EP1807411A1 - Cyanothiophenes, the production thereof and their use as medicaments - Google Patents

Abstract

The invention relates to cyanothiophenes of general formula (I), in which the R's are defined in the claims, and relates to their tautomers, stereoisomers, mixtures and salts that have valuable pharmacological properties, in particular, a glucagon receptor-antagonistic action.

Description

 Cyanothiophenes, their preparation and their use as pharmaceuticals

The present invention relates to substituted cyanothiophenes, their preparation and their use for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors.

Diabetes is a complex disease characterized by hyperglycemia due to lack of insulin production or lack of insulin action. The metabolic complications of diabetes - hyperglycemia and ketosis - are linked to the relative or absolute increase in the ratio of glucagon to insulin. Consequently, glucagon is a hyperglycemic factor that causes the increase in blood sugar.

Therefore, suitable antagonists that block the glucagon receptor are agents for the treatment of diabetes, whereby the production of glucose in the liver is inhibited and the levels of glucose in the patient are reduced.

Several publications disclose peptidic and non-peptidic glucagon receptor antagonists (McCormick et al., Curr. Pharm. Des. 7, 1451 (2001)). In particular, inhibition of glucagon-stimulated glucose production in humans has been reported for Bay 27-9955 (Petersen et al., Diabetologia 44, 2018 (2001)).

The present invention was based on the object to show new non-peptidic agents that are suitable as highly effective glucagon receptor antagonists for the treatment of diabetes.

Cyanothiophenes and their use as glucagon receptor antagonists are already known. For example, US patent applications US 2004/0097552 and US 2004/0097557 describe substituted cyanothiophenes which substituted in the 2-position by an amide, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or heterocyclylamino group.

Furthermore, bicyclic heterocycles having glucagon receptor antagonistic activity are disclosed in international applications WO 2004/024066 and WO 2004/024065.

Surprisingly, it has now been found that 3-cyanothiophenes which carry a halogen atom or a cyano, nitro or alkoxy group in the 4-position and / or are substituted in the 2-position by a bicycloalkylcarbonylamino group are highly effective glucagon receptor antagonists, which are particularly are suitable for the production of medicaments.

The present invention thus relates to the compounds of general formula I.

their tautomers, enantiomers, diastereomers, mixtures thereof and their salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases, which have valuable pharmacological properties, in particular an inhibitory action on glucagon receptors, their use for the treatment and prevention of diseases , in particular diabetes and their production.

In the above formula (I)

R ¹ is a Ci _-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group, where the hydrogen atoms of the amino group can be substituted independently of one another by a C _1-3 -alkyl group or a phenyl or pyridyl group which is optionally substituted by a C _1-3 -alkyl group,

or a phenyl or pyridyl group which _-3 alkyl groups may be substituted in each case by one to three Ci,

R ² is a hydrogen, fluorine, chlorine, bromine or iodine atom or a cyano, nitro, C _{1- 3} -Alykl-, trifluoromethyl or Ci _-4 alkyloxy and

R ^{3 is} a bicyclo [2.2.1] hept-2-enyl group or

a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ -, -CH ₂ -CH ₂ - or -CH = CH- group.

Preference is given to those compounds of the general formula (I) in which

R ¹ is a Ci- ₄ alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

wherein the hydrogen atoms of the amino group may be independently substituted by a Ci _-3 alkyl group or a group optionally substituted by a C ₃ alkyl group, phenyl or pyridyl group,

or a phenyl or pyridyl group which _-3 alkyl groups may be substituted in each case by one to three Ci,

R ² is a fluorine, chlorine, bromine or iodine atom or a cyano, nitro, Ci- ₃ -Alykl-, trifluoromethyl or Ci _-4 alkyloxy and

R ^{3 is} a bicyclo [2.2.1] hept-2-enyl group or a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ -, -CH ₂ -CH ₂ - or -CH = CH group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

Particular preference is given to those compounds of the general formula (I) in which

R ¹ is a Ci _-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

wherein the hydrogen atoms of the amino group may be independently substituted by a Ci- ₃ alkyl group or a group optionally substituted by a C ₃ alkyl group, phenyl or pyridyl group,

or a phenyl or pyridyl group which _-3 alkyl groups may be substituted in each case by one to three Ci,

R ² is a fluorine, chlorine, bromine or iodine atom or a cyano, nitro or Ci _-4 alkyl and oxy group

R ^{3 is} a bicyclo [2.2.1] hept-2-enyl group or

a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ -, -CH ₂ -CH ₂ - or -CH = CH group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts. A second preferred subgroup relates to those compounds of the general formula (I) in which

R ¹ is a Ci- ₄ alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

wherein the hydrogen atoms of the amino group may be independently substituted by a Ci _-3 alkyl group or a group optionally substituted by a Ci- ₃ alkyl group, phenyl or pyridyl group,

or a phenyl or pyridyl group, each of which may be substituted by one to three d _-3 -alkyl groups,

R ² is a hydrogen, fluorine, chlorine, bromine or iodine atom or a cyano, nitro, Ci- ₃ -Alykl-, trifluoromethyl or Ci _-4 alkyloxy and

R ^{3 is} a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ - or -CH ₂ -CH ₂ - group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts,

but especially those compounds of general formula (I) in which

R ¹ is a Ci _-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or lod¬ atom or by an amino group,

wherein the hydrogen atom may be substituted e of the amino group independently of one another by a Ci _-3 alkyl group or a group optionally substituted by a Ci- ₃ alkyl group, phenyl or pyridyl group, or a phenyl or pyridyl group which may each be substituted by one or two C _1-3 -alkyl groups,

R ^{2 is} a fluorine, chlorine, bromine or iodine atom or a cyano, nitro, Ci _-3 -AIyW-, trifluoromethyl or Ci _-4 -Alkyloxygruppe and

R ^{3 is} a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ - or -CH ₂ -CH ₂ - group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

Very particular preference is given to those compounds of the general formula (I) in which

R ^{1 is} a C ₂ -4 -alkyl group which is terminally substituted by an N-phenyl-N-methyl-amino group,

or a phenyl group which may be substituted by one or two methyl groups,

R ^{2 is} a chlorine or bromine atom or a cyano or nitro group and

R ^{3 is} a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ - or -CH ₂ -CH ₂ - group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

The following compounds of general formula (I) are particularly noteworthy: (a) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-chloro-3-cyano-5- (2,5-dimethyl-phenyl) -thiophene,

(b) 2 - [(2R) -bicyclo [2.2.2] oct-2-ylcarbonylamino] -4-chloro-3-cyano-5- (2,5-dimethyl-phenyl) -thiophene,

(c) 4-chloro-3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene,

(d) 4-bromo-3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene,

(e) 3,4-dicyano-2- (cyclohexylcarbonylamino) -5-phenyl-thiophene,

(f) 3-cyano-2- (cyclohexylcarbonylamino) -4-nitro-5-phenyl-thiophene,

(g) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-bromo-3-cyano-5- (2,5-dimethyl-phenyl) -thiophene,

(h) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-bromo-3-cyano-5- {3- [methyl- (4-methylphenyl) - amino] -propyl} -thiophene and

(i) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -3,4-dicyano-5- {3- [methyl- (4-methylphenyl) -amino] thiophene propyl}

and their salts.

According to the invention, the compounds of general formula I are obtained by processes known per se, for example by the following processes:

a) reaction of a compound of the general formula

in which R ¹ and R ² are defined as mentioned above,

with an acid chloride of the general formula

R ³ -COCl (III),

in which R ³ is defined as mentioned above.

The reaction is expediently in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane optionally in the presence of an inorganic or organic base such as pyridine or 4-dimethylamino-pyridine at temperatures between -20 and 200 ⁰ C, but preferably at temperatures between -10 and 160 ⁰ C performed

b) For the preparation of a compound of the formula (I) in which R ^{2 is} a fluorine, chlorine, bromine or iodine atom or a nitro group: chlorination, bromination, iodination or nitration of a compound of the general formula

in which R ¹ and R ³ are defined as mentioned above.

The chlorination can, for example, with N-chlorosuccinimide in solvents such as glacial acetic acid, carbon tetrachloride or dichloromethane at temperatures between 25 10

and 100 ⁰ C are performed. Alternatively, chlorine, especially in conjunction with Lewis acids such as aluminum chloride, can be used as a reagent.

The bromination can be conveniently carried out with N-bromosuccinimide in solvents such as glacial acetic acid, carbon tetrachloride or dichloromethane at temperatures between 25 and 100 ⁰ C, preferably at 60-75 ⁰ C. Alternatively, bromine, especially in conjunction with Lewis acids such as aluminum chloride, can be used as a reagent.

The iodination can be conveniently carried out with N-iodosuccinimide in solvents such as glacial acetic acid, carbon tetrachloride or dichloromethane at temperatures between 25 and 100 ⁰ C. Alternatively, iodine may also be used as the reagent, especially in conjunction with Lewis acids such as aluminum chloride.

The nitration is conveniently carried out with concentrated nitric acid or nitrating acid in solvents such as acetic acid or acetic anhydride at temperatures between -5 ⁰ C and 40 ⁰ C, preferably at room temperature. Alternatively, nitronium tetrafluoroborate in dichloromethane can also be used.

c) For the preparation of a compound of the formula (I) in which R ^{2 is} a cyano group: reaction of a compound of the general formula

in which R ¹ and R ³ are defined as mentioned above, with cyanide. 11

The reaction is carried out, for example, with copper (I) cyanide in solvents such as N, N-dimethylformamide, dimethylacetamide, dioxane, benzene, toluene, or acetone itril with heating, preferably under reflux.

d) For the preparation of a compound of the formula (I) in which R ^{2 is} a fluorine atom: Reaction of a compound of the general formula

in which R ¹ and R ³ are defined as mentioned above and in which no further fluorine, chlorine, bromine, iodine atoms or nitro groups are present, with n-butyllithium and subsequent reaction with N-fluorodibenzenesulfonimide.

The reaction with n-butyllithium is carried out in solvents such as diethyl ether or tetrahydrofuran at temperatures below -78 ° C, preferably in tetrahydrofuran. The subsequent reaction with N-fluorodibenzenesulfonimide is also carried out in solvents such as diethyl ether or tetrahydrofuran at temperatures below -78 ° C, preferably in tetrahydrofuran.

e) To prepare a compound of formula (I) in which R is a group a C ¹ _-4 alkyl group which may be terminally substituted by an amino group, wherein the hydrogen atoms of the amino group independently of one another by a Ci _-3 - alkyl group or an optionally substituted by a d- ₃ alkyl group substituted phenyl or pyridyl group, means: reaction of a compound of the general formula

(VI) 12

in which R ² and R ³ are defined as mentioned above and

X represents a leaving group such as a chlorine, bromine or iodine atom or a tosyl or Triflatgruppe, with a corresponding secondary amine and then optionally converting the substituents on the amino group thus introduced.

The reaction is conveniently carried out without the addition of further solvents (except the secondary amine) with heating, e.g. by microwave radiation.

Subsequently, any protecting groups used during the reaction may be cleaved off and / or

the compounds of general formula I thus obtained are separated into their enantiomers and / or diastereomers and / or

the resulting compounds of the formula I are converted into their salts, in particular for the pharmaceutical application into their physiologically tolerated salts with inorganic or organic acids.

Furthermore, as already mentioned, the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers. Thus, for example, cis / trans mixtures can be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be separated into their enantiomers.

Thus, for example, the resulting cis / trans mixtures can be chromatographed into their cis and trans isomers, the resulting compounds of the general formula I which are present in racemates can be prepared by methods known per se (see Allinger NL and US Pat Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of the general formula I having at least 2 asymmetric carbon atoms due to their physical properties. 13

calico-chemical differences according to methods known per se, e.g. by chromatography and / or fractional crystallization auf¬ separate into their diastereomers, which, if they are obtained in racemic form, then as mentioned above into the enantiomers can be separated.

The enantiomer separation is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with a, with the racemic compound, salts or derivatives such. Ester or amide-forming optically active substance, especially acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, wherein from the pure diastereomeric salts or derivatives the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-O-p-toluoyl-tartaric acid, malic acid, mandelic acid,

Camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols are (+) - or (-) - menthol and, for example, (+) - or (-) - menthyloxycarbonyl as the optically active acyl radical in amides.

Furthermore, the compounds of the formula I obtained can be converted into their salts, in particular for the pharmaceutical application, into their physiologically tolerated salts with inorganic or organic acids. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the novel compounds of the formula I thus obtained, if they contain a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerated salts. Examples of suitable bases are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. 14

The compounds of the general formulas II to VI used as starting materials are either known from the literature or obtained by processes known per se from the literature (see Examples I to VIII).

As already mentioned, the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibiting action on glucagon receptors.

The biological properties of the new compounds were tested as follows:

Glucagon binding assay

The binding of the compounds of formula I of the invention to the glucagon receptor was determined in a displacement binding assay based on the displacement of radiolabelled glucagon from a membrane fraction containing the recombinant human glucagon receptor. The human glucagon receptor-encoding cDNA was cloned into the expression vector pcDNA3.1 (Invitrogene). BHK-21 cells (Baby hamster kidney C-13 cells, ATCC) were transfected with this construct and a stable cell clone was selected and isolated by treatment with G-418 (Gibco). A membrane fraction containing the recombinant human glucagon receptor was prepared from this clone by the following steps: Confluent growing cells were detached from ice-cooled PBS buffer (Gibco) with 0.05% EDTA and suspended. After centrifugation, the pellet was suspended in a buffer (10 mM Tris / HCl, pH 7.2, 0.01 mM PMSF (phenylmethylsulfonyl fluoride)) and incubated for 90 minutes at 4 ° C. After treatment of the lysate with a homogenizer (Dounce), cell nuclei and other cellular components were separated by centrifugation at 500 g for 10 minutes. The supernatant was then centrifuged at 100,000 g for 35 minutes to pellet the membranes. The precipitated membranes were incubated in incubation buffer (50 mM Tris / HCl, pH 7.2; 15

10 mM NaCl; 5 mM MgCl ₂ ; 1mM EDTA; 0.2% BSA (bovine serum albumin)) sus¬ pendiert, aliquoted and stored at -80 ⁰ C.

The displacement of glucagon were measured by the Membranfrak¬ tion 20 .mu.g, 50.00 cpm 1251 glucagon (Amersham Pharmacia) and a concentration of the test substance for 60 minutes at 20 ⁰ C in a volume of 100 .mu.l in Inkubations¬ buffer in a microtiter plate (OptiPlate, Packard Instruments) were incubated. The bound radioligand was separated from the free ligand by filtration and washing through GC / B filters (Packard) on a Multiscreen Vacuum Filtration System (Millipore). The measurement was carried out in a Topcount scintillation counter (Packard). Binding in the presence of 1 μM unlabeled glucagon (Wherl GmbH) was defined as unspecific. Analysis of the data was performed to determine the percentage of bound activity in the presence of a test substance. The results were calculated as IC ₅ o values. The compounds listed in Examples 1 to 25 give IC ₅₀ values smaller

The glucagon receptor antagonists of the invention may be administered orally, transdermally, by inhalation or parenterally. The compounds according to the invention are present as active constituents in customary administration forms, for example in compositions which consist essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as, for example, tablets, dragees, capsules, wafers, powders , Solutions, suspensions, emulsions, syrups, suppositories, transdermal systems etc. An effective dose of the compounds according to the invention is in an oral application between 1 and 100, preferably between 1 and 50, more preferably between 5-30 mg / dose, in intravenous or intramuscular use between 0.001 and 50, preferably between 0.1 and 10 mg / dose. For inhalation erfindungs¬ according to solutions are suitable which contain from 0.01 to 1, 0, preferably 0.1 to 0.5% active ingredient. For the inhalation application, the use of powders is preferred. It is likewise possible to use the compounds according to the invention as infusion solution, preferably in a physiological saline solution or nutrient salt solution. 16

The compounds according to the invention can be used alone or in combination with other active compounds according to the invention, optionally also in combination with other pharmacologically active substances from the group consisting of: acarbose, beraprost, bexarotene, captopril, denileukin, diftitox, etanercept, farglitazar, fidarestat, glibenclamide , glibornuride, gliclazide, glimepiride, glipizide, glucagon, ilomastat, imidapril, insulin, lanreotide, linogliride, lisinopril, metformin, mexiletine, miglitol, minalrestat, mitiglinide, moxonidine, nafagrel, nateglinide, octreotide, orlistat, oxcarbazepine, pegvisomant, pioglitazone, ponalrestat , pramlintide, ramipril, repaglinide, rosiglitazone, sirolimus, sorbinil, tolrestat, troglitazone, voglibose, zenarestat and zopolrestat.

Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used. 17

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example

Condensation products of fatty alcohols with ethylene oxide, or protective agents such as p-hydroxybenzoates.

Injection solutions are prepared in the usual manner, e.g. with the addition of preserving agents, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.

The capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.

Suitable suppositories can be prepared, for example, by mixing with excipients which are provided for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

A therapeutically effective daily dose is between 1 and 800 mg, preferably 10 - 300 mg per adult.

The following examples illustrate the present invention without, however, limiting its scope: 18

Used abbreviations:

DMF N, N-dimethylformamide

Preparation of the starting compounds:

Example I 2-Amino-3-covano-4-thifluoromethyl-5- (2,5-dimethylphenyl) -thiophene

a. 4,4,4-trifluoro-2- (2,5-dimethylphenyl) -3-oxo-butyronitrile

26.1 g (145 mmol) of 2,5-dimethylphenylacetonitrile are dissolved in ethanol and washed with

20.2 g (112 mmol) of potassium tert-butylate are added. After stirring for 30 minutes

21.4 g (142 mmol) of ethyl trifluoroacetate were added dropwise. The mixture is then heated to reflux for 4 hours. The reaction solution is freed from the solvent in vacuo. The residue is mixed with water and washed with ether. The aqueous phase is treated with conc. Hydrochloric acid and extracted with ether. The organic phase is dried over magnesium sulfate and concentrated. Yield: 34 g (78% of theory) Mass spectrum: (MH) ^" = 240

b. 1.1.1 -trifluoro-3- (2,5-dimethylphen-2-propyl-2-one

34 g (241 mmol) of 4,4,4-trifluoro-2- (2,5-dimethylphenyl) -3-oxo-butyronitrile are dissolved in 80 ml of glacial acetic acid and extracted with 40 ml of 60 percent strength. Sulfuric acid added. Then heated to reflux for 30 hours. After cooling the reaction solution, the glacial acetic acid is distilled off, the residue is mixed with water and extracted with ether. The organic phase is washed with water, 10%. Wash sodium carbonate solution and water. After drying over magnesium sulfate, the organic phase is concentrated to dryness. The residue is distilled in vacuo. Yield: 21.3 g (70% of theory) CnH ₁₁ F ₃ O (216.20) 19

c. 2-Amino-3-cano-4-trifluoro-5- (2,5-dimethylphenphthiophene) 21.3 g (99 mmol) 1, 1, 1-trifluoro-3- (2,5-dimethylphenyl) -propane-2- The mixture is dissolved in 70 ml of ethanol and admixed with 6.54 g (99 mmol) of malononitrile, 3.17 g (99 mmol) of sulfur and 11 ml (100 mmol) of N-methylm-orphol in. Subsequently, the mixture is heated in the microwave apparatus (CEM Discovery). 30 minutes at 120 ^° C. at 200 W. Thereafter, the solvent is distilled off and the residue is chromatographed on silica gel (toluene / ethyl acetate = 9: 1) .The product is crystallized from petroleum ether / ethyl acetate.

Yield: 8 g (27% of theory)

Mass spectrum: (M + H) ⁺ = 297

Example Il

2-Amino-3-cyano-5- (2,5-dimethylphenyl) thiophene Prepared analogously to Example I by reacting (2,5-dimethylphenyl) acetaldehyde, malononitrile, sulfur and triethylamine in DMF. Mass spectrum: (M + H) ⁺ = 229

Example III

2-Amino-3-cvano-4-trifluoro-5-phenyl-thiophen

Prepared analogously to Example I by reacting 1,1,1-trifluoro-3-phenyl-propan-2-one, malononitrile, sulfur and N-methylmorpholine in glycol. Melting point: 172 ° C

Mass spectrum: (M-H) = 267

Example IV

2-amino-4-bromo-3-cvano-5- (2.5-dimethylphenyl) -thiophene

a. 4,5-dibromo-3-cvano-2-nitrothiophene 20

4.00 g (10.9 mmol) of 3,4,5-tribromo-2-nitrothiophene and 1.38 g (15.4 mmol) of copper (I) cyanide are dissolved in 10 mL of DMF and stirred at 90 ^° C. for 43 hours. Thereafter, the solvent is removed in vacuo and the residue is mixed with 100 ml of water and 100 ml of ethyl acetate. The phases are separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel (petroleum ether / ethyl acetate = 4: 1). Yield: 370 mg (11% of theory) C ₅ Br ₂ N ₂ O ₂ S (311.94)

Rf = 0.30 (silica gel, petroleum ether / ethyl acetate = 9: 1)

b. 4-Bromo-3-cvano-5- (2.5-dimethylphenyl) -2-nitrothiophene

To a solution of 100 mg (0.32 mmol) of 4,5-dibromo-3-cyano-2-nitrothiophene in 2 ml of dioxane are added 50 mg (0.33 mmol) of 2,5-dimethylphenylboronic acid and 20 mg (0.027 mmol) of [1, 1 'Bis (diphenylphosphino) ferrocene] palladium (II) chloride. The reaction mixture is stirred at room temperature for 30 hours and then mixed with 50 ml of water and 50 ml of ethyl acetate. The phases are separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated on a rotary evaporator.

Yield: 55 mg (51% of theory)

Rf = 0.64 (silica gel, petroleum ether / ethyl acetate = 4: 1)

c. 2-amino-4-bromo-3-cvano-5- (2,5-dimethylphenyl) -thiophene

To a solution of 50 mg (0.15 mmol) of 4-bromo-3-cyano-5- (2,5-dimethylphenyl) -2-nitrothiophene in 10 ml of acetone at room temperature 1.6 ml (1.2 mmol) of titanium (III) chloride ( 10% in 20-30% hydrochloric acid). The reaction mixture is stirred for 1 hour at room temperature and then with 10 percent strength. Sodium hydroxide solution made basic. The aqueous phase is extracted with ethyl acetate, the 21

combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. Yield: 27 mg (59% of theory) of Ci ₃ HnBrN ₂ S (307.21) mass spectrum: (M + H) ⁺ = 309, 307

Rf = 0.38 (silica gel, petroleum ether / ethyl acetate = 4: 1)

Example V

2-Amino-5- (3-chloro-propyl-3-cyanothiophene Under a nitrogen atmosphere, 5.0 g (24.9 mmol) of 5-chloropentanal in 1.64 g

(24.9 mmol) of malononitrile and with 7.43 g (72.8 mmol) of alumina

(basic, activity level I) and stirred for 20 minutes at room temperature.

Then dichloromethane is added and filtered with suction from the solid. The filtrate is dried over magnesium sulfate and freed from the solvent. The crude product thus obtained is dissolved in 5.5 ml of ethanol and admixed with 750 mg (23.4 mmol) of sulfur. At room temperature, 1.44 ml (13.9 mmol) of diethylamine are added dropwise.

Subsequently, the reaction solution is stirred at 35 ° C for 16 hours. Thereafter, the solvent is removed in vacuo. The residue is on silica gel

(Petroleum ether / ethyl acetate = 80:20 -> 63:37) chromatographed. Yield: 781 mg (18% of theory)

C ₈ H ₉ CIN ₂ S (200.70)

Rr value: 0.4 (silica gel, petroleum ether / ethyl acetate = 2: 1)

Example VI 2-Amino-5- (3-chloropropyl) -3-cano-4-methylthiophene

Prepared analogously to Example I from 6-chlorohexan-2-one, malononitrile, sulfur and diethylamine in ethanol.

Yield: 26% of theory

C ₉ H ₁₁ CIN ₂ S (214.72) Mass spectrum: (M + H) ⁺ = 217, 215

Rr value: 0.7 (silica gel, petroleum ether / ethyl acetate = 1: 1) 22

Example VII

2-Amino-3-cvano-5-phenylthiophene

Prepared analogously to Example I from phenylacetaldehyde, malononitrile, sulfur and N-methylmorpholine in ethanol. Melting point: 177-178 ° C

Rr value: 0.34 (silica gel, toluene / ethyl acetate = 4: 1)

Example VIII 2-Amino-3-cano-4-methoxy-5-propylthiophene 6.00 g (36.5 mmol) of 2- (1-methoxy-pentylidene) -malononitrile are dissolved in 7.5 ml of methanol and treated with 1.20 g (37.4 mmol) of sulfur and 4.02 ml (36.5 mmol) of N-methylm orphol in offset. The reaction solution is heated in the microwave reactor for 15 minutes at 110 ⁰ C. Thereafter, the solvent is removed in vacuo and the residue chromatographed on silica gel (toluene / ethyl acetate = 96: 4). Yield: 0.68 g (10% of theory) C ₉ H ₁₂ N ₂ OS (196.27) Mass spectrum: (M + H) ⁺ = 197

Production of final products:

General production instructions for Examples 1 to 8

1 mmol of the corresponding norboman, norbornene or bicyclo [2.2.2] octano-carboxylic acid is dissolved in 5 ml of dichloromethane, treated with 0.3 ml of oxalyl chloride and stirred for 1 hour at room temperature. Thereafter, it is concentrated to the residue. The corresponding acid chloride is added to a cooled to 5 ⁰ C solution of 0.3 g (1 mmol) of 2-amino-3-cyano-4-trifluoromethyl-5- (2,5-dimethylphenyl) thiophene (Example I) and 0.24 ml ( 3 mmol) of pyridine in 5 ml of dichloromethane was added dropwise. The reaction solution is stirred for 12 hours at room temperature, diluted with dichloromethane, and washed twice with 1 N hydrochloric acid. The organic phase is dried over magnesium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (cyclohexane / ethyl acetate = 9: 1). 23

Melting point name

Example [ ⁰ C]

2 - [(1S, 2S, 4R) -bicyclo [2.2.1] hept-2-ylcarbonyl-

242 amino] -3-cyano-4-trifluoromethyl-5- (2.5- dimethylphenyl) -thiophene

2 - [(1S, 2S, 4S) -bicyclo [2.2.1] hept-5-en-2-yl

209-211 carbonylamino] -3-cyano-4-trifluoromethyl-5- thiophene (2,5-dimethylphenyl)

2 - [(1R, 2S, 4S) -bicyclo [2.2.1] hept-2-ylcarbonyl-

230 amino] -3-cyano-4-trifluoromethyl-5- (2.5- dimethylphenyl) -thiophene

2 - [(1S, 2R, 4S) -bicyclo [2.2.1] hept-5-en-2-yl

226-227 carbonylamino] -3-cyano-4-trifluoromethyl-5- (2,5-dimethylphenyl) thiophene

2 - [(1R, 2R, 4S) -bicyclo [2.2.1] hept-2

239-240 ylcarbonylamino] -3-cyano-4-trifluoromethyl-5-

thiophene (2,5-dimethylphenyl)

2 - [(1R, 2R, 4R) -bicyclo [2.2.1] hept-5-en-2-yl

213-214 carbonylamino] -3-cyano-4-trifluoromethyl-5-

thiophene (2,5-dimethylphenyl)

2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonyl

231-233 amino] -3-cyano-4-trifluoromethyl-5- (2,5-dimethylphenyl) thiophene

2- [bicyclo [2.2.2] oct-2-ylcarbonylamino] -4-

8 242-244 chloro-3-cyano-4-trifluoromethyl-5- (2,5-dimethyl- phenyl) thiophene 24

Example 9

2-r (1S.2R.4R) -biccloror2.2-hept-2-ylcarbonylaminol-3-cvano-5- (2,5-dimethylphenoxy) thiophene

Prepared analogously to Example 1-8 from (+) - (1 S, 2R, 4R) -bicyclo [2.2.1] heptane-2-carboxylic acid and 2-amino-3-cyano-5- (2,5-dimethyl -phenyl) -thiophene (Example I). Yield: 35% of theory Melting point: 168-169 ⁰ C. R f value: 00:59 (silica gel; toluene / Essigester = 4: 1).

Example 10

2-r (1S.2R.4R) -Biccloror2.2.1lhept-2-ylcarbonylaminol-4-chloro-3-cano-5- (2,5-dimethyl-phenvD-thiophene

0.5 g (1.4 mmol) of 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -3-cyano-5- (2,5-dimethyl-phenyl) -thiophene (Example 9 ) are dissolved in 30 ml of glacial acetic acid at 7O ⁰ C and 0.22g (1.6 mmol) of N-chlorosuccinimide added. The reaction solution is stirred at 70 ^° C. for 2 hours. After cooling, it is made up to 100 ml with water and extracted three times with ethyl acetate. The organic phases are washed twice with 10 percent strength. Sodium carbonate solution and washed twice with water and then closing to the residue. The residue is chromatographed on silica gel (cyclohexane / ethyl acetate = 9: 1) and the purified product is crystallized from methanol. Yield: 0.1 g (18% of theory) C ₂ H I ₂₁ CIN ₂ OS (384.92) 25

Melting point: 117-119 ⁰ C.

Mass spectrum: (MH) ^" = 385, 383

Rr value: 0.69 (silica gel, toluene / ethyl acetate = 4: 1)

Example 11

2-r (2R) -Bicvclof2.2.21oct-2-ylcarbonylaminol-4-chloro-3-cvano-5- (2,5-dimethylphenylenethiophene

Prepared analogously to Example 10 from 2 - [(R) -bicyclo [2.2.2] oct-2-ylcarbonylamino] -3-cyano-5- (2,5-dimethyl-phenyl) -thiophene.

Yield: 36% of theory

C ₂₂ H ₂₃ CIN ₂ OS (398.95)

Melting point: 208-210 ⁰ C.

Mass spectrum: (M + H) ⁺ = 401, 399

Example 12

4-Chloro-3-cvano-2- (cvclohexylcarbonylamino) -5-phenyl-thiophene

a. 3-Cano-2- (cyclohexylcarbonylamino) -5-phenylthiophene Prepared analogously to Example 1-8 from 2-amino-3-cyano-5-phenylthiophene (Example VII) and cyclohexanecarboxylic acid chloride in pyridine.

Yield: 81% of theory )

Melting point: 208 to 210 ⁰ C

b. 4-Chloro-3-cvano-2- (cvclohexvlcarbonvlamino) -5-phenvlthiophen 26

Prepared analogously to Example 10 from 3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene.

Yield: 29% of theory

Melting point: 175-18O ⁰ C.

Mass spectrum: (MH) ^" = 345, 343

Example 13 4-Bromo-3-cano-2- (cyclohexylcarbonylamino) -5-phenylthiophene

1.1 g (4 mmol) of 3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene (example

12a) are suspended at 5O ⁰ C in 5 ml of glacial acetic acid and treated within 10 minutes with 0.62 g (4 mmol) of N-bromosuccinimide. After stirring for a further 2 hours

Temperature and subsequent cooling, the crystals are filtered off with suction and washed with glacial acetic acid.

Amount: 300 mg (22% of theory)

Melting point: 167-168 ⁰ C

Mass spectrum: (M + H) ⁺ = 391, 389

Example 14

3.4-Dicvano-2- (cvclohexylcarbonylamino) -5-phenyl-thiophene

0.75 g (1.9 mmol) of 4-bromo-3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene (Example 13) and 0.26 g (2.9 mmol) of copper (I) cyanide are dissolved in 5 ml of anhydrous DMF for 12 hours heated to reflux. After cooling, the reaction mixture is 27

concentrated and the residue chromatographed on silica gel (cyclohexane / ethyl acetate = 95: 5). The purified product is dissolved in dichloromethane, a little methanol added, and the dichloromethane removed by distillation. The precipitate is sucked off. Yield: 0.29 g (45% of theory) Melting point: 208-212 ⁰ C mass spectrum: (M + H) ⁺ = 336 Rf value: 00:51 (silica gel; toluene / Essigester = 4: 1).

Example 15 3-Cano-2- (cyclohexylcarbonylamino) -4-nitro-5-phenyl-thiophene

1 g (3 mmol) of 3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene (Example 12a) are initially charged in 80 ml of acetic anhydride. At 5 ⁰ C is slowly added dropwise 4 ml 60 percent. Nitric acid too. After stirring for 10 minutes at this temperature, the solution is warmed to room temperature and stirred for a further 2 hours. The reaction mixture is added to 10 ml of ice and stirred. Subsequently, the phases are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. The residue is treated with methanol and dichloromethane, distilled off the dichloromethane and the precipitate was filtered off with suction. Yield: 0.1 g (9% of theory)

Melting point: 213-214 ⁰ C

Mass spectrum: (MH) ^" = 354

Rf value: 0.63 (silica gel, toluene / ethyl acetate = 4: 1) 28

Example 16 3-Cano-2- (cyclohexylcarbonylamino) -4-methoxy-5-propylthiophene

0.68 g (3.5 mmol) of 2-amino-3-cyano-4-methoxy-5-propylthiophene (Example VIII) and 0.84 ml (10.4 mmol) of pyridine are dissolved in 25 ml of dichloromethane. Within 10 minutes, are added dropwise at 10 ⁰ C 12:48 ml of cyclohexanecarbonyl chloride in 5 ml of dichloromethane. The solution is stirred for 12 hours at room temperature and extracted with dilute hydrochloric acid and with water, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (toluene / ethyl acetate = 95: 5). The isolated product is recrystallized from diisopropyl ether. Yield: 0.32 g (30% of theory) Melting point: 146-147 ⁰ C mass spectrum: (M + H) ⁺ = 307

Example 17

2-f (1S.2R.4R) -Biccloror2.2.1lhept-2-ylcarbonylaminol-4-bromo-3-cvano-5- (2,5-dimethyl-phenvP-thiophene

Prepared analogously to Example 1-8 from 2-amino-4-bromo-3-cyano-5- (2,5-dimethylphenyl) -thiophene (Example IV) and (1 S, 2R, 4R) -bicyclo [2.2.1] heptane-2-carboxylic acid chloride. Yield: 63% of theory Mass spectrum: (M + H) ⁺ = 431, 429

Rf value: 0.72 (silica gel, petroleum ether / ethyl acetate = 4: 1) 29

Example 18

2-r (1S.2R.4R) -Biccloror2.2.1lhept-2-ylcarbonylaminol-4-bromo-3-cvano-5- (3-fmethyl- (4-methylphenyl-aminol-propyl-thiophene hydrochloride

a. 2-r (1S.2R.4R) -Biccloror2.2.1 lhept-2-ylcarbonylaminol-5- (3-chloropropyl) -3-cyanoviophene

Prepared analogously to Example 1 -8 from 2-amino-5- (3-chloropropyl) -3-cyano-thiophene (Example V) and (1S, 2R, 4R) -bicyclo [2.2.1] heptane-2-carboxylic acid chloride.

Yield: 48% of theory

Mass spectrum: (M + H) ⁺ = 325, 323

Rr value: 0.58 (silica gel, petroleum ether / ethyl acetate = 3: 1)

b. 2 - [(1S.2R.4R) -Biccloror2.2.1 lhept-2-ylcarbonylamino1-4-bromo-5- (3-chloropropyn-3-cyanothiophene

A solution of 100 mg (0.31 mmol) of 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -5- (3-chloropropyl) -3-cyano-thiophene in 0.4 ml of dichloromethane is mixed with 82 mg (0.62 mmol) of anhydrous aluminum chloride. Then 18 μL (0.34 mmol) of bromine are added. It is heated for 3 hours to reflux. Then another 50 mg (0.38 mmol) of aluminum chloride and 10 / vi (0.19 mmol) of bromine wer¬ added. The mixture is stirred for 16 hours at room temperature and heated again for 2 hours to the reflux. Subsequently, the reaction solution to 5 percent. Sodium bisulfite solution poured. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product (110 mg) obtained after removal of the solvent is immediately further reacted. 30

c. 2 - [(1S.2R.4RVBicvclo [2.2.1 lhept-2-ylcarbonylanninol-4-bromo-3-cvano-5- (3- [methyl- (4-methylphenvn-aminol-propyl) -thiophene hydrochloride 110 mg (0.271 mmol) of 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-bromo-5- (3-chloropropyl) -3-cyano-thiophene are treated with 0.6 ml (4.6 mmol) of N-methyl-p-toluidine and heated in a microwave reactor for 45 minutes at 160 ⁰ C, then 2.5 ml of 2 N hydrochloric acid and 5 ml of water.The reaction solution is extracted with ethyl acetate.The organic phase is washed with Water, 2N sodium carbonate solution, water and saturated sodium chloride solution and dried over magnesium sulfate.The residue obtained after removal of the solvent is purified by preparative HPLC (Agilent).

Yield: 13 mg (9% of theory over 2 steps) C ₂₄ H ₂₈ BrN ₃ OS x HCl (522.93) Mass Spectrum: (M + H) ⁺ = 488, 486

Example 19

2-r (1S, 2R, 4R) -biccloror2.2.1lhept-2-ylcarbonylaminol-3,4-dicvano-5- (3-methyl- (4-methylphenyl) amino-propyl-3-hydrazine hydrochloride

Prepared analogously to Example 14 from 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-bromo-3-cyano-5- {3- [methyl- (4- methylphenyl) -amino] -propyl} -thiophene hydrochloride (Example 18) and copper (I) cyanide in DMF.

Yield: 16% of theory

C ₂₅ H ₂₈ N ₄ OS x HCl (469.04) Mass spectrum: (M + H) ⁺ = 433

Example 20

2 - [(1S.2R.4R) -Bicvclof2.2.1lhept-2-ylcarbonylaminol-5- (3-chloropropyl) -3-cvano-4-methylthiophene 31

Prepared analogously to Example 1-8 from 2-amino-5- (3-chloropropyl) -3-cyano-5-methylthiophene (Example VI) and (1S, 2R, 4R) -bicyclo [2.2.1] heptan-2 -carbonsäurechlorid. Yield: 43% of theory

Mass spectrum: (M + H) ⁺ = 339, 337

Rr value: 0.46 (silica gel, petroleum ether / ethyl acetate = 4: 1)

Example 21 2-r (1S.2R.4R) -Bicvclof2.2.1lhept-2-ylcarbonylaminol-3-cvano-4-methyl-5- (3-fmethyl- (4-methylphenyl) -aminol-propyl) -thiophene hvdrochlorid

Prepared analogously to Example 18c from 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -5- (3-chloropropyl) -3-cyano-4-methylthiophene (Example 20) and N-methyl-p-toluidine.

Yield: 48% of theory

C ₂₅ H ₃ IN ₃ OS x HCl (458.06)

Melting point: 116-129 ° C (decomposition) Mass spectrum: (M + H) ⁺ = 422

Example 22

2-r (1S.2R.4R) -Bicvclof2.2.1lhept-2-ylcarbonylamino1-3-cvano-4-methyl-5- (3-fmethyl- (2-pyridinyl-aminol-propyl-thiophene dihydrochloride 32

Prepared analogously to Example 18c from 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -5- (3-chloropropyl) -3-cyano-4-methylthiophene (Example 20) and 2- (methylamino) pyridine. Yield: 12% of theory C ₂₃ H ₂₈ N ₄ OS x 2HCl (481.48) Mass spectrum: (M + H) ⁺ = 409

Example 23 2-Bicyclo [2.2.21oct-2-ylcarbonylaminol-5- (3-chloropropyl) -3-cano-4-methylthiophene

Prepared analogously to Example 1-8 from 2-amino-5- (3-chloropropyl) -3-cyano-4-methylthiophene (Example VI) and bicyclo [2,2,2] octane-2-carboxylic acid chloride. Yield: 82% of theory Mass spectrum: (M + H) ⁺ = 353, 351 R _f value: 0.56 (silica gel, petroleum ether / ethyl acetate = 4: 1)

Example 24

2- (bicyclo [2.2.21oct-2-ylcarbonylamino) -3-cano-4-methyl-5- (3- [methyl- (4-methyl-phenvD-aminol-propyl-thiophene-hydrochloride

Prepared analogously to Example 18c from 2- (bicyclo [2.2.2] oct-2-ylcarbonylamino) -5- (3-chloropropyl) -3-cyano-4-methylthiophene (Example 23) and N-methyl-p-toluidine. 33

Yield: 47% of theory

C ₂₆ H ₃₃ N ₃ OS x HCl (472.09)

Melting point: 133-140 ⁰ C (strong sintering from 125 ⁰ C)

Mass spectrum: (M + H) ⁺ = 436

Example 25

2- (bicyclo) -2,2,21oct-2-ylcarbonylaminol-3-cvano-4-methyl-5- (3- [methyl- (2-pyridyl) -aminol-propyl) -hihiophene-dihydrochloride

a. 2- (bicyclo) -2,2,21oct-2-ylcarbonylaminol-3-canoano-4-methyl-5-r3- (N-methyl-allylamino) -propyl-thiophene

Prepared analogously to Example 18c from 2- (bicyclo [2.2.2] oct-2-ylcarbonylamino) -5- (3-chloropropyl) -3-cyano-4-methylthiophene (Example 23) and N-methyl-allylamine.

Yield: 98% of theory C ₂₂ H _{3 I} N ₃ OS (385.57)

Mass spectrum: (M + H) ⁺ = 386

b. 2- (bicyclo) -2,2,21oct-2-ylcarbonylaminol-3-cvano-4-methyl-5- (3-methylamino-propyl-thiophene) To a solution of 573 mg (1.49 mmol) of 2- (bicyclo [2.2.2] oct -2-ylcarbonylamino] -3-cyano-4-methyl-5- [3- (N-methyl-allylamino) -propyl] -thiophene in 3.5 ml dichloromethane under a nitrogen atmosphere 696 mg (4.46 mmol) 1, 3-Dimethylbarbitur - acid and 17 mg (0.015 mmol) tetrakis (triphenylphosphine) palladium (0) was added, the reaction mixture is heated for 16 hours at 35-40 ⁰ C. Thereafter, the solvent is removed in vacuo and the residue dissolved in saturated bicarbonate solution Natriumcarbo-. was added. the mixture is extracted with ether / dichloromethane, the organic phase is the solvent is washed with saturated brine, dried over magnesium sulfate and removed in vacuo. the crude product thus obtained (560 mg) is further reacted immediately. C ₉ H ₂₇ N ₃ OS ( 345.50) 34

Mass spectrum: (M + H) ⁺ = 346

c. 2- (bicyclo) -2,2,21oct-2-ylcarbonylaminol-3-cano-4-methyl-5- (3-methyl- (2-pyridinyl-aminol-propyl-thiophene-dihydrochloride 200 mg (0.579 mmol) 2- (bicyclo) 2.2.2] oct-2-ylcarbonylamino] -3-cyano-4-methyl-5- (3-methylamino-propyl) -thiophene are dissolved under a nitrogen atmosphere in 1.5 ml

DMF dissolved and with 0.17 ml (1.78 mmol) 2-bromopyridine and 160 mg (1.16 mmol)

Potassium carbonate added. The mixture is heated in the microwave apparatus for 60 minutes

100 ⁰ C. After addition of another 0.1 ml (1.05 mmol) of 2-bromopyridine is heated again for 6 hours in the microwave apparatus at 130 ⁰ C. After filtration of

Insoluble, the solvent is removed in vacuo and the residue purified by preparative HPLC (Agilent, RP phase).

Yield: 59 mg (21% of theory)

C ₂₄ H ₃₀ N ₄ OS x 2 HCl (495.51) Melting point:> 80 ° C (decomposition)

Mass spectrum: (M + H) ⁺ = 423

Example 26

Tablets per tablet active ingredient 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg

Magnesium stearate 5 mq

500 mg

The finely ground active substance, lactose and part of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved 35

and mixed together. The mixture is compressed into tablets of suitable shape and size.

Example 27

Tablets per tablet

Active ingredient 80 mg

Corn starch 190 mg

Lactose 55 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mq

400 mg

The finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.

Example 28

Dragees per dragee

Active ingredient 5 mg

Cornstarch 41, 5 mg

Lactose 30 mg

Polyvinylpyrrolidone 3 mg Magnesium Stearate 0.5 mg

80 mg 36

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ° C. and the granules are subsequently poured through the same sieve. After admixing magnesium stearate, curved tablet cores with a diameter of 6 mm are pressed on a tableting machine. The dragee cores thus produced are coated in a known manner with a layer which consists essentially of sugar and talcum. The finished dragees are polished with wax.

Example 29

Capsules per capsule

Active ingredient 50 mg

Corn starch 268.5 mg Magnesium stearate 1.5 mg

320 mg

Substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into hard gelatin capsules size 1.

Example 30

Ampullenlösunα

Active ingredient 50 mg

Sodium chloride 50 mg

Aqua pro inj. 5 ml

The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and treated with sodium chloride as isotonic, the resulting solution is filtered pyrogen-free and the filtrate under aseptic conditions in ampoules 37

bottled, which are then sterilized and sealed. The vials contain 5 mg, 25 mg and 50 mg active ingredient.

Example 31

suppositories

Active ingredient 50 mg

Adeps solidus 1650 mα

1700 mg

The hard fat is melted. At 40 ^° C., the ground active substance is dispersed homogeneously. It is cooled to 38 ° C and poured into slightly pre-cooled suppository molds.

Example 32

Draαees with 75 mα active substance

1 drag core contains:

Active substance 75.0 mg

Calcium phosphate 93.0 mg

Corn starch 35.5 mg

Polyvinylpyrrolidone 10.0 mg

Hydroxypropylmethylcellulose 15.0 mg

Magnesium stearate 1, 5 mq

230.0 mg

production:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half of the stated amount of magnesium stearate. On a tableting machine compacts are produced with a diameter of about 13 mm, these are on a suitable machine 38

grated through a sieve with 1, 5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired shape.

Core weight: 230 mg. Stamp: 9 mm, curved

The dragee cores produced in this way are coated with a film which consists essentially of hydroxypropylmethylcellulose. The finished film dragees are shined with beeswax. Dragee weight: 245 mg.

Example 33

Tablets with 100 mα active substance

Composition: 1 tablet contains:

Active substance 100.0 mg

Lactose 80.0 mg

Corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg

Magnesium stearate 2.0 mg

220.0 mg

Production method: Active ingredient, milk sugar and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. After screening the wet mass (2.0 mm mesh size) and dried in a rack drier at 50 ⁰ C er¬ is sieved neut (1, 5 mm mesh size) and mixed into the lubricant. The pre߬ ready mixture is processed into tablets. Tablet weight: 220 mg

Diameter: 10 mm, biplan with facet on both sides and one-sided part notch. 39

Example 34

Tablets with 150 mα active substance

Composition:

1 tablet contains:

Active substance 150.0 mg

Lactose powdered 89.0 mg

Corn starch 40.0 mg

Colloidal silicic acid 10.0 mg

Polyvinylpyrrolidone 10.0 mg

Magnesium stearate 1, 0 mq

300.0 mg

production:

The active substance mixed with milk sugar, corn starch and silicic acid is moistened with a 20% strength aqueous solution of polyvinylpyrrolidone and filtered through a sieve

1, 5 mm mesh size beaten. The granules dried at 45 ° C are again rubbed through the same sieve and mixed with the stated amount of magnesium stearate. Out of the mix

Pressed tablets.

Tablet weight: 300 mg

Stamp: 10 mm, flat

40

Example 35

Hard gelatin capsules with 150 mg active substance

1 capsule contains:

Active ingredient 150.0 mg

Corn starch drink. about 180.0 mg

Milk sugar powder approx. 87.0 mg

Magnesium stearate 3.0 mg approx. 420.0 mg

production:

The active ingredient is mixed with the excipients, passed through a sieve of 0.75 mm mesh size and mixed homogeneously in a suitable device. The final mixture is filled into size 1 hard gelatin capsules.

Capsule filling: approx. 320 mg

Capsule shell: hard gelatin capsule size 1.

Example 36

Suppositories with 150 mg active substance

1 suppository contains:

Active ingredient 150.0 mg of polyethylene glycol 1500 550.0 mg

Polyethylene glycol 6000 460.0 mg

Polyoxyethylene sorbitan monostearate 840.0 mg

2000.0 mg

production:

After the suppository mass has melted, the active ingredient is distributed homogeneously therein and the melt is poured into pre-cooled molds. 41

Example 37

Suspension with 50 mα active substance

100 ml suspension contain:

Active ingredient 1, 00 g

Carboxymethylcellulose Na salt 0.10 g of methyl p-hydroxybenzoate 0.05 g of propyl p-hydroxybenzoate 0.01 g

Cane sugar 10.00 g

Glycerin 5.00 g

Sorbitol solution 70% 20.00 g

Aroma 0.30 g of distilled water. ad 100 ml

production:

Dest. Water is heated to 70 ⁰ C. Herein, p-hydroxybenzoic acid methyl ester and propyl ester and also glycerol and carboxymethylcellulose sodium salt are dissolved with stirring. It is cooled to room temperature and with stirring

Active ingredient added and dispersed homogeneously. After addition and dissolution of the sugar, the sorbitol solution and the aroma, the suspension is evacuated to vent with stirring.

5 ml of suspension contain 50 mg of active ingredient.

Example 38

Ampoules with 10 mα active substance

Composition:

Active ingredient 10, 0 mg

0.01 n hydrochloric acid s.q.

Aqua bidest ad 2, 0 ml 42

production:

The active substance is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 2 ml ampoules.

Example 39

Ampoules with 50 mg active substance

Composition:

Active ingredient 50.0 mg

0.01 n hydrochloric acid s.q.

Aqua bidest ad 10.0 ml

production:

The active ingredient is dissolved in the required amount of 0.01 N HCl, isotonic with saline, sterile filtered and filled into 10 ml ampoules.

Claims

43Patentansprüche

1. Compounds of the general formula

(I)

in the

R ¹ is a Ci- ₄ alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

wherein the hydrogen atoms of the amino group may be independently substituted by a Ci _-3 alkyl group or an optionally substituted by a Ci _-3 alkyl phenyl or pyridyl group,

or a phenyl or pyridyl group which _-3 alkyl groups may be substituted in each case by one to three Ci,

R ² is a hydrogen, fluorine, chlorine, bromine or iodine atom or a cyano, nitro, Ci- ₃ -Alykl-, trifluoromethyl or Ci _-4 alkyloxy and

R ^{3 is} a bicyclo [2.2.1] hept-2-enyl group or

a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ -, -CH ₂ -CH ₂ - or -CH = CH group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts. 44

2. Compounds of general formula (I) according to claim 1, in which

R ¹ is a Ci _-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

wherein the hydrogen atoms of the amino group may be independently substituted by a Ci _-3 alkyl group or a group optionally substituted by a Ci- ₃ alkyl group, phenyl or pyridyl group,

or a phenyl or pyridyl group, which may each be substituted by one to three C 1-3 -alkyl groups,

R ^{2 is} a fluorine, chlorine, bromine or iodine atom or a cyano, nitro, C ₁ -SAIyW-, trifluoromethyl or Ci _-4 -Alkyloxygruppe and

R ^{3 is} a bicyclo [2.2.1] hept-2-enyl group or

a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ -, -CH ₂ -CH ₂ - or -CH = CH- group, mean

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

3. Compounds of general formula (I) according to claim 2, in which

R ^{1 is} a C _1-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group, 45

wherein the hydrogen atoms of the amino group may be independently substituted by a Ci _-3 alkyl group or an optionally substituted by a Ci _-3 alkyl phenyl or pyridyl group,

or a phenyl or pyridyl group which may each be substituted by one to three ci- _3- alkyl groups,

R ² is a fluorine, chlorine, bromine or iodine atom or a cyano, nitro or C-ι _-4 alkyl oxy group and

R ^{3 is} a bicyclo [2.2.1] hept-2-enyl group or

a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ -, -CH ₂ -CH ₂ - or -CH = CH group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

4. Compounds of general formula (I) according to claim 1, in which

R ¹ is a Ci _-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

where the hydrogen atoms of the amino group can be substituted independently of one another by a C _1-3 -alkyl group or a phenyl or pyridyl group which is optionally substituted by a C _1-3 -alkyl group,

or a phenyl or pyridyl group which _-3 alkyl groups may be substituted in each case by one to three Ci,

R ² is a hydrogen, fluorine, chlorine, bromine or iodine atom or a cyano, nitro, Ci-3 Alykl-, trifluoromethyl or Ci _-4 alkyloxy and 46

R ^{3 is} a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ - or -CH ₂ -CH ₂ - group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

5. Compounds of general formula (I) according to claim 4, in which

R ¹ is a Ci _-4 alkyl group which may be terminally substituted by a fluorine, chlorine, bromine or iodine atom or by an amino group,

wherein the hydrogen atoms of the amino group may be independently substituted by a C _1-3 alkyl group or an optionally substituted by a Ci _-3 alkyl phenyl or pyridyl group,

or a phenyl or pyridyl group, which groups in each case by one or two C-ι- ₃ alkyl may be substituted in,

R ^{2 is} a fluorine, chlorine, bromine or iodine atom or a cyano, nitro, Ci _-3 -AIyW-, trifluoromethyl or Ci _-4 -Alkyloxygruppe and

R ^{3 is} a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ - or -CH ₂ -CH ₂ - group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

6. Compounds of general formula (I) according to claim 5, in which 47

R ¹ is a C _2-4 alkyl group which is terminally substituted by an N-phenyl-N-methyl-amino group,

or a phenyl group which may be substituted by one or two methyl groups,

R ^{2 is} a chlorine or bromine atom or a cyano or nitro group and

R ^{3 is} a cyclohexyl group in which the carbon atom in position 2 can be bridged with the carbon atom in position 5 via a -CH ₂ - or -CH ₂ -CH ₂ - group,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.

7. The following compounds of general formula (I):

(a) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-chloro-3-cyano-5- (2,5-dimethyl-phenyl) -thiophene,

(b) 2 - [(2R) -bicyclo [2.2.2] oct-2-ylcarbonylamino] -4-chloro-3-cyano-5- (2,5-dimethyl-phenyl) -thiophene,

(c) 4-chloro-3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene,

(d) 4-bromo-3-cyano-2- (cyclohexylcarbonylamino) -5-phenylthiophene,

(e) 3,4-dicyano-2- (cyclohexylcarbonylamino) -5-phenyl-thiophene,

(f) S-cyano ^ -cyclohexylcarbonylamino-nitro-δ-phenylthiophene, 48

(g) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-bromo-3-cyano-5- (2,5-dimethyl-phenyl) -thiophene,

(h) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -4-bromo-3-cyano-5- {3- [methyl- (4-methylphenyl) - amino] -propyl} -thiophene and

(i) 2 - [(1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylcarbonylamino] -3,4-dicyano-5- {3- [methyl- (4-methylphenyl) -amino] thiophene propyl}

and their salts.

8. Physiologically acceptable salts of the compounds according to any one of claims 1 to 7 with inorganic or organic acids or bases.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a physiologically acceptable salt according to claim 8 in addition to optionally one or more inert carriers and / or diluents.

10. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament which is suitable for the treatment of diabetes.

11. A process for the preparation of a medicament according to claim 9, characterized in that a compound according to at least one of claims 1 to 8 is incorporated into one or more inert carriers and / or diluents by non-chemical means.

12. A process for the preparation of the compounds of general formula I according to claims 1 to 8, characterized in that

a) a compound of the general formula 49

in which R ¹ and R ^{2 are defined} as mentioned in claims 1 to 8,

with an acid chloride of the general formula

R ³ -COCl (III),

in which R ^{3 is defined} as defined in claims 1 to 8, or is reacted

b) for the preparation of a compound of the formula (I) in which R ^{2 is} a fluorine, chlorine, bromine or iodine atom or a nitro group: a compound of the general formula

in which R ¹ and R ^{3 are} as defined in claims 1 to 8 are defined, fluorinated, chlorinated, brominated, iodinated or nitrided, or

c) for the preparation of a compound of the formula (I) in which R ^{2 represents} a cyano group: a compound of the general formula

50

in which R ¹ and R ^{3 are} as defined in claims 1 to 8, is reacted with cyanide, or

d) for preparing a compound of formula (I) in which R is a group a C ¹ _-4 alkyl group which may be terminally substituted by an amino group, wherein the hydrogen atoms of the amino group independently of one another by a Ci _-3 - alkyl group or optionally substituted by a Ci _-3 alkyl phenyl or pyridyl group may be substituted, represents: a compound of general formula

in which R ² and R ^{3 are} as defined in claims 1 to 8 and X is a leaving group, is reacted with a corresponding secondary amine and then optionally the substituents are converted to the thus introduced amino group,

and or

subsequently, if necessary, protective groups used during the reaction are split off and / or

the compounds of general formula I thus obtained are separated into their enantiomers and / or diastereomers and / or

the resulting compounds of the formula I are converted into their salts, in particular for the pharmaceutical application into their physiologically acceptable salts with inorganic or organic acids.