DE1795788A1 - PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents
PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEMInfo
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- DE1795788A1 DE1795788A1 DE19671795788 DE1795788A DE1795788A1 DE 1795788 A1 DE1795788 A1 DE 1795788A1 DE 19671795788 DE19671795788 DE 19671795788 DE 1795788 A DE1795788 A DE 1795788A DE 1795788 A1 DE1795788 A1 DE 1795788A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
vom 26. April I967 aufgrund der britischen Patentanmeldung Nr. I9I74/67dated April 26, 1967 due to the British Patent application no. 19I74 / 67
Die vorliegende Erfindung betrifft Serumlipoide vermindernde Pyridinderivate, sowie deren Herstellung und pharmazeutissche Präparate, die diese enthalten. Diese Pyridinderivate haben auch gefäßerweiternde Eigenschaften.The present invention relates to pyridine derivatives which reduce serum lipids, and to their preparation and pharmaceuticals Preparations containing them. These pyridine derivatives also have vasodilatory properties.
Im Hinblick auf sich mehrende Beweise, die zeigen, daß eine übermäßige Serumlipoldkonzentration in Wechselwirkung mit einem grundlegenden pathogenen Mechanismus und Symptomen verschiedener Krankheiten, wie Gefäßkrankheiten, Diabetes mellitus und Hyperthyroidismus, steht, ist eine Herabsetzung der Serumlipoidkonzentration während der Behandlung solcher Krankheiten wichtig.In view of the mounting evidence showing that a excessive serum lipol concentration in interaction with a basic pathogenic mechanism and symptoms of various diseases such as vascular disease, diabetes mellitus and hyperthyroidism, is a decrease in serum lipoid concentration important during the treatment of such diseases.
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Die Herabsetzung der Serumlipoidkonzentration kann man durch Hemmung der Lipoidmobilisierung, wie beispielsweise durch. die Herabsetzung der Gesamtabgabe von Lipoiden an den Kreislauf in Form freier Fettsäuren aus gespeicherten Triglyceriden in Adiposegewebe, erreichen.The reduction of the serum lipoid concentration can be done by Inhibition of lipoid mobilization, such as by. the reduction in the overall release of lipoids to the circulation in the form of free fatty acids from stored triglycerides in adipose tissue.
Es wurde nun gefunden, daß Pyridinderivate der allgemeinen Formel It has now been found that pyridine derivatives of the general formula
0
CH2-O-C-A0
CH 2 -OCA
und deren therapeutisch verträgliche Salze, worin A eine geradkettige oder verzweigtkettige Alkylgruppe mit höchstens 12 Kohlenstoffatomen oder eine der Gruppen -CH2-CH=CH2, and their therapeutically acceptable salts, in which A is a straight-chain or branched-chain alkyl group with at most 12 carbon atoms or one of the groups -CH 2 -CH = CH 2 ,
XH,XH,
oderor
"Cr"Cr
, worin R eine Alkylgruppe, vorzugsweise die Methylgruppe ist, bedeutet, gefäßerweiternde Eigenschaften haben und von besonderem Wert für die Herabsetzung übermäßiger Serumlipoidkonzentrationen sind.wherein R is an alkyl group, preferably the methyl group, have vasodilatory properties and are of particular value for reducing excessive serum lipoid concentrations .
Der Ausdruck »therapeutisch verträgliches Salz» wird in der Technik so gebraucht, um ein Säureadditionssalz zu bezeichnetn, das physio- ._ The term "therapeutically acceptable salt" is used in the art as to bezeichnetn to an acid addition salt, the physio ._
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logisch unschädlich ist, wenn es in einer Dosis und einem Intervall (wie beispielsweise einer Verabreichungsfrequenz) verabreicht wird, die für die betreffende therapeutische Verwendung der Verbindung wirksam sind. Typische therapeutisch verträgliche Säureadditionssalze sind beispielsweise, aber nicht ausschließlich, Salze von Mineralsäuren, wie Salzsäure, Bromwasserstoffsäure, Phosphorsäure oder Schwefelsäure, von organischen Säuren^ wie Essigsäure, Milchsäure, Lävulinsäure, Zitronensäure, Fumarsäure, Maleinsäure, Succinsäure, Weinsäure, Benzoesäure und Sulfonsäuren, wie Methansulfensäure» und SuIfaminsäure.is logically harmless if it is in one dose and one Interval (such as an administration frequency) effective for the therapeutic use of the compound in question. Typical therapeutic Compatible acid addition salts are, for example, but not exclusively, salts of mineral acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, of organic acids such as acetic acid, lactic acid, levulinic acid, Citric acid, fumaric acid, maleic acid, succinic acid, tartaric acid, benzoic acid and sulfonic acids such as methanesulfenic acid » and sulfamic acid.
Die vorliegende Erfindung betrifft außerdem ein Verfahren zur Herstellung der oben erwähnten Verbindungen, Die als Ausgangsmaterialien für die verschiedenen Verfahren verwendeten Verbindungen können nach bekannten Methoden hergestellt werden.The present invention also relates to a process for the preparation of the above-mentioned compounds which are used as Starting materials used for the various processes can be prepared by known methods will.
Dieses Verfahren ist dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel F —«f**'^^^*—CH„-Y, worin YThis method is characterized in that one connection of the general formula F - «f ** '^^^ * - CH" -Y, where Y
1U^ 1 U ^
ein Halogenatom oder eine Hydroxylgruppe bedeutet, mit einer Verbindung X-A, worin A die obige Bedeutung hat und X eine Carboxylgruppe, Metallcarboxylatgruppe oder aktivierte Carboxylgruppe bedeutet, in welch letzterem Fall die Ausgangsverbindung ein Derivat einer Carbonsäure, wie ein Säurehalogenid, ein Alkylester oder ein Säureanhydrid, gemischtes Anhydrid mit Alkoxyameisensäuren, Carbonsäuren, Sulfonsäuren oder anorganischen Säuren oder ein Derivat ist, das man durch Umsetzung zwischenrepresents a halogen atom or a hydroxyl group, with a compound X-A, wherein A has the above meaning and X is Carboxyl group, metal carboxylate group or activated carboxyl group means in which latter case the starting compound is a derivative of a carboxylic acid, such as an acid halide, an alkyl ester or an acid anhydride, mixed anhydride with alkoxyformic acids, carboxylic acids, sulfonic acids or inorganic ones Acids or a derivative that can be obtained by reacting between
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einer Carbonsäure und einem Carbodiimid oder einer ähnlich funktionierenden Verbindung, wie N,N1-Carbonyldiimidazol oder N-Äthyl-5-phenyl-isoxazolium-3' -sulfonat, gewonnen hat, wobei X eine Metallcarboxylatgruppe ist, wenn Y ein Halogenatom ist, umsetzt und die erhaltene Base ggf. durch Umsetzung mit einer Säure in ihr therapeutisch verträgliches Salz überführt.a carboxylic acid and a carbodiimide or a similarly functioning compound, such as N, N 1 -carbonyldiimidazole or N-ethyl-5-phenyl-isoxazolium-3'-sulfonate, where X is a metal carboxylate group when Y is a halogen atom and the base obtained is converted into its therapeutically acceptable salt, if necessary by reaction with an acid.
Die Umsetzung kann in Gegenwart von wässrigen oder wasserfreien organischen Lösungsmitteln, wie Chloroform, Diäthyläther, Tetrahydrofuran, Benzol und Toluol, oder ohne Lösungsmittel durchgeführt werden. Speziell, wenn X eine Carboxylgruppe und Y eine Hydroxylgruppe bedeutet, kann ein saurer Katalysator, wie Schwefelsäure, Salzsäure, p-Toluolsulfonsäure, Benzolsulfonsäure oder Salze mit hoher bis mittlerer Säurestärke, einschließ-Iich4nit Wasserstoff ionen gesättigter Ionenaustauscher, verwendet werden. In diesem Fall kann das während der Umsetzung gebildete Wasser, um ein günstigeres Gleichgewicht zu erhalten, aus dem Reaktionsgemisch durch Azeotropdestillation entfernt oder durch Trockenmittel, wie wasserfreies Kupfer-II-oder Mangan-sulfat oder Molekularsiebe, aufgenommen werden. Wenn die Ausgangsverbindung ein Säurehaiοgenid ist, kann durch eine Base, wie Pyridin oder Triäthylamin der freigesetzte Halogenwasserstoff neutralisiert und die Reaktion katalysiert werden.The reaction can be carried out in the presence of aqueous or anhydrous organic solvents such as chloroform, diethyl ether, tetrahydrofuran, Benzene and toluene, or without a solvent. Especially when X is a carboxyl group and Y is a hydroxyl group, an acid catalyst such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid or salts with high to medium acid strength, including iich4nit Hydrogen ions saturated ion exchangers are used will. In this case, the water formed during the reaction can be used to obtain a more favorable equilibrium from the The reaction mixture is removed by azeotropic distillation or by drying agents, such as anhydrous copper (II) or manganese sulfate or molecular sieves. If the starting compound is an acid halide, a base such as Pyridine or triethylamine neutralized the released hydrogen halide and catalyzed the reaction.
In der klinischen Praxis werden die Verbindungennach der Erfindung normalerweise oral oder durch Injektion in der Form pharmazeutischer Präparate verabreicht, die den aktiven Bestandteil entweder als freie Base oder als therapeutisch ver-In clinical practice the compounds of the invention become usually administered orally or by injection in the form of pharmaceutical preparations containing the active ingredient either as a free base or as a therapeutically
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traglich.es Säureadditionssalz, wie beispielsweise als Hydrochlorid, Hydrosulfat oder dgl., in Verbindung mit einem pharmazeutisch vertraglichen Trägermaterial enthalten. Demnach sollen die all gerne iiPoder speziellen Bezeichnungen für die neuen Verbindungen nach der Erfindung sowohl die freien Basen als auch die Säureadditipnssalze der freien Basen einschließen, es sei denn, die Bedeutung, in der solche Ausdrücke verwendet werden, wie in den speziellen Beispielen, wäre nicht mit dieser breiten Bedeutung vereinbar. Das Trägermaterial kann ein festes, halbfestes oder flüssiges Verdünnungsmittel oder eine einnehmbare Kapsel sein. Diese pharmazeutischen Präparate machen einen weiteren Aspekt dieser Erfindung aus. Gewöhnlich wird die aktive Substanz zwischen 0,1 und 95 Gew..-96 des Präparatesy spezieller zwischen 0,5 und 20 Gew.-$ von Präparaten, die für die Injektion bestimmt sind, und zwischen 2 und 50 Gew.-?6 von Präparaten, die für orale Verabreichung geeignet sind, ausmachen.Traglich.es acid addition salt, such as the hydrochloride, Hydrosulfate or the like, in conjunction with a pharmaceutical contractual carrier material included. Therefore should they all like iiP or special names for the new compounds according to the invention include both the free bases and the acid addition salts of the free bases, unless the meaning in which such terms are used, as in the specific examples, were inconsistent with this broad meaning compatible. The carrier material can be a solid, semi-solid or liquid diluent or a be ingestible capsule. These pharmaceutical preparations form another aspect of this invention. Usually the active substance is between 0.1 and 95 wt ..- 96 of the preparation more specifically, between 0.5 and 20% by weight of preparations intended for injection, and between 2 and 50 Wt .-? 6 of preparations suitable for oral administration are, make up.
Zur Herstellung pharmazeutischer Präparate, die eine Verbindung nach der Erfindung in der Form eim· Dosierungseinheit für orale Verabreichung enthalten, kann die gewählte Verbindung mit einem festen, pulverförmigen Trägermaterial vermischt werden, wie beispielsweise mit Lactose, Saccharose, Sorbit, Mannit, Stärke, wie Kartoffelstärke, Maisstärke, Amylopectin, Zellulosederivaten oder Gelatine, und ein Schmiermittel, wie Magnesiumstearat, Calciumstearat, ein Polyäthylenglycolwachs und dgl. kann ebenfalls zugemischt werden, worauf dann die Gemische unter Ausbildung von Tabletten verpreßt werden. WennFor the manufacture of pharmaceutical preparations containing a compound according to the invention in the form of a dosage unit for oral administration, the compound of choice may be mixed with a solid, powdery carrier material be, such as with lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch, amylopectin, Cellulose derivatives or gelatin, and a lubricant such as magnesium stearate, calcium stearate, a polyethylene glycol wax and the like. Can also be mixed in, whereupon the mixtures are compressed to form tablets. if
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überzogene Tabletten erforderlich sind, können die wie oben beschrieben hergestellten Kerne mit einer konzentrierten Zuckerlösung überzogen werden, die beispielsweise Gummi arabicum, Gelatine, Talkum, Titandioxid oder dgl. enthalten kann. Wechselweise kann die Tablette auch mit einem Lack überzogen werden, der in einem leicht flüchtigen organischen Lösungsmittel oder Gemisch organischer Lösungsmittel gelöst ist. Zu diesen Überzügen können Farbstoffe zugesetzt werden, damit man leicht zwischen Tabletten mit einem Gehalt unterschiedlicher aktiver Komponenten oder unterschiedlicher Mengen der aktiven Verbindung unterscheiden kann.Coated tablets may be required as described above produced cores are coated with a concentrated sugar solution, for example gum arabic, Gelatin, talc, titanium dioxide or the like. Contain. Alternately the tablet can also be coated with a varnish that is in a highly volatile organic solvent or Mixture of organic solvents is dissolved. Dyes can be added to these coatings to make them easy between tablets containing different active components or different amounts of the active compound can distinguish.
Durch Verwendung verschiedener Schichten der aktiven Substanz, welche durch langsam sich lösende Überzüge voneinander getrennt sind, erhält man Tabletten mit verzögerter Abgabe, Ein anderer Weg zur Herstellung von Tabletten mit verzögerter Abgabe ist der, die Dosis der aktiven Substanz in Granalien mit Überzügen unterschiedlicher Dickeaufzuteilen und die Granalien zusammen mit der Trägersubstanz zu Tabletten zu verpressen. Auch kann die aktive Substanz in sich langsam lösende Tabletten eingearbeitet werden, die beispielsweise aus Fett- und Wachssubstanzen bestehen, oder sie kann sogar in einer Tablette aus einer unlöslichen Substanz verteilt werden, wie beispielsweise einer physiologisch inerten Kunststoffsubstanz.By using different layers of the active substance, which are separated from each other by slowly dissolving coatings sustained release tablets are obtained. Another way of producing sustained release tablets is that of dividing the dose of the active substance into granules with coatings of different thickness and the granules to be compressed into tablets together with the carrier substance. The active substance can also be incorporated into slowly dissolving tablets made, for example, of fat and wax substances or it may even be dispersed in a tablet of an insoluble substance such as a physiologically inert plastic substance.
Brausepulver stellt man durch Vermischen der aktiven Substanz mit nicht giftigen Carbonaten oder Hydrogenearbonaten, wie Calciumcarbonat, Kaliumcarbonat und Kaliumhydrogencarbonat,Effervescent powder is made by mixing the active substance with non-toxic carbonates or hydrogen carbonates, such as Calcium carbonate, potassium carbonate and potassium hydrogen carbonate,
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festen, nicht giftigen Säuren, wie Weinsäure, Zitronensäure, und beispielsweise Aromastoffen, her.solid, non-toxic acids such as tartaric acid, citric acid and, for example, flavorings.
Zur Herstellung weicher Gelatinekapseln (peArörmiger, geschlossener Kapseln), die aus Gelatine und beispielsweise .Glycerin oder ähnlichen Materialien für geschlossene Kapseln bestehen, kann die aktive Substanz mit einem Pflanzenöl vermischt werden. Harte Gelatinekapseln können Granulate der aktiven Substanz in Verbindung mit festen, pulverförmigen Trägersubstanzen enthalten, wie Lactose, Saccharose, Sorbit, Mannit, einer Stärke, wie beispielsweise Kartoffelstärke, Maisstärke oder Amylopectin, einem Zellulosederivat oder Gelatine. The active substance can be mixed with a vegetable oil to produce soft gelatine capsules (pe-shaped, closed capsules) made of gelatine and, for example, glycerine or similar materials for closed capsules. Hard gelatin capsules can contain granules of the active substance in conjunction with solid, powdery carrier substances, such as lactose, sucrose, sorbitol, mannitol, a starch such as potato starch, corn starch or amylopectin, a cellulose derivative or gelatin.
Flüssige Präparate für die orale Verabreichung können in der Form von Sirupen oder Suspensionen vorliegen, wie beispielsweise Lösungen mit einem Gehalt von 0,2 bis 20 Gew.-^ der aktiven Substanz, wobei der Rest aus Zucker und einem Gemisch. von Äthanol, WasserfGlycerin und Propylenglycol besteht. Gegebenenfalls können solche flüssigen Präparate Färbemittel, geschmackverbessernde Mittel, Saccharin und Carboxymethylzellulose als Verdickungsmittel enthalten.Liquid preparations for oral administration may be in the form of syrups or suspensions, such as solutions containing from 0.2 to 20% by weight of the active substance, the remainder being sugar and a mixture. of ethanol, water f glycerine and propylene glycol. If necessary, such liquid preparations can contain coloring agents, taste-improving agents, saccharin and carboxymethyl cellulose as thickening agents.
Lösungen für die parenterale Verabreichung durch Injektion können wässrige Lösungen eines wasserlöslichen, pharmazeutisch verträglichen Salzes der aktiven Substanz sein, vorzugsweise in einer konzentration von 0,5 bis 10 Gew.-96. Die Lösungen können auch Stabilisierungsmittel und/oder PuffersubstanzenSolutions for parenteral administration by injection can be aqueous solutions of a water-soluble, pharmaceutically acceptable salt of the active substance, preferably in a concentration of 0.5 to 10 % by weight. The solutions can also contain stabilizers and / or buffer substances
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enthalten und bequemerweise in Ampullen verschiedener Dosierungseinheiten vorgesehen sein«contained and conveniently in ampoules of various dosage units be provided"
Beispiel 1 - 5-Fluor-3-pyridinmethyl-5-fluo:rnikotinatExample 1 - 5-fluoro-3-pyridinemethyl-5-fluoro: nicotinate
5-Fluornikotinsäure (5,94 g) wurde 4,5 Stunden mit 24 ml Thionylchlorid unter Rückfluß erhitzt. Überschüssiges Thionylchlord wurde abgedampft, und der Rest wurde 10 Minuten mit einem Gemisch von Chloroform (20 ml) und Pyridin (8 ml) auf 80 C erhitzt. Die Lösung wurde in einem Bisbad gekühlt, und eine Lösung von 5-Pluor-3-pyridinmethanol (5f10 g) in 15 ml Chloroform wurde unter Rühren während 30 Minuten zugegeben. Das Reaktionsgemisch wurde bei Raumtemperatur zwei Stunden gerührt, dann ließ man es über Nach stehen. Das Gemisch, wurde auf Eiswasser gegossen und die Chloroformphase abgetrennt und zweimal mit einer gesättigten wässrigen Lösung von Natriumhydrogenearbonat gewaschen. Die Chloroformlösung wurde über wasserfreiem Natriumsulfat getrocknet, filtriert und das Lösungsmittel abgedampft, um 9,0 g von nahezu farblosem Produkt zu ergeben. F. 105,5 - 106,0°C; Analyseni Gef. C 57,84; H 3,35; F 15,41; N 11,11$; Ber. für C12HgF2N2O2: C 57,60; H 3,22; F 15,19? N 11,20$;5-fluoronicotinic acid (5.94 g) was refluxed with 24 ml of thionyl chloride for 4.5 hours. Excess thionyl chloride was evaporated and the residue was heated to 80 ° C. for 10 minutes with a mixture of chloroform (20 ml) and pyridine (8 ml). The solution was cooled in a bis-bath and a solution of 5-pluoro-3-pyridinemethanol (5f10 g) in 15 ml of chloroform was added with stirring over 30 minutes. The reaction mixture was stirred at room temperature for two hours, then allowed to stand overnight. The mixture was poured onto ice water and the chloroform phase was separated and washed twice with a saturated aqueous solution of sodium hydrogen carbonate. The chloroform solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to give 9.0 g of nearly colorless product. M.p. 105.5-106.0 ° C; Analyzes i Found C, 57.84; H 3.35; F 15.41; N $ 11.11; Ber. for C 12 HgF 2 N 2 O 2 : C, 57.60; H 3.22; F 15.19? N $ 11.20;
Beispiel 2 - 5-Fluor-3-pyridinmethyl-5-fluornikontinatExample 2 - 5-fluoro-3-pyridinemethyl-5-fluoronicontinate
Zu einer gerührten Suspension von 5-Fluornikotinsäure (7»05 g) und 5-S*luor-3-pyridinmethanol (6,35 g) in 70 ml wasserfreiem Dioxan wurde eine Lösung von N,N-Dicyclohexylcarbdiimid (10,3 g) in 50 ml wasserfreiem Dioxan während einer StundeTo a stirred suspension of 5-fluoronicotinic acid (7 »05 g) and 5-S * luoro-3-pyridinemethanol (6.35 g) in 70 ml of anhydrous Dioxane became a solution of N, N-dicyclohexylcarbdiimide (10.3 g) in 50 ml of anhydrous dioxane over one hour
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unter Eiskühlung zugesetzt. Das Reaktion gemisch wurde bei Raumtemperatur während 16 Stunden gerührt und dann auf eine kleine Menge von kaltem Äthylacetat gegossen. Der ausgefällte Harnstoff wurde abfiltriert und das FiItrat eingedampft. Der gelbe halbfeste Rückstand wurde in einer kleinen Menge Chloroform gelöst,auf eine kurze Aluminiumoxydsäule gegeben und mit 200 ml Chloroform eluiert. Der Rest wurde nach Eindampfen der Chloroformlösung aus Petroläther mit etwas zugesetztem Äthanol umkristallisiert. Das Produkt, 4,2 g, P. 105 - 106°C, war identisch mit einem Produkt, das gemäß Beispiel 1 hergestellt worden war.added while cooling with ice. The reaction mixture was at Stirred room temperature for 16 hours and then to a small amount of cold ethyl acetate poured. The precipitated urea was filtered off and the filtrate was evaporated. Of the yellow semi-solid residue was dissolved in a small amount of chloroform, placed on a short aluminum oxide column and with 200 ml of chloroform eluted. The residue was after evaporation of the chloroform solution from petroleum ether with something added Recrystallized ethanol. The product, 4.2 g, P. 105-106 ° C, was identical to a product prepared according to Example 1 had been.
Beispiel 3 - 5-Fluor-3-pyridinmethylnikotinatExample 3 - 5-fluoro-3-pyridine methyl nicotinate
Nikotinsäure (317 s) wurde eine Stunde mit Thionylchlorid O1»9 s) unter Rückfluß erhitzt. Abdampfen von überschüssigem Thionylchlorid ergab 4,95 S rohes Nikotinsäurechloridhydrochlorid, das mit 10 ml wasserfreiem Benzol bedeckt wurde. Zu diesem Gemisch wurde eine Lösung von 5-Fluor-3-pyridinmethanol in einem Gemisch von 12 ml Triäthylamin und 4θ ml Benzol unter Rühren zugesetzt. Das resultierende Gemisch wurde fünf Stunden unter Rückfluß erhitzt. Nach dem Kühlen wurde das Triäthylaminhydrochlorid abfiltriert und mit Benzol gewaschen. Die vereinigten Waschflüssigkeiten und das Piltrat wurden in Vakuum eingedampft, um einen halbfesten Rückstand zu ergeben. Das Rohprodukt wurde aus Petroläther umkristallisiert, um 3,5 g Kristalle mit einem Schmelzpunkt F. von 65-67 G zu ergeben. Wiederholte Umkristallistionen aus PetrolätherNicotinic acid (317 s) was refluxed for one hour with thionyl chloride O 1 »9 s). Evaporation of excess thionyl chloride gave 4.95 S of crude nicotinic acid chloride hydrochloride which was covered with 10 ml of anhydrous benzene. A solution of 5-fluoro-3-pyridinemethanol in a mixture of 12 ml of triethylamine and 40 ml of benzene was added to this mixture with stirring. The resulting mixture was refluxed for five hours. After cooling, the triethylamine hydrochloride was filtered off and washed with benzene. The combined washes and piltrate were evaporated in vacuo to give a semi-solid residue. The crude product was recrystallized from petroleum ether to give 3.5 g of crystals with a melting point of 65-67 G. Repeated recrystallizations from petroleum ether
. 509831/0898. 509831/0898
ergaben ein völlig farbloses Produkt mit F. 68,5 - 69,5°C. Analysen: Ber. für C^H FN^i C 62,07} H 3,91} F 8,18}resulted in a completely colorless product with a mp of 68.5-69.5 ° C. Analysis: Ber. for C ^ H FN ^ i C 62.07} H 3.91} F 8.18}
N 12,07} 0 13,7890. Gef.: C 62,03} H 3,87} F 8,05} N 12,14#.N 12.07} 0 13.7890. Found: C 62.03} H 3.87} F 8.05} N 12.14 #.
Beispiel 4 - 3-Py*1 idinäthyl-3-pyridinacetatExample 4 - 3-Py * 1 idinethyl-3-pyridine acetate
Ein Gemisch von 3-Pyridinessigsäure (10,4 g), 3-Pyridinmethanol (9,3 g) und konzentrierter Schwefelsäure (10 ml) in 200 ml Benzol wurde sechs Stunden unter Rückfluß erhitzti Das gebildete Reaktionswasser wurde kontinuierlich durch Azeotropdestillation abgenommen. Die Benzolphase wurde abgegossen und der ölige Rückstand in 50 ml kaltem Wasser gelöst und die Lösung mit wässrigem Natriumcarbonat alkalisch gemacht. Das alkalische Gemisch wurde mehrmals mit DiäthyI-äther extrahiert, der Extrakt über wasserfreiem Kaliumcarbonat getrocknet, filtriert und das Lösungsmittel eingedampft, um 9,1 g Produkt zu ergeben. Destillation im Vakuum ergibt 7,3 g Produkt, Kp. 162 - 162,5°C/O,3 mmHg} n^5= 1,55^0} Hydrochlorid F. 126 - 127°C. Analysen (des Hydrochorids)1 Gef. : C 52,8} H 5,26} N 8,76; 0 9,96} Cl 22,659ε} Ber. für N2O2Cl2 : C 53,34; H 5,12} N 8,89} 0 10,15} Cl 22,49#.A mixture of 3-pyridine acetic acid (10.4 g), 3-pyridinemethanol (9.3 g) and concentrated sulfuric acid (10 ml) in 200 ml of benzene was refluxed for six hours. The water of reaction formed was continuously removed by azeotropic distillation. The benzene phase was poured off and the oily residue was dissolved in 50 ml of cold water and the solution was made alkaline with aqueous sodium carbonate. The alkaline mixture was extracted several times with diethyl ether, the extract dried over anhydrous potassium carbonate, filtered and the solvent evaporated to give 9.1 g of product. Distillation in vacuo gives 7.3 g of product, b.p. 162-162.5 ° C / 0.3 mmHg} n ^ 5 = 1.55 ^ 0} hydrochloride, mp 126-127 ° C. Analyzes (of the hydrochloride) 1 found : C 52.8} H 5.26} N 8.76; 0 9.96} Cl 22.659ε} Ber. for N 2 O 2 Cl 2 : C, 53.34; H 5.12} N 8.89} 0 10.15} Cl 22.49 #.
In analoger Weise wurde die folgende Verbindung hergestellt« 5-Fluor-3-pyridinmethyl-3-pyridinacetatThe following compound was prepared in an analogous manner: 5-fluoro-3-pyridinemethyl-3-pyridineacetate
Rückflußzeit 20 Stunden mit p-Toluolsulfonsäure anstelle von Schwefelsäure. Ausbeute 605ε. F. 58,0 - 60,0°C. Analysen» Gef . s C 63,33; H 4,77? F 7,55} N 11,53^5 Ber. für C13H11FN2O2: C 63,41; H 4,50} F 7,72; N 11,389ε.Reflux time 20 hours with p-toluenesulfonic acid instead of sulfuric acid. Yield 605ε. M.p. 58.0-60.0 ° C. Analyzes »Gef. s C 63.33; H 4.77? F 7.55} N 11.53 ^ 5 Calc. for C 13 H 11 FN 2 O 2 : C, 63.41; H 4.50} F 7.72; N 11.389ε.
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Beispiel 5 - 5-Fluorpyridin-3-methyl-5-methylpyrazol-3-carboxylat Example 5 - 5-fluoropyridine-3-methyl-5-methylpyrazole-3-carboxylate
5-Fluoxpyridin-3-niethyl-5-methyl-pyrazol-3-carboxylat wurde auf gleiche Weise hergestellt, wie nachfolgend für Pyridin-3-methyl-5-methylpyrazol-3-carboxylat beschrieben ist, doch wurde Toluol als Lösungsmittel verwendet,5-fluoxpyridine-3-diethyl-5-methyl-pyrazole-3-carboxylate prepared in the same manner as for pyridine 3-methyl-5-methylpyrazole-3-carboxylate below is described, but toluene was used as the solvent,
5-Methylpyrazol-3-carbonsäure (5»05 g) und 3-Py-ridinmethanol (4,36 g) werden zusammen mit p-Toluolsulfonsäuremonohydrat (19 g) in 10ü ml Benzol unter Rückfluß erhitzt. Es wird eine Wasserabtrenneinrichtung verwendet, um das Wasser in dem Reaktionsgemisch abzuziehen. Nach 27 Stunden wird die Benzophase des Reaktionsgemisches dekantiert, und der Rückstand wird mit überflüssigem wässrige« Natriumbicarbonat behandelt· Das wässrige Gemisch wird mit der dekantierten BensbLphase und drei Anteilen Chloroform extrahiert. Die vereinigten Extrakte werden über wasserfreiem Natriumsulfat getrocknet, filtriert und das Lösungsmittel wird verdampft und ergibt Uß g gelbes Öl, das beim Kühlen spontan kristallisiert.5-methylpyrazole-3-carboxylic acid (5 »05 g) and 3-Py-ridinmethanol (4.36 g) are heated together with p-toluenesulfonic acid monohydrate (19 g) in 10 ml of benzene under reflux ü. A water separator is used to remove the water in the reaction mixture. After 27 hours the benzophase of the reaction mixture is decanted and the residue is treated with excess aqueous sodium bicarbonate. The aqueous mixture is extracted with the decanted benzophase and three portions of chloroform. The combined extracts are dried over anhydrous sodium sulfate, filtered and the solvent is evaporated to give U3 g of a yellow oil which crystallizes spontaneously on cooling.
Nach dem Umkristallisieren aus Benzol schmolz das Produkt bei' 123,5 bis 134,5°C. Analyseni Gef. C 60,5} H, 5,12; N 19,4}
0 14,9$
Berechnet für CnH11N3O2J C 60,82j H 5,11; N 19,34; 0 14,73$.After recrystallization from benzene, the product melted at 123.5-134.5 ° C. Analyzes i Found: C, 60.5} H, 5.12; N 19.4} 0 $ 14.9
Calculated for C n H 11 N 3 O 2 JC 60,82j H, 5.11; N 19.34; 0 $ 14.73.
Die Werte für S-^yyThe values for S- ^ yy
oxylat: Ausbeute 75$, F. 141,5 bis 143°C.oxylate: yield $ 75, mp 141.5-143 ° C.
Analyse: Gef. C 55,96; H 4,36; F 7,96; N 17*75% Ber. für C11H10FNjO2, C 56,17; H 4,29; F 8,08; N 17,86%. Analysis: Found C, 55.96; H 4.36; F 7.96; N 17 * 75% calc. for C 11 H 10 FNjO 2 , C 56.17; H 4.29; F 8.08; N 17.86%.
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Nach dem gleichen Verfahren wurde 5-Fluorpyridin-3-niethylpyra2QL· 3-carboxylat hergestellt.Using the same procedure, 5-fluoropyridine-3-niethylpyra2QL 3-carboxylate produced.
Ausbeute 75%, F. 162°C, Äquivalentgewicht, gef. 219, ber. 221.Yield 75%, mp 162 ° C, equivalent weight, found. 219, ber. 221.
Beispiel 6 - 5-Fluor-3-pyridinmethylacetatExample 6 - 5-fluoro-3-pyridinemethyl acetate
Zu 50 ml gerührtem Essigsäureanhydrid wurde bei Raumtemperatur langsam 5-Fluor-3-pyridinmethanol (10,2 g) zugesetzt. Die Reaktionslösung ließ man drei Tage stehen und trieb dann im Vakuum das überschüssige Essigsäureanhydrid aus. Der Rückstand wurde im Vakuum destilliert und ergab 9»3g farbloses Produkt, Kp. 102 - 1O5°C/1O mm Hg, n^ = 1,4850. Analysen: Gef. C 57,02; H 4,87; F 11,07; N 8,45%; Berechnet für CgHgFNOgt C 56,80; H 4,76; F 11,23; N 8,28%;To 50 ml of stirred acetic anhydride was slowly added 5-fluoro-3-pyridinemethanol (10.2 g) at room temperature. The reaction solution was left to stand for three days and then the excess acetic anhydride was driven off in vacuo. The residue was distilled in vacuo and gave 9-3 g of colorless product, boiling point 102-1O5 ° C./1O mm Hg, n ^ = 1.4850. Analyzes: Found C, 57.02; H 4.87; F 11.07; N 8.45%; For CgHgFNOgt C 56.80; H 4.76; F 11.23; N 8.28%;
Beispiel 7 - 5-Fluor-3-pyridinmethylcaprylatExample 7 - 5-fluoro-3-pyridine methyl caprylate
Zu einer gerührten Lösung von 5-Fluor-3-pyridinmethanol (3,8 g) und 13 ml Triäthylamin in 100 ml wasserfreiem Benzol wurde bei Raumtemperatur langsam eine Lösung Caprylsäurechlorid (4,9 g) in 25 ml Benzol zugesetzt. Das Gemisch wurde 30 Minuten bei Raumtemperatur gerührt und sodann während zwei Stunden auf Rückflußbedingungen erhitzt. Nach dem Kühlen wurde der Niderschlag von Aminhydrochlorid abfiltriert und mit Benzol gewaschen. Die vereinigten Waschflüssigkeiten und Filtrat wurden im Vakuum eingedampft, um 8,3 g flüssigen Rückstand zu ergeben. Dieser wurde im Vakuum destilliert und ergab 5,1 g nahezu farblose Flüssigkeit, Kp. 145 - 15O°C/OfO5 mm Hg;To a stirred solution of 5-fluoro-3-pyridinemethanol (3.8 g) and 13 ml of triethylamine in 100 ml of anhydrous benzene, a solution of caprylic acid chloride (4.9 g) in 25 ml of benzene was slowly added at room temperature. The mixture was stirred at room temperature for 30 minutes and then refluxed for two hours. After cooling, the precipitate of amine hydrochloride was filtered off and washed with benzene. The combined washings and filtrate were evaporated in vacuo to give 8.3 g of liquid residue. This was distilled in vacuo to give 5.1 g of almost colorless liquid, bp 145 - 15O ° C / f O O5 mm Hg.
50 9 831/089850 9 831/0898
H0 5 = 1,4730. Analysen: Gef.: C 66,25; H 7,86; F 7,33; N 51605ε; Ber. für C1^H20FNO2: C 66,38; H 7,96; F 7,50; N 5,55$. H 0 5 = 1.4730. Analyzes: Found: C 66.25; H 7.86; F 7.33; N 51605ε; Ber. for C 1 → H 20 FNO 2 : C, 66.38; H 7.96; F 7.50; N $ 5.55.
Beispiel 8 - 5-Fluor-3-pyridinraethylpivalatExample 8 - 5-fluoro-3-pyridinraethyl pivalate
Zu einer gut gerührten und eisgekühlten Lösung von 5-Fluor-3-pyridinmethanol (6,35 g) und I5 ml Triäthylamin in 100 ml trockenem Benzol wurde eine Lösung von Pivaloylchlorid (6,0 g) in 10 ml trockenem Benzol während einer Stunde zugegeben. Das Reakticiisgemisch wurde kf5 Stunden bei Raumtemperatur gerührt und dann filtriert. Das Filtrat wurde zweimal mit 50 ml einer gesättigten Wässrigen Lösung von Natriumhydrοgencarbonat gewaschen und dann über wasserfreiem Natriumsulfat getrocknet. Filtriert und Eindampfen des Lösungsmittels ergab 8,7 S eines gelbroten Öles, das im Vakuum destilliert wurde, um 5,45 farbloses Produkt zu ergeben. Kp. II9 - 121 C/i3mm Hg; n^5= 1,470; Analysen: Gef.: C 62,50; H 6,53t F 8,91; N 6,809ε; Berechnet für C1 .,H1 ^FNO2: C 62,54; H 6,68; F 8,99; N 6,63%. 5-Fluor-3-pyridinmethy!vinylacetat wurde in analoger Weise hergestellt. Ausbeute 55$i Kp.' 89 - 91°c/ 0,8 mm Hg; τξ5 = 1,497; Analysen: Gef.: C 61,05; H 5,55; F 9,63; N 7,15; Berechnet für C10H10FNO2: C 61,53; H 5,16; F 9,73; N 7,18.To a well stirred and ice-cooled solution of 5-fluoro-3-pyridinemethanol (6.35 g) and 15 ml of triethylamine in 100 ml of dry benzene, a solution of pivaloyl chloride (6.0 g) in 10 ml of dry benzene was added over one hour . The reaction mixture was stirred for 5 hours at room temperature and then filtered. The filtrate was washed twice with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate and then dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent gave 8.7 S of a yellow-red oil which was distilled in vacuo to give 5.45 of a colorless product. Bp II9-121 C / i3mm Hg; n ^ 5 = 1.470; Analyzes: Found: C 62.50; H 6.53t F 8.91; N 6.809ε; Calculated for C 1. , H 1 → FNO 2 : C, 62.54; H 6.68; F 8.99; N 6.63%. 5-Fluoro-3-pyridinemethyl vinyl acetate was prepared in an analogous manner. Yield 55 $ i bp ' 89-91 ° C / 0.8 mm Hg; τξ 5 = 1.497; Analyzes: Found: C, 61.05; H 5.55; F 9.63; N 7.15; Calculated for C 10 H 10 FNO 2 : C, 61.53; H 5.16; F 9.73; N 7.18.
Beispiel 9 - 5-Fluor-3-pyridinmethyl-3-methyl-5~isoxazolcarboxylatExample 9 - 5-Fluoro-3-pyridinemethyl-3-methyl-5-isoxazole carboxylate
COOCH2 COOCH 2
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Claims (1)
geradkettige oder verzweigtkettige Alkylgruppe mit höchstens 12 Kohlenstoffatomen oder eine der Gruppenand their therapeutically acceptable salts, wherein A is a
straight-chain or branched-chain alkyl group with a maximum of 12 carbon atoms or one of the groups
F -H^ ^*- CH2-O-C0
F -H ^ ^ * - CH 2 -OC
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE15717/66A SE327987B (en) | 1966-11-16 | 1966-11-16 | |
| GB03687/67A GB1213162A (en) | 1966-11-16 | 1967-03-23 | Serum lipid lowering pyridine derivatives and their preparation |
| GB19174/67A GB1157186A (en) | 1966-11-16 | 1967-04-26 | Serum Lipid Lowering Pyridine Derivatives |
| DE1967A0057350 DE1670003B2 (en) | 1966-11-16 | 1967-11-13 | 3-HYDROXYMETHYL-5-FLUOROPYRIDINE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1795788A1 true DE1795788A1 (en) | 1975-07-31 |
Family
ID=27436557
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19671795791 Pending DE1795791A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE19671795789 Pending DE1795789A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE19671795790 Pending DE1795790A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE19671795788 Pending DE1795788A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19671795791 Pending DE1795791A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE19671795789 Pending DE1795789A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
| DE19671795790 Pending DE1795790A1 (en) | 1966-11-16 | 1967-11-13 | PYRIDINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
Country Status (1)
| Country | Link |
|---|---|
| DE (4) | DE1795791A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3042769A1 (en) * | 1980-11-13 | 1982-06-09 | Bayer Ag, 5090 Leverkusen | C-3 LINKED 1,4-DIHYDROPYRIDINE, THEIR USE IN MEDICINAL PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF |
-
1967
- 1967-11-13 DE DE19671795791 patent/DE1795791A1/en active Pending
- 1967-11-13 DE DE19671795789 patent/DE1795789A1/en active Pending
- 1967-11-13 DE DE19671795790 patent/DE1795790A1/en active Pending
- 1967-11-13 DE DE19671795788 patent/DE1795788A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE1795790A1 (en) | 1975-06-19 |
| DE1795789A1 (en) | 1975-07-31 |
| DE1795791A1 (en) | 1975-06-19 |
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