DE10320732A1 - Rapid-acting anesthetics with short duration of action, especially useful during surgical intervention, comprises thiazolo-(3,2-a)-(1,3)-diazepine-3-carboxylic acid derivatives - Google Patents

Abstract

New, rapid-acting anesthetics comprise 8-substituted 5,6,7,8-tetrahydro-thiazolo-(3,2-a)-(1,3)-diazepine-3-carboxylic acid derivatives (I), in dissolved in non-dissolved form. New, rapid-acting anesthetics comprise thiazolo-diazepines of formula (I) or their acid addition salts (specifically the hydrochloride, hydrobromide, phosphate, nitrate, acetate, maleate, succinate, fumarate, salicylate, sorbate, lactate, p-toluenesulfonate or naphthalene-1,5-disulfonate), in dissolved in non-dissolved form. [Image] R1, R3 - R6H, 1-7C alkyl, halo, substituted 1-4C haloalkyl, 1-4C alkoxy or 1-4C haloalkoxy; or aryl (e.g. phenyl or naphthyl) or heteroaryl (e.g. furyl, pyrrolyl, thienyl, imidazolyl, pyridinyl, pyridazinyl or pyrimidinyl), both optionally substituted and bonded directly or via N, S or a carbon bridge; R2H, Me, Et, propyl, isopropyl, butyl, substituted 1-10C alkyl, halo, optionally substituted amino or amide; X : O, S or NH (optionally reduced to hydroxy or mercapto functions); (I) optionally contains further substituents (such as halo, optionally substituted amino, 1-4C alkyl, 1-4C haloalkyl, 1-4C alkoxy, 1-4C haloalkoxy, alkylthio, alkylamino, aryl, heteroaryl, cycloalkyl, aryloxy, heteroaryloxy, arylthio or arylamino); and R3 + R4 or R4 + R5 may together complete an alicyclic, aryl or heteroaryl ring. An independent claim is also included for the preparation of (I). ACTIVITY : Anesthetic. In tests in mice, intraperitoneal administration of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo-(3,2-a)-(1,3)-diazepine-3-carboxylate (Ia) induced sleep in less than 1 minute and caused a sleeping time of 2.4 minutes at 100 mg/kg or 9.1 minutes at 200 mg/kg. (Ia) had LD50 681.4 mg/kg (Litchfield and Wilcoxon) in mice. MECHANISM OF ACTION : None given in the source material.

Description

The Invention relates to new active ingredients for rapid induction as well for maintenance and reinforcement from anesthesia, especially for surgical procedures and a method for their manufacture.

It is known for surgical operations to administer various drugs intravenously Ensure effects such as loss of consciousness, insensitivity to pain, Muscle relaxation and control of visceral reflexes. The usage of intravenous Active substances increased the flexibility and allows the reduction of doses of inhalation anesthetics.

Such intravenous anesthetics, according to the requirements of surgery, have been made available through the introduction by Thiopental, an ultra fast acting barbiturate. A general anesthesia becomes very common initiated by the injection of thiopental to produce sleep before the administration of other active ingredients that are required about anesthesia while of the surgical procedure. Thiopental sodium, other fast barbiturates and benzodiazepines play an important role Role in practical anesthesiology. Thiopental sodium is the standard for comparison with new anesthetic agents.

Barbiturates work in the entire central nervous system (CNS) and are able to produce all types of CNS damping; this ranges from mild sedation to general anesthesia. Barbiturates can also increase the inhibitory effect of the neurotransmitter GABA on the GABA _A receptors. The GABA _A receptor, which is the main type of GABA receptors in the brain, is a membrane-integrated chloride ion channel that controls the majority of the inhibitory neurotransmission in the CNS.

Intravenous single doses of thiopental sodium produce an unconsciousness within from 10 to 20 seconds. The depth of anesthesia usually increases up to 40 seconds and falls then until finally consciousness returns after about 20 to 30 minutes. In the event of greater Thiopental doses, however, require a recovery from this procedure several hours (Hughes et al in Anesthesiologiy 1992, 76, 334-341). thiopental is slowly metabolized in the liver. Along with other factors such as binding to plasma proteins, changes in pH in the blood or fluctuations in the blood flow this affects the depth of anesthesia, the recovery time and also the duration of the thiopental effect (Breimer, in Clin. Pharmacokinet. 1997, 2, 93-109).

thiopental Sodium becomes intravenous applied. It can be taken as a single dose (bolus), intermittent or be injected as a continuous infusion. Continuous infusions however increase the likelihood of overdoses with a correspondingly extended one Recovery period. For single or intermittent injections of thiopental sodium, the concentration should not be 2.5% in aqueous Exceed solution. With extravascular Injections with higher concentration than 2.5 can severe pain and necrotic changes occur. As a result an intra-arterial injection of concentrated thiopental solutions, the arterial endothelium is immediately destroyed in deeper layers, afterwards also endarterial vessels. in addition come thrombosis caused by arterial spasms. Vascular ischemia and even gangrene can the consequence (Marshall and Longnecker, in Goodmann and Gilman, the pharmacological basis of therapeutics, 1996, 321-323).

The anesthetic The effect of thiopental sodium is parallel to the concentration in the blood that reaches the CNS because of its high fat solubility of thiopental sodium penetration of the blood-brain barrier without noticeable delays allows. The termination of the anesthetic Effect takes place quickly, after about 5 minutes and is only through the redistribution of the drug in well-perfused tissue. After one rapid initial Waste falls the blood concentration slower over for several hours since the active ingredient is caused by body fat is absorbed and then metabolized. The result is that thiopental Sodium induces a long-lasting hangover. A total dose one should not exceed 1 g thiopental in general Avoid recovery times that are too long. The larger the initial loading dose of thiopental Sodium needs to be, the bigger it needs to be the subsequent doses should also be the same, even for patients Size. patients where big Initial doses of thiopental sodium are required of anesthesia wake up even though the plasma concentration still present should maintain a sleep phase. The cause of this acute Tolerance is not known (Marshall et al in Goodman and Gilman, the pharmacological basis of therapeutics 1996, 321-323). Out because of this, thiopental sodium cannot be used to treat a longer anesthesia It is only suitable as an initial anesthetic.

The Recovery phase after a thiopental administration should be characterized through a gentle and quick awakening from unconsciousness. However, if postoperative pain occurs, there may be severe restlessness enter and need analgesics be administered. However, thiopental and other barbiturates are very weak analgesics and can even sensitivity across from Increase pain. In addition, the recovery phase after a thiopental anesthesia is often accompanied by chills, there while the anesthetic is the body temperature is reduced and now return to a normal value got to. In addition, there is a drop in blood pressure, which is why the patients are to be moved carefully.

thiopental Sodium leads to a dose-dependent Depression of breathing, which can be severe. The minute volume can be significantly reduced, as can the functional breathing capacity, in particular if there is an urge to cough (Marshall et al., in A Practice of Anesthesia, Henly, D. and Cohen, P., eds. 1995, 119-145). Through increased doses of thiopental sodium can these effects increase, and breathing can only be maintained by moving the diaphragm become.

In make internal bleeding or other forms of hypovolumina, circulatory instability, sepsis, poisoning or shock may be the administration of normal doses to thiopental Sodium blood pressure drop, circulatory collapse and cardiac problems have as a consequence. The cerebral blood flow and the cerebral metabolism rate are under the influence of thiopental sodium and other barbiturates reduced. The intracerebral pressure is significantly reduced. This On the other hand, effect is used clinically in pathological situations, where an increased intracrineal pressure is expected (Shapiro, in Anesthesiology, 1975, 43, 445-471). Thiopental sodium has little effect on uterine contraction, but it's permeable to it the placenta and acts on the fetus.

benzodiazepines were introduced to treat anxiety, and a big one Number of derivatives with sedative anxiolytic, anticonvulsive and muscle relaxant properties were created. sleep and can pass out with big Doses of benzodiazepines are brought about. benzodiazepines are not analgesics, which, when used alone, are not Introduce anesthesia. It is necessary to combine several active ingredients to make one surgical required level of anesthesia to achieve, with a balanced interplay of sedation, Analgesia, amnesia, relaxation and absence of reflexes. As Sole active ingredients are useful in processes that involve benzodiazepines do not require analgesia, such as B. endoscopy, cardiac arrest, Cardiac catheterization and a range of radio diagnostic interventions (Marshall et al., In Goodman and Gilman, the pharmacological basics of therapeutics, 1996, 233-235).

Around an anesthesia bring about, become intravenous to benzodiazepines administered. This reduces uncomfortable burning and venous thrombosis avoided, which accompany the administration of diazepam can, Benzodiazepines should be running very slowly in a side arm intravenous Infusion. After the injection of diazepam, the In contrast to thiopental, active ingredient is rapidly distributed in the brain it takes several minutes before the consciousness begins to cloud. Therefore, diazepam becomes a in the sense of a pre-anesthetic medication Hour before the patient is brought into the operating room. In the usual Dosages used to maintain or maintain anesthesia bring about, cause the benzodiazepines to sedate, reduce anxiety and amnesia in at least half of all patients. This Amnesia can last up to six hours (Marshall et al., In Goodman and Gilman, the pharmacological basis of therapeutics 1996, 233-335). benzodiazepines cause only a moderate decrease in circulation and Breathing. higher Cans can a 20% drop in systemic blood pressure and vascular resistance cause. A temporary one Apnea can follow a rapid injection of diazepam and options ventilation should always be available. Causes diazepam no emesis does not prevent it and has little effect for renal, hepatic or reproductive functions. Although diazepam has caused relaxation of the centrally controlled muscles it has no effect on the neuromuscular system and neither amplifies it it still antagonizes the effects of specific muscle relaxants.

An essential molecular target for the benzodiazepines are the inhibitory neurotransmitter receptors, which are activated directly by the amino acid GABA. The predominant type of GABA receptors in the brain, called the GABA _A receptor, is an integral membrane-based chloride ion channel that controls the majority of the rapid inhibitory neurotransmission in the CNS. GABA _B receptors are not affected by benzodiazepine. The benzodiazepines bind directly to the receptor / ion channel complex and modulate its activity allosterically. In contrast to barbiturates, benzodiazepines do not directly influence the GABA _A receptors, but rather need GABA to develop their effect (Marshall et al., In Goodman and Gilmann, the pharmacological basis of therapeutics 1996, 233-235).

The The object of the invention is to create new active ingredients, Maintenance and reinforcement of anesthesia indicate which one is faster compared to known hypnotics onset and a shorter Show duration of action without developing an acute habit or significant To cause side effects, such as those in administration of thiopental sodium occur.

gefunden. R₁, R₃, R₄, R₅, R₆ in der Formel I repräsentieren unabhängig voneinander Wasserstoff, geradkettiges oder verzweigtes Alkyl mit ein bis sieben Kohlenstoffatomen, Halogen, substituiertes Haloalkyl, Alkoxy oder Haloalkoxy, in dem das Alkyl geradkettig oder verzweigt ist, mit ein bis vier Kohlenstoffatomen. Die Haloderivate können mono-, di-, tri- oder polyhalogeniert sein. Optionale Substituenten schließen ein Halogen, Amino, substituiertes Amino, Alkyl mit ein bis vier Kohlenstoffatomen, Halo-(C₁-C₄) Alkyl, Alkoxy oder Haloalkoxy mit ein bis vier Kohlenstoffatom in der Alkylgruppe.The thiazolo [3,2-a] [1,3] diazepine derivatives of the general formula I listed in claim 1 were surprising:

found. R ₁ , R ₃ , R ₄ , R ₅ , R ₆ in formula I independently represent hydrogen, straight-chain or branched alkyl having one to seven carbon atoms, halogen, substituted haloalkyl, alkoxy or haloalkoxy in which the alkyl is straight-chain or branched , with one to four carbon atoms. The halo derivatives can be mono-, di-, tri- or polyhalogenated. Optional substituents include halogen, amino, substituted amino, alkyl of one to four carbon atoms, halo (C ₁ -C ₄ ) alkyl, alkoxy or haloalkoxy having one to four carbon atoms in the alkyl group.

R ₁ , R ₃ , R ₄ , R ₅ and R ₆ in formula I additionally independently represent aryl, substituted aryl, heteroaryl, substituted heteroaryl, directly attached or attached via NH, S or a carbon bridge, such as. B. carbocyclic aromatics including phenyl, naphthyl, heterocyclic groups including furyl, pyrrolyl, thienyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl groups. Optional substituents on these groups include halogen such as chlorine, bromine and fluorine, C ₁ -C ₅ linear or branched alkyl chains such as e.g. As methyl, ethyl, propyl, isopropyl, alkoxy with one to three carbon atoms, such as. B. methoxy and ethoxy or haloalkoxy having one to three carbon atoms; Alkylthio, alkylamino, arylthio, heteroarylthio, arylamino, heteroarylthio, arylamino, heteroarylamino.
R ₂ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or substituted straight-chain or branched alkyl having up to ten carbon atoms, or halogen, amino or substituted amino, including corresponding amides. Optional substituents include: alkyls, cycloalkyl, aryl or heteroaryl groups.
R ₃ can also form substituted alicyclic rings, aryl or heteroaryl ring systems together with R ₄ . R ₄ can also form substituted alicyclic rings, aryl or heteroaryl ring systems together with R ₅ . X in formula I is oxygen, sulfur or NH, optionally also reduced to hydroxyl or mercapto functions. These hydroxy or mercapto functions can be alkylated with R ₆ , which represents straight-chain or branched alkyl groups with one to seven carbon atoms, or arylated with carbocyclic aromatics, such as, for example, B. substituted phenyl and naphthyl, heterocyclic groups including, for example, substituted furyl, pyrrolyl, thinyl imidazolyl, pyridinyl, pyridazinyl and pyrimidinyl.

The compounds of the invention can also present as salts. The acids, with which said compounds can form such salts preferably hydrohalic acids, such as B. hydrochloric acid and hydrobromic acid, Phosphoric acid, Nitric acid, monofunctional and bifunctional carboxylic acids, hydroxycarboxylic acids, such as z. B. acetic acid, maleic acid, Succinic acid, fumaric acid, Tartaric acid, Salicylic acid, sorbic acid, lactic acid, sulfonic acids, such as para-toluene sulfonic acid, and naphthalene-1,5-disulfonic acid.

The under claims contain further advantageous embodiments of the invention and possibilities to make the connections.

The proposed new thiazolo [3,2-a] [1,3] diazepine derivatives overcome many of the disadvantages and problems mentioned at the outset, which are usually associated with the administration of thiopental sodium or benzodiazepines as intravenous anesthetic active substances, and are intravenous Anesthetics are those that not only produce anesthesia, but can also maintain anesthesia, especially during a surgical procedure. Compared to thiopental sodium, the compounds according to the invention show a very rapid onset of action and a shorter duration of action. You develop in the process no acute habituation and show no significant side effects, such as those that occur with the administration of thiopental sodium.

dargestellt nach an sich bekannten Methoden, publiziert durch R. Kuhn et al. in Ann. Chem. 1951, 571, 44–56 und B. Plouvier et al in J. Heterocyclic Chem. 1989, 26, 1643–51.In principle, thiazolo [3,2-a] [1,3] diazepine compounds are readily available and could be obtained (see figure) using methods described by P. Molina et al (J. Org. Chem. 1993, 58, 5264-5270) and P. Imming (Arch. Pharm., Weinheim, 1995, 238, 207-215). To prepare the compounds according to the invention according to general formula I, 2-amino-5-substituted thiazole-4-carboxylates of general formula II

represented by known methods, published by R. Kuhn et al. in Ann. Chem. 1951, 571, 44-56 and B. Plouvier et al in J. Heterocyclic Chem. 1989, 26, 1643-51.

bei denen Y für Brom oder Chlor steht, vorzugsweise Brom und wasserfreies Kaliumcarbonat, in einem geeigneten Lösungsmittel, wie beispielsweise Toluol, Ethylbenzol, o-, m-, und p-Xylol, Oktan, Nonan und Isopropylbenzol, vorzugsweise Toluol und Ethylbenzol, bei Temperaturen zwischen 100°C und 150°C, vorzugsweise zwischen 100°C und 120°C, acyliert.The compounds of formula II were with suitable acid chloride derivatives of formula III

where Y is bromine or chlorine, preferably bromine and anhydrous potassium carbonate, in a suitable solvent such as toluene, ethylbenzene, o-, m-, and p-xylene, octane, nonane and isopropylbenzene, preferably toluene and ethylbenzene, at temperatures between 100 ° C and 150 ° C, preferably between 100 ° C and 120 ° C, acylated.

die durch Chromatographie über Kieselgel oder neutrales Aluminiumoxid gereinigt werden können, werden zyklisiert mit sekundären Aminen, wie z. B. Diethylamin, Pyrrolidin, Morpholin, Piperidin, N-Methylpiperazin, vorzugsweise Pyrrolidin und Piperidin, in einem geeigneten Lösungsmittel, wie z. B. Toluol, Ethylbenzol, o-, m-, und p-Xylol, Isopropylbenzol, vorzugsweise Toluol, o-Xylol, bei Temperaturen zwischen 100°C und 180°C, vorzugsweise zwischen 120°C und 130°C.The resulting products of the general formula IV

which can be purified by chromatography on silica gel or neutral aluminum oxide, are cyclized with secondary amines, such as. B. diethylamine, pyrrolidine, morpholine, piperidine, N-methylpiperazine, preferably pyrrolidine and piperidine, in a suitable solvent, such as. B. toluene, ethylbenzene, o-, m-, and p-xylene, isopropylbenzene, preferably toluene, o-xylene, at temperatures between 100 ° C and 180 ° C, preferably between 120 ° C and 130 ° C.

welche wiederum durch Chromatographie über Kieselgel oder neutrales Aluminiumoxid gereinigt werden können.Products of the general formula V are produced

which in turn can be purified by chromatography on silica gel or neutral aluminum oxide NEN.

umgesetzt, welche dann direkt zur Umsetzung gebracht wurden mit R₆-XH und wasserfreien Kaliumcarbonat in einem geeigneten Lösungsmittel wie z.B. Aceton, Ethanol, Methylethylketon, Dimethylformamid, Dimethylsulfoxid, Diphenyläther, vorzugsweise Methylethylketon, Dimethylformamid bei Temperaturen zwischen 60°C und 200°C, vorzugsweise zwischen 120°C und 160°C. Die entstehenden erfindungsgemäßen Verbindungen der allgemeinen Formel I können ebenfalls gereinigt werden durch Chromatographie über Kieselgel und neutralem Aluminiumoxid.The compounds of the formula V were converted to 8-chloro analogs of the general formula VI using phosphorus oxytrichloride

implemented, which were then directly reacted with R ₆ -XH and anhydrous potassium carbonate in a suitable solvent such as acetone, ethanol, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, diphenyl ether, preferably methyl ethyl ketone, dimethylformamide at temperatures between 60 ° C and 200 ° C, preferably between 120 ° C and 160 ° C. The resulting compounds of general formula I according to the invention can also be purified by chromatography on silica gel and neutral aluminum oxide.

Representative possibilities for such Syntheses are described in Examples 1 and 2.

The The invention will be explained in more detail below with the aid of examples.

Mice both Gender (22-28 g) were used to evaluate the ultra-fast acting hypnotic activity perform. The mice were caged kept at temperatures of 20 ± 2 ° C with a day-night cycle of 12 hours and fed with standard food and water ad libitum. The connections of the Formula I have been solved with 15% Cremophor EL (a derivative of castor oil and ethylene oxide, Sigma Chemical Co) in distilled water. The hypnotic activity was then examined for intravenous (iv) and after intraperitoneal (ip) administration. Two doses the compound, according to formula I (50 and 100 mg / kg) intravenous injected into two groups of mice. Each group consisted of ten mice. Sleep time was recorded for each mouse and compared with the sleep times of a control group. The effect of the connection with formula I for intravenous Gift additionally thiopental sodium (Intraval sod. May & Baker LTD, England) was also used evaluated. Three groups of mice, each consisting of ten animals was used. The first Group (control group) was the solvent with 15% cremophore EL injected, the second group was at 50 mg / kg and the third Group treated with 100 mg / kg of the compound according to formula I. All mice 50 mg / kg of thiopental sodium were then administered intravenously in the three groups. The elapsed time between loss and reentry of the "righting reflexes "(sleep time) was for each animal recorded and compared to the control group. Representative for that is Example 3.

Two Dosages of the compound according to formula I (100 and 200 mg / kg) were injected intraperitoneally in two groups of mice. Both Groups consisted of ten animals. The sleep time was for everyone Animal registered and compared to the control group, the one got ultra-fast hypnotic. The effect of the connection accordingly Formula I for intraperitoneal administration as an additive to the sleep time induced by thiopental sodium (Intraval sod. May & Baker LTD, England) was also evaluated.

Three Groups of mice, consisting of 10 animals each, were used. The first group (Control group) was treated by injection with the solvent "15% Cremophor EL", the second group was treated with 100 mg / kg and the third group treated with 200 mg / kg of Compound according to Formula I. All mice in the three groups were then 65 mg / kg thiopental sodium injected intraperitoneally (Dandiya and Cullumbine, in J. Pharmacol. Exp. Ther. 1959, 125, 353-359). The Sleep time was for each animal recorded and compared to the control group. Representative is example 4.

Five groups of mice, each consisting of ten animals, were used to determine acute toxicity and to calculate LD ₅₀ values. The compound, corresponding to formula I, was dissolved in 15% Cremophore EL and administered intraperitoneally in doses of 100, 200, 400, 800 and 1,600 mg / kg. The final volume of injections in all groups did not exceed 0.2 ml / mouse. Twenty-four hours later, the percent mortality of each group was recorded and the LD ₅₀ values calculated using the method described by Litchfield and Wilcoxon in J. Pharmacol. Exp. Ther. 1949, 96.99. Example 5 is representative.

Ten mice were used to conduct an acute tolerance experiment. each Mouse received 200 mg / kg of the compound according to formula I, dissolved in 15% cremophore, intraperitoneally, three times a day for three consecutive days. After each of the nine administrations, the sleep time induced by compound according to Formula I was recorded for each mouse. Example 6 is representative.

The biological evaluation of the new compounds according to formula I of the invention showed that the compounds act very quickly Represent hypnotics. These compounds start to work very quickly compared to thiopental. With all used Animals responded in less than 60 seconds, some of them Animals even before the injection needle was removed from the animal. The duration of action with intravenous or intraperitoneal application is significantly shorter, compared with the standard anesthetic Thiopental sodium. additionally the compounds according to formula I showed no signs an acute tolerance like that about multiple dosing of thiopental sodium is reported. Therefore the compounds corresponding to formula I of the invention have that Potential not only for pre-anesthetic Medication and to initiate anesthesia but also the potential together with thiopental sodium to maintain anesthesia over one longer Period to be used, better than thiopental sodium alone.

The Compounds corresponding to formula I of the invention and their salts show with different acids an ultra-fast hypnotic activity. The invention presented includes pharmaceutical formulations, along with non-toxic pharmaceutically acceptable ingredients, one or more compounds contained according to the present invention or from one or more such compounds according to the invention exist, as well as processes for the presentation of these formulations.

The Invention closes also pharmaceutical formulations in different dosage units. This means that formulations are available in individual pieces, e.g. B. tablets, coated tablets, capsules, pills and ampoules, in which the Active compound content in part or in multiples corresponds to the individual dose. For example, the dosage unit 1, 2, 3 or 4 individual cans or 1/2, 1/3 or 1/4 of an individual Dose included. An individual dose preferably contains the amount of active Compound which is administered in one administration of the whole, half, the Third or quarter of a daily Dosage corresponds.

Under are non-toxic, inert pharmaceutically suitable additives to understand solid, semi-solid or liquid diluents, fillers and auxiliaries of all kinds.

tablets, Dragees, capsules, pills, granules, solutions and sprays are said to be preferred pharmaceutical formulations may be mentioned.

• – Füllstoffe, wie Stärke, Lactose, Sucrose, Glucose, Mannitol und Siliciumdioxid,
• – Bindestoffe, wie Carboxymethylcellulose, Alginate, Gelatine und Polyvinylpyrrolidone,
• – Feuchtmittel, wie Agar-agar, Calciumcarbonat und Natriumhydrogencarbonat,
• – die Löslichkeit beeinflussende Stoffe, wie Paraffin,
• – Resorptionsbeschleuniger, wie quartäre Ammoniumsalze,
• – Feuchthaltemittel, wie Cetylalkohol und Glycerolmonostearat,
• – Absorbtionsmittel, wie Kaolin und Bentonit,
• – Feuchthaltemittel, wie Talkum, Calciumstearat, Magnesiumstearat und festes Polyethylenglycol,
• – verträglichkeitsteigernde Zusätze
• – Zusätze zur gezielten Wirkstoff-Freigabe, beispilesweise für eine Freigabeverzögerung, z. B. durch An- oder Einbindung an bzw. in polymere Substanzen und Wachse,

oder Mischungen daraus.The tablets, dragees, capsules and pills can contain the active compound or compounds together with the usual ingredients, for example

• Fillers such as starch, lactose, sucrose, glucose, mannitol and silicon dioxide,
• Binders such as carboxymethyl cellulose, alginates, gelatin and polyvinylpyrrolidones,
• - dampening solutions such as agar-agar, calcium carbonate and sodium hydrogen carbonate,
• Substances influencing solubility, such as paraffin,
• Absorption accelerators, such as quaternary ammonium salts,
• Humectants, such as cetyl alcohol and glycerol monostearate,
• Absorbents, such as kaolin and bentonite,
• Humectants, such as talc, calcium stearate, magnesium stearate and solid polyethylene glycol,
• - tolerance-enhancing additives
• - Additives for targeted release of active ingredients, for example for a release delay, e.g. B. by attachment to or integration into or in polymeric substances and waxes,

or mixtures thereof.

The Tablets, dragees, capsules and pills can be coated and known per se Coatings and optionally with compatibility-increasing additives his.

she can also be such that they target the active connections release, for example in certain areas of the intestinal tract, and / or also in a delayed Way, e.g. B. also by connection and penetration to or in polymeric substances and waxes.

The active connection or the active connections, optionally together with one or more of the additives mentioned above can also in the form of microcapsules known per se.

In addition to One or more active compounds according to the invention can be solutions and emulsions for the parenteral administration usually still contain additives, such as solvents, solubilizers and emulsifying agents, e.g. B. water, ethyl alcohol, isopropyl alcohol, Diethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, caster oil and sesame oil, glycerin, Formaldehyde, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol or mixtures of these substances in sterile form, which is isotonic with blood.

The Therapeutically active compounds should preferably be found in the above mentioned pharmaceutical formulations occur in concentrations between 0.1 and 99.5, preferably approximately 0.5 to 95 percent by weight of the total mixture.

The mentioned above Pharmaceutical formulations can also contain other pharmaceutical formulations Contain formulations, also other pharmaceutically active Compounds of the invention.

The mentioned above pharmaceutical formulations are prepared in the usual way according to known methods, e.g. B. by mixing the active Compounds or active compounds with the additive or the additives. The invention also includes the use of the active connection or active connections according to the Invention, as well as pharmaceutical formulations, the one or contain several active compounds of formula I, in or as anesthetic Drug.

The dose used is determined by generally recognized factors, like body weight of the patient and / or severity or type of pathological situation of the patient. From these points of view, the dosage can for one certain patients are determined by the medical therapist in accordance with the practices known from the medical healing arts. The exact instructions for pharmaceutical administration of the compounds and active ingredients according to the invention necessarily depend on the Requirements of the individual case, the type of treatment and of course also depends on the diagnosis of the attending doctor.

It seems understandable that various modifications and modifications by skilled people of the invention as described can be made without with it outside of the mind and the scope of this sensation. insofar the scope of protection is also not based on the following examples for explanation limited the invention.

Example 1:

Ethyl 2- [4-chlorobutanamido] thiazole-4-carboxylate:

A mixture of ethyl 2-aminothiazole-4-carboxylate (7.0 g, 0.04 mol) and 4-chlorobutyrylchloride (11.3 g, 9.0 ml, 0.08 mol) in toluene (100 ml) is heated to boiling under reflux for four hours. The toluene is removed under reduced pressure. Water is added to the residue with stirring and the solid is filtered off. It is washed, dried and recrystallized from water to give the stated product (10.2 g, 92% yield), mp. 171 ° C., m / e 276.6 (in accordance with the empirical formula C ₁₀ H ₁₃ ClN ₂ O ₃ S, calc. 276.73 ). ¹ H NMR and ¹³ C NMR (Table 1).

Table 1: ¹ H NMR and ¹³ C NMR assignment of ethyl 2- [4-chlorobutanamido] thiazole-4-carboxylate

Example 2:

Ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] [1,3] diazepine-3-carboxylate:

A mixture of ethyl 2- [4-chlorobutanamido] thiazole-4-carboxylate (1.0 g, 0.004 mol) and piperidine (0.7 g, 0.8 ml, 0.008 mol) in toluene (50 ml) is boiled under reflux for 3 hours heated. The reaction mixture is cooled, poured into water and stirred. The toluene phase is separated off, dried and evaporated. The remaining crude product is purified by repeated chromatography on silica gel and neutral aluminum oxide, elution with EtOAc / hexane (50:50 v / v) and CHCl ₃ / hexane (80:20 v / v). Mp 210 ° C, m / e 240.2 (according to the empirical formula C ₁₀ H ₁₂ SN ₂ O ₃ , calc. 240.28). ¹ H NMR and ¹³ C NMR (Table 2).

Table 2: ¹ H NMR and ¹³ CNMR assignments of ethyl 8-oxo-5,6,7,8-tetrahydrothiazolo [3,2-a] [1,3] diazepine-3-carboxylate

The NMR data of the compounds from Examples 1 and 2 are in the Tables 1 and 2 listed. The assignments were also saved by APT, DEPT, COZY and HMQC recording technology for everyone Connection.

Example 3:

The intravenous Administration of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] - [1,3] diazepine-3-carboxylate (Example 2), 50 and 100 mg / kg, leads to sleep in all mice within a few seconds (Table 3). Accelerated breathing was seen at three out of ten mice, treated with 100 mg / kg observed. Shortness of breath was observed in one in ten mice, also treated with 100 mg / kg. Both dosages of the compound 50 and 100 mg / kg strongly potentiated the hypnotic effect by 50 mg / kg intravenously administered thiopental sodium is generated (Table 3).

Table 3: Hypnotic effect of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] - [1,3] diazepine-3-carboxylate (Example 2), 50 and 100 mg / kg intravenously (iv) and the effect of these doses on the sleeping time, brought about by an iv application of 50 mg / kg thiopental sodium in mice

Table 4: Hypnotic effect of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] - [1,3] diazepine-3-carboxylate (Example 2), 100 and 200 mg / kg intraperitoneally (ip), and the effect of these doses on the sleep time of mice, treated intraperitoneally with 65 mg / kg thiopental sodium

Example 4:

intraperitoneal (ip) Administration of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] - [1,3] diazepine-3-carboxylate (Example 2), 100 and 200 mg / kg, leads to sleep in all mice an onset of sleep after less than 1 minute (table 4). Tachypnea was seen in two out of ten mice, at a dose of 100 mg / kg were observed, confusion and accelerated breathing were observed also observed in three out of ten mice treated with 200 mg / kg. Dosages of compound 100 and 200 mg / kg potentiated significantly the hypnotic effect produced by 65 mg / kg, intrapritoneal, Thiopental sodium (Table 4).

Example 5:

acute Toxicity tests have been performed by the method described by Litchfield and Wilcoxon, J. Pharmacol. Exp. Ther. 1949, 96: 99.

The calculated LD ₅₀ value of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] - [1,3] diazepine-3-carboxylate (Example 2) was determined with 681.4 mg / kg found the 95% confidence limits at 482.8–876.4.

Example 6:

Testing Acute tolerance was performed after the intraperitoneal Administration of 200 mg / kg ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo [3,2-a] - [1,3] diazepine-3-carboxylate (Example 2), 3 times a day three consecutive days. There were no significant ones Differences between sleep times after the first and ninth (last) administration of the compound. The sleep time after the First administration of the compound was 10.3 ± 1.4 minutes, after the ninth Administration 8.7 ± 2.1 Minutes.

Claims (19)

New fast-acting anesthetics for inducing, maintaining and intensifying anesthesia, in particular for surgical interventions, containing in dissolved or undissolved form at least one thiazolo- [3,2-a] [1,3] diazepine derivative of the general formula I:

where - R ₁ , R ₃ , R ₄ , R ₅ , R ₆ independently of one another are hydrogen, straight-chain or branched alkyl having one to seven carbon atoms, halogen, substituted haloalkyl, alkoxy or haloalkoxy in which the alkyl is straight-chain or branched represent up to four carbon atoms, and independently of one another aryl, substituted aryl, heteroaryl, substituted heteroaryl, directly attached or attached via NH, S or a carbon bridge, such as. B. carbocyclic aromatics, including phenyl, naphthyl, heterocyclic groups, including furyl, pyrrolyl, thienyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl groups, may be - R _{2 is} hydrogen, methyl, ethyl, propyl, isopropyl, butyl or a substituted straight chain or branched alkyl group with up to ten carbon atoms, or halogen, amino, substituted amino or an amide and - X can be oxygen, sulfur, NH or optionally reduced to hydroxyl or mercapto functions. New fast-acting anesthetics according to claim 1, characterized in that halo derivatives used as radicals R ₁ , R ₃ , R ₄ , R ₅ , R ₆ are independently mono-, di-, tri- or polyhalogenated. New fast-acting anesthetics according to claim 1, characterized in that the at least one thiazolo- [3,2-a] [1,3] diazepine derivative of the general formula I contains additional substituents, such as halogen, amino, substituted amino, alkyl to four carbon atoms, haloalkyl (C ₁ to C ₄ ), haloalkyl, alkoxy or haloalkoxy having one to four carbon atoms in the alkyl group, alkylthio, alkylamino, aryl, heteroaryl, cycloalkyl, aryloxy, haloaryloxy, arylthio, arylamino. New fast-acting anesthetics according to claim 1, characterized in that the radicals R ₃ and R _{4 form} substituted alicycles, aryl or heteroaryl rings. New fast-acting anesthetics according to claim 1, characterized in that the radicals R ₄ and R _{5 form} substituted alicyclic aryl or heteroaryl ring systems. New fast-acting anesthetics according to claim 1, characterized in that the hydroxy or mercapto functions of X are alkylated with the radical R ₆ , which is straight-chain or branched alkyl having one to seven carbon atoms, an alicyclic radical, an aryl or a heteroaryl radical can represent. New fast-acting anesthetics according to claim 1, characterized in that the at least one thiazolo- [3,2-a] [1,3] diazepine derivative of general formula I is represented by one or more salts, which with acids, preferably hydrohalic acids, are formed, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, mono- or bifunctional carboxylic acids, hydroxy, such as B. acetic acid, maleic acid, Succinic acid, fumaric acid, Tartaric acid, salicylic acid, sorbic acid, Lactic acid, sulfonic acids, such as para-toluenesulfonic acid, and naphthalene-1,5-disulfonic acid. New fast-acting anesthetics according to claim 1, characterized in that the at least one thiazolo- [3,2-a] [1,3] diazepine derivative of the general formula I in a pharmaceutical formulation as intravenous Active ingredient to be administered, for example in the form of a solution or as to be solved Granules. New fast-acting anesthetics according to claim 1, characterized in that the at least one thiazolo- [3,2-a] [1,3] diazepine derivative of the general formula I in a pharmaceutical formulation as an active ingredient to be administered orally or rectally, for example in the form of tablets, coated tablets, capsules, pills or suppositories, is present. New fast-acting anesthetics according to claim 9, characterized in that the tablets, dragees, capsules or pills other additives included, e.g. B. - fillers, like strength, Lactose, sucrose, glucose, mannitol and silicon dioxide, - binding agents, such as carboxymethyl cellulose, alginates, gelatin and polyvinyl pyrrolidones, - dampening solution, such as agar-agar, calcium carbonate and sodium hydrogen carbonate, - the solubility influencing substances, such as paraffin, - absorption accelerator, like quaternaries Ammonium salts, - humectant, such as cetyl alcohol and glycerol monostearate, Absorbents, such as kaolin and bentonite, - humectant, such as talc, calcium stearate, magnesium stearate and solid polyethylene glycol, - tolerance increasing additions - Additions to targeted drug release, for example for a delay in release, z. B. by attachment or integration into or in polymeric substances and waxes, or mixtures thereof. New fast-acting anesthetics according to claim 9, characterized in that the tablets, dragees, capsules or pills known coatings and coatings exhibit. New fast-acting anesthetics according to claims 8 and 9, characterized in that in the pharmaceutical formulation additionally known solutions or emulsions for parenteral drug delivery is included. New fast-acting anesthetics according to claims 8 and 9, characterized in that in the pharmaceutical formulation Additives, such as solvents, solubilizers and emulsifying agents, e.g. B. water, ethyl alcohol, isopropyl alcohol, Diethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, caster oil and sesame oil, glycerin, Formaldehyde, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol, or mixtures of these are included. New fast-acting anesthetics according to claims 8 and 9, characterized in that the at least one thiazolo [3,2-a] [1,3] diazepine derivative of the general formula I in the pharmaceutical formulation in a concentration between 0.1 and 99.5 percent by weight, preferred between 0.5 and 95 percent by weight. New fast-acting anesthetics according to claims 8 and 9, characterized in that the at least one thiazolo [3,2-a] [1,3] diazepine derivative of the general formula I in the pharmaceutical formulation in a dosage is available, which of the usual or individual required dose for the drug application corresponds. New fast-acting anesthetics according to claims 8 and 9, characterized in that the at least one thiazolo- [3,2-a] [1.3] diazepine derivative of the general formula I in the pharmaceutical formulation in a dosage is present which is a multiple, for example two to four times the usual or individual required dose for the drug application corresponds. New fast-acting anesthetics according to claims 8 and 9, characterized in that the at least one thiazolo [3,2-a] [1,3] diazepine derivative of the general formula I in the pharmaceutical formulation in a dosage is present, which is only a portion, for example half to a quarter, the most common or individually required dose for the drug application equivalent. Process for the preparation of the new fast-acting anesthetics according to one or more of the preceding claims, characterized in that - known 2-amino-5-substituted thiazole-4-carboxylates of the general formula II

with suitable acid chloride derivatives of the general formula III

where Y is bromine or chlorine, preferably bromine and anhydrous potassium carbonate, in a suitable solvent such as toluene, ethylbenzene, o-, m-, and p-xylene, octane, nonane and isopropylbenzene, preferably toluene and ethylbenzene, at temperatures between 100 ° C and 150 ° C, preferably between 100 ° C and 120 ° C, - that the resulting compounds of the general formula IV

at temperatures between 100 ° C and 180 ° C, preferably between 120 ° C and 130 ° C, in a suitable solvent such as. B. toluene, ethylbenzene, o-, m-, and p-xylene, isopropylbenzene, preferably toluene, o-xylene, are cyclized with secondary amines, such as. B. Diethylamine, pyrrolidine, morpholine, piperidine, N-methylpiperazine, preferably pyrrolidine and piperidine, - that the compounds of the general formula V formed by the cyclization

with phosphorus oxychloride to give compounds of general formula VI

react - and that the compounds of general formula VI with R ₆ -XH and anhydrous potassium carbonate in one suitable solvents such as. B. acetone, ethanol, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, diphenyl ether, preferably methyl ethyl ketone or dimethylformamide, at temperatures between 60 ° C and 200 ° C, preferably 120 ° C and 160 ° C, are implemented. A method according to claim 8, characterized in that the resulting intermediates (compounds of general Formulas IV and V) and the resulting end product (thiazolo- [3,2-a] [1,3] diazepine derivative of general formula I) in each case by chromatography on silica gel or neutral aluminum oxide.