EP1589013A2

Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines with adenosine receptor-binding activity and their use as cardiovascular preparations

Abstract

Es werden Verbindungen der Formel (I) beschrieben, ein Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel.

EP1589013A2, drawing sheet 1 — Sheet 1 of 26

Term

Term ended

Projected expiry passed 19 March 2022, 4.5 years ago.

Parties

Owner: BAYER SCHERING PHARMA AG
Assigned now: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT
Applicants: Bayer Health Care Aktiengesellschaft
Inventors: Rosentreter, Ulrich, Dr., 42349 Wuppertal, Germany
Krämer, Thomas, Dr., 42111 Wuppertal, Germany
Vaupel, Andrea, Dr., 04125 Riehen, Switzerland
Hübsch, Walter, Dr., 42113 Wuppertal, Germany
and 5 more inventorsShow fewer
Diedrichs, Nicole, Dr., 42553 Velbert, Germany
Krahn, Thomas, Dr., 58135 Hagen, Germany
Dembowsky, Klaus, Dr., 81249 München, Germany
Stasch, Johannes-Peter, Dr., 42651 Solingen, Germany
Shimada, Mitsuyuki, Nara 630-8323, Japan

Reach

Cites: 7 earlier patents⁠
Family: 13 members in 6 offices⁠EP4CA2DE2JP2US2WO

Classification

CPC: C07D405/04A61P1/16A61P3/10A61P9/00A61P11/00A61P13/00+7 more
IPC: C07D401 04A61K31 443A61K31 4433A61P1 16A61P3 10A61P9 00+11 more

12 claims: 8 independent, 4 dependent

1
Compounds of formula (I) wherein R 1 and R 2 are bonded to adjacent phenyl ring atoms and together with the two ring carbon atoms form a 5- to 7-membered saturated or partially unsaturated ring which can contain one or two heteroatoms from the N, O and / or S series and which are mono- or di-independently from each other, by (C 1 -C 4 ) -Alkyl, which in turn by hydroxy, (C 1 -C 4 ) Alkoxy or phenyl may be substituted, cyano, halogen or oxo may be substituted, R 3 (C. 1 -C 8 ) -Alkyl, which is up to three times, independently of one another, by hydroxy, (C 1 -C 4 ) Alkoxy, (C 3 -C 7 ) Cycloalkyl, (C 2 -C 4 ) Alkenyl, (C 2 -C 4 ) Alkynyl, halogen or (C 6 -C 10 ) Aryloxy may be substituted (C 6 -C 10 ) Aryl, up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 ) Alkoxy, carboxyl, (C 1 -C 4 ) Alkoxycarbonyl or mono- or di- (C 1 -C 4 ) alkylamino may be substituted, (C 1 -C 8 ) Alkoxy, which is replaced by hydroxy, (C 1 -C 4 ) Alkoxy, (C 3 -C 6 ) Cycloalkyl, (C 2 -C 4 ) Alkenyl, (C 6 -C 10 ) Aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, (C 6 -C 10 ) Aryloxy, halogen, cyano, (C 1 -C 4 ) Alkoxycarbonyl, amino or mono- or di- (C 1 -C 4 ) -alkylamino can be substituted, hydrogen, hydroxy, halogen, nitro, cyano or -NH-C (O) - R 5 means wherein R 5 (C. 1 -C 8 ) Alkyl, which is replaced by hydroxy or (C 1 -C 4 ) Alkoxy may be substituted, (C 3 -C 7 ) Cycloalkyl or (C 6 -C 10 ) Aryl, up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 ) Alkoxy, carboxyl, (C 1 -C 4 ) Alkoxycarbonyl or mono- or di- (C 1 -C 4 ) alkylamino can be substituted means and R 4 (C. 2 -C 4 ) Alkenyl, (C 3 -C 7 ) Cycloalkyl or (C 1 -C 8 ) -Alkyl means, where alkyl up to three times, independently of one another, by halogen, trifluoromethyl, trifluoromethylthio, (C 3 -C 7 ) -Cycloalkyl, hydroxy, -CO-NH-R 6 , (C 1 -C 4 ) Alkoxy, (C 1 -C 4 ) Alkoxycarbonyl, (C 2 -C 4 ) Alkenyl, (C 6 -C 10 ) Aryl or 5- to 10-membered heteroaryl with up to three heteroatoms and / or hetero-chain links from the series N, NO (N-oxide), O and / or S can be substituted, in which Aryl and heteroaryl in turn up to three times, independently of one another, by halogen, trifluoromethyl, (C 1 -C 4 ) Alkyl, which in turn by carboxyl or (C 1 -C 4 ) Alkoxycarbonyl may be substituted, (C 1 -C 4 ) Alkoxy, carboxyl, (C 1 -C 4 ) Alkoxycarbonyl, amino, mono- or di- (C 1 -C 4 ) alkylamino, nitro, cyano or hydroxy can be substituted, and R 6 Hydrogen, (C 1 -C 8 ) Alkyl, which is replaced by hydroxy or (C 1 -C 4 ) Alkoxy may be substituted, (C 3 -C 7 ) Cycloalkyl or (C 6 -C 10 ) Aryl, up to three times, independently of one another, by halogen, nitro, (C 1 -C 4 ) Alkoxy, carboxyl, (C 1 -C 4 ) Alkoxycarbonyl or mono- or di- (C 1 -C 4 ) alkylamino can be substituted means and their salts, hydrates, hydrates of the salts and solvates.
6
Process for the preparation of compounds of formula (I) as defined in claim 1, characterized in that one Compounds of formula (II) in which the residues R 1 , R 2 and R 3 have the meaning given in claim 1, with compounds of the formula (III) R 4 -X (III), in which R 4 has the meaning given in claim 1 and X represents a leaving group, implements.
7
Compounds of formula (I) as defined in claim 1 for the prophylaxis and / or treatment of diseases.
8
Composition containing at least one compound of formula (I) as defined in claim 1 and at least one further auxiliary.
9
Use of compounds of formula (I) as defined in claim 1 for the manufacture of medicaments for the prophylaxis and / or treatment of diseases of the cardiovascular system (cardiovascular diseases).
10
Use of compounds of formula (I) as defined in claim 1 for the manufacture of medicaments for the prophylaxis and / or treatment of diseases of the genitourinary system and cancer.
11
Use of compounds of formula (I), as defined in claim 1, for the manufacture of medicaments for the prophylaxis and / or treatment of inflammatory and neuroinflammatory diseases, neurodegenerative diseases and pain conditions.
12
Use of compounds of formula (I) as defined in claim 1 for the manufacture of medicaments for the prophylaxis and / or treatment of diseases of the respiratory tract, liver fibrosis and cirrhosis and diabetes.

Independent claims8

118 paragraphs, as filed

The present invention relates to new 2-thio-3,5-dicyano-4-aryl-6-aminopyridines, a process for their preparation and their use as medicaments.

Adenosine, a nucleoside from adenine and D-ribose, is an endogenous factor with cell-protective activity, especially under cell-damaging conditions with limited oxygen and substrate supply, such as ischemia in a wide variety of organs (e.g. heart and brain).

Adenosine arises intracellularly when adenosine 5'-monophosphate (AMP) and S-adenosylhomocysteine are broken down as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter by binding to specific receptors.

Under normoxic conditions, the concentration of free adenosine in the extracellular space is very low. However, the extracellular concentration of adenosine increases dramatically in the affected organs under ischemic or hypoxic conditions. For example, it is known that adenosine inhibits platelet aggregation and increases blood flow to the coronary arteries. It also affects the heart rate, the release of neurotransmitters and lymphocyte differentiation.

These effects of adenosine aim to increase the oxygen supply of the affected organs or to reduce the metabolism of these organs in order to adapt the organ metabolism to the organ blood flow under ischemic or hypoxic conditions.

The action of adenosine is mediated via specific receptors. So far, the subtypes A1, A2a, A2b and A3 are known. The effects of these adenosine receptors are mediated intracellularly by the messenger cAMP. In the case of adenosine binding to the A2a or A2b receptors, activation of the membrane-bound adenylate cyclase leads to an increase in the intracellular cAMP, while binding of the adenosine to the A1 or A3 receptors results in a decrease in the adenylate cyclase intracellular cAMP content caused.

According to the invention, "adenosine receptor-selective ligands" refer to substances which bind selectively to one or more subtypes of the adenosine receptors and which either mimic the action of adenosine (adenosine agonists) or can block its action (adenosine antagonists).

Adenosine receptor-selective ligands can be divided into different classes according to their receptor selectivity, for example ligands that bind selectively to the A1 or A2 receptors of adenosine, and in the latter also those that selectively bind to the A2a or A2b Bind receptors of adenosine. Adenosine receptor ligands are also possible, which bind selectively to several subtypes of the adenosine receptors, for example Ligands that bind selectively to the A1 and A2, but not to the A3 receptors of adenosine.

The previously mentioned receptor selectivity can be determined by the action of the substances on cell lines which, after stable transfection with the corresponding cDNA, express the respective receptor subtypes (see in this regard the publication ME Olah, H. Ren, J. Ostrowski, KA Jacobson, GL Stiles , "Cloning, expression, and characterization of the unique bovine A1 adenosine receptor. Studies on the ligand binding site by site-directed mutagenesis." In J. Biol. Chem. 267 (1992) pages 10764-10770, the disclosure of which is hereby fully incorporated by reference).

The effect of the substances on such cell lines can be determined by biochemical measurement of the intracellular messenger substance cAMP (see the publication KN Klotz, J. Hessling, J. Hegler, C. Owman, B. Kull, BB Fredholm, MJ Lohse, "Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells "in Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998) pages 1-9, the disclosure of which is hereby fully incorporated by reference).

The ligands known from the prior art, which are considered to be "adenosine receptor-specific", are predominantly derivatives based on natural adenosine (S.-A. Poulsen and RJ Quinn, "Adenosine receptors: new opportunities for future drugs" in Bioorganic and Medicinal Chemistry 6 (1998) pages 619-641; KJ Broadley, "Drugs modulating adenosine receptors as potential therapeutic agents for cardiovascular diseases" in Exp. Opin. Ther. Patents 10 (2000) pages 1669-1692). However, the adenosine ligands known from the prior art mostly have the disadvantage that they do not really have a receptor-specific effect, are less effective than natural adenosine, or are only very weakly effective after oral administration. Therefore, due to the disadvantages mentioned above, they are mainly used only for experimental purposes.

The object of the present invention is to find or provide pharmacologically active substances which are suitable for the prophylaxis and / or treatment of various diseases, in particular diseases of the cardiovascular system (cardiovascular diseases), and which preferably act as adenosine receptor-selective ligands.

The present invention relates to compounds of the formula (I)<chemistry id="chem0001" num="0001"><img file="EP1589013A2_D0001.tif" /></chemistry> wherein<dl id="dl0001"><dt>R1 and R2</dt><dd>are bonded to adjacent phenyl ring atoms and together with the two ring carbon atoms form a 5- to 7-membered saturated or partially unsaturated ring which can contain one or two heteroatoms from the N, O and / or S series and which are mono- or di-independently from each other, by (C1-C4) -Alkyl, which in turn by hydroxy, (C1-C4) Alkoxy or phenyl can be substituted, cyano, halogen or oxo can be substituted,</dd><dt>R3</dt><dd>(C.1-C8) -Alkyl, which is up to three times, independently of one another, by hydroxy, (C1-C4) Alkoxy, (C3-C7) Cycloalkyl, (C2-C4) Alkenyl, (C2-C4) Alkynyl, halogen or (C6-C10) Aryloxy may be substituted (C6-C10) Aryl, up to three times, independently of one another, by halogen, nitro, (C1-C4) Alkoxy, carboxyl, (C1-C4) Alkoxycarbonyl or mono- or di- (C1-C4) alkylamino may be substituted, (C1-C8) Alkoxy, which is replaced by hydroxy, (C1-C4) Alkoxy, (C3-C6) Cycloalkyl, (C2-C4) Alkenyl, (C6-C10) Aryl, 5- to 10-membered heteroaryl with up to three heteroatoms from the series N, O and / or S, (C6-C10) Aryloxy, halogen, cyano, (C1-C4) Alkoxycarbonyl, amino or mono- or di- (C1-C4) -alkylamino can be substituted, hydrogen, hydroxy, halogen, nitro, cyano or -NH-C (O) - R5 means</dd></dl> wherein<dl id="dl0002" compact="compact"><dt>R5</dt><dd>(C.1-C8) Alkyl, which is replaced by hydroxy or (C1-C4) Alkoxy may be substituted, (C3-C7) Cycloalkyl or (C6-C10) Aryl, up to three times, independently of one another, by halogen, nitro, (C1-C4) Alkoxy, carboxyl, (C1-C4) Alkoxycarbonyl or mono- or di- (C1-C4) alkylamino can be substituted means</dd></dl> and<dl id="dl0003" compact="compact"><dt>R4</dt><dd>(C.2-C4) Alkenyl, (C3-C7) Cycloalkyl or (C1-C8) -Alkyl means, where alkyl up to three times, independently of one another, by halogen, trifluoromethyl, trifluoromethylthio, (C3-C7) -Cycloalkyl, hydroxy, -CO-NH-R6, (C1-C4) Alkoxy, (C1-C4) Alkoxycarbonyl, (C2-C4) Alkenyl, (C6-C10) Aryl or 5- to 10-membered heteroaryl with up to three heteroatoms and / or hetero-chain links from the series N, NO (N-oxide), O and / or S can be substituted,</dd></dl> in which<dl id="dl0004" compact="compact"><dt>Aryl</dt><dd>and heteroaryl in turn up to three times, independently of one another, by halogen, trifluoromethyl, (C1-C4) Alkyl, which in turn by carboxyl or (C1-C4) Alkoxycarbonyl may be substituted, (C1-C4) Alkoxy, carboxyl, (C1-C4) Alkoxycarbonyl, amino, mono- or di- (C1-C4) alkylamino, nitro, cyano or hydroxy can be substituted,</dd></dl> and<dl id="dl0005" compact="compact"><dt>R6</dt><dd>Hydrogen, (C1-C8) Alkyl, which is replaced by hydroxy or (C1-C4) Alkoxy may be substituted, (C3-C7) Cycloalkyl or (C6-C10) Aryl, up to three times, independently of one another, by halogen, nitro, (C1-C4) Alkoxy, carboxyl, (C1-C4) Alkoxycarbonyl or mono- or di- (C1-C4) alkylamino can be substituted means</dd></dl> and their salts, hydrates, hydrates of the salts and solvates.

Depending on the substitution pattern, the compounds of the formula (I) can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner. The present invention likewise relates to the tautomers of the compounds of the formula (I).

Salts of the compounds of formula (I) can be physiologically acceptable salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, trifluoroacetic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid are particularly preferred.

Salts which can also be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine , N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.

As Hydrates or. Solvate According to the invention, those forms of the compounds of the formula (I) are designated which, in the solid or liquid state, form a molecular compound or a complex by hydration with water or coordination with solvent molecules. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Likewise, the hydrates or solvates of salts of the compounds according to the invention are also suitable.

The invention also includes prodrugs of the compounds according to the invention. According to the invention, prodrugs are those forms of the compounds of the formula (I) which can themselves be biologically active or inactive, but which can be converted into the corresponding biologically active form under physiological conditions (for example metabolically or solvolytically).

In the context of the present invention, unless otherwise stated, the substituents have the following meaning:<ul id="ul0001" list-style="none"><li>halogen generally represents fluorine, chlorine, bromine or iodine. Fluorine, chlorine or bromine are preferred. Fluorine or chlorine are very particularly preferred.</li><li>(C.1-C8) Alkyl, (C1-C6) Alkyl or (C1-C4) Alkyl generally represents a straight-chain or branched alkyl radical having 1 to 8, 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1 to 6 carbon atoms is preferred. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is particularly preferred. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.</li><li>(C.2-C4) Alkenyl generally represent a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.</li><li>(C.2-C4) Alkynyl generally represents a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms. Examples include: ethynyl, n-prop-2-yn-1-yl and n-but-2-yn-1-yl.</li><li>(C.1-C8) Alkoxy, (C1-C6) Alkoxy or (C1-C4) Alkoxy generally represents a straight-chain or branched alkoxy radical having 1 to 8, 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 6 carbon atoms is preferred. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is particularly preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.</li><li>(C.1-C4) Alkoxycarbonyl generally represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms, which is linked via a carbonyl group. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.</li><li>Mono- or Di- (C1-C4) alkylamino in the context of the invention stands for an amino group having one or two identical or different straight-chain or branched alkyl substituents, each having 1 to 4 carbon atoms. Examples include: methylamino, ethylamino, n-propylamino, isopropylamino, t-butylamino,N, N-Dimethylamino, N, N-Diethylamino, N-Ethyl-N-methylamino, N-Methyl-N-n-propylamino, N-Isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.</li><li>(C.3-C7) Cycloalkyl or (C3-C6) Cycloalkyl generally represents a cyclic alkyl radical having 3 to 7 or 3 to 6 carbon atoms. Cyclic alkyl radicals having 3 to 6 carbon atoms are preferred. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.</li><li>(C.6-C10) Aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.</li><li>(C.6-C10) Aryloxy generally represents an aromatic radical as defined above which is linked via an oxygen atom.</li><li>5- to 10-membered heteroaryl with up to 3 heteroatoms and / or hetero-chain links from the series N, NO (N-oxide), O and / or S. generally represents a mono- or bicyclic, optionally benzo-condensed heteroaromatic which is linked via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic. Examples include: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, oxdiazolyl, isoxazolyl, benzofuranyl, benzothienyl or benzimidazolyl. The corresponding heteroaromatics with fewer heteroatoms, such as, for example, one or 2 heteroatoms from the series N, O and / or S or smaller ring sizes, such as, for example, 5- or 6-membered heteroaryl, are derived from this definition. In general, 5- or 6-membered aromatic heterocycles having one or two heteroatoms from the N, O and / or S series are preferred. Examples include: pyridyl, pyrimidyl, pyridazinyl, furyl, imidazolyl or thienyl.</li><li>5- to 7-membered heterocycle generally represents a saturated or partially unsaturated, optionally benzocondensed heterocycle with up to 3 heteroatoms from the series N, O and / or S. Examples include: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, dihydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, hexahydropyranyl . The corresponding heterocycles with fewer heteroatoms, such as, for example, are derived from this definition with one or 2 heteroatoms from the series N, O and / or S or a smaller ring size such as, for example, 5- or 6-membered heterocyclyl. Saturated heterocycles with up to 2 heteroatoms from the series N, O and / or S, in particular, are preferred Piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl.</li></ul>

Compounds of the formula (I) are preferred wherein<dl id="dl0006" compact="compact"><dt>R1 and R2</dt><dd>are bonded to neighboring phenyl ring atoms and together with the two ring carbon atoms form a 5- to 7-membered saturated ring which can contain one or two heteroatoms from the series N and / or O and which, once or twice, independently of one another, is methyl, this in turn by hydroxy, (C1-C4) Alkoxy or phenyl may be substituted, fluorine or chlorine may be substituted,</dd><dt>R3</dt><dd>Means hydrogen or chlorine</dd></dl> and<dl id="dl0007" compact="compact"><dt>R4</dt><dd>(C.2-C4) Alkenyl or (C1-C4) -Alkyl means, where alkyl up to twice, independently of one another, by halogen, trifluoromethyl, trifluoromethylthio, (C3-C7) -Cycloalkyl, hydroxy, -CO-NH-R6, (C1-C4) Alkoxy, (C1-C4) Alkoxycarbonyl, (C2-C4) Alkenyl, (C6-C10) Aryl or 5- or 6-membered heteroaryl can be substituted with up to three heteroatoms from the series N, O and / or S, in which Aryl and heteroaryl in turn up to three times, independently of one another, by halogen, trifluoromethyl, (C1-C4) Alkyl, which in turn by carboxyl or (C1-C4) Alkoxycarbonyl may be substituted, (C1-C4) Alkoxy, carboxyl, (C1-C4) -Alkoxycarbonyl, nitro, cyano or hydroxy may be substituted, and R6 Hydrogen or (C1-C4) Alkyl means</dd></dl> and their salts, hydrates, hydrates of the salts and solvates.

Compounds of the formula (I) are particularly preferred wherein<dl id="dl0008" compact="compact"><dt>R1 and R2</dt><dd>attached to neighboring phenyl ring atoms and for one group<chemistry id="chem0002" num="0002"><img file="EP1589013A2_D0002.tif" /></chemistry> or<chemistry id="chem0003" num="0003"><img file="EP1589013A2_D0003.tif" /></chemistry> stand,</dd><dt>R3</dt><dd>Means hydrogen</dd></dl> and<dl id="dl0009" compact="compact"><dt>R4</dt><dd>Propenyl, methyl, ethyl or n-propyl means, the alkyl radicals themselves up to twice, independently of one another, by hydroxy, methoxy, trifluoromethyl, trifluoromethylthio, fluorine, imidazolyl, pyridyl, phenyl, which in turn by fluorine, cyano, nitro, methoxy , Methoxycarbonyl (-C (O) -O-CH3) or methoxycarbonylmethyl (-CH2-C (O) -O-CH3) may be substituted, methoxycarbonyl (-C (O) -O-CH3), Amido (-C (O) -NH2) or N-methylamido (-C (O) -NH-CH3) can be substituted,</dd></dl> and their salts, hydrates, hydrates of the salts and solvates.

Compounds of the formula (I) in which R1 and R2 are bound to neighboring phenyl ring atoms, which are in the para and meta position to the point of attachment of the pyridine ring.

Also particularly preferred are compounds of formula (I) wherein<dl id="dl0010" compact="compact"><dt>R1 and R2</dt><dd>attached to neighboring phenyl ring atoms and for one group<chemistry id="chem0004" num="0004"><img file="EP1589013A2_D0004.tif" /></chemistry> or<chemistry id="chem0005" num="0005"><img file="EP1589013A2_D0005.tif" /></chemistry> stand,</dd><dt>R3</dt><dd>Hydrogen means</dd></dl> and<dl id="dl0011" compact="compact"><dt>R4</dt><dd>Propenyl, methyl, ethyl or n-propyl means, the alkyl radicals themselves up to twice, independently of one another, by hydroxyl, methoxy, trifluoromethyl, trifluoromethylthio, fluorine, imidazolyl, optionally thiazolyl, pyridyl or phenyl which is substituted by methyl, which in turn by fluorine , Cyano, nitro, methoxy, methoxycarbonyl (-C (O) -O-CH3) or methoxycarbonylmethyl (-CH2-C (O) -O-CH3) may be substituted, methoxycarbonyl (-C (O) -O-CH3), Amido (-C (O) -NH2) or N-methylamido (-C (O) -NH-CH3) can be substituted,</dd></dl> and their salts, hydrates, hydrates of the salts and solvates.

Compounds of the formula (I) are also particularly preferred , wherein<dl id="dl0012" compact="compact"><dt>R1 and R2</dt><dd>attached to neighboring phenyl ring atoms and for one group<chemistry id="chem0006" num="0006"><img file="EP1589013A2_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP1589013A2_D0007.tif" /></chemistry> stand,</dd><dt>R3</dt><dd>Means hydrogen,</dd></dl> and<dl id="dl0013" compact="compact"><dt>R4</dt><dd>Means methyl, ethyl or n-propyl, where the alkyl radicals themselves up to twice, independently of one another, by hydroxy, trifluoromethyl, trifluoromethylthio, fluorine, imidazolyl, optionally substituted by methyl thiazolyl, phenyl, which in turn by cyano, nitro, methoxycarbonyl C (O) -O-CH3) or methoxycarbonylmethyl (-CH2-C (O) -O-CH3) is substituted, or amido (-C (O) -NH2) can be substituted,</dd></dl> and their salts, hydrates, hydrates of the salts and solvates.

The compounds of Examples 1, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 18, 19, 22, 24, 26, 28, 29, 30, 31, 33 are also particularly preferred. 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 and their salts, hydrates, hydrates of the salts and solvates .

The general definitions or explanations of residues or explanations listed above or in preferred areas can be combined with one another as desired, that is to say also between the respective areas and preferred areas. They apply accordingly to the end products as well as to the preliminary and intermediate products.

The present invention further relates to a process for the preparation of the compounds of the formula (I), characterized in that Compounds of formula (II)<chemistry id="chem0008" num="0008"><img file="EP1589013A2_D0008.tif" /></chemistry> in which the residues R1, R2 and R3 have the meaning given above, in a solvent, optionally in the presence of a base, with compounds of the formula (III) R4-X (III), in which<dl id="dl0014"><dt>R4</dt><dd>has the meaning given above and</dd><dt>X</dt><dd>represents a leaving group such as halogen, in particular chlorine, bromine or iodine, or mesylate, tosylate, triflate or 1-imidazolyl,</dd></dl> implements.

The method described above can be illustrated using the following formula scheme:<chemistry id="chem0009" num="0009"><img file="EP1589013A2_D0009.tif" /></chemistry>

Suitable solvents for the process according to the invention are all organic solvents which are inert under the reaction conditions. These include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile, pyridine (DMSO), chlorinated hydrocarbons such as dichloromethane, chlorobenzene or dichloroethane. Water is also suitable as a solvent. Dimethylformamide is preferred. It is also possible to use mixtures of the solvents mentioned above.

The usual inorganic or organic bases are suitable as bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide or alkali metal carbonates such as sodium or potassium carbonate or sodium or potassium hydrogen carbonate or sodium or potassium methoxide or sodium or potassium ethoxide or potassium tert-butoxide or amides such as sodium amide, lithium bis ( trimethylsilyl) amide or lithium diisopropylamide or organometallic compounds such as butyllithium or phenyllithium or amines such as triethylamine and pyridine. The alkali carbonates or bicarbonates are preferred, in particular sodium carbonate or sodium bicarbonate.

The base can be used in an amount of 1 to 10 mol, preferably 1 to 5 mol, in particular 1 to 4 mol, based on 1 mol of the compounds of the formula (II).

The reaction generally takes place in a temperature range from -78 ° C to + 120 ° C, preferably in the range from -78 ° C to + 40 ° C, especially at room temperature.

The reaction can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). Generally one works at normal pressure.

Compounds of the formula (III) are commercially available, known to the person skilled in the art or can be prepared by methods customary in the literature.

Compounds of the formula (II) are known to the person skilled in the art or can be prepared by methods customary in the literature. In particular, reference can be made to the following publications, the respective contents of which are included by reference:<ul id="ul0002" list-style="bullet" compact="compact"><li>Dyachenko et al., Russian Journal of Chemistry, vol. 33, no. 7, 1997, pages 1014-1017 and vol. 34, no. 4, 1998, pages 557-563;</li><li>Dyachenko et al., Chemistry of Heterocyclic Compounds, Vol. 34, No. 2, 1998, pages 188-194;</li><li>Qintela et al., European Journal of Medicinal Chemistry, Vol. 33, 1998, pages 887-897;</li><li>Kandeel et al., Zeitschrift für Naturforschung 42b, 107-111 (1987).</li></ul>

Compounds of the formula (II) can also be prepared, for example, from compounds of the formula (IV) by reaction with an alkali metal sulfide.

This production method can be illustrated using the following formula scheme:<chemistry id="chem0010" num="0010"><img file="EP1589013A2_D0010.tif" /></chemistry>

The alkali sulfide used is preferably sodium sulfide in an amount of 1 to 10 mol, preferably 1 to 5 mol, in particular 1 to 4 mol, based on 1 mol of the compounds of the formula (IV).

Suitable solvents are all organic solvents which are inert under the reaction conditions. These include N, N-dimethylformamide, N-methylpyrrolidinone, pyridine and acetonitrile. N, N-Dimethylformamide is preferred. It is also possible to use mixtures of the solvents mentioned above.

The reaction generally takes place in a temperature range from + 20 ° C. to + 150 ° C., preferably in the range from + 20 ° C. to + 120 ° C., in particular at + 60 ° C. to + 100 ° C.

The reaction can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). Generally one works at normal pressure.

Compounds of the formula (IV) are known to the person skilled in the art or can be prepared by customary methods known from the literature. In particular, reference may be made to Kambe et al., Synthesis, 531 (1981), the content of which is incorporated by reference.

Surprisingly, the compounds of formula (I) have an unforeseeable spectrum of pharmacological activity and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.

The compounds of formula (I) are suitable for the prophylaxis and / or treatment of a whole series of diseases, for example in particular diseases of the cardiovascular system (cardiovascular diseases).

For the purposes of the present invention, diseases of the cardiovascular system or cardiovascular diseases are understood to mean, in particular, the following diseases, for example: coronary heart disease, hypertension (high blood pressure), restenosis such as restenosis after balloon dilatation of peripheral blood vessels, arteriosclerosis, tachycardia, arrhythmias, peripheral and cardiac vascular diseases, stable and unstable angina and atrial fibrillation.

The compounds of the formula (I) are also particularly suitable, for example, for reducing the myocardial area affected by an infarction.

The compounds of the formula (I) are furthermore particularly suitable, for example, for the prophylaxis and / or treatment of thromboembolic disorders and ischemia such as myocardial infarction, rash and transient ischemic attacks.

Further areas of indication for which the compounds of the formula (I) are suitable are, for example, in particular the prophylaxis and / or treatment of diseases of the urogenital area, such as irritable bladder, erectile dysfunction and female sexual dysfunction, but also the prophylaxis and / or treatment of inflammatory diseases, such as Asthma and inflammatory dermatoses, from neuroinflammatory diseases of the central nervous system, such as conditions after a cerebral infarction, Alzheimer's disease, and also from neurodegenerative diseases such as Parkinson's disease, as well as from pain and cancer.

Another area of indication is, for example, the prophylaxis and / or treatment of diseases of the respiratory tract such as asthma, chronic bronchitis, pulmonary emphysema, bronchiectasis, cystic fibrosis (cystic fibrosis) and pulmonary hypertension.

Furthermore, the compounds of the formula (I) can also be used, for example, in particular for the prophylaxis and / or treatment of liver fibrosis and cirrhosis.

Finally, the compounds of the formula (I) are also suitable, for example, in particular for the prophylaxis and / or treatment of diabetes, in particular diabetes mellitus.

The present invention also relates to the use of the substances of the formula (I) for the production of medicaments and pharmaceutical compositions for the prophylaxis and / or treatment of the aforementioned clinical pictures.

The present invention further relates to a method for the prophylaxis and / or treatment of the aforementioned clinical pictures with the substances of the formula (I).

The pharmaceutical activity of the aforementioned compounds of formula (I) can be demonstrated by their action as selective ligands on one or more subtypes of the adenosine receptors, in particular as selective ligands on adenosine A1, adenosine A2a and / or adenosine A2b Receptors, preferably as selective ligands on adenosine A1 and / or adenosine A2b receptors.

In the context of the present invention, "selective" means those adenosine receptor ligands in which, on the one hand, a clear effect on one or more adenosine receptor subtypes and, on the other hand, no or a significantly weaker effect on one or more other adenosine receptor ligands. Subtypes can be observed, whereby reference is made to the test methods described in section A. II.

An advantage of the compounds of the formula (I) according to the invention is that they have a more selective action compared to adenosine receptor ligands of the prior art.

In particular, compounds of the formula (I) in which R1 and R2 for a group -O-CH2-O-, -O-CH2-CH2-O- or -O-CH (CH2OH) -CH2-O- are generally agonistic on adenosine A1 receptors.

In particular, compounds of the formula (I) in which R1 and R2 for a group -O-CF2-O-, generally antagonistic to adenosine A1 receptors.

The receptor selectivity can be determined by the biochemical measurement of the intracellular messenger cAMP in the transfected cells which specifically express only a subtype of the adenosine receptors. In the case of A2a or A2b agonists (coupling preferably via GS proteins) an increase in the intracellular cAMP content is observed, in the case of A2a or A2b antagonists a decrease in the intracellular cAMP content after pre-stimulation with adenosine or adenosine-like substances is observed (see publications B. Kull, G. Arslan, C. Nilsson, C. Owman, A. Lorenzen, U. Schwabe, BB Fredholm, "Differences in the order of potency for agonists but not antagonists at human and rat adenosine A2A receptors", Biochem. Pharmacol., 57 (1999) pages 65-75; and SP Alexander, J. Cooper, J. Shine, SJ Hill, "Characterization of the human brain putative A2B adenosine receptor expressed in Chinese hamster ovary (CHO.A2B4) cells", Br. J. Pharmacol., 119 (1996) pages 1286-90, the respective disclosures of which are hereby incorporated by reference). Accordingly, A1 agonists (coupling preferably via Gi proteins) lead to a decrease and A1 antagonists to an increase in the cAMP content.

Thus, compounds of formula (I) which bind selectively to adenosine A1 receptors are preferred, preferably for myocardial protection and for the prophylaxis and / or treatment of tachycardias, atrial arrhythmias, heart failure, heart attack, acute kidney failure, diabetes and Painful conditions.

Compounds of the formula (I) which bind selectively to adenosine A2a receptors are preferably suitable for the prophylaxis and / or treatment of thrombo-embolic diseases, of neurodegenerative diseases such as Parkinson's disease and for wound healing.

Compounds of formula (I) which bind selectively to adenosine A2b receptors are preferably suitable for the prophylaxis and / or therapy of liver tibrosis, heart attack, neuroinflammatory diseases, Alzheimer's disease, urogenital incontinence and respiratory diseases such as asthma and chronic bronchitis.

The present invention furthermore relates to medicaments and pharmaceutical compositions which comprise at least one compound of the formula (I), preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.

For the application of the compounds of the formula (I), all customary application forms come into consideration, that is to say orally, parenterally, by inhalation, nasally, sublingually, rectally, locally, such as, for example, in the case of templates or stents, or externally, such as, for example, transdermally. In parenteral administration, intravenous, intramuscular, subcutaneous administration should be mentioned in particular, for example as a subcutaneous depot. Oral application is particularly preferred.

The active ingredients can be administered alone or in the form of preparations. For oral administration, suitable preparations include tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions. The active ingredient must be present in such an amount that a therapeutic effect is achieved. In general, the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight, ie the active ingredient should be present in amounts which are sufficient to reach the specified dosage level.

For this purpose, the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.

Examples of auxiliaries include: water, non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), Sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).

In the case of oral administration, tablets can also contain generally customary additives such as sodium citrate together with additives such as starch, gelatin and the like. Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.

In general, it has proven to be advantageous, in the case of parenteral administration, to use amounts of about 0.1 to about 10,000 µg / kg, preferably about 1 to about 1,000 µg / kg, in particular about 1 µg / kg to about 100 µg / kg body weight to deliver effective results. In the case of oral administration, the amount is approximately 0.1 to approximately 10 mg / kg, preferably approximately 0.5 to approximately 5 mg / kg, in particular approximately 1 to approximately 4 mg / kg of body weight.

Depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out, it may be necessary to deviate from the amounts mentioned.

The present invention is illustrated by the following examples, which in no way limit the invention.

A. Assessment of physiological effectiveness

Evidence of cardiovascular effects

Langendorff heart of the rat:

After the chest is opened, anesthetized rats have their hearts removed and inserted into a conventional Langendorff apparatus. The coronary arteries are perfused at a constant volume (10 ml / min) and the resulting perfusion pressure is registered via a corresponding pressure sensor. A decrease in perfusion pressure in this arrangement corresponds to a relaxation of the coronary arteries. At the same time, the pressure that is developed by the heart during each contraction is measured via a balloon inserted into the left ventricle and another pressure sensor. The frequency of the isolated beating heart is calculated from the number of contractions per unit of time.

II.

Proof of receptor selectivity

a) Adenosine A1, A2a, A2b and A3 receptor selectivity

Cells of the CHO (Chinese Hamster Ovary) permanent line are stably transfected with the cDNA for the adenosine receptor subtypes A1, A2a, A2b and A3. The binding of the substances to the A2a or A2b receptor subtypes is determined by measuring the intracellular cAMP content in these cells using a conventional radioimmunological assay (cAMP-RIA).

If the substances act as agonists, an expression of the binding of the substances leads to an increase in the intracellular cAMP content. The reference compound used in these experiments is the adenosine-analogous compound NECA (5-N-ethylcarboxamido-adenosine), which does not bind selectively but with high affinity to all adenosine receptor subtypes and has an agonistic effect (Klotz, KN, Hessling, J., Hegler, J., Owman, C., Kull, B., Fredholm, BB, Lohse, MJ, Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells, Naunyn Schmiedebergs Arch Pharmacol, 357 (1998), 1-9).

The adenosine receptors A1 and A3 are coupled to a Gi protein, ie stimulation of these receptors leads to an inhibition of the adenylate cyclase and thus to a lowering of the intracellular cAMP level. Adenylate cyclase is stimulated with forskolin to identify A1 / A3 receptor agonists. However, additional stimulation of the A1 / A3 receptors inhibits adenylate cyclase, so that A1 / A3 receptor agonists can be detected via a comparatively low level of cAMP in the cell.

To demonstrate an antagonistic effect on adenosine receptors, the recombinant cells transfected with the corresponding receptor are pre-stimulated with NECA and the effect of the substances on a reduction in the intracellular cAMP content is investigated by this pre-stimulation. The reference compound used in these experiments is XAC (xanthine amine congener), which does not bind selectively but with high affinity to all adenosine receptor subtypes and has an antagonistic effect (Müller, CE, Stein, B., Adenosine receptor antagonists: structures and potential therapeutic applications, Current Pharmaceutical Design, 2 (1996), 501-530).

b) Adenosine A1, A2a, A2b receptor selectivity

Cells of the permanent line CHO (Chinese Hamster Ovary) are stably transfected with the cDNA for the adenosine receptor subtypes A1, A2a, A2b. The adenosine A1 receptors are via Gi-Proteins and the adenosine A2a and A2b receptors coupled to the adenylate cyclase via Gs proteins. Accordingly, the formation of cAMP in the cell is inhibited or stimulated. The expression of the luciferase is then modulated via a cAMP-dependent promoter. The Luciferase test is optimized with the aim of high sensitivity and reproducibility, low variance and good suitability for execution on a robot system by varying several test parameters, such as Cell density, duration of the cultivation phase and test incubation, forskolin concentration, medium composition. The following test protocol is used for the pharmacological characterization of the cells and for robot-based substance test screening:

The stock cultures are in DMEM / F12 medium with 10% FCS (fetal calf serum) at 37 ° C under 5% CO2 bred and split 1:10 after every 2-3 days. Test cultures are sown from 1000 to 3000 cells per well in 384-well plates and grown for approx. 48 hours at 37 ° C. The medium is then passed through a physiological saline solution (130 mM NaCl, 5 mM KCI, 2 mM CaCl2, 20mM HEPES, 1mM MgCl2• 6H20.5 mM NaHCO3, pH 7.4). The substances dissolved in DMSO are diluted 3 times 1:10 with this physiological saline solution and pipetted to the test cultures (maximum DMSO final concentration in the test mixture: 0.5%). This gives final substance concentrations of, for example, 5 µM to 5 nM. 10 minutes later, forskolin is added to the A1 cells and then all cultures are incubated for 4 hours at 37 ° C. Then 35 µl solution consisting of 50% lysis reagent (30 mM di-sodium hydrogen phosphate, 10% glycerol, 3% TritonX100, 25 mM TrisHCl, 2 mM dithiotreitol (DTT), pH 7.8) and 50% is added to the test cultures. from luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mM MgSO44, 15 mM DTT, pH 7.8), shaken for about 1 minute and the luciferase activity measured with a camera system.

B. embodiments

Used abbreviations:

<dl id="dl0015" compact="compact"><dt>DMSO</dt><dd>Dimethyl sulfoxide</dd><dt>d. Th.</dt><dd>of theory</dd><dt>HPLC</dt><dd>High pressure, high performance liquid chromatography</dd><dt>NMR</dt><dd>Nuclear magnetic resonance spectroscopy</dd><dt>DMF</dt><dd>Dimethylformamide</dd><dt>i. V.</dt><dd>in a vacuum</dd></dl>

example 1

2-Amino-4- (1,3-benzodioxol-5-yl) -6- (2-hydroxyethyl) sulfanyl-3,5-pyridinedicarbonitrile

75 mg (0.19 mmol) 2-amino-4- (1,3-benzodioxol-5-yl) -6-sulfanyl-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7 ), 1014-1017 (1997); 34 (4), 557-563 (1998)] are stirred in 1 ml DMF together with 47 mg (0.38 mmol) 2-bromoethanol and 63 mg (0.75 mmol) sodium hydrogen carbonate overnight at room temperature. Then water is added and the precipitated product is suctioned off and dried in vacuo. Yield: 55 mg (85.8% of theory Th.) Mass spectrum: Molar mass 340 searched for, found [M + H]+= 341 1H-NMR spectrum [DMSO-d6]: δ = 3.4 [2H] tr; 3.65 [2H] q; 5.0 [1H] tr; 6.15 [2H] s; 7.0 - 7.2 [3H] m; 7.8 - 8.2 [2H] s wide.

Example 2

2-Amino-4- (1,3-benzodioxol-5-yl) -6- (benzylsulfanyl) -3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 1. Yield: 74 mg (100% of theory) Mass spectrum: searched molar mass 386, found [M + H]+= 387 1H-NMR spectrum [DMSO-d6]: δ = 4.5 [2H] s; 6.15 [2H] s; 7.0 - 7.2 [3H] m; 7.3 - 7.6 [5H] m; 7.8 - 8.2 [2H] s wide.

Example 3

2-Amino-4- (2,2-difluoro-1,3-benzodioxol-5-yl) -6 - [(2-pyridinylmethyl) sulfanyl] -3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 1. Yield: 50 mg (79% of theory) Mass spectrum: Molar mass 423 searched for, found [M + H]+= 424 1H-NMR spectrum [DMSO-d6]: δ = 4.6 [2H] s; 6.8 [1H] m; 6.95 [1H] dd; 7.6 - 7.8 [4H] m; 7.9 - 8.4 [2H] s wide; 8.55 [1H] d.

Example 4

2-Amino-6- (benzylsulfanyl) -4- (2,3-dihydro-1,4-benzodioxin-6-yl) -3,5-pyridine-dicarbonitrile

100 mg (0.32 mmol) 2-amino-6-sulfanyl-4- (2,3-dihydro-1,4-benzodioxin-6-yl) -3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014-1017 (1997); 34 (4), 557-563 (1998)] are stirred in 2 ml DMF together with 110 mg (0.64 mmol) benzyl bromide and 108 mg (1.29 mmol) sodium hydrogen carbonate for 5.5 h at room temperature. Then water is added and extracted three times with ethyl acetate. The combined organic phases are dried with magnesium sulfate and evaporated in vacuo. The residue is taken up in diethyl ether and, after renewed evaporation, gives crystalline product. Yield: 106 mg (82% of theory) Mass spectrum: Molar mass 400 sought, found [M + H]+= 401 1H-NMR spectrum [DMSO-d6]: δ = 4.3 [4H] m; 4.5 [2H] s; 6.9 - 7.1 [3H] m; 7.2 - 7.4 [3H] m; 7.5 [2H] m; 7.8 - 8.2 [2H] s wide.

Example 5

2-Amino-6 - ((2-hydroxyethyl) sulfanyl) -4- (2,3-dihydro-1,4-benzodioxin-6-yl) -3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 1. Yield: 15 mg (13% of theory) Mass spectrum: searched molecular weight 354, found [M + H]+= 355 1H-NMR spectrum [DMSO-d6]: δ = 3.4 [2H] tr; 3.65 [2H] q; 4.3 [4H] s; 5.0 [1H] tr; 7.0 - 7.1 [3H] m; 7.8 - 8.1 [2H] s wide.

Example 6

2-Amino-6 - [(2-hydroxyethyl) sulfanyl] -4- [2- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxin-6-yl] -3,5-pyridinedicarbonitrile

30th mg (0.09 mmol) 2-amino-6-sulfanyl-4- [2- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxin-6-yl] -3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014-1017 (1997); 34 (4), 557-563 (1998)] are stirred in 1.5 ml DMF together with 22 mg (0.18 mmol) 2-hydroxyethyl bromide and 29 mg (0.35 mmol) sodium hydrogen carbonate overnight at room temperature. The reaction solution is purified directly by preparative HPLC on reversed phase silica gel. Yield: 2.1 mg (6% of theory) Mass spectrum: searched molecular weight 384, found [M + H]+ = 385 1H-NMR spectrum [DMSO-d6]: δ = 3.3 [2H] tr; 3.65 [4H] m; 4.05 [1H] dd; 4.3 [1H] m; 4.4 [1H] dd; 5.0 [1H] tr; 5.15 [1H] trm; 7.0 - 7.1 [3H] m; 7.8 - 8.1 [2H] s wide.

Example 7

2-Amino-6- [benzylsulfanyl] -4- [2- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxin-6-yl] -3,5-pyridinedicarbonitrile

The reaction was carried out analogously to Example 6. Yield: 4.6 mg (12% of theory) Mass spectrum: Molar mass 430 sought, found [M + H]+= 431 1H-NMR spectrum [DMSO-d6]: δ = 3.7 [2H] m; 4.05 [1H] dd; 4.3 [1H] m; 4.4 [1H] dd; 4.5 [2H] s; 5.1 [1H] tr; 7.0 - 7.1 [3H] m; 7.2-7.6 [5H] m; 7.8 - 8.1 [2H] s wide.

The compounds listed in the following table (Examples 8 to 54) are prepared analogously. The identity of the compounds is verified by LC-MS.<tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="4" colsep="1" rowsep="1"><colspec colnum="1" colname="col1" colwidth="39.37mm" /><colspec colnum="2" colname="col2" colwidth="39.37mm" /><colspec colnum="3" colname="col3" colwidth="39.37mm" /><colspec colnum="4" colname="col4" colwidth="39.37mm" /><thead valign="top"><row><entry namest="col1" nameend="col1" align="center">Example No.</entry><entry namest="col2" nameend="col2" align="center">structure</entry><entry namest="col3" nameend="col3" align="center">searched molecular weight</entry><entry namest="col4" nameend="col4" align="center">found [M + H] +</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="center">8</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">411</entry><entry namest="col4" nameend="col4" align="center">412</entry></row><row><entry namest="col1" nameend="col1" align="center">9</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">397</entry><entry namest="col4" nameend="col4" align="center">398</entry></row><row><entry namest="col1" nameend="col1" align="center">10</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">431</entry><entry namest="col4" nameend="col4" align="center">432</entry></row><row><entry namest="col1" nameend="col1" align="center">11</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">376</entry><entry namest="col4" nameend="col4" align="center">377</entry></row><row><entry namest="col1" nameend="col1" align="center">12</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">368</entry><entry namest="col4" nameend="col4" align="center">369</entry></row><row><entry namest="col1" nameend="col1" align="center">13</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">390</entry><entry namest="col4" nameend="col4" align="center">391</entry></row><row><entry namest="col1" nameend="col1" align="center">14</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">376</entry><entry namest="col4" nameend="col4" align="center">377</entry></row><row><entry namest="col1" nameend="col1" align="center">15</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">387</entry><entry namest="col4" nameend="col4" align="center">388</entry></row><row><entry namest="col1" nameend="col1" align="center">16</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">367</entry><entry namest="col4" nameend="col4" align="center">368</entry></row><row><entry namest="col1" nameend="col1" align="center">17</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">387</entry><entry namest="col4" nameend="col4" align="center">388</entry></row><row><entry namest="col1" nameend="col1" align="center">18</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">424</entry><entry namest="col4" nameend="col4" align="center">425</entry></row><row><entry namest="col1" nameend="col1" align="center">19</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">422</entry><entry namest="col4" nameend="col4" align="center">423</entry></row><row><entry namest="col1" nameend="col1" align="center">20</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">401</entry><entry namest="col4" nameend="col4" align="center">402</entry></row><row><entry namest="col1" nameend="col1" align="center">21</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">354</entry><entry namest="col4" nameend="col4" align="center">355</entry></row><row><entry namest="col1" nameend="col1" align="center">22</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">354</entry><entry namest="col4" nameend="col4" align="center">355</entry></row><row><entry namest="col1" nameend="col1" align="center">23</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">336</entry><entry namest="col4" nameend="col4" align="center">337</entry></row><row><entry namest="col1" nameend="col1" align="center">24</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">342</entry><entry namest="col4" nameend="col4" align="center">343</entry></row><row><entry namest="col1" nameend="col1" align="center">25</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">387</entry><entry namest="col4" nameend="col4" align="center">388</entry></row><row><entry namest="col1" nameend="col1" align="center">26</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">411</entry><entry namest="col4" nameend="col4" align="center">412</entry></row><row><entry namest="col1" nameend="col1" align="center">27</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">404</entry><entry namest="col4" nameend="col4" align="center">405</entry></row><row><entry namest="col1" nameend="col1" align="center">28</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">458</entry><entry namest="col4" nameend="col4" align="center">459</entry></row><row><entry namest="col1" nameend="col1" align="center">29</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">356</entry><entry namest="col4" nameend="col4" align="center">357</entry></row><row><entry namest="col1" nameend="col1" align="center">30</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">431</entry><entry namest="col4" nameend="col4" align="center">432</entry></row><row><entry namest="col1" nameend="col1" align="center">31</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">367</entry><entry namest="col4" nameend="col4" align="center">368</entry></row><row><entry namest="col1" nameend="col1" align="center">32</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">324</entry><entry namest="col4" nameend="col4" align="center">325</entry></row><row><entry namest="col1" nameend="col1" align="center">33</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">353</entry><entry namest="col4" nameend="col4" align="center">354</entry></row><row><entry namest="col1" nameend="col1" align="center">34</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">392</entry><entry namest="col4" nameend="col4" align="center">393</entry></row><row><entry namest="col1" nameend="col1" align="center">35</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">368</entry><entry namest="col4" nameend="col4" align="center">369</entry></row><row><entry namest="col1" nameend="col1" align="center">36</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">385</entry><entry namest="col4" nameend="col4" align="center">386</entry></row><row><entry namest="col1" nameend="col1" align="center">37</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">376</entry><entry namest="col4" nameend="col4" align="center">377</entry></row><row><entry namest="col1" nameend="col1" align="center">38</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">384</entry><entry namest="col4" nameend="col4" align="center">385</entry></row><row><entry namest="col1" nameend="col1" align="center">39</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">336</entry><entry namest="col4" nameend="col4" align="center">337</entry></row><row><entry namest="col1" nameend="col1" align="center">40</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">340</entry><entry namest="col4" nameend="col4" align="center">341</entry></row><row><entry namest="col1" nameend="col1" align="center">41</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">398</entry><entry namest="col4" nameend="col4" align="center">399</entry></row><row><entry namest="col1" nameend="col1" align="center">42</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">412</entry><entry namest="col4" nameend="col4" align="center">413</entry></row><row><entry namest="col1" nameend="col1" align="center">43</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">412</entry><entry namest="col4" nameend="col4" align="center">413</entry></row><row><entry namest="col1" nameend="col1" align="center">44</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">390</entry><entry namest="col4" nameend="col4" align="center">391</entry></row><row><entry namest="col1" nameend="col1" align="center">45</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">390</entry><entry namest="col4" nameend="col4" align="center">391</entry></row><row><entry namest="col1" nameend="col1" align="center">46</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">386</entry><entry namest="col4" nameend="col4" align="center">387</entry></row><row><entry namest="col1" nameend="col1" align="center">47</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">422</entry><entry namest="col4" nameend="col4" align="center">423</entry></row><row><entry namest="col1" nameend="col1" align="center">48</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">429</entry><entry namest="col4" nameend="col4" align="center">430</entry></row><row><entry namest="col1" nameend="col1" align="center">49</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">449</entry><entry namest="col4" nameend="col4" align="center">450</entry></row><row><entry namest="col1" nameend="col1" align="center">50</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">429</entry><entry namest="col4" nameend="col4" align="center">430</entry></row><row><entry namest="col1" nameend="col1" align="center">51</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">405</entry><entry namest="col4" nameend="col4" align="center">406</entry></row><row><entry namest="col1" nameend="col1" align="center">52</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">382</entry><entry namest="col4" nameend="col4" align="center">383</entry></row><row><entry namest="col1" nameend="col1" align="center">53</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">382</entry><entry namest="col4" nameend="col4" align="center">383</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="center">54</entry><entry namest="col2" nameend="col2" /><entry namest="col3" nameend="col3" align="center">415</entry><entry namest="col4" nameend="col4" align="center">416</entry></row></tbody></tgroup></table></tables>

Every citation, both ways

Citations
Document	Relation	Office	Cited during
WO0125210A2	Cites	World Intellectual Property Organization (WIPO)	Search report
WO0162233A2	Cites	World Intellectual Property Organization (WIPO)	Search report
WO0206237A1	Cites	World Intellectual Property Organization (WIPO)	Search report
EP0285267A2	Cites	European Patent Office (EPO)	Search report
EP0908458A1	Cites	European Patent Office (EPO)	Search report
WO9412493A1	Cites	World Intellectual Property Organization (WIPO)	Search report
WO9916766A1	Cites	World Intellectual Property Organization (WIPO)	Search report

13 members in 6 offices

This recordMember, by publication datePriority claim

Priority claims9

Priority claims
Document	Office	Kind	Date
10115922	Germany	A	2001-03-30
10115922	Germany	A	2001-03-30
10115922	Germany	–	2001-03-30
02732498	European Patent Office (EPO)	A	2002-03-19
02732498	European Patent Office (EPO)	A	2002-03-19
02732498	–	–	–
10115922	–	–	–
DE2001115922	–	–	–
EP20020732498	–	–	–

Members13

Family members, oldest first
Document	Office	Kind
CA2442256A1	Canada	A1	2002-10-10
DE10115922A1	Germany	A1	2002-10-10
WO02079195A1	World Intellectual Property Organization (WIPO)	A1	2002-10-10
EP1377569A1	European Patent Office (EPO)	A1	2004-01-07
US2004102626A1	United States of America	A1	2004-05-27
JP2004523592A	Japan	A	2004-08-05
EP1589013A2This record	European Patent Office (EPO)	A2	2005-10-26
EP1377569B1	European Patent Office (EPO)	B1	2005-11-02
EP1589013A3	European Patent Office (EPO)	A3	2005-11-09
DE50204779D1	Germany	D1	2005-12-08
US7078417B2	United States of America	B2	2006-07-18
JP4460835B2	Japan	B2	2010-05-12
CA2442256C	Canada	C	2010-06-15

12 legal events, as the office reported them to INPADOC

Over the term

Point at a mark for the event

Events

Legal events, newest first
	Event	Code
2012-03-28	Application deemed to be withdrawnWithdrawn18D	18D
2012-02-24	Information on the status of an ep patent application or granted ep patentGrantedSTATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWNSTAA	STAA
2011-08-24	Party data changed (applicant data changed or rights of an application transferred)RAP1	RAP1
2009-09-16	Party data changed (applicant data changed or rights of an application transferred)RAP1	RAP1
2009-09-09	Party data changed (applicant data changed or rights of an application transferred)RAP1	RAP1
2006-07-12	Designation fees paidAKX	AKX
2006-06-21	Request for examination filed17P	17P
2005-11-09	Designated contracting statesAK	AK
2005-10-26	Divisional application: reference to earlier applicationAC	AC
2005-10-26	Designated contracting statesAK	AK
2005-09-23	Search report despatchedORIGINAL CODE: 0009013PUAL	PUAL
2005-09-09	Public reference made under article 153(3) epc to a published international application that has entered the european phaseORIGINAL CODE: 0009012PUAI	PUAI