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WO1997043292A1 - Nouvelles thiazolopyridines - Google Patents

Nouvelles thiazolopyridines Download PDF

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Publication number
WO1997043292A1
WO1997043292A1 PCT/EP1997/002376 EP9702376W WO9743292A1 WO 1997043292 A1 WO1997043292 A1 WO 1997043292A1 EP 9702376 W EP9702376 W EP 9702376W WO 9743292 A1 WO9743292 A1 WO 9743292A1
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Prior art keywords
alkyl
oxo
formula
group
carbonylmethyl
Prior art date
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PCT/EP1997/002376
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English (en)
Inventor
Rolf Eisenburger
Friedemann Reiter
Isabel Schemainda
Klaus Seibel
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Astellas Deutschland GmbH
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Klinge Pharma GmbH and Co
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Priority to AU28950/97A priority Critical patent/AU2895097A/en
Publication of WO1997043292A1 publication Critical patent/WO1997043292A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • 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
  • 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.
  • corticosteroids are used as substances with a multiple mode of action, for example, with respect to an increased ⁇ 2 receptor synthesis as well as an inhibition of leukotrienee synthesis.
  • 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.
  • bronchial asthma 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, ⁇ 2 sympathomimetic agents in the form of isoproterenol and/or the above- named metaproterenol.
  • 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, ⁇ 2 sympathomimetic agents in the form of isoproterenol and/or the above- named metaproterenol.
  • an object is to create, at least in a toxicological respect, for example, improved new thiazolopyridine derivatives
  • 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
  • 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
  • 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
  • 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
  • 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
  • subject-matter ofthe invention is l,2-d ⁇ hydro-2-oxoth ⁇ azolopy ⁇ d ⁇ ne compounds according to the above-named formula (I) (I)
  • R represents halogen
  • R and R are the same or different
  • R can be alkyl, alkenyl, alkinyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and
  • R can be hydrogen, alkyl, alkenyl, alkinyl, cycloalkyl, hydroxyalkyl, acyl or alkanesulfonyl, or
  • forming a ring can be selected from the following heterocycles: N v (CH 2 ), tn
  • 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:
  • heterocyclic ring can optionally have a double and
  • n can be 2 or 3
  • p can be 3 to 5 or 6 or 3 or 4 to 7
  • R can be hydrogen, alkyl, hydroxymethyl, carboxyl or alkoxycarbonyl, as well as R can be hydrogen or an alkyl residue, wherein
  • R and R ⁇ can form an alkylene bridge, in a preferred manner a C1 -C4, especially a
  • 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,
  • alkmylene optionally substituted once or twice by alkyl, hydroxy or alkoxy, or
  • 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
  • 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
  • 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,
  • 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
  • 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,
  • 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,
  • 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
  • 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,
  • 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
  • R and R can be the same or different
  • R represents C j-C ⁇ -alkyl, C3-C6-alkenyl, C3-C6-alkinyl, C3-C6-cycloalkyl, CJ -CO-
  • R represents hydrogen, C ⁇ -C6-alkyl, C3-C6-alkenyl, C3-C6-alk ⁇ nyl, C3-C6-
  • R and R can form a heterocyclic ring together in the residue
  • this ring in this case can be selected from the following heterocycles:
  • heterocyclic ring can optionally contain at least one double bond
  • n can be 2 or 3
  • p can be 3 to 5 or 6 or 3 or 4 to 7
  • R can be hydrogen, Ci-C ⁇ -alkyl, hydroxymethyl, carboxyl or C2-C 5 -alkoxycarbonyl, as well as
  • R can be hydrogen or a Ci-C ⁇ -alkyl residue
  • R and R can form a Cj-C ⁇ -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,
  • C ⁇ -C ⁇ o-alkylene or C2-Cifj-alkenylene each optionally substituted once or twice by C ⁇ -C4-alkyl, hydroxy or C ⁇ -C4-alkoxy, wherein the double bond can also be to ring Q in the latter case,
  • C3-C ⁇ o-alk ⁇ nylene optionally substituted once or twice by C * -C4-alkyl, hydroxy or C ⁇ -C4-alkoxy, or
  • R is selected independently from R from hydrogen or C * -C ⁇ -alkyl, or
  • C2-C ⁇ o-alkylene is C2-C ⁇ o-alkylene, C4-C ⁇ o-alkenylene or C 4 -C * o-alk ⁇ nylene each optionally substituted once or twice by C * -C4-alkyl, hydroxy or C * -C4-alkoxv ein-, or
  • 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)
  • halogen is either fluorine, chlorine, bromine or iodine
  • Ci-C ⁇ -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
  • C ⁇ -C6-hydroxyalkyl contains a hydroxyl group in one of the above-named C ⁇ -C6-alkyl groups, among which the hydroxymethyl- and the hydroxyethyl group are preferred,
  • C ⁇ -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 -C ⁇ o-alkylaminoalkyl carries one of the above-named C ⁇ -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, C ⁇ -C4-alkylam ⁇ no contains one of the above-named C ⁇ -C4-alkyl groups among which the methylammo-, ethylamino-, propylamino-, isopropylamino-, butylamino- and the tert-butylamino group are preferred,
  • C2-C8-d ⁇ alkylam ⁇ no 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-d ⁇ alkylam ⁇ noalkyl carries one of the above-named C2-C8-d ⁇ alkylam ⁇ no groups on one of the above-named Cj-C ⁇ -alkyl residues, among which the dimethylaminomethyl-, dimethylaminoethyl-, dimethylaminopropyl-, dimethylaminobutyl-, diethylaminomethyl-, diethylaminoethyl-, diethylaminopropyl-, d ⁇ ropylaminomethyl-, 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-C ⁇ -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 hydrochlo ⁇ des, 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)
  • Rl IS a halogen in pos ⁇ t ⁇ on-6
  • R is selected from Ci-Cs-alkyl, C3-C6-alkenyl, C3-C6-alk ⁇ nyl, C3-C6-cycloalkyl,
  • Ci-C ⁇ -hydroxyalkyl C2-C6-alkoxyalkyl or C4-C ⁇ o-d ⁇ alkylam ⁇ noalkyl and
  • R is selected from hydrogen, Cj-C ⁇ -alkyl, C3-C6-alkenyl, C3-C6-alk ⁇ nyl, C3-C6- cycloalkyl, C ⁇ -C6-hydroxyalkyl, Ci-C ⁇ -acyl or C * -C6-alkanesulfonyl,
  • R and R can be the same or different or together form a heterocyclic ring, wherein in the case of a heterocychc ring,
  • A is selected from C ⁇ -C4-alkylene or C2-C4-alkenylene optionally substituted by a methyl group, and
  • O is selected from
  • the ring can optionally contain a double bond
  • n 3 to 7
  • n 2 or 3
  • p 3 to 7, 4
  • R represents hydrogen, C * -C3-alkyl, hydroxymethyl, carboxyl or C2-C5-alkoxycar- bonyl and
  • R is hydrogen or C ⁇ -C3-alkyl
  • 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-alk ⁇ nylene,
  • alkylene-, alkenylene- or alkmylene groups can each be optionally substituted by C*-C4-alkyl, hydroxy or C ⁇ -C4-alkoxy, or
  • 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
  • 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 C ⁇ -C4 ⁇ alkyl, hydroxy or C ⁇ -C4-alkoxy or in which a respective
  • methylene group can be isosterically replaced by O or S or NR , wherein R is
  • R selected independently from hydrogen or C ⁇ -C3-alkyl.
  • a particular preferred embodiment according to the invention represents compounds according to the formula (I) (I)
  • R* IS bromine or chlorine in pos ⁇ t ⁇ on-6
  • R is selected from C * -C4-alkyl, C3-C4-alkenyl, C3-C4-alk ⁇ nyl, C3-C5-c ⁇ cloalkyl, C2-
  • R is selected from C ⁇ -C4-alkyl, C3-C4-alkenyl, C3-C4-alk ⁇ nyl, C ⁇ -C3-acyl or C1-C3- alkanesulfonyl, wherein
  • 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
  • azetidine pyrrohdine, piperidine, hexahydroazepine, piperazine, homopiperazine or morphohne, wherein the ring can be respectively substituted by C ⁇ -C3-alkyl, hydroxy, C1-C3 -hydroxyalkyl, C2-C4-d ⁇ alkylam ⁇ no or an oxo group adjacent to a nitrogen atom,
  • A represents a methylene group
  • the ring can optionally contain a double bond
  • n 3 to 6
  • p 3 to 5 or 6 or 3 to 7
  • R represents hydrogen or C ⁇ -C3-alkyl
  • R represents hydrogen
  • D in the case of a bond to Q over a carbon atom is selected from Ci-C ⁇ -alkylene or C2-C6-alkenylene, wherein the double bond can also be to Q, or is selected from C3-C6-alk ⁇ nylene, wherein a respective methylene group can optionally be
  • 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-alk ⁇ nylene, in which a respective methylene group can
  • R is selected from hydrogen or C * -C3-alkyl.
  • R-** IS bromine and chlorine in pos ⁇ t ⁇ on-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
  • 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
  • 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
  • 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 hydrochlo ⁇ des, hydrobromides, hydro
  • R.1 and A have the meanings given above, or their reactive derivatives, with compounds ofthe following formula (III),
  • 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-t ⁇ chlorphenyl ester, pentachlorophenyl ester, cyanomethyl ester, esters of N-hydroxysuccinimide, of N- hydroxyphthahmide, of 1-hydroxybenzotriazol, of N-hydroxypipe ⁇ dine, of 2- hydroxypy ⁇ dine or of 2-mercaptopy ⁇ d ⁇ ne, 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
  • aliphatic chloroformates for example chlor
  • 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-d ⁇ methylam ⁇ nopropyl)carbodum ⁇ de hydrochloride, N,N'-carbonyldnm ⁇ dazol, 1 -ethoxycarbonyl-2-ethoxy- 1 ,2- dihydroquinohne, etc If carbodnmides are used as the condensation agent, reagents such as N-hydroxysucc ⁇ n ⁇ m ⁇ de, N-hydroxyphthalimide, 1-hydroxvbenzot ⁇ azol, N- hydroxypipe ⁇ dine, etc can be advantageously added
  • 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
  • aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons (for example dichloromethane, chloroform, 1,2- dichloroethane, t ⁇ chloroethylene), 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
  • 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, t ⁇ butylamine, N-methylmorpholine or pyndine
  • alkali metal carbonates sodium carbonate, potassium carbonate
  • alkali metal hydrogen carbonates sodium hydrogen carbonate, potassium hydrogen carbonate
  • organic bases such as, for example, triethylamine, ethyl dusopropylamine, t ⁇ butylamine, 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
  • 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 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, t ⁇ fluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-, p- toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy residue
  • a reactive group L can be a terminal epoxide group, for example
  • 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
  • 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 carried out in the presence of bases, whereby the same as named above in method (a) can be used If chlorides or bromides are
  • 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
  • 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 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
  • 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
  • the bases can be recovered from the salts by alkahzation, for example with aqueous ammonia solution, alkali carbonate or dilute lye
  • CDI * carbonyldiimidazol
  • EDC * N-(3-dimethylaminopropyl)-N'-ethyl- carbodiimide hydrochloride
  • EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
  • TEA triethylamine
  • Ci 9 H 25 BrN 4 O 2 S MG (453 4)
  • 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.
  • 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 %).
  • 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.
  • MeOH methanol iPrOh — isopropanol
  • CijH- 8 BrN 3 O 3 S MG (400.3)
  • 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
  • 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
  • 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
  • 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
  • solid administration medicinal forms such as, for example, emulsions, suspensions, solubihsates or solutions as well as substances filled
  • 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
  • the compounds according to the invention can be administered per injections
  • intramuscular, intravenous or intraglutial application preparations are especially considered as injection preparations
  • 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
  • peroral administration medicinal forms can also be present as lozenges or chewing gum, etc
  • pernasal application compositions can also come into use
  • 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 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 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
  • lyophihsates such as mannite, dextran, saccharose, human albumin, lactose, PVP or gelatin varieties
  • lyophihsates such as mannite, dextran, saccharose, human albumin, lactose, PVP or gelatin varieties
  • lyophihsates such as mannite, dextran, saccharose, human albumin, lactose, PVP or gelatin varieties
  • 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
  • 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.
  • the individual dosage units of the active ⁇ ngred ⁇ ent(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
  • 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.
  • 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
  • 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
  • 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 respective suitable medicinal form is selected depending on the therapeutic application
  • medicinal therapeutic agents such as tablets or capsules, especially depot forms, are administered above all
  • inhalation therapeutic agents or injectable agents present themselves
  • 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
  • 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.
  • 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
  • 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
  • active ingredient according to the invention 0 050 g glycerin 0 500 g sorbite, 70% solution 0 500 g sodium saccha ⁇ nate 0 010 g methyl-p-hydroxybenzoate 0 040 g aromatic agent q s sterile wasser q s to 5 ml
  • 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
  • active ingredient according to the invention 0 050 g fatty acid glyce ⁇ de 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
  • 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
  • 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
  • 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 t ⁇ carballylate
  • 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, methanosulfon
  • compositions of the invention 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
  • 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
  • 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
  • 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 du ⁇ ng an asthmatic attack Furthermore, based on the application as an aerosol, possible systemic side effects can be considerably prevented, especially in sensitive persons
  • applicators for inhalation of the pharmaceutical formulations containing one or more of the active ingredients according to the invention 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
  • active ingredient according to the invention 0.500 mg 0.66 stabilizer 0.075 mg 0.10
  • active ingredient according to the invention 0.250 mg 0.32
  • 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.
  • the suspension can also be produced in a suitable cooled stabilizer solution in HFC 134a/227
  • active ingredient according to the invention 0.500 mg lactose Ph.Eur. to 2.5 mg or to 5.0 mg
  • 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.
  • 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.
  • 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
  • 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
  • so-called perforation bottles vials
  • 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
  • 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 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
  • Fig. 1 Schematic Representation of Experimental Protocol for Bronchio
  • Fig. 5 Representation of the Protein Discharge as a Result of Increased
  • Fig. 8 Electric Field Stimulation on Isolated Tracheal Rings of the Guinea
  • the electric field stimulation 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)
  • capsaicin which depletes the intracellulare peptide store
  • the trachael ring preparation was pre-treated with indomethacine (3x10 mol/l) in order to prevent a spontaneous development by release of prostanoids
  • a pre-treatment with propranolol was conducted (1x10 mol/l) in order to exclude adrenergic effects
  • Thiorphan (1x10 "
  • PAF platelet- activating factor
  • 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
  • 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 condition of hyper-reactivity can be produced in an experiment by application of natural inflammation mediators which play a role in asthma.
  • 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).
  • 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)
  • 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
  • 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)
  • 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
  • Bronchoconstriction induced in this manner can already be considerably inhibited by compounds according to the invention in very small dosage (results, see Tab. IV).
  • 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
  • chronic venous insufficiency represents a further subject-matter of use of the compounds according to the invention
  • 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.

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Abstract

Nouveaux composés de thiazolopyridines de formule (I), leurs procédés de production, leurs intermédiaires et médicaments contenant une dose de ces composés, ainsi que leur utilisation dans le traitement de différentes maladies, notamment les troubles asthmatiques dont les maladies entraînant une obstruction des bronches et des poumons. Les nouveaux composés ont la particularité de présenter une substitution spécifique des composants amide tout en possédant des propriétés pharmaceutiques de valeur.
PCT/EP1997/002376 1996-05-10 1997-05-09 Nouvelles thiazolopyridines Ceased WO1997043292A1 (fr)

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DE19618970.5 1996-05-10
DE19618970A DE19618970A1 (de) 1996-05-10 1996-05-10 Neue Thiazolopyridine

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WO2003031432A1 (fr) * 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
US7767695B2 (en) 2001-09-14 2010-08-03 High Point Pharmaceuticals, Llc Substituted piperidines

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US6964974B2 (en) 2000-09-08 2005-11-15 Hoffmann-La Roche Inc. 2,3-oxidosqualene-lanosterol cyclase inhibitors

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767695B2 (en) 2001-09-14 2010-08-03 High Point Pharmaceuticals, Llc Substituted piperidines
WO2003031432A1 (fr) * 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
JP2005507906A (ja) * 2001-10-12 2005-03-24 ノボ　ノルディスク　アクティーゼルスカブ 置換ピペリジン類、およびヒスタミンｈ３受容体関連疾患の治療のためのその使用
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
EP2243776A1 (fr) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Piperidines substituées et leur utilisation dans le traitement de maladies liées au recepteur histaminique H3

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