New Thiazolopyridines

The invention relates to new thiazolopyridine compounds, methods for their production, intermediates, 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 invention is characterized in detail in the claims

Technical Background

Illnesses of the respiratory tract are spreading in an increasing degree in the western industrialized nations Approximately 5 % ofthe population in western countries suffer from bronchial asthma, whereby the incidence in children lies approximately two- to three-fold higher than in adults This ever-expanding, serious illness leads to an increased number of deaths The symptoms ofthe asthmatic state command respect above all due to bronchiospasms, mucosal edema and disturbances of glandular secretion with viscous and excessively, secreted mucous (hypercπnism and dyscπnism) with simultaneously increased bronchial hyper-reactivity The asthmatic event involves a disturbed homeostasis of various mediators such as, for example, histamine, leukotπenes or prostaglandins, among others In general, an inflammatory event also comes along with the bronchial asthma illness Anti-asthmatic agents known up to now represent either specific, highly selective mediator-antagonists or selective, effective β- adrenergic pharmaceuticals with a relatively high bronchiodilatory β2 effect and lower cardiostimulating βi effect, such as metaproterenol for example Aside from these substances leading to a relaxation ofthe smooth bronchial musculature, is thiaphylhne which, in contrast to the first named bronchiodilatory substances, functions by another mechanism This often prescribed medicinal agent is not only used in acute attacks, but also in long-term treatment in spite of the fact that the potency of this drug is very low

Disodium chromoglycate and/or chromoglycinic acid is known as an inhibitor for the release of mediators which decreases the bronchial hyper-reactabihty Among the anti-

cholinergic substances, atropine and/or its derivatives ipratropium and oxitropium are employed in individual cases.

A series of corticosteroids are used as substances with a multiple mode of action, for example, with respect to an increased β2 receptor synthesis as well as an inhibition of leukotrienee synthesis. Aside from the fact that these hormonal compounds have no direct bronchiolytic effect, this group of compounds results in a series of serious, undesired side-effects such as, for example, disturbances of carbohydrate, protein as well as fat metabolism, of electrolyte and water balance (edema formation), of the endocrine system, for example in the form of diabetogenic effects or of adrenal cortical insufficiency, increase ofthe interocular pressure, etc.

In spite ofthe fact that knowledge of the pathophysiology and developmental mechanisms of bronchial asthma have made substantial progress in the last years, successes in pharmacotherapy in the treatment of asthmatic forms are not particularly satisfying up to now.

Above all, it has become clear thereby that a very complicated event underlies asthmatic illnesses; the significance of which essential mechanisms, for example the above- mentioned effect of mediators, was recognized.

The applied active ingredients known to date in the treatment of bronchial asthma leave much to be desired, especially because they either display no direct bronchiolytic activity, such as, for example, the above discussed glucocortocoids or nedocromil and ketotifen and/or compounds which do not diminish bronchial hyper-reactivity, such as, for example, β ₂ sympathomimetic agents in the form of isoproterenol and/or the above- named metaproterenol.

Up to now, no active ingredient has been found for which at least one of these restrictions would not apply.

Aside from benzothiazohnones, thiazolopyπdines are already known from JP-A-63 017881 which are substituted with a piperidine group and represent amide derivatives of oxothiazolopyπdyl carboxylic acids with simple amino, hydroxy and ketopipeπdines wherein the amino group is not substituted A thrombocyte aggregation inhibiting effect is ascribed to these compounds Usefulness of these compounds described in both of the above-named publications for the treatment of asthmatic conditions is not disclosed

Furthermore, it is known that some 2-oxo-thιazolo[5,4-b]pyπdιnes have useful pharmacological properties Thus, l,2-dιhydro-2-oxo-thιazolopyπdyl carboxylic acids, their esters and nitriles are descπbed in JP 59-130890 which have anti-pyretic, anti- lnflammatory and analgesic properties In comparison to the above art, the same activities are ascribed in JP-A-59 095290 to pipeπdines and piperazides of these carboxylic acids substituted in a simple manner

Just like oxothiazolopipeπdine carboxyhc acids, piperazides and homopiperazides which are substituted in a particular manner on the second nitrogen atom on the (homo)- piperazine ring are disclosed in EP-A-0 296 455 as compounds with anti-thrombolytic, inflammation- and platelet aggregation-inhibiting as well as analgesic properties

In EP-A-232 740, which forms the structurally closest art, piperazine substituted thiazolopyπdines and benzothiazol compounds are already known to which analgesic, anti-arthritic and thrombocyte aggregation-inhibiting activities are ascribed aside from an anti-anaphylactic effect However, the majority of the piperazine substituted compounds exemplified therein can be further substituted with an NO-group on the piperazine ring, which, however, possess the danger of a cancerogemc effect known to experts such that the use is generally to be advised against The toxicity of N-mtroso compounds emerges for example, from E. Mutschler Arzneimittelwirkungen, Stuttgart (1991), pp 731-732 among others

In addition, a small range of the derivatives disclosed in EP-A-232 740 can carry a non- substituted amino group on the piperazine ring This type of substitution produces a

hydrazine function A series of hydrazine derivatives are known which themselves, and to a large degree after their metabolism, constitute strongly effective cytostatic agents which are strong cytotoxins with activities causing mitosis inhibition and chromatin breakage (see P T Ammon, Arzneimittelneben- und Wechselwirkungen, Stuttgart, (1986), p 942) In this connection, it should also be mentioned that hydrazine itself possesses lung damaging effects such that strong misgivings are generally advised with derivatives of this type, especially with long-term therapies

The use of these derivatives with a hydrazine or nitroso function can exert a damaging influence such that, from the viewpoint of medicinal therapy, the application of medicinal agents of this type with potentially toxic functional groups meets with misgivings in long-term therapy, especially of chronic illnesses Therefore, in the pharmaceutical therapy of chronic illnesses, only such compounds should be applied which are toxicologically safe

Therefore, an object is to create, at least in a toxicological respect, for example, improved new thiazolopyridine derivatives

The solution of this problem consists in providing compounds which represent cyclic amide derivatives of l,2-dιhydro-2-oxothιazolopyπdyl carboxyhc acids of the following general formula (I)

(I)

-NR ² R ³

whose substituents are characterized in detail below

In an unexpected manner, the danger of toxic side-effects was considerably eliminated by the new mono or disubstitutions ofthe terminal amino components

N

R ³

according to the invention, which are defined below and completely new, completely different pharmacological activities, especially in the form of direct bronchiodilatory and mediator inhibiting effects, were attained as compared to structurally related compounds with a non-substituted amino group in a direct bond to the nitrogen

It was surprisingly found that the compounds according to the invention are suitable for the treatment of bronchial asthma, also demonstrate a high tolerability, and therapeutically intervene at as many places as possible of the pathological event as a consequence of asthmatic conditions Thereby, the danger of serious side-effects of the structurally similar compounds known up to now which are used, for example, as a thrombocyte aggregation inhibitors or analgesic agents was advantageously avoided to a large extent Therefore, the compounds according to the invention with the new medical indications are safe from a toxicological viewpoint This is surprising in as much as the known structurally closest compounds with a free amino group, as described at the beginning, possess an entirely different activity spectrum, wherein their known activity is limited to different analgesic, anti-phylogistic, anti-thrombotic or platelet aggregation inhibiting effects without suitability for the treatment of asthmatic conditions In other words, the structurally new compounds according to the invention are useful as a basis for the named medical indications not only with respect to their toxicological safety, but also in view of their new pharmacological activities Therefore, this is to be characterized in many respects as the result of a surprising inventive step

The special feature ofthe multiple effects of the new compounds lies above all in the inhibition of the following processes bronchial hyper-reactivity, extravasation of blood

protein, of bronchiospasms which are induced by mediator release from immunocompetent cells, bronchioconstnction induced by release of neuropeptides from C fibers (eNANC) as well as bronchioconstnction induced by PAF, wherein a direct bronchial spasmolytic activity is exhibited

In this connection, the new compounds according to the invention simultaneously demonstrate, among others, an especially pronounced bronchiodilatory action with an antagonizing activity in therapy with respect to multiple mediators and thereby open completely new medical treatment possibilities, especially in therapy of asthmatic illnesses

As further interesting indications of the new compounds according to the invention, chronic venous insufficiency as well as the treatment of migraine attacks or the use of these medicaments as antitussives in chronic cough or for suppressing chronic pain are considered for example

The substances can also be used in diagnositic methods in connection with testing ofthe bronchioreactivity The detailed illustration and presentation of the test results on which the found new medical indications of the compounds are based are found in the experimental pharmocology section in connection with the illustration of the synthesis of end products and intermediates according to the description of the production examples for medicaments

Accordingly, subject-matter ofthe invention is l,2-dιhydro-2-oxothιazolopyπdιne compounds according to the above-named formula (I)

(I)

wherein

R represents halogen, and

2 3

R and R are the same or different,

2 R can be alkyl, alkenyl, alkinyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and

3

R can be hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl, hydroxyalkyl, acyl or alkanesulfonyl, or

2 3

R and R form a heterocyclic ring together, wherein the substitutuent

— N ^* *■ i

R ³

forming a ring can be selected from the following heterocycles:

N v (CH ₂ ), tn

Xa)

or

NH

N

Xb) or

N NH

\ / (CH ₂ ) _n

Xc) or

/ \ N O

\ / (CH ₂ ) _n

Xd)

and these rings can be substituted once or twice 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 each optionally substituted by one or more alkyl groups,

Q is selected from the following heterocycles:

IXa)

or

or

wherein the heterocyclic ring can optionally have a double and

m can be 3 to 5 or 6 or 3 or 4 to 7, n can be 2 or 3, and p can be 3 to 5 or 6 or 3 or 4 to 7,

4

R can be hydrogen, alkyl, hydroxymethyl, carboxyl or alkoxycarbonyl, as well as

R can be hydrogen or an alkyl residue, wherein

4 5

R and R~ can form an alkylene bridge, in a preferred manner a C1 -C4, especially a

C1-C3 alkylene bridge, optionally together under formation of a bicyclic ring

system,

D in the case that the bond to Q occurs over a carbon atom, can represent a single bond,

alkylene optionally substituted once or twice, each by alkyl, hydroxy or alkoxy, or

alkenylene optionally substituted once or twice, each by alkyl, hydroxy or alkoxy, wherein the double bond of the alkenylene group can also be to ring Q,

can be alkmylene optionally substituted once or twice by alkyl, hydroxy or alkoxy, or

can be an alkylene-, alkenylene- or alkmylene residue, wherein a methylene group can be isosterically replaced by an oxygen atom, sulfur atom or a NR residue, wherein

R is selected independently from R from hydrogen or alkyl, or

D in the case that the bond to Q occurs over a nitrogen atom,

is alkylene, alkenylene or alkmylene optionally substituted once or twice, each by alkyl, hydroxy or alkoxy,

wherein a methylene group can be isosterically replaced by an oxygen atom , sulfur atom or an NR residue, as well as

stereoisomeres and salts,

whereby in the above-named substitutions

the alkylene- and alkenylene- as well as alkmylene residues each preferably have up to 8, 10 or 12 carbon atoms, wherein their possible alkyl- and alkoxy substituents can each have in a preferred manner at least 1 to at the most 4, 6 and 8 carbon atoms,

furthermore, alkenyl- and alkinyl residues as well as the alkyl-, cycloalkyl- and hydroxyalkyl residues, the alkoxyalkyl-, alkylaminoalkyl- and aminoalkyl residues and/or the dialkylaminoalkyl residues optionally coming into

2 3 4 5 consideration in the residues R , R , R and/or R can each have in a preferred manner up to 8 or 10, in a particularly preferred manner 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 residues can preferably amount to 2 and/or 3 or 4 and/or up to 6, 8, 10 or 12, 15 or 18 carbon atoms,

the named acyl- and alkanesulfonyl residues can have in a preferred manner up to 8, 10 or 12, especially at least 1, 2, 3 or 4 and up to 5 or 6 carbon atoms,

the alkoxycarbonyl residues can have up to 6, 8 or 10 carbon atoms, but in a preferred manner, 2, 3, 4 or 5 carbon atoms,

4 5 the residues R and R taken together in the formation of a bicyclic ring system

preferably represent a Cι-C4-alkylene bridge, particularly preferably a C1-C3- alkylene bridge,

the named aliphatic saturated and/or unsaturated hydrocarbon residues with possible functional groups can each be, independent of each other, straight or branched chain, and in the case of 2 or more, for example 3, alkly residues in the named groupings, for example in the alkylaminoalkyl- or dialkylaminoalkyl residues, the alkyl residues can be, independent of each other, the same or different and can each also be straight or branched chain, and wherein it holds that

depending on the bond relationship in the individual case, the minimum number of carbon atoms in the named substituents can each amount to 1 , 2 or also 3 carbon atoms, l e 2 or 3 carbon atoms in the case of alkenyl groupings and 3 carbon atoms in the case of three-fold unsaturated alkinyl compounds, wherein this holds in the same manner for the cyclic carbon compounds, among which the cyclopropyl group has the lowest possible number of 3 carbon atoms,

as well as preferably stereoisomers thereof, such as optionally cis/trans isomers, endo/exo isomers, enantiomers, diastereomers as pure isomers or in the form of their mixtures as well as their acid addition salts

An embodiment of the new compounds of the invention according to formula (I)

(I)

are compounds, in which

R is halogen, wherein

2 3

R and R can be the same or different, and

2

R represents C j-Cό-alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, CJ -CO-

hydroxyalkyl, C2-C6-alkoxyalkyl, C2-C6-amιnoalkyl, C3-Cιo-alkylamιnoalkyl, C4- Cio-dialkylaminoalkyl and

3

R represents hydrogen, Cι-C6-alkyl, C3-C6-alkenyl, C3-C6-alkιnyl, C3-C6-

cycloalkyl, C ^* -C6-hydroxyalkyl, C\-C(,-acy\, Cj-Cό-alkanesulfonyl,

2 3

R and R can form a heterocyclic ring together in the residue

R'

— N

V

wherein this ring in this case can be selected from the following heterocycles:

N (CH ₂ ) m

Xa) or

/ NH N

Xb)

or

N NH

\ / (CH ₂ ) _n

Xc) or

N O

\ / (CH ₂ ) _n

Xd)

and these rings can be substituted once or twice by Cι-C4~alkyl, hydroxy, C1-C4- alkoxy, amino, Cι-C4-alkylamιno, C2-C8-dιalkylamιno, Cι-C4-hydroxyalkyl, C3- Cιo-dιalkylamιnoalkyl or by an oxo group adjacent to a nitrogen atom,

is selected from Ci-Cό-alkylene or C2-Cfi-alkenylene each optionally substituted

by one or more C ι-C3-alkyl groups,

is selected from the following heterocycles

IXa)

or

or

wherein the heterocyclic ring can optionally contain at least one double bond and

m can be 3 to 5 or 6 or 3 or 4 to 7, n can be 2 or 3, and p can be 3 to 5 or 6 or 3 or 4 to 7,

4

R can be hydrogen, Ci-Cό-alkyl, hydroxymethyl, carboxyl or C2-C 5 -alkoxycarbonyl, as well as

R can be hydrogen or a Ci-Cό-alkyl residue,

4 5 wherein R and R can form a Cj-Cβ-alkylene bridge, optionally under formation of a bicyclic ring system,

D in the case that the bond to Q occurs over a carbon atom, is a single bond,

Cι-Cιo-alkylene or C2-Cifj-alkenylene each optionally substituted once or twice by Cι -C4-alkyl, hydroxy or Cι-C4-alkoxy, wherein the double bond can also be to ring Q in the latter case,

C3-Cιo-alkιnylene optionally substituted once or twice by C ^* -C4-alkyl, hydroxy or Cι-C4-alkoxy, or

C ^* -C*o-alkylene, C2-Cιo-alkenylene or C3-C ^* _υ -alkιnylene, in which a methylene

group is isosteπcally replaced by O or S or NR , wherein

R is selected independently from R from hydrogen or C ^* -Cό-alkyl, or

D in the case that the bond to Q occurs over a nitrogen atom,

is C2-Cιo-alkylene, C4-Cιo-alkenylene or C ₄ -C ^* o-alkιnylene each optionally substituted once or twice by C ^* -C4-alkyl, hydroxy or C ^* -C4-alkoxv ein-, or

C2-Cιo-alkylene, C4-Cιo-alkenylene, or C4-Cιo-alkιnylene, in which a methylene

group is isosterically replaced by O or S or NR ,

as well as stereoisomers thereof and acid addition salts

A further embodiment according to the invention are compounds in which the substituents R*, R , R , R , R and/or R labelled therein as well as A together with the remaining substitutions given in the above definitions according to formula (I)

(i)

have the following meanings, in which

halogen is either fluorine, chlorine, bromine or iodine,

Ci-Cό-alkyl are straight chained or branched and can be a methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-, tert-butyl-, cyclopropylmethyl-, pentyl-, isopen- tyl-, tert-pentyl-, neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or hexyl group,

alkylene can represent the methylene-, ethylene-, propylene-, tetramethylene-, pentamethylene-, hexamethylene-, heptamethylene-, octamethylene-, nonamethylene- or decamethylene group,

C3-C6-alkenyl are straight chained or branched and can represent an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3- methyl-2-butenyl-, 2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3- butenyl group,

alkenylene can be an ethenylene-, propenylene-, butenylene-, pentenylene-, hexenylene-, hexadienylene-, heptenylene-, octenylene-, nonenylene- or decenylene group,

C3-C6-alkinyl are straight chained or branched and can be a propargyl-, 2-butinyl-, 3- butinyl-, 4-pentinyl-, 5-hexinyl- or 4-methyl-2-pentinyl group,

alkinylene represents the propinylene-, butinylene-, pentinylene-, hexinylene-, heptinylene-, octinylene-, noninylene- or decinylene group and

C3-C6-cycloalkyl represents the cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl group, wherein the

Cι-C6-hydroxyalkyl contains a hydroxyl group in one of the above-named Cι-C6-alkyl groups, among which the hydroxymethyl- and the hydroxyethyl group are preferred,

Cι-C4-alkoxy contains, aside from the oxygen atom, one of the above-named Q-C4- alkyl groups, among which the methoxy-, ethoxy-, isopropoxy- or tert-butoxy group are preferred,

C2-C6-alkoxyalkyl contains one of the above-named alkoxy groups in one of the above- named alkyl groups, among which the methoxymethyl-, methoxyethyl-, methoxypropyl- or ethoxyethyl group are preferred,

C2-C5-alkoxycarbonyl groups contain, aside from the carbonyl group, one of the above- mentioned C* -C4-alkoxy groups, among which the methoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl- and tert-butoxycarbonyl group are preferred,

C2-C6-aminoalkyl contains an amino group in one of the above-named alkyl residues, among which the aminoethyl-, aminopropyl- or arninobutyl group are preferred,

C ₃ -Cιo-alkylaminoalkyl carries one of the above-named Cι-C4-alkyl groups on the amino group of one of the above-named C2-Cf5-aminoalkyl groups, among which the methylaminoethyl-, methylaminopropyl-, methylaminobutyl-, ethylaminoethyl- or ethylaminopropyl group are preferred,

Cι-C4-alkylamιno contains one of the above-named Cι-C4-alkyl groups among which the methylammo-, ethylamino-, propylamino-, isopropylamino-, butylamino- and the tert-butylamino group are preferred,

C2-C8-dιalkylamιno carries two of the same or different of the above-named C1-C4- alkyl groups on the nitrogen atom, among which the dimethylamino-, diethylamino-, dipropylamino-, dusopropylamino-, lsopropyl-methylammo-, dibutylamino- and tert- butyl-methylamino group are preferred,

C3-C*o-dιalkylamιnoalkyl carries one of the above-named C2-C8-dιalkylamιno groups on one of the above-named Cj-Cό-alkyl residues, among which the dimethylaminomethyl-, dimethylaminoethyl-, dimethylaminopropyl-, dimethylaminobutyl-, diethylaminomethyl-, diethylaminoethyl-, diethylaminopropyl-, dφropylaminomethyl-, dipropylaminoethyl-, tert-butyl-methylaminomethyl- and the tert- butyl-methylaminoethyl group are preferred,

Cj-Cg-acyl is a residue of an aliphatic saturated or unsaturated straight chained, branched or cyclic carboxylic acid, among which formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-, methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-, cyclobutylcarbonyl-, hexanoyl- and dimethylacryloyl group are preferred, and

Ci-Cζ-alkanesulfonyl preferably represent the methanesulfonyl-, ethanesulfonyl-, propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and hexanesulfonyl group and the acid addition salts can be present in the form of the hydrochloπdes, hydrobromides, hydroiodides, sulfates and phosphates as well as the acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succmates, tartrates or tosylates

A further preferred embodiment according to the invention represents compounds according to the formula (I),

(I)

in which the labelled substituents have the following meanings

Rl IS a halogen in posιtιon-6,

2 R is selected from Ci-Cs-alkyl, C3-C6-alkenyl, C3-C6-alkιnyl, C3-C6-cycloalkyl,

Ci-C^-hydroxyalkyl, C2-C6-alkoxyalkyl or C4-Cιo-dιalkylamιnoalkyl and

3

R is selected from hydrogen, Cj-Cό-alkyl, C3-C6-alkenyl, C3-C6-alkιnyl, C3-C6- cycloalkyl, Cι-C6-hydroxyalkyl, Ci-Cζ-acyl or C ^* -C6-alkanesulfonyl,

2 3

R and R can be the same or different or together form a heterocyclic ring, wherein in the case of a heterocychc ring,

— N

V

is selected from

N (CH ₂ ) m

Xa) or

NH

N

Xb) or

N NH

\ /

(CH ₂ ) _n

Xc) or

/ \ N O

\ /

(CH ₂ ) _n

Xd)

and these rings can be substituted by Cι-C3-alkyl, hydroxy, Ci-C^-alkoxy, C ^* - C3-hydroxyalkyl, C2-C8-dιalkylamιno or an oxo group adjacent to a nitrogen atom,

A is selected from Cι-C4-alkylene or C2-C4-alkenylene optionally substituted by a methyl group, and

O is selected from

IXa)

or

or

wherein the ring can 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,

4

R represents hydrogen, C ^* -C3-alkyl, hydroxymethyl, carboxyl or C2-C5-alkoxycar- bonyl and

R is hydrogen or Cι-C3-alkyl or

4 5

R and R form, optionally together, a C1 -C3 -alkylene bridge under formation of a bicyclic ring system,

D in the case of a double bond to Q over a carbon atom, is selected from a single bond from Ci-Cg-alkylene or C2-Cg-alkenylene, wherein the double bond can also be to ring Q, or is selected from C4-Cs-alkιnylene,

wherein these alkylene-, alkenylene- or alkmylene groups can each be optionally substituted by C*-C4-alkyl, hydroxy or Cι-C4-alkoxy, or

in which a respective methylene group can optionally be isosterically replaced by O or S or NR , wherein R is selected independently from R , from hydrogen or

C ^* -C3-alkyl, or

D in the case of a bond to Q over a nitrogen atom, is selected from C2-Cg-alkylene,

C4-C8-alkenylene or C4-C8-alkinylene, each of which can be optionally substituted by Cι-C4~alkyl, hydroxy or Cι-C4-alkoxy or in which a respective

methylene group can be isosterically replaced by O or S or NR , wherein R is

selected independently from R from hydrogen or Cι -C3-alkyl.

A particular preferred embodiment according to the invention represents compounds according to the formula (I)

(I)

in which the labelled substituents have the following meanings

R* IS bromine or chlorine in posιtιon-6,

2 R is selected from C ^* -C4-alkyl, C3-C4-alkenyl, C3-C4-alkιnyl, C3-C5-c\cloalkyl, C2-

C3-hydroxyalkyl or C ₄ -C8-dιalkylamιnoalkyl,

3

R is selected from Cι-C4-alkyl, C3-C4-alkenyl, C3-C4-alkιnyl, Cι-C3-acyl or C1-C3- alkanesulfonyl, wherein

2 3

R and R can be the same or different or can together form a heterocyclic ring, and in the case of the formation of a heterocyclic ring

R'

— N

V

can be selected from azetidine, pyrrohdine, piperidine, hexahydroazepine, piperazine, homopiperazine or morphohne, wherein the ring can be respectively substituted by Cι-C3-alkyl, hydroxy, C1-C3 -hydroxyalkyl, C2-C4-dιalkylamιno or an oxo group adjacent to a nitrogen atom,

A represents a methylene group, and

Q is selected from

IXa)

or

or

wherein the ring can 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,

4

R represents hydrogen or Cι -C3-alkyl and

R represents hydrogen,

D in the case of a bond to Q over a carbon atom, is selected from Ci-Cβ-alkylene or C2-C6-alkenylene, wherein the double bond can also be to Q, or is selected from C3-C6-alkιnylene, wherein a respective methylene group can optionally be

isosterically replaced by O or NR in these alkylene-, alkenylene- or alkmylene residues and

R is selected from hydrogen or C ^* -C3-alkyl, or

D in the case of a bond to Q over a nitrogen atom, is selected from C2-C6-alkylene, C4-C6-alkenylene or C4-C6-alkιnylene, in which a respective methylene group can

optionally be isosterically replaced by O or NR , wherein

R is selected from hydrogen or C ^* -C3-alkyl.

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

(I)

represent compounds, wherein

R-** IS bromine and chlorine in posιtιon-6 and

A is a methylene group,

Q is selected from pyrrohdine, piperidine, hexahydroazepine, piperazine and homopiperazine, D is selected from ethylene, ethenylene, propylene and butylene and

N

R ³

is selected from methylammo, ethylamino, propylamino, allylamino, tert- butylamino, dimethylamino, diethylamino, dipropylamino, dnsopropylamino, diallylamino, methylpropylamino, methylallylamino, methyl-tert-butylamino, ethylallylamino, pyrrohdinyl, 2-oxopyrrohdιnyl, pipeπdinyl, morpholino and hexahydroazepinyl

The compounds of formula (I) can optionally exist as cis- and trans- and/or E- and Z- lsomers, if, for example, A or D contains a double bond Subject-matter of the invention are the pure isomers as well as their mixtures Further, compounds of formula (I) can contain one or more asymmetric carbon atoms and consequently exist in various optic isomers (enantiomers, diastereomers) The invention includes all optic isomers and their racemic or non-racemic mixtures Finally, compounds of formula (I) can exist as endo/exo-isomers in case the ring system Q is bicyclic The pure exo- and endo-isomers as well as their mixtures are also encompassed by the invention

Subject-matter of the invention is further pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids Preferred examples for addition salts with suitable inorganic acids are hydrochloπdes, hydrobromides, hydroiodides, sulfates and phosphates Addition salts of organic acids are preferably acetates, benzoates, citrates, fumarates, gluconates, malates, maleates, methanesulfonates, lactates, oxalates, succmates, tartrates and tosylates

Compounds the formula (I) as well as their acid addition salts can also be optionally present as hydrates or other solvates The invention includes such hydrates and solvates

Production of the End Products

The compounds according to the invention in the form of the end products are produced in an analogous manner according to known methods The different variants a) to d) are considered as so-called analogous methods such as they are described in the following as further claimed subject-matter

Method (a)

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

(II)

in which R.1 and A have the meanings given above, or their reactive derivatives, with compounds ofthe following formula (III),

/R ²

H-Q-D -N

\R ³ (III)

wherein Q, D, R^ and R--* are as defined above

Reactive derivatives of compound (II) can be, for example, activated esters, anhydrides, acid halides (especially acid chlorides) or simple lower alkyl esters Suitable acitivated esters are, for example, p-mtrophenyl ester, 2,4,6-tπchlorphenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, of N- hydroxyphthahmide, of 1-hydroxybenzotriazol, of N-hydroxypipeπdine, of 2- hydroxypyπdine or of 2-mercaptopyπdιne, etc Anhydrides can be symmetric anhydrides

or mixed, as they are obtained, for example, with pivaloyl chloride or with chloroformates Aromatic (for example chloroformic phenyl ester), arahphatic (for example chloroformic benzyl ester) or aliphatic chloroformates (for example chloroformic methyl ester, -ethyl ester or -isobutyl ester) can be used for this

Reaction of compounds according to formula (II) with compounds according to formula (III) can also be earned out in the presence of condensation agents such as dicyclohexylcarbodiimide, l -ethyl-3-(3-dιmethylamιnopropyl)carbodumιde hydrochloride, N,N'-carbonyldnmιdazol, 1 -ethoxycarbonyl-2-ethoxy- 1 ,2- dihydroquinohne, etc If carbodnmides are used as the condensation agent, reagents such as N-hydroxysuccιnιmιde, N-hydroxyphthalimide, 1-hydroxvbenzotπazol, N- hydroxypipeπdine, etc can be advantageously added

Compounds of formula (III) can be used for reaction as free bases as well as in the form of their acid addition salts For this, the salts of inorganic acids are to be preferred, l e hydrochloπdes, hydrobromides or sulfates

Reaction of compounds according to formula (II), or their reactive derivatives with compounds according to formula (III) are normally carried out in a suitable, preferably inert solvent As examples, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (for example dichloromethane, chloroform, 1,2- dichloroethane, tπchloroethylene), ethers (for example diethyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate, acetonitrile or polar aprotic solvents such as, for example, dimethylsulfoxide, dimethylformamide or N-methylpyrrohdone are to be named Pure solvents as well as mixtures of two or more can be used

The reaction is optionally carried out in the presence of an auxiliary base Suitable examples for this are alkali metal carbonates (sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate), or organic bases such as, for example, triethylamine, ethyl dusopropylamine, tπbutylamine, N-methylmorpholine or pyndine A suitable excess of the compound

according to formula (III) can also be used as a base. If compounds according to formula (III) are used in form of their acid addition salts, then it is appropriate to consider the amount of auxiliary base used as equivalent

The reaction temperatures can - depending on reactivity ofthe educts - vary in a wide range. Generally, 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 ofthe solvent used.

The starting compounds according to formula (II) and according to formula (III) are known and/or can be produced according to known methods in an analogous manner The production of various examples for these starting compounds is further described below in conection with the illustration of the synthesis of end products and intermediates

Method (b ι

The end products in form of the compounds according to formula (I) can also be produced in that a compound of formula (IV)

in which R^ , A, Q and D have the the meaning given above and L represents a suitable nucleofuge or reactive group, is reacted with a compound of formula (V),

H-N

V

(V)

wherein R-2 and RP in formula (V) have the above meanings

In compounds of formula (IV), the leading group L can be a reactive derivative of an alcohol, for example, represent a halide atom such as chlorine, bromine or iodine as a halide or it can be a sulfonic acid ester, 1 e for example a methanesulfonyloxy residue, tπfluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p- toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue A reactive group L can be a terminal epoxide group, for example

The reaction of compounds according to the formulae (IV) and (V) usuallv occurs in a suitably inert solvent Solvents of this type can be, for example, aromatic hydrocarbons (benzene, toluene, xylene), ethers (for example tetrahydrofuran, dioxane, glycol dimethyl ether), ethylacetate, acetonitrile, ketones (acetone, ethyl methyl ketone), polar protic solvents such as alcohols (ethanol, isopropanol, butanol, glycol monomethyl ether) or polar aprotic solvents such as for example dimethylsulfoxide, dimethylform¬ amide or N-methyl pyrrolidone Pure solvent as well as mixtures of two or more can be used Preferably, the reactions are carried out in the presence of bases, whereby the same as named above in method (a) can be used If chlorides or bromides are employed as compounds according to formula (IV), then the reaction can be accelerated by addition of alkali metal iodides (sodium iodide, potassium iodide) The reaction temperatures can vary depending on the reactivity of the educts between 0°C and 180°C, but preferably he between 20°C and 130°C

The intermediates of formula (IV) according to the invention can be produced in such a manner that the carboxylic acids of formula (II), or their activated derivatives, are reacted under conditions named in method (a) with compounds of the formula (VI)

H -Q-D-L

(VI)

in which Q, D, and L are defined as above, wherein L represents a suitable nucleofuge or reactive group They can also be advantageously produced by reacting the carboxylic acids of formula (II) with amino alcohols of formula (VI), in which L is a hydroxy group, and the alcoholic hydroxyl group in the obtained intermediates according to formula (IV) is converted according to methods known to experts into the above named reactive denvitives, i e for example halides or sulfonic acid esters

Intermediates according to the invention in the form of compounds of formula (IV), in which Q corresponds to the formulae

LXa)

and

and wherem R*, A and D are defined as 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 with the exception of compounds according to formula (IV), in which Q is

H, alkyl

such as they are described in JP 63/017881

Therefore, these new intermediates according to formula (IV) as well as their use for the production of end products according to formula (I) according to the invention are also subject-matter of the invention

In connection with the illustration of synthesis examples for intermediates, exemplary selected compounds of formula (IV) according to the invention are given in the following Table IV with their respective substituent meanings without any limitations

The end products accordmg to the invention can also be synthesized by means ofthe following analogy methods according to variants c) and d)

Method (ci

Compounds of formula (I), in which R3 IS an alkyl-, alkenyl-, alkinyl- or cycloalkyl residue according to the above definitions, can also be produced, aside from methods (a) and (b), by reacting compounds of formula (I) in which R-- ^* is hydrogen, with a suitable alkylation agent of formula (VII)

(VII)

wherein R^ IS an alkyl-, alkenyl-, alkinyl- or cycloalkyl residue according to definition and L is as defined above Reaction of compounds (I, R ^* - ¹ = H) with compounds (VII) can occur under conditions in this connection as they are descπbed in method (b)

Method fd i

Compounds of formula (I), in which R-* represents an acyl residue or alkanesulfonyl residue according to the above definition, can also be produced, aside from the methods (a) and (b), by reacting compounds of formula (I), in which R-* is hydrogen, with a carboxyhc acid and/or an alkanesulfonic acid of formula (VIII), in which R-' is an acyl and/or alkanesulfonyl residue according to definition,

>3 _ OH (VIII)

or by bringing their derivatives capable of reaction to reaction Preferable derivatives are carboxylic acids and/or sulfonic acids of formula (VIII) capable of reaction are symmetric or unsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydrides or carboxyhc acid and/or sulfonic acid halides, especially carboxylic acid and/or sulfonic acid chlorides The reaction of the acids of formula (VIII) and/or their derivatives capable of reaction with the compounds [of formula (I), R-^ = H] thereby occur preferably in the presence of auxiliary bases in solvents and under conditions as they are described in method (a)

The compounds of formula (I) produced according to method (a), (b), (c) or (d) can be isolated and purified in a known manner, for example, by subjecting the residue after distillation ofthe solvent to dispersion, extraction, re-precipitation or re-crystallization or another purification method In this connection, column chromatography on suitable support material or preparative medium or high pressure chromatography is preferred

Compounds of formula (I) are first normally obtained in the form of their free bases or hydrates or solvates thereof, depending on the type of isolation or purification Their addition salts with pharmaceutically acceptable acids are normally obtained by reacting the base with the desired acid m a suitable solvent Depending on the number of basic centers of the compounds of formula (I), one or more of the equivalent acids per mol base can be bound

Suitable solvents are, for example, chlorinated hydrocarbons such as dichloromethane or chloroform; ethers such as diethyl ether, dioxane or tetrahydrofuran, acetonitrile, ketones such as acetone or ethyl methyl ketone, esters such as methylacetate or ethylacetate or low molecular alcohols such as methanol, ethanol or isopropanol; and water Pure solvents as well as mixtures of two or three solvents can be used The salts can be recovered by crystallization, precipitation or evaporation ofthe solvent In this connection, they optionally accumulate as hydrates or solvates

The bases can be recovered from the salts by alkahzation, for example with aqueous ammonia solution, alkali carbonate or dilute lye

SYNTHESIS EXAMPLES for end products of the invention according to formula (I)

The abbreviations stand for the following terms in the production examples

MP = melting point,

BP = boiling point, decomp = decomposition,

RT = room temperature, h = hour(s), min = minutes

Η-NMR-Spectrum = proton resonance spectrum, taken at 100 MHz. The chemical shifts are given in ppm against TMS as a standard (δ = 0 0), wherein

s = singlet, d ^* = doublet, dd = double doublet,

t = triplet, q = quartet, m (mz) = (centered) multiplet;

THF = tetrahydrofuran,

DMF = dimethylformamide,

DMSO = dimethylsulfoxide, abs. = absolute;

HBr = hydrogen bromide,

CDI ^* =carbonyldiimidazol,

EDC ^* = N-(3-dimethylaminopropyl)-N'-ethyl- carbodiimide hydrochloride,

EEDQ = 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline,

HOBT = 1-hydroxybenzotriazol,

TEA = triethylamine.

SYNTHESIS OF THE END PRODUCTS ACCORDING TO FORMULA (I)

Example 1

6-chloro-l-[4-(2-dimethylaminoethyl)-piperidyl]-carbonylm ethyI-2-oxo-1.2- dihydrothiazolo[5.4-b]pyridine hydrochloride (substance 51 as a hydrochloride)

33 4 g (136 6 mmol) 6-chloro-l-carboxymethyl-2-oxo-l,2-dιydrothιazolo[5 4-b]pyπdιne and 24 4 g (150 3 mmol) CDI are heated to reflux in 340 ml abs THF for lh under stirring, wherein a clear solution results Subsequently, this is cooled, 37 6 g (164 mmol) 4-(2-dιmethylamιnoethyl)-pιpeπdιne dihydrochloride are added at 5-10°C and 50 2 ml (361 mmol) TEA is added dropwise thereafter at the same temperature under stirring The suspension is stirred at RT for 5h without further cooling Subsequently, this is concentrated to approximately half under vacuum and the remainder is dispersed between 500 ml water and ethylacetate The organic phase is washed twice with water, dried over sodium sulfate and the solvent is removed under vacuum The resinous residue is dissolved in CHCl ₃ /CH ₃ OH/conc NH ₃ at the ratio of 90/9/1 and filtered through a silica gel layer The fractions containing the product are concentrated and rotated off The resinous crude product is dissolved in 330 ml isopropanol under heating and added to 28 ml ca 8 M isopropanolic hydrochloric acid The hydrochloride separated in the cold is drawn off, dried and recrystallized from 550 ml methanol Colorless crystals with a MP of 254-259°C (decomp ) are obtained in a yield of 27 2 g (48 %)

C ₁₇ H ₂₃ ClN ₄ O ₂ S . HCl MG = (419 4)

IR-spectrum (KBr) v(C=O) 1685, 1635 cnϊ ¹ v(C=C) 1575 cm ^"1

H-NMR-spectrum (D ₂ O) 0 90 - 1 90 (7H, m, (CH ₂ ) ₃ CH)

2 65 (lH, mz, CONCH) 2 75 (6H, s, N ⁺ (CH ₃ ) ₂ )

2 90 - 3 30 (3H, m, N ⁺ CH ₂ ,CONCH)

3 80 (lH, mz, CONCH)

4 20 (lH, mz, CONCH)

4 75 (IH, d, NCHCO, J = 18 Hz) 4 96 (IH, d, NCHCO, J = 18 Hz)

7 43 (IH, d, pyndine, J = 1 9 Hz)

8 15 (lH, d, pyndine, J = l 9 Hz)

Example 2

6-chloro-l-[4-(2-diethyIaminoethyl)-piperidyl]-carbonylme thyl-2-oxo-1.2- dihydrothiazolo[5.4-b)pyridine hydrobromide

(substance 60 as a hydrobromide)

Analogously to example 1, 4 0 g (16 4 mmol) 6-chloro-l-carboxymethyl-2-oxo-l 2- dιhydrothιazolo[5 4-b]pyπdιne and 2 9 g (18 0 mmol) CDI are heated under reflux in 50 ml abs THF for lh Subsequently, this is cooled, 5 0 g (19 6 mmol) 4-(2-dιethyl- amιnoethyl)-pιpeπdιne dihvdrochloπde and 5 5 ml (39 2 mmol) TEA dissolved in 40 ml abs THF are added dropwise thereafter under stirring and ice cooling The suspension is stirred at RT overnight without further cooling Subsequently, the solvent is drawn off under vacuum to a large extent and the residue is dispersed between 100 ml water and 200 ml ethylacetate The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under vacuum The resinous crude product is chromatographically pre-puπfied over silica gel mit CHCI3/CH3OH in the ratio of 90/10 as an elution agent and subsequently subjected to flash chromatography with CHCI ₃ /CH ₃ OH in the ratio of 97/3 The isolated product (3 2 g) is crystallized from a small amount of chlorobutane/dnsopropyl ether 2 3 g (34 %) colorless crystals are recovered

1 3 g of the free base is dissolved in 5 ml isopropanol and converted into the hydrobromide by introduction of gaseous HBr at RT The colorless crystals have a MP of 216-223 °C (decomp ) and are recovered in a yield of 1 0 g (64 %)

C, ₉ H ₂₇ ClN ₄ O ₂ S . HBr MG = (491 9)

IR-spectrum (KBr) v(C=O) 1680, 1645 cm ^" v(C=C) 1575 cm ^"

Η-NMR-spectrum (D ₂ O) 1 1 1 (6H, t, CH ₃ J = 7 3 Hz)

1 20 - 1 90 (7H, m, (CH ₂ ) ₃ CH)

2 60 (lH, mz, CONCH)

3 10 (7H, mz, N ⁺ (CH ₂ ) ₃ and CONHCH)

3 80 (1H, mz, CONCH)

4 20 (lH, mz, CONCH)

4 74 (IH, d, NCHCO, J = 18 Hz) 4 94 (IH, d, NCHCO, J = 18 Hz

7 42 (1 H, d, pyndine, J = 1 9 Hz)

8 12 (lH, d, pyndine, J = l 9 Hz)

Example 3

6-bromo-l-{4-(2-(2-oxopyrrolidin-l-yl)-ethyl]-piperidyl}- carbonylmethyl-2-oxo-l,2- dihydrothiazolo [5.4-b] pyridine (substance 134)

Analogously to example 1, 3 5 g (12 1 mmol) 6-bromo-l-carboxymethyl-2-oxo-l,2- dιhydrothιazolo[5 4-b]pyπdιne and 2 2 g (13 3 mmol) CDI in 50 ml abs THF are heated

under reflux for lh Subsequently, this is cooled, 3 4 g (14 5 mmol) 4-[2-(2-oxo- pyrrolιdιn-l-yl)-ethyl]-pιpendιne hydrochloride are added and 2 4 ml (16 9 mmol) TEA dissolved in 40 ml abs THF is added dropwise thereafter The suspension is stirred at RT overnight without further cooling Subsequently, the solvent is removed under vacuum to a large extent and the residue is dispersed between water and ethylacetate The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under vacuum The amorphous crude product is chromatographically purified twice over silica gel with CHCl ₃ /CH ₃ OH in the ratio of 98/2 as an elution agent and subsequently recrystallized from 1 -chlorobutane 2 8 g (49 %) of colorless crystals with a MP of 159°C are obtained

C ₁₉ H ₂₃ BrN ₄ O ₃ S MG = (467 4)

IR-spectrum (KBr) v(C=O) 1690, 1670, 1650 cm v(C=C) 1570 cm ^"

Η-NMR-spectrum (CDC1 ₃ ) 1 00 - 2 60 (1 IH, m, (CH ₂ ) ₃ CH and pynOlidine-CH ₂ CH ₂ CO)

265(1H, mz, CONCH)

290- 360 (5H, m, 5 CONCH)

390(1H,mz, CONCH)

450(1H,mz, CONCH)

4 60 (IH, d, NCHCO, J = 16 Hz) 4 82 (IH, d, NCHCO, J = 16 Hz)

7 37 (lH, d, pyndine, J = 1 9 Hz)

8 33 (IH, d, pyndine, J = 1 9 Hz)

Example 4

6-bromo-l-[4-(2-pyrroIidylethyIiden)-piperidyl]-carbonylm ethy.-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine hydrochloride

(substance 192 as a hydrochloride)

Analogously to example 1 , 2 60 g (9 0 mmol) 6-bromo-l-carboxymethyl-2-oxo-l,2- dιhydrothιazolo[5 4-b]pyπdιne and 1 65 g (10 0 mmol) CDI are heated under reflux in 50 ml abs THF for lh After cooling to 5°C, 2 40 g (9 5 mmol) 4-(2- pyrrolιdylethyhden)pιpeπdιne dihydrochloride are added under stirring and 3 50 ml (25 mmol) TEA are added dropwise The suspension is stirred at RT overnight without further cooling This is diluted with 75 ml dichloromethane, extracted with 10% sodium hydroxide solution, the organic phase is washed with water, dried over sodium sulfate and concentrated under vacuum The resinous residue is chromatographed over silica gel with CHCl ₃ /CH ₃ OH/NH ₃ in the ratio of 90/10/1 as an elution agent The purified product (2 8 g) is dissolved in 30 ml isopropanol and added to 5 ml ca 2 8 M isopropanolic hydrochloric acid The hydrochloride precipitated out in the cold is recrystallized from methanol under the addition of diethyl ether Colorless crystals with a MP of 232-242°C (decomp ) are obtained The yield amounts to 2 5 g (57 %)

C,9H2 ₃ BrN ₄ O2S HCl MG = (487 9)

IR-spectrum (KBr) v(C=O) 1685, 1635 cm ^" v(C=C) 1565 cm ^"1

1H-NMR-spectrum (D ₂ O) 1 92 4H, mz, pyrrohdιne-CH ₂ CH ₂ )

2 30 4H, mz, =C(CH ₂ ) ₂ )

2 70 - 3 80 (10H, m, N ⁺ (CH ₂ ) ₃ and CON(CH ₂ ) ₂ )

4 88 (2H, s, NCH ₂ CO)

5 36 (lH, t, =CHCH ₂ )

7 55 (IH, d, pyridine, J = 1 8 Hz)

8 23 (IH, d, pyndine, J = 1 8 Hz)

Example 5

6-bromo-l-[4-(2-dipropyIamino-ethyl)-piperidyl]-carbonylr nethyl-2-oxo-l,2- dihydrothiazo!ol5.4-b]pyridine hydrochloride (substance 65 as a hydrochloride)

9 5 g (49 8 mmol) EDC and 8 3 g (49 8 mmol) HOBT are added under ice cooling to a mixture of 12 0 g (41 5 mmol) 6-bromo-l-carboxymethyl-2-oxo-l,2- dιhydrothιazolo[5 4-b]pyπdιne, 13 0 g (45 7 mmol) 4-(2-dιpropylamιnoethyl)-pιpeπdιne dihydrochloride and 14 5 ml (103 8 mmol) TEA in 300 ml abs dichloromethane The clear solution is stirred at RT overnight without further cooling Subsequently, the batch is washed once with 1 M NaOH and twice with water The organic phase is dried over sodium sulfate and the solvent is removed under vacuum The resinous residue is dissolved in CHCl ₃ /CH ₃ OH in the ratio of 90/10 and filtered through a silica gel layer The fractions containing the product are combined and rotated off 9 0 g (45%) of pure base are obtained by means of MPLC (CHCI3/CH3OH in the ratio of 95/5) This is dissolved under heating in 20 ml isopropanol and added to 9 3 ml ca 4 M isopropanolic hydrochloric acid The hydrochloride precipitated in the cold is drawn off, dried and recrystallized from 20 ml ethanol/ 5 ml diethyl ether Colorless crystals with a MP of 215-217°C (decomp ) are recovered in a yield of 7 7 g (36 %)

C ₁₇ H ₂₁ BrN ₄ O ₂ S . HCl MG = (519 9)

IR-spectrum (KBr) v(C=O) 1670, 1650 cm v(C=C) 1570 cm -1

Η-NMR-spectrum (D ₂ O) 0 79 (6H, t, 2 CH ₃ , J = 7 4 Hz)

1 00 - 1 90 (1 IH, m, (CH ₂ ) ₃ CH and

2 CH ₃ CH ₂ )

2 60 (lH, mz, CONCH)

2 80 - 3 20 (7H, m, N ⁺ (CH ₂ ) ₃ and

CONCH)

3 90 (lH, mz, CONCH)

4 20 (lH, mz, CONCH)

4 75 (IH, d, NCHCO, J = 18 Hz) 4 96 (IH, d, NCHCO, J = 18 Hz)

7 55 (I H, d, pyndine, J = 1 8 Hz)

8 23 (IH, d, pyndine, J ^**** 1 8 Hz)

Example 6

6-bromo-l-[4-(2-pyrrolidylethyl)-piperidyl]-carbonylmethy l-2-oxo-l,2- dihydrothiazolo[5.4-blpyridine (substance 117)

Analogously to example 5, 62 0 g (214 mmol) 6-bromo-l-carboxymethyl-2-oxo-l ,2- dιhydrothιazolo[5 4-b]pyndιne, 56 0 g (220 mmol) 4-(2-pyrrohdylethyl)-pιperιdιne dihydrochloride and 70 ml (500 mmol) TEA in 600 ml abs dichlormethane are cooled to 5°C under stirring 46 0 g (240 mmol) EDC and 38 0 g (240 mmol) HOBT (85%) are added, stirred for 3 h without further cooling and left to stand at RT overnight The reaction solution is extracted wth 300 ml 10% sodium hydroxide solution, washed three times with water, dried over sodium sulfate and the solvent is removed under vacuum The solid remaining as a residue is heated to reflux with 300 ml acetone under stirring for purification and, after cooling, drawn off again at RT The extraction with acetone boiling under reflux is repeated twice Colorless crystals with a MP of 165-166°C in a yield of 67 0 g (72 %) are obtained

Ci ₉ H ₂₅ BrN ₄ O ₂ S MG = (453 4)

IR-spectrum (KBr) v(C=O) 1675, 1650 cm ^"

v(C=C) 1570 cm ^"

Η-NMR-spectrum (CDC1 ₃ ): 1.00 - 2.00 (1 IH, m, (CH ₂ ) ₃ CH and

CH ₂ CH ₂ 2.30 - 2.90 (7H, m, N(CH ₂ ) ₃ and

CONCH 3.15 (lH, mz, CONCH) 3.90 (lH, mz, CONCH) 4.50 (lH, mz, CONCH) 4.62 (IH, d, NCHCO, J = 16 Hz) 4.81 (IH, d, NCHCO, J = 16 Hz) 7.38 (lH, d, pyridine, J = 1.9 Hz) 8.38 (I H, d, pyridine, J - 1 .9 Hz)

Example 7

6-bromo-l-[4-(2-pyrrolidylethyl)-piperidyl]-carbonylrneth yI-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine hydrochloride (substance 117 as a hydrochloride)

58.5 g (129 mmol) 6-bromo-l-[4-(2-pyrrolιdylethyl)-pιperidyl]-carbonylmethyl -2-oxo- l,2-dihydrothiazolo[5.4-b]pyridine are dissolved under heating in 300 ml isopropanol with 100 ml ca. 2.8 M isopropanolic hydrochloric acid and slowly cooled again to RT. The crystallization is completed by cooling to 4°C overnight. The air dried hydrochloride is drawn off and recrystallized from a mixture of 65 ml methanol and 45 ml 2.7 M methanolic hydrochloric acid under addition of 200 ml diethyl ether. Colorless crystals with a MP of 228-235°C (decomp.) are recovered in a yield of 52.4 g (62 %).

C ₁₉ H ₂₅ BrN ₄ O ₂ S . HCl MG = (489.9)

IR-spectrum (KBr). v(C=O) 1695, 1650 cm ^"1 v(C=C) 1570 cm ^"1

Η-NMR-spectrum (D ₂ O): 0.80 - 2.10 (HH, m, (CH ₂ ) ₃ )CH and CH ₂ CH ₂ ) 2.65 (lH, mz, CONCH) 2.90 - 3.60 (7H, m, N ⁺ (CH ₂ ) ₃ and

CONCH) 3.80 (lH, mz, CONCH) 4.20 (l H, mz, CONCH) 4 75 (IH, d, NCHCO, J = 17 Hz) 4 91 (I H, d, NCHCO, J = 17 Hz) 7.56 (lH, d, pyndine, J = l 8 Hz) 8.22 (IH, d, pyndine, J = 1 8 Hz)

Example 8

l-{4-[2-(N-alIyl-N-methylamino)-ethyl]-piperidyl}-carbony lmethyl-6-bromo-2-oxo- l,2-dihydrothiazoIo|5.4-bjpyridine hydrochloride (substance 79 as a hydrochloride)

Analogously to example 5, 28.0 g (145 mmol) EDC and 24 0 g (145 mmol) HOBT are added to a mixture of 35.0 g (121 mmol) 6-bromo-l-carboxymethyl-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridιne, 34.0 g (133 mmol) 4-[2-(N-allyl-N-methylamιno)- ethylj-piperidine dihydrochloride and 42 ml (303 mmol) TEA in 1 1 abs. dichloromethane under ice cooling. The clear solution is stirred at RT overnight without further cooling. Subsequently, the batch is washed once with 1 M NaOH and twice with water The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is purified over silica gel (CHCI3/CH3OH in the ratio of 95/5) and dispersed in 200 ml tert-butyl methyl ether 31.0 g (56%) of colorless crystals.

These are dissolved in 200 ml isopropanol and added to 50 ml ca 3 M isopropanolic hydrochloric acid The hydrochloride precipitated in the cold is drawn off, dried and and recrystallized from a small amount of ethanol/diethyl ether Colorless crystals with a MP of 174-175°C are recovered in a yield of 13 0 g (22 %)

C- ₉ H25BrN ₄ O ₂ S . HCl MG = (489.9)

IR-spectrum (KBr) v(C=0) 1685, 1635 cm ^" v(C=C) 1570 cm ^'1

•H-NMR-spectrum (D ₂ O) 1 00 - 1 80 (7H, m, (CH ₂ ) ₃ )CH

2 67 (4H, s and m, CH ₃ N ⁺ and

CONCH)

3 07 (3H, m, N ⁺ CH ₂ and CONCH) 3 60 (2H, d, N ⁺ CH ₂ CH=)

3 73 (lH, mz, CONCH)

4 20 (lH, mz, CONCH)

4 72 (IH, d, NCHCO, J = 17 5 Hz)

4 91 (IH, d, NCHCO, J = 17 5 Hz)

5 30 - 5 60 (3H, m, CH ₂ =CH)

7 52 (1H, d, pyndine, J = 1 7 Hz)

8 20 (IH, d, pyndine, J = 1 7 Hz)

Example 9

6-bromo-l-{3-[4-(2-pyrrolidyl-ethyI)-piperidyl]-carbonylp ropyl}-l,2- dihydrothiazolo[5.4-b] pyridine hydrochloride (substance 124 as a hydrochloride)

Analogously to example 5, 2 2 g (1 1 3 mmol) EDC and 1 9 g (11 4 mmol) HOBT are added to a mixture of 3 0 g (9 5 mmol) 6-bromo-l-(3-carboxypropyl)-2-oxo-l,2-

dihydrothiazolo[5.4-b]pyridine, 2.7 g (10.4 mmol) 4-(2-pyrrolidyl-ethyl)-pιperidine dihydrochloride and 3.3 ml (23.6 mmol) TEA in 100 ml abs. dichloromethane under ice cooling. The clear solution is stirred at RT overnight without further cooling. Subsequently, the batch is washed once with 1 M NaOH and twice with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is purified over silica gel (CHCl ₃ /CH3OH/NH ₃ in the ratio of 90/9/1). 3.7 g (80 %) of a yellow resin are recovered. The free base is dissolved in 20 ml isopropanol and added to 4 ml ca. 4 M isopropanolic hydrochloric acid. The hydrochloride precipitated in the cold is drawn off, dried and recrystallized from 10 ml ethanol. Colorless crystals with a MP of 162-163°C are obtained. The yield amounts to 2.3 g (47 %).

C ₂ ,H ₂₉ BrN ₄ O ₂ S HCl MG = (517.9)

IR-spectrum (KBr): v(C=O) 1675, 1620 cm ^" v(C=C) 1560 cm ^"1

Η-NMR-spectrum (D ₂ O): 0.60 - 2.10 (13H, m, (CH ₂ ) ₃ CH,

CH ₂ CH ₂ and NCH ₂ CH2CH ₂ CO)

2.10 - 2.60 (3H, m, CH ₂ CO and CONCH)

2.60 - 3.30 (5H, m, CONCH and

N ⁺ (CH ₂ ) ₂ (pyrrolidme)

3.30 - 4.20 (6H, m, CH ₂ N ⁺ . 2 CONCH

7.72 (IH, d, pyndin-. 1 = 1.8 Hz)

8.14 (IH, d, pyridin = 1.8 Hz)

Example 10

6-chloro-l-[4-(2-diallylamino-ethyl)-piperidyI]-carbonylmeth yl-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine hydrochloride (substance 91 as a hydrochloride)

The solution of 4.0 g (16.3 mmol) 6-chloro-l-carboxymethyl-2-oxo-l,2- dihydrothiazolo[5.4-b]-pyridine, 3.7 g (18.0 mmol) 4-(2-diallylamino-ethyl)piperidine and 4.4 g (18.0 mmol) EEDQ in 70 ml THF is heated under reflux for 4 h. Subsequently, the solvent is drawn off under vacuum to a large extent and the remainder is distributed between water and ethylacetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under vacuum. The resinous crude product is chromatographically pre-purified over silica gel (CHCl ₃ /CH ₃ OH in the ratio of 95/5) and subsequently recrystallized several times (acetonitrile/ 1 -chlorobutane and/or isopropanol). 3.0 g (42 %) of colorless crystals are obtained. The free base is dissolved in isopropanol and added to 4.6 ml ca. 4 M isopropanolic hydrochloric acid. The hydrochloride precipitated in the cold is drawn off, dried and recrystallized from methanol. Colorless crystals with a MP of 195-197°C are obtained in a yield of 2.3 g (30 %).

C ₂ ,H2 ₇ ClN ₄ O ₂ S . HCl MG = (471.4)

IR-spectrum (KBr): v(C=O) 1670, 1650 cm ^' v(C=C) 1570 cm ^"1

1H-NMR-spectrum (D ₂ O): 0.90 - 1.90 (7H, m, (CH ₂ ) ₃ CH)

2.60 (IH, mz, CONCH)

3.10 (3H, mz, CH ₂ N ⁺ and CONCH)

3.63 (4H, d, 2 N ⁺ CH ₂ CH=)

3.75 (IH, mz, CONCH)

4.20 ((lH, mz, CONCH)

4.75 (IH, d, NCHCO, J = 18 Hz)

4.96 (IH, d, NCHCO, J = 18 Hz)

5.30 - 6.00 (6H, m, 2 CH ₂ =CH)

7 43 (IH, d, pyndine, J = 1 9 Hz)

8 16 (lH, d, pyndine, J = l 9 Hz)

Example 11

6-bromo-l-[4-(2-diallylamino-ethyl)-piperazinyl]-carbonyl methyl-2-oxo-l,2- dihydrothiazolo[5.4-b] pyridine dihydrochloride (substance 324 as a dihydrochloride)

Analogously to example 10, a solution of 4 0 g (13 8 mmol) 6-bromo-l-carboxymethyl- 2-oxo-l ,2-dιhydrothιazolo[5 4-b]pyndιne, 3 2 g (15 2 mmol) 4-(2-dιallylamιno-ethyl)- piperazine and 3 8 g (15 2 mmol) EEDQ in 70 ml THF are heated under reflux for 4h Subsequently, the solvent is drawn off under vacuum to a large extent and the remainder is dispersed between water and ethylacetate The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under vacuum The crystalline crude product is pre-purified over silica gel (CHCI3/CH3OH in the ratio of 98/2) and subsequently recrystallized from acetonitrile/ dnsopropyl ether 5 4 g (81 %) of colorless crystals are obtained The free base is dissolved in isopropanol and added to 1 1 ml ca 4 M isopropanolic hydrochloric acid The hydrochloride precipitated in the cold is drawn off, dried and recrystallized from methanol Colorless crystals with a MP of 205-208°C are obtained m a yield of 5 4 g (71 %)

C ₂₀ H ₂ 6BrN ₅ θ2S . 2HC1 MG = (553 3)

IR- spectrum (KBr) v(C=0) 1685, 1660 cm ^" v(C=C) 1570 cm ^"

Η-NMR-spectrum (D ₂ O) 3 20 - 4 10 (16H, m, 6 N ⁺ CH ₂ and CON(CH ₂ ) ₂

4 88 (2H, s NCH ₂ CO)

5 40 - 6 00 (6H, m, 2 CH ₂ =CH)

7 59 (IH, d, pyridine, J = 2 0 Hz)

8 1 1 (IH, d, pyndine, J = 2 0 Hz)

Example 12

6-chloro-l-14-(2-cyclopropylamino-ethyl)-piperidyl]-carbo nylmethyl-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine hydrochloride (substance 74 as a hydrochloride)

The suspension of 5 0 g (1 1 5 mmol) 6-chloro-l-[4-(2-methanesulfonyloxyethyl)- pιpeπdyl]-carbonylmethyl-2-oxo-l,2-dιhydrothιazolo[5 4-b]pyndme (substance 462) in 15 ml DMF is added to 5 0 ml (70 mmol) cyclopropylamme and stirred at 65°C for 3 5 h After cooling, the whole lot is poured in 100 ml ice water The sticky, precipitated solid is taken up in chloroform, the solution is dried over sodium sulfate and evaporated again Subsequently, this is chromatographed over silica gel with CHCI3/CH3OH in the ratio of 95/5 to 90/10 as an elution agent The free base purified in this manner (2 6 g, 58 % of a vitreous solid) is dissolved in 20 ml isopropanol and converted into the hydrochloride with 3 3 ml ca 4 M isopropanolic hydrochloric acid The precipitated crystals are recrystallized from 85% ethanol/diethyl ether Colorless crystals are recovered with a MP of 231 -234°C in a yield of 1 9 g (38 %)

C ₁₈ H ₂₃ ClN ₄ O ₂ S . HCl MG = (431 4)

IR-spectrum (KBr) v(C=O) 1680, 1650 cm ^" v(C=C) 1570 cm ^'1

•H-NMR-spectrum (D ₂ O) 0 70 (4H, mz, cyclopropane-CH ₂ CH ₂ ) 0 85 - 1 90 (8H, m,(CH ₂ ) ₃ CH and NH) 2 40 - 2 80 (2H, m, N ⁺ CH and CONCH) 2 85 - 3 30 (3H, m, N ⁺ CH ₂

and CONCH)

3 80 (lH, mz, CONCH)

4 20 (lH, mz, CONCH)

4 73 (1 H, d, NCHCO, J = 18 Hz) 4 94 (IH, d, NCHCO, J = 18 Hz)

7 40 (IH, d, pyndine, J = 1 9 Hz)

8 12 (IH, d, pyndine, J = 1 9 Hz)

Example 13

6-bromo-l-I4-(4-allylaminobutyl)-piperidyl]-carbonylmethy l-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine hydrochloride (substance 230 as a hydrochloride)

Analogously to example 12, the solution of 12 0 g (23 mmol) 6-bromo-l-[4-(4- methanesulfonyloxybutyl)-pipendyl]-carbonylmethyl-2-oxo-l ,2-dihydrothiazolo[5 4- b]pyridιne (substance 491) in 60 ml DMF is added to 17 6 ml (230 mmol) allylamine and stirred at 50°C overnight After cooling, this is poured into ice water and extracted twice with ethylacetate The combined organic phases are washed with water, dried and concentrated under vacuum The remaining sticky solid is chromatographed over silica gel with CHC1 ₃ 'CH ₃ OH/conc NH ₃ in the ratio of 97/3/0 3 to 95/5/0 5 as an elution agent The free base purified in this manner (4 7 g, 44 % of a resinous solid) is dissolved in 50 ml isopropanol and converted into the hydrochloride with 4 ml ca 6 5 M isopropanolic hydrochloric acid The precipitated crystals are recrystallized from isopropanol Colorless crystals with a MP of 151-155°C are recovered in a yield of 2 4 g (21 %)

C ₂₀ H ₂₇ BrN ₄ O ₂ S . HCl (503 9)

IR-spectrum (KBr) v(C=O) 1685, 1655 cm ^"1

v(C=C) 1570 cm ^'

1H-NMR-spectrum (D ₂ O) 0 80 - 1 80 (1 1H, m,

(CH ₂ ) ₂ CH(CH ₂ ) ₃ ) 2 59 (IH, mz, CONCH)

2 86 (2H, t, N ⁺ CH ₂ , J = 7 0 Hz)

3 04 (lH, mz, CONCH)

3 47 (2H, d, N ⁺ CH ₂ CH=, J = 6 0 Hz)

3 80 (lH, mz, CONCH)

4 10 (lH, mz, CONCH)

4 82 (2H, s, NCH ₂ CO)

5 20 - 5 90 (3H, m, CH=CH ₂ )

7 51 (IH, d, pyndine, J = 1 8 Hz)

8 21 (I H, d, pyndine, J = 1 8 Hz)

Example 14

6-bromo-l-[4-(4-cyclopropylmethylaminoburyl)-piperidyl]- carbonylmethyl-2-oxo-l,2-dihydrothiazolo(5.4-b]pyridine hydrochloride (substance 235 as a hydrochloride)

The suspension of 6 5 g (12 1 mmol) 6-bromo-l-[4-(4-ιodobutyl)-pιpeπdyl]- carbonylmethyl-2-oxo-l ,2-dιhydrothιazolo[5 4-b]pyndιne (substance 489) in 25 ml DMF is added to 7 5 ml (84 mmol) (cyclopropylmethyl)amιne and stirred at 50°C overnight After cooling, this is poured in 100 ml ice water and extracted twice with ethylacetate The combined organic phases are washed with water, dried and concentrated under vacuum The remaining resinous residue is chromatographed over silica gel with CHCl ₃ /CH ₃ OH/conc NH ₃ m the ratio of 97/3/0 3 to 95/5/0 5 as an elution agent The free base purified in this manner (2 3 g, 40 % of a resinous solid) is dissolved in 30 ml isopropanol and converted to the hydrochloride with 2 ml ca 6 5 M

isopropanolic hydrochloric acid Creme colored crystals are recovered with a MP of 198-207°C (decomp ) The yield amounts to 2 0 g (32 %)

C ₂ ,H2 ₉ BrN ₄ O ₂ S . HCl MG = (517 9)

IR-spectrum (KBr) v(C=O) 1675, 1650 cm ^'1 v(C=C) 1565 cm ^'1

Η-NMR-spectrum (D ₂ O) 0 16 (2H, mz, cyclopropane-CH ₂ ) 0 50 (2H, mz, cyclopropane-CH ₂ ) 0 60 - 1 80 (12H, m,(CH ₂ ) ₂ CH(CH ₂ ) ₃ and cyclopropane-CH) 2 40 - 3 20 (6H, m, N ^* (CH ₂ ) ₂ and

2CONCH)

375 (lH,mz,CONCH)

410 (IH, mz,CONCH) 480 (2H,s,NCH ₂ CO)

7 51 (IH, s, pyridine)

8 19 (IH, s, pyridine)

Example 15

6-bromo-l- { 4-{2-(N-allyl-N-cyclopropylcarbonylamino)-ethyl]-piperidyl } - carbonylmethyl-2-oxo-l,2-dihydrothiazolo[5.4-b]-pyridine (substance 88)

0 60 ml (8 96 mmol) cyclopropane acyl acid chloride are added dropwise at 0°C under stirring to a solution of 2 7 g (5 67 mmol) 6-bromo-l-[4-(2-allylamιnoethyl)-pιpendyl]- carbonylmethyl-2-oxo-l,2-dιhydrothiazolo[5 4-b]pyndιne (substance 76) and 1 7 ml (12 5 mmol) TEA in 25 ml abs dichloromethane After addition is completed, this is stirred further for 30 min under ice cooling and at RT for 5 h This is extracted several

times with water, dried over sodium sulfate and the solution is concentrated under vacuum The remaining residue is chromatographed over silica gel with CHCI3/CH ₃ OH in the ratio of 98/2 as an elution agent and the product purified in this manner is crystallized from ethylacetate Colorless crystals with a MP of 138-139°C are obtained in einer yield of 1 9 g (57 %)

C ₂₂ H ₂₇ BrN ₄ O ₃ S MG = (507.5) IR-spectrum (KBr) v(C=O) 1685, 1650, 1610 cm ^"1 v(0=C) 1570 cm ¹

Η-NMR-spectrum (CDCI3) 0 60 - 2 00 (12H, m, (CH ₂ ) ₂ CHCH ₂ and cyclopropyl-C ₃ H5

2 64 (1 H, mz, CONCH)

3 15 (lH, mz, CONCH)

3 40 (2H, t, NCUCH ₂ J = 7 0 Hz)

3 70 - 4 20 (3H, m, CONCH and NCH ₂ CH=)

4 50 (lH, mz, CONCH)

4 59 (IH, d, NCHCO, J = 16 8 Hz)

4 81 (IH, d, NCHCO, J = 16 8 Hz)

5 00 - 6 00 (3H, m, CH=CH ₂ )

7 36 (IH, d, pyndine, J = 2 0 Hz)

8 34 (IH, d, pyndine, J = 2 0 Hz)

Example 16

6-bromo-l- { 4-[4-(N-allyI-N-methylamino)-butyl]-piperidyI } -carbonyImethyl-2-oxo- l,2-dihydrothiazolo[5.4-b]pyridine hydrochloride (substance 231 as a hydrochloride)

The solution of 2.15 ml (34.4 mmol) methyl iodide in 20 ml acetone is dropped into a solution of 13.0 g (27.8 mmol) 6-bromo-l-[4-(4-allylamino-butyl)-piperidyl]- carbonylmethyl-2-oxo-l,2-dihydrothiazolo[5.4-b]pyridine (substance 230) and 4.7 ml (33.8 mmol) TEA in 130 ml acetone at 5°C. Subsequently, this is stirred at RT for 5 h without further cooling and left to stand overnight. This is poured into 500 ml water, the mixture is alkalized with 30 ml 2 M sodium hydroxide solution and extracted twice with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate and concentrated under vacuum. The resinous residue is chromatographed over silica gel with CHCl3/CH ₃ OH/conc.NH ₃ in the ratio of 95/5/0.5 as an elution agent. The free base purified in this manner (3.2 g, 25 % of a yellow resin) is dissolved in 50 ml isopropanol and converted into the hydrochloride with 10 ml ca. 6 M isopropanolic hydrochloric acid. Colorless crystals with a MP of 206-21 1°C (decomp.) are obtained in a yield of 3.20 g (22 %).

C ₂ |H ₂₉ BrN ₄ O ₂ S . HCl MG = (517.9)

IR-spectrum (KBr): v(C=O) 1685, 1635 cm ^" v(C=C) 1570 cm ^"

Η-NMR-spectrum (D ₂ O): 0.75 - 1.90 (1 1H, m,

(CH ₂ ) ₂ CH(CH ₂ ) ₃ ) 2.45 - 3.15 (7H, m, 2 CONCH and

N ⁺ CH ₂ and N ⁺ CH ₃ ) 3.50 - 3.90 (3H, m, CONCH and

N ⁺ CH ₂ CH=) 4.15 (lH, mz, CONCH) 4.82 (2H, s, NCH ₂ CO) 5.30 - 6.00 (3H, m, CH=CH ₂ ) 7.54 (IH, s, pyridine) 8.22 (IH, s, pyridine)

The end products produced according to the above examples are given in the following Table 1 according to number. The remaining compounds listed therein are produced in an analogous manner. All melting points are given in the column at the far right.

Table 1:

Synthesis examples for end products according to formula (I)

(Z = acid ofthe addition salt) ((Zers.) = (decomp.))

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

¹ EtOH = ethanol

MeOH = methanol iPrOh — isopropanol

MeOtBi -i= methyl tert-butyl ether iPr ₂ O = diisopropyl ether

Et ₂ O = diethyl ether

EE = ethylacetate

BuCI ^** = 1 -chlorobutane

MeCN = acteonitrile

In the following, further examples for concrete compounds are listed in Table 2 for the illustration of the end products according to the invention The meanings of the substituents are given in the respective columns The exemplified compounds can be present as a base as well as in the form of the above-characterized pharmaceutically acceptable salts

Table 2:

Exemplary Selected Compounds as End Products according to formula (I)

Table 2 (continued) 67

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued) 79

Table 2 (continued)

Table 2 (continued) 81

Table 2 (continued) 82

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued) 87

Table 2 (continued)

Table 2 (continued) 89

Table 2 (continued) 90

Table 2 (continued)

Table 2 (continued)

Table 2 (continued)

Table 2 (continued) 94

Table 2 (continued)

Table 2 (continued) 96

Table 2 (continued) 97

Table 2 (continued) 98

Table 2 (continued)

Table 2 (continued)

The following concretely described compounds are particularly preferred among the above listed and experimentally described compounds

6-chloro- 1 -[4-(2-dιmethylamιnoethyl)-pιpeπdyl]-carbonylmethyl-2-ox o- 1 ,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-chloro- 1 -[4-(2-dιethylamιnoethyl)-pιpeπdyl]-carbonylmethyl-2-oxo -l ,2- dιhydrothιazolo[5 4-b]pyπdme or its hydrobromide,

6-chloro- l-[4-(2-cyclopropylamιno-ethyl)-pιpeπdyl]-carbonylmethyl- 2-oxo- 1 ,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-chloro- l-[4-(2-pιpeπdylethyl)-pιpeπdyl]-carbonylmethyl-2-oxo- 1 ,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-chloro- l-[4-(3-pyrrolιdylpropyl)-pιpeπdyl]-carbonylmethyl-2-oxo- 1,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-chloro- l-[4-(3-dιmethylamιnopropyl)-pιperazιnyl]-carbonylmethyl -2-oxo- 1,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-bromo- 1 -[4-(2-allylamιnoethyl)-pιpeπdyl]-carbonylmethyl-2-oxo- 1,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-bromo- l-[4-(2-cyclobutylamιno-ethyl)-pιpeπdyl]-carbonylmethyl-2 -oxo- 1,2- dιhydrothιazolo[5 4-b]pyrιdιne or its hydrochloride,

6-bromo- l-[4-(3-dιmethylammopropyl)-pιpeπdyl]-carbonylmethyl-2-ox o- 1,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-bromo- 1 -[4-(3-dimethylaminopropyl)-piperazinyl]-carbonylmethyl-2-ox o- 1 ,2- dιhydrothιazolo[5 4-b]pyπdιne or its dihydrochloride,

6-bromo-l-[3-(2-pyrrolιdylethyl)-pyrrohdyl]-carbonylmeth yl-2-oxo-l,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-bromo- l-[4-(2-dιmethylamιnoethyl)-pιpeπdyl]-carbonylmethyl-2-o xo- 1,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-bromo- l-[4-(2-dιethylamιnoethyl)-pιpendyl]-carbonylmethyl-2-oxo - 1,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrobromide,

6-bromo- 1 -[4-(2-pyrrohdylethylιden)-pιpeπdyl]-carbonylmethyl-2-oxo - 1 ,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-chloro- 1 -[4-(2-dιpropylamιnoethyl)-pιpeπdyl]-carbonylmethyl-2-ox o- 1 ,2- dιhydrothιazolo[5 4-b]pyπdme or its hydrochloride,

l -{4-[2-(N-allyl-N-methylamιno)ethyl]-pιpeπdyl}-carbonylme thyl-6-chlor-2-oxo-l ,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-chloro- 1 -[4-(2-pyrrolιdylethyl)-pιpeπdyl]-carbonylmethyl-2-oxo- 1 ,2- dιhydrothιazolo[5 4-b]pyπdme or its hydrochloride,

6-bromo- 1 -[4-(2-dιpropylamιnoethyl)-pιpendyl]-carbonylmethyl-2-oxo - 1 ,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

l-{4-t2-(N-allyl-N-methylamιno)ethyl]-pιpendyl}-carbony lmethyl-6-brom-2-oxo-l,2- dιhydrothιazolo[5 4-b]pyπdιne or its hydrochloride,

6-bromo- 1 -[4-(2-pyrrolidylethyl)-piperidyl]-carbonylmethyl-2-oxo- 1 ,2- dihydrothiazolo[5.4-b]pyridine or its hydrochloride.

These preferred compounds as well as the remaining compounds according to formula (I) are present especially in the form ofthe hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, fumarate, malate, methanesulfonate or tartrate, as long as they are not already named as a particular salt in the above.

Synthesis of the Intermediates According to Formula (IV) of the Invention

(IV)

Example I

6-chloro-l-[4-(hydroxymethyl)-piperidyl]-carbonylmethyl-2 -oxo-l,2- dihydrothiazolo[5.4-b]pyridine (substance 442)

Analogously to example 10, a solution of 35.0 g (143 mmol) 6-chloro- 1 -carboxymethyl- 2-oxo-l ,2-dihydrothiazolo[5.4-b]pyridine, 17.6 g (153 mmol) 4-hydroxymethylpi- peridine and 37.8 g (153 mmol) EEDQ in 450 ml THF is heated under reflux for 8h. Subsequently, the solvent is drawn off under vacuum to a large extent and the remainder is dispersed between water and ethylacetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under vacuum. The residue is taken up in 500 ml chlororoform, the precipitated solid is drawn off and recrystallized from acetonitrile. Colorless crystals with a MP of 215-217°C are recovered in a yield of 24.3 g (50 %).

Cι ₄ Hι ₆ clN ₃ O ₃ S MG = (341 8)

IR-spectrum (KBr) v(C=O) 1670, 1635 cm- v(C=C) 1570 cm ^-1

^l H-NMR-spectrum (DMSO-d ₆ ) 0 80 - 2 00 (5H, m, CH ₂ CHCH ₂ )

2 60 (lH, mz, CONCH)

3 20 (1H, mz, CONCH)

3 33 (2H, d, CH ₂ O, J = 7 0 Hz)

3 90 (lH, mz, CONCH)

4 30 (1H, mz, CONCH)

4 54 (IH, t, OH, exchangeable) 4 95 (2H, s, CH ₂ CO)

7 99 (IH, d, pyndine, J = 1 9 Hz)

8 36 (IH, d, pyndine, J = 1 9 Hz)

Example II

6-bromo-l-[4-(2-hydroxyethyl)-piperidyI}-carbonylmethyI-2 -oxo-l,2- dihydrothiazolo[5.4-blpyridine (substance 452)

Analogously to example 1, 40 0 g (138 mmol) 6-bromo- 1 -carboxymethyl-2-oxo- 1 ,2- dιhydrothιazolo[5 4-b]pyπdme and 24 6 g (152 mmol) CDI m 300 ml abs THF are heated under reflux for lh Subsequently, this is cooled to 0°C, a solution of 21 4 g (166 mmol) 4-(2-hydroxyethyl)-pιpeπdιne in 100 ml abs THF is added dropwise, stirred for a further 4 5 h under ice cooling and left to stand at RT overnight Subsequently, the solvent is drawn off under vacuum to a large extent and the remainder is dispersed between 600 ml each of water and ethylacetate The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under vacuum The resinous crude product is chromatographically pre-puπfied over silica gel (CHcl ₃ /CH ₃ OH in the

ratio of 90/10) and subsequently recrystallized from 100 ml ethylacetate. Light beige crystals with a MP of 158°C are obtained in a yield 38.4 g (69 %)

CijH- ₈ BrN ₃ O ₃ S MG = (400.3)

IR-spectrum (KBr): v(C=O) 1680, 1650 cm- ¹ v(C=C) 1570 cm-'

Η-NMR-spectrum (cDcl ₃ /DMSO-d ₆ )

0 80 - 2 05 (7H, m, (CH ₂ ) ₃ CH)

2 50 - 3 05 (2H, m, CONCH and OH)

3 16 (1H, mz, CONCH)

3 65 (2H, t, CH ₂ O, J = 6 2 Hz) 3.80 (1H, mz, CONCH)

4.50 (lH, mz, CONCH)

4 69 (1 H, d, NCHCO, J = 16 Hz) 4 88 (IH, d, NCHCO, J = 16 Hz) 7.47 (IH, d, pyndine, J = 1 8 Hz) 8.32 (IH, d, pyndine, J = 1 8 Hz)

Example III

6-chloro-l-[4-(iodomethyl)-piperidyl]-carbonylmethyI-2-ox o-l,2- dihydrothiazoloI5.4-b]pyπdine (substance 444)

1.4 g (20.5 mmol) imidazole and 4.2 g (16.1 mmol) triphenylphosphine, and subsequently 3 9 g (15 4 mmol) iodine under cooling with ice water, are added under stirring to a suspension of 5.0 g (14 6 mmol) 6-chloro- 1 -[4-(hydroxymethyl)-piperidyl]- carbonylmethyl-2-oxo-l,2-dihydrothιazolo[5 4-b]pyridine (substance 442) in 100 ml

abs. dichloromethane. After addition is completed, this is stirred for 2h without further cooling and left to stand at RT overnight. This is extracted several times with diluted sodium disulfide solution, washed with water, dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatographically pre-purified over silica gel in chloroform and subsequently crystallized from 30 ml ethylacetate. Almost colorless crystals with a MP of 158-159°C are obtained in a yield of 5.2 g (79 %).

Cι ₄ Hι ₅ clIN ₃ O ₂ S MG = (451.7)

IR-spectrum (KBr): v(C=O) 1670, 1650 cm ^" v(C=C) 1570 cm ^'1

Η-NMR-spectrum (cDcl ₃ ): 1.00 - 2.20 (5H, m, CH ₂ CHCH ₂ ) 2.66 (1H, mz, CONCH) 3.13 (3H, mz and d, CH ₂ I and

CONCH, J = 6.0 Hz) 4.00 (IH, mz, CONCH) 4.63 (2H, mz and d, CONCH and

NCHCO, J = 16 Hz) 4.82 (IH, d, NCHCO, J = 16 Hz) 7.25 (I H, d, pyridine, J = 2.0 Hz) 8.28 (IH, d, pyridine, J = 2.0 Hz)

Example IV

6-bromo-l-l4-(4-iodobutyI)-piperidyl]-carbonylmethyl-2-ox o-l,2- dihydrothiazolo[5.4-b] pyridine (substance 489)

Analogously to example III, 4 40 g (62 8 mmol) imidazole, 13 0 g (50 mmol) triphenylphosphine, and subsequently 2 0 g (47 mmol) iodine in portions under ice cooling at 12-18°C, are added to a suspension of 19 2 g (44 8 mmol) 6-bromo- 1-[4-(4- hydroxybutyl)-pιpeπdyl]-carbonylmethyl-2-oxo- 1 ,2-dιhydrothιazolo[5 4-b]pyrιdιne (substance 486) in 200 ml abs dichloromethane under stirring After addition is completed, this is stirred for 5h without further cooling and left to stand at RT overnight This is extracted several times with diluted sodium disulfite solution, washed with water, dried over sodium sulfate and the solvent is drawn off under vacuum The residue, a dark colored resin (38 g), is chromatographically purified over silica gel in chloroform and subsequently crystallized by tπturation with methyl tert-butyl ether Light yellow colored crystals with a MP of 141-143°C are obtained in a yield of 14 2 g (58 %)

Cι ₇ H ₂ ,BrIN ₃ O ₂ S MG = (538 3)

IR-spectrum (KBr) v(C=O) 1675, 1650 cm ^" v(C=C) 1570 cm ^'

H-NMR-spectrum (cDcl ₃ ) 1 00 - 2 00 (l lH, m,

(CH ₂ ) ₂ CH(CH ₂ ) ₃ )

2 66 (1H, mz, CONCH)

3 10 (1H, mz, CONCH)

3 21 (3H, t, CH ₂ I, J = 7 Hz)

3 90 (lH, mz, CONCH)

4 50 (lH, mz, CONCH)

4 61 (lH, d, NCHCO, J = 16 Hz) 4 81 (IH, d, NCHCO, J = 16 Hz)

7 37 (IH, d, pyndine, J = 1 9 Hz)

8 34 (IH, d, pyndine, J = 1 9 Hz)

Example V

6-bromo-l-[4-(2-methanesulfonyloxyethyl)-piperidyl]-carbo nylmethyl-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine

(substance 461)

7 4 ml (95 mmol) methanesulfonic acid chloride are added dropwise under cooling at 0°C to a suspension of 36.0 g (90 mmol) 6-bromo- l -[4-(2-hydroxyethyl)-pιperidyl]- carbonylmethyl-2-oxo-l,2-dihydrothiazolo[5.4-b]pyridιne (substance 452), 360 ml abs dichloromethane and 13 8 ml (100 mmol) TEA. After addition is completed, this is stirred further for lh without cooling, the solution is washed twice with ice water, dried over sodium sulfate and the solution is concentrated under vacuum The crystalline crude product is recrystallized from 1 1 1 acetonitrile Light beige crystals with a MP of 189-191°C are obtained in a yield of 37 0 g (86 %)

C ₁₆ H ₂ oBrN ₃ O ₃ S ₂ MG = (478 4)

IR-spectrum (KBr). v(C=O) 1675, 1645 cm v(C=C) 1570 cm

Η-NMR-spectrum (cDcl ₃ /DMSO-d ₆ )

1 00 - 2.00 (7H, m, (CH ₂ ) ₃ CH)

2.60 (lH, mz, CONCH)

3.05 (3 H, s, CH ₃ SO ₂ )

3.20 (lH, mz, CONCH)

3.90 (lH, mz, CONCH)

4.31 (2H, t, CH ₂ O, J = 5.5 Hz)

4.50 (IH, mz, CONCH)

4.71 (IH, d, NCHCO, J = 16 Hz)

4 87 (IH, d, NCHCO, J = 16 Hz)

7 45 (IH, d, pyridine, J = 1.7 Hz)

8 34 (IH, d, pyndine, J = 1 7 Hz)

Example VI

6-bromo-l-[4-(4-methanesulfonyloxybutyl)-piperidyl]-carbo nylmethyI-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine

(substance 491)

Analogously to example V, 7 6 ml (100 mmol) methanesulfonic acid chloride are added dropwise under cooling at 5-8°C to a suspension of 38 2 g (90 mmol) 6-bromo- 1-[4-(4- hydroxybutyl)-pιpendyl]-carbonylmethyl-2-oxo- 1 ,2-dιhydrothιazolo[5 4-b]pyndιne (substance 486), 340 ml abs dichloromethane and 15 4 ml (1 10 mmol) TEA After addition is completed, this is stirred for 5h without further cooling, the solution is washed several times with ice water, dried over sodium sulfate and the solution is concentrated under vacuum The resinous residue is taken up in 200 ml hot toluene and crystalizes out under slow cooling in the form of light beige crystals They have a MP of 108-1 10°C The yield amounts to 41 4 g (92 %)

C ₁₈ H ₂₄ BrN ₃ O ₅ S ₂ MG = (506 5)

IR-spectrum (KBr) v(C=O) 1680, 1650 cm ^' v(C=C) 1570 cm ^"

1H-NMR-spectrum (cDcl ₃ ) 1 00 - 2 00 (1 1H, m,

(CH ₂ ) ₂ CH(CH ₂ ) ₃ )

2 65 (1H, mz, CONCH)

3 02 (3H, s, CH ₃ SO ₂ )

3 15 (1H, mz, CONCH)

3 90 (lH, mz, CONCH)

4 25 (2H, t, CH ₂ O, J = 6 Hz)

4.53 (lH, mz, CONCH) 4.61 (IH, NCHCO, J = 16 Hz) 4.82 (IH, NCHCO, J = 16 Hz) 7.38 (IH, d, pyridine, J - 2.0 Hz) 8.34 (IH, d, pyridine, J = 2.0 Hz)

The remaining exemplary produced intermediate product products nos. 453, 462 and 486 according to formula (IV) given in the following Table 3 were synthesized in an analogous manner.

Table 3:

Synthesis Examples for Intermediate Products according to formula (IV)

MeCN = acetonitrile EE = ethylacetate MeOH = methanol MeOtBu= methyl tert-butyl ether

In the following Table 4, a series of intermediates in form of selected concrete compounds are also exemplary described.

Table 4:

Exemplary Intermediate Products of the formula (IV)

Table 4 (continued)

114

Table 4 (continued)

Table 4 (continued)

116

Table 4 (continued) 117

Table 4 (continued)

Among the intermediates according to formula (IV) already listed above or experimentally described, the following compounds are also particularly preferred:

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-l-[4-(3-hydroxypropyl)-piperidyl]-carbonylmethyl -2-oxo-l,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- dihydrothιazolo[5.4-b]pyridine.

SYNTHESIS EXAMPLES FOR THE PRODUCTION OF STARTING COMPOUNDS

The synthesis of starting compounds can be carried out according to known methods in an analogous manner, as was already illustrated at the beginning of the description of the synthesis variants As an example for this, 6-chloro-l-carboxymethyl-2-oxo-l,2- dihydrothiazolo[5.4-b]pyridine, which was described according to the literature EP-A- 0 232 740, can be named as a representative for others

In the following, various examples for the representation of the starting compounds are described for reasons of better understanding of the synthesis of the end products according to the invention

Example a

6-chloro-l-(2-carboxyethyl)-2-oxo-l,2-dihydrothiazolo[5.4 -b]pyridine

A mixture of 20 0 g (107 mmol) 6-chloro-2-oxo-l,2-dιhydrothιazolo[5 4-b]pyrιdιne according to EP-A-0 232 740, 8 0 ml (121 mmol) acrylnitnle, 0 40 g potassium hydroxide and 70 ml pyridine are stirred at 100°C for 18h After cooling, the black solution is poured into 300 ml 2 M acetic acid, the precipitated crude 6-chloro-l-(2- cyanethyl)-2-oxo-l,2-dihydrothiazolo[5.4-b]pyridine is drawn off and dried under vacuum The yield amounts to 22 1 g (86 %)

22 0 g (91 8 mmol) of the nitrile are suspended in 220 ml cone hydrochloric acid and stirred at 70°C for lh After cooling, this is poured into 200 ml ice water, the precipitated crude product is drawn off and digested with 200 ml methanol The newly drawn off product is recrystallized from 650 ml methanol Its yield amounts to 8 0 g (34 %) in the form of beige crystals of 6-chIoro-l-(2-carboxyethyl)-2-oxo-l,2- dihydrothiazoIo[5.4-b]pyridine whose MP lies at 204-209°C (decomposition)

Example b

6-bromo-l-carboxymethyl-2-oxo-l,2-dihydroth.azolo[5.4-b]- pyridine

A solution of 75 g (1 137 mol) potassium hydroxide in 635 ml methanol is saturated at 2°C with hydrogen sulfide. A solution of 90 0 g (0 379 mol) 5-bromo-2-chloro-3- nitropyπdine in 400 ml methanol is added dropwise to this solution under stirring, wherein the temp is held under 15°C This is stirred for a further 2 h at 15-20°C and subsequently concentrated under vacuum The residue is dissolved in 1 1 1 25 M sodium hydroxide solution, heated to 50°C and 90 0 g (0 472 mol) sodium disulfite is stirred in in small portions This is stirred further for 2h, cooled and the solution is neutralized with acetic acid The obtained precipitate of 3-Amino-5-bromo-2-mercaptopyridine is drawn off, thoroughly washed with water, dried over phosphorous pentaoxide and further reacted as a crude product

27 7 ml (0 228 mol) chloroformic tπchloromethyl ester ("diphosgene"), dissolved in 200 ml dioxane, are added dropwise under stirring to a suspension of the obtained aminobromo-mercaptopyπdine in 1 1 dioxane and heated after addition is completed to 70-75°C for lh This is cooled to RT, the product is drawn off, washed with dioxane and stirred for a half hour with 200 ml water The 6-bromo-2-oxo-l,2- dihydrothiazolo[5.4-b]-pyridine is newly drawn off and dried under vacuum over phosphorous pentaoxide The yield amounts to 78 9 g (90 %) The compound accumulates in the form of brown-yellow crystals with a MP of ca 250°C (decomp )

66 ml sodium ethylate solution (20% in ethanol, 170 mmol) are added in portions at 0- 5°C to a suspension of 39 4 g (170 mmol) 6-bromo-2-oxo-l,2-dιhydrothιazolo[5 4- b]pyπdιne in 400 ml DMF, 38 ml (340 mmol) bromoacetic acid ethyl ester are subsequently added dropwise at 10-15°C and stirred for 4h without further cooling Thereafter, the reaction mixture is poured into 750 ml ice water, the precipitate produced is isolated, washed with water and the moist crude product is recrystallized

from 200 ml ethanol The yield of 6-bromo-l-ethoxycarbonylmethyI-2-oxo-l,2- dihydrothiazoIo[5.4-b]-pyridine with a MP of 131-132°C amounts to 35 5 g (66 %)

A suspension of 35 5 g (1 12 mmol) of the ethyl ester in a mixture of 350 ml acetic acid and 23 ml cone hydrochloric acid is heated under reflux for 12h under stirring After cooling to RT, the fine precipitate is drawn off, washed with water and dried under vacuum over phosphorous pentaoxide The yield amounts to 26 6 g (82 %) The 6- bromo-l-carboxymethyl-2-oxo-l,2-dihydrothiazolo[5.4-b)pyridi ne obtained in this manner has a MP of 261-262°C

Example c

6-bromo-l-(3-carboxypropyl-2-oxo-l,2-dihydrothiazolo[5.4- b]pyridine

33 4 ml sodium ethylate solution (20% in ethanol, 86 6 mmol) are added at ca 10°C to a suspension of 20 0 g (86 6 mmol) 6-bromo-2-oxo-l,2-dιhydrothιazolo[5 4-b]pyπdιne in 200 ml DMF, 24 4 ml (173 mmol) 4-bromobutyπc acid ethyl ester is subsequently added dropwise at 10-12°C and stirred further at RT for 8h Thereafter, the reaction mixture is poured into 700 ml ice water and left to stand at 5°C overnight, the precipitate is drawn off, washed with water and dried under vacuum over phosphorous pentaoxide For further purification, this is chromatographed over silica gel with CHCI3/CH3OH in a ratio of 95/5 as an elution agent The yield of 6-bromo-l-(3- ethoxycarbonylpropyl)-2-oxo-l,2-dihydrothiazolo[5.4-b]pyridi ne amounts to 13 2 g (44 %).

13 0 g (37 7 mmol) of the ethyl ester are heated under reflux for 5h in a mixture of 60 ml acetic acid and 7 5 ml cone hydrochloric acid Thereafter, this is cooled, and poured into 100 ml ice water The product is drawn off, washed with water and dried under vacuum over phosphorous pentaoxide The yield of 6-bromo-l-(3-carboxypropyl-2- oxo-l,2-dihydrothiazolo[5.4-b]pyridine with a MP of 175-177°C amounts to 9 6 g (81 %)

Example d

4-[2-(2-oxo-l-pyrrolidinyl)-ethyl]-piperidine hydrochloride

59.4 ml (763 mmol) methanesulfonic acid chloride are added dropwise under stirring at 5-10°C to a solution of 159 g (693 mmol) l-tert-butoxycarbonyl-4-(2-hydroxyethyl)- piperidme and 1 16 ml (832 mmol) TEA in 800 ml abs. dichloromethane and stirred after addition is completed for a further 30 min at the same temperature. Subsequently, the reaction solution is extracted with 400 ml water, washed twice, each with 50 ml water and dried over sodium sulfate. After drawing off the solvent under vacuum, crude 1- tert-butoxycarbonyl-4-(2-methansulfonyloxyethyl)-piperidine is obtained as a viscous, slowly crystallizing oil (21 1 g. 99 %), that is used without further purification.

1 1.0 ml (143 mmol) 2-pyrrolidone are added dropwise under stirring at 5°C to a suspension of 5.9 g sodium hydride (80% in paraffin oil, 195 mmol), held for a further 10 min at the same temperature, and 40.0 g (130 mmol) of crude 1 -tert-butoxycarbonyl- 4-(2-methanesulfonyloxyethyl)piperidine as a solid are subsequently added in portions. This is stirred for a further 4h at RT, then hydrolyzed by adding 200 ml water dropwise and the mixture is extracted with 200 ml dichloromethane. The organic phase is washed with water, concentrated under vacuum and de-gassed at 50°C/0.1 mbar. The obtained brown oil is chromatographically purified over silica gel with chloroform, later CHCl ₃ /CH ₃ OH (98/2). Yield is 23 g (60 %) colorless oil of l-tert-butoxycarbonyl-4- [2-(2-oxo-l-pyrroHdinyl)-ethyl]-piperidine.

23.0 g (77.6 mmol) l-tert-butoxycarbonyl-4-[2-(2-oxo-l-pyrrolidinyl)-ethyl]pipe ridine are heated under reflux to boiling for lh with a mixture of 100 ml ethanol and 15 ml cone, hydrochloric acid. Subsequently, this is concentrated under vacuum to dryness and the resinous residue is dried under vacuum over phosphorous pentaoxide. By crystallization from 20 ml isopropanol, 4-[2-(2-oxo-l-pyrrolidinyl)-ethyll-piperidine

hydrochloride is obtained as colorless, hygroscopic crystals The yield amounts to 1 1 3 g (62 %), the MP lies at 121-127°C

Example e

4-(2-dimethylarninoethylene)-piperidine dihydrochloride

29 9 g (150 mmol) l -tert-butoxycarbonyl-4-pιperιdone and 62 3 g (160 mmol) 2- dimethylammoethyl-tnphenylphosphonium bromide in 300 ml abs THF are present and added m portions to 19 5 g (170 mmol) potassium tert-butylate under stirring at 10- 20°C After addition is completed, the mixture is stirred at RT for a further 6h and left to stand o\ermght Subsequently, the large part of the solution is drawn off under vacuum, the remainder is taken up in 300 ml toluene, washed several times with water and the organic phase is subsequently extracted with 200 ml 5% hydrochloric acid The toluene phase is once again extracted by shaking with 30 ml water The combined acidic aqueous phases are washed with 40 ml toluene and subsequently alkalized with cone sodium hydroxide solution, the released product is taken up in 200 and 100 ml toluene The combined organic phases are washed with water and evaporated 44 5 g (93 %) crude l-tert-butoxycarbonyl-4-(2-dimethylaminoethylene)-piperidine are obtained as a light yellow oily liquid

35 g of this crude product are stirred in 200 ml ca 2 75 M methanolic hydrochloric acid at RT for 2h and subsequently heated under reflux to boiling for 6h Thereafter, this is concentrated under reduced pressure to dryness and the solid residue is recrystallized from isopropanol under addition of a little isopropanolic hydrochloric acid The yield of 4-(2-dimethylaminoethylene)-piperidine dihydrochloride with a MP of 231-236 °C(decomp ) amounts to 24 1 g (77 %)

Example f

4-[4-(4-piperidyl)-butyI]-morpholine dihydrochloride

44 0 ml (567 mmol) methanesulfonic acid chloride are added dropwise under stirring at 5-10°C to a solution of 133 5 g (515 mmol) l-tert-butoxycarbonyl-4-(4-hydroxybutyl)- pipendine and 86 ml (618 mmol) TEA in 660 ml abs dichloromethane and, after addition is completed, stirred for a further 30 min at the same temperature Subsequently, the reaction solution is extracted with 300 ml water, washed twice, each with 50 ml water, and dried over sodium sulfate After drawing off the solvent under vacuum, crude l-tert-butoxycarbonyl-4-(4-methanesulfonyloxybutyl)-piperidi ne is obtained as a yellow oil in a yield of 168 2 g (99 %) which is used without further purification

A solution of 58 0 g (173 mmol) crude 1 -tert-butoxycarbonyI-4-(4- methanesulfonyloxybutyl)-pφeπdιne and 30 1 ml (346 mmol) morphohne in 120 ml ethanol is stirred at 50°C for 7h Subsequently, the solution is concentrated to a large extent and the concentrate is dispersed between 300 ml 0 5 M sodium hydroxide solution and dichloromethane The aqueous phase is extracted again by shaking with dichloromethane, the combined organic phases are washed with water, dried over sodium sulfate and the solvent is drawn off under vacuum For purification, the residue is filtered through a thin silica gel column with CHCl ₃ /CH ₃ OH in a ratio of 95/5 as a solvent 54 8 g (97 %) 4-[4-(l-tert-butoxycarbonyl 4-piperidyl)-butyl]-morpholine are obtained in the form of colorless, wax-like crystals

38 6 ml (386 mmol) cone hydrochloric acid is added to a solution of 54 0 g (165 6 mmol) 4-[4-(l-tert-butoxycarbonyl-4-pιpeπdyl)-butyl]-morpholιne in 300 ml ethanol and heated under reflux to boiling for 40 min Subsequently, the solution is concentrated under vacuum and the residue is recrystallized from 200 ml isopropanol The yield of 4- [4-(4-piperidyl)-butyl|-morpholine dihydrochloride with a MP of 224-231°C (decomp ) amounts to 39 6 g (80 %)

Example g

4-(2-dimethyIaminoethyl)-hexahydroazepine dihydrochloride

13 7 g (64 3 mmol) l-tert-butoxycarbonyl-hexahydroazepιne-4-one and 28 0 g (67.5 mmol) 2-dιmethylamιnoethyl-trιphenylphosphonιum bromide are placed in 150 ml toluene and added in portions to 8 6 g (75 mmol) potassium tert-butylate under stirring at 5-10°C After addition is completed, the mixture is stirred overnight without further cooling Thereafter, this is washed several times with water and the organic phase is extracted with 40 and 20 ml 10% hydrochloric acid. The toluene phase is extracted again by shaking with 30 ml water The combined acidic aqueous phases are washed with 30 ml toluene and subsequently alkalized with cone sodium hydroxide solution, the released product is taken up twice with 50 ml toluene The combined organic phases are washed with water and evaporated 1 1 6 g (67 %) of crude 1-tert-butoxycarbonyl- 4-(2-dimethyIaminoethylene)-hexahydroazepine as a light yellow oily liquid A further amount (2 7 g 16 %) can be recovered by concentrating the alkaline water phase, dissolving the residue in 20 ml water and renewed extracting by shaking with toluene

14 1 g (52 mmol) of the crude product are dissolved in 100 ml methanol and hydrated with 2 5 g 5% palladium carbon as a catalyst at normal pressure until completion of hydrogen uptake The filtrate is filtered and concentrated under vacuum, wherein 12 1 g (81 %) of crude l-tert-butoxycarbonyI-4-(2-dimethylaminoethyl)-hexahydroazep ine are obtained as a yellow oil

12 0 g (44 mmol) crude l-tert-butoxycarbonyl-4-(2-dιmethylamιnoethyl)- hexahydroazepine are stirred with 50 ml ca 2 7 M methanolic hydrochloric acid at RT for 2h and subsequently heated under reflux to boiling for 3h This is concentrated under vacuum and the resinous residue is crystallized from 50 ml isppropanol under addition of 10 ml isopropanolic hydrochloric acid The yield of 4-(2-dimethylaminoethyl)- hexahydroazepine dihydrochloride in the form of colorless, hydroscopic crystals with a MP of 186-188°C amounts to 7.2 g (67 %).

Example h

l-(4-dimethylaminobutine-2-yl-l)-piperazine trihydrochloride

27.4 g (198 mmol) potassium carbonate are added to a solution of 30.0 g (161 mmol) 1- tert-butoxycarbonylpiperazine and 14.7 ml (194 mmol) 3-bromopropine in 80 ml DMF and the mixture is heated under stirring to 75-80°C for 7h After cooling, this is drawn off from the salts, the filtrate is concentrated under vacuum and poured onto ice water. This is extracted several times with chloroform, the combined organic phases are washed with 2 M sodium hydroxide solution, and subsequently water, dried over sodium sulfate and the solvent is drawn off under vacuum The residue is chromatographically purified over silica gel with chloroform, later CHCI ₃ /CH ₃ OH in a ratio of 98/2 20.0 g (55 %) l-tert-butoxycarbonyl-4-(propin-2-yl-l)-piperazine are obtained as a yellow oil

13 5 g (60 0 mmol) l-tert-butoxycarbonyl-4-(propιn-2-yl-l)-pιperazine and 6 8 g (66 2 mmol) bis-(dιmethylamιno)-methane are dissolved in 135 ml dioxane and stirred for 6h at 80°C with 0 2 g copper(I) chloride Subsequently, the solution is concentrated to ca. 30 ml, taken up in chloroform, filtered and washed twice with water This is dried over sodium sulfate, the solvent is drawn off under vacuum and the dark brown oily residue is chromatographically purified over silica gel with CHCl ₃ /CH ₃ OH in the ratio of 95/5 as an elution agent. The yield of l-tert-butoxycarbonyI-4-(4-dimethylaminobutin-2- yl-l)-piperazine amounts to 9.63 g (57 %)

9 0 g (32.1 mmol) l-tert-butoxycarbonyl-4-(4-dιmethylaminobutιn-2-yl-l)-pιp erazine are heated under reflux to boiling for 3h in 45 ml methanol with 12.5 ml cone hydrochloric acid. Thereafter, the mixture is concentrated under vacuum, the residue is dissolved in 100 ml water and decolorized with activated carbon The filtered solution is newly concentrated under vacuum and the solid residue is recrystallized from 100 ml methanol. The yield of l-(4-dimethylaminobutin-2-yl-l)-piperazine trihydrochloride in the form of colorless crystals with a MP of >190°C (decomp.) amounts to 7 6 g (82 %)

Example i

2-[(3-(l-pyrrolidyl)-propyI]-morpholine dihydrochloride

A solution of 21 2 g (94 0 mmol) di-tert-butyldicarbonate in 40 ml abs THF is added dropwise under stirring at 7-15°C to a solution of 13 0 g (89 5 mmol) 2-(3- hydroxypropyl)-morpholιne in 60 ml abs THF and subsequently stirred at RT for a further 2h Thereafter, the solvent is evaporated and the residue is de-gased until 100°C/0 1 mbar The yield of crude 4-tert-butoxycarbonyl-2-(3-hydroxypropyl)- morpholine, which is further reacted without purification, amounts to 22 0 g (100 %)

7 7 ml (98 6 mmol) methanesulfonic acid chloride are added dropwise under stirring at 0°C to a solution of 22 0 g (89 5 mmol) crude 4-tert-butoxycarbonyl-2-(3- hydroxypropyl)-morphohne and 15 0 ml (107 6 mmol) TEA in 1 10 ml abs dichloromethane and the resulting suspension is stirred at the same temperature for a further 1 h Subsequently, the mixture is diluted with 100 ml dichloromethane, extracted twice with 50 ml water and the clear organic phase is dried over sodium sulfate After drawing off the solvent under vacuum, 28 3 g (98 %) of crude 4-tert-butoxycarbonyl- 2-(3-methansulfonyloxypropyl)-morpholine is obtained as a yellow oil which is reacted without further purification

A solution of 14 5 g (44 8 mmol) crude 4-tert-butoxycarbonyl-2-(3- methansulfonyloxypropyl)-morphohne and 14 8 ml (179 mmol) pyrrohdine in 50 ml ethanol is stirred at RT overnight Subsequently, the solution is concentrated to a large extent and the concentrate is dispersed between 200 ml 0 5 M sodium hydroxide solution and dichloromethane The aqueous phase is extracted again by shaking with dichloromethane, the combined organic phases are washed with water, dried over sodium sulfate and the solvent is drawn off under vacuum For purification, the residue is chromatographed over silica gel with CHCl ₃ /CH ₃ OH in the ratio of 90/10, later CHCl ₃ /CH ₃ OH/conc NH ₃ in the ratio of 90/10/0 5 as solvents 9 5 g (71 %) 4-tert-

butoxycarbonyl-2-[3-(l-pyrroHdyl)-propyl]-morphoIine are obtained in form of a yellow, gradually crystallizing oil

7.0 ml (70 mmol) cone hydrochloric acid are added to a solution of 9.5 g (31 8 mmol) of this compound in 50 ml ethanol, this is stirred at RT overnight and heated under reflux to boiling for 40 min. Subsequently, the solution is concentrated under vacuum and the residue is recrystallized from 20 ml isopropanol under addition of 3 ml diisopropyl ether The yield of 2-[(3-(l-pyrroIidyl)-propyl}-morpholine dihydrochloride with a MP of 176-179°C amounts to 5.6 g (65 %)

PRODUCTION OF THE MEDICAMENTS

The production of medicaments with an amount of one or more compounds according ot the invention occurs in a typical manner by means of well-known pharmaceutical technical methods Additionally, the compounds according to the invention are processed as such or in the form of their salts, optionally in combination with further active ingredients, together with suitable pharmaceutically acceptable adjuvants and carriers to the various medicinal forms, for example to solid, peroral administration medicaments such as tablets, coated tablets, chewable tablets and subhngual tablets These medicinal forms can be coated as dosage units, depending on the objective of taste improvement, control of the release of active ingredient in the stomach and intestinal canal (for example, gastric fluid resistance, small intestine solubility, accelerated or retarded release) with the respective suitable lacquer or polymer substances For production of the medicaments, solid administration medicinal forms such as, for example, emulsions, suspensions, solubihsates or solutions as well as substances filled into solid gelatin capsules, come into consideration The capsule preparations can also be produced as hard gelatin capsules in which the active ingredient can optionally be filled under admixing of finely-dispersed powdered carriers, optionally after suitable granulation The active ingredient can also be produced together with adjuvants which are hquifiable in heat, such as, for example, solids or suitable polyethylene glycols, etc, which solidify in the cold in the soft or hard gelatin capsules after filling Hard gelatin capsule preparations can also be produced by filling flat tablets with a somewhat smaller diameter than the capsule diameter into the narrow space of the capsule material or by embedding suitably formed oblong tablets into the open capsule bottom The capsule preparations can also be coated in a typical manner with suitable polymer lacquer components for taste improvement reasons or controlled active ingredient release and/or gastric fluid resistance or small intestine solubility

Externally applicable forms are also considered in the production of the medicament such as, for example, ointments, cremes, gels, solutions or plasters with an amount of

the compounds according to the invention, wherein other customary transdermal systems can also be prepared

Rectal administration forms, such as, for example, suppositories or rectal capsules can also be prepared with the compounds according to the invention, optionally in combination with other active ingredients, for the indications specified at the beginning or further below Sprays, wet-dressing pastes or balms are to be named as typical medicaments, especially for support in asthma treatment

Additionally, the compounds according to the invention, optionally in combination with other active ingredients, can be administered per injections Thereby, intramuscular, intravenous or intraglutial application preparations are especially considered as injection preparations For this purpose, the active ingredient as a base, optionally with solubilization agents, or in the salt form, if required in combination with buffer substances or suitable salts and compounds for adjusting the isotonicity and further carriers, are mixed and brought into solution The injection agents can also be produced as suspensions, crystal suspensions or lyophihsates Subcutaneous application depot preparations in the form of pressed implants or formed implants also belong among these

The peroral administration medicinal forms can also be present as lozenges or chewing gum, etc In particular cases, pernasal application compositions can also come into use Furthermore, the compounds according to the invention can also be processed to inhalation forms, if desired, to controlled dosage aerosols

The content of one or more compounds according to the invention, optionally in combination with one or more other active ingredients for the named indications, can amount to between 0 01 or 0 1 and 99 or 99 9 % by weight, especially between 1 and 96 % by weight

All common substances known to the skilled person are suitable as adjuvents and carriers for the desired medicinal forms. Solvents, gelatinizing agents, tabletting and incapsulation adjuvents, suppository bases, suspending agents, thickening agents, emulsifiers, polymers and other compounds for control of release, such as lacquers or anti-adhesion agents and lubricating agents, dispersion agents, de-foaming agents, solubility promoters or solubilizers, permeation promoters and complex formers or inclusion compounds such as, for example, cyclodextrins, are among these

Anti-oxidants, vitamins, sweeteners, taste corrigents, preservatives, flavoring agents, colorants, buffer substances, builders for the production of lyophihsates, such as mannite, dextran, saccharose, human albumin, lactose, PVP or gelatin varieties are considered as further additives Aside from the above-mentioned adjuvents, granulation agents, separating agents, direct tabletting agents, lubricants, fillers, binding agents in the form of lactose, starch varieties, cellulose derivatives, such as MC, HPC, silica, flame dispersed silicone dioxide, talc, stearates (magnesium stearate), phosphates (such as dicalcium phosphate), microcrystalline cellulose are considered, among others, for the production of tablets. Multi-layer tablets or core/coat tablets for producing pressed implants or controlled active ingredient delivery can also be produced in a known manner.

Depending on the form, the medicaments with an amount of the compounds according to the invention, optionaUy m combination with further active ingredients suitable for the respective indications, can be applied perorally, parenterally, per inhalation, pernasally, transdermally or by other topical ways and manners, intravenously, sub- or percutaneously, intragluterally, etc

Depending on the severity of the illness, general condition and age of the patients, the administered doses and/or dosis units are different, whereby a distinction is also to be made between acute treatment and long-term therapy. The daily dosage can amount to between 0 01 and 100 mg per kg body weight, preferably lies at 0.1 to 20 mg per kg, especially preferred at 1 to 2 5 to 10 or 15 mg per kg body weight. Thereby, the

individual dosage units of the active ιngredιent(s) according to the invention can respectively amount to 0 01 , 0 1 , 0.2, 0 5, 1, 2, 5, 10, 20, 50 or 100, but maximally 200 mg per administration

The active ingredients according to the invention in the form of their acid addition salts, hydrates or solvates can be processed individually or in combination with each other to the desired medicaments, optionally under addition of other active ingredients. In the case of the combination of active ingredients according to the invention with other medicinal agents, these can also be optionally present in different medicinal forms separately from each other, for example, as tablets next to vials, depending on the requirements

Further sub _j ect-matter is a method for treatment of the human or animal body, in which a compound or a compound mixture according to formula (I), wherein the substituents have the meanings described above, are administered for the treatment of bronchial asthma, of bronchial hyper-reactivity, of bronchospasms, of bronchoconstriction, of chronic venous insufficiencies, migraines, chronic cough, for bronchospasmolysis or supression of chronic pain, optionally in combination with further active ingredients or other active ingredients suitable in the named indications

Furthermore, the invention relates to a compound or a compound mixture according to formula (I) for use in a therapeutic method, in which the therapeutic use is carried out in connection with one or more medical indications in bronchial asthma, bronchial hyper- reactivity, bronchospasms, bronchoconstriction, chronic venous insufficiencies, migraines, chronic cough or bronchospasmolysis or supression of chronic pain, optionally in combination with further active ingredients or other active ingredients suitable in the named indications

The use of one or more compounds according to formula (I) for the production of medicaments for the treatment of the human or animal body, especially in connection with one or more medical indications in bronchial asthma, bronchial hyper-reactivity,

bronchospasms, bronchoconstriction, of chronic venous insufficiencies, migraines, chronic cough, for bronchospasmolysis or supression of chronic pain, optionally in combination with further medicinal compounds suitable in these indications, and/or the use of the compounds according to formula (I) in a corresponding diagnosis method also represent an embodiment according to the invention.

Equally, a method for the production of medicaments with an amount of one or more compounds according to formula (I) which consists in the processing of these active ingredients together with the respective suitable pharmaceutically acceptable carriers and adjuvents to the finished medicinal form also belongs to the scope of protection according to the invention

Depending on the medicinal indication being considered, the respective suitable medicinal form is selected depending on the therapeutic application Thus, for long-term treatment of bronchial asthma or venous insufficiency, for example, transdermal systems or solid peroral administration medicinal therapeutic agents such as tablets or capsules, especially depot forms, are administered above all For arresting acute attacks, inhalation therapeutic agents or injectable agents present themselves

Further subject-matter of the present invention is the use of one or more compounds according to the general formula (I) for therapeutic treatment, especially in connection with the medical indications described above

Furthermore, an embodiment according to the invention consists in the creation of medicaments whose production is more closely illustrated in the following by means of examples

PRODUCTION EXAMPLES FOR PHARMACEUTICLES

1. Solid, Peroral Administration Medicaments

a) Tablets

active ingredient according to the invention 12,000 g lactose 5,200 g starch, soluble 1,800 g hydroxypropylmethylcellulose 900 g magnesium stearate 100 g

The above components are mixed with each other and compacted in a conventional manner, wherein a tablet weight of 180 mg is set. Each tablet contains 100 mg active ingredient. If desired, the tablets obtained in this manner are coated, provided with a film coat and/or enterically coated.

b) Coated Tablet Core

active ingredient according to the invention 10,000 g flame dispersed silicon dioxide 500 g corn starch 2,250 g stearic acid 350 g ethanol 3.0 1 gelatin 900 g purified water 10.0 1 talcum 300 g magnesium stearate 180 g

From these components, a granulate is produced which is pressed to the desired coated tablet cores. Each core contains 50 mg of active ingredient. The core can be further

processed in a customary manner to coated tablets If desired, a gastric fluid resistant or retarding film coat can be applied in a known manner

c) Drink Suspension in Vials

active ingredient according to the invention 0 050 g glycerin 0 500 g sorbite, 70% solution 0 500 g sodium sacchaπnate 0 010 g methyl-p-hydroxybenzoate 0 040 g aromatic agent q s sterile wasser q s to 5 ml

The above-mentioned components are mixed in a customary manner to a suspension and filled in a suitable drink vial having 5 ml content

d) Poorly Soluble Sublingual Tablets

active ingredient according to the invention 0 030 g lactose 0 100 g stearic acid 0 004 g talcum purum 0 015 g sweetener q s aromatic agent q s rice starch q s to 0 500 g

The active ingredient is compacted together with the adjuvents under high pressure to sublingual tablets, favorably in oblong form

e) Soft Gel Capsule

active ingredient according to the invention 0 050 g

fatty acid glyceπde mixture (Miglyole ) q s to 0 500 g

The active ingredient is impasted together with the fluid carrier mixture and mixed together with further adjuvents suitable for the mcapsulation and filled into elastic soft gelatin capsules which are sealed

f) Hard Gelatin Capsules

active ingredient according to the invention 0 100 g magnesium stearate 0 030 g flame dispersed silicon dioxide 0 030 g lactose q s to 0 3 ml

The active ingredient is intimately blended together with the adjuvents and filled with the corresponding dosage accuracy into the bottom part of hard gelatin capsules which are mechanically sealed with the respective top part

2. Topically Administratable Medicinal Forms

a) Hydrophilic Ointment

active ingredient according to the invention 0 500 g

Euceπnum anhydncum 60 000 g microcrystalline wax 15 000 g vaseline oil q s to 100 000 g

The above-mentioned adjuvents are melted and further processed together with the active ingredient to an ointment in a customary manner

3. Inhalation Therapeutic

Further subject-matter is a pharmaceutical formulation which is characterized in that it contians an active ingredient according to the invention as a base or a physiologically acceptable salt thereof together with carriers and/or diluents customary for this and suitable for administration by means of inhalation

In this connection, particularly suitable physiologically acceptable salts of the active ingredients according to formula (I) are, as already partially illustrated in the synthesis section, acid addition salts derived from inorganic or organic acids such as for example especially hydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate, p- toluolsulfonate, methanosulfonate, ascorbate, salicylate, acetate, formate, succinate, lactate, glutarate, gluconate or tπcarballylate

The administration of the compounds of the invention by means of inhalation occurs according to the invention in conventional ways customary for administrations of this form, for example in the form of a commercial controlled dosage aerosol or in combination with a spacer In controlled dosage aerosols, a metering valve is delivered with whose help, a dosed amount of the composition is administered For spraying, the present compositions can be formulated for example as aqueous solutions or suspensions and be administered by means of an atomizer Aerosol spray formulations in which the active ingredient is either suspended with one or two stabilizers in a propellant as a carrier and/or diluent, for example tetrafluoroethane or HFC 134a and/or heptafluoropropane or HFC 227 can equally be used, whereby, however, non- fluorinated hydrocarbons or other propellants which are gaseous at normal pressure and room temperature, such as propane, butane or dimethyl ether, can be preferred for ecological reasons Thereby, propellant-free manual pump systems or dry powder systems as desπbed below can also be used

Suitably, the propellant aerosols can also contain surface active adjuvents, such as for example isopropyl mynstate, polyoxyethylene sorbitan fatty acid ester, sorbitan tnoleate, lecithins or oleic acid

For administration by means of inhalation and/or insufflation, the medicaments with an amount of compounds according to the invention can also be formulated in the form of dry powder compositions, for example as an active tngredient-soft pellets or as an active ingredient-powder mixture with a suitable carrier, such as for example lactose and/or glucose The powder compositions can be formulated and administered as single doses or as multiple doses

The compounds according to the invention are preferably administered by means of a controlled dosage aerosol or in the form of a dry powder dosage formulation, wherein the latter preferably contains glucose and/or lactose as a carrier substance Therefore, a therapy method for treatment of asthma and other respiratory tract illnesses is made available with the present invention which, based on the small required effective dose, represents a simple treatment method that can be easily and safely used by the patient himself, especially in acute cases, 1 e duπng an asthmatic attack Furthermore, based on the application as an aerosol, possible systemic side effects can be considerably prevented, especially in sensitive persons

As applicators for inhalation of the pharmaceutical formulations containing one or more of the active ingredients according to the invention, all applicators are generally suitable which are suitable for controlled dosage aerosols and/or a dry powder dosage formulation, such as for example usual applicators for the nose, mouth and or pharynx, or also devices standing under propellant gas for the delivery of a spray (as controlled dosage aerosol or dry powder dosage formulation) as they are also used for inhalations in the nose, mouth and/or pharynx

A further embodiment can also consist of an aqueous solution of the compounds according to the invention, which also optionally contains further active ingredients and/or additives, which are applied by means of an ultrasound atomizer

a) Controlled Dosage Aerosol

Intended dose per aerosol per stroke % by weight

active ingredient according to the invention 0.500 mg 0.66 stabilizer 0.075 mg 0.10

HFC 134a 75.500 mg 99.24

b) Controlled Dosage Aerosol

Intended dose per aerosol per stroke % by weight

active ingredient according to the invention 0.250 mg 0.32

Stabilizer 0.038 mg 0.05

HFC 227 79 180 mg 99.63

In the examples a) and b) the micronized active ingredient according to the invention is, after previous dispersion in a small amount of the stabilizer, placed in a suspension vessel in which the bulk amount of propellant gas solution is found The corresponding suspension is dispersed by means of a suitable stirring system (for example high performance mixer or ultrasound mixer) until an ultra-fine dispersion results. The suspension is then continuously held in flux in a filling apparatus suitable for cold propellants or pressure fillings. Alternatively, the suspension can also be produced in a suitable cooled stabilizer solution in HFC 134a/227

The examples c) to d) describe the composition and production of dosage dry powder formulations.

c) Dosage-Dry Powder Formulation

mg/dose

active ingredient according to the invention 0.500 mg

d) Dosage-Dry Powder Formulation

mg/dose

active ingredient according to the invention 0.500 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg

e) Dosage-Dry Powder Formulation mg/dose

active ingredient according to the invention 0.250 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg

Im example c) the active ingredient is formulated after micronization under addition of steam as pellets with an MMAD between 0,1 and 0,3 mm diameter and brought to use in a multi-dose powder applicator.

In the examples d) and e) the active ingredient is micronized and bulk material is mixed with the lactose in the given amounts, and subsequently, filled in a multi-dose powder inhilator.

4. Injection therapeutics

a) Parenteral Solution

compound according to the invention 5 000 g sodium hydrogen phosphate 5 000 g sodium tartrate 12 000 g sodium sacchannate 0 900 g benzyl alcohol 7 500 g water for injection purposes to 1000 000 ml

The solution is produced according to the customary method, sterilized and filled mto 10 ml vials One vial contains 50 mg of the compound according to the invention

b) Parenteral Dispersion

compound according to the invention 10 000 g soya lecithin 20 000 g saturated triglycerides 100 000 g sodium hydroxide 7 650 g water for injection purposes to 1000 000 ml

The compound according to the invention is dispersed in the saturated triglycerides Then the soya lecithin is added under stirring, and subsequent to this, the aqueous solution of sodium hydroxide is added with subsequent homogenization The dispersion is sterilized and filled into 10 ml vials A vial contains 50 mg of the compound according to the invention

According to need, instead of ampules with injection solution, so-called perforation bottles (vials), which can also be optionally preserved, and infusion solutions with an amount of one or more active ingredients according to the invention can also be made available in the customary manner under addition of buffer substances for adjustment to physiological pH value and/or the isotonicity, optionally further required nutrients,

vitamins, amino acids, stabhzers and other necessary adjuvents, possibly in combination with further medicinal agents suitable for the mentioned indications

In all of the examples set forth above, the active ingredient or the medicinal agent in the form of the respective suitable pharmaceutical acceptable salts and/or acid addition salts can be present, insofar as the base is not preferred in each case

The examples described above can be modified within the framework of the ability of the skilled person depending on need without restriction of the claimed scope of protection

In the following, the pharmaceutical test results obtained in connection with the newly found indications based on the specifically structured new compounds in comparison to known active ingredients of the art are reproduced The experimental results are discussed in connection therewith

In the named examples, the active ingredient can also be present in the form of the respective suitable pharmaceutically acceptable salts The examples described above can be modified within the framework of the ability of the skilled person depending on need without restriction of the claimed scope of protection

PHARMACOLOGICAL EXPERIMENT SECTION

Pharmacological Findings

Studies on the Special Features of the Action Spectrum of the New Compounds for the Indication Bronchial Asthma

In Figures 1 to 8, the following studies are presented with test results.

Fig. 1: Schematic Representation of Experimental Protocol for Bronchio

Spasmolytic Action on the Isolated Tracheal Ring Preparation of Guinea Pig Contracted with Barium Chloride

Male and female guinea pigs were anesthetized by i.p application of 1.2 mg/kg uerthane. Subsequently, the trachea was prepared and passed into a Krebs-Henseleit solution and isolated tracheal rings were excised The ring preparations were transected on the cartilidge ring side and clamped with the isometric pressure guage in the organ bath with the same nutrient solution (37°C ± 1°C and exposed to gas with carbogene = 95% O2 + 5% CO2) and suitable initial load The recording of the muscle tension changes was conducted over a multi-channel recorder The analysis was carried out per computer in an on-line method with ACAD software

Abb. 2: Schematic Representation of the Experimental Protocol for the

Relaxation of the Spontaneous Tension in Isolated Tracheal Ring Preparation of Guinea Pig

Male and female guinea pigs were anesthetized by i p. application of 1 2 mg/kg uerthane. Subsequently, the trachea was prepared and passed into a Krebs-Henseleit solution and isolated tracheal rings were excised. The ring preparations were transected on the cartilidge ring side and clamped with the isometric pressure guage in the organ bath with the same nutrient solution (37°C ± 1°C and exposed to gas with carbogene =

95% O2 + 5% CO2) and suitable initial load The recording of the muscle tension changes was conducted over a multi-channel recorder The analysis was carried out per computer in an on-line method with ACAD software

Fig. 3: Schematic Representation of the Experimental Method for

Generation and Measurement of PAF-induced Bronchoconstriction

Male and female guinea pigs were anesthetized by 1 p application of 1 2 mg/kg urethane Subsequently, the animals were supplied with air at a constant volume over a tracheotomy tube by means of a respiration pump For suppression of spontaneous breathing, the N vagi was transected The V jugulans was cannulated for the application of the antagonists and/or the antagonist substances In accordance with the methods of Konzett-Rossler, the changes of the pulmonary positive pressure respiration were measured over a pressure gauge tn the shunt of the tracheotomy tube as an expression of the change ofthe respiratory tract diameter

Fig. 4: Schematic Representation of the Experimental Method for

Generation and Measurement of Bronchial Hyper-reactivity on the Anesthetized Guinea Pig

Male and female guinea pigs were anesthetized by 1 p application of 1 2 mg/kg urethane Subsequently, the animals were supplied with air at a constant volume over a tracheotomy tube by means of a respiration pump For suppression of spontaneous breathing, the N vagi was transected The V.jugulaπs was cannulated for the application of the antagonists and/or the antagonist substances In accordance with the methods of Konzett-Rossler, the changes of the pulmonary positive pressure respiration were measured over a pressure gauge in the shunt of the tracheotomy tube as an expression of the change ofthe respiratory tract diameter

Fig. 5: Representation of the Protein Discharge as a Result of Increased

Vessel Permeability by Means of Evans Blue

Intravenous injection of Evans Blue at the end of the infusion of mediator/test substance (see Fig. 4); 5 min thereafter, perfusion of the circulation system for removal of the intravasal Evans Blue; then preparation of the trachea and the bronchi; finally, extraction of Evans Blue from the tissue by means of formamide and photometric measurement of the dye concentration.

Fig. 6: Inhibition of the Extravasation of Blood Protein Caused by Increased

Vessel Permeability by Substance No. 117

Average values (N = 8 - 10) of the percent inhibition of the extravasation of Evans Blue in the respiratory tract of the guinea pig are represented as an expression of the extravasation of blood protein caused by increased vessel permeability.

Fig. 7: Schematic Representation of the Experimental Method for

Generation and Measurement of Bronchiospasm Induced by Mediator Release by Means of C48/80 or HIgG

Male and female guinea pigs were anesthetized by i.p. application of 1.2 mg/kg urethane. Subsequently, the animals were supplied with air at a constant volume over a tracheotomy tube by means of a respiration pump. For suppression of spontaneous breathing, the N.vagi was transected. The V.jugularis was cannulated for the application of the antagonists and/or the antagonist substances. In accordance with the methods of Konzett-Rossler, the changes of the pulmonary positive pressure respiration were measured over a pressure gauge in the shunt of the tracheotomy tube as an expression of the change of the respiratory tract diameter.

Fig. 8: Electric Field Stimulation on Isolated Tracheal Rings of the Guinea

Pig

The electric field stimulation (EFS) was carried out on isolated tracheal rings of guinea pigs at 40 volts, 0.5 msec impulse duration and a frequency of 10 Hz for 20 seconds. This electric field stimulation on tracheal ring preparations of the guinea pig in vitro leads to a rapid and temporary cholonergic contraction (which is blockable with

atropine) and subsequent longer lasting non-adrenergenic and non-cholonergic contraction (e-NANC) which can be abolished by pre-treatment with capsaicin (which depletes the intracellulare peptide store) Before electrical accumulation, the trachael ring preparation was pre-treated with indomethacine (3x10 mol/l) in order to prevent a spontaneous development by release of prostanoids In the same way, a pre-treatment with propranolol was conducted (1x10 mol/l) in order to exclude adrenergic effects Thiorphan (1x10 ^" mol/l) was added into the organ bath in order to prevent a rapid degredation of the released peptides which are responsible for the e-NANC contraction ofthe tracheal muscles

EXPLANATION OF THE TABLES

The values given in the following Tables I to V for the comparative compounds relate to the following reference substances with the numbers 519, 520, 521 and 522, wherein theophylline with the no. 521 and nedocromil with the no. 522 represent classic anti- asthmatic agents; although tiaramide, as a thiazol derivative, has a similar structure (compare DE-B- 1770571) in comparison to the compounds according to the invention, substance no. 520 in the form of a thiazol with a dimethylamino substituent on the fixed nitrogen heterocycle bridged over the alkylene residue represents the structurally closest compound. This is not encompassed within the scope of the compounds according to the invention.

tiaramide

sub

theophylline

substance 521

nedocromil

substance 522

1. Direct Bronchospasmolytic Action in Vitro on Tracheal Ring Preparations of the Guinea Pig

One of the most serious symptoms of asthma is the obstruction of the respiratory tract Aside from hypertrophy and edema of the bronchial wall, an excess of viscous mucous and the constriction of the hypertrophy bronchial musculature play the most important role in this obstruction of the respiratory tract

The constriction of the bronchial musculature can be produced in the model of isolated trachael ring preparation of the guinea pig in vitro with the aid of spasmogenically effective substances

In the experiments for testing the direct spasmolytic action of our substances, we used barium chloride as an agonist because it induces a long lasting receptor-independent contraction of the smooth bronchial musculature (method, see Fig. 1)

This test served in our primary search system as the second most important cπtenum, next to the PAF-induced bronchoconstriction, in order to eliminate ineffective substances

Additionally, the direct spasmolysis on spontaneous tonus on the isolated tracheal musculature of the guinea pig was tested (method, see Fig. 2) The spontaneous tonus which is known to be maintained by endogenous release of prostanoids is a senstive measure for the relaxing effect on the smooth bronchial musculature Our substances show higher effectiveness than the comparative substances in this, as well as in the barium chloride test (results, see Tab. I)

Tab.I: Direct Bronchospasmolytic Action In Vitro on Tracheal Ring

Preparations of Guinea Pig

Tab. I (continued)

2. Inhibition of PAF-induced Bronchoconstriction

One of the most important mediators which play a role in asthma is the platelet- activating factor (PAF) It has potent biological effects on the most varied of tissues and inflammation cells and was detected in high concentrations in part in the bronchio- alveolar space of asthmatics It is formed from membrane phospholipids under action of phospholipase A2 and an acetyltransferase in eosinophils, neutrophils, macrophages, thrombocytes and mast cells

This mediator has a potent chemotactic action on eosinophils and activates their functions It causes a permeability increase and edema formation in respiratory tracts and finally leads to a development of a bronchial hyper-reactivity However, PAF does not have a direct effect on the bronchial musculature, but leads to bronchospasm and other asthma relevant symptoms through a complex release of numerous mediators

The inhibiting effect of the compounds according to the invention was used in comparison with the PAF-induced bronchoconstriction (method, see Fig. 3) as a measure of the influence of a substantial partial occurance of bronchial asthma (results, Tab. II)

This test system was used because of its simplicity and relevance as a primary search system in order to effectively differentiate from ineffective substances

For assessment of the dose-response relationship, compare the final remark in the last paragraph ofthe following experimental description for Table III

Tab.II: Inhibition of PAF-induced Broncho-constriction in %

3. Inhibition of Bronchial Hyper-reactivity

A property of the bronchial system of asthma sufferers which is recognized as important is the excessive reactivity to stimuli which are meaningless for healthy persons

This condition of hyper-reactivity can be produced in an experiment by application of natural inflammation mediators which play a role in asthma.

For this, infusions of PAF, substance P or Bradykinin were used over one hour on anesthetized guinea pig. The hyper-reactive condition was tested by means of a subminimal dose of methacholine which was measured by means of the changes of the pulmonary respiratory pressure (method, see Fig. 4)

A special feature ofthe newly synthesized substances is the capability to suppress hyper- reactivity produced in such a manner to a very high degree (results, see Tab. III). In this connection, attention is to be paid to the fact that, in a comparison of the test substances with the standard substances, the maximal obtainable effect as a function of the dose asymptotically approaches the value 100 such that an increase of inhibition from 50% to 75%, for example, does not linearly correspond to an increase of the effectiveness by a factor of 1.5 Therefore, the increase of the effectiveness can be more exactly read from the comparison of the doses which are necessary for production of a similar level of effectiveness (see Tab. Ilia) These facts are also true in an analogous manner for Tables II, IV and V.

Tab.III: Inhibition of Bronchial Hyper-reactivity in %

Tab. Ilia: Inhibition of Bronchial Hyper-reactivity in %

4. Inhibition of the Extravasation of Blood Protein

Pathological and histological examinations as well as the analysis of sputum and bronchial fluids have shown that the protein discharge from the blood vessels of the lung based on increased vessel permeability are an important characteristic of bronchial asthma.

Corresponding mediators which can induce protein discharge based on increased vessel permeability are generated in blood and in the respiratory tract from asthma patients.

The escaping plasma proteins are responsible for the increased mucous formation and its high viscosity as well as for epithalaxia, thickening of the basal membrane and hypertrophy of the smooth musculature m the bronchi and bronchiols of asthmatics

In the animal experiments on the anethesitized guinea pig, an increased vessel permeability and, therewith, an protein discharge can be triggered by infusion of the asthma relevant mediators PAF, substance P and Bradykinin

This protein discharge can be quantified with the Evans Blue technique Synthetic diazo dyes such as Evans Blue bind spontaneously and quantitatively to plasma proteins, whereby their escape into tissues can be detected (method, see Fig. 4 and Fig. 5)

The treatment of test animals with the compounds according to the invention such as, for example, compound no. 117, leads to a 53-75% inhibition of protein discharge, which is to be gathered from Fig. 6

5. Inhibition of Bronchospasm Induced by Mediator Release from Immuno¬ competent Cells

The release of mediatos is a further important process in the asthmatic event Thereby, cells found in tissue (mast cells) and foreign cells (lymphocytes, eosinophihc and basophihc granulocytes, thrombocytes) release information mediators such as histamine, prostaglandins, leucotπenes, platelet activating factor, cytokines, basic proteins, etc Aside from a further cell activation, epithihal destruction and exudation/odema, these also lead to an acute bronchoconstriction The influence of the latter was tested in the two following experimental mediator release models Thereby, in one model, the specific histamine liberator C48/8O ^was injected, whereas in the other model, heat aggregated, human immunoglobulin G was intravenously administered which releases a series of spasmogenic inflammation mediators from immunocompetent cells via

complement proteins C3 _a and C5 _a under triggering of a bronchospasm (method see Fig.

7).

Bronchoconstriction induced in this manner can already be considerably inhibited by compounds according to the invention in very small dosage (results, see Tab. IV).

Tab.IV: Inhibition of Bronchospasm Induced by Mediator Release in %

6. Inhibition of Bronchoconstriction Induced by the Release of Neuropeptides from C-fibers (eNANC)

Work over the last years has characterized a series of peptides from nerve endings (C- fibers in the lung) which can modify the function of bronchial systems independently from the cholinergic and adrenergic system

These neuropeptides such as substance P, neurokinin A, neurokinin B or the calcitonin gene-related peptide (CGRP) influence muscle tonus of bronchi and lung vessels and increase bronchial mucous secretion and produce the so-called neurogenic inflammation

Therewith, they seriously influence the asthmatic event and other pathomechanisms

The electrical stimulation of the C-fibers of the respiratory tract was used to trigger the natural release process of neuropeptides, wherein the degree of release was measured by means of the resulting contraction of the bronchial musculature These measurements are possible under the experimental prerequisites described under the pharmacological- experiment at the beginning of Fig. 8, for method see Fig. 8

Our substances also show a pronounced effect in this test system (results, see Tab. V)

Tab.V: Inhibition of e-NANC Bronchoconstriction in %

l oz

Further Medicinal Indications

The experiments based on the test systems described herein (with the exception of the direct broncholytic effect) also demonstrate a therapeutical effectiveness of the compounds according to the invention in indications other than bronchial asthma

The inhibition of the protein discharge of blood protein caused by an increased vessel permeability (Test 4) as it was detected with the aid of Evans Blue, in combination with an inhibition of the release of mediators (Test 5) which increased the vessel permeability in connection with inflammation systems, represent an ideal therapeutically advantageous spectrum of effects for treatment of chronic venous insufficiency

Therefore, based on these experimental results, chronic venous insufficiency represents a further subject-matter of use of the compounds according to the invention

The experimental results which also demonstrate the inhibition of the release of neuropeptides from C-fibers (e-NANC), see Test 6, also create the possibility to use the medicinal agents according to the invention in the indications migraine and chronic cough as well as against the development of chronic pain

Summary of Results

The findings of the comparative test results show, in a completely unexpected manner, an excellent anti-asthmatic effectiveness compared to classic asthma therapeutic agents as well as compared to a structurally comparable compound (tiramide) Thereby, it is to be established that the use of structurally close compounds is not to be taken into consideration based on toxicological considerations Additionally, the comparative compound no 520, as a typical representative of the structurally close compounds, shows a subtantially more weakly pronounced activity

It is also completely surprising for the expert that the compounds according to the invention simultaneously exhibit not only an essentially stronger activity in comparison

16J to classic anti-asthmatic agents, but also in many cases even a potentiated effectiveness at various sites of action of the pathologic asthma event. Furthermore, the compounds according to the invention also exhibit a surprising effect in chronic venous insufficiency, migraine, chronic cough and in the supression of chronic pain. This far superior action of the compounds according to the invention in comparison to known asthmatic therapeutic agents and the remaining structurally related thiazol compounds was not obvious for the expert, neither through the structurally close, but differentially effective state of the art, nor through an overview of the literature on the structurally strongly deviating classic anti-asthmatic agents.