EP1608659A1

EP1608659A1 - Benzofuro-1,4-diazepin-2-one derivatives

Info

Publication number: EP1608659A1
Application number: EP04719947A
Authority: EP
Inventors: Rüdiger Fischer; Bernd Kalthof; Rudi Grützmann; Elisabeth Woltering; Beatrix Stelte-Ludwig; Martina Wuttke; Pablo Jesus Hernandez Blasco; Carmelo Pina Gadea
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2003-03-24
Filing date: 2004-03-12
Publication date: 2005-12-28
Also published as: DE10312969A1; WO2004085440A1; CA2519987A1; JP2006521308A

Abstract

The invention relates to novel benzofuro-1,4-diazepin-2-one derivatives, to a method for producing said derivatives and to their use as P2X4 receptor antagonists for producing medicaments for the treatment and/or prophylaxis of diseases, in particular arteriosclerosis, restenosis and other inflammatory diseases.

Description

Benzofuro-l, 4-diazepin-2-one derivatives

The present invention relates to new benzofuro-l, 4-diazepin-2-one derivatives, ₃ processes for their preparation and their use as P2X receptor antagonists for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular arteriosclerosis, restenosis and other inflammatory diseases.

Atherosclerosis is a multifactorial disease that affects many different factors. Inflammatory processes play a central role here, in which inflammation-inducing cytokines such as CD40L and IFNγ are involved [P. Libby, Nature 420 (6917): 868-74 (2002)]. The purinergic receptor P2X ₄ belongs to the P2X family. So far, six different P2X receptors have been described in humans. These are calcium-permeable channels that can be activated by ATP [F. Virgilio et al., Blood 91 (3): 587-600 (2001); RA North, A. Surprenant, Annu. Rev. Pharmacol. Toxicol. 40: 563-80 (2000)]. It could be shown that the P2X channel is highly expressed in highly vascularized organs and vessels [K. Yamamoto et al., Circ. Res. 87 (5): 385-91 (2000)]. Surprisingly, the P2X ₄ receptor is also expressed on human monocytes. When human monocytes were incubated with CD40L and IFNγ, a five-fold increase in P2X expression was observed. Also in the vascular wall of the rabbit aorta after damage by balloon angioplasty and cholesterol feeding [TJ. Pulvirenti et al., J. Neurocytol. 29 (9): 623-31 (2000)] and in the arteriosclerotically altered vascular sections of the apoE knockout mouse, a high expression of the P2X receptor was found. Since activated monocytes play a key role in the early stage of atherogenesis and restenosis and the activation of the monocytes by the cytokines mentioned, inhibition of activation leads to a reduction in atherogenesis [P. Libby, Nature 420 (6917): 868-74 (2002)]. Since the activation of monocytes by CD40L and IFNγ is apparently associated with an increase in P2X4 receptor expression and the associated increased calcium influx, blocking the P2X ₄ receptors should reduce the inflammatory processes [F. Di Virgilio, A. Solini, Br. J. Pharmacol. 135 (4): 831-42 (2002)]. Thus, diseases in which inflammatory processes play a role could be treated by blocking the P2X receptors.

In addition to the indications atherosclerosis and restenosis and their complications (stroke, angina pectoris, heart attack, kidney failure, circulatory disorders of the limbs), other inflammatory diseases such as psoriasis and rheumatoid arthritis could also become accessible via the mechanism of treatment mentioned. The synthesis of some benzofuro [3,2-e] -1,4-diazepin-2-one derivatives is described in J. Heterocyclic Chem. 16, 189-90 (1979) and ibid. 20, 1251-1254 (1983). Benzofuro-1,4-diazepine derivatives with anti-ulcer activity are disclosed in EP 350 131-A.

The present invention relates to compounds of the general formula (I)

in which

R ¹ halogen

and

R ^{2 is} hydrogen, halogen, nitro, cyano or a group of the formula -C (0) -OR, -C (O) - NR ⁴ R ⁵ , -S0 ₂ -OR ³ or -S0 ₂ -NR ⁴ R ⁵ , wherein

R, R and R independently of one another represent hydrogen or (CC _δ ^ alkyl,

or

R ^{1 is} hydrogen

and

R ^ halogen, nitro, cyano or a group of the formula -C (0) -OR ^J , -C (0) -NR 4 ⁴ τR> 5 ^D , -S0 ₂ -OR or -S0 ₂ -NR ⁴ R ⁵ , wherein

R, R and R independently of one another represent hydrogen or (C _r C6) -alkyl,

means.

The compounds of the invention may also be in the form of their salts, solvates and solvates of their salts. In the context of the present invention, the substituents generally have the following meaning:

In the context of the invention, (-C-Cfi) -alkyl and (C _r C) -alkyl stand for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methyl, ethyl, n-propyl, isopropyl and tert-butyl.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or bromine are preferred.

Depending on the substitution pattern, the compounds according to the invention 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.

Furthermore, certain compounds can exist in tautomeric forms. This is known to those skilled in the art and such compounds are also within the scope of the invention.

The compounds according to the invention can also be present as salts. In the context of the invention, physiologically acceptable salts are preferred.

Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid are preferred , Toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as metal or ammonium salts. Preferred examples are alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example magnesium or calcium salts), and also ammonium salts which are derived from ammonia or organic amines, for example ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, di - or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, N-methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds according to the invention and their salts can also be present in the form of their solvates, in particular in the form of their hydrates.

Compounds of the general formula (I) in which

R ¹ chlorine or bromine

and

R ^{2 is} hydrogen, chlorine, bromine, nitro, cyano or a group of the formula -C (0) -OR ³ or -C (0) -NR ⁴ R ⁵ , wherein

R ³ , R ⁴ and R ⁵ independently of one another represent hydrogen or (-CC ₄ ) -alkyl,

or

R ^{1 is} hydrogen

and

R ^{2 is} chlorine, bromine, nitro, cyano or a group of the formula -C (0) -OR ³ or -C (0) -NR ⁴ R ⁵ , wherein

R ³ , R ⁴ and R ⁵ independently of one another represent hydrogen or (-CC) alkyl,

means.

Compounds of the general formula (Ia) are particularly preferred

in which R ¹ chlorine or bromine

and

R is hydrogen, chlorine, bromine, nitro or cyano,

or

R ^{1 is} hydrogen

and

R chlorine, bromine, nitro or cyano

means.

In addition, a process for the preparation of the compounds according to the invention was found, characterized in that compounds of the formula (II)

in which R ^{1 has} the meanings given above,

in an inert solvent in the presence of a base with a compound of formula (III)

in which R ^{2 has} the meanings given above and

X ^{1 represents} a suitable leaving group such as chlorine, bromine or iodine,

first to compounds of formula (IV)

in which R ¹ and R ^{2 have} the meanings given above,

reacted, then with intermediate isolation or in a one-pot reaction in the presence of a base to give compounds of the formula (V)

in which R and R have the meanings given above,

cyclized, then in an inert solvent in the presence of a base with a compound of formula (VI)

in which

X ² and X ^{3 are the} same or different and represent a suitable leaving group such as chlorine, bromine or iodine,

in compounds of the formula (VTi)

in which R ¹ , R ² and X ^{3 have} the meanings given above,

transferred, finally reacted with ammonia with cyclization in an inert solvent and the resulting compounds of the formula (I), if appropriate with the appropriate solvents and / or bases or acids, are converted into their solvates, salts and / or solvates of the salts.

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for process step (II) + (HI) -> (IV). These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, toluene, xylolane, hydrocarbons such as benzene, xylolane, hexanol, toluene, xylolane, hexanol, tolene, xanol, hexanol, tolene, xylolohexanol, tolene, xololane, hexanol, toluene, xylolane, hexanol, tolene, xanol, hexanol, tolene, xanol, hexanol, tolene, xylol, hexanol, tolene, xylol, hexanol, tolene, xanol, hexanol, tolene, xanol, hexanol, tolene, xanol, hexanol, tolene, xanol, hexanol, toluene, xylol, hexanol, tolene, xylol, hexanol such as, Esters such as ethyl acetate, ketones such as acetone or 2-butanone, heteroaromatics such as pyridine, amides such as dimethylformamide, dialkyl sulfoxides such as dimethyl sulfoxide, or nitriles such as acetonitrile. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide is preferred.

The usual inorganic or organic bases are suitable as bases for process step (II) + (HI) -> • (IV). These preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydrides such as sodium hydride, amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, 4-NN-dimethylaminopyridine, 4-pyrrolidinopyridine , Triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBΝ) or 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU). Triethylamine is particularly preferred.

The base is used here in an amount of 1 to 5 mol, preferably in an amount of 1 to 2 mol, based on 1 mol of the compound of the formula (II).

The reaction generally takes place in a temperature range from 0 ° C. to + 150 ° C., preferably in a temperature range from + 20 ° C. to + 100 ° C. The implementation can with normal, increased or be carried out at reduced pressure (for example from 0.5 to 5 bar). Generally one works at normal pressure.

Inert organic solvents which do not change under the reaction conditions are likewise suitable as solvents for process step (TV) - (V). These include halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofoftirane, glycol dimethyl ether or dietliylene glycol dimethyl ether, alcohols such as methanol, ethanol, isopropanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, ethanol, methanol, ethanol n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, ketones such as acetone or 2-butanone, heteroaromatics such as pyridine, amides such as dimethylformamide, dialkyl sulfoxides such as dimethyl sulfoxide, or nitriles such as acetonitrile. It is also possible to use mixtures of the solvents mentioned. Methanol and ethanol are preferred.

The usual inorganic or organic bases are suitable as base for process step (IN) - »(V). These preferably include alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, alkali hydroxides such as lithium, sodium or potassium hydroxide, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, alkali hydrides such as sodium hydride , Amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, 4-N, N-dimethylamino-pyridine, 4-pyrrölidinopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, l, 5- Diazabicyclo [4.3.0] non-5-ene (DBΝ) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Sodium methoxide and sodium ethoxide are particularly preferred.

The base is used in an amount of 0.5 to 5 mol, preferably in an amount of 1 to 2 mol, based on 1 mol of the compound of the formula (TV).

The reaction generally takes place in a temperature range from 0 ° C. to + 120 ° C., preferably in a temperature range from + 20 ° C. to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Suitable solvents for process step (V) + (VI) -> (VII) are all inert solvents which do not change under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xololane, hydrocarbons such as benzene, xolohexane, hydrocarbons such as benzene, xolohexanol, hexanol, tolene, xololane, hydrocarbons, such as benzene, xololane, hexanol, tolene, xololane, hydrocarbons, such as benzene, xol, hexanol, benzene, xol, hexanol, toluene, xol, hexanol, benzene, xol, hexanol, benzene, xol, hexanol, benzene, xol, hexanol, toluene, xol, hexanol, toluene, xol, hexanol, benzene, xol, hexanol, benzene, toluene, X, benzene, xylene, Esters such as ethyl acetate, ketones such as acetone or 2-butanone, amides such as dimethylformamide, dialkyl sulfoxides such as dimethyl sulfoxide, or nitriles such as acetonitrile. It is also possible to use mixtures of the solvents mentioned. Dichloromethane and trichloromethane are preferred.

Suitable bases for process step (V) + ^" (VI) -> (VII) are the customary inorganic or organic bases. These preferably include alkali or alkaline earth metal carbonates and hydrogen carbonates such as sodium, potassium or calcium carbonate and sodium carbonate. or potassium hydrogen carbonate, alkali hydrides such as sodium hydride, amides such as lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as pyridine, 4-N, N-dimethylaminopyridine, 4-pyrrolidinopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, N-methylpiperidine , l, 5-diazabicyclo [4.3.0] non-5-ene (DBΝ) or l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), particularly preferred is sodium hydrogen carbonate.

The base is used in an amount of 1 to 10 mol, preferably in an amount of 1 to 5 mol, based on 1 mol of the compound of the formula (V).

The reaction generally takes place in a temperature range from -20 ° C to + 50 ° C, preferably in a temperature range from -20 ° C to + 20 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Suitable solvents for process step (VII) → (I) are all inert solvents which do not change under the reaction conditions. These include halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Dioxane is preferred.

The compounds of the formulas (II), (1LT) and (VI) are commercially available, known from the literature or can be prepared by methods customary in the literature [cf. e.g. J. Med. Chem. 13, 674-680 (1970)].

The process according to the invention can be illustrated by the following formula: scheme

NaHCO,

The compounds according to the invention have an unforeseeable, valuable pharmacological spectrum of activity and are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds according to the invention act as antagonists of the P2X receptor.

Because of their pharmacological properties, the compounds according to the invention can be used alone or in combination with other medicaments for the treatment and / or prophylaxis of inflammatory diseases. In particular, they are suitable for the treatment of chronic inflammatory diseases of the vascular intima such as arteriosclerosis and restenosis, inflammatory diseases of the central nervous system such as multiple sclerosis and pain, inflammatory diseases of the connective tissue such as rheumatoid arthritis, chronic polyarthritis, panniculitis and tendinitis, and disease Bechterew, from inflammatory skin diseases such as psoriasis, psoriasis and neurodermatitis, from chronic inflammatory bowel diseases such as enteritis, enterocolitis, Crohn's disease and ulcerative colitis, from inflammatory diseases of the small airways and from myositis and endocarditis.

The compounds of the invention can be used alone or in combination with others if necessary

Active substances preferably from the group of CETP inhibitors, antidiabetics, antioxidants, thyroid hormones and / or thyroid mimetics, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase gene expression, squalene synthase inhibitors, ACAT inhibitors, Cholesterol absorption inhibitors, fibrates, MTP inhibitors, trigyceride depressants, nicotinic acid and derivatives, antiplatelet agents, anticoagulants, calcium antagonists, ACE inhibitors, angiotensin II receptor antagonists, beta-blockers and steroidal and non-steroidal drugs are administered.

The effectiveness of the compounds according to the invention can be checked, for example, by the tests described in the example section.

The present invention further relates to medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent. Oral application is preferred.

The active substances can be administered in suitable administration forms for these administration routes. For oral administration, state-of-the-art functional, fast and / or modified application forms that deliver the active ingredient are suitable, e.g. Tablets (non-coated and coated tablets, e.g. with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions. The parenteral application can be bypassing a resorption step (e.g. intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous or intraperitoneal). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, e.g. L inhalation drug forms (including powder inhalers, nebulizers), nasal drops / solutions, sprays, lingual, sublingual or buccal tablets or capsules to be applied, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions , Ointments, creams, milk, pastes, powder, implants or stents.

The active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients. These include carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinylpyrrolidone), synthetic and / or natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) or flavorings and / or odors.

In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 0.005 to 3 mg kg, of body weight in order to achieve effective results in the case of parenteral administration. When administered orally, the amount is about 0.001 to 100 mg kg, preferably about 0.005 to 30 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, 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. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume.

The following exemplary embodiments explain the invention. The invention is not limited to the examples.

Abbreviations:

1CI chemical ionization (for MS)

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DMF NN-dimethylformamide

DMSO dimethyl sulfoxide the theory (with yield)

ESI electrospray ionization (for MS)

LC / MS liquid chromatography-coupled mass spectroscopy

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

R _f retention index (at DC)

Rt retention time (for LC / MS)

LC / MS methods:

Method 1:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Uptisphere C 18, 50 mm x 2.0 mm, 3.0 μm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min - »4.5 min 0.75 ml / min → 5.5 min 1.25 ml / min; UV detection: 210 nm.

Method 2:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-SIL 120 ODS-4 HE, 50 mm x 2.0 mm, 3 μm; Eluent A: 1 1 water + 1 ml 50% formic acid, eluent B: 1 1 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A - »0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 µm, A. Output connections:

Example I

(3-aminobenzofuran-2-yl) - (3-bromophenyl) -methanone

2.00 g (16.8 mmol) of 2-hydroxybenzonitrile, 4.67 g (16.8 mmol) of 3-bromophenacyl bromide and 1.87 g (18.5 mmol) of triethylamine in 20 ml of dimethylformamide are stirred at 70 ° C. for 2 h. After adding 100 ml of ethyl acetate, the reaction mixture is washed with water (3 x 100 ml) and saturated sodium chloride solution (2 x 100 ml). The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in 30 ml of ethanol. After adding 5.98 g (18.5 mmol) of sodium ethanolate, the mixture is heated under reflux for 2 h. 50 ml of ethyl acetate are added and the mixture is washed with water (3 x 100 ml) and saturated sodium chloride solution (2 x 100 ml). The organic phase is dried over magnesium sulfate. After removal of the solvent under reduced pressure, 5.08 g (92% of theory) of the desired product are obtained.

MS (DCI): m / z = 315.9 [M + H] ⁺

^! H-NMR (200 MHz, DMSO-d ₆ ): δ = 7.27-7.36 (m, 1H); 7.49-7.65 (m, 5H); 7.77-7.84 (m, 1H); 8.04-8.20 (m, 3H).

Example II

2-bromo-N- {2 - [(3-bromophenyl) carbonyl] benzofuran-3-yl} acetamide

3.53 g (17.5 mmol) of bromoacetyl bromide are added at 0 ° C. to a mixture of 5.03 g (15.9 mmol) of the compound from Example I and 5.35 g (63.6 mmol) of sodium hydrogen carbonate in 250 ml of chloroform. The mixture is stirred at 0 ° C for 1 h. After removing the solvent under reduced pressure, 200 ml of ethyl acetate is added, and the mixture is washed with saturated sodium hydrogen carbonate solution (100 ml) and saturated sodium chloride solution (100 ml). The organic phase is dried over magnesium sulfate. After removal of the solvent under reduced pressure, 5.81 g (83% of theory) of the desired product are obtained.

MS (CI): m / z = 436 [M + H] ⁴

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 4.20 (s, 2H); 7.37-8.14 (m, 8H); 10.98 (s, 1H).

B. Examples:

example 1

5- (3-bromophenyl) -l, 3-dihydro-2H-benzofuro [3,2-e] -l, 4-diazepin-2-on

245 ml (123 mmol) of a 0.5 M solution of ammonia in dioxane are added to 5.37 g (12.3 mmol) of the compound from Example II in 100 ml of diethyl ether. The mixture is stirred for 2 days at room temperature. 100 ml of ethyl acetate are added and the mixture is washed with water (3 x 250 ml) and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. 1.81 g (42% of theory) of the desired product are obtained.

R _f = 0.24 (dichloromethane / methanol 100: 2)

MS (ESI): m / z = 355 [M + Ηf

LC / MS (method 1): R _t = 3.47 min., M / z = 354 [M] ⁺

Η NMR (200 MΗz, DMSO-d ₆ ): δ = 4.45 (s, 2Η); 7.37-7.80 (m, 6H); 7.88-7.93 (m, 1H); 7.96-8.03 (m, 1H); 11.59 (s, 1H).

The following are obtained in an analogous manner: Example 2

l, 3-dihydro-5- (3-nitrophenyl) -2H-benzofuro [3,2-e] -l, 4-diazepin-2-one

LC / MS (method 2): R _t = 3.5 min., M / z = 321 [M + Η] ⁴

Example 3

9-bromo-l, 3-dihydro-5-phenyl-2H-benzofuro [3,2-e] -l, 4-diazepin-2-on

LC / MS (Method 2): R _t = 3.5 min., M / z = 355 [M + Η] ⁺ .

C. Description of the biological tests:

a) Cellular Assav:

The P2X receptor is a ligand-activated ion channel. Binding of the agonist ATP leads to activation of the P2X receptor, opening of the ion channel and influx of extracellular calcium into the cell. This calcium influx is measured using the calcium-sensitive photoprotein aequorin. For this purpose, a recombinant CHO cell line (Chinese hamster ovary cells) with constitutive expression of the human P2X ₄ receptor and of apoaequorin was produced.

To carry out the experiment, the CHO cells are sown 1-2 days beforehand on microtiter plates in 96-, 384- or 1536-well format, depending on the used microtiter plate format with 5000 (96 format), 2000 (384- Format) or 500 (1536 format) cells per well. On the day of the experiment, the cell culture medium is removed and the cells are incubated for 4 hours in physiological saline (Tyrode buffer) with 5 μg / ml coelenterazine. Test substances are added 5 minutes before the actual experiment. To activate the P2X receptor, ATP is then added in a concentration of 1-2 μM and the ATP-induced calcium signal is measured in a luminometer as aequorin luminescence.

Substances with antagonistic activity at the P2X receptor can inhibit the ATP-induced calcium signal either by interference with the binding of ATP to the P2X ₄ receptor, by preventing the opening of the channel or by blocking the influx of calcium through the opened channel.

Embodiments 1-3 show ICsn values of 0.5, 2 and 0.6 μM in this test.

b ATP-induced oxygen radical formation (ROS) in primary human monocytes:

The assay is performed in Hank's Balanced Salt Solution (HBSS) to which 10 mM glucose is added. Monocytes are e.g. isolated using the "Becton Dickinson Vacutainer System" as described by the manufacturer and suspended in HBSS. In principle, the detection of oxygen radicals is carried out using the luminol-enhanced chemiluminescence method in the presence of Horse Radish Peroxidase (HRPO) [H. Lundqvist, C. Dahlgren, Free Radic. Biol. Med. 20 (6): 785-92 (1996)].

First the substance to be examined, luminol (50 μM final concentration), HRPO (10 U / ml final concentration) are incubated with 5 × 10 ⁵ monocytes for 15 min at 37 ° C. Then that will

Test batch ATP (100 μM final concentration) added. The final volume in the test batch is 200 ul. Immediately after adding ATP, the ROS formation is monitored with a microplate lumino meter over a period of 120 seconds.

c) ATP-induced chemotaxis of primary human monocytes:

Monocytes are isolated from blood using standard methods. The chemotaxis of the monocytes is observed in a Transwell system [CC Bleul et al., J. Exp. Med. 184: 1101-1109 (1996)]. The membrane used (3 μm pore size, polyethylene terephthalate, Falcon) is first coated with fibronectin. 10 ⁵ monocytes in RPMI 1640 medium are added to the upper chamber. The lower chamber contains varying concentrations of stimulus or constant stimulus concentration (500 μM ATP or 10 nM MCP-1) and varying concentrations of the test substance. The substances to be examined are in both chambers. The test mixture is incubated for 3 h at 37 ° C. and 5% CO ₂ [W. Falk et al., J. Immunol. Methods 38: 239-247 (1980)]. After the incubation, the cells that have migrated to the lower chamber are determined.

D. Working Examples for Pharmaceutical Compositions:

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) and 2 mg magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are dried with the magnesium stearate for 5 min. long mixed. This mixture is compressed with a conventional tablet press (tablet format see above). A pressing force of 15 kN is used as a guideline for the pressing. Oral suspension:

Composition:

1000 of the compound of Example 1, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the Fa. FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stopped for about 6 hours.

Claims

claims:

Compounds of the general formula (I)

in which

R ¹ halogen

and

R ^{2 is} hydrogen, halogen, nitro, cyano or a group of the formula -C (0) -OR,

C (0) -NR ⁴ R ', -S0 ₂ -OR ^J or -S0 ₂ -NR 4 ⁴ τR> 5 ³ , wherein

R> 3, R and R independently of one another represent hydrogen or (-CC ₆ ) -alkyl,

or

R ^{1 is} hydrogen

and

R is halogen, nitro, cyano or a group of the formula -C (0) -OR ^;> , -C (0) -NR 4 ⁴ rR, 5

-S0 ₂ -OR 'or -S0 ₂ -NR ⁴ R ³ , wherein

R, R and R independently of one another represent hydrogen or (-CC ₆ ) -alkyl,

means

and their salts, solvates and solvates of the salts.

Compounds of general Foπnel (I) according to claim 1, in which

R ¹ chlorine or bromine

and R is hydrogen, chlorine, bromine, nitro, cyano or a group of the formula -C (0) -OR or -C (0) -NR ⁴ R ⁵ , in which

R, R and R independently of one another represent hydrogen or (-CC) alkyl,

or

R ^{1 is} hydrogen

and

R ² chlorine, bromine, nitro, cyano or a group of the formula -C (0) -OR or -C (O) -

NR ⁴ R ⁵ , wherein

R, R and R independently of one another represent hydrogen or (C _r C) -alkyl,

means.

Compounds of formula (Ia)

in which

R ¹ chlorine or bromine

and

R is hydrogen, chlorine, bromine, nitro or cyano,

or

R ^{1 is} hydrogen

and

R chlorine, bromine, nitro or cyano means

and their salts, solvates and solvates of the salts.

Process for the preparation of compounds of the formula (I) or (Ia) as defined in claims 1 to 3, characterized in that compounds of the formula (II)

in which R has the meanings given above,

in an inert solvent in the presence of a base with a compound of the formula (TU)

in which R ^{2 has} the meanings given above and

X ^{1 represents} a suitable leaving group such as chlorine, bromine or iodine,

first to compounds of formula (TV)

in which R ¹ and R ^{2 have} the meanings given above,

in which

X and X ^{3 are the} same or different and represent a suitable leaving group such as chlorine, bromine or iodine,

in compounds of formula (VII)

in which R, R and X have the meanings given above,

5. Compounds according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. Use of compounds according to one of claims 1 to 3 for the manufacture of medicaments.

7. Medicament containing at least one of the compounds according to one of claims 1 to 3 in combination with at least one pharmaceutically acceptable, pharmaceutically acceptable carrier or excipient.

8. Use of compounds according to one of claims 1 to 3 for the preparation of a

Medicinal product for the treatment and / or prophylaxis of arteriosclerosis and restenosis.

9. Medicament according to claim 7 for the treatment and / or prophylaxis of arteriosclerosis and restenosis.

10. A method for combating arteriosclerosis and restenosis in humans and animals by administering an effective amount of at least one compound according to one of claims 1 to 3.