DE19618970A1 - New thiazolopyridines - Google Patents

Abstract

The invention relates to new thiazolopyridine compounds according to formula (I), methods for their production, intermediates and medicaments with an amount of these compounds as well as their use in the therapy of various illnesses, especially asthmatic illnesses including obstructive bronchial as well as lung illnesses. The new compounds distinguish themselves by particular substitution of the amide components while possessing valuable pharmaceutical properties.

Description

The invention relates to novel thiazolopyridine compounds, Process for their preparation, intermediates, drugs containing a content of these compounds and their Use in the therapy of various diseases, in particular asthmatic diseases, including obstructive bronchial and lung diseases. The Er The invention is characterized in detail in the claims.

Technical background

Diseases of the airways spread to the western Industrialized countries increasingly. About 5% of Be Populations in western countries suffer from asthma bronchial, with the incidence in children about two to three times as high as adults. This, in the more widespread, serious illness leads to a increasing number of deaths. Symptoms asthmatic In particular, severe states are characterized by a bronchospasm Mus, a mucous membrane and disorders of glandular secretion with tough and excessively secreted mucus (hypercrine and dyscrinia) with increased bronchial hyperlipeness reactivity. The asthma is with a disturbed  Homeostasis of various mediators, such. B. of u. a. hi stamin, leukotrienes or prostaglandins. With the Bronchial asthma disease is generally also an Ent accompanied by firing events. The previously known anti-asthma tika provide either specific, highly selective media tor antagonists or selectively effective β-adrenergic drugs ka with a relatively high bronchodilatory β₂ effect and lower cardiostimulating β₁ effect, such. B. the Metaproterenol. Besides these for the relaxation of the smooth This also includes bronchial muscle leading substances Theophylline, however, in contrast to the former bronchodilator drugs by another me mechanism works. This commonly prescribed drug will not only in the acute attack, but also in the Langzeitbe action, although the potency of this drug is very low.

As an inhibitor of the release of mediators is the Disodium chromoglycate or chromoglycic acid known, which reduces bronchial hyperresponsiveness. Under The anticholinergic substances are in some cases the Atropine or its derivatives ipratropium and oxitropium used.

As substances with a diverse mechanism of action, for example, both in terms of increased β₂-Re zeptorsynthese as well as an inhibition of leukotriene A series of corticosteroids are applied. Apart from that, these hormonal substances are not direct exert broncholytic action, this Verbindungsgrup has pe a number of serious unwanted by-products kungen, such. B. Disorders of carbohydrate, protein as well as the fat metabolism, the electrolyte and water balance (Edema), the endocrine system, z. B. in the form diabe togeneric effects or adrenal insufficiency, Er increase in intraocular pressure, etc. result.  

Although the findings in pathophysiology and Ent Staging mechanisms of bronchial asthma in recent Years have made significant progress, the previous therapeutic success in the treatment of the asthmatic group of forms is not particularly satisfactory quietly.

It has become especially clear that the asthmatic Illnesses is based on a very complex event, of which essential mechanisms in their meaning, such as z. B. the above-mentioned effect of mediators, he were known.

The known to date, in the treatment of asthma bronchiale applied drugs let in particular the Half to be desired, because they either no direct unfold broncholytic action, such as. B. the above discu glucocorticoids or the nedocromil and ketotifen or substances that do not bronchial hyperreactivity mitigate, such. B. β₂-sympathomimetics in the form of isoprote renols or the above metaproterenol.

So far no active substance could be found, for which not at least one of these restrictions would apply.

From JP-A-63 017881 are already thiazolopyridines in addition Benzothiazolinones known with a piperidine group substituted and amide derivatives of oxothiazolopyridyl carboxylic acids with simple amino, hydroxy and ketopiperi represent dinen, wherein the amino group is unsubstituted is. These compounds become a platelet aggregate tion inhibiting effect attributed. A usefulness this in the two aforementioned publications be written compounds for the treatment of asthmatic Zu stalls is not revealed.  

It is also known that some 2-oxothiazolo [5,4-b] pyri dine have useful pharmacological properties. So become in the JP 59-130890 1,2-dihydro-2-oxo-thiazolopyri dicarboxylic acids, their esters and nitriles described the antipyretic, anti-inflammatory and analgesic egg characteristics. The same effects are disclosed in JP-A-59-095290 in comparison to the above prior art in a simpler way substituted piperidids and piper attributed to acids of these carboxylic acids.

Piperazides and homopiperazides of the same oxothiazolopyri din-carboxylic acids attached to the second nitrogen atom of the (homo) -pipera zinringes are substituted in a specific way, are described in EP-A-0 296 455 as substances with antithromboti rule, inflammatory and platelet aggregation-inhibiting so as analgesic properties revealed.

From EP-A-232 740 which structurally closest The prior art forms are already piperazine substances tuierte Thiazolopyridine and Benzothiazolverbindungen be which, in addition to an antianaphylactic effect also analgesic, antiarthritic and platelet aggregates attributable to onsinhibierende activities. The more number of piperazine-substituted ones exemplified therein Compounds, however, may continue on the piperazine ring be substituted by an NO group, which, however, those in the The known risk of carcinogenic effects so that their use is generally discouraged is. The toxicity of N-nitroso compounds is lost for example from E. Mutschler: Arzneimittelwir Kungen, Stuttgart (1991), pages 731-732.

In addition, a smaller scope can be found in EP-A-232 740 did not disclose derivatives on the piperazine ring bear substituted amino group. This kind of Substitu  tion causes a hydrazine function. There are a number of Hydrazine derivatives known themselves and largely even after their metabolism highly effective cytotoxic drugs represent the potent cytotoxins with mitosis-inhibiting and Chromatin break-causing activities are (see P.T. Ammon, drug side effects and interactions, Stuttgart, (1986), page 942). In this connection he would still be too believe that hydrazine itself causes lung-damaging effects so that generally in such derivatives, esp of long-term therapies, there are strong concerns.

The use of these derivatives with a hydrazine or Ni Trosofunktion can exert a damaging influence, so that from the drug therapeutic point of view the application derar tiger drugs with potentially toxic functional Groups in long-term therapy, especially of chroni serious illnesses. At the Arz Therapy of chronic diseases should therefore only such substances are administered, the toxicologically unbe are thoughtful.

It was therefore the task, for example, at least in toxicologically improved new thiazolopyridine to create derivatives.

The solution to this problem is the provision of Compounds containing cyclic amide derivatives of 1,2-dihydro-2- oxothiazolopyridylcarboxylic acids of the following general Formula (I)

represent their substituents below in detail are characterized.

It has succeeded in an unexpected way, by the novel according to the invention, defined below mono- or disub Constitution of the Terminal Amino Component

to largely eliminate the risk of toxic side effects and in contrast to the structurally closest ones Substances with a non-substituted amino group in direk Bonding to nitrogen completely new, completely different pharmacological activities, in particular in the form of di direct bronchodilatory and mediator-inhibiting effect to achieve.

It has surprisingly been found that the Invention suitable substances for the treatment of bronchial asthma are net and even with long-term administration, a high Ver show endurance as well as in as many places as possible Theological events due to asthmatic condition the, in particular the bronchoconstriction and mediatorbe dingten disturbances, therapeutically intervene. Favorable wise, there is the risk of serious side effects the previously known, structurally similar active ingredients, the z. B. as platelet aggregation inhibitors or analgesics be used largely off. The invention proper connections with the new medical indicator Therefore, they are harmless from a toxicological point of view. This is surprising insofar as the known struktu closely related substances with a free amino group, such as described at the beginning, a very different range of activity  possess their known activity on the analgesic, anti-inflammatory, antithrombo or platelet aggregation-inhibiting effects without Suitability for the treatment of asthmatic conditions is limited. In other words, the structurally new he inventive substances are not only in terms of their toxicological safety, but also with regard to on their new pharmacological effects as a basis for the medical indications mentioned benefit. This is therefore in many ways as a result of over to designate surprising inventive activity.

The special feature of the variety of effects of the new substances lies mainly in the inhibition following processes: the bronchial hyperreactivity, the extravasation of blood eggs white, from bronchospasm, which mediated by mediator release immunocompetent cells induced by free formation of neuropeptides from the C fibers (eNANC) indu and bronchoconstriction induced by PAF Bronchoconstriction, at the same time a direct bron chospasmolytic effect is unfolded.

The novel compounds of the invention show in The Therefore, at the same time, in particular one pronounced bronchodilatory effect with an antago nisierenden activity with regard to a variety of Me diators and open up completely new medical Be options for action, especially in therapy asth matic diseases.

As further interesting indications of the new invention appropriate substances come, for example, the chronic venous Insufficiency as well as the treatment of migraine attacks or the use of these drugs as antitussives chronic cough or to suppress chronic Pain in consideration.  

The substances can also be used in diagnostic procedures in connection with an examination of bronchoreagibili use. The detailed explanation and presentation the test results on which the found new ones support new indications medical indications, can be found in the experimental Pharmacology section in the conclusion to the explanation of the synthesis of end and Zwi products according to the description of Herstellungsbei play for medicines.

The invention accordingly 1,2-dihydro-2-oxo thiazolopyridine compounds according to the above Formula (I)

wherein
R¹ represents halogen, and
R² and R³ are the same or different,
R² is alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and
R³ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, acyl or alkanesulfonyl
can mean, or
R² and R³ together form a heterocyclic ring, where in the ring-forming substituent

may be selected from the following heterocycles:

and these rings may be monosubstituted or disubstituted by alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, dialkylaminoalkyl or an oxo group adjacent to a nitrogen atom,
A is selected from alkylene or alkenylene optionally substituted by one or more alkyl groups,
Q is selected from the following heterocycles:

wherein the heterocyclic ring may optionally have a double bond and
m 3 to 5 or 6 or 3 or 4 to 7
n 2 or 3, and
p can be 3 to 5 or 6 or 3 or 4 to 7,
R⁴ is hydrogen, alkyl, hydroxymethyl, carboxyl or alkoxycarbonyl, as well as
R⁵ may be hydrogen or an alkyl radical, where
R⁴ and R⁵ optionally together to form a bi cyclic ring system, an alkylene bridge, in before zugter way, a C₁-C₄-, in particular C₁-C₃-alkylene bridge form,
D in the case where the bond to Q is via a carbon atom, a single bond,
optionally alkyl, hydroxy or alkoxy mono- or di-substituted alkylene, or
optionally in each case by alkyl, hydroxy or Al koxy one or two times substituted alkenylene can represent, wherein the double bond of the alkenylene group can also be made to the ring Q,
an alkynyl optionally monosubstituted or disubstituted by alkyl, hydroxy or alkoxy, or
may denote an alkylene, alkenylene or alkynylene radical in which a methylene group may be replaced by an oxygen atom, sulfur atom or an NR⁶ radical isoster, wherein
R⁶ is selected from hydrogen or alkyl independently of R⁵, or
D in the case that the bond to Q via a nitrogen atom takes place,
an alkylene which is optionally monosubstituted or disubstituted by alkyl, hydroxy or alkoxy, alkenylene or alkynylene,
wherein a methylene group may be replaced by an oxygen atom, sulfur atom or an NR⁶-residue isoster, as well as their
Stereoisomers and salts,
wherein in the abovementioned substitutions
the alkylene and alkenylene and alkynylene radicals preferably each have up to 8, 10 or 12 carbon atoms, their possible alkyl and alkoxy substituents each preferably having at least 1 to at most 4, 6 and 8 carbon atoms,
also in the radicals R², R³, R⁴ and / or R⁵ given if appropriate alkenyl and alkynyl radicals as well as the alkyl, cycloalkyl and Hydroxyalkylre ste, the alkoxyalkyl, alkylaminoalkyl and Aminoal kylreste or dialkylaminoalkyl in a preferred manner in each case up to 8 or 10, more preferably at least 1, 2, 3, 4, 5 and up to 6 Koh lenstoffatome may have and the total number of carbon atoms in the alkylaminoalkyl and Dial kylaminoalkylresten preferably 2 or 3 or 4 or can carry up to 6, 8, 10 or 12, 15 or 18 carbon atoms,
said acyl and alkanesulfonyl radicals may have in the preferred manner up to 8, 10 or 12, in particular at least 1, 2, 3 or 4 and up to 5 or 6 carbon atoms,
the alkoxycarbonyl radical may have up to 6, 8 or 10 carbon atoms, but preferably 2, 3, 4 or 5 carbon atoms,
the radicals R⁴ and R⁵ taken together in the formation of a bicyclic ring system preferably a C₁-C₄-Al alkylene bridge, more preferably represent a C₁-C₃-alkylene bridge,
said aliphatic saturated and / or unge saturated hydrocarbon radicals with any funk tional groups may each be independently ge rad- or branched-chain, and in the case of 2 or more, for example 3 alkyl radicals in said groups, eg. B. in the Alkylaminoalkyl- or Dialkylaminoalkylresten, the alkyl radicals inde pendent of each other the same or different and also each may be straight and / or branched, and where is that
the minimum number of carbon atoms in the genann th substituents depending on the bonding ratios in each case each 1, 2 or 3 carbon atoms, ie 2 or 3 carbon atoms in the case of alkenyl groups and 3 carbon atoms in the case of triunsaturated alkynyl compounds may be, this being in the same applies to the cyclic carbon compounds, under which the cyclopropyl group has the lowest possible number of 3 carbon atoms,
and preferably their stereoisomers, as given cis / trans isomers, endo / exo isomers, enantiomers, diastereomers as pure isomers or in the form of their mixtures and their acid addition salts.

An inventive embodiment of the new substances according to of the formula (I)

are compounds in which
R¹ is halogen, where
R² and R³ may be the same or different, and
R² is C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkoxyalkyl, C₂-C₆-aminoalkyl, C₃-C₁₀-alkylaminoalkyl , C₄-C₁₀-dialkylaminoalkyl and
R³ is hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-acyl, C₁-C₆-Al kansulfonyl represent,
R² and R³ together in the rest

can form a heterocyclic ring, wherein the This ring in this case from the following heterocyc len can be selected:

and these rings one or two times by C₁-C₄alkyl, hydroxy, C₁-C₄alkoxy, amino, C₁-C₄alkylamino, C₂-C₈-di alkylamino, C₁-C₄-hydroxyalkyl, C₃-C₁₀-dialkylaminoalkyl or a may be substituted to a nitrogen atom adjacent oxo group,
A is selected from C₁-C₆-alkylene optionally substituted by one or more C₁-C₃-alkyl groups or C₂-C₆-Al kenylene,
Q is selected from the following heterocycles:

wherein the heterocyclic ring may optionally contain at least one double bond, and
m 3 to 5 or 6 or 3 or 4 to 7
n 2 or 3, and
p can be 3 to 5 or 6 or 3 or 4 to 7,
R⁴ is hydrogen, C₁-C₆-alkyl, hydroxymethyl, carboxyl or C₂-C₅-alkoxycarbonyl, and
R⁵ can denote hydrogen or a C₁-C₆-alkyl radical,
where R⁴ and R⁵ may optionally together form a C₁-C₃-alkylene bridge with the formation of a bicyclic ring system,
D in the case where the bond to Q is via a carbon atom, a single bond,
optionally in each case by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy mono- or disubstituted C₁-C₁₀-Al alkylene or C₂-C₁₀-alkenylene, in which latter case the double bond can also take place to the ring Q,
optionally mono- or disubstituted by C₁-C₄-alkyl, hydroxy or C₁-C₄-Al alkoxy C₃-C₁₀-Al kinylene or
C₁-C₁₀-alkylene, C₂-C₁₀-alkenylene or C₃-C₁₀-alkynylene in which a methylene group is replaced by O or S or NR⁶ isoster, wherein
R⁶ is selected from hydrogen or C₁-C₆-alkyl independently of R⁵, or
D in the case that the bond to Q via a nitrogen atom takes place,
optionally in each case by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy mono- or disubstituted C₂-C₁₀-Al alkylene, C₄-C₁₀-alkenylene or C₄-C₁₀-alkynylene, or C₂-C₁₀-alkylene, C₄-C₁₀ Alkenylene, or C₄-C₁₀ alkynyls in which a methylene group is replaced by O or S or NR⁶ isoster,
and their stereoisomers and acid addition salts.

Another embodiment of the invention are Verbindun in which the substituents R 1, R 2, R³, R⁴, R⁵ and / or R⁶ and A together with the others in Substitutions given above according to the formula (I)

have the following meanings in which
Halogen is either fluorine, chlorine, bromine or iodine,
C₁-C₆-alkyl straight-chain or branched and a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl, pentyl, Isopen tyl-, tert-pentyl, neopentyl, cyclopropylethyl, cyclo-butylmethyl or hexyl can mean
Alkylene may be the methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene group,
C₃-C₆ alkenyl be straight-chain or branched, and allyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentyl tenyl, 4-pentenyl, 2-methyl-2 represents -butenyl, 3-methyl-2-bu tenyl, 2-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl or 2,2-dimethyl-3-butenyl group,
Alkenylene may denote an ethenylene, propenylene, butenylene, pentylene, hexenylene, hexadienylene, heptenylene, octenylene, nonenylene or decenylene group,
C₃-C₆ alkynyl may be straight-chain or branched and may denote a propyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl or 4-methyl-2-pentynyl group,
Alkynylene, the propynylene, Butinylen-, Pentinylen-, Hexi nylen-, Heptinylen-, Octinylen-, Noninylen- or Decinylen group and
C₃-C₆ cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the
C₁-C₆-hydroxyalkyl contains a hydroxyl group in one of the above-mentioned C₁-C₆-alkyl groups, among which the hydroxymethyl and the hydroxyethyl group are preferred,
C₁-C₄-alkoxy in addition to the oxygen atom contains one of the abovementioned C₁-C₄-alkyl groups, among which the methoxy, ethoxy, isopropoxy or tert-butoxy group are preferred,
C₂-C₆ alkoxyalkyl contains one of the abovementioned alkoxy groups in one of the abovementioned alkyl groups, of which the methoxymethyl, methoxyethyl, methoxypropyl or ethoxyethyl group are preferred,
C₂-C₅ alkoxycarbonyl groups contain, in addition to the carbonyl group, one of the abovementioned C₁-C₄ alkoxy groups, of which the methoxycarbonyl, ethoxycarbonyl, isopropoxy carbonyl and tert-butoxycarbonyl groups are preferred,
C₂-C₆ aminoalkyl contains an amino group in one of the abovementioned alkyl radicals, among which the aminoethyl, aminopropyl or aminobutyl group are preferred,
C₃-C₁₀ alkylaminoalkyl carries one of the abovementioned C₁-C₄alkyl groups on the amino group of one of the abovementioned C₂-C₆ aminoalkyl groups, of which the methylaminoethyl, methylaminopropyl, methylaminobutyl, ethylaminoethyl or ethylaminopropyl group are preferred,
C₁-C₄alkylamino contains one of the abovementioned C₁-C₄alkyl groups, of which the methylamino, ethylamino, propylamino, isopropylamino, butylamino and tert-butylamino groups are preferred,
C₂-C₈-dialkylamino on the nitrogen carries two identical or different ver of the above C₁-C₄-alkyl groups, including the dimethylamino, diethylamino, Dipro pylamino-, diisopropylamino, isopropyl-methylamino, di-butylamino and tert-butyl methylamino group are preferred,
C₃-C₁₀-dialkylaminoalkyl carries one of the abovementioned C₂-C₈-di alkylamino groups on one of the abovementioned C₁-C₆ alkyl radicals, among which the dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminomethyl, diethylaminoethyl, diethylaminopro pyl , Dipropylaminomethyl, dipropylaminoethyl, tert-butyl-methylaminomethyl and the tert-butyl-methylaminoethyl group are preferred,
C₁-C₆ acyl is the radical of an aliphatic saturated or unsaturated, straight-chain, branched or cyclic carboxylic acid, of which formyl, acetyl, propionyl, acryloyl, butyryl, isobutyryl, methacryloyl, cyclopropylcarbonyl, pentanoyl, Pivaloyl, cyclobutylcarboxyl, hexanoyl and dimethylacryloyl groups are preferred, and
C₁-C₆ alkanesulfonyl is preferably the methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentane sulfonyl and hexanesulfonyl group and the acid addition salts in the form of the hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates and the acetates, Ben zoate, citrates, Fumarates, gluconates, malates, maleates, Me thansulfonate, lactates, oxalates, succinates, tartrates or toluenesulfonates may be present.

Another preferred embodiment of the invention represent compounds according to the formula (I),

in which the designated substituents have the following meanings:
R¹ is halogen in the 6-position,
R² is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl or C₄-C₁₀ dialkylaminoalkyl and
R³ is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-acyl or C₁-C₆-alkanesulfonyl,
R² and R³ may be the same or different or together form a heterocyclic ring, wherein

in the case of formation of a heterocyclic ring

is selected and these rings by C₁-C₃-alkyl, Hy can be substituted, C₁-C₃-alkoxy, C₁-C₃-hydroxyalkyl, C₂-C₈-dialkyl amino or an adjacent to a nitrogen atom oxo group,
A is optionally substituted by a methyl group substituted C₁-C₄-alkylene or C₂-C₄-alkenylene and
Q out

wherein the ring may optionally contain a double bond,
m, n and p have the following meanings:
m = 3 to 7
n = 2 or 3 and
p = 3 to 7,
R⁴ represents hydrogen, C₁-C₃ alkyl, hydroxymethyl, Car boxyl or C₂-C₅ alkoxycarbonyl and
R⁵ is hydrogen or C₁-C₃ alkyl or
R⁴ and R⁵ may together form a C₁-C₃-Alkylenbrücke un ter formation of a bicyclic ring system,
D is in the case of a bond to Q via a carbon atom of a single bond, selected from C₁-C₈-alkylene or C₂-C₈-alkenylene, wherein the double bond can also be made to the ring Q, or is selected from C₄-C₈-Al kinylen .
wherein these alkylene, alkenylene or alkynylene groups may optionally be substituted by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy, or
in which optionally one methylene group may be replaced by O or S or NR⁶ isoster, wherein R⁶ is selected from hydrogen or C₁-C₃-alkyl independently of R⁵, or
D is in the case of a bond to Q via a Stickstoffa tom of C₂-C₈-alkylene, C₄-C₈-alkenylene or C₄-C₈-alkylene nylene selected, which may be in each case by C₁-C₄-alkyl, hydroxy or C₁-C₄ Alkoxy may be substituted or in which, where appropriate, each one Methylengrup pe may be replaced by O or S or NR⁶ isoster, wherein R⁶ is independently of R⁵ selected from hydrogen or C₁-C₃-Al kyl.

A particularly preferred embodiment of the invention represent compounds according to the formula (I),

in which the designated substituents have the following meanings:
R¹ is bromine or chlorine in the 6-position,
R2 is selected from C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, C₃-C₅ cycloalkyl, C₂-C₃ hydroxyalkyl or C₄-C₈ dialkylaminoalkyl,
R³ is selected from C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, C₁-C₃ acyl or C₁-C₃ alkanesulfonyl wherein
R² and R³ may be the same or different or together may form a heterocyclic ring, and

in the case of the formation of a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, hexahydroazepine, piperazine, homopiperazine or morpholine, where at the ring each by C₁-C₃-alkyl, hydroxy, C₁-C₃-Hy droxyalkyl, C₂-C₄-dialkylamino or an oxo group adjacent to a nitrogen atom may be substituted,
A represents a methylene group, and
Q is out

wherein the ring may optionally contain a double bond,
m, n and p have the following meanings:
m = 3 to 6,
n = 2 or 3, and
p = 3 to 5 or 6 or 3 to 7,
R⁴ represents hydrogen or C₁-C₃ alkyl and
R⁵ is hydrogen,
D is selected in the case of a bond to Q via a Kohlenstoffa tom of C₁-C₆-alkylene or C₂-C₆-alkenylene, wherein the double bond can also be made to the ring Q, or is selected from C₃-C₆-alkynyls, wherein in the sen Alkylene, alkenylene or Alkinylenresten optionally depending Weil a methylene group by O or NR⁶ isoster he sets can be and
R⁶ is selected from hydrogen or C₁-C₃ alkyl, or
D is selected in the case of a bond to Q via a nitrogen atom of C₂-C₆-alkylene, C₄-C₆-alkenylene or C₄-C₆-alkynylene, in which optionally one methylene group may be replaced by O or NR⁶ isoster, wherein
R⁶ is selected from hydrogen or C₁-C₃ alkyl.

A very particularly preferred Ausgestal invention tion of the compounds according to the general formula (I)

represent compounds in which
R¹ is bromine and chlorine in the 6-position and
A is a methylene group,
Q is pyrrolidine, piperidine, hexahydroazepine, piperazine and homopiperazine,
D are selected from ethylene, ethenylene, propylene and butylene and

from methylamino, ethylamino, propylamino, allylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, diallylamino, methylpropylamino, methylallylamino, methyl-tert-butylamino, ethylalylamino, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, morpholino and hexahydroazepinyl
are selected.

The compounds of formula (I) may optionally as cis and Trans- or E and Z isomers occur, for example, when A or D contains a double bond. Subject of the Invention are both the pure isomers as their Mischun In addition, compounds of the formula (I) may be an or contain several asymmetric carbon atoms and demzu follow in different optical isomers (enantiomers, Diastereomers) occur. The invention includes all op table isomers and their racemic or non-racemi mixtures. Finally, connections can of the formula (I) as endo / exo isomers, if the Ring system Q is bicyclic. The pure exo and endo iso Meren and their mixtures are just from the invention if included.  

The invention further pharmacological ver Acid addition salts of the compounds of the formula (I) with inorganic or organic acids. preferred Examples of addition salts with suitable inorganic Acids are hydrochlorides, hydrobromides, hydroiodides, Sul fate and phosphates. Addition salts of organic acids are preferably acetates, benzoates, citrates, fumarates, gluconates, Malates, maleates, methanesulfonates, lactates, oxalates, suc cinates, tartrates and toluenesulfonates.

Compounds of formula (I) and their acid addition salts may also be present as hydrates or other solvates. The invention includes such hydrates and solvates.  

Production of final products

The substances according to the invention in the form of the end products are Herge according to known methods in an analogous manner provides. As so-called analogy come Ver various variants a) to d), as described in fol As claimed further he described subject matter become.

Method (a)

End products in the form of the compounds of formula (I) are obtained by reacting carboxylic acids of the formula (II),

in which R¹ and A have the meaning given above, or their reactive derivatives with compounds of the following For mel (III),

wherein Q, D, R² and R³ are as defined above.

Reactive derivatives of compound (II) may be, for example its activated ester, anhydrides, acid halides (esp special acid chlorides), simple lower alkyl esters. Ge suitable activated esters are z. For example, p-nitrophenyl ester, 2,4,6-Trichlorophenylester, Pentachlorphenylester, Cyanome methyl ester, ester of N-hydroxysuccinimide, N-hydroxy phthalimides, 1-hydroxybenzotriazole, N-hydroxypi  peridins, 2-hydroxypyridine, 2-mercaptopyridine etc. Anhydrides can be both symmetrical anhydrides or mixed, such as with pivaloyl chloride or with chloroformates. This can be aro matic (phenyl chloroformate), araliphatic (Benzyl chloroformate) or aliphatic Chlorfor miate (ethyl chloroformate, isobutyl ester) verwen be.

The reaction of the compounds of the formula (II) with the Compounds according to formula (III) can also in the presence of Condensing agents such as dicyclohexylcarbodiimide, 1-ethyl 3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, N, N'-car bonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydro quinoline, etc. are carried out. Carbodiimides are used As a condensing agent, can be advantageous reagents such N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzo triazole, N-hydroxypiperidine, etc. may be added.

The compounds of the formula (III) can be used both as free Bases as well as in the form of their acid addition salts for Umset be used. To prefer here are the salts inorganic acids, for example hydrochlorides, Hydrobromides or sulfates.

The reaction of the compounds of the formula (II) or their reactive derivatives with the compounds of the formula (III) is usually in a suitable, preferably iner th solvent carried out. As examples may be mentioned aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (eg dichloromethane, Chlo roform, 1,2-dichloroethane, trichlorethylene), ethers (e.g. Diethyl ether, tetrahydrofuran, dioxane, glycol dimethyle ether), ethyl acetate, acetonitrile or polar aprotic Lö semittel such. For example, dimethyl sulfoxide, dimethylformamide N-Me  thylpyrrolidon. It can be both pure solvents as well Mixtures of two or more are used.

The reaction is optionally stopped in the presence of an auxiliary base leads. Suitable examples are alkali metal carbon sodium (sodium carbonate, potassium carbonate), alkali metal hydro gencarbonate (sodium bicarbonate, potassium bicarbonate nat), or organic bases such as triethyl amine, ethyldiisopropylamine, tributylamine, N-methylmorpholine or pyridine. As a base, a corresponding over shot of the compound of formula (III) can be used. If the compounds according to formula (III) in the form of their Acid addition salts used, it is appropriate that Amount of auxiliary base used equivalent to consideration term.

The reaction temperatures can - depending on the reactivity of the Educts - vary within a wide range. In general the reaction is carried out at temperatures between -40 ° C and 180 ° C, preferably between -10 ° C and 130 ° C, especially at the boiling point of the solution used means.

The starting compounds according to formula (II) and according to formula (III) are known or can be prepared by known methods in be prepared analogously. The production ver various examples of these starting materials will continue below following the explanation of the synthesis of final and Intermediates described.  

Method (b)

The end products in the form of the compounds according to formula (I) can also be prepared by having a compound of the formula (IV),

in which R¹, A, Q and D have the abovementioned meaning and L is a suitable leaving group or reactive group represents, with a compound of formula (V),

is reacted, wherein in the formula (V) R² and R³ are the above have meanings.

In the compounds of the formula (IV), the leaving group pe L be a reactive derivative of an alcohol, for example as halide, a halogen atom such as chlorine, bromine or Pose death or she may be a sulfonic acid ester, so for example, a methanesulfonyloxy, trifluoromethane sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy or m-nitro benzenesulfonyloxy radical. A reactive group L can z. B. be a terminal epoxide group.  

The reaction of the compounds according to the formulas (IV) and (V) is usually carried out in a suitable inert Lö solvents. Such solvents may, for. B. its aroma hydrocarbons (benzene, toluene, xylene), ethers (eg, tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile, ketones (acetone, ethyl methyl ketone), po lare protic solvents such as alcohols (ethanol, Isopro panol, butanol, glycol monomethyl ether) or polar aproti cal solvents such. For example, dimethyl sulfoxide, dimethyl form amide or N-methylpyrrolidone. It can be both pure solutions medium as well as mixtures of two or more used become. Preferably, the reactions are in the presence of bases, the same as in the procedure above ren (a) can be used. Be as Compound according to formula (IV) chlorides or bromides set, so can the implementation by adding Alka accelerate lime iodides (sodium iodide, potassium iodide). The reaction temperatures can vary depending on the reactivity of Starting materials vary between 0 ° C and 180 ° C, are preferred however, between 20 ° C and 130 ° C.

The intermediates of the formula (IV) according to the invention nen z. B. be prepared in such a way that the car of the formula (II) or their activated derivatives under the conditions mentioned in process (a) with Ver Compounds of the formula (VI)

H-Q-D-L (VI)

in which Q, D, and L are as defined above, where L is a suitable leaving or reactive group put. You can also advantageously produced by it be that the carboxylic acids of the formula (II) with amino alcohols of the formula (VI) in which L is a hydroxy group, and in the resulting intermediates according to  Formula (IV) the alcoholic hydroxyl group according to in the In the above-mentioned Reacti ven derivatives, ie z. B. halides or sulfonic acid esters transferred.

Intermediates according to the invention in the form of the compounds of the formula (IV) in which Q is the formulas

and wherein R¹, A and D are as defined above and L is a hydroxy group, a chlorine-bromine or iodine atom, an alkanesulfonyloxy group, a perfluoroalkanesulfonyloxy group or an arylsulfonyloxy group are new, but with the exception of compounds according to the formula (IV), where Q

means as described in JP 63/017881.

These new intermediates according to the formula (IV) and their use for the preparation of the end of the invention Products according to formula (I) are therefore also subject matter the invention.

In Table 4 below, following are the explanation of synthesis examples for intermediates exemplified compounds of the invention Formula (IV) without any limitation with their respective Substituent meanings reproduced.

But the end products of the invention can also be on hand of the following analogy methods according to variants c) and d) synthesize:

Method (c)

Compounds of the formula (I) in which R³ is an alkyl, Al kenyl, alkynyl or cycloalkyl radical as above Definitions is beyond the scope of the procedure (a) and (b) also by making compounds of the formula (I) in which R³ is hydrogen, with a suitable alkylating agent of the formula (VII),

R³-L (VII)

wherein R³ is a by definition alkyl, alkenyl, Alkynyl or cycloalkyl radical and L is as defined above is. The reaction of the compounds (I, R³ = H) with the  Compounds (VII) can be carried out under conditions as described in process (b).

Method (d)

Compounds of the formula (I) in which R³ is an acyl radical or alkanesulfonyl radical as defined above can be, except according to the methods (a) and (b) also be prepared by reacting compounds of the formula (I) in which R³ is hydrogen with a carboxylic acid or an alkanesulfonic acid of the formula (VIII), R³ in the definition of an acyl or alkanesulf fonyl residue means

R³-OH (VIII)

or with their reactive derivatives for the reaction brings. Preferred reactive derivatives of the carboxylic acid Ren or sulfonic acids of the formula (VIII) are symmetrical or unsymmetrical carboxylic acid anhydrides or sulfonic acid reanhydride or carboxylic acid or sulfonic acid halides, in particular carboxylic acid or sulfonic acid chlorides. The Um tion of the acids of the formula (VIII) or their reactive Derivatives with the compounds [of formula (I), R³ = H] er preferably follows in the presence of auxiliary bases in Lö semite and conditions as used in the process (a) are described.

Those prepared by the processes (a), (b), (c) or (d) Compounds of the formula (I) can be known per se Be isolated and purified, for example by after distilling off the solvent, the residue distribution, extraction, reprecipitation or recrystallization on or another cleaning method. before  To this end, the column chromatography are suitable Carrier material or the preparative medium or high pressure chromatography.

The compounds of the formula (I) are usually added to next in the form of their free bases or their hydrates or Solvates obtained, depending on the type of insulation and cleaning. Their addition salts with pharmaceutically acceptable acids is obtained in the usual manner by reaction of the base with the desired acid in a suitable solvent. ever by number of the basic centers of the compounds of the formula (I) may contain one or more equivalent acids per mole of base be bound.

Suitable solvents are, for. As chlorinated hydrocarbon substances such as dichloromethane or chloroform; Ether like Di ethyl ether, dioxane or tetrahydrofuran; acetonitrile; keto ne, such as acetone or ethyl methyl ketone; Esters such as methyl acetate or ethyl acetate or low molecular weight alcohols such as metha nol, ethanol or isopropanol; and water. It can both pure solvents as well as mixtures of two or three solvents be used. The salts can by Auskri stall, precipitate or evaporate the solvent to be won. They may fall as hydrates or Solvate on.

From the salts, the bases can be added by alkalization recover, for example with aqueous ammonia solution, Alkaline carbonate or dilute alkali solution.

synthesis Examples for end products of the invention according to the formula (I)

In the production examples for end products, the abbreviations stand for the following terms:
M.p. = melting point,
Kp. = Boiling point,
Dec. = Decomposition,
RT = room temperature,
h = hour (s),
min = minutes.
1 H-NMR spectrum = proton resonance spectrum recorded at 100 MHz. The chemical shifts are given in ppm versus TMS as standard (δ = 0.0), where
s = singlet,
d = doublet,
dd = double doublet,
t = triplet,
q = quartet,
m (mz) = (centered) multiplet;
THF = tetrahydrofuran,
DMF = dimethylformamide,
DMSO = dimethyl sulfoxide,
Section. = absolute;
HBr = hydrogen bromide,
CDI = carbonyldiimidazole,
EDC = N- (3-dimethylaminopropyl) -N'-ethyl carbodiimide hydrochloride,
EEDQ = 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline,
HOBT = 1-hydroxybenzotriazole,
TEA = triethylamine.

Synthesis of the end products according to the formula (I) example 1 6-chloro-1- [4- (2-dimethylaminoethyl) -piperidyl] carbonyl methyl 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydrochloride (Substance 51 as hydrochloride)

33.4 g (136.6 mmol) of 6-chloro-1-carboxymethyl-2-oxo-1,2-di-ydrothiazolo [5.4-b] pyridine and 24.4 g (150.3 mmol) of CDI who in 340 ml abs , THF 1h with stirring to reflux, he heated, forming a clear solution. It is then cooled, are added at 5-10 ° C 37.6 g (164 mmol) of 4- (2-dimethyl minoethyl) piperidine dihydrochloride and then dripped at the same temperature with stirring 50.2 ml (361 mmol) of TEA on. The suspension is stirred for 5 h at RT without further cooling. The mixture is then concentrated in vacuo to about half the volume and the residue is partitioned between 500 ml each of water and ethyl acetate. The organic phase is washed twice with water, dried over sodium sulfate and the solvent is removed in vacuo. The resinous residue is dissolved in CHCl₃ / CH₃OH / conc.NH₃ in the ratio 90/9/1 and filtered through a pad of silica gel. The product-containing fractions are combined and spun off. The resinous Rohpro product is dissolved in 330 ml of isopropanol with heating and mixed with 28 ml of about 8M isopropanolic hydrochloric acid. The precipitated in the cold hydrochloride is filtered off with suction, ge dried and recrystallized from 550 ml of methanol. Obtained colorless crystals with a mp of 254-259 ° C (dec.) In a yield of 27.2 g (48%).
C₁₇H₂₃ClN₄O₂S · HCl, MW = (419.4)
IR spectrum (KBr):
ν (C = O) 1685, 1635 cm ^-1
ν (C = C) 1575 cm ^-1
1 H-NMR spectrum (D₂O):
0.90-1.90 (7H, m, (CH₂) ₃CH)
2.65 (1H, mz, CONCH)
2.75 (6H, s, N⁺ (CH₃) ₂)
2.90-3.30 (3H, m, N⁺CH₂, CONCH)
3.80 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.75 (1H, d, NCHCO, J = 18 Hz)
4.96 (1H, d, NCHCO, J = 18 Hz)
7.43 (1H, d, pyridine, J = 1.9 Hz)
8.15 (1H, d, pyridine, J = 1.9 Hz)

Example 2 6-chloro-1- [4- (2-diethylaminoethyl) -piperidyl] carbonyl methyl 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydrobromide (Substance 60 as hydrobromide)

Analogously to Example 1, 4.0 g (16.4 mmol) of 6-chloro-1 carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine and 2.9 g (18.0 mmol) of CDI in 50 ml of abs. THF for 1 h under reflux heated. It is then cooled, gives 5.0 g (19.6 mmol) 4- (2-diethylaminoethyl) -piperidine dihydrochloride to and Then, with stirring and ice-cooling, 5.5 ml (39.2 mmol) TEA, dissolved in 40 ml abs. THF, one. The suspension is stirred without further cooling overnight at RT. On closing the solvent is largely removed in vacuo and partition the residue between 100 ml of water and 200 ml of ethyl acetate. The organic phase is washed with water, Dried over sodium sulfate and the solvent removed in Vacuum. The resinous crude product is on silica gel with CHCl₃ / CH₃OH in the ratio 90/10 as eluent chromato prepurified graphically and then with CHCl₃ / CH₃OH im Ratio 97/3 subjected to flash chromatography. The isolated product (3.2 g) is made up of a small amount  Chlorobutane / diisopropyl ether crystallized. It will be 2.3 g (34%) colorless crystals.

1.3 g of the free base are dissolved in 5 ml of isopropanol and transferred by introducing gaseous HBr at RT in the Hydrobro mid. The colorless crystals have a mp of 216-223 ° C (dec.) And are obtained in a yield of 1.0 g (64%).
C₁₉H₂₇ClN₄O₂S · HBr, MW = (491.9)
IR spectrum (KBr):
ν (C = O) 1680, 1645 cm ^-1
ν (C = C) 1575 cm ^-1
1 H-NMR spectrum (D₂O):
1.11 (6H, t, CH₃, J = 7.3 Hz)
1.20-1.90 (7H, m, (CH₂) ₃CH)
2.60 (1H, mz, CONCH)
3.10 (7H, mz, N⁺ (CH₂) ₃ and CONHCH)
3.80 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.74 (1H, d, NCHCO, J = 18 Hz)
4.94 (1H, d, NCHCO, J = 18 Hz)
7.42 (1H, d, pyridine, J = 1.9 Hz)
8.12 (1H, d, pyridine, J = 1.9 Hz)

Example 3 6-bromo-1- {4- [2- (2-oxopyrrolidin-1-yl) ethyl] -piperidyl} - carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine (Substance 134)

Analogously to Example 1, 3.5 g (12.1 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine and 2.2 g (13.3 mmol) of CDI in 50 ml abs. THF refluxed for 1 h. It is then cooled, 3.4 g (14.5 mmol) of 4- [2- (2-oxo-pyrrolidin-1-yl) ethyl] piperidine hydrochloride are added dropwise and then added dropwise with stirring and ice cooling 2.4 ml (16.9 mmol) TEA, dissolved in 40 ml abs. THF, one. The suspen sion is stirred without further cooling overnight at RT. Then the solvent is extensively removed in vacuo and the residue is partitioned between water and ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The amorphous crude product is chromatographed twice on silica gel with CHCl₃ / CH₃OH in the ratio 98/2 as the eluent chromatographically and then crystallized from 1-chlorobutane to. There are obtained 2.8 g (49%) of colorless crystals with a mp. Of 159 ° C.
C₁₉H₂₃BrN₄O₃S, MW = (467.4)
IR spectrum (KBr):
ν (C = O) 1690, 1670, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃):
1.00-2.60 (11H, m, (CH₂) ₃CH and pyrrolidine-CH₂CH₂CO)
2.65 (1H, mz, CONCH)
2.90-3.60 (5H, m, 5 CONCH)
3.90 (1H, mz, CONCH)
4.50 (1H, mz, CONCH)
4.60 (1H, d, NCHCO, J = 16 Hz)
4.82 (1H, d, NCHCO, J = 16 Hz)
7.37 (1H, d, pyridine, J = 1.9 Hz)
8.33 (1H, d, pyridine, J = 1.9 Hz)

Example 4 6-Bromo-1- [4- (2-pyrrolidylethyliden) -piperidyl] carbonyl methyl 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydrochloride (Substance 192 as hydrochloride)

Analogously to Example 1, 2.60 g (9.0 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4.b] pyridine and 1.65 g (10.0 mmol) of CDI in 50 ml abs. THF refluxed for 1 h. After cooling to 5 ° C., 2.40 g (9.5 mmol) of 4- (2-pyrrolidylethylidene) piperidine dihydrochloride are added with stirring and 3.50 ml (25 mmol) of TEA are added dropwise. The suspension is stirred without further cooling overnight at RT. It is diluted with 75 ml of dichloromethane, extracted with 10% Na tronlauge, the organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. The resinous residue is chromatographed with CHCl₃ / CH₃OH / NH₃ in a ratio of 90/10/1 as eluent on silica gel. The purified product (2.8 g) is dissolved in 30 ml of isopropanol and treated with 5 ml of about 2.8M isopropanolic hydrochloric acid. The crystallized out in the cold hydrochloride is recrystallized from Me methanol with the addition of diethyl ether. There are obtained colorless crystals with a mp of 232-242 ° C (dec.). The yield is 2.5 g (57%).
C₁₉H₂₃BrN₄O₂S · HCl, MW = (487.9)
IR spectrum (KBr):
ν (C = O) 1685, 1635 cm ^-1
ν (C = C) 1565 cm ^-1
1 H-NMR spectrum (D₂O):
1.92 (4H, mz, pyrrolidine-CH₂CH₂)
2.30 (4H, mz, = C (CH₂) ₂)
2.70-3.80 (10H, m, N⁺ (CH₂) ₃ and CON (CH₂) ₂)
4.88 (2H, s, NCH₂CO)
5.36 1H, t, = C H CH₂
7.55 (1H, d, pyridine, J = 1.8 Hz)
8.23 (1H, d, pyridine, J = 1.8 Hz)

Example 5 6-Bromo-1- [4- (2-dipropylamino-ethyl) -piperidyl] carbonyl methyl 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydrochloride (Substance 65 as hydrochloride)

To the mixture of 12.0 g (41.5 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 13.0 g (45.7 mmol) of 4- ( 2-dipropylaminoethyl) piperidine dihydrochloride and 14.5 ml (103.8 mmol) TEA in 300 ml abs. Dichloromethane is added while cooling with ice 9.5 g (49.8 mmol) of EDC and 8.3 g (49.8 mmol) of HOBT. The clear solution is stirred without further cooling overnight at RT. The mixture is then washed once with 1M NaOH and twice with water. The organic phase is dried over sodium sulphate and the solvent is removed in vacuo. The resinous residue is dissolved in CHCl₃ / CH₃OH in a ratio of 90/10 and filtered through a Kie selgelschicht. The product-containing fractions are combined and spun off. Using MPLC (CHCl₃ / CH₃OH in the ratio 95/5) gives 9.0 g (45%) of pure base. The se is dissolved in 20 ml of isopropanol with heating and treated with 9.3 ml of about 4M isopropanolic hydrochloric acid. The precipitated in the cold hydrochloride is filtered off with suction, ge dried and from 20 ml of ethanol / 5 ml of diethyl ether umkri stallisiert. Colorless crystals with a mp of 215-217 ° C (dec.) In a yield of 7.7 g (36%).
C₁₇H₂₁BrN₄O₂S · HCl, MG = (519, 9)
IR spectrum (KBr):
ν (C = O) 1670, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
0.79 (6H, t, 2 CH₃, J = 7.4 Hz)
1.00-1.90 (11H, m, (CH₂) ₃CH and 2 CH₃C H₂ )
2.60 (1H, mz, CONCH)
2.80-3.20 (7H, m, N⁺ (CH₂) ₃ and CONCH)
3.90 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.75 (1H, d, NCHCO, J = 18 Hz)
4.96 (1H, d, NCHCO, J = 18 Hz)
7.55 (1H, d, pyridine, J = 1.8 Hz)
8.23 (1H, d, pyridine, J = 1.8 Hz)

Example 6 6-Bromo-1- [4- (2-pyrrolidylethyl) -piperidyl] -carbonylmethyl- 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine (Substance 117)

Analogously to Example 5, 62.0 g (214 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 56.0 g (220 mmol) of 4- (2- Pyrrolidylethyl) piperidine dihydrochloride and 70 ml (500 mmol) TEA in 600 ml abs. Dichloromethane cooled with stirring to 5 ° C. 46.0 g (240 mmol) of EDC and 38.0 g (240 mmol) of HOBT (85%) are added and stirring is continued for 3 h without cooling and allowed to stand at RT overnight. The reaction solution is extracted with 300 ml of 10% sodium hydroxide solution, washed three times with water, dried over sodium sulfate and the solvent is removed in vacuo. The solid remaining as a residue is heated for purification with 300 ml of acetone with stirring to reflux and filtered off with suction after cooling to RT. The extraction with refluxing the acetone is repeated twice more. This gives colorless crystals with a mp of 165-166 ° C in a yield of 67.0 g (72%).
C₁₉H₂₅BrN₄O₂S, MW = (453.4)
IR spectrum (KBr):
ν (C = O) 1675, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃):
1.00-2.00 (11H, m, (CH₂) ₃CH and CH₂CH₂)
2.30-2.90 (7H, m, N (CH₂) ₃ and CONCH)
3.15 (1H, mz, CONCH)
3.90 (97627 00070 552 001000280000000200012000285919751600040 0002019618970 00004 975081H, mz, CONCH)
4.50 (1H, mz, CONCH)
4.62 (1H, d, NCHCO, J = 16 Hz)
4.81 (1H, d, NCHCO, J = 16 Hz)
7.38 (1H, d, pyridine, J = 1.9 Hz)
8.38 (1H, d, pyridine, J = 1.9 Hz)

Example 7 6-Bromo-1- [4- (2-pyrrolidylethyl) -piperidyl) -carbonylmethyl- 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydrochloride (Substance 117 as hydrochloride)

58.5 g (129 mmol) of 6-bromo-1- [4- (2-pyrrolidylethyl) -piperi dyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine in 300 ml of isopropanol Dissolved 100 ml of about 2.8M isopropa nolic hydrochloric acid with warming and slowly cooled as the to RT. The crystallization is completed by cooling to 4 ° C overnight. The product is filtered off with suction and crystallized from the air-dried hydrochloride from a mixture of 65 ml of methanol and 45 ml of 2.7 M methanolic hydrochloric acid with the addition of 200 ml of diethyl ether. Colorless crystals are obtained with a mp of 228-235 ° C (dec.) In a yield of 52.4 g (62%).
C₁₉H₂₅BrN₄O₂S · HCl, MW = (489.9)
IR spectrum (KBr):
ν (C = O) 1695, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
0.80-2.10 (11H, m, (CH₂) ₃) CH and CH₂CH₂)
2.65 (1H, mz, CONCH)
2.90-3.60 (7H, m, N⁺ (CH₂) ₃ and CONCH)
3.80 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.75 (1H, d, NCHCO, J = 17 Hz)
4.91 (1H, d, NCHCO, J = 17 Hz)
7.56 (1H, d, pyridine, J = 1.8 Hz)
8.22 (1H, d, pyridine, J = 1.8 Hz)

Example 8 1- {4- [2- (N-allyl-N-methylamino) ethyl] -piperidyl} carbonyl methyl 6-bromo-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine Hy drochloride (substance 79 as hydrochloride)

Analogously to Example 5, the mixture of 35.0 g (121 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 34.0 g (133 mmol) of 4 - [2- (N-Allyl-N-methylamino) ethyl] -piperidine dihydrochloride and 42 ml (303 mmol) TEA in 1 liter abs. Dichloromethane under ice cooling 28.0 g (145 mmol) EDC and 24.0 g (145 mmol) HOBT. The clear solution is stirred without further cooling overnight at RT. The mixture is then washed once with 1M NaOH and twice with water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The resinous residue is purified on silica gel (CHCl₃ / CH₃OH in the ratio 95/5) and digested in 200 ml of tert-butyl methyl ether: 31.0 g (56%) of colorless crystals. These are dissolved in 200 ml of isopropanol and mixed with 50 ml of about 3M isopropanoic hydrochloric acid. The precipitated in the cold hydrochloride is filtered off with suction, dried and recrystallized from a small amount of ethanol / diethyl ether. There are obtained colorless crystals with a mp. Of 174-175 ° C in a yield of 13.0 g (22%).
C₁₉H₂₅BrN₄O₂S · HCl, MW = (489.9)
IR spectrum (KBr):
ν (C = O) 1685, 1635 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
1.00-1.80 (7H, m, (CH₂) ₃) CH
2.67 (4H, s and m, CH₃N⁺ and CONCH)
3.07 (3H, m, N⁺CH₂ and CONCH)
3.60 (2H, d, N⁺C H ₂CH =)
3.73 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.72 (1H, d, NCHCO, J = 17.5 Hz)
4.91 (1H, d, NCHCO, J = 17.5 Hz)
5.30-5.60 (3H, m, CH₂ = CH)
7.52 (1H, d, pyridine, J = 1.7 Hz)
8.20 (1H, d, pyridine, J = 1.7 Hz)

Example 9 6-Bromo-1- {3- [4- (2-pyrrolidyl-ethyl) -piperidyl] carbonyl propyl} -1,2-dihydrothiazolo [5.4-b] pyridine hydrochloride (Substance 124 as hydrochloride)

Analogously to Example 5, 3.0 g (9.5 mmol) of 6-bromo-1- (3-carboxypropyl) -2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 2, are added to the mixture. 7 g (10.4 mmol) of 4- (2-pyrrolidylethyl) -piperidine dihydrochloride and 3.3 ml (23.6 mmol) of TEA in 100 ml of abs. Dichloromethane with ice cooling 2.2 g (11.3 mmol) EDC and 1.9 g (11.4 mmol) HOBT. The clear solution is stirred without further cooling overnight at RT. The mixture is then washed once with 1M NaOH and twice with water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The resinous residue is purified on silica gel (CHCl₃ / CH₃OH / NH₃ in the ratio 90/9/1). 3.7 g (80%) of yellow resin are recovered. The free base is dissolved in 20 ml of isopropanol and mixed with 4 ml of about 4M isopropanolic Salzsäu re. The precipitated in the cold hydrochloride is filtered off, dried and lisiert Umkristall from 10 ml of ethanol. There are obtained colorless crystals with a mp of 162-163 ° C. The yield is 2.3 g (47%).
C₂₁H₂₉BrN₄O₂S · HCl, MW = (517.9)
IR spectrum (KBr):
ν (C = O) 1675, 1620 cm ^-1
ν (C = C) 1560 cm ^-1
1 H-NMR spectrum (D₂O):
0.60-2.10 13H, m, (CH₂) ₃CH, CH₂CH₂ and NCH₂C H ₂CH₂CO
2.10-2.60 (3H, m, CH₂CO and CONCH)
2.60-3.30 (5H, m, CONCH and N⁺ (CH₂) ₂ (pyrrolidine)
3.30-4.20 (6H, m, CH₂N⁺, 2CONCH and NC H ₂CH₂CH₂CO)
7.72 (1H, d, pyridine, J = 1.8 Hz)
8.14 (1H, d, pyridine, J = 1.8 Hz)

Example 10 6-chloro-1- [4- (2-diallylamino-ethyl) -piperidyl] carbonyl Methyl 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine Hydro chloride (substance 91 as hydrochloride)

The solution of 4.0 g (16.3 mmol) 6-chloro-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 3.7 g (18.0 mmol) 4- (2-Diallylamino-ethyl) -piperidine and 4.4 g (18.0 mmol) of EEDQ in 70 ml of THF are refluxed for 4 hours. At closing, the solvent is largely removed in vacuo and the residue is partitioned between water and ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The resinous crude product is chromatographed on silica gel before (CHCl₃ / CH₃OH in the ratio 95/5) and then recrystallized several times (acetonitrile / 1-chlorobutane or isopropanol). 3.0 g (42%) of colorless crystals are obtained. The free base is dissolved in isopropanol and admixed with 4.6 ml of about 4M isopropanolic hydrochloric acid. The precipitated in the cold hydrochloride is filtered off with suction, dried and recrystallized from methanol. There are obtained colorless Kri stalle with a mp of 195-197 ° C in a yield of 2.3 g (30%).
C₂₁H₂₇ClN₄O₂S · HCl, MW = (471.4)
IR spectrum (KBr):
ν (C = O) 1670, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
0.90-1.90 (7H, m, (CH₂) ₃CH)
2.60 (1H, mz, CONCH)
3.10 (3H, mz, CH₂N⁺ and CONCH)
3.63 (4H, d, 2 N⁺C H ₂CH =)
3.75 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.75 (1H, d, NCHCO, J = 18 Hz)
4.96 (1H, d, NCHCO, J = 18 Hz)
5.30-6.00 (6H, m, 2 CH₂ = CH)
7.43 (1H, d, pyridine, J = 1.9 Hz)
8.16 (1H, d, pyridine, J = 1.9 Hz)

Example 11 6-Bromo-1- [4- (2-diallylamino-ethyl) -piperazinyl] carbonyl methyl 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine dihydro chloride (substance 324 as dihydrochloride)

Analogously to Example 10, the solution is heated from 4.0 g (13.8 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 3.2 g (15 , 2 mmol) of 4- (2-diallylaminoethyl) -piperazine and 3.8 g (15.2 mmol) of EEDQ in 70 ml of THF for 4h under reflux. Then the solvent is largely taken off in vacuo and the residue is partitioned between water and ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The crystalline crude product is pre-purified on Kie selgel (CHCl₃ / CH₃OH in the ratio 98/2) and then recrystallized from acetonitrile / diisopropyl ether. There are obtained 5.4 g (81%) of colorless crystals. The free base is dissolved in isopropanol and treated with 11 ml of about 4M isopropanolic hydrochloric acid. The precipitated in the cold hydrochloride is filtered off with suction, dried and recrystallized from methanol. This gives colorless crystals with a mp of 205-208 ° C in a yield of 5.4 g (71%).
C₂₀H₂₆BrN₅O₂S · 2HCl, MW = (553.3)
IR spectrum (KBr):
ν (C = O) 1685, 1660 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
3.20-4.10 (16H, m, 6N⁺CH₂ and CON (CH₂) ₂) z4.88 (2H, s, NCH₂CO)
5.40-6.00 (6H, m, 2 CH₂ = CH)
7.59 (1H, d, pyridine, J = 2.0 Hz)
8.11 (1H, 1, pyridine, J = 2.0 Hz)

Example 12 6-chloro-1- [4- (2-cyclopropylamino-ethyl) -piperidyl] -carbo nylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydro chloride (substance 74 as hydrochloride)

The suspension of 5.0 g (11.5 mmol) of 6-chloro-1- [4- (2-methanesulfonyloxyethyl) -piperidyl] -carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine ( Substance 462) in 15 ml of DMF is treated with 5.0 ml (70 mmol) of cyclopropylamine and stirred at 65 ° C for 3.5 h. After cooling, the whole is poured into 100 ml of ice water. The deposited sticky solid is taken up in chloroform, the solution is dried over sodium sulphate and evaporated again. It is then chromatographed with CHCl₃ / CH₃OH in a ratio of 95/5 to 90/10 as the eluent on silica gel. The thus purified free Ba se (2.6 g, 58% glassy solid) is dissolved in 20 ml of isopropanol and with 3.3 ml of about 4M isopropanolic hydrochloric acid into the hydrochloride. The deposited crystals are recrystallized from 85% ethanol / diethyl ether. Colorless crystals are obtained with a mp of 231-234 ° C in a yield of 1.9 g (38%).
C₁₈H₂₃ClN₄O₂S · HCl, MW = (431.4)
IR spectrum (KBr):
ν (C = O) 1680, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
0.70 (4H, mz, cyclopropane-CH₂CH₂)
0.85-1.90 (8H, m, (CH₂) ₃CH and NH)
2.40-2.80 (2H, m, N⁺CH and CONCH)
2.85-3.30 (3H, m, N⁺CH₂ and CONCH)
3.80 (1H, mz, CONCH)
4.20 (1H, mz, CONCH)
4.73 (1H, d, NCHCO, J = 18 Hz)
4.94 (1H, d, NCHCO, J = 18 Hz)
7.40 (1H, d, pyridine, J = 1.9 Hz)
8.12 (1H, d, pyridine, J = 1.9 Hz)

Example 13 6-Bromo-1- [4- (4-allylaminobutyl) -piperidyl] -carbonylmethyl- 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine hydrochloride (Substance 230 as hydrochloride)

Analogously to Example 12, the solution of 12.0 g (23 mmol) of 6-bromo-1- [4- (4-methanesulfonyloxybutyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b ] pyridine (substance 491) in 60 ml of DMF with 17.6 ml (230 mmol) of allylamine and stirred at 50 ° C overnight. After cooling, pour into ice-water and extract twice with ethyl acetate. The combined organic phases are washed with water, dried and concentrated in vacuo. The remaining sticky solid is chromatographed with CHCl₃ / CH₃OH / conc.NH₃ in a ratio of 97/3 / 0.3 to 95/5 / 0.5 as eluent on silica gel. The thus purified free base (4.7 g, 44% resinous solid) is dissolved in 50 ml of isopropanol and transferred with 4 ml of about 6.5M isopropanolic hydrochloric acid in the hydrochloride. The deposited crystals are recrystallized from isopropanol. It gives colorless crystals with a mp. 151-155 ° C in a yield of 2.4 g (21%).
C₂₀H₂₇BrN₄O₂S · HCl, (503,9)
IR spectrum (KBr):
ν (C = O) 1685, 1655 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
0.80-1.80 (11H, m, (CH₂) ₂CH (CH₂) ₃)
2.59 (1H, mz, CONCH)
2.86 (2H, t, N⁺CH₂, J = 7.0 Hz)
3.04 (1H, mz, CONCH)
3.47 (2H, d, N⁺C H ₂CH =, J = 6.0 Hz)
3.80 (1H, mz, CONCH)
4.10 (1H, mz, CONCH)
4.82 (2H, s, NCH₂CO)
5.20-5.90 (3H, m, CH = CH₂)
7.51 (1H, d, pyridine, J = 1.8 Hz)
8.21 (1H, d, pyridine, J = 1.8 Hz)

Example 14 6-Bromo-1- [4- (4-cyclopropylmethylaminobutyl) -piperidyl] - carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine Hydrochloride (substance 235 as hydrochloride)

The suspension of 6.5 g (12.1 mmol) of 6-bromo-1- [4- (4-iodo-butyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine (Substance 489) in 25 ml of DMF is treated with 7.5 ml (84 mmol) of (cyclopropylmethyl) amine and stirred overnight at 50 ° C. After cooling, it is poured into 100 ml of ice water and extracted twice with ethyl acetate. The combined organic phases are washed with water, dried and concentrated in vacuo. The remaining resinous residue is chromatographed with CHCl₃ / CH₃OH / conc.NH₃ in a ratio of 97/3 / 0.3 to 95/5 / 0.5 as eluent on silica gel. The thus purified free base (2.3 g, 40% resinous solid) is dissolved in 30 ml of isopropanol and transferred with 2 ml of about 6.5M isopropanolic hydrochloric acid in the hydrochloride. One obtains cream-colored crystals with a melting point of 198-207 ° C (Zers.). The yield is 2.0 g (32%).
C₂₁H₂₉BrN₄O₂S · HCl, MW = (517.9)
IR spectrum (KBr):
ν (C = O) 1675, 1650 cm ^-1
ν (C = C) 1565 cm ^-1
1 H-NMR spectrum (D₂O):
0.16 (2H, mz, cyclopropane-CH₂)
0.50 (2H, mz, cyclopropane-CH₂)
0.60-1.80 (12H, m, (CH₂) ₂CH (CH₂) ₃ and cyclopropane-CH)
2.40-3.20 (6H, m, N⁺ (CH₂) ₂ and 2 CONCH)
3.75 (1H, mz, CONCH)
4.10 (1H, mz, CONCH)
4.80 (2H, s, NCH₂CO)
7.51 (1H, s, pyridine)
8.19 (1H, s, pyridine)

Example 15 6-bromo-1- {4- [2- (N-allyl-N-cyclopropylcarbonylamino) ethyl] - piperidyl} carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine (Substance 88)

To the solution of 2.7 g (5.67 mmol) of 6-bromo-1- [4- (2-allylamino-ethyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine (Substance 76) and 1.7 ml (12.5 mmol) TEA in 25 ml abs. Dichloromethane is added dropwise at 0 ° C with stirring 0.60 ml (8.96 mmol) of cyclopropane carboxylic acid chloride. After completion of the addition, the mixture is stirred for a further 30 min under ice cooling and 5 h at RT. It is extracted several times with water, dried over sodium sulfate, and the solution is concentrated in vacuo. The residue which remains is chromatographed on silica gel with CHCl₃ / CH₃OH in the ratio 98/2 as eluent, and the product thus purified is crystallized from ethyl acetate. This gives colorless crystals with a mp. Of 138-139 ° C in a yield of 1.9 g (57%).
C₂₂H₂₇BrN₄O₃S, MW = (507.5)
IR spectrum (KBr):
ν (C = O) 1685, 1650, 1610 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃):
0.60-2.00 (12H, m, (CH₂) ₂CHCH₂ and cyclopropyl-C₃H₅)
2.64 (1H, mz, CONCH)
3.15 (1H, mz, CONCH)
3.40 (2H, t, NC H ₂CH₂, J = 7.0 Hz)
3.70-4.20 (3H, m, CONCH and NCH₂CH =)
4.50 (1H, mz, CONCH)
4.59 (1H, d, NCHCO, J = 16.8 Hz)
4.81 (1H, d, NCHCO, J = 16.8 Hz)
5.00-6.00 (3H, m, CH = CH₂)
7.36 (1H, d, pyridine, J = 2.0 Hz)
8.34 (1H, d, pyridine, J = 2.0 Hz)

Example 16 6-bromo-1- {4- [4- (N-allyl-N-methylamino) -butyl] -piperidyl} - carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine Hydrochloride (substance 231 as hydrochloride)

A solution of 13.0 g (27.8 mmol) of 6-bromo-1- [4- (4-allylaminobutyl) -piperidyl] -carbonylmethyl-2-oxo-1,2-dihydro-thiazolo [5.4- b] pyridine (substance 230) and 4.7 ml (33.8 mmol) of TEA in 130 ml of acetone are added dropwise at 5 ° C, the solution of 2.15 ml (34.4 mmol) of iodomethane in 20 ml of acetone. At closing is stirred without further cooling for 5 h at RT and allowed to stand overnight. It is poured into 500 ml of water, al kalisiert the mixture with 30 ml of 2M sodium hydroxide solution and extracted twice with dichloromethane. The combined organi rule phases are washed with water, dried over Natriumsul fat and concentrated in vacuo. The resinous residue was chromatographed with CHCl₃ / CH₃OH / conc.NH₃ in a ratio of 95/5 / 0.5 as eluent on silica gel. The so-purified free base (3.2 g, 25% yellow resin) is dissolved in 50 ml of isopropanol and transferred with 10 ml of about 6M isopropanolic hydrochloric acid in the hydrochloride. There are obtained colorless crystals with a mp of 206-211 ° C (dec.) In a yield of 3.20 g (22%).
C₂₁H₂₉BrN₄O₂S · HCl, MW = (517.9)
IR spectrum (KBr):
ν (C = O) 1685, 1635 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (D₂O):
0.75-1.90 (11H, m, (CH₂) ₂CH (CH₂) ₃)
2.45-3.15 (7H, m, 2 CONCH and N⁺CH₂ and N⁺CH₃)
3.50-3.90 (3H, m, CONCH and N⁺C H ₂CH =)
4.15 (1H, mz, CONCH)
4.82 (2H, s, NCH₂CO)
5.30-6.00 (3H, m, CH = CH₂)
7.54 (1H, s, pyridine)
8.22 (1H, s, pyridine)

The final pro Products are listed in the following Table 1 according to numbers ben. The other connections listed in it are in produced analogously. All melting points are in the column on the far right.  

Table 1

The following are for explanation of the invention End products further examples of concrete substances in the Table 2 listed. In the respective columns are the Meanings of the substituents indicated. The exemplify th compounds can be used both as a base and in the form the above-defined pharmaceutically acceptable Salts are present.  

Table 2

Among the substances listed above and described experimentally, the compounds specifically referred to below are particularly preferred:
6-chloro-1- [4- (2-dimethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (2-diethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrobromide,
6-Chloro-1- [4- (2-cyclopropylamino-ethyl) -piperidyl] -carboxylyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (2-piperidylethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (3-pyrrolidylpropyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (3-dimethylaminopropyl) piperazinyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-allylaminoethyl) -piperidyl] -carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-cyclobutylamino-ethyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (3-dimethylaminopropyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (3-dimethylaminopropyl) piperazinyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its dihydrochloride,
6-bromo-1- [3- (2-pyrrolidylethyl) -pyrrolidyl] -carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-dimethylaminoethyl) piperidyl) carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-diethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrobromide,
6-bromo-1- [4- (2-pyrrolidylethylidene) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (2-dipropylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
1- {4- [2- (N-allyl-N-methylamino) ethyl] -piperidyl} -carbonylmethyl-6-chloro-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (2-pyrrolidylethyl) -piperidyl] -carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-dipropylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
1- {4- [2- (N -allyl-N-methylamino) ethyl] -piperidyl} -carbonylmethyl-6-bromo-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-pyrrolidylethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride.

Unless already mentioned as special salts in the above ge called, are these preferred compounds as well as the other substances according to the formula (I) in particular in the form of the hydrochloride, hydrobromide, sulfate, phosphate, Ace tats, citrates, fumarates, malate, methanesulfonate or tar pretended.  

Synthesis of the intermediates according to the invention of the formula (IV)

Example I 6-chloro-1- [4- (hydroxymethyl) -piperidyl] carbonylmethyl-2- oxo-1,2-dihydrothiazolo [5.4-b] pyridine (Substance 442)

The solution is heated analogously to Example 10 from 35.0 g (143 mmol) of 6-chloro-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, 17.6 g (153 mmol). 4-Hydroxymethylpi peridin and 37.8 g (153 mmol) of EEDQ in 450 ml of THF 8h under reflux. Then the solvent is largely taken off in vacuo and the residue is partitioned between water and ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The residue is taken up in 500 ml of chloroform, the precipitated solid is filtered off and crystallized from acetonitrile. Colorless crystals with a mp of 215-217 ° C in a yield of 24.3 g (50%) are obtained.
C₁₄H₁₆ClN₃O₃S, MW = (341.8)
IR spectrum (KBr):
ν (C = O) 1670, 1635 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (DMSO-d₆):
0.80-2.00 (5H, m, CH₂CHCH₂)
2.60 (1H, mz, CONCH)
3.20 (1H, mz, CONCH)
3.33 (2H, d, CH₂O, J = 7.0 Hz)
3.90 (1H, mz, CONCH)
4.30 (1H, mz, CONCH)
4.54 (1H, t, OH, interchangeable)
4.95 (2H, s, CH₂CO)
7.99 (1H, d, pyridine, J = 1.9 Hz)
8.36 (1H, d, pyridine, J = 1.9 Hz)

Example II 6-Bromo-1- [4- (2-hydroxyethyl) -piperidyl] carbonylmethyl-2- oxo-1,2-dihydrothiazolo [5.4-b] pyridine (Substance 452)

Analogously to Example 1, 40.0 g (138 mmol) of 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine and 24.6 g (152 mmol) of CDI in 300 ml of abs , THF refluxed for 1 h. It is then cooled to 0 ° C, added dropwise with cooling, the solution of 21.4 g (166 mmol) of 4- (2-hydroxy ethyl) piperidine in 100 ml of abs. THF, stirred under ice-cooling for a further 4.5 h and allowed to stand at RT overnight. At closing, the solvent is largely taken off in vacuo and the residue is partitioned between 600 ml each of water and ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The resinous crude product is chromatographically pre-chromatographed on silica gel (CHCl₃ / CH₃OH in the ratio 90/10) and then recrystallized from 100 ml of ethyl acetate. There are light beige crystals with a mp. Of 158 ° C in a yield 38.4 g (69%).
C₁₅H₁₈BrN₃O₃S, MW = (400.3)
IR spectrum (KBr):
ν (C = O) 1680, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃ / DMSO-d₆):
0.80-2.05 (7H, m, (CH₂) ₃CH)
2.50-3.05 (2H, m, CONCH and OH)
3.16 (1H, mz, CONCH)
3.65 (2H, t, CH₂O, J = 6.2 Hz)
3.80 (1H, mz, CONCH)
4.50 (1H, mz, CONCH)
4.69 (1H, d, NCHCO, J = 16 Hz)
4.88 (1H, d, NCHCO, J = 16 Hz)
7.47 (1H, d, pyridine, J = 1.8 Hz)
8.32 (1H, d, pyridine, J = 1.8 Hz)

Example III 6-chloro-1- [4- (iodomethyl) -piperidyl] carbonylmethyl-2-oxo- 1,2-dihydrothiazolo [5.4-b] pyridine (Substance 444)

To the suspension of 5.0 g (14.6 mmol) of 6-chloro-1- [4- (hydroxy-methyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine (substance 442) in 100 ml abs. Dichloromethane is added with stirring 1.4 g (20.5 mmol) of imidazole and 4.2 g (16.1 mmol) of triphenylphosphine and then while cooling with ice water 3.9 g (15.4 mmol) of iodine. After completion of the addition, the mixture is stirred for 2 h without further cooling and allowed to stand at RT overnight. It is extracted several times with dilute sodium disulphite solution, washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The har Zige residue is pre-purified chromatographically in silica gel on silica gel and then crystallized from 30 ml of ethyl acetate. This gives almost colorless crystals with a mp of 158-159 ° C in a yield of 5.2 g (79%).
C₁₄H₁₅ClIN₃O₂S, MW = (451.7)
IR spectrum (KBr):
ν (C = O) 1670, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃):
1.00-2.20 (5H, m, CH₂CHCH₂)
2.66 (1H, mz, CONCH)
3.13 (3H, mz and d, CH₂I and CONCH, J = 6.0 Hz)
4.00 (1H, mz, CONCH)
4.63 (2H, mz and d, CONCH and NCHCO, J = 16 Hz)
4.82 (1H, d, NCHCO, J = 16 Hz)
7.25 (1H, d, pyridine, J = 2.0 Hz)
8.28 (1H, d, pyridine, J = 2.0 Hz)

Example IV 6-Bromo-1- [4- (4-iodobutyl) -piperidyl] carbonylmethyl-2-oxo- 1,2-dihydrothiazolo [5.4-b] pyridine (Substance 489)

Analogously to Example III, to the suspension of 19.2 g (44.8 mmol) of 6-bromo-1- [4- (4-hydroxybutyl) -piperidyl] -carbonylmethyl-2-oxo-1,2-dihydrothiazolo [ 5.4-b] pyridine (sub stance 486) in 200 ml abs. Dichloromethane with stirring 4.40 g (62.8 mmol) of imidazole, 13.0 g (50 mmol) of triphenylphosphine and then with ice cooling in portions at 12-18 ° C 12.0 g (47 mmol) of iodine. After completion of the addition, the mixture is stirred for 5 h without further cooling and allowed to stand at RT overnight. It is extracted several times with dilute sodium disulfite solution, washed with water, dried over sodium sulfate and the solvent is removed in vacuo. The residue, a dark ge colored resin (38 g) is purified by chromatography on silica gel chromatographed in chloroform and then crystallized by trituration with methyl tert-butyl ether. Obtained pale yellowish colored crystals with a mp. Of 141-143 ° C in a yield of 14.2 g (58%).
C₁₇H₂₁BrIN₃O₂S, MW = (538.3)
IR spectrum (KBr):
ν (C = O) 1675, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃):
1.00-2.00 (11H, m, (CH₂) ₂CH (CH₂) ₃)
2.66 (1H, mz, CONCH)
3.10 (1H, mz, CONCH)
3.21 (3H, t, CH₂I, J = 7 Hz)
3.90 (1H, mz, CONCH)
4.50 (1H, mz, CONCH)
4.61 (1H, d, NCHCO, J = 16 Hz)
4.81 (1H, d, NCHCO, J = 16 Hz)
7.37 (1H, d, pyridine, J = 1.9 Hz)
8.34 (1H, d, pyridine, J = 1.9 Hz)

Example V 6-Bromo-1- [4- (2-methanesulfonyloxyethyl) -piperidyl] carbonyl methyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine (Substance 461)

To the suspension of 36.0 g (90 mmol) of 6-bromo-1- [4- (2-hydroxyethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine (substance 452), 360 ml abs. Dichloromethane and 13.8 ml (100 mmol) of TEA are added dropwise with cooling at 0 ° C 7.4 ml (95 mmol) of methanesulfonyl chloride. After completion of the addition, the mixture is stirred for 1 h without cooling, the solution is washed twice with ice water, dried over sodium sulfate and the solution is concentrated in vacuo. The crystalline crude product is recrystallized from 1.1 l of acetonitrile. There are obtained pale beige crystals with a mp. Of 189-191 ° C in a yield of 37.0 g (86%).
C₁₆H₂₀BrN₃O₅S₂, MW = (478.4)
IR spectrum (KBr):
ν (C = O) 1675, 1645 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃ / DMSO-d₆):
1.00-2.00 (7H, m, (CH₂) ₃CH)
2.60 (1H, mz, CONCH)
3.05 (3H, s, CH₃SO₂)
3.20 (1H, mz, CONCH)
3.90 (1H, mz, CONCH)
4.31 (2H, t, CH₂O, J = 5.5 Hz)
4.50 (1H, mz, CONCH)
4.71 (1H, d, NCHCO, J = 16 Hz)
4.87 (1H, d, NCHCO, J = 16 Hz)
7.45 (1H, d, pyridine, J = 1.7 Hz)
8.34 (1H, d, pyridine, J = 1.7 Hz)

Example VI 6-Bromo-1- [4- (4-methanesulfonyloxybutyl) -piperidyl] carbonyl methyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine (Substance 491)

38.2 g (90 mmol) of 6-bromo-1- [4- (4-hydroxybutyl) -piperidyl] -carbonyl-methyl-2-oxo-1,2-dihydrothiazolo are added dropwise to the suspension analogously to Example V. b] pyridine (substance 486), 340 ml abs. Dichloromethane and 15.4 ml (110 mmol) of TEA with cooling at 5-8 ° C 7.6 ml (100 mmol) Methansulfonsäu chloride. After completion of the addition, the mixture is stirred for 5 h without cooling, the solution is washed several times with ice water, dried over sodium sulfate and the solution is concentrated in vacuo. The resinous residue is taken up in 200 ml of hot toluene and crystallized with slow cooling in the form of light beige crystals. They have a mp of 108-110 ° C. The yield is 41.4 g (92%).
C₁₈H₂₄BrN₃O₅S₂, MW = (506.5)
IR spectrum (KBr):
ν (C = O) 1680, 1650 cm ^-1
ν (C = C) 1570 cm ^-1
1 H-NMR spectrum (CDCl₃):
1.00-2.00 (11H, m, (CH₂) ₂CH (CH₂) ₃)
2.65 (1H, mz, CONCH)
3.02 (3H, s, CH₃SO₂)
3.15 (1H, mz, CONCH)
3.90 (1H, mz, CONCH)
4.25 (2H, t, CH₂O, J = 6 Hz)
4.53 (1H, mz, CONCH)
4.61 (1H, NCHCO, J = 16 Hz)
4.82 (1H, NCHCO, J = 16 Hz)
7.38 (1H, d, pyridine, J = 2.0 Hz)
8.34 (1H, d, pyridine, J = 2.0 Hz)

The others produced by way of example, in the following Intermediate Nos. 453, 462 listed in Table 3 and 486 according to the formula (IV) were synthesized in an analogous manner thesized.  

Table 3

In the following Table 4 are still a number of Intermediates in the form of selected concrete Compounds described by way of example.  

Table 4

Particular preference is given to intermediates according to the formula (IV) already mentioned above or experimentally described also the following substances:
6-chloro-1- [4- (hydroxymethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (hydroxymethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-chloro-1- [4- (2-hydroxyethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (2-hydroxyethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-chloro-1- [4- (3-hydroxypropyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazole o [5.4-b] pyridine,
6-bromo-1- [4- (3-hydroxypropyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-chloro-1- [4- (4-hydroxybutyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (4-hydroxybutyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-Chloro-1- [4- (6-hydroxyhexyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or
6-Bromo-1- [4- (6-hydroxyhexyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine

Synthesis examples for the preparation of starting compounds

The synthesis of the starting compounds can be as a in the description of the synthetic variants he already was läutert, according to known methods in an analogous manner carry out. An example of this is representative for others, 6-chloro-1-carboxymethyl-2-oxo-1,2-dihydro thiazolo [5.4-b] pyridine call, according to the literature EP-A-0 232 740 has been presented.

The following are for the sake of better understanding the synthesis of the final products of the invention different Examples of the representation of starting compounds be wrote:

Example a 6-chloro-1- (2-carboxyethyl) -2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine

The mixture of 20.0 g (107 mmol) of 6-chloro-2-oxo-1,2-di hydrothiazolo [5.4-b] pyridine according to EP-A-0 232 740, 8.0 ml (121 mmol) of acrylonitrile, 0.40 g of potassium hydroxide and 70 ml of Py Ridin is stirred at 100 ° C for 18 h. After cooling, pour The black solution in 300 ml of 2M acetic acid sucks this out falling crude 6-chloro-1- (2-cyanoethyl) -2-oxo-1,2-dihydro thiazolo [5.4-b] pyridine and dried in vacuo. The off prey is 22.1 g (86%).

22.0 g (91.8 mmol) of the nitrile are concentrated in 220 ml. salt acid and stirred at 70 ° C for 1 h. After cooling If you pour into 200 ml of ice water, the deposited sucks Crude product and digested with 200 ml of methanol. That again extracted product is recrystallized from 650 ml of methanol Siert. Its yield is 8.0 g (34%) in the form of beige Crystals of 6-chloro-1- (2-carboxyethyl) -2-oxo-1,2-dihydro  thiazolo [5.4-b] pyridines, the mp of which is located at 204-209 ° C (Decomposition).

Example b 6-bromo-1-carboxymethyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine

The solution of 75 g (1.137 mol) of potassium hydroxide in 635 ml Methanol is saturated with hydrogen sulfide at 2 ° C. To This solution is added dropwise with stirring, a solution of 90.0 g (0.379 mol) of 5-bromo-2-chloro-3-nitropyridine in 400 ml Me ethanol, keeping the temp. below 15 ° C. you stir for a further 2 h at 15-20 ° C and then concentrated in the Va a vacuum. The residue is dissolved in 1 l of 1.25M sodium hydroxide solution, heated to 50 ° C and stirred 90.0 g (0.472 mol) of sodium disulphide fit in small portions. It is stirred for a further 2 h, cooled and neutralizes the solution with acetic acid. The obtained Precipitate 3-amino-5-bromo-2-mercaptopyridine from sucked, washed thoroughly with water, in vacuo over Phosphorus pentoxide dried and further reacted as a crude product puts.

For suspension of the obtained amino-bromotr-mercaptopyridine 27.7 ml are added dropwise in 1 l of dioxane under an argon atmosphere (0.228 mol) trichloromethyl chloroformate ("Di phosgene "), dissolved in 200 ml of dioxane, with stirring and heated after completion of addition for 1 h at 70-75 ° C. It cools RT, sucks the product, washed with dioxane and stirred one half an hour with 200 ml of water. The 6-bromine is sucked in 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine again and dries in vacuo over phosphorus pentoxide. The yield be carries 78.9 g (90%). The compound falls in the form of brown pale yellow crystals with a melting point of about 250 ° C (decomp.) on.  

To the suspension of 39.4 g (170 mmol) 6-bromo-2-oxo-1,2- dihydrothiazolo [5.4-b] pyridine in 400 ml of DMF is added 0-5 ° C in portions 66 ml of sodium ethylate solution (20% in eth nol, 170 mmol), 38 ml (340 mmol) of bromine are then added dropwise Essigsäureethylester at 10-15 ° C and stirred for 4h without white tere cooling. Thereafter, the reaction mixture is poured into 750 ml of ice water, the resulting precipitate isolated, Washes with water and crystallises the still moist raw material product from 200 ml of ethanol. The yield of 6-bromo-1 ethoxycarbonylmethyl-2-oxo-1,2-dihydrothiazolo [5,4-b] -pyrido din with a mp of 131-132 ° C is 35.5 g (66%).

The suspension of 35.5 g (112 mmol) of the ethyl ester in egg ner mixture of 350 ml of acetic acid and 23 ml of conc. Salzsäu The mixture is heated to reflux for 12 h with stirring. After cooling At RT, the fine precipitate is filtered off with suction, washed with water Water and dried in vacuo over phosphorus pentoxide. The Yield is 26.6 g (82%). Since thus obtained 6-bromo-1 carboxymethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine a mp of 261-262 ° C on.

Example c 6-Bromo-1- (3-carboxypropyl-2-oxo-1,2-dihydrothiazolo [5,4-b] pyridine

To the suspension of 20.0 g (86.6 mmol) 6-bromo-2-oxo-1,2- dihydrothiazolo [5.4-b] pyridine in 200 ml of DMF is added about 10 ° C 33.4 ml of sodium ethylate solution (20% in ethanol, 86.6 mmol), then 24.4 ml (173 mmol) of 4-bromine butter are added dropwise acid ethyl ester at 10-12 ° C and stirred for a further 8h at RT. Thereafter, the reaction mixture is poured into 700 ml of ice water and allowed to stand overnight at 5 ° C, sucks the precipitate Wash, wash with water and dry in vacuo over phosphorus  pentoxide. For further purification with CHCl₃ / CH₃OH in Ratio 95/5 as eluent on silica gel chromatogra initialed. The yield of 6-bromo-1- (3-ethoxycarbonylpropyl) - 2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine is 13.2 g (44%).

13.0 g (37.7 mmol) of the ethyl ester are in a mixture from 60 ml of acetic acid and 7.5 ml of conc. Hydrochloric acid 5h below Reflux heated. It is then cooled and poured into 100 ml of ice water poured. The product is filtered off with suction, washed with water Wash and dry in vacuo over phosphorus pentoxide. The Yield of 6-bromo-1- (3-carboxypropyl-2-oxo-1,2-dihydro thiazolo [5.4-b] pyridine with a mp of 175-177 ° C be carries 9.6 g (81%)

Example d 4- [2- (2-Oxo-1-pyrrolidinyl) -ethyl] -piperidine hydrochloride

To dissolve 159 g (693 mmol) of 1-tert-butoxycarbonyl-4- (2- hydroxyethyl) piperidine and 116 ml (832 mmol) TEA in 800 ml Section. Dichloromethane is added dropwise at 5-10 ° C with stirring 59.4 ml (763 mmol) of methanesulfonyl chloride and stirred to completion determined addition further 30 min at the same temperature. to closing the reaction solution with 400 ml of water ex traced, washed twice with 50 ml of water each time and dried over sodium sulfate. After removal of the Lösemit under vacuum, crude 1-tert-butoxycarbonyl-4- (2- methanesulfonyloxyethyl) piperidine as a countless, long sam crystallizing oil (211 g, 99%), the without a long re cleaning is used.

To the suspension of 5.9 g of sodium hydride (80% in paraffin oil, 195 mmol) in 130 ml of abs. DMF is added dropwise at 5 ° C 11.0 ml (143 mmol) of 2-pyrrolidone with stirring, holds another 10  min at the same temperature and then adds portions 40.0 g (130 mmol) of crude 1-tert-butoxycarbonyl-4- (2- methanesulfonyloxyethyl) piperidine as a solid. you Stirring for a further 4 h at RT, then hydrolysed by dripping of 200 ml of water and the mixture is extracted with 200 ml Dichloromethane. The organic phase is gewa with water rule, concentrated in vacuo and degassed at 50 ° C / 0.1 mbar. The resulting brown oil is chromatographed on silica gel with chloroform, later CHCl₃ / CH₃OH (98/2), purified by chromatography. Yield 23 g (60%) of colorless oil of 1-tert-butoxycarb onyl-4- [2- (2-oxo-1-pyrrolidinyl) ethyl] -piperidine.

23.0 g (77.6 mmol) of 1-tert-butoxycarbonyl-4- [2- (2-oxo-1-pyr rolidinyl) -ethyl] piperidine are mixed with a mixture 100 ml of ethanol and 15 ml of conc. Hydrochloric acid for 1 h under reflux heated to boiling. Then concentrated in vacuo to Dry and dry the resinous residue in vacuo over phosphorus pentoxide. By crystallization from 20 ml of iso Propanol gives 4- [2- (2-oxo-1-pyrrolidinyl) -ethyl] -pi peridine hydrochloride as a colorless, hygroscopic crystal le. The yield is 11.3 g (62%); the Schmp. lies at 121-127 ° C.

Example e 4- (2-Dimethylaminoethylene) -piperidine dihydrochloride

29.9 g (150 mmol) of 1-tert-butoxycarbonyl-4-piperidone and 62.3 g (160 mmol) of 2-dimethylaminoethyl-triphenylphospho niumbromid be in 300 ml of abs. THF submitted and under Stirring at 10-20 ° C in portions with 19.5 g (170 mmol) of Ka lium tert-butoxide added. After completion of the addition, stirring Continue mixing for 6h at RT and let stand overnight. Then draw most of the solvent in the Vacuum off, the residue is taken up in 300 ml of toluene, washed  several times with water and finally extracted the organi phase with 200 ml of 5% hydrochloric acid. The toluene phase is shaken out again with 30 ml of water. The United acidic aqueous phases are washed with 40 ml of toluene and then with conc. Caustic soda alkalized; the liberated product is made up with 200 and 100 ml of toluene accepted. The combined organic phases are washed with what washed and evaporated. This gives 44.5 g (93%) of ro hes 1-tert-butoxycarbonyl-4- (2-dimethylaminoethylene) -pi peridin as a pale yellow oily liquid.

35 g of this crude product are in 200 ml of about 2.75M metha Nolic hydrochloric acid stirred for 2 h at RT and then 6 h heated to boiling under reflux. After that, under ver reduced pressure to dryness and solid back was isopropanol with the addition of little isopropanoli recrystallized hydrochloric acid. The yield of 4- (2-di methylaminoethylene) -piperidine dihydrochloride with a Melting point of 231-236 ° C (dec.) Is 24.1 g (77%).

Example f 4- [4- (4-piperidyl) -butyl] -morpholine dihydrochloride

To dissolve 133.5 g (515 mmol) of 1-tert-butoxycarbonyl-4- (4-hydroxybutyl) piperidine and 86 ml (618 mmol) TEA in 660 ml abs. Dichloromethane is added dropwise at 5-10 ° C with stirring 44.0 ml (567 mmol) of methanesulfonyl chloride and stirred after completion of the addition, continue for 30 min at the same temperature door. Subsequently, the reaction solution with 300 ml Was extracted, washed twice with 50 ml of water and dried over sodium sulfate. After removing the solvent by means of vacuum, crude 1-tert-butoxycarbonyl-4 is obtained. (4-methanesulfonyloxybutyl) -piperidine as a yellow oil in one  Yield of 168.2 g (99%), without further purification is used.

The solution of 58.0 g (173 mmol) of crude 1-tert-butoxycarb onyl 4- (4-methanesulfonyloxybutyl) -piperidine and 30.1 ml (346 mmol) morpholine in 120 ml of ethanol is 7h at 50 ° C ge stir. Then you narrowed the solution largely and distribute the concentrate between each 300 ml of 0.5M sodium hydroxide solution and dichloromethane. The aqueous phase is shaken again with dichloromethane, the combined organic Stir with water, dry over sodium sulfate and draw remove the solvent in vacuo. The residue becomes a cleaner tion with CHCl₃ / CH₃OH in the ratio 95/5 as solvent filtered through a short silica gel column. You get 54.8 g (97%) 4- [4- (1-tert-Butoxycarbonyl-4-piperidyl) -butyl] - morpholine in the form of colorless, waxy crystals.

To dissolve 54.0 g (165.6 mmol) of 4- [4- (1-tert-butoxycarb onyl-4-piperidyl) -butyl] -morpholine in 300 ml of ethanol 38.6 ml (386 mmol) of conc. Hydrochloric acid and heated for 40 min refluxing to boiling. Subsequently, the solution is in Concentrated vacuum and the residue from 200 ml of isopropanol recrystallized. The yield of 4- [4- (4-piperidyl) -bu tyl] -morpholine dihydrochloride with a mp of 224-231 ° C. (Dec) is 39.6 g (80%).

Example g 4- (2-Dimethylaminoethyl) hexahydroazepine dihydrochloride

13.7 g (64.3 mmol) of 1-tert-butoxycarbonyl-hexahydroazepine-4- on and 28.0 g (67.5 mmol) of 2-dimethylaminoethyl-triphenyl Phosphonium bromide are presented in 150 ml of toluene and un stirring at 5-10 ° C in portions with 8.6 g (75 mmol) Ka lium tert-butoxide added. After completion of the addition, stirring  the mixture without further cooling overnight. Afterwards washes Man several times with water and extract the organic phase with 40 and 20 ml of 10% hydrochloric acid. The toluene phase is still once shaken with 30 ml of water. The united sau ren aqueous phases are washed with 30 ml of toluene and subsequently with conc. Caustic soda alkalized; the free The product is taken up with twice 50 ml of toluene. The combined organic phases are washed with water and evaporated. 11.6 g (67%) of crude are obtained 1-tert-butoxycarbonyl-4- (2-dimethylaminoethylene) -hexahydro azepine as a pale yellow oily liquid. Another lot (2.7 g, 16%) can be concentrated by concentrating the alkaline What Serphase, dissolving the residue in 20 ml of water and he Extract again with toluene.

14.1 g (52 mmol) of the crude product are dissolved in 100 ml of methanol dissolved and with 2.5 g of 5% palladium carbon as catalyst at Normal pressure until the completion of the hydrogen uptake hy driert. It is filtered and the filtrate is concentrated in vacuo, wherein 12.1 g (81%) of crude 1-tert-butoxycarbonyl-4- (2-di methylaminoethyl) -hexahydroazepine as a yellowish oil erhal be.

12.0 g (44 mmol) of crude 1-tert-butoxycarbonyl-4- (2-dimethyl aminoethyl) -hexahydroazepin be with 50 ml about 2.7M me ethanolic hydrochloric acid stirred for 2 h at RT and then Heated to boiling for 3h under reflux. It is concentrated in a vacuum and crystallizes the resinous residue from 50 ml Isopropanol with the addition of 10 ml of isopropanolic salt acid. The yield of 4- (2-dimethylaminoethyl) hexahydro azepine dihydrochloride in the form of colorless, hygroscopic Crystals with a mp of 186-188 ° C is 7.2 g (67%).  

Example h 1- (4-dimethylaminobutin-2-yl-1) piperazine trihydrochloride

To dissolve 30.0 g (161 mmol) of 1-tert-Butoxycarbonylpi perazine and 14.7 ml (194 mmol) of 3-bromopropyne in 80 ml of DMF Are added 27.4 g (198 mmol) of potassium carbonate and heated Mix with stirring for 7 h at 75-80 ° C. After cooling if it is filtered off from salts, the filtrate is concentrated in vacuo and pours on ice water. It is extracted several times with chloro form, the combined organic phases with 2M Na wash tronaqueous solution and then water, dried over sodium sulfate and the solvent is removed in vacuo. The residue is on silica gel with chloroform, later CHCl₃ / CH₃OH im Ratio 98/2 purified by chromatography. You get 20.0 g (55%) of 1-tert-butoxycarbonyl-4- (propyn-2-yl-1) -pi perazine as a yellowish oil.

13.5 g (60.0 mmol) of 1-tert-butoxycarbonyl-4- (propyn-2-yl-1) - piperazine and 6.8 g (66.2 mmol) of bis (dimethylamino) -methane are dissolved in 135 ml of dioxane and treated with 0.2 g of copper (I) Chloride stirred at 80 ° C for 6 h. Then you narrow the Lö solution to about 30 ml, takes up in chloroform, filtered the solution and wash it twice with water. It is dried over sodium sulphate, the solvent is removed in vacuo and cleanse the dark brown oily residue of chromatogra on silica gel with CHCl₃ / CH₃OH in the ratio 95/5 than Eluent. The yield of 1-tert-butoxycarbonyl-4- (4- dimethylaminobutin-2-yl-1) -piperazine is 9.63 g (57%).

9.0 g (32.1 mmol) of 1-tert-butoxycarbonyl-4- (4-dimethylamino butin-2-yl-1) -piperazine are dissolved in 45 ml methanol with 12.5 ml conc. Hydrochloric acid heated to boiling for 3h under reflux. Then the mixture is concentrated in vacuo, dissolves the back stood in 100 ml of water and destained with charcoal. The filtered solution is concentrated again in vacuo and the  solid residue recrystallized from 100 ml of methanol. The Yield of 1- (4-dimethylaminobutin-2-yl-1) -piperazine tri hydrochloride in the form of colorless crystals with a mp. of <190 ° C (dec.) is 7.6 g (82%).

Example i 2 - [(3- (1-pyrrolidyl) -propyl] -morpholine dihydrochloride

To dissolve 13.0 g (89.5 mmol) of 2- (3-hydroxypropyl) -mor pholine in 60 ml abs. THF is added dropwise at 7-15 ° C with stirring the solution of 21.2 g (94.0 mmol) of di-tert-butyl dicarbonate in 40 ml abs. THF and then stirred for a further 2 h at RT. Thereafter, the solvent is evaporated and the residue until Degassed 100 ° C / 0.1 mbar. The yield of crude 4-tert-but oxycarbonyl-2- (3-hydroxypropyl) -morpholine, which without Reini is still 22.0 g (100%).

To dissolve 22.0 g (89.5 mmol) of crude 4-tert-butoxycarb onyl-2- (3-hydroxypropyl) -morpholine and 15.0 ml (107.6 mmol) TEA in 110 ml abs. Dichloromethane is added dropwise at 0 ° C under Stir 7.7 ml (98.6 mmol) of methanesulfonyl chloride and stir the resulting suspension at the same temperature for 1 h continue. Subsequently, the mixture with 100 ml of dichlor diluted methane, extracted twice with 50 ml of water and the clear organic phase dried over sodium sulfate. After removal of the solvent in vacuo, 28.3 g (98%) crude 4-tert-butoxycarbonyl-2- (3-methanesulfonyloxy propyl) -morpholine as a yellowish oil, which without further Rei is implemented.

The solution of 14.5 g (44.8 mmol) crude 4-tert-butoxycarb onyl 2- (3-methanesulfonyloxypropyl) -morpholine and 14.8 ml (179 mmol) of pyrrolidine in 50 ml of ethanol is added overnight RT stirred. Subsequently, the solution is concentrated largely  and distribute the concentrate between 200 ml of 0.5M sodium bicarbonate caustic soda and dichloromethane. Shake the aqueous phase again with dichloromethane, wash the united or ganic phases with water, dried over sodium sulfate and withdraws the solvent in vacuo. The residue will be for purification with CHCl₃ / CH₃OH in the ratio 90/10, later CHCl₃ / CH₃OH / conc.NH₃ in the ratio 90/10 / 0.5 as a solvent chromatographed on silica gel. This gives 9.5 g (71%) 4-tert-butoxycarbonyl-2- [3- (1-pyrrolidyl) propyl] morpholine in the form of a yellowish, gradually crystallizing Oil.

To dissolve 9.5 g (31.8 mmol) of this compound in 50 ml Ethanol is added 7.0 ml (70 mmol) of conc. Hydrochloric acid, stir overnight at RT and heated to reflux for 40 min Boil. The solution is then concentrated in vacuo and the residue from 20 ml of isopropanol with the addition of 3 ml of diisopropyl ether recrystallized. The yield 2 - [(3- (1-pyrrolidyl) -propyl] -morpholine dihydrochloride with egg The melting point of 176-179 ° C is 5.6 g (65%).  

Production of the medicines

The manufacture of medicinal products containing one or several compounds of the invention takes place in üb Licher manner by means of common pharmaceutical-technical Method. For this purpose, the substances of the invention as or in the form of their salts, optionally in combination tion with other active substances, together with appropriate pharmaceutically acceptable excipients and carriers to the processed various forms of medication, for example solid, perorally administrable medicines, such as tablets dragees, chewing and sublingual tablets. This remedy can be formulated as dose units, depending on the objective, flavor enhancement, control of drug release in the gastric and intestinal tract (eg gastric juice resistance, small intestine solubility, accelerated or sustained release), with the respectively suitable paint or polymer substances cover. For the production of medicines come also liquid administrable dosage forms such. B. Emul ions, suspensions, solubilisates or solutions, as well in soft gelatin capsules filled masses into consideration. The Capsule preparations can also be used as hard gelatine capsules in which the active ingredient optionally under Admixture of finely divided powdery carriers, ge if necessary, be bottled after suitable granulation. The active ingredient can also be ver together with in the heat liquid excipients, such. As fatty substances or suitable Neten polyethylene glycols, etc., which in the cold after the Solidify into the soft or hard gelatine capsules, produce. Hard gelatine capsule preparations can also be by making flat tablets with something smaller diameter than the capsule diameter in the  Cavity of the capsule material fills or ge accordingly formed oblong tablets into the open capsule bottoms sets. The capsule preparations can also be used for reasons of Taste improvement or controlled drug-free or the resistance to gastric juice or small intestine solubility in the usual way with suitable polymeric coating components cover.

In the preparation of medicines containing The compounds of the invention are also externally Applicable forms into consideration, such as. As ointments, creams, Gels, solutions or patches, although other common Transdermal systems can be prepared.

It can be with the compounds of the invention, ge if necessary in combination with other active substances for the at the beginning or below listed indications, too rectally administrable forms such. B. suppositories or Make rectal capsules. As typical medicines would be still sprays, cover pastes or balm, in particular for To call support in the treatment of asthma.

The substances according to the invention, optionally in combination with other active ingredients, can also be by In administer it. As injection preparations come there in particular intramuscular, intravenous or intra Glutäal administered preparations into consideration. This is the Active ingredient as base, optionally with solubilizing agent or in salt form, if necessary in combination with buffer substances or suitable salts and substances for Adjustment of isotonicity and other carrier media ver mixed and dissolved. The Injectabilia can be also as suspensions, crystal suspensions or lyophylls  make sate. These include subcutaneously administered Depot preparations in the form of implant compacts or molds lingen.

The perorally administrable remedy forms can also be used as Lutschpastillen or chewing gum, etc. are present. In special Cases can also pernasally administered preparations for Application reach. Furthermore, the erfindungsge also substances to inhalation forms, if desired Process metered aerosols.

The content of one or more substances according to the invention optionally in conjunction with one or more other active ingredients for the indicated indications, can between 0.01 or 0.1 and 99 or 99.9 wt .-%, in particular dere between 1 and 96 wt .-% amount.

As excipients and carriers for the desired drug all substances familiar in the art are suitable. These include solvents, gelling agents, tableting and Encapsulation aids, suppository bases, suspen agents, thickeners, emulsifiers, polymers and other release controls, as well as varnishes or disintegrants, counter-sticks and lubricants, Disper greases, defoaming agents, solubilizers or so Lubilizers, permeation promoters and complexing agents or inclusion compounds, such as. B. cyclodextrins.

Other additives include antioxidants, vitamins, Sweeteners, flavoring agents, preservatives tel, flavorings, dyes, buffer substances, skeleton image for the production of lyophilizates, such as mannitol, dextran, Sucrose, human albumin, lactose, PVP or gelatin types,  into consideration. For the production of tablets come alongside above-mentioned excipients still granulating, Trennmit tel, direct tableting, lubricants, fillers, bin in the form of lactose, starches, cellulose derivatives te, such as MC, HPC, silica, flame dispersed silica di oxide, talcum, stearates (magnesium stearate), phosphates (such as Dicalcium phosphate), microcrystalline cellulose & c. a.m., in Consideration. In a known manner, multi-layer Ta blanks or core / coated tablets to obtain a press lingen for controlled drug delivery are made.

The medicaments containing the inventive Compounds, optionally in combination with others, active substances suitable for the respective indications, depending on the form can be oral, parenteral, by inhalation nem, pernasal, transdermal or other topical species and Way, intravenous, subcutaneous or percutaneous, intraglutaeal, etc. be applied.

The administered doses or dosage units are depending on Severity of illness, general condition and age of Pa were different, but also between the acute treatment and the long-term therapy is different. The daily do can be between 0.01 and 100 mg per kg of body weight be, preferably at 0.1 to 20 mg per kg, in particular preferably at 1 to 2, 5 to 10 or 15 mg per kg Körperge weight lie. The single dose units of the or the active compounds according to the invention in each case 0.01, 0.1, 0.2, 0.5, 1, 2, 5, 10, 20, 50 or 100, maximum 200 each mg per administration.

The active compounds according to the invention can be in the form of their Acid addition salts, hydrates or solvates individually or in  Combination with each other, if necessary also with addition other active substances, to the desired medicines verar BEITEN. In the case of the combination Wirkwirk invention Substances with other drugs may also give them If necessary, according to the requirements, in different Arz Neiformen separately next to each other in the drug packages present, z. B. as tablets in addition to ampoules.

Another object of the invention is a method for the treatment of the human or animal body, in which a substance or a mixture of substances according to formula (I), wherein the substituents are as defined above have, for the treatment of bronchial asthma, the bron chial hyperreactivity, of bronchospasm, the broncho Constriction, of chronic venous insufficiencies, Mi green, chronic cough, for bronchospasmolysis or Un Suppression of chronic pain, if necessary in Combination with other agents or others in the indicated indications of appropriate active ingredients administered becomes.

Furthermore, the invention relates to a substance or Stoffge mixture according to formula (I) for use in a therapeuti in which the therapeutic use in the Related to one or more medical indications bronchial asthma, bronchial hyperreactivity, Bronchospasm, bronchoconstriction, chronic venous Insufficiency, migraine, chronic cough or Bron chospasmolysis or suppression of chronic pain, optionally in combination with others in the genann Indications for appropriate drugs becomes.  

Also, the use of one or more substances according to formula (I) for the manufacture of medicaments for the treatment of human or animal body, especially in the Zu Correlation with one or more medical indicators in bronchial asthma, bronchial hyperreactivity, Bronchospasm, bronchoconstriction, chronic venous Insufficienien, migraine, chronic cough, the Broncho spasmolysis or suppression of chronic pain in combination with others, in this indicator NEN appropriate drugs or the use of the Substances according to formula (I) in a corresponding diagnostic decorative method provides an embodiment of the invention represents.

Likewise belongs to the scope of the invention Ver drive for the production of medicines containing a salary on one or more compounds of the formula (I) which in the processing of these agents together with each suitable, pharmaceutically acceptable carrier and auxiliary substances to the finished dosage form.

Depending on the medical indication in question is the appropriate dosage form depending on the therapeutic Application selected. So be for a long-term treatment ment, z. From bronchial asthma or venous insufficiency, especially transdermal systems or solid peroral available medications such as tablets or capsules, especially sustained release forms are administered. For the crop Acute seizures can be inhaled or In jectabilia.  

Another object of the invention is the use tion of one or more compounds according to the general Formula (I) for therapeutic treatment, in particular in Related to the medical referred to above Indications.

Furthermore, there is an embodiment of the invention in the Creation of medicines, their preparation in the following is explained in more detail by way of examples.  

Production examples for drugs 1. Solid, perorally administrable drugs a) tablets

Active ingredient according to the invention | 12,000 g lactose 5 200 g Starch, soluble 1 800 g hydroxypropyl methylcellulose 900 g magnesium stearate 100 g

The above ingredients are mixed together and compacted in a conventional manner, using a tablet weight of 180 mg. Each tablet ent holds 100 mg of active ingredient. If desired, so he coated tablets, provided with a film coating or enteric coated.

b) Dragee cores

Active ingredient according to the invention | 10,000 g flame-dispersed silica 500 g corn starch 2 250 g stearic acid 350 g ethanol 3.0 l gelatin 900 g purified water 10.0 l talc 300 g magnesium stearate 180 g

From these ingredients, a granulate is produced, the is pressed to the desired dragee cores. Every core contains 50 mg of active ingredient. The cores can be in conven way to make dragees. If desired, can also an enteric or retarding film over be applied train in a known manner.

c) Drinking suspension in ampoules

Compound of the invention | 0.050 g glycerin 0.500 g Sorbitol, 70% solution 0.500 g Saccharin 0.010 g Methyl-p-hydroxybenzoate 0.040 g Flavoring agent, q. s. @ sterile water, q.s. ad 5 ml

The abovementioned constituents are customary Mixture into a suspension and into suitable drinking ampoules filled with 5 ml of contents.

d) poorly soluble sublingual tablet

Compound of the invention | 0.030 g lactose 0.100 g stearic acid 0.004 g Talc purum 0.015 g Sweeteners, q.s. @ Flavoring agent, q.s. @ Rice starch, q.s. ad 0.500 g

The active substance is combined with the excipients under ho Hem pressure to sublingual tablets, conveniently in oblong form, compacted.

e) soft gelatin capsule

Compound of the invention | 0.050 g Fatty acid glyceride mixture (Miglyole®), q.s. ad 0.500 g

The active ingredient is mixed with the liquid carrier mixture pasted and together with others for the encapsulation suitable excipients and mixed in elastic soft bottled gelatin capsules that are sealed.

f) hard gelatin capsule

Active ingredient according to the invention | 0.100 g magnesium stearate 0.030 g flame-dispersed silica 0.030 g Milk sugar, q.s. ad 0.3 ml

The active ingredient is intimately ver together with the excipients and with the appropriate dosage accuracy in the bottoms of hard gelatin capsules filled, which mechanically closed with the respective tops who the.  

2. Topically administrable dosage forms Hydrophilic ointment

Compound of the invention | 0.500 g Eucerinum® anhydricum 60,000 g microcrystalline wax 15,000 g Vaseline oil, q.s. ad 100,000 g

The above-mentioned auxiliaries are melted and along with the active ingredient to an ointment in conventional Way processed.

3. Inhalation Therapeutics

A further subject is a pharmaceutical preparation, which is characterized in that it has a erfindungsge the active ingredient as a base or a physiologically acceptable Salt thereof together with for administration by Inhala tion suitable and customary carriers and / or dilution contains nern.

In this context, particularly suitable physiological acceptable salts of the active compounds of formula (I) are for Part already mentioned in the synthesis description of anor ganic or organic acid derived acidity onssalze, such. B. especially hydrochloride, hydrobromide, Sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p-toluene sulphonate, methanosulphonate, ascorbate, salicylate, Acetate, formate, succinate, lactate, glutarate, gluconate or the tricarballylate.  

The administration of the compounds of the invention with Inhalation takes place according to the invention on conventional len, for such administrations usual ways, eg. In Form of a commercially available metered dose inhaler or Kombina tion with a spacer. The metered dose inhaler is a dosing supplied with the aid of a metered quantity the composition is administered. For spraying see compositions, for example, as an aqueous Formulated solutions or suspensions and by means of a Be administered nebulizer. Aerosol Sprühformulierun in which the active substances either with one or two Stabilizers in a propellant as a carrier and / or Thinner to be suspended; z. For example, tetrafluoroethane or HFC 134a and / or heptafluoropropane or HFC 227 can even if used, but for ecological reasons the non-fluorinated hydrocarbons or others Normal pressure and room temperature gaseous propellants, such as Propane, butane or dimethyl ether, may be preferred. In this case, also propellant-free manual pumping systems or, as described below, dry powder systems for use sentence.

Conveniently, the propellant aerosols can also oberflä chenaktiven auxiliary substances, such as. B. isopropyl myri stat, polyoxyethylene sorbitan fatty acid ester, sorbitan trio leat, lecithin or oleic acid.

For administration by inhalation or insufflation k NEN the drugs containing the invention Substances also in the form of dry powder compositions be formulated, for. B. as active ingredient soft pellets or as Active ingredient powder mixture with a suitable carrier, such as As lactose and / or glucose. The powder composition  can formulate as a single dose or as a multiple dose be liert and administered.

The compounds of the invention are preferably with of a metered dose inhaler or in the form of a dry powder ver-dosing formulation administered, the latter as a carrier substance preferably glucose and / or lactose. The present invention therefore becomes a therapy method for the treatment of asthma and other respiratory disorders Diseases provided due to the low required The effective dose is a simple treatment ren, especially in the acute case, ie an asthmatic attack, by the patient himself can be applied easily and safely. Furthermore can be due to the application as an aerosol in particular with sensitive persons possible systemic Nebenwir largely avoided.

As applicators for inhalation of the inventive Substances containing pharmaceutical preparations are suitable In general, all applicators that are suitable for Do sieraerosole or a dry powder dosage formulation are suitable, such. B. for the nose, mouth and / or throat usual applicators, or under a propellant for Delivery of a spray (as a metered dose inhaler or dry powder ver-Dosierformulierung) standing devices, as they are also for Inhalations in the nose, mouth and / or throat Use find a solution.

Another embodiment may also consist in that an aqueous solution of the compounds according to the invention, optionally further active ingredients and / or Additi contains applied by means of a Ultraschallverneblers.  

a) Metered dose inhaler

b) metered dose inhaler

In Examples a) and b) is micronized invention according to active ingredient after prior dispersion in a ge wrestle amount of stabilizer placed in a suspension vessel, in which the bulk of the propellant gas solution is located. The appropriate suspension is by means of a suitable Stirring system (eg high-performance mixer or ultrasonic Mi shear) until an ultrafine dispersion arises. The suspension is then continuously in one Suitable for cold propellant or pressure fillings Filling device held in flow. Alternatively, the Sus  pension also in a suitable cooled Stabilisatorlö be prepared in HFC 134a / 227.

Examples c) to d) describe the composition and Preparation of dosing dry powder formulations.

c) dosing dry powder formulation

mg / dose Active ingredient according to the invention | 0.500 mg

d) dry powder dosage formulation

mg / dose Active ingredient according to the invention | 0.500 mg Lactose Ph. Eur. @ up to 2.5 mg or up to 5.0 mg

e) dry powder dosage formulation

mg / dose Active ingredient according to the invention | 0.250 mg Lactose Ph. Eur. @ up to 2.5 mg or up to 5.0 mg

In Example c) the active ingredient is after Mirkonisierung under Add steam as pellets with a NMAD in between 0.1 and 0.3 mm in diameter formulated and more dose powder applicator applied.  

In Examples d) and e) the active ingredient is micronized and bulk material with the lactose in the indicated amounts mixed and then into a multidose powder inhaler filled.

4. Injection therapeutics a) parenteral solution

compound of the invention | 5,000 g Natriumhydrogenphosphat 5,000 g sodium tartrate 12,000 g Saccharin 0.900 g benzyl alcohol 7,500 g Water for injections ad 1000,000 ml

The solution is prepared by the usual method, sterilized and filled into 10 ml ampoules. An ampoule contains 50 mg of the compound of the invention.

b) parenteral dispersion

compound of the invention | 10,000 g soy lecithin 20,000 g saturated triglycerides 100,000 g sodium hydroxide 7.650 g Water for injections ad 1000,000 ml

The compound of the invention is in the saturated Triglycerides dispersed. Then, with stirring, the soy added lecithin and then the aqueous Lö  Sodium hydroxide solution followed by homogenization added. The dispersion is sterilized and placed in 10 ml ampoules bottled. An ampoule contains 50 mg of the invented to the invention connection.

If necessary, instead of ampoules with Injekti onsolution also includes infusion solutions containing one or more active compounds according to the invention in conventional Way with the addition of buffer substances to adjust the physiological pH or isotonicity and given if any other necessary nutrients, vitamins, ami acids, stabilizers and other necessary auxiliary substances fen, possibly in combination with others for the genann provide indications for suitable drugs.

In all the examples given above, the Active substance or the drugs in the form of each appro Neten pharmaceutically acceptable salts or acid addition salts are present, as far as the base is not available depending on the case is awarded.

The examples described above can be in the Rah of expert skill as needed without Ein modify the limitation of the claimed scope of protection.

The following are the ones related to those found new indications obtained pharmacological test results based on the specially structured new substances in the Comparison to recognized active compounds of the prior art nik reproduced. Following this will be the comparison trial results discussed.  

In the examples mentioned, the active ingredient may also be in the form the respectively suitable pharmaceutically acceptable salts or acid addition salts are present. The above be written examples can be found in the context of the fachmänni as required without restriction of the bean modify the scope of protection.  

Pharmacological-Experimental Section Pharmacological findings Investigations on the peculiarities of the spectrum of activity of new substances for the indication bronchial asthma

Figures 1 to 8 show the following tests with test results:

Fig. 1: Schematic representation of the experimental protocol for the bronchospasmolytic effect on the isolated, barium chloride-contracted tracheal ring preparation of the guinea pig

Male and female guinea pigs were replaced by i.p. Anesthetized application of 1.2 mg / kg urethane. subsequently, The trachea was dissected out and placed in a Krebs-Henseleit solution spent and isolated tracheal rings ago cut out. The ring preparations were attached to the cartilage severed ring side and into the organ bath with the same Nährlö solution (37 ° C ± 1 ° C and with carbogen = 95% O₂ + 5% CO₂, be guest) and under appropriate preload with the isometri clamped pressure transducer. The recording of the Mus Celton changes took place via a multichannel recorder. The evaluation was done in on-line procedure over a ACAD software performed by computer.  

Fig. 2: Schematic representation of the experimental protocol for the relaxation of spontaneous tonsus on the isolated tracheal ring preparation of the guinea pig

Male and female guinea pigs were replaced by i.p. Anesthetized application of 1.2 mg / kg urethane. subsequently, The trachea was dissected out and placed in a Krebs-Henseleit solution spent and isolated tracheal rings ago cut out. The ring preparations were attached to the cartilage severed ring side and into the organ bath with the same Nährlö solution (37 ° C ± 1 ° C and with carbogen = 95% O₂ + 5% CO₂, be guest) and under appropriate preload with the isometri clamped pressure transducer. The recording of the Mus Celton changes took place via a multichannel recorder. The evaluation was done in on-line procedure over a ACAD software performed by computer.

Fig. 3: Schematic representation of the experimental methodology for the generation and measurement of PAF-induced bronchoconstriction

Male and female guinea pigs were replaced by i.p. Anesthetized application of 1.2 mg / kg urethane. subsequently, ßend the animals were via a tracheostomy tube by means of egg respirator with volume constant ventilation. For suppression spontaneous respiration, the N. vagi were severed. For the Application of the agonists or the test substance was the Cannulated with V.jugularis. Following the method of Kon Zett-Rössler were the changes of the pulmonary beat pressure as an expression of the change in the airway diameter, via a pressure transducer in the shunt of Tracheal cannula measured.  

Fig. 4: Schematic representation of the experimental methodology for the generation and measurement of bronchial hyperreactivity in the anesthetized guinea pig

Male and female guinea pigs were replaced by i.p. Anesthetized application of 1.2 mg / kg urethane. Subsequently The animals were transplanted via a tracheostomy tube by means of a Respiratory pump volume constant ventilated. To suppress the Spontaneous breathing, the N. vagi were severed. For the Appli cation of the agonists or of the test substance became the Cannulated with V.jugularis. Following the method of Kon Zett-Rössler were the changes of the pulmonary beat pressure as an expression of the change in the airway diameter, via a pressure transducer in the shunt of Tracheal cannula measured.

Fig. 5: Representation of protein release due to increased vascular permeability using Evans Blue

Intravenous injection of Evans Blue at the end of mediator / test infusion (see Figure 4); 5 min afterward Circulation of the bloodstream to remove the intravascular Evans Blue; then preparation of the trachea and bronchi, finally extraction of Evans blue on the tissue with formamide and photometric measurement of the Farbstoffkon concentration.

Fig. 6: Inhibition of extravasation of blood protein caused by increased vascular permeability through substance no. 117

Shown are mean values (N = 8-10) of the percentage Inhibition of extravasation of Evans Blue in the airways of the guinea pig as an expression of increased Ge vessel permeability caused extravasation of blood protein.  

Fig. 7: Schematic representation of the experimental method for the generation and measurement of bronchospasm induced by mediator release using C48 / 80 or HIgG

Male and female guinea pigs were replaced by i.p. Anesthetized application of 1.2 mg / kg urethane. subsequently, ßend the animals were via a tracheostomy tube by means of egg respirator with volume constant ventilation. For suppression spontaneous respiration, the N. vagi were severed. For the Application of the agonists or the test substance was the Cannulated with V.jugularis. Following the method of Kon Zett-Rössler were the changes of the pulmonary beat pressure as an expression of the change in the airway diameter, via a pressure transducer in the shunt of Tracheal cannula measured.

Fig. 8: Electric field stimulation on isolated guanella pig tracheal rings

Electrical field stimulation (EFS) was performed on isolated guinea pig tracheal rings at 40 volts, 0.5 msec pulse duration and a frequency of 10 Hz for 20 seconds. This in vitro electric field stimulation on guinea pig tracheal ring preparations results in a rapid and transient cholinergic contraction (which is blockable with atropine), a subsequent, longer lasting non-adrenergic and noncholinergic contraction (e-NANC), which is achieved by pretreatment with capsa icin (which is the intracellular peptide storage). Prior to electrical stimulation, the tracheal ring preparations were pretreated with indomethacin (3 × 10 ^-6 mol / l) to avoid spontaneous development by release of prostanoids. Likewise, a pretreatment with propranolol (1 × 10 ^-6 mol / l) was carried out in order to exclude adrenergic effects. Thiorphan (1 x 10 ^-5 mol / l) was added to the organ bath to avoid rapid degradation of the released peptides responsible for e-NANC contraction of the tracheal muscles.

Explanation of the tables

The values given in the following Tables I to V for the comparative compounds refer to the following Reference substances Nos. 519, 520, 521 and 522, the theophylline with the number 521 and the nedocromil with the number 522 represent classical antiasthmatics; the Although Tiaramide has as Thiazolderivat compared to the Substances according to the invention have a similar structure (cf. DE-B-17 70 571), but substance no. 520 is in the form of a thiazole having a dimethylamino substituent on the attached via the alkylene radical attached Stickstoffhe terocyclus is the most structurally similar compound. This is does not include the scope of the substances according to the invention.

1. Direct bronchospasmolytic action in vitro on Tra Chealring preparations of guinea pigs

One of the most serious disease symptoms of asthma is the airway obstruction. At this narrowing the breath Pathways play in addition to hypertrophy and edema of the bronchial wall as well as an excess of tenacious mucus and the constriction of the Hypertrophied bronchial muscles are the most important role.

This constriction of the bronchial musculature can be seen on Mo dell the isolated tracheal ring preparation of the sea porcine active in vitro with the aid of spasmogen Generate substances.

Barium chloride was used as an agonist in the studies investigating the direct spasmolytic action of our substances because it induces a long-lasting receptor-independent contraction of the smooth bronchial muscle (see Fig. 1).

This test served as our primary search system second most important criterion besides the PAF-induced Bron choconstriction to eliminate ineffective substances.

In addition, direct spasmolysis was performed on the spontaneous tons of isolated guinea pig tracheal muscles (see Fig. 2 for the method). The spontaneous tonic, which is known to be sustained by endogenous release of prostanoids, is a sensitive measure of the relaxant effect on the smooth bronchial musculature. In this as well as in the barium chloride test our substances show higher efficacy than the comparison substances (results see Tab. I).

Table I

Direct bronchospasmolytic action in vitro on guinea pig tracheal ring preparations

2. Inhibition of PAF-induced bronchoconstriction

One of the major mediators involved in asthma play, is the platelet activating factor (PAF). He has potent biological effects on a variety of tissues and inflammatory cells and was in part high concentrations nachge in the bronchoalveolar space of asthmatics grasslands. It is made from membrane phospholipids under the action of Phospholipase A₂ and an acetyltransferase in Eosinophi len, neutrophils, macrophages, platelets and mast cells educated.

This mediator has a potent chemotactic effect Eosinophils and activates their functions. He requires one Permeability increase and edema formation in the respiratory tract and eventually leads to the development of a bronchial hyper reactivity. PAF, however, has no direct effect on the Bronchial muscles, but leads through a complex Release of numerous mediators for bronchospasm and other asthma-relevant symptoms.

The inhibitory effect of the compounds according to the invention was compared to the PAF-induced bronchoconstriction (method see Fig. 3) as a measure of influencing a we sentlichen part of the bronchial asthma (results Tab. II) used.

This test system was made because of its simplicity and Rele vanz used as a primary search system to make effective from un to distinguish effective substances.

For the assessment of the dose-efficacy relationships cf. the Concluding remark in the last paragraph of the following experiment writing to Tab. III.  

Table II

Inhibition of PAF-induced broncho constriction in%

3. Inhibition of bronchial hyperreactivity

A recognized feature of the bronchial system of the asthmatic is the overreactive reactivity Stimuli that are meaningless for the healthy.

This state of hyperreactivity can be experimentally by application of natural inflammatory mediators he witnesses who play a role in asthma.

Infusions were used for 1 hour on the anesthetized guinea pig of PAF, substance P or bradykinin. The hyperreactive state was assessed by a sub-threshold dose of methacholine, which was measured by changes in pulmonary ventilation pressure (see Fig. 4).

A peculiarity of the newly synthesized substances is the ability to produce the resulting hyperreactivity in very ho hem dimensions (see Table III for results). there is when comparing the test substances with the standard sub Note that the maximum achievable We kung depending on the dose asymptotic value 100 approaches, so that z. B. an increase in inhibition of 50% to 75% nonlinear an increase in effectiveness around corresponds to the factor 1.5. The increase in effectiveness can therefore be read more exactly from the comparison of the cans, necessary to generate a similar level of effectiveness are agile (see Tab. IIIa). This situation applies ana log also for Tables II, IV and V.  

Table III

Inhibition of bronchial hyperreactivity in%

Table IIIa

Inhibition of bronchial hyperreactivity in%

4. Inhibition of extravasation of blood protein

Pathological and histological examinations as well as the Analysis of sputum and bronchial fluid have shown that the protein discharge from the blood vessels of the lungs increased vascular permeability is an important feature Stomach are bronchial asthma.

Appropriate mediators, which due to protein leakage can induce increased vascular permeability Blood and in the airways generated by asthma patients.

The exiting plasma proteins are multiplied for the Slime formation and its high viscosity, as well as for the Epithelial detachment, thickening of the basement membrane and hypertrosis phie the smooth muscle in the bronchi and bronchi blamed by asthmatics.

In animal experiments on anesthetized guinea pig leaves an increased vascular permeability and thus a protein exits through infusion of the asthmatic mediators PAF, substance P and bradykinin trigger.

This protein release can be quantified with the Evans Blue Tech. Synthetic diazo dyes such as Evans blue bind spontaneously and quantitatively to plasma proteins, where they can be detected by their escape into the tissue (for method see Fig. 4 and Fig. 5).

The treatment of experimental animals with the substances according to the invention, such. As the compound no. 117, leads to a 53-75% inhibition of protein output, as shown in Fig. 6 can be seen.

5. Inhibition of immune release from mediator release tenten cells induced bronchospasm

The release of mediators is another important process in asthmatic events. In this case, tissue-stable (mast cells) and foreign cells (lymphocytes, eosinophilic and basophilic granulocytes, platelets) release mediators such as histamine, prostaglandins, leukotrienes, platelet-activating factor, cytokines, basic proteins, etc. free. In addition to further cell activation, epithelial destruction, exudation / edema, these also lead to acute bronchoconstriction. The influence of the latter was tested in the two following experimental mediator release models. In one model, the specific histamine liberator C _{48/80 was} injected, while in the other model, heat-aggregated, human immunoglobulin G was administered intravenously, which releases a number of spasmogener inflammatory mediators from immunocompetent cells causing a Broncho spasmus via Komplementprotei ne C _3a and C _5a ( Method see Fig. 7).

A bronchoconstriction induced in this way can by the compounds of the invention already at very ge Ringer dosage largely inhibited (results see Tab. IV).  

Table IV

Inhibition of Mediator Release Induced Bronchospasm in%

6. Inhibition of the release of neuropeptides C-fibers (eNANC) induced bronchoconstriction

Works from the last few years have a number of pepti from nerve endings (C-fibers in the lungs) irrespective of the function of the bronchial system from the cholinergic and adrenergic system.

These neuropeptides like substance P, neurokinin A, neurokinin B or the calcitonin gene-related peptide (CGRP) flow the muscle tone of bronchi and pulmonary vessels and increase the bronchial mucous secretion and produce the so called neurogenic inflammation.

In doing so, they seriously attack the asthmatic events and other pathomechanisms.

The electrical stimulation of the C-fibers of the respiratory tract was used to trigger the natural release process of the neuro-peptides, the extent of the release being measured by the resulting contraction of the bronchial musculature. These measurements are possible under the experimental conditions explained in the pharmacological-experimental part at the beginning of FIG. 8; For the method see Fig. 8.

Also in this test system our substances show one pronounced effect (results see Tab. V).  

Table V

Inhibition of e-NANC bronchoconstriction in%

Further medical indications

The investigations on the test system described here me (except for the direct broncholytic effect) also show bronchial asthma in other indications a therapeutic efficacy of Ver invention bonds.

The inhibition of increased vascular permeability conditional extravasation of blood protein (test 4) as they Evans blue was detected in combination with inhibition of mediator release (Test 5), the vascular permeability associated with inflammation increase symptoms, an ideal, therapeutically beneficial tes spectrum of effects for the treatment of chronic represents venous insufficiency.

Because of these experimental results represents the chronic Venous insufficiency therefore another object of the Use of compounds according to the invention.

The experimental results, which include inhibition of the release tion of neuropeptides from the C fibers (e-NANC), see Test 6, show, also create the opportunity he inventive drugs in the indications migraine and chronic cough, as well as against the emergence of the chro niche pain.

summary of results

The findings from the comparative test results show in completely unexpected way an excellent antiasthmati effective against classic asthma therapies as well as towards a structurally comparable verb (Tiramides). It should be noted that the use structurally closest compounds from toxicolo  out of consideration. Comparative Compound No. 520 also shows as more typical Representatives of structurally closest substances in ver different tests a much weaker Ak tivity.

For the expert, it is also completely surprising that the Compounds of the invention at the various An of the pathological asthma phenomenon one in comparison to the classical antiasthmatics not only much stronger activity, but much even a potentiated efficacy. In addition, the substances according to the invention also exercise one surprising effect in chronic venous insufficiency ciency, the migraine, chronic cough and at the sub depression of chronic pain. This far superior Effect of the substances according to the invention in comparison to the known asthma therapies and the rest structurally related thiazole compounds was not known to the art the structural, but different in effect State of the art still through an overall view of the literature to structurally strongly deviating classical antiasthmati ka suggested.

Claims (38)

1. 1,2-Dihydro-2-oxothiazolopyridine compounds of the formula (I) wherein
R¹ represents halogen, and
R² and R³ are the same or different, and
R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl, and
R³ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, acyl or alkanesulfonyl
mean, or
R² and R³ together form a heterocyclic ring, where in the ring-forming substituent is selected from the following heterocycles: these rings being optionally monosubstituted or disubstituted by alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, dialkylaminoalkyl or an oxo group adjacent to a nitrogen atom,
A is selected from optionally substituted by one or more Al alkyl groups alkylene and alkenylene,
Q is selected from the following heterocycles: wherein the heterocyclic ring may have a double bond, and
m is an integer from 3 to 7
n 2 or 3, and
p is an integer from 3 to 7,
R⁴ is hydrogen, alkyl, hydroxymethyl, carboxyl or alkoxycarbonyl, as well as
R⁵ is hydrogen or an alkyl radical, where
R⁴ and R⁵ optionally together to form a bi cyclic ring system, an alkylene bridge, in before zugter way a C₁-C₄-, especially C₁-C₃-alkylene bridge form,
D in the case where the bond to Q is via a carbon atom, a single bond,
optionally alkyl, hydroxy or alkoxy mono- or di-substituted alkylene, or
optionally in each case by alkyl, hydroxy or alkoxy mono- or disubstituted alkenylene represents, wherein the double bond of the alkenylene group can also be made to the ring Q,
an alkynyl optionally monosubstituted or disubstituted by alkyl, hydroxy or alkoxy, or
an alkylene, alkenylene or alkynylene radical meaning tet, wherein a methylene group may be replaced by an oxygen atom, sulfur atom or an NR⁶-residue isoster, wherein
R⁶ is selected from hydrogen and alkyl independently of R⁵, or
D in the case that the bond to Q via a nitrogen atom takes place,
an alkylene which is optionally monosubstituted or disubstituted by alkyl, hydroxy or alkoxy, alkenylene or alkynylene,
wherein a methylene group may be replaced by an oxygen atom, sulfur atom or an NR⁶-residue isoster, as well as their
Stereoisomers and salts,
wherein in the abovementioned substitutions
the alkylene and alkenylene radicals and alkynylene radicals preferably each have up to 8 to 12 carbon atoms, with their possible alkyl and alkoxy substituents preferably each having at least 1 to at most 4 to 8 carbon atoms,
also in the radicals R², R³, R⁴ and / or R⁵ given if appropriate alkenyl and alkynyl radicals as well as the alkyl, cycloalkyl and hydroxyalkyl radicals, the alkoxyalkyl, alkylaminoalkyl and aminoalkyl radicals or the dialkylaminoalkyl radical are each preferably up to 8 to 10, particularly preferably at least 1, 2, 3, 4, 5 and up to 6 carbon atoms, and the total number of carbon atoms in the alkylaminoalkyl and dialkylaminoalkyl radicals may be 2 to 6, 8, 10, 12, 15 or 18 carbon atoms,
said acyl and alkanesulfonyl radicals may have in the preferred manner up to 8, 10 or 12, in particular at least 1, 2, 3 or 4 and up to 5 or 6 carbon atoms,
the alkoxycarbonyl radical may have up to 6, 8 or 10 carbon atoms, but preferably 2, 3, 4 or 5 carbon atoms,
the radicals R⁴ and R⁵ taken together in the formation of a bicyclic ring system preferably a C₁-C₄-Al alkylene bridge, more preferably represent a C₁-C₃-alkylene bridge,
said aliphatic saturated and / or unge saturated hydrocarbon radicals with any funk tional groups may each be independently ge rad- or branched-chain, and in the case of 2 or more, preferably 3 alkyl radicals in the ge called groups, especially in the alkylamino or alkyl Dialkylaminoalkyl radicals which may be identical or different alkyl radicals and also each straight and / or branched chain, and wherein is that
the minimum number of carbon atoms in the genann th substituents depending on the bonding ratios in each case 1, 2 or even 3 carbon atoms, 2 or 3 carbon atoms in the case of Alkenylgruppie ments and 3 carbon atoms in the case of triunsaturated alkynyl compounds may be, this in the same The following applies to the cyclic carbon compounds, among which the cyclopropyl group has the lowest possible number of carbon atoms,
and preferably their stereoisomers, as given cis / trans isomers, endo / exo isomers, enantiomers, diastereomers as pure isomers or in the form of their mixtures and their acid addition salts. 2. Compounds of Formula (I) wherein
R¹ is halogen, where
R² and R³ may be the same or different, and
R² is C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkoxyalkyl, C₂-C₆-aminoalkyl, C₃-C₁₀-alkylaminoalkyl, C₄-C₁₀-dialkylaminoalkyl and
R³ is hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-acyl, C₁-C₆-Al kansulfonyl represent,
R² and R³ together in the rest can form a heterocyclic ring, wherein the ser ring is selected in this case from the following Heterocyc len: these rings once or twice by C₁-C₄-alkyl, hydroxy, C₁-C₄-alkoxy, amino, C₁-C₄-alkylamino, C₂-C₈-di alkylamino, C₁-C₄-hydroxyalkyl, C₃-C₁₀-dialkylamino alkyl or an oxo group adjacent to a nitrogen atom may be substituted,
A is selected from C₁-C₆-alkylene optionally substituted by one or more C₁-C₃-alkyl groups and C₂-C₆-Al kenylene,
Q is selected from the following heterocycles: wherein the heterocyclic ring may optionally contain at least one double bond, and
m is an integer from 3 to 7
n 2 or 3, and
p is an integer from 3 to 7,
R⁴ is hydrogen, C₁-C₆-alkyl, hydroxymethyl, carboxyl or C₂-C₅-alkoxycarbonyl, and
R⁵ is hydrogen or a C₁-C₆-alkyl radical,
where R⁴ and R⁵ optionally together form a C₁-C₃-alkylene bridge with the formation of a bicyclic ring system,
D in the case where the bond to Q is via a carbon atom, a single bond,
optionally C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy mono- or disubstituted C₁-C₁₀-Al alkylene or C₂-C₁₀-alkenylene, wherein in the latter Fal le the double bond can also be made to the ring Q,
optionally mono- or disubstituted by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy C₃-C₁₀-Al kinylene or
C₁-C₁₀-alkylene, C₂-C₁₀-alkenylene or C₃-C₁₀-alkynylene, in which a methylene group is replaced by O or S or NR⁶ isoster, mean in which
R⁶ is selected independently of R⁵ from hydrogen and C₁-C₆-alkyl, or
D in the case that the bond to Q via a nitrogen atom takes place,
optionally in each case by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy mono- or disubstituted C₂-C₁₀-Al alkylene, C₄-C₁₀-alkenylene or C₄-C₁₀-alkynylene, or
C₂-C₁₀-alkylene, C₄-C₁₀-alkenylene, or C₄-C₁₀-alkynylene in which a methylene group is replaced by O or S or NR⁶ isoster,
Stereoisomers and the acid addition salts. 3. Compounds according to one of claims 1 or 2, characterized in that the substituents R¹, R², R³, R⁴, R⁵ and / or R⁶ mentioned therein and A are used in the context of the substitutions given in the preceding claims according to the formula ( I) have the following meanings in which
Halogen is either fluorine, chlorine, bromine or iodine,
C₁-C₆-alkyl may be straight-chain or branched and a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl, pentyl, isopentyl, tert Pentyl, neopentyl, cyclopropylethyl, cyclobutylmethyl or hexyl group,
Alkylene represents the methylene, ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene or decamethylene group,
C₃-C₆ alkenyl may be straight-chain or branched and an allyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 4-pentenyl, 2-methyl-2-alkenyl represents butenyl, 3-methyl-2-butenyl, 2-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl or 2,2-dimethyl-3-butenyl group,
Alkenylene is an ethenylene, propenylene, butenylene, pentylene, hexenylene, hexadienylene, heptenylene, octenylene, nonenylene or decenylene group,
C₃-C₆-alkynyl may be straight-chain or branched and represents a propargyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl or 4-methyl-2-pentynyl group,
Alkynylene, the propynylene, Butinylen-, Pentinylen-, Hexi nylen-, Heptinylen-, Octinylen-, Noninylen- or Decinylen group and
C₃-C₆ cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, wherein the
C₁-C₆-hydroxyalkyl contains a hydroxyl group in one of the above-mentioned C₁-C₆-alkyl groups, among which the hydroxymethyl and the hydroxyethyl group are preferred,
C₁-C₄-alkoxy in addition to the oxygen atom contains one of the abovementioned C₁-C₄-alkyl groups, among which the methoxy, ethoxy, isopropoxy or tert-butoxy group are preferred,
C₂-C₆ alkoxyalkyl contains one of the abovementioned alkoxy groups in one of the abovementioned alkyl groups, of which the methoxymethyl, methoxyethyl, methoxypropyl or ethoxyethyl group are preferred,
C₂-C₅ alkoxycarbonyl groups contain, in addition to the carbonyl group, one of the abovementioned C₁-C₄ alkoxy groups, of which the methoxycarbonyl, ethoxycarbonyl, isopropoxy carbonyl and tert-butoxycarbonyl groups are preferred,
C₂-C₆ aminoalkyl contains an amino group in one of the abovementioned alkyl radicals, among which the aminoethyl, aminopropyl or aminobutyl group are preferred,
C₃-C₁₀ alkylaminoalkyl carries one of the abovementioned C₁-C₄alkyl groups on the amino group of one of the abovementioned C₂-C₆ aminoalkyl groups, of which the methylaminoethyl, methylaminopropyl, methylaminobutyl, ethylaminoethyl or ethylaminopropyl group are preferred,
C₁-C₄alkylamino contains one of the abovementioned C₁-C₄alkyl groups, of which the methylamino, ethylamino, propylamino, isopropylamino, butylamino and tert-butylamino groups are preferred,
C₂-C₈-dialkylamino on the nitrogen carries two identical or different ver of the above C₁-C₄-alkyl groups, including the dimethylamino, diethylamino, Dipro pylamino-, diisopropylamino, isopropyl-methylamino, di-butylamino and tert-butyl methylamino group are preferred,
C₃-C₁₀-dialkylaminoalkyl carries one of the above-mentioned C₂-C₈-di alkylamino groups on one of the aforementioned C₁-C₆-alkyl radicals, among which dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminomethyl, diethylaminoethyl, diethylaminopro pyl-, dipropylaminomethyl-, dipropylaminoethyl-, tert-butyl-methylaminomethyl- and the tert-butyl-methylaminoethyl group are preferred,
C₁-C₆ acyl is the radical of an aliphatic saturated or unsaturated, straight-chain, branched or cyclic carboxylic acid, of which formyl, acetyl, propionyl, acryloyl, butyryl, isobutyryl, methacryloyl, cyclopropylcarbonyl, pentanoyl, Pivaloyl, cyclobutylcarboxyl, hexanoyl and dimethylacryloyl groups are preferred, and
C₁-C₆ alkanesulfonyl is preferably the methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentane sulfonyl and hexanesulfonyl group, and the
Acid addition salts in the form of hydrochlorides, Hydrobromi de, hydroiodides, sulfates and phosphates and the acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succinates, tartrates or toluenesulfonates can be present. 4. Compounds according to the preceding claims, characterized in that in the formula (I) designated substituents have the following meanings:
R¹ is halogen in the 6-position,
R² is selected from C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₂-C₆ alkoxyalkyl or C₄-C₁₀ dialkylaminoalkyl and
R³ is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-acyl or C₁-C₆-alkanesulfonyl,
R² and R³ may be the same or different or together form a heterocyclic ring, wherein in the case of formation of a heterocyclic ring is selected and these rings may be substituted by C₁-C₃-alkyl, Hy droxy, C₁-C₃-alkoxy, C₁-C₃-hydroxyalkyl, C₂-C₈-Di alkylamino or an adjacent to a nitrogen atom disclosed oxo group,
A is optionally substituted by a methyl group substituted C₁-C₄-alkylene or C₂-C₄-alkenylene and
Q out wherein the ring may optionally contain a double bond,
m is an integer from 3 to 7
n 2 or 3, and
p is an integer from 3 to 7,
R⁴ represents hydrogen, C₁-C₃ alkyl, hydroxymethyl, Car boxyl or C₂-C₅ alkoxycarbonyl and
R⁵ is hydrogen or C₁-C₃ alkyl or
R⁴ and R⁵ may together form a C₁-C₃-Alkylenbrücke un ter formation of a bicyclic ring system,
D is in the case of a bond to Q via a carbon atom of a single bond, selected from C₁-C₈-alkylene or C₂-C₈-alkenylene, wherein the double bond can also be made to the ring Q, or is selected from C₄-C₈-Al kinylen .
wherein these alkylene, alkenylene or alkynylene groups may optionally be substituted by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy, or
in which optionally one methylene group may be replaced by O or S or NR⁶ isoster, wherein R⁶ is selected from hydrogen or C₁-C₃-alkyl independently of R⁵, or
D is in the case of a bond to Q via a nitrogen atom of C₂-C₈-alkylene, C₄-C₈-alkenylene or C₄-C₈-Al kinylene, which may be in each case by C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy in which optionally one methylene group in each case can be replaced by O or S or NR⁶ isoster, where R⁶ is selected independently of R⁵ from hydrogen or C₁-C₃-alkyl. 5. Compounds according to one of claims 1 to 4, characterized in that in the formula (I) designated substituents have the following meanings:
R¹ is bromine or chlorine in the 6-position,
R² is selected from C₁-C₄alkyl, C₃-C₄alkenyl, C₃-C₄alkynyl, C₃-C₅cycloalkyl, C₂-C₃hydroxyalkyl and C₄-C₈-dialkylaminoalkyl,
R³ is selected from C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, C₁-C₃ acyl and C₁-C₃ alkanesulfonyl wherein
R² and R³ may be the same or different or together may form a heterocyclic ring, and in the case of formation of a heterocyclic ring are selected from azetidine, pyrrolidine, piperidine, hexahydroazepine, piperazine, homopiperazine or morpholine, wherein the ring is in each case by C₁-C₃-alkyl, hydroxy, C₁-C₃-hydroxyalkyl, C₂-C₄-dialkylamino or an oxo group adjacent to a nitrogen atom may be substituted,
A represents a methylene group, and
Q is out wherein the ring may optionally contain a double bond,
m, n and p have the following meanings:
m = 3 to 6,
n = 2 or 3 and
p = 3 to 6,
R⁴ represents hydrogen or C₁-C₃ alkyl and
R⁵ is hydrogen,
D is selected in the case of a bond to Q via a carbon atom of C₁-C₆-alkylene and C₂-C₆-alkenylene, wherein the double bond can also be made to the ring Q, or is selected from C₃-C₆-alkynyls, wherein in the sen Alkylene, alkenylene or Alkinylenresten optionally depending Weil a methylene group by O or NR⁶ isoster he sets can be and
R⁶ is selected from hydrogen and C₁-C₃alkyl, or
D is selected in the case of a bond to Q via a nitrogen atom of C₂-C₆-alkylene, C₄-C₆-alkenylene and C₄-C₆-alkynylene, in which optionally each methylene group may be replaced by O or NR⁶ isoster, wherein
R⁶ is selected from hydrogen and C₁-C₃ alkyl. 6. A compound according to any one of claims 1 to 5, characterized in that in the general formula (I) R¹ is bromine and chlorine in the 6-position and
A is a methylene group,
Q of pyrrolidine, piperidine, hexahydroazepine, piperazine and homopiperazine as well
D are selected from ethylene, ethenylene, propylene and butylene and the remainder selected from methylamino, ethylamino, propylamino, allylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, diallylamino, Methylpropylami no, methylallylamino, methyl-tert-butylamino, Ethylal lylamino, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, morpholino and hexahydroazepinyl is. 7. A compound according to formula (I) according to any one of claims 1 to 6, characterized in that they are in the form of the hydro chlorides, hydrobromides, sulphates, phosphate, acetate, Citrate, fumarate, malate, methanesulfonate or tartrate is present.   8. A compound according to formula (I) according to any one of claims 1 to 6, characterized in that it in the form of
6-chloro-1- [4- (2-dimethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (2-diethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrobromide,
6-Chloro-1- [4- (2-cyclopropylamino-ethyl) -piperidyl] -carboxylyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-chloro-1- [4- (2-piperidylethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-Chloro-1- [4- (3-pyrrolidylpropyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride, or
6-Chloro-1- [4- (3-dimethylaminopropyl) piperazinyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride is present. 9. A compound according to any one of claims 1 to 6, characterized in that it in the form of
6-bromo-1- [4- (2-allylaminoethyl) -piperidyl] -carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-cyclobutylamino-ethyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (3-dimethylaminopropyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (3-dimethylaminopropyl) piperazinyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its dihydrochloride, or
6-bromo-1- [3- (2-pyrrolidylethyl) -pyrrolidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride is present. 10. A compound according to any one of claims 1 to 6, characterized in that it in the form of
6-bromo-1- [4- (2-dimethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
6-bromo-1- [4- (2-diethylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrobromide, or
6-bromo-1- [4- (2-pyrrolidylethylidene) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride is present. 11. A compound according to any one of claims 1 to 6, characterized in that it in the form of
6-chloro-1- [4- (2-dipropylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride,
1- {4- [2- (N-Allyl-N-methylamino) ethyl] -piperidyl} -carbonylmethyl-6-chloro-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride, or
6-Chloro-1- [4- (2-pyrrolidylethyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride is present. 12. A compound according to any one of claims 1 to 6, characterized in that it in the form of
6-bromo-1- [4- (2-dipropylaminoethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride, or
1- {4- [2- (N-Allyl-N-methylamino) ethyl] -piperidyl} -carbonylmethyl-6-bromo-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride is present. 13. A compound according to any one of claims 1 to 6, characterized in that it in the form of
6-bromo-1- [4- (2-pyrrolidylethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or its hydrochloride is present. 14. Process for the preparation of the compounds according to the formula (I) according to one of claims 1 to 13,
characterized in that either

• (a) carboxylic acids of the formula (II), in which R¹ and A have the meanings given in claims 1 to 13, or their reactive Deriva te
  with compounds of the formula (III), HQD-NR²R³ (III) in which Q, D, R² and R³ have the meanings given in claims 1 to 13, preferably in a solvent, or in that
• (b) a compound of the formula (IV) in which R¹, A, Q and D have the meanings given in claims 1 to 13 and L represents a suitable leaving group or reactive group, with a compound of the formula (V) preferably be reacted in a suitable solvent, wherein
  R² and R³ have the meanings given in claims 1 to 13, or that
• (c) for the preparation of compounds of formula (I) in which
  R³ is an alkyl, alkenyl, alkynyl or cycloalkyl radical as defined in process variant (b),
  Substances in which R³ is hydrogen,
  with a suitable alkylating agent of the formula (VII) R³-L (VII) in which R³ is, as defined, an alkyl, alkenyl, alkynyl or cycloalkyl radical and L has the meaning given above in process variant (b),
  reacting with each other, wherein the reaction of the compounds (I) with R³ = H can be carried out with the compounds of the formula (VII) and under the conditions described for procedural variant (b), or that
• (d) compounds of the formula (I) in which R³ is an acyl radical or alkanesulfonyl radical as defined in claim 1, are prepared by reacting compounds of the formula (I) in which R³ is hydrogen with a carboxylic acid or a Alkanesulfonic acid of the formula (VIII) in which R³ is an acyl or alkanesulfonyl by definition, R³-OH (VIII) or with their reactive derivatives, vorzugswei se reactive derivatives of carboxylic acids or sulfonic acids according to the formula (VIII) in the form of symmetri shear or unsymmetrical carboxylic acid anhydrides or sulfonic anhydrides or carboxylic acid or sulfonic acid halides, in particular carboxylic acid or sulfonic acid chlorides, are reacted,
  wherein the reaction of the acids according to the formula (VIII) or their reactive derivatives with the compounds according to the formula (I), in which R³ = H is preferably carried out in the presence of auxiliary bases in solvents and under the same conditions as for the vorste method variant (a) apply.

15. The method according to claim 14, characterized in that the reaction according to process variant (a) by re active derivatives of the compound (II) in the form of activating th esters, anhydrides, acid halides, especially acid rechloriden, simple lower alkyl esters, be preferred as p-nitrophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, N-hydroxypiperidine, 2-hydroxypyridine or 2-mercaptopyridine, wherein the anhydrides are both in the form of symmetrical as well as mixed anhydrides can be used, as have been obtained formate with pivaloyl chloride or chloroformates, preferably in the form of aro matic chloroformates such as phenyl chloroformate, araliphatic chloroformates such as Chlorameisensäurebenzy ester, or aliphatic chloroformates such as the Chlora meisensäureethylester or corresponding isobutyl esters, or
the reaction of the compounds of the formula (II) with the compounds of the formula (III) according to process variant (a) in the presence of condensing agents, preferably in the presence of dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide HCl, N, N'-carbonyldiimidazole or 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, wherein in the case of using carbodiimides as condensing agent advantageously reagents such as N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole or added N-hydroxypiperidine and the connec tions of formula (III), both as free bases and in the form of their acid addition salts reacted who can, preferably as salts of inorganic acids, such as the hydrochlorides, hydrobromides or sulfates. 16. The method according to any one of claims 14 or 15, characterized in that the reaction according to the Verfahrensvari ante (a) in an inert solvent or optionally in a mixture of several or different inert solvents, preferably in aromatic hydrocarbons, such as benzene, toluene or xylene, halogenated hydrocarbons, such as dichloromethane, chloroform, 1,2-di chloroethane or trichlorethylene, ethers, such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, ethyl acetate, acetonitrile or polar aprotic solvents, such as dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone, optionally in the presence of an auxiliary base, such as alkali metal carbonates, preferably sodium carbonate or Kaliumcarbo nat, alkali metal bicarbonates such as Natriumhydrogencar carbonate or potassium bicarbonate, or organic bases, such as triethylamine, ethyldiisopropylamine, tri butylamine, N-methylmorpholine or pyridine carried out we can be used as the base, a corresponding excess of the compound of formula (III) and in the case of use of the compounds of formula (III) as acid addition salts, the amount of auxiliary base used is expediently equivalent to take into account, and
the reaction temperature in the above reaction according to the process variant (a) between -40 ° C and 180 ° C, preferably between -10 ° C and 130 ° C, especially at the boiling point of the solvent or the mixture of the solvents used and
the reaction of the compounds of the formulas (IV) and (V) according to process variant (b) in an inert solvent or a mixture of two or more solvents, preferably in aromatic hydrocarbons, such as benzene, toluene, xylene, ethers, such as tetrahydrofuran , Dioxane or glycol dimethyl ether, ethyl acetate, acetonitrile, ketones such as acetone or ethyl methyl ketone, polar protic solvents, preferably alcohols such as ethanol, isopropanol, butanol or glycol monomethyl ether or polar aprotic solvents such as dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone
the reaction in the presence of bases according to the same before standing definitions of the process variant (a) can be carried out and the reaction temperatures vary depending on the reactivity of the educts between 0 ° C and 180 ° C, preferably between 20 ° C and 130 ° C. , wherein to accelerate the reaction in the case of Chlori the or bromides of the compounds of formula (IV) can be carried out addition of alkali metal iodides such as sodium or potassium iodides. 17. The method according to claim 14, characterized in that the Ver used according to the Verfahrensvariatent (b) compound of the formula (IV) is reacted as an intermediate in which the substituents have the following meanings:
L is a reactive derivative of an alcohol, preferably as a halide, a halogen atom such as chlorine, bromine or iodine, or
a sulfonic acid ester, preferably in the form of the Methansul fonyloxy-, trifluoromethanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, p-Brombenzolsul fonyloxy- or m-Nitrobenzolsulfonlyoxygruppe, or
a terminal epoxide group. 18. Compounds according to the formula (IV) wherein
R¹, A and D have the meaning indicated in claims 1 to 13 and Be
L represents a hydroxy group, chlorine, bromine or iodine atom, an alkanesulfonyloxy group, perfluoroalkanesulfonyloxy group or an arylsulfonyloxy group,
Q out with the proviso that compounds in which Q according to formula IXa) is the radical corresponds, wherein R⁴ is hydrogen or alkyl, are taken out. 19. A compound according to formula (IV) according to claim 18, characterized in that it is in the form of
6-chloro-1- [4- (hydroxymethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (hydroxymethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-chloro-1- [4- (2-hydroxyethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (2-hydroxyethyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-chloro-1- [4- (3-hydroxypropyl) -piperidyl] -carbonyl-ethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (3-hydroxypropyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-chloro-1- [4- (4-hydroxybutyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-bromo-1- [4- (4-hydroxybutyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine,
6-Chloro-1- [4- (6-hydroxyhexyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine, or
6-bromo-1- [4- (6-hydroxyhexyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine. 20. A compound according to formula (IV) according to claim 18, characterized in that it is in the form of
6-chloro-1- [4- (iodomethyl) -piperidyl) carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or
6-bromo-1- [4- (4-iodo-butyl) -piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine. 21. A compound according to the formula (IV) according to claim 18, characterized in that it is in the form of
6-bromo-1- [4- (2-methanesulfonyloxyethyl) -piperidyl] -carboxylyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine or
6-bromo-1- [4- (4-methanesulfonyloxybutyl) piperidyl] carbonylmethyl-2-oxo-1,2-dihydrothiazolo [5.4-b] pyridine. 22. Process for the preparation of compounds according to the formula (IV) characterized in that in the formula (IV) the substituents
R¹, A, Q, D and L have the meanings indicated in process variant (b) according to claim 14, wherein carbo-acids of the formula (II) or their activated derivatives either with compounds of the formula (VI) HQDL (VI) embedded image in which Q, D and L have the meanings indicated above, or in that the carboxylic acids of the formula (II) are reacted with amino alcohols according to formula (VI), wherein L represents a hydroxy group, after which the alcoholic cal hydroxyl group is converted into the reactive derivatives, preferably into the corresponding halides or sulfonic acid esters. 23. substance or mixture of substances according to one of claims 1 to 13 for use in a therapeutic method for Be action of the human or animal body or in a corresponding diagnostic method. 24. substance or mixture for use in a thera Peutic method according to claim 23, characterized gekennzeich net, that the therapeutic application related to one or more medical indications in asthma bronchial, bronchial hyperreactivity, bronchospasm, Bronchoconstriction, chronic venous insufficiency, Mi grus, chronic cough, or for bronchospasmolysis or Suppression of chronic pain is given if in combination with appropriate pharmaceutically acceptable ble excipients and carriers and / or one or more other active ingredients. 25. Use of one or more substances according to one of Claims 1 to 13 for the manufacture of a medicament for Treatment of the human or animal body in the in the preceding claim 24 mentioned medical Indika tions.   26. Medicinal products containing one or more Active substances according to one or more of claims 1 to 13, optionally in conjunction with a pharmaceutical acceptable carrier besides toxicologically harmless Excipients and / or in combination with other active ingredients fen. 27. Process for the preparation of a medicament according to An Claim 26, characterized in that one or more Compounds according to one or more of claims 1 to 13 with suitable, pharmaceutically acceptable carrier and Excipients to the finished dosage form is processed. 28. Use of one or more compounds according to one or more of claims 1 to 13 for the treatment of Bronchial asthma, bronchoconstriction, broncho spasm, migraine, chronic venous insufficiency, chronic cough or for bronchospasmolysis or Suppression of chronic pain. 29. Medicament according to claim 26, characterized that it is in the form of an inhalant, for example wise in the form of a spray together with suitable pharma ceutically acceptable propellants, carriers and excipients is present. 30. Medicament according to claim 26, characterized that it together in the form of a suitable injection preparation with suitable, pharmaceutically acceptable carrier and Excipients is present. 31. Medicament according to claim 26, characterized in the form of a solid, perorally administrable form as a tablet, capsule, dragee, if necessary in a retard ter form present.   32. Medicament according to claim 26, characterized that it is in the form of an ointment or balm or in the form of a externally administrable solution is present. 33. Medicament according to claim 29 for administration with metered dose inhaler or in the form of a dry powder dosing formulation. 34. Medicament according to one of claims 26 and 29 to 33, characterized in that a metering unit for Ein administration of 0.01 to 2.0 mg or 0.1-10 or 20 mg Active ingredient according to claims 1 to 13 contains. 35. Use according to claim 29, characterized that the pharmaceutically acceptable carrier and / or diluent is a propellant aerosol. 36. Medicament according to claim 29 or 35, characterized records that the propellant aerosol tetrafluoroethane and / or Heptafluoropropane or propane, butane or dimethyl ether or whose mixtures are. 37. Medicament according to one of claims 29, 35 or 36, characterized in that the propellant gas aerosol surfaces contains active adjuvants. 38. Medicament according to one of claims 26 or 29, since characterized in that it as a dry powder Dosierformu lation contains glucose and / or lactose.