. B. simvastatatin, fluvastatin, pravastatin, Cerivastatin, Lovastatin or Atorvastin can be administered.
Die sehr geringe Resorbierbarkeit zeigt sich bei der Prüfung in einem typischen Resorptionsmodell, beispielweise im Caco-Zellmodell, das zur Bestimmung der Resobierbarkeit breit eingesetzt wird (A. R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).The very low resorbability is shown in the test in a typical Absorption model, for example in the Caco cell model, which is used to determine the Resorbability is widely used (A.R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).
Aus den Meßdaten ist abzulesen, daß die erfindungsgemäßen Verbindungen der Formel I gegenüber den im Stand der Technik beschriebenen Verbindungen eine geringere Resorption aufweisen.It can be seen from the measurement data that the compounds of the invention Formula I compared to the compounds described in the prior art have lower absorption.
Claims (9)
worin bedeuten
R1, R2, R3, R4, R5, R6 unabhängig voneinander (C0-C15)-Alkylen-L, wobei ein oder mehrere C-Atome des Alkylenrests, durch eine der Gruppen -O-, -(C=O)-, -CH=CH-, -C∼C-, -N((C1-C6)-Alkyl)- oder -NH- ersetzt sein können,
H, F, Cl, Br, J, CF3, NO2, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, wobei in den Alkylresten ein, mehrere, oder alle Wasserstoff(e) durch Fluor ersetzt sein können;
SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n-Phenyl, SO2-(C1-C6)- Alkyl, SO2-(CH2)n-Phenyl, wobei n = 0-6 sein kann und der Phenylrest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C1-C7)-Acyl, Phenyl, O- (CH2)n-Phenyl, wobei n = 0-6 sein kann, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
R7 Methyl, Ethyl, Propyl, Butyl;
R8 H, OH, NH2, NH-(C1-C6)-Alkyl;
R9 Methyl, Ethyl, Propyl, Butyl;
R10 Methyl, Ethyl, Propyl, Butyl;
Rx, Ry, Rz unabhängig voneinander H, F, Cl, Br, J, CF3, NO2, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1- C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)- Alkyl, wobei in den Alkylresten ein, mehrere, oder alle Wasserstoff(e) durch Fluor ersetzt sein können;
SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n-Phenyl, SO2-(C1-C6)- Alkyl, SO2-(CH2)n-Phenyl, wobei n = 0-6 sein kann und der Phenylrest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C1-C7)-Acyl, Phenyl, O- (CH2)n-Phenyl, wobei n = 0-6 sein kann, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
wobei immer mindestens einer der Reste R1 bis R6 die Bedeutung (C0-C15)-Alkylen-L, wobei ein oder mehrere C-Atome des Alkylenrests, durch eine der Gruppen -O-, -(C=O)-, -CH=CH-, -C∼C-, -N((C1-C6)-Alkyl)- oder -NH- ersetzt sein können, besitzen muß,
sowie deren pharmazeutisch verträglichen Salze.1. Compounds of the formula I
in what mean
R1, R2, R3, R4, R5, R6 independently of one another (C 0 -C 15 ) alkylene-L, where one or more C atoms of the alkylene radical are replaced by one of the groups -O-, - (C = O) - , -CH = CH-, -C∼C-, -N ((C 1 -C 6 ) alkyl) - or -NH- can be replaced,
H, F, Cl, Br, J, CF 3 , NO 2 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) alkyl, wherein in the alkyl radicals may have one, more or all of the hydrogen (s) replaced by fluorine;
SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S- (C 1 -C 6 ) alkyl, S- ( CH 2 ) n -phenyl, SO- (C 1 -C 6 ) alkyl, SO- (CH 2 ) n -phenyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -Phenyl, where n = 0-6 and the phenyl radical can be substituted up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, ( C 1 -C 6 ) alkyl, NH 2 may be substituted;
NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 1 -C 7 ) acyl, phenyl, O- (CH 2 ) n - Phenyl, where n = 0-6, where the phenyl ring can be substituted one to three times with F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 - C 6 ) alkyl, (C 1 -C 6 ) alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) alkyl, CONH 2 ;
R7 is methyl, ethyl, propyl, butyl;
R8 is H, OH, NH 2 , NH- (C 1 -C 6 ) alkyl;
R9 is methyl, ethyl, propyl, butyl;
R10 is methyl, ethyl, propyl, butyl;
Rx, Ry, Rz independently of one another H, F, Cl, Br, J, CF 3 , NO 2 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) - alkyl, where one, more or all of the hydrogen (s) in the alkyl radicals can be replaced by fluorine;
SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S- (C 1 -C 6 ) alkyl, S- ( CH 2 ) n -phenyl, SO- (C 1 -C 6 ) alkyl, SO- (CH 2 ) n -phenyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -Phenyl, where n = 0-6 and the phenyl radical can be substituted up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, ( C 1 -C 6 ) alkyl, NH 2 may be substituted;
NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 1 -C 7 ) acyl, phenyl, O- (CH 2 ) n - Phenyl, where n = 0-6, where the phenyl ring can be substituted one to three times with F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 - C 6 ) alkyl, (C 1 -C 6 ) alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) alkyl, CONH 2 ;
where at least one of the radicals R1 to R6 always has the meaning (C 0 -C 15 ) alkylene-L, where one or more C atoms of the alkylene radical are replaced by one of the groups -O-, - (C = O) -, - CH = CH-, -C∼C-, -N ((C 1 -C 6 ) alkyl) - or -NH- may have to be replaced,
and their pharmaceutically acceptable salts.
R1, R2, R3, R4, R5, R6 unabhängig voneinander-NH-(C0-C6)-Alkyl-L, -(C0-C6)-Alkyl-O-L, -C(=O)-NH-(C0-C6)-Alkyl-L, H, F, Cl, Br, J, CF3, NO2, CN, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1- C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)- Alkyl, wobei in den Alkylresten ein, mehrere, oder alle Wasserstoff(e) durch Fluor ersetzt sein können;
SO2-NH2, SO2NH(C1-C6)-Alkyl, SO2N[(C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n-Phenyl, SO2-(C1-C6)- Alkyl, SO2-(CH2)n-Phenyl, wobei n = 0-6 sein kann und der Phenylrest bis zu zweifach mit F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2 substituiert sein kann;
NH2, NH-(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, NH(C1-C7)-Acyl, Phenyl, O- (CH2)n-Phenyl, wobei n = 0-6 sein kann, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, J, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
wobei immer mindestens einer der Reste R1 bis R6 die Bedeutung -NH-(C0-C6)-Alkyl-L, -(C0-C6)-Alkyl-O-L oder -C(=O)-NH-(C0-C6)-Alkyl-L besitzen muß,
sowie deren pharmazeutisch verträglichen Salze.2. Compounds of formula I, according to claim 1, characterized in that mean
R1, R2, R3, R4, R5, R6 independently of one another -NH- (C 0 -C 6 ) -alkyl-L, - (C 0 -C 6 ) -alkyl-OL, -C (= O) -NH- (C 0 -C 6 ) alkyl-L, H, F, Cl, Br, J, CF 3 , NO 2 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 - C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C 1 -C 6 ) alkyl, where one, more or all of the hydrogen (s) in the alkyl radicals can be replaced by fluorine;
SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) alkyl, SO 2 N [(C 1 -C 6 ) alkyl] 2 , S- (C 1 -C 6 ) alkyl, S- ( CH 2 ) n -phenyl, SO- (C 1 -C 6 ) alkyl, SO- (CH 2 ) n -phenyl, SO 2 - (C 1 -C 6 ) -alkyl, SO 2 - (CH 2 ) n -Phenyl, where n = 0-6 and the phenyl radical can be substituted up to twice with F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, ( C 1 -C 6 ) alkyl, NH 2 may be substituted;
NH 2 , NH- (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , NH (C 1 -C 7 ) acyl, phenyl, O- (CH 2 ) n - Phenyl, where n = 0-6, where the phenyl ring can be substituted one to three times with F, Cl, Br, J, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 - C 6 ) alkyl, (C 1 -C 6 ) alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) alkyl, CONH 2 ;
where at least one of the radicals R1 to R6 always has the meaning -NH- (C 0 -C 6 ) -alkyl-L, - (C 0 -C 6 ) -alkyl-OL or -C (= O) -NH- (C Must have 0 -C 6 ) alkyl-L,
and their pharmaceutically acceptable salts.
Priority Applications (54)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL15655200A IL156552A0 (en) | 2000-12-21 | 2000-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| DE10064402A DE10064402A1 (en) | 2000-12-21 | 2000-12-21 | New diphenyl-azetidinone derivatives useful for the treatment of hyperlipidemia, arteriosclerosis and hypercholesterolemia |
| SK778-2003A SK7782003A3 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| KR10-2003-7008503A KR20030063462A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| PL01362173A PL362173A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| HR20030499A HRP20030499A2 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| PL01362512A PL362512A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| JP2002551556A JP2004516289A (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives, methods for their preparation, drugs containing the compounds and uses thereof |
| AT01271371T ATE342899T1 (en) | 2000-12-21 | 2001-12-11 | DIPHENYLAZETIDINONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND THEIR USE |
| CA002431995A CA2431995A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| HU0401073A HUP0401073A2 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| CNB018210430A CN1221546C (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives, processes for their preparation, medicaments containing these compounds and their use |
| CNB018210449A CN1222522C (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for prodn. thereof medicaments contg. these compounds, and their use |
| IL15654801A IL156548A0 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| RU2003122217/04A RU2282628C2 (en) | 2000-12-21 | 2001-12-11 | Derivatives of diphenylazethidinone, pharmaceutical composition based on thereof and method for its preparing |
| YU47803A YU47803A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| MXPA03005019A MXPA03005019A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use. |
| DE50110906T DE50110906D1 (en) | 2000-12-21 | 2001-12-11 | DIPHENYLAZETIDINONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE MEDICAMENT CONTAINING THESE COMPOUNDS AND THEIR USE |
| YU46903A YU46903A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds and their use |
| KR10-2003-7008330A KR20030061462A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| HU0401067A HUP0401067A2 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| AT01991821T ATE338039T1 (en) | 2000-12-21 | 2001-12-11 | DIPHENYLAZETIDINONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND THEIR USE |
| PCT/EP2001/014532 WO2002050068A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| CA002431985A CA2431985A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| JP2002551564A JP2004516293A (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives, process for their preparation, medicaments containing these compounds and their use |
| EEP200300238A EE200300238A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, their use, drug and method of its preparation |
| PCT/EP2001/014533 WO2002050060A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| CZ20031733A CZ20031733A3 (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives and pharmaceutical preparations in which the derivatives are comprised |
| AU2002219173A AU2002219173B2 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| HK04102849.5A HK1059936B (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| EP01991821A EP1345924B1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| NZ526592A NZ526592A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| NZ526594A NZ526594A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| HK04102853.8A HK1060119B (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| EP01271371A EP1345932B1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| DE50111293T DE50111293D1 (en) | 2000-12-21 | 2001-12-11 | DIPHENYLAZETIDINONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE MEDICAMENT CONTAINING THESE COMPOUNDS AND THEIR USE |
| EEP200300237A EE200300237A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, their use, drug and method of its preparation |
| HR20030501A HRP20030501A2 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| AU2002231688A AU2002231688A1 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| RU2003122219/04A RU2275370C2 (en) | 2000-12-21 | 2001-12-11 | Derivatives of diphenylazethidinone, medicinal agents comprising these compounds and their using |
| AU1917302A AU1917302A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicamentscontaining these compounds, and their use |
| BR0116322-1A BR0116322A (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives, process for their preparation, medicines containing these compounds and their use |
| BR0116482-1A BR0116482A (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives, process for preparation, medicaments containing these compounds and their use. |
| SK781-2003A SK7812003A3 (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| CZ20031731A CZ20031731A3 (en) | 2000-12-21 | 2001-12-11 | Diphenylazetidinone derivatives and pharmaceutical preparations in which the derivatives are comprised |
| MXPA03005018A MXPA03005018A (en) | 2000-12-21 | 2001-12-11 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use. |
| ARP010105906A AR034282A1 (en) | 2000-12-21 | 2001-12-19 | DERIVATIVES OF DIFENYLAZETIDINONE, MEDICATIONS CONTAINING THESE COMPOUNDS, PROCEDURE FOR PREPARATION, AND ITS USE FOR THE PREPARATION OF MEDICINES |
| ARP010105908A AR033600A1 (en) | 2000-12-21 | 2001-12-19 | DIFENILAZETIDINONA, MEDICATIONS CONTAINING THESE COMPOUNDS, PROCEDURE FOR THEIR PREPARATION, AND ITS USE TO PREPARE MEDICATIONS |
| US10/021,044 US6703386B2 (en) | 2000-12-21 | 2001-12-19 | Diphenylazetidinone derivatives, process for their preparation, medicaments comprising these compounds and their use |
| US10/021,028 US6498156B2 (en) | 2000-12-21 | 2001-12-19 | Diphenylazetidinone derivatives, process for their preparation, medicaments comprising these compounds and their use |
| ZA200304092A ZA200304092B (en) | 2000-12-21 | 2003-05-27 | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use. |
| ZA200304095A ZA200304095B (en) | 2000-12-21 | 2003-05-27 | Diphenyl azetinidone derivatives, method for the production thereof, medicaments containing these compounds, and their use. |
| NO20032735A NO20032735L (en) | 2000-12-21 | 2003-06-16 | Diphenyllazetidinone derivatives, process for their preparation, drugs containing these compounds and their use |
| NO20032733A NO20032733L (en) | 2000-12-21 | 2003-06-16 | Diphenyllazetidinone derivatives, process for their preparation, drugs containing these compounds and their use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10064402A DE10064402A1 (en) | 2000-12-21 | 2000-12-21 | New diphenyl-azetidinone derivatives useful for the treatment of hyperlipidemia, arteriosclerosis and hypercholesterolemia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE10064402A1 true DE10064402A1 (en) | 2002-06-27 |
Family
ID=7668537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE10064402A Withdrawn DE10064402A1 (en) | 2000-12-21 | 2000-12-21 | New diphenyl-azetidinone derivatives useful for the treatment of hyperlipidemia, arteriosclerosis and hypercholesterolemia |
Country Status (3)
| Country | Link |
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| DE (1) | DE10064402A1 (en) |
| RU (2) | RU2275370C2 (en) |
| ZA (2) | ZA200304095B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UY30117A1 (en) * | 2006-01-31 | 2007-06-29 | Tanabe Seiyaku Co | AMIS TRISUSTITUDED COMPOUND |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5631365A (en) * | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| MX9606319A (en) * | 1994-06-20 | 1997-05-31 | Schering Corp | Substituted azetidinone compounds useful as hypocholesterolemic agents. |
| RU2144533C1 (en) * | 1994-12-09 | 2000-01-20 | Такеда Кемикал Индастриз, Лтд. | Derivatives of tetrazole, method of their synthesis and pharmaceutical compositions based on them |
| DE19845402B4 (en) * | 1998-10-02 | 2005-04-07 | Aventis Pharma Deutschland Gmbh | Heterocyclic substituted propanolamine derivatives, process for their preparation, pharmaceutical compositions containing them and their use |
| DE19825804C2 (en) * | 1998-06-10 | 2000-08-24 | Aventis Pharma Gmbh | 1,4-Benzothiepin-1,1-dioxide derivatives, processes for their preparation and medicaments containing these compounds |
| DE19845406C2 (en) * | 1998-10-02 | 2001-10-18 | Aventis Pharma Gmbh | Substituted 1,3-diaryl-2-pyridin-2-yl-3- (pyridin-2-ylamino) propanol derivatives, process for their preparation, medicaments containing these compounds and their use |
-
2000
- 2000-12-21 DE DE10064402A patent/DE10064402A1/en not_active Withdrawn
-
2001
- 2001-12-11 RU RU2003122219/04A patent/RU2275370C2/en not_active IP Right Cessation
- 2001-12-11 RU RU2003122217/04A patent/RU2282628C2/en not_active IP Right Cessation
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2003
- 2003-05-27 ZA ZA200304095A patent/ZA200304095B/en unknown
- 2003-05-27 ZA ZA200304092A patent/ZA200304092B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200304095B (en) | 2004-04-19 |
| RU2282628C2 (en) | 2006-08-27 |
| RU2275370C2 (en) | 2006-04-27 |
| ZA200304092B (en) | 2004-04-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8127 | New person/name/address of the applicant |
Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH, 65929 FRANKFURT, |
|
| 8130 | Withdrawal |