Patent Grant
7291642
The present invention provides bradykinin-B1 antagonists of the formula
in which A, Ar, G, Q, R1 and R4 are as defined below, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases having useful properties, their preparation, medicaments comprising the pharmacologically effective compounds, their preparation and their use.
In the formula (I) above, in a first embodiment,
where the phenyl and phenylene groups present in the definitions mentioned above may be mono-, di-, tri- or tetrasubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino-carbonylamino, nitro, cyano, C1-3-alkylcarbonyl, C1-3-alkylsulphonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkylaminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkylcarbonylamino, carboxy-C1-3-alkyl, C1-3-alkyloxycarbonyl-C1-3-alkyl, phenyl, phenyloxy, hydroxyl, C1-4-alkyloxy, monofluoromethyloxy, difluoromethyloxy or trifluoromethyloxy groups or by N-pyrrolidinocarbonyl, N-pyrrolidinosulphonyl, N-piperidinocarbonyl or N-piperidinosulphonyl, where the methylene group present in the piperidine rings mentioned above may be replaced in the 4-position by O, S, SO, SO2, NH or N(C1-3-alkyl), and the substituents may be identical or different, except for substitution by two, three or four nitro groups,
where the naphthyl groups present in the definitions mentioned above may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl, amino or di-(C1-3-alkyl)-amino groups and the substituents may be identical or different,
where, unless indicated otherwise, the term “heteroaryl group” mentioned above in the definitions is to be understood as meaning a monocyclic 5- or 6-membered or a bicyclic 9- or 10-membered heterocyclic aromatic ring system, which, in addition to at least one carbon atom, contains one or more heteroatoms selected from N, O and/or S, for example
a monocyclic 5-membered heteroaryl group attached via a carbon or nitrogen atom which
or a monocyclic 6-membered heteroaryl group which contains one, two or three nitrogen atoms,
or a bicyclic 9-membered heteroaryl group consisting of one of the 5-membered heteroaryl groups mentioned above which is fused to one of the 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms or a carbon and an adjacent nitrogen atom forming a bicycle, where the 5-membered heteroaryl group may also be replaced by a cyclopentadienyl group or the 6-membered heteroaryl group may also be replaced by a phenyl ring,
or a bicyclic 10-membered heteroaryl group which consists of a phenyl ring and one of the 6-membered heteroaryl groups mentioned above or of two of the 6-membered heteroaryl groups mentioned above which are in each case condensed via two adjacent carbon atoms forming a bicycle,
and the term “heteroarylene group” mentioned above in the definitions is to be understood as meaning the mono- or bicyclic heteroaryl groups mentioned above which, however, are attached to the adjacent groups via two carbon atoms or via one carbon and one nitrogen atom,
where the alkyl and alkoxy groups present in the definitions mentioned above which have more than two carbon atoms may, unless indicated otherwise, be straight-chain or branched, and
where some or all of the hydrogen atoms of the methyl or ethyl groups present in the definitions mentioned above may be replaced by fluorine atoms,
or their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.
Examples of monocyclic heteroaryl groups are the pyridyl, N-oxypyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1,2,3]triazinyl, [1,3,5]triazinyl, [1,2,4]triazinyl, pyrrolyl, imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolyl, [1,2,5]oxadiazolyl, [1,3,4]oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl or [1,2,4]thiadiazolyl group.
Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzo[b]thiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, benz[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,3]thiadiazolyl, benzo[d][1,2,3]triazinyl, benzo[1,2,4]triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, N-oxyquinolinyl, indazolyl, purinyl, naphthyridinyl, pteridinyl, isoquinolinyl, quinazolinyl, N-oxyquinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or benz[1,2,3]oxadiazolyl group.
Examples of the C1-6-alkyl groups mentioned above in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert.-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl or 3-hexyl group.
A second embodiment of the present invention consists in the compounds of the above formula (I) in which
where the phenyl and phenylene groups present in the definitions mentioned above may be mono-, di-, tri- or tetrasubstituted by fluorine, chlorine or bromine atoms, by C1-5-alkyl, trifluoromethyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino-carbonylamino, nitro, cyano, C1-3-alkylcarbonyl, C1-3-alkylsulphonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkylaminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkylcarbonylamino, phenyl, phenyloxy, hydroxyl, C1-4-alkyloxy, monofluoromethyloxy, difluoromethyloxy or trifluoromethyloxy groups or by N-pyrrolidinocarbonyl, N-pyrrolidinosulphonyl, N-piperidinocarbonyl or N-piperidinosulphonyl, where the methylene group present in the piperidine rings mentioned above may be replaced in the 4-position by O, S, SO, SO2, NH or N(C1-3-alkyl), and the substituents may be identical or different, except for substitution by two, three or four nitro groups,
where the naphthyl groups present in the definitions mentioned above may be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, amino or di-(C1-3-alkyl)-amino groups and the substituents may be identical or different,
where, unless indicated otherwise, a “heteroaryl group” is to be understood as meaning a monocyclic 5- or 6-membered or a bicyclic 9- or 10-membered heterocyclic aromatic ring system, for example
a monocyclic 5-membered heteroaryl group attached via a carbon or nitrogen atom which
or a monocyclic 6-membered heteroaryl group which contains one or two nitrogen atoms,
or a bicyclic 9-membered heteroaryl group consisting of one of the 5-membered heteroaryl groups mentioned above which is fused to one of the 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms or a carbon and an adjacent nitrogen atom forming a bicycle, where the 5-membered heteroaryl group may also be replaced by a cyclopentadienyl group or the 6-membered heteroaryl group may also be replaced by a phenyl ring,
or a bicyclic 10-membered heteroaryl group which consists of a phenyl ring and one of the 6-membered heteroaryl groups mentioned above or of two of the 6-membered heteroaryl groups mentioned above which are in each case condensed via two adjacent carbon atoms forming a bicycle,
and the term “heteroarylene group” mentioned above in the definitions is to be understood as meaning the mono- or bicyclic heteroaryl groups mentioned above which, however, are attached to the adjacent groups via two carbon atoms or via one carbon and one nitrogen atom,
where the alkyl and alkoxy groups present in the definitions mentioned above which have more than two carbon atoms may, unless indicated otherwise, be straight-chain or branched, and
where some or all of the hydrogen atoms of the methyl or ethyl groups present in the definitions mentioned above may be replaced by fluorine atoms,
or their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.
A third embodiment of the present invention consists in the compounds of the above formula (I) in which
a phenyl group which is optionally tetrasubstituted by fluorine, chlorine or bromine atoms, cyano, C1-3-alkyl, trifluoromethyl, C1-3-alkyloxy or trifluoromethoxy groups, where the substituents may be identical or different,
a benzo[b]thiophenyl, quinolinyl, naphthyl, benz[1,2,5]oxadiazolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyrazolyl, pyridinyl or isoxazolyl group which is optionally mono-, di- or trisubstituted by chlorine or bromine atoms or methyl, amino, methylamino or dimethylamino groups or
the group —(CH2)m— in which m is the number 2 or 3 and in which one, two or three hydrogen atoms independently of one another are replaced by methyl or ethyl groups,
the group —(CH2)p— in which p is the number 2 and in which one or two hydrogen atoms independently of one another are replaced by methyl or ethyl groups,
A fourth embodiment of the present invention consists in the compounds of the above formula (I) in which
the group —(CH2)m— in which m is the number 2 or 3 and in which one or two hydrogen atoms independently of one another are replaced by methyl groups,
the group —(CH2)p— in which p is the number 2 and in which one or two hydrogen atoms independently of one another are replaced by methyl groups,
where the phenyl groups mentioned above or the phenyl groups present in the groups mentioned above independently of one another may, unless indicated otherwise, be mono- or disubstituted by fluorine, chlorine or bromine atoms, cyano, C1-3-alkyl, trifluoromethyl, C1-3-alkyloxy or trifluoromethoxy groups, but are preferably unsubstituted,
their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.
Very particularly preferred compounds of the above formula (I) which may be mentioned are, for example, the following:
A further embodiment of the present invention which is to be specifically mentioned consists in the compounds of the formula (I′)
in which
where the alkyl and alkoxy groups present in the definitions mentioned above which have more than two carbon atoms may, unless indicated otherwise, be straight-chain or branched,
where some or all of the hydrogen atoms of the methyl or ethyl groups present in the definitions mentioned above may be replaced by fluorine atoms, and
where the phenyl groups present in the definitions mentioned above may be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, C1-3-alkyl, trifluoromethyl, C1-3-alkyloxy or trifluoromethyloxy groups,
their tautomers, their enantiomers, their diastereomers, their mixtures and their salts.
A second embodiment of the present invention which may be particularly mentioned consists in the compounds of the formula (I′) in which
The compounds of the formula (I) are prepared by methods known in principle. The following processes have been found to be particularly useful for preparing the compounds of the formula (I) according to the invention:
The reaction is preferably carried out at a temperature of from 40° C. to 150° C. in a solvent, such as, for example, tetrahydrofuran, dioxane, n-hexane, cyclohexane, benzene, toluene or xylene. The reaction is carried out with addition of P2S5 or sulphur.
Depending on the type of the moiety A, the intermediates (III) and (V) can be prepared via formation of a carboxamide bond from carboxylic acid and amino building blocks selected from the group consisting of (where in the formulae (VIa) to (VId) below the ethylene group attached to Ar has the meanings of group Q in formula (I) only in an exemplary manner)
where Ar, R1, R2, R3, m, n and o are as defined at the outset and PG is an amino protective group, for example the tert.-butyloxycarbonyl protective group, the benzyloxycarbonyl, methoxycarbonyl or ethoxycarbonyl group.
Possible routes for preparing the carboxylic acid and amino building blocks (VIa) to (VIk) are known to the person skilled in the art. These building blocks are prepared by processes known per se from the literature.
Attachment of a carboxylic acid building block of the formula (VIa) to an amino building block of formula (VIe) gives intermediates of the formula (III) in which A corresponds to a group of the formula (IIa).
Attachment of a carboxylic acid building block of the formula (VIa) to an amino building block of formula (VIf) gives intermediates of the formula (III) in which A corresponds to group of the formula (IIg).
Attachment of an amino building block of the formula (VIc) to a carboxylic acid building block of formula (VIg) gives intermediates of the formula (III) in which A corresponds to a group of the formula (IIb).
Attachment of an amino building block of the formula (VIc) to a carboxylic acid building block of formula (VIh) gives intermediates of the formula (III) in which A corresponds to a group of the formula (IIe).
Attachment of an amino building block of the formula (VIc) to a carboxylic acid building block of formula (VIh) gives intermediates of the formula (III) in which A corresponds to a group of the formula (IIf).
Attachment of an amino building block of the formula (VI) to a carboxylic acid building block of formula (VIj) gives intermediates of the formula (III) in which A corresponds to a group of the formula (IIh).
Attachment of an amino building block of the formula (VIc) to a carboxylic acid building block of formula (VIk) gives intermediates of the formula (III) in which A corresponds to a group of the formula (IIi).
Attachment of a carboxylic acid building block of the formula (VIb) to an amino building block of formula (VIe) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIa).
Attachment of a carboxylic acid building block of the formula (VIb) to an amino building block of formula (VIf) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIg).
Attachment of an amino building block of the formula (VId) to a carboxylic acid building block of formula (VIg) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIb).
Attachment of an amino building block of the formula (VId) to a carboxylic acid building block of formula (VIh) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIe).
Attachment of an amino building block of the formula (VId) to a carboxylic acid building block of formula (VIi) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIf).
Attachment of an amino building block of the formula (VId) to a carboxylic acid building block of formula (VIj) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIh).
Attachment of an amino building block of the formula (VId) to a carboxylic acid building block of formula (VIk) gives intermediates of the formula (V) in which A corresponds to a group of the formula (IIi).
The abovementioned attachments of carboxylic acids to amines with formation of carboxamides can be carried out using customary methods for amide formation.
The coupling is preferably carried out using processes known from peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Vol. 15/2) where, for example, carbodiimides, such as, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)carbodiimide, O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HBTU) or -tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) are employed. The reaction rate can be increased by addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt). The couplings are usually carried out using equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between −30° C. and +30° C., preferably between −20° C. and +25° C. If required, the preferred additional auxiliary base is N-ethyl-diisopropylamine (DIEA) (Hünig base).
reaction of a cyclic urea of the formula
in which R1, R2 and n are defined as mentioned at the outset with an electrophilic synthesis building block of the formula
N≡—Ar-Q-X, (VIII)
in which Ar and Q are defined as mentioned at the outset and X is a nucleofugic group, for example the chlorine, bromine or iodine atom, the methanesulphonyl or toluenesulphonyl group.
The reaction is carried out in the presence of a base, such as, for example, potassium tert.-butoxide or sodium hydride, preferably in a solvent such as dimethylformamide or dimethyl sulphoxide.
Possible routes for preparing the synthesis building blocks (VII) and (VIII) are familiar to the person skilled in the art. These building blocks are prepared by processes known per se from the literature.
The reaction is carried out in the presence of a base, such as, for example, butyllithium or lithium diisopropylamide, preferably in a solvent such as tetrahydrofuran or in a solvent mixture of tetrahydrofuran with hexane or toluene.
Possible routes for preparing the synthesis building blocks (IX) and (X) are familiar to the person skilled in the art. These building blocks are prepared by processes known per se from the literature.
The compounds of the formula (I) obtained can, if they contain suitable basic functions, be converted, in particular for pharmaceutical applications, into their physiologically acceptable salts with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
Moreover, the novel compounds of the formula (I) can, if they contain carboxylic acid functions, be converted, if desired, into their addition salts with inorganic or organic bases, in particular for pharmaceutical applications into their physiologically acceptable addition salts. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The present invention relates to racemates if the compounds of the formula (I) have only one element of chirality. However, the application also embraces the individual diastereomeric pairs of enantiomers or mixtures thereof which are present when more than one element of chirality is present in the compounds of the formula (I), and the individual optically active enantiomers which constitute the racemates mentioned.
The subject matter of the present invention also embraces the compounds according to the invention and their salts in which one or more hydrogen atoms are replaced by deuterium.
The novel compounds of the formula (I) and their physiologically acceptable salts have useful pharmacological properties. They are bradykinin-B1 antagonists.
For example, the compounds
CHO cells expressing the hBK1 receptor are cultivated in Dulbecco's modified medium. The medium from confluent cultures is removed and the cells are washed with PBS buffer, scraped off and isolated by centrifugation. The cells are then homogenized in suspension and the homogenate is centrifuged and resuspended. The protein content is determined and the membrane preparation obtained in this manner is then frozen at −80° C.
After thawing, 200 μl of the homogenate (50 to 100 μg of proteins/assay) are incubated at room temperature with 0.5 to 1.0 nM of kallidin (DesArg10, Leu9), [3,4-prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 μl for 60 minutes. The incubation is terminated by rapid filtration through GF/B glass fibre filters which had been pretreated with polyethyleneimine (0.3%). The protein-bound radioactivity is measured in a TopCount NXT. Non-specific binding is defined as radioactivity bound in the presence of 1.0 μM of kallidin (DesArg10, Leu9), [3,4-prolyl-3,43H(N)]. The concentration/binding curve is analysed using a computer-assisted nonlinear curve fitting. The Ki which corresponds to the test substance is determined using the data obtained in this manner.
In the test described, substances A to E have the following Ki values:
By virtue of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors. The compounds according to the invention can be used in methods which serve to alleviate or treat pain, where a therapeutically effective amount of the compound according to the invention is administered to a patient. Thus, they are suitable, for example, for treating patients having chronic pain, neuropathic pain, postoperative pain, inflammatory pain, perioperative pain, migraine, arthralgia, neuropathies, nerve injuries, diabetic neuropathy, neurodegeneration, neurotic skin diseases, stroke, irritable bladder, irritable colon, respiratory disorders, such as asthma or chronic obstructive lung disease, irritations of the skin, the eyes or the mucosa, duodenum ulcers and stomach ulcers, stomach inflammation or other inflammatory disorders, pain caused by osteoarthritis or back pain, and also pain associated with another aetiology.
For treating pain, it may be advantageous to combine the compounds according to the invention with stimulating substances such as caffeine or other pain-alleviating active compounds. If active compounds suitable for treating the cause of the pain are available, these can be combined with the compounds according to the invention. If, independently of the pain treatment, other medical treatments are also indicated, for example for high blood pressure or diabetes, the active compounds required can be combined with the compounds according to the invention.
The dosage necessary for obtaining a pain-alleviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case 1 to 3 times per day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations being particularly suitable for inhalation. They can be incorporated into customary pharmaceutical preparations, such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered aerosols or suppositories, if appropriate together with one or more customary inert carriers and/or diluents, for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.
Generally, there are IR, 1H NMR and/or mass spectra for the compounds that were prepared. The ratios given for the mobile phases are in volume units of the solvents in question. For NH3, the given volume units are based on a concentrated solution of NH3 in water.
Unless indicated otherwise, the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.
For chromatographic purification, silica gel from Millipore (MATREX™, 35-70 μm) or Alox (E. Merck, Darmstadt, Alumina 90 standardized, 63-200 μm, article No. 1.01097.9050) are used.
In the descriptions of the experiments, the following abbreviations are used:
A solution of 1.0 g (6.28 mmol) of tert.-butyl N-methyl-β-alaninate, 1.54 g (6.28 mmol) of 2,3-dichlorobenzenesulphonyl chloride and 0.70 g (6.92 mmol) of triethylamine in 30 ml of tetrahydrofuran was stirred at room temperature overnight and then evaporated to dryness. About 50 ml of water were added to the residue, and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with about 20 ml of saturated sodium chloride solution and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane).
C14H19Cl2NO4S (368.28) Yield: 19.5% of theory 1H-NMR (d6-DMSO): δ=1.39 (s, 9H); 2.50 (t, 2H); 2.87 (s, 3H); 3.46 (t, 2H); 7.59 (t, 1H); 7.96 (2d, 2H) ppm
For two hours, a solution of 430 mg (1.17 mmol) of tert.-butyl 3-[(2,3-dichlorobenzenesulphonyl)methylamino]propionate and 2.0 ml of trifluoroacetic acid in 30 ml of tetrahydrofuran was stirred at room temperature and then evaporated to dryness. About 30 ml of water were added to the residue and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product obtained in this manner was reacted further without additional purification.
C10H11Cl2NO4S (312.17) Yield: 98% of theory 1H-NMR (d6-DMSO): δ=2.54 (t, 2H); 2.89 (s, 3H); 3.47 (t, 2H); 7.58 (t, 1H); 7.96 (2d, 2H) ppm
With ice bath cooling, 5.82 ml (15.57 mmol) of benzyl chloroformate (45% in toluene) were added to a solution of 2.37 g (12.98 mmol) of 4-(2-aminoethyl)benzonitrile hydrochloride and 4.34 ml (31.14 mmol) of triethylamine in 95 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 2:1 to 1:1).
C9H10N2 (146.19) Yield: 67% of theory 1H-NMR (d6-DMSO): δ=2.81 (t, 2H), 3.27 (t, 2H), 4.99 (s, 2H), 7.26-7.43 (m, 8H), 7.73 (d, 2H) ppm
With ice bath cooling, 0.43 g (17.03 mmol) of sodium hydride (95%) was added to a solution of 3.183 g (11.36 mmol) of benzyl [2-(4-cyanophenyl)ethyl]carbamate in 70 ml of tetrahydrofuran. The mixture was stirred for a further 5 minutes with cooling and at room temperature for 10 minutes. 1.06 ml (17.03 mmol) of methyl iodide were then added to the reaction mixture, which was subsequently stirred at room temperature overnight. With ice bath cooling, the mixture was then quenched with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product obtained in this manner was reacted further without additional purification.
C10H12N2 (160.22) Yield: 97% of theory 1H-NMR (d6-DMSO): δ=2.77-2.93 (m, 5H), 3.50 (t, 2H), 4.92/5.02 (2s br, 2H, rotamers), 7.19-7.47 (m, 7H), 7.71 (s br, 2H) ppm
A solution of 3.33 g (11.32 mmol) of 4-(2-methylaminoethyl)benzonitrile, 14 ml of ethylenediamine and 0.182 g (5.66 mmol) of sulphur was stirred at 100° C. for one hour and then evaporated to dryness. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was triturated with diethyl ether.
C20H23N3O2 (337.43) Yield: 86% of theory 1H-NMR (d6-DMSO): δ=2.81 (m, 5H), 3.47 (t, 2H), 3.59 (s, 4H), 4.97/5.05 (2s br, 2H, rotamers), 6.84 (s br, NH), 7.15-7.40 (m, 7H), 7.73 (d br, 2H) ppm
1.29 g (10.57 mmol) of dimethylaminopyridine and 2.31 g (10.57 mmol) of di-tert-butyl dicarbonate in 50 ml of dichloromethane were added successively to a solution of 3.27 g (9.69 mmol) of benzyl {2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}methylcarbamate in 50 ml of dichloromethane. The reaction mixture was stirred at room temperature for 3.5 hours. The mixture was then washed with 0.5 N hydrochloric acid, with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/ethanol 15:1).
C25H31N3O4 (437.54) Yield: 97% of theory 1H-NMR (d6-DMSO): δ=1.18 (s, 9H), 2.78-2.88 (m, 5H), 3.46 (t, 2H), 3.84 (m, 4H), 5.00/5.06 (2s br, 2H, rotamers), 7.20 (d br, 2H), 7.28-7.41 (m, 7H) ppm
A suspension of 4.0 g (9.14 mmol) of tert.-butyl 2-{4-[2-(benzyl-oxycarbonylmethylamino)ethyl]phenyl}4,5-dihydroimidazole-1-carboxylate and 0.4 g of palladium/10% carbon in 80 ml of methanol was hydrogenated in an autoclave for two hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. The crude product obtained in this manner was immediately reacted further without additional purification.
C17H25N3O2 (303.41) Yield: 98% of theory [M+H]+=304, [M-butene-CO2+H]+=204
A solution of 210 mg (0.67 mmol) of 3-[(2,3-dichlorobenzenesulphonyl)-methylamino]propionic acid, 257 mg (0.80 mmol) of TBTU and 1.0 ml of triethylamine in 40 ml of tetrahydrofuran was stirred at room temperature for one hour, 204 mg (0.67 mmol) of tert.-butyl 2-[4-(2-methylaminoethyl)phenyl]-4,5-dihydroimidazole-1-carboxylate were then added and the mixture was stirred overnight. The mixture was evaporated to dryness, about 40 ml of potassium carbonate solution (10%) were added to the residue and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography (mobile phase: dichloromethane/methanol 150:1).
C27H34Cl2N4O5S (597.55) Yield: 59.7% of theory 1H-NMR (d6-DMSO): δ=1.19 (2s, 9H, rotamers); 2.40-2.95 (m, 10H); 3.35-3.53 (m, 4H); 3.77-3.92 (m, 4H); 7.25 (t, 2H); 7.38 (t, 2H); 7.54-7.62 (m, 1H); 7.89-7.98 (m, 2H) ppm
A solution of 230 mg (0.385 mmol) of tert.-butyl 2-{4-[2-({3-[(2,3-dichloro-benzenesulphonyl)methylamino]propionyl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 3.0 ml of trifluoroacetic acid in 30 ml of dichloromethane was stirred at room temperature overnight and then evaporated to dryness. About 40 ml of potassium carbonate solution (10%) were added to the residue, and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to about 10 ml. About 15 ml of etheral hydrochloric acid were added and the mixture was evaporated to dryness. The residue was triturated with about 10 ml of ether, this suspension was re-evaporated and the product obtained in this manner was dried under reduced pressure.
C22H26Cl2N4O3S×HCl (533.90) Yield: 68.1% of theory 1H-NMR (d6-DMSO): δ=2.38/2.60 (2t, 2H, rotamers); 2.78-2.98 (m, 8H); 3.27-3.44 (m, 2H); 3.49-3.60 (m, 2H); 3.99 (s, 4H); 7.47-7.62 (m, 3H); 7.88-8.04 (m, 4H); 10.70/10.72 (2s, 2H, rotamers) ppm
Analogously to 1i), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylbutyramide hydrochloride was prepared from 48 mg (0.09 mmol) of tert.-butyl 2-{4-[2-({4-[(2,3-dichlorobenzenesulphonyl)methylamino]butyryl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 1 ml of trifluoroacetic acid in 5 ml of dichloromethane.
C23H28Cl2N4O3S×HCl (511.47) Yield: 91% of theory 1H-NMR (d6-DMSO): δ=1.62/1.70 (2m, 2H, rotamers), 2.09 (s, 2H), 2.10/2.22 (2t, 2H, rotamers), 2.80/2.81 (2s, 3H, rotamers), 2.85/2.88 (2s, 3H, rotamers), 2.85/2.94 (2t, 2H, rotamers), 3.14/3.21 (2t, 2H, rotamers), 3.99 (s, 4H), 7.45-7.61 (m, 3H), 7.91-8.01 (m, 4H), 10.66/10.69 (2s br, NH, rotamers) ppm
Analogously to 1i), 4-[(2,3-dichlorobenzenesulphonyl)phenylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylbutyramide was prepared from 0.252 g (0.35 mmol) of tert.-butyl 2-{4-[2-({4-[(2,3-dichloro-benzenesulphonyl)phenylamino]butyryl}methylamino)ethyl]phenyl}-4,5-di-hydroimidazole-1-carboxylate and 0.5 ml of trifluoroacetic acid in 2 ml of dichloromethane.
C28H30Cl2N4O3S (573.55) Yield: 94% of theory 1H-NMR (d6-DMSO): δ=1.51/1.59 (2m, 2H, rotamers), 2.18/2.29 (2t, 2H, rotamers), 2.73/2.83 (2t, 2H, rotamers), 2.77/2.84 (2s, 3H, rotamers), 3.46 (q, 2H), 3.59 (m, 4H), 3.74/3.82 (2t, 2H, rotamers), 7.18-7.40 (m, 7H), 7.46 (t, 1H), 7.70-7.82 (m, 3H), 7.92 (d, 1H) ppm
Analogously to 1i), 4-[(2,3-dichlorobenzenesulphonyl)isopropylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylbutyramide was prepared from 0.269 g (0.42 mmol) of tert.-butyl 2-{4-[2-({4-[(2,3-dichlorobenzenesulphonyl)isopropylamino]butyryl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 0.6 ml of trifluoroacetic acid in 2 ml of dichloromethane.
C25H32Cl2N4O3S (539.53) Yield: 82% of theory 1H-NMR (d6-DMSO): δ=1.08 (d, 3H), 1.11 (d, 3H), 1.61/1.70 (2m, 2H, rotamers), 2.08/2.23 (2t, 2H, rotamers), 2.75/2.83 (2t, 2H, rotamers), 2.81/2.86 (2s, 3H, rotamers), 3.15/3.26 (2t, 2H, rotamers), 3.48 (m, 2H), 3.58 (s, 4H), 3.91 (m, 1H), 7.25/7.29 (2d, 2H, rotamers), 7.57 (m, 1H), 7.73/7.76 (2d, 2H, rotamers), 7.94 (m, 1H), 8.01 (m, 1H) ppm
Analogously to 1i), 4-[(2,3-dichlorobenzenesulphonyl)cyclopropylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylbutyramide was prepared from 0.31 g (0.48 mmol) of tert.-butyl 2-{4-[2-({4-[(2,3-dichloro-benzenesulphonyl)cyclopropylamino]butyryl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 0.7 ml of trifluoroacetic acid in 2 ml of dichloromethane.
C25H30Cl2N4O3S (537.51) Yield: 78% of theory 1H-NMR (d6-DMSO): δ=0.41 (m, 2H), 0.59 (m, 2H), 1.73/1.82 (2m, 2H, rotamers), 2.15/2.30 (2t, 2H, rotamers), 2.45/2.50 (2m, 2H, rotamers), 2.77/2.86 (2t, 2H, rotamers), 2.82/2.89 (2s, 3H rotamers), 3.28/3.39 (2t, 2H, rotamers), 3.50 (m, 2H), 3.58 (s, 4H), 7.26/7.30 (2d, 2H, rotamers), 7.59 (m, 1H), 7.73/7.75 (2d, 2H, rotamers), 7.94-8.03 (m, 2H) ppm
Analogously to 1i), 2-(benzenesulphonylmethylamino)-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylacetamide hydrochloride was prepared from 0.5 g (0.97 mmol) of tert.-butyl 2-[4-(2-{[2-(benzenesulphonylmethylamino)acetyl]methylamino}ethyl)phenyl]-4,5-dihydroimidazole-1-carboxylate and 5 ml of trifluoroacetic acid in 15 ml of dichloromethane.
C21H26N4O3S×HCl (450.98) Yield: 57% of theory 1H-NMR (d6-DMSO): δ=2.55/2.64 (2s, 3H, rotamers), 2.77-3.03 (m, 5H), 3.55 (m, 2H), 3.68/3.99 (2s, 2H, rotamers), 4.00 (s br, 4H), 7.52 (dd, 2H), 7.57-7.76 (m, 4H), 7.80 (d, 1H), 8.02 (m, 2H), 10.80/10.85 (2s, 2H, rotamers) ppm
Analogously to 1i), 3-(benzenesulphonylmethylamino)-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylpropionamide hydrochloride was prepared from 0.52 g (0.98 mmol) of tert.-butyl 2-[4-(2-{[3-(benzene-sulphonymethylamino)propionyl]methylamino}ethyl)phenyl]4,5-dihydroimidazole-1-carboxylate and 5 ml of trifluoroacetic acid in 25 ml of dichloromethane.
C22H28N4O3S×HCl (465.01) Yield: 35% of theory 1H-NMR (d6-DMSO): δ=2.35/2.54 (2t, 2H, rotamers), 2.62/2.70 (2s, 3H, rotamers), 2.78-2.98 (m, 5H), 3.07/3.15 (2t, 2H, rotamers), 3.54 (m, 2H), 3.99 (s, 4H), 7.51 (t, 2H), 7.60-7.80 (m, 5H), 8.02 (dd, 2H), 10.75/10.79 (2s, 2H, rotamers) ppm
Analogously to 1i), 3-[1-(2,3-dichlorobenzenesulphonyl)piperidin-2-yl]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylpropionamide hydrochloride was prepared from 0.44 g (0.68 mmol) of tert.-butyl 2-{4-[2-({3-[1-(2,3-dichlorobenzenesulphonyl)piperidin-2-yl]propionyl}methylamino)ethyl]phenyl}4,5-dihydroimidazole-1-carboxylate and 5 ml of trifluoroacetic acid in 15 ml of dichloromethane.
C26H32Cl2N4O3S×HCl (587.99) Yield: 64% of theory 1H-NMR (d6-DMSO): δ=1.08-1.30 (m, 1H), 1.45-1.72 (m, 6H), 1.73-2.13 (m, 3H), 2.70/2.75 (2s, 3H, rotamers), 2.83/2.90 (2t, 2H, rotamers), 2.98-3.13 (m, 1H), 3.33-3.57 (m, 2H), 3.58-3.73 (m, 1H), 3.80-3.93 (m, 1H), 3.99 (s, 4H), 7.49 (t, 2H), 7.57 (m, 1H), 7.88-8.07 (m, 4H), 10.73/10.79 (2s, 2H, rotamers) ppm
Analogously to 1i), 3-[1-(4-chloro-2,5-dimethylbenzenesulphonyl)piperidin-2-yl]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylpropionamide hydrochloride was prepared from 0.39 g (0.60 mmol) of tert.-butyl 2-{4-[2-({3-[1-(4-chloro-2,5-dimethylbenzenesulphonyl)piperidin-2-yl]propionyl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 4 ml of trifluoroacetic acid in 40 ml of dichloromethane.
C28H37ClN4O3S×HCl (581.60) Yield: 46% of theory 1H-NMR (d6-DMSO): δ=1.08-1.25 (m, 1H), 1.43-1.71 (m, 6H), 1.73-2.10 (m, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 2.68-3.10 (m, 6H), 3.33-3.62 (m, 3H), 3.78 (m, 1H), 3.99 (s, 4H), 7.50 (m, 3H), 7.81 (s, 1H), 7.94-8.03 (m, 2H), 10.70/10.74 (2s, 2H, rotamers) ppm
Analogously to 1i), 3-(1-benzenesulphonylpiperidin-2-yl)-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylpropionamide hydrochloride was prepared from 0.28 g (0.48 mmol) of tert.-butyl 2-{4-[2-({3-[1-benzenesulphonylpiperidin-2-yl]propionyl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 3 ml of trifluoroacetic acid in 40 ml of dichloromethane.
C26H34N4O3S×HCl (519.10) Yield: 24% of theory 1H-NMR (d6-DMSO): δ=1.06-1.25 (m, 1H), 1.27-1.63 (m, 6H), 1.74-1.93 (m, 1H), 2.04-2.24 (m, 2H), 2.28-3.08 (m, 6H), 3.52 (m, 2H), 3.58-3.72 (m, 1H), 3.83-4.02 (m, 1H), 3.99 (s, 4H), 7.48-7.70 (m, 5H), 7.82 (d, 2H), 8.00 (dd, 2H), 10.68/10.71 (2s, 2H, rotamers) ppm
Analogously to 1i), 3-[1-(2,3-dichlorobenzenesulphonyl)pyrrolidin-2(S)-yl]-N-{2-[4-(4,5dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylpropionamide hydrochloride was prepared from 0.24 g (0.38 mmol) of tert.-butyl 2-{4-[2-({3-[1-(2,3-dichlorobenzenesulphonyl)pyrrolidin-2(S)-yl]propionyl}methylamino)ethyl]phenyl}-4,5-dihydroimidazole-1-carboxylate and 2 ml of trifluoroacetic acid in 30 ml of dichloromethane.
C25H30C2N4O3S×HCl (573.96) Yield: 37% of theory 1H-NMR (d6-DMSO): δ=1.45-1.93 (m, 6H), 2.06/2.21 (2t, 2H, rotamers), 2.80/2.88 (2s, 3H, rotamers), 2.82-2.97 (m 2H), 3.36 (m, 2H), 3.51 (t, 2H), 3.79-3.99 (m, 1H), 4.00 (s, 4H), 7.47-7.62 (m, 3H), 7.90-8.00 (m, 4H), 10.62/10.66 (2s, 2H, rotamers) ppm
Analogously to 1i), 1-(2,3-dichlorobenzenesulphonyl)piperidin-3-yl-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylcarboxamide was prepared from 0.27 g (0.43 mmol) of tert.-butyl 2-[4-(2-{[1-(2,3-dichlorobenzenesulphonyl)piperidine-3-carbonyl]methylamino}ethyl)phenyl]-4,5-dihydroimidazole-1-carboxylate and 1 ml of trifluoroacetic acid in 5 ml of dichloromethane.
C24H28Cl2N4O3S (523.48) Yield: 29% of theory 1H-NMR (d6-DMSO): δ=1.08-1.84 (m, 4H), 2.65-2.95 (m, 8H), 3.43-3.75 (m, 4H), 3.60 (s, 4H), 7.25 (dd, 2H), 7.57 (m, 1H), 7.72 (dd, 2H), 7.96 (m, 2H), (imidazoline-NH not visible) ppm
A solution of 1.47 g (8.41 mmol) of 4-cyanophenylpropionic acid, 3.1 g (9.65 mmol) of TBTU and 5.0 ml of triethylamine in 150 ml of tetrahydrofuran was stirred at room temperature for 30 minutes, 2.5 g (8.41 mmol) of N-(3-aminopropyl)-2,3-dichloro-N-methylbenzenesulphonamide were than added and the mixture was stirred overnight. The mixture was evaporated to dryness, potassium carbonate solution (10%) was added to the residue and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, drive over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography (mobile phase: dichloromethane/methanol 150:1 to 100:1).
C20H21Cl2N3O3S (454.37) Yield: 42% of theory 1H-NMR (d6-DMSO): δ=1.61 (m, 2H), 2.36 (t, 2H), 2.82 (s, 3H), 2.89 (t, 2H), 3.01 (m, 2H), 3.18 (t, 2H), 7.04 (d, 2H), 7.57 (t, 1H), 7.72 (d, 2H), 7.80 (t br, NH), 7.94 (m, 2H) ppm
A solution of 0.7 g (1.54 mmol) of 3-(4-cyanophenyl)-N-{3-[(2,3-dichloro-benzenesulphonyl)methylamino]propyl}propionamide, 3 ml of ethylenediamine and 0.10 g (3.12 mmol) of sulphur was stirred at 100° C. for 15 minutes. Water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on alumina (mobile phase: dichloromethane/methanol 100:1) and then crystallized from ethyl acetate/diethyl ether.
C22H26Cl2N4O3S (497.44) Yield: 47% of theory 1H-NMR (d6-DMSO): δ=1.62 (p, 2H), 2.37 (t, 2H), 2.82 (t, 2H), 2.83 (s, 3H), 3.02 (dt, 2H), 3.20 (t, 2H), 3.59 (s br, 4H), 6.80 (s br, 1H), 7.23 (d, 2H), 7.57 (t, 1H), 7.70 (d, 2H), 7.80 (t, 1H), 7.95 (m, 2H) ppm
Analogously to 13b), N-{3-[(2,3-dichlorobenzenesulphonyl)methylamino]propyl}-3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylpropionamide was prepared from 0.7 g (1.49 mmol) of 3-(4-cyanophenyl)-N-{3-[(2,3-dichlorobenzenesulphonyl)methylamino]propyl}-N-methylpropionamide, 0.1 g (3.12 mmol) of sulphur and 3 ml of ethylenediamine.
C23H28Cl2N4O3S×HCl (547.93) Yield: 51% of theory 1H-NMR (d6-DMSO): δ=1.71 (m, 2H), 2.60 (t, 2H), 2.75-2.93 (m, 8H), 3.15-3.85 (m, 8H), 6.80 (s br, 1H), 7.28 (d, 2H), 7.57 (m, 1H), 7.72 (d, 2H), 7.95 (dd, 2H) ppm
Analogously to 13b), 3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methyl-N-{3-[phenyl(toluene-4-sulphonyl)amino]propyl}propionamide was prepared from 1.82 g (3.83 mmol) of 3-(4-cyanophenyl)-N-methyl-N-{3-[phenyl(toluene-4-sulphonyl)amino]propyl}propionamide, 122 mg (3.83 mmol) of sulphur and 7 ml of ethylenediamine.
C29H34N4O3S (518.67) Yield: 68% of theory 1H-NMR (d6-DMSO): δ=1.48 (p, 2H), 2.39 (s, 3H), 2.46-2.59 (m, 2H), 2.69/2.83 (2s, 3H, rotamers), 2.74-2.84 (m, 2H), 3.20-3.35 (m, 2H), 3.50/3.55 (2t, 2H, rotamers), 3.59 (s br, 4H), 6.82 (s br, 1H), 7.00-7.09 (m, 2H), 7.18-7.47 (m, 9H), 7.72 (t, 2H) ppm
Analogously to 13b), N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]propionamide was prepared from 1.15 g (2.65 mmol) of N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-(4-cyanophenyl)propionamide, 85 mg (2.65 mmol) of sulphur and 4 ml of ethylenediamine.
C23H29ClN4O3S (477.02) Yield: 67% of theory 1H-NMR (d6-DMSO): δ=2.35 (t, 2H), 2.37 (s, 3H), 2.47 (s, 3H), 2.76 (s, 3H), 2.82 (t, 2H), 3.10-3.26 (m, 4H), 3.58 (s, 4H), 7.22 (d, 2H), 7.52 (s, 1H), 7.70 (s, 1H), 7.72 (d, 2H), 7.89 (t, 1H), (imidazoline-NH not visible) ppm
A solution of 0.5 g (2.04 mmol) of 2,3-dichlorobenzenesulphonyl chloride, 0.26 g (2.04 mmol) of 1-(2-aminoethyl)-2-imidazolidone and 1 ml (7.18 mmol) of triethylamine in 10 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction mixture was then washed with 1 N HCl and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. The product obtained in this manner was reacted further without additional purification.
C11H13Cl2N3O3S (338.21) Yield: 87% of theory 1H-NMR (d6-DMSO): δ=2.99 (m, 2H), 3.07 (m, 2H), 3.15 (m, 2H), 3.27 (m, 2H), 6.27 (s br, NH), 7.56 (t, 1H), 7.92 (d, 1H), 7.96 (d, 1H), 8.13 (t br, NH) ppm
A solution of 0.57 g (1.69 mmol) of 2,3-dichloro-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide and 0.23 g (1.7 mmol) of potassium carbonate in 10 ml dimethylformamide was stirred at room temperature for 10 minutes, 0.16 ml (1.69 mmol) of dimethyl sulphate were then added and the mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate and concentrated. The product obtained in this manner was crystallized using diethyl ether.
C12H15Cl2N3O3S (352.24) Yield: 72% of theory 1H-NMR (d6-DMSO): δ=2.88 (s, 3H), 3.17 (t, 2H), 3.24 (t, 2H), 3.26-3.38 (m, 4H), 6.28 (s br, NH), 7.56 (t, 1H), 7.95 (m, 2H) ppm
34 mg (0.84 mmol) of NaH (60%) were added to a solution of 290 mg (0.82 mmol) of 2,3-dichloro-N-methyl-N-[2-(2-oxoimidazolidin-1-yl)ethyl]benzenesulphonamide in 10 ml of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. 177 mg (0.84 mmol) of 4-(2-bromoethyl)benzonitrile were then added. The reaction mixture was stirred at 50° C. overnight. The mixture was then poured into water, 1 N HCl was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 0-3%).
C21H22Cl2N4O3S (481.40) Yield: 38% of theory 1H-NMR (d6-DMSO): δ=2.84 (m, 2H), 2.85 (s, 3H), 3.15-3.26 (m, 6H), 3.26-3.37 (m, 4H), 7.45 (d, 2H), 7.56 (t, 1H), 7.74 (d, 2H), 7.94 (d, 2H) ppm
A solution of 137 mg (0.29 mmol) of 2,3-dichloro-N-(2-{3-[2-(4-cyanophenyl)ethyl]-2-oxoimidazolidin-1-yl}ethyl)-N-methylbenzenesulphonamide, 2 ml of ethylenediamine and 4.6 mg (0.14 mmol) of sulphur was stirred at 100° C. for two hours. Water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/NH3 13:1:0.1 to 8:1:0.1). Using etheral hydrochloric acid, the product was then converted into the hydrochloride and freeze-dried.
C23H27Cl2N5O3S (560.92) Yield: 31% of theory 1H-NMR (d6-DMSO): δ=2.86 (s, 2H), 2.87 (m, 2H), 3.17-3.27 (m, 6H), 3.29-3.39 (m, 4H), 3.99 (s, 4H), 3.99 (s, 4H), 7.53 (d, 2H), 7.59 (t, 1H), 7.95 (d, 2H), 7.96 (d, 2H), 10.66 (s, NH) ppm
At room temperature, 0.23 g (9.03 mmol) of sodium hydride (95%) was added to a solution of 1.482 g (6.02 mmol) of tert.-butyl [2-(4-cyanophenyl)ethyl]carbamate in 25 ml of tetrahydrofuran/25 ml of dimethylformamide. The mixture was stirred for a further 15 minutes. 1.49 ml (15.04 mmol) of 1-bromo-3-chloropropane were then added, and the reaction mixture was stirred at room temperature overnight. With ice bath cooling, the mixture was then quenched with water, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 4:1).
C17H23ClN2O4 (322.83) Yield: 26% of theory 1H-NMR (d6-DMSO): δ=1.33 (s br, 9H), 1.88 (m, 2H), 2.86 (t, 2H), 3.22 (t, 2H), 3.39 (t, 2H), 3.58 (t, 2H), 7.41 (d, 2H), 7.76 (d, 2H) ppm
A solution of 626 mg (1.94 mmol) of tert.-butyl (3-chloropropyl)-[2-(4-cyanophenyl)ethyl]carbamate and 5.0 ml of trifluoroacetic acid in 20 ml of dichloromethane was stirred at room temperature for 1.5 hours and then evaporated to dryness. The residue was triturated with diethyl ether. The precipitate formed was then filtered off and dried under reduced pressure over calcium chloride. The product obtained in this manner was reacted further without additional purification.
C12H15ClN2×C2HF3O2 (336.74) Yield: 85% of theory 1H-NMR (d6-DMSO): δ=2.08 (m, 2H), 3.02 (t, 2H), 3.08 (t, 2H), 3.25 (t, 2H), 3.73 (t, 2H), 7.50 (d, 2H), 7.82 (d, 2H), 8.84 (s br, 1H) ppm
With ice bath cooling, a solution of 0.13 g (0.62 mmol) of 4-nitrophenyl chloroformate in 5 ml tetrahydrofuran was added to a solution of 0.25 g (0.62 mmol) of N-(2-aminoethyl)-2,3-dichloro-N-methylbenzenesulphonamide trifluoroacetate and 0.26 ml (1.87 mmol) of triethylamine in 5 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for one hour. The precipitate formed was then filtered off and the filtrate was evaporated to dryness. The crude product obtained in this manner was reacted further without additional purification.
C16H15Cl2N3O6S (448.28) Yield: 100% of theory Rf=0.96 (silica gel, dichloromethane/methanol 9:1)
0.19 ml (1.37 mmol) of triethylamine was added to a solution of 0.31 g (0.62 mmol) of 4-nitrophenyl {2-[(2,3-dichlorobenzenesulphonyl)methylamino]ethyl}carbamate and 0.23 g (0.69 mmol) of 4-[2-(3-chloropropylamino)ethyl]benzonitrile trifluoroacetate in 12 ml of tetrahydrofuran, and the mixture was stirred at 60° C. for 1.5 hours. The mixture was then washed with 1N hydrochloric acid, with saturated sodium hydrogen sulphate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/ethanol 40:1).
C22H25Cl3N4O3S (531.88) Yield: 48% of theory 1H-NMR (d6-DMSO): δ=1.86 (m, 2H), 2.85 (t, 2H), 2.89 (s, 3H), 3.17 (t, 2H), 3.20-3.32 (m, 4H), 3.38 (t, 2H), 3.57 (t, 2H), 6.39 (t br, 1H), 7.46 (d, 2H), 7.56 (t, 1H), 7.75 (d, 2H), 7.93 (d, 2H) ppm
31 mg (0.28 mmol) of potassium tert.-butoxide were added to a solution of 0.147 g (0.28 mmol) of 2,3-dichloro-N-(2-{1-(3-chloropropyl)-3-[2-(4-cyanophenyl)-ethyl]ureido}ethyl)-N-methylbenzenesulphonamide in 8 ml of dimethylformamide, and the mixture was stirred at room temperature for 24 hours. The mixture was then evaporated to dryness. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic extracts were washed with water, saturated sodium hydrogen sulphate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/ethanol 40:1).
C22H24Cl2N4O3S (495.42) Yield: 88% of theory 1H-NMR (d6-DMSO): δ=1.77 (m, 2H), 2.84 (t, 2H), 2.87 (s, 3H), 3.10 (t, 2H), 3.20 (t, 2H), 3.31-3.46 (m, 6H), 7.43 (d, 2H), 7.56 (t, 1H), 7.73 (d, 2H), 7.94 (d, 2H) ppm
A solution of 0.135 g (0.27 mmol) of 2,3-dichloro-N-(2-{3-[2-(4-cyanophenyl)ethyl]-2-oxotetrahydropyrimidin-1-yl}ethyl)-N-methylbenzenesulphonamide, 2 ml of ethylenediamine and 17 mg (0.545 mmol) of sulphur was stirred at 100° C. for one hour. Water was then added, and the reaction mixture was extracted with ethyl acetate. The organic extracts were washed with water and saturated sodium chloride solution, drive over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/ethanol/aqueous ammonia solution 12:1:0.1 to 8:1:0.1).
C24H29Cl2N5O3S (538.49) Yield: 26% of theory 1H-NMR (d6-DMSO): δ=1.76 (m, 2H), 2.78 (t, 2H), 2.88 (s, 3H), 3.09 (t, 2H), 3.20 (t, 2H), 3.23-3.45 (m, 6H), 3.59 (s, 4H), 7.27 (d, 2H), 7.56 (t, 1H), 7.73 (d, 2H), 7.94 (d, 2H), (imidazoline-NH not visible) ppm
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methyl-N-{2-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.62 g (1.32 mmol) of N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methylbutyramide, 48 mg (1.49 mmol) of sulphur and 3 ml of N-methylethylenediamine.
C24H30Cl2N4O3S (525.49) Yield: 62% of theory 1H-NMR (d6-DMSO): δ=1.61/1.72 (2m, 2H, rotamers), 2.07/2.22 (2t, 2H, rotamers), 2.69 (s, 3H), 2.75/2.81 (2t, 2H, rotamers), 2.81 (s, 3H), 2.86 (s, 3H), 3.13/3.22 (2t, 2H, rotamers), 3.29/3.34 (2t, 2H, rotamers), 3.47 (t, 2H), 3.67 (t, 2H), 7.28 (m, 2H), 7.43 (m, 2H), 7.57 (t, 1H), 7.93 (m, 2H) (imidazoline-NH not visible) ppm
Analogously to 13b), 3-[(2,3-dichlorobenzenesulphonyl)methylamino]cyclohexane-N-(2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl})-N-methylcarboxamide was prepared from 0.215 g (0.423 mmol) of N-[2-(4-cyanophenyl)ethyl]-3-[(2,3-dichlorobenzenesulphonyl)methylamino]cyclohexane-N-methylcarboxamide, 6.8 mg (0.211 mmol) of sulphur and 1.2 ml of ethylenediamine.
C26H32Cl2N4O3S×C2HF3O2 (665.55) Yield: 30% of theory 1H-NMR (d6-DMSO): δ=1.01-1.59 (m, 7H), 1.64/1.73 (2m, 1H, rotamers), 2.33/2.65 (2m, 1H, rotamers), 2.70-2.94 (m, 3H), 2.73/2.77 (2s, 3H, rotamers), 2.80/2.86 (2s, 3H, rotamers), 3.36-3.75 (m, 2H), 4.00 (s, 4H), 7.47/7.53 (2d, 2H, rotamers), 7.58 (t, 1H), 7.85/7.90 (2d, 2H, rotamers), 7.87-8.07 (m, 2H), 10.47 (s br, 1H) ppm
Analogously to 13b), 3-[(2,3-dichlorobenzenesulphonyl)methylamino]cyclopentane-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-methylcarboxamide was prepared from 0.185 g (0.374 mmol) of N-[2-(4-cyanophenyl)ethyl]-3-[(2,3-dichlorobenzenesulphonyl)methylamino]cyclopentane-N-methylcarboxamide, 6.0 mg (0.187 mmol) of sulphur and 1 ml of ethylenediamine.
C25H30Cl2N4O3S×C2HF3O2 (651.53) Yield: 59% of theory 1H-NMR (d6-DMSO): δ=1.45-1.78 (m, 6H), 2.73-3.02 (m, 3H), 2.79 (s, 3H), 2.91 (s, 3H), 2.48-3.62 (m, 2H), 4.01 (s, 4H), 4.17 (m, 1H), 7.52 (m, 2H), 7.58 (t, 1H), 7.87 (m, 2H), 7.98 (m, 2H), 10.47/10.49 (2s br, 1H) ppm
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}-N-ethylbutyramide was prepared from 0.74 g (1.53 mmol) of N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-ethylbutyramide, a spatula tip of sulphur and 5 ml of ethylenediamine.
C24H30Cl2N4O3S (525.49) Yield: 37% of theory 1H-NMR (d6-DMSO): δ=1.00/1.04 (2t, 3H, rotamers), 1.66/1.75 (2m, 2H, rotamers), 2.16/2.26 (2t, 2H, rotamers), 2.76/2.83 (2t, 2H, rotamers), 2.82/2.86 (2s, 3H, rotamers), 3.17 (m, 2H), 3.25 (m, 2H), 3.32 (m, 2H), 3.41 (m, 2H), 3.58 (s br, 2H), 7.25/7.30 (2d, 2H, rotamers), 7.57 (t, 1H), 7.73/7.75 (2d, 2H, rotamers), 7.94 (m, 2H), (imidazoline-NH not visible) ppm
Analogously to 13b), N-cyclopropyl-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.84 g (1.70 mmol) of N-[2-(4-cyanophenyl)ethyl]-N-cyclopropyl-4-[(2,3-dichlorobenzenesulphonyl)methylamino]butyramide, 0.143 g (4.46 mmol) of sulphur and 3 ml of ethylenediamine.
C25H30Cl2N4O3S (537.50) Yield: 54% of theory 1H-NMR (d6-DMSO): δ=0.63 (m, 2H), 0.76 (m, 2H), 1.75 (m, 2H), 2.44 (t, 2H), 2.52 (m, 1H), 2.79 (t, 2H), 2.85 (s, 3H), 3.25 (t, 2H), 3.48 (t, 2H), 3.59 (s, 4H), 7.25 (d, 2H), 7.57 (t, 1H), 7.74 (d, 2H), 7.94 (d, 2H), (imidazoline-NH not visible) ppm
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.297 g (0.654 mmol) of N-[2-(4-cyanophenyl)ethyl]4-[(2,3-dichloro-benzenesulphonyl)methylamino]butyramide, 42 mg (1.31 mmol) of sulphur and 1.8 ml of ethylenediamine.
C22H26Cl2N4O3S×C2HF3O2 (611.46) Yield: 46% of theory 1H-NMR (d6-DMSO): δ=1.71 (m, 2H), 2.05 (m, 2H), 2.82 (s, 3H), 2.83 (t, 2H), 3.19 (t, 2H), 3.33 (m, 2H), 4.00 (s, 4H), 7.50 (d, 2H), 7.57 (t, 1H), 7.86 (d, 2H), 7.89-7.97 (m, 2H), 10.45 (s br, 1H) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-3-[(2,5-dichlorobenzenesulphonyl)methylamino]-N-methylpropionamide.
C22H26Cl2N4O3S (497.44) Yield: 39% of theory. 1H-NMR (d6-DMSO): δ=2.40/2.60 (2t, 2H, rotamers), 2.74-2.93 (m, 8H), 3.28-3.55 (m, 4H), 3.61 (s, 4H), 7.20 (s br, 1H), 7.28 (dd, 2H), 7.75 (m, 4H), 7.91 (dd, 1H) ppm
Prepared analogously to Example 13b from 3-[(benzo[b]thiophene-2-sulphonyl)methylamino]-N-[2-(4-cyanophenyl)ethyl]-N-methylpropionamide.
C24H28N4O3S2×HCl (484.64) Yield: 49% of theory. 1H-NMR (d6-DMSO): δ=2.42/2.62 (2t, 2H, rotamers), 2.75-2.97 (m, 8H), 3.16-3.33 (m, 2H), 3.54 (m, 2H), 3.99 (s, 4H), 7.47-7.62 (m, 4H), 7.96 (dd, 2H), 8.03-8.17 (m 3H), 10.76 (d, 2H) ppm
Prepared analogously to Example 13b from 3-[(2-chlorobenzenesulphonyl)-methylamino]-N-[2-(4-cyanophenyl)ethyl]-N-methylpropionamide.
C22H27ClN4O3S×HCl (462.99) Yield: 23% of theory. 1H-NMR (d6-DMSO): δ=2.37/2.60 (2t, 2H, rotamers), 2.76-2.98 (m, 8H), 3.25-3.43 (m, 2H), 3.53 (m, 2H), 4.00 (s, 4H), 7.47-7.60 (m, 3H), 7.68 (m, 2H), 7.95 (m, 3H), 10.63 (d, 2H) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-2-[1-(2,3-dichlorobenzenesulphonyl)pyrrolidin-2-yl]-N-methylacetamide.
C24H28Cl2N4O3S×HCl (523.48) Yield: 44% of theory. 1H-NMR (d6-DMSO): δ=1.40-1.97 (m, 4H), 2.22-2.68 (m, 2H), 2.76-3.00 (m, 5H), 3.23-3.43 (m, 2H), 3.52 (m, 2H), 3.99 (s, 4H), 4.15 (m, 1H), 7.49 (m, 2H), 7.60 (m, 1H), 7.87-8.04 (m, 4H), 10.72 (d, 2H) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-N-methyl-3-[methyl-(2,4,6-trimethylbenzenesulphonyl)amino]propionamide.
C25H34N4O3S×HCl (470.63) Yield: 42% of theory. 1H-NMR (d6-DMSO): δ=2.22-2.35 (m, 4H), 2.44-2.57 (m, 7H), 2.61/2.68 (2s, 3H, rotamers), 2.76-2.95 (m, 5H), 3.18/3.25 (2t, 2H, rotamers), 3.51 (t, 2H), 4.00 (s, 4H), 7.07 (d, 2H), 5.50 (m, 2H), 7.97 (m, 2H), 10.65 (d, 2H) ppm
Prepared analogously to Example 13b from 3-[(2-chloro-6-methylbenzenesulphonyl)methylamino]-N-[2-(4-cyanophenyl)ethyl]-N-methylpropionamide.
C23H29ClN4O3S×HCl (477.02) Yield: 33% of theory. 1H-NMR (d6-DMSO): δ=2.33/2.56 (2t, 2H, rotamers), 2.61/2.63 (2s, 3H, rotamers), 2.72-2.98 (m, 8H), 3.23-3.40 (m, 2H), 3.54 (m, 2H), 4.00 (s, 4H), 7.40 (m, 1H), 7.50 (m, 4H), 7.95 (m, 2H), 10.62 (d, 2H) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-N-methyl-3-[methyl(quinoline-8-sulphonyl)amino]propionamide.
C25H29N5O3S×HCl (479.60) Yield: 43% of theory. 1H-NMR (d6-DMSO): δ=2.32/2.53 (2t, 2H, rotamers), 2.76-2.95 (m, 8H), 3.35-3.55 (m, 4H), 3.99 (s, 4H), 7.49 (d, 2H), 7.67-7.80 (m, 2H), 7.96 (m, 2H), 8.28-8.40 (m, 2H), 8.53 (m, 1H), 9.06 (d, 1H), 10.66 (d, 2H) ppm
Prepared analogously to Example 13b from 3-(4-cyanophenyl)-N-methyl-N-{2-[methyl-(2,4,6-trimethylbenzenesulphonyl)amino]ethyl}propionamide.
C25H34N4O3S×HCl (470.63) Yield: 70% of theory. 1H-NMR (d6-DMSO): δ=2.24/2.25 (2s, 3H, rotamers), 2.46-2.78 (m, 14H), 2.89 (m, 2H), 3.13-3.26 (m, 2H), 3.45 (t, 2H), 3.99 (s, 4H), 7.05 (s, 2H), 7.50 (m, 2H), 8.02 (d, 2H), 10.83 (s, 2H) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-3-[(4-trifluoromethoxybenzenesulphonyl)methylamino]-N-methylpropionamide.
C23H27F3N4O4S×HCl (512.55) Yield: 41% of theory. 1H-NMR (d6-DMSO): δ=2.38/2.56 (2t, 2H, rotamers), 2.65-2.98 (m, 8H), 3.10/3.20 (2t, 2H, rotamers), 3.53 (m, 2H), 3.99 (s, 4H), 7.51 (m, 2H), 7.62 (m, 2H), 7.93 (m, 4H), 10.61 (d, 2H) ppm
Prepared analogously to Example 13b from N-{2-[(4-chloro-2,5-dimethylbenzenesulphonyl)methylamino]ethyl}-3-(4-cyanophenyl)-N-methylpropionamide.
C24H31ClN4O3S×HCl (491.05) Yield: 63% of theory. 1H-NMR (d6-DMSO): δ=2.36/2.37 (2s, 3H, rotamers), 2.46/2.47 (2s, 3H, rotamers), 2.56-2.74 (m, 2H), 2.77-2.99 (m, 8H), 3.23-3.35 (m, 2H), 3.42-3.54 (m, 2H), 3.98 (s, 4H), 7.52 (m, 3H), 7.70/7.72 (2s, 1H, rotamers), 7.98 (d, 2H), 10.75 (s, 2H) ppm
Prepared analogously to Example 13b from 3-[(5-chloro-2-methoxybenzenesulphonyl)methylamino]-N-[2-(4-cyanophenyl)ethyl]-N-methylpropionamide.
C23H29ClN4O4S×HCl (493.02) Yield: 47% of theory. 1H-NMR (d6-DMSO): δ=2.32/2.54 (2t, 2H, rotamers), 2.70-2.98 (m, 8H), 3.21/3.31 (2t, 2H, rotamers), 3.53 (m, 2H), 3.89/3.90 (2s, 3H, rotamers), 4.00 (s, 4H), 7.30 (m, 1H), 7.52 (m, 2H), 7.69 (m, 2H), 7.96 (m, 2H), 10.64 (d, 2H) ppm
Prepared analogously to Example 13b from 3-(4-cyanophenyl)-N-{2-[(2,3-dichlorobenzenesulphonyl)methylamino]ethyl}-N-methylpropionamide.
C22H26Cl2N4O3S×HCl (497.44) Yield: 48% of theory. 1H-NMR (d6-DMSO): δ=2.62/2.72 (2t, 2H, rotamers), 2.80-2.99 (m, 8H), 3.40 (m, 2H), 3.51 (m, 2H), 3.99 (s, 4H), 7.49-7.62 (m, 3H), 7.95 (m, 2H), 8.00 (d, 2H), 10.80 (s, 2H) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-3-(cyclopropanesulphonylmethylamino)-N-methylpropionamide.
C19H28Cl2N4O3S×HCl (392.52) Yield: 23% of theory. 1H-NMR (d6-DMSO): δ=0.81-1.02 (m, 4H), 2.38/2.59 (2t, 2H, rotamers), 2.55-3.00 (m, 9H), 3.22-3.36 (m, 1H), 3.41-3.63 (m, 3H), 4.00 (s, 4H), 7.53 (dd, 2H), 7.94 (dd, 2H), 9.60 (s br, 2H) ppm
Prepared analogously to Example 13b from 4-{3-[4-(2,3-dichlorobenzenesulphonyl)-[1,4]diazepan-1-yl]-3-oxopropyl}benzonitrile.
C23H26Cl2N4O3S×HCl (509.45) Yield: 37% of theory. 1H-NMR (d6-DMSO): δ=1.77 (m, 2H), 2.71 (q, 2H), 2.95 (t, 2H), 3.30-3.66 (m, 8H), 3.92 (s, 4H), 7.49 (d, 2H), 7.57 (t, 1H), 7.86-7.98 (m, 4H), 10.25 (s br, 2H) ppm
Prepared analogously to Example 13b from 4-{3-[4-(2,3-dichloro-benzenesulphonyl)piperazin-1-yl]-3-oxopropyl}benzonitrile.
C22H24Cl2N4O3S×HCl (495.42) Yield: 40% of theory. 1H-NMR (d6-DMSO): δ=2.66 (t, 2H), 2.85 (t, 2H), 3.20 (s br, 4H), 3.51 (s br, 4H), 3.74 (s, 4H), 7.36 (d, 2H), 7.59 (t, 1H), 7.78 (d, 2H), 7.97 (dt, 2H), (imidazoline-NH not visible) ppm
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-2-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-methylacetamide.
C21H24Cl2N4O3S×HCl (483.41) Yield: 22% of theory. 1H-NMR (d6-DMSO): δ=2.70-3.00 (m, 8H), 3.54 (m, 2H), 4.00 (s, 4H), 4.01/4.24 (2s, 2H, rotamers), 7.52 (m, 3H), 7.98 (m, 4H), 10.65/10.67 (2 s br, 1H, rotamers) ppm
A solution of 2.08 g (9.06 mmol) of 3-(benzylmethylamino)propionic acid, 2.72 g (8.96 mmol) of tert.-butyl 2-[4-(2-methylaminoethyl)phenyl]-4,5-dihydroimidazole-1-carboxylate (see procedure 1 g), 5.05 ml (36.24 mmol) of triethylamine and 2.91 g (9.06 mmol) of TBTU in 350 ml of tetrahydrofuran was stirred at room temperature overnight. The mixture was then evaporated to dryness, and the residue was purified by column chromatography (mobile phase: dichloromethane/methanol/aqueous ammonia solution 9:1:0.1).
C28H38N4O3 (478.63) Yield: 84% of theory 1H-NMR (d6-DMSO): δ=1.19/1.20 (2s, 9H), 2.05-2.95 (m, 8H), 2.07/2.13 (2s, 3H), 2.81/2.92 (2s, 3H), 3.47 (m, 2H), 3.83 (m, 4H), 7.18-7.32 (m, 7H), 7.38 (t, 2H) ppm
A suspension of 3.59 g (7.50 mmol) of tert.-butyl 2-[4-(2-{[3-(benzylmethylamino)propionyl]methylamino}ethyl)phenyl]4,5-dihydroimidazole-1-carboxylate and 0.36 g of palladium hydroxide in 40 ml of methanol was hydrogenated in an autoclave for ten hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/aqueous ammonia solution 9:1:0.1 to 4:1:0.1).
C21H32N4O3 (388.50) Yield: 32% of theory 1H-NMR (d6-DMSO): δ=1.19/1.22 (2s, 9H), 2.18-2.94 (m, 6H), 2.23/2.27 (2s, 3H), 2.82/2.93 (2s, 3H), 3.49 (m, 2H), 3.84 (m, 4H), 7.23/7.27 (2d, 2H), 7.38/7.40 (2d, 2H) ppm
6.88 μl (65.77 μmol) of diisopropylethylamine and a solution of 3.26 mg (13.15 μmol) of 3,5-dichlorobenzenesulphonyl chloride in 150 μl of acetonitrile were added to a solution of 7.3 mg (13.15 μmol) of tert.-butyl 2-(4-{2-[methyl-(3-methylaminopropionyl)amino]ethyl}phenyl)-4,5-dihydroimidazole-1-carboxylate in 100 μl of acetonitrile. The reaction mixture was stirred at room temperature for 1.5 hours. 500 μl of a solution of trifluoroacetic acid and water (95/5) were then added, and the mixture was stirred at room temperature for a further 30 min. The reaction mixture was then evaporated to dryness in a Christ-Speedvac. The crude product obtained in this manner was purified by HPLC.
C22H26Cl2N4O3S×C2HF3O2 (611.46) Yield: 66% of theory Retention time (HPLC): 3.87 min
The following compounds were prepared analogously to Example 41:
C22H28N4O3S×C2HF3O2 (542.57) Yield: 51% of theory Retention time (HPLC): 3.11 min
C25H34N4O3S×C2HF3O2 (584.66) Yield: 50% of theory Retention time (HPLC): 3.55 min
C22H26ClN5O5S×C2HF3O2 (622.02) Yield: 43% of theory Retention time (HPLC): 3.41 min
C23H29ClN4O3S×C2HF3O2 (591.05) Yield: 51% of theory Retention time (HPLC): 3.31 min
C25H34N4O3S×C2HF3O2 (584.66) Yield: 65% of theory Retention time (HPLC): 3.51 min
C26H29ClN4O3S×C2HF3O2 (627.08) Yield: 56% of theory Retention time (HPLC): 3.96 min
C23H30N4O3S×C2HF3O2 (556.60) Yield: 58% of theory Retention time (HPLC): 3.25 min
C22H27BrN4O3S×C2HF3O2 (621.47) Yield: 52% of theory Retention time (HPLC): 3.24 min
C23H28Cl2N4O3S×C2HF3O2 (625.49) Yield: 70% of theory Retention time (HPLC): 3.56 min
C26H35N5O6S2×C2HF3O2 (691.74) Yield: 51% of theory Retention time (HPLC): 3.20 min
C22H27N5O5S×C2HF3O2 (587.57) Yield: 45% of theory Retention time (HPLC): 3.23 min
C23H27F3N4O4S×C2HF3O2 (626.57) Yield: 74% of theory Retention time (HPLC): 3.39 min
C22H26N6O4S×C2HF3O2 (584.57) Yield: 24% of theory Retention time (HPLC): 3.15 min
C23H26ClF3N4O3S×C2HF3O2 (645.02) Yield: 50% of theory Retention time (HPLC): 3.55 min
C26H36N4O4S×C2HF3O2 (614.68) Yield: 61% of theory Retention time (HPLC): 3.64 min
C22H26F2N4O3S×C2HF3O2 (578.55) Yield: 62% of theory Retention time (HPLC): 3.28 min
C22H26Cl2N4O4S×C2HF3O2 (627.46) Yield: 53% of theory Retention time (HPLC): 3.22 min
C26H30N4O3S×C2HF3O2 (592.63) Yield: 56% of theory Retention time (HPLC): 3.37 min
C22H26Cl2N4O3S×C2HF3O2 (611.46) Yield: 72% of theory Retention time (HPLC): 3.42 min
C27H38N4O3S×C2HF3O2 (612.71) Yield: 62% of theory Retention time (HPLC): 3.84 min
C24H32N4O3S×C2HF3O2 (570.63) Yield: 52% of theory Retention time (HPLC): 3.39 min
C23H30N4O3S×C2HF3O2 (556.60) Yield: 40% of theory Retention time (HPLC): 3.14 min
C22H26ClFN4O3S×C2HF3O2 (595.01) Yield: 63% of theory Retention time (HPLC): 3.29 min
C23H26ClN5O3S×C2HF3O2 (602.03) Yield: 59% of theory Retention time (HPLC): 3.25 min
C23H30N4O5S2×C2HF3O2 (620.67) Yield: 72% of theory Retention time (HPLC): 3.01 min
C28H32N4O3S×C2HF3O2 (618.67) Yield: 39% of theory Retention time (HPLC): 3.58 min
C23H29FN4O3S×C2HF3O2 (574.59) Yield: 61% of theory Retention time (HPLC): 3.28 min
C22H27N5O5S×C2HF3O2 (587.57) Yield: 53% of theory Retention time (HPLC): 3.22 min
C25H34N6O4S×C2HF3O2 (628.67) Yield: 59% of theory Retention time (HPLC): 2.98 min
C23H27F3N4O3S×C2HF3O2 (610.57) Yield: 61% of theory Retention time (HPLC): 3.46 min
C20H26N4O4S×C2HF3O2 (532.54) Yield: 84% of theory Retention time (HPLC): 3.01 min
C23H29ClN4O3S×C2HF3O2 (591.05) Yield: 22% of theory Retention time (HPLC): 3.27 min
C22H26Cl2N4O3S×C2HF3O2 (611.46) Yield: 63% of theory Retention time (HPLC): 3.30 min
C23H29N5O6S×C2HF3O2 (617.60) Yield: 48% of theory Retention time (HPLC): 3.26 min
C20H26N4O3S×C2HF3O2 (548.60) Yield: 70% of theory Retention time (HPLC): 3.03 min
C24H28N4O3S2×C2HF3O2 (598.66) Yield: 52% of theory Retention time (HPLC): 3.36 min
C28H35N5O3S×C2HF3O2 (635.70) Yield: 79% of theory Retention time (HPLC): 3.09 min
C23H30N4O3S×C2HF3O2 (556.60) Yield: 53% of theory Retention time (HPLC): 3.22 min
C28H32N4O4S×C2HF3O2 (634.67) Yield: 60% of theory Retention time (HPLC): 3.61 min
C23H28Cl2N4O3S×C2HF3O2 (625.49) Yield: 25% of theory Retention time (HPLC): 3.46 min
C26H36N4O4S×C2HF3O2 (614.68) Yield: 53% of theory Retention time (HPLC): 3.46 min
C23H26F3N5O5S×C2HF3O2 (655.57) Yield: 60% of theory Retention time (HPLC): 3.53 min
The following compounds were also prepared analogously to Example 41:
C21H27ClN4O3S2×C2HF3O2 (597.07) Yield: 22% of theory 1H-NMR (d6-DMSO): δ=1.60/1.69 (2m, 2H, rotamers), 2.11/2.28 (2t, 2H, rotamers), 2.67/2.71 (2s, 3H, rotamers), 2.81/2.91 (2s, 3H, rotamers), 2.83-3.02 (m, 4H), 3.54 (m, 2H), 4.00 (s, 4H), 7.35 (d, 1H), 7.50-7.58 (m, 3H), 7.85/7.88 (2d, 2H, rotamers), 10.42 (s br, 1H) ppm
C23H29ClN4O3S×C2HF3O2 (591.04) Yield: 31% of theory 1H-NMR (d6-DMSO): δ=1.60/1.69 (2m, 2H, rotamers), 2.08/2.22 (2t, 2H, rotamers), 2.77/2.81 (2s, 3H, rotamers), 2.80/2.88 (2s, 3H, rotamers), 2.83/2.94 (2t, 2H, rotamers), 3.10/3.18 (2t, 2H, rotamers), 3.52 (t, 2H), 4.00 (s, 4H), 7.50-7.58 (m, 3H), 7.67 (m, 2H), 7.85/7.87 (2d, 2H, rotamers), 7.94 (m, 1H), 10.42 (s br, 1H) ppm
C25H34N4O3S×C2HF3O2 (584.65) Yield: 30% of theory 1H-NMR (d6-DMSO): δ=1.60/1.68 (2m, 2H, rotamers), 2.08/2.22 (2t, 2H, rotamers), 2.34 (s, 3H), 2.46/2.47 (2s, 3H, rotamers), 2.69/2.73 (2s, 3H, rotamers), 2.80/2.88 (2s, 3H, rotamers), 2.85/2.94 (2t, 2H, rotamers), 3.03/3.10 (2t, 2H, rotamers), 3.52 (t, 2H), 4.00 (s, 4H), 7.31/7.36 (2d, 2H, rotamers), 7.49-7.58 (m, 3H), 7.85/7.88 (2d, 2H, rotamers), 10.42/10.43 (2s, 1H, rotamers) ppm
C22H32N6O3S×C2HF3O2 (574.62) Yield: 22% of theory 1H-NMR (d6-DMSO): δ=1.57/1.67 (2m, 2H, rotamers), 2.09/2.27 (2t, 2H, rotamers), 2.30 (s, 3H), 2.61/2.65 (2s, 3H, rotamers), 2.81/2.91 (2s, 3H, rotamers), 2.83-3.00 (m, 4H), 3.60 (s, 3H), 4.00 (s, 4H), 7.53/7.58 (2d, 2H, rotamers), 7.68 (s, 1H), 7.85/7.88 (2d, 2H, rotamers), 10.41/10.44 (2s, 1H, rotamers) ppm
C24H32N4O5S2×C2HF3O2 (634.69) Yield: 32% of theory 1H-NMR (d6-DMSO): δ=1.58/1.67 (2m, 2H, rotamers), 2.12/2.27 (2t, 2H, rotamers), 2.68/2.72 (2s, 3H, rotamers), 2.81/2.90 (2s, 3H, rotamers), 2.83-3.04 (m, 4H), 3.33 (s, 3H), 3.54 (m, 2H), 4.00 (s, 4H), 7.53/7.56 (2d, 2H, rotamers), 7.85/7.89 (2d, 2H, rotamers), 8.00/8.02 (2d, 2H, rotamers), 8.17 (d, 2H), 10.42/10.44 (2s, 1H, rotamers) ppm
C23H29BrN4O3S×C2HF3O2 (635.50) Yield: 23% of theory 1H-NMR (d6-DMSO): δ=1.57/1.66 (2m, 2H, rotamers), 2.11/2.26 (2t, 2H, rotamers), 2.65/2.68 (2s, 3H, rotamers), 2.81/2.91 (2s, 3H, rotamers), 2.83-3.01 (m, 4H), 3.54 (m, 2H), 4.00 (s, 4H), 7.50-7.63 (m, 3H), 7.76 (t, 1H), 7.83-7.95 (m, 4H), 10.41/10.43 (2s, 1H, rotamers) ppm
C21H26BrClN4O3S2×C2HF3O2 (675.97) Yield: 27% of theory Retention time (HPLC): 3.51 min
C21H26BrClN4O3S2×C2HF3O2 (675.97) Yield: 32% of theory Retention time (HPLC): 3.41 min
C21H26Cl2N4O3S2×C2HF3O2 (631.52) Yield: 23% of theory Retention time (HPLC): 3.50 min
C22H31N5O3S2×C2HF3O2 (591.67) Yield: 19% of theory Retention time (HPLC): 2.97 min
C22H31ClN6O3S×C2HF3O2 (609.07) Yield: 40% of theory Retention time (HPLC): 2.97 min
C23H29Cl2N5O3S×C2HF3O2 (640.51) Yield: 38% of theory Retention time (HPLC): 3.21 min
C23H27Cl3N4O3S×C2HF3O2 (659.94) Yield: 25% of theory Retention time (HPLC): 3.51 min
C23H28Cl2N4O3S×C2HF3O2 (625.49) Yield: 32% of theory Retention time (HPLC): 3.32 min
C23H28Cl2N4O3S×C2HF3O2 (625.49) Yield: 26% of theory Retention time (HPLC): 3.42 min
C23H29BrN4O3S×C2HF3O2 (635.50) Yield: 34% of theory Retention time (HPLC): 3.29 min
C23H29FN4O3S×C2HF3O2 (574.59) Yield: 30% of theory Retention time (HPLC): 3.11 min
C23H29FN4O3S×C2HF3O2 (574.59) Yield: 33% of theory Retention time (HPLC): 3.14 min
C23H29ClN4O3S×C2HF3O2 (591.05) Yield: 28% of theory Retention time (HPLC): 3.24 min
C24H29F3N4O3S×C2HF3O2 (624.60) Yield: 36% of theory Retention time (HPLC): 3.24 min
C24H31ClN4O4S×C2HF3O2 (621.07) Yield: 31% of theory Retention time (HPLC): 3.25 min
C24H32N4O3S×C2HF3O2 (570.63) Yield: 21% of theory Retention time (HPLC): 3.19 min
C24H32FN4O4S×C2HF3O2 (586.63) Yield: 32% of theory Retention time (HPLC): 3.10 min
C25H32ClN5O4S×C2HF3O2 (648.10) Yield: 34% of theory Retention time (HPLC): 2.98 min
C25H34N4O5S×C2HF3O2 (616.65) Yield: 33% of theory Retention time (HPLC): 3.09 min
C25H34N4O5S×C2HF3O2 (616.65) Yield: 37% of theory Retention time (HPLC): 3.02 min
C26H36N4O3S×C2HF3O2 (598.68) Yield: 32% of theory Retention time (HPLC): 3.37 min
C27H32N4O3S×C2HF3O2 (606.66) Yield: 28% of theory Retention time (HPLC): 3.35 min
C27H38N4O3S×C2HF3O2 (612.71) Yield: 29% of theory Retention time (HPLC): 3.46 min
C23H29N5O5S×C2HF3O2 (601.60) Yield: 2% of theory Retention time (HPLC): 3.11 min
C24H29N5O3S×C2HF3O2 (581.61) Yield: 2% of theory Retention time (HPLC): 3.06 min
C23H29Cl2N5O3S×C2HF3O2 (640.51) Yield: 2% of theory Retention time (HPLC): 3.15 min
C27H38N4O3S×C2HF3O2 (612.71) Yield: 18% of theory Retention time (HPLC): 3.53 min
C27H38N4O4S×C2HF3O2 (628.71) Yield: 30% of theory Retention time (HPLC): 3.58 min
C23H28Cl2N4O3S×C2HF3O2 (625.49) Yield: 27% of theory Retention time (HPLC): 3.37 min
C23H28ClFN4O3S×C2HF3O2 (609.04) Yield: 21% of theory Retention time (HPLC): 3.22 min
C24H31FN4O3S×C2HF3O2 (588.62) Yield: 25% of theory Retention time (HPLC): 3.22 min
C24H31N5O6S×C2HF3O2 (631.62) Yield: 42% of theory Retention time (HPLC): 3.20 min
C24H32N4O3S×C2HF3O2 (570.63) Yield: 24% of theory Retention time (HPLC): 3.16 min
C27H38N4O4S×C2HF3O2 (628.71) Yield: 37% of theory Retention time (HPLC): 3.37 min
C26H36N4O3S×C2HF3O2 (598.68) Yield: 16% of theory Retention time (HPLC): 3.48 min
C24H30Cl2N4O3S×C2HF3O2 (639.52) Yield: 37% of theory Retention time (HPLC): 3.45 min
C23H28F2N4O3S×C2HF3O2 (592.58) Yield: 19% of theory Retention time (HPLC): 3.21 min
C28H40N4O3S×C2HF3O2 (626.74) Yield: 32% of theory Retention time (HPLC): 3.77 min
C24H28ClN5O3S×C2HF3O2 (616.06) Yield: 26% of theory Retention time (HPLC): 3.19 min
C23H29N5O5S×C2HF3O2 (601.60) Yield: 18% of theory Retention time (HPLC): 3.16 min
C21H28N4O4S×C2HF3O2 (546.56) Yield: 47% of theory Retention time (HPLC): 2.93 min
C21H28N4O4S×C2HF3O2 (546.56) Yield: 42% of theory Retention time (HPLC): 2.89 min
C21H28N4O3S2×C2HF3O2 (562.63) Yield: 23% of theory Retention time (HPLC): 2.95 min
C29H34N4O4S×C2HF3O2 (648.70) Yield: 33% of theory Retention time (HPLC): 3.50 min
C27H31ClN4O3S×C2HF3O2 (641.11) Yield: 21% of theory Retention time (HPLC): 3.49 min
C27H37N5O6S2×C2HF3O2 (705.77) Yield: 45% of theory Retention time (HPLC): 3.09 min
C24H28ClF3N4O3S×C2HF3O2 (659.04) Yield: 31% of theory Retention time (HPLC): 3.45 min
C23H28Cl2N4O4S×C2HF3O2 (641.49) Yield: 28% of theory Retention time (HPLC): 3.11 min
C25H34N4O3S×C2HF3O2 (584.66) Yield: 28% of theory Retention time (HPLC): 3.31 min
C24H32N4O5S2×C2HF3O2 (634.69) Yield: 22% of theory Retention time (HPLC): 2.91 min
C26H36N6O4S×C2HF3O2 (642.69) Yield: 57% of theory Retention time (HPLC): 2.91 min
C25H30N4O3S2×C2HF3O2 (612.69) Yield: 35% of theory Retention time (HPLC): 3.31 min
C24H28F3N5O5S×C2HF3O2 (669.60) Yield: 23% of theory Retention time (HPLC): 3.41 min
C23H28ClN5O5S×C2HF3O2 (636.04) Yield: 34% of theory Retention time (HPLC): 3.29 min
C24H32N4O3S×C2HF3O2 (570.63) Yield: 25% of theory Retention time (HPLC): 3.18 min
C25H33N5O4S×C2HF3O2 (613.65) Yield: 58% of theory Retention time (HPLC): 2.86 min
C23H29N5O5S×C2HF3O2 (601.60) Yield: 32% of theory Retention time (HPLC): 3.12 min
C23H30N4O3S×C2HF3O2 (556.60) Yield: 21% of theory Retention time (HPLC): 3.04 min
C27H32N4O3S×C2HF3O2 (606.66) Yield: 16% of theory Retention time (HPLC): 3.27 min
C29H34N4O3S×C2HF3O2 (632.70) Yield: 17% of theory Retention time (HPLC): 3.50 min
C24H29F3N4O3S×C2HF3O2 (624.60) Yield: 27% of theory Retention time (HPLC): 3.35 min
C23H28Cl2N4O3S×C2HF3O2 (625.49) Yield: 28% of theory Retention time (HPLC): 3.21 min
C29H37N5O3S×C2HF3O2 (649.73) Yield: 36% of theory Retention time (HPLC): 3.00 min
C21H28N4O3S2×C2HF3O2 (562.63) Yield: 39% of theory Retention time (HPLC): 3.01 min
C27H36N4O5S×C2HF3O2 (642.69) Yield: 22% of theory Retention time (HPLC): 3.16 min
C22H29N5O3S×C2HF3O2 (557.59) Yield: 11% of theory Retention time (HPLC): 2.81 min
C24H31ClN4O3S×C2HF3O2 (605.07) Yield: 26% of theory Retention time (HPLC): 3.32 min
C23H29ClN4O3S×C2HF3O2 (591.05) Yield: 28% of theory Retention time (HPLC): 3.23 min
C24H29F3N4O3S×C2HF3O2 (624.60) Yield: 30% of theory Retention time (HPLC): 3.32 min
C22H31N5O4S×C2HF3O2 (575.60) Yield: 17% of theory Retention time (HPLC): 2.99 min
C21H30N6O3S×C2HF3O2 (560.59) Yield: 29% of theory Retention time (HPLC): 2.62 min
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-propylbutyramide.
C25H32Cl2N4O3S (539.52) Yield: 48% of theory [M+H]+=539/541/543
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-isopropylbutyramide.
C25H32Cl2N4O3S (539.52) Yield: 28% of theory [M+H]+=539/541/543
Prepared analogously to Example 13b from N-[2-(4-cyanophenyl)ethyl]-4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-(2,2,2-trifluoroethyl)butyramide.
C24H27Cl2F3N4O3S (579.46) Yield: 53% of theory [M+H]+=579/581/583
The following compounds can also be prepared analogously to the above-mentioned examples:
Prepared analogously to Example 13b) from N-[2-(4-cyanophenyl)ethyl]4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-(2-fluoroethyl)butyramide.
C24H25Cl2FN4O3S (543.48) [M+H]+=543/545/547
Prepared analogously to Example 13b) from N-[2-(4-cyanophenyl)ethyl]4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-phenylbutyramide.
C28H30Cl2N4O3S (573.53) [M+H]+=573/575/577
The examples below describe pharmaceutical administration forms comprising, as active compound, any compound of the formula I:
Dry Ampoule with 75 mg of Active Compound per 10 ml
Composition:
Production:
Active compound and mannitol are dissolved in water. The charged ampoules are freeze dried. Water for injection is used to dissolve to give the solution ready for use.
Tablet with 50 mg of Active Compound
Composition:
Production:
(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.
Diameter of the tablets: 9 mm.
Tablet with 350 mg of Active Compound
Composition:
Production:
(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.
Diameter of the tablets: 12 mm.
Capsule with 50 mg of Active Compound
Composition:
Production:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into hard gelatin two-piece capsules of size 3 in a capsule-filling machine.
Capsule with 350 mg of Active Compound
Composition:
Production:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring.
This powder mixture is packed into hard gelatin two-piece capsules of size 0 in a capsule-filling machine.
Suppositories with 100 mg of Active Compound
1 suppository comprises:
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2004 054 053 | Nov 2004 | DE | national |
| 10 2005 013 967 | Mar 2005 | DE | national |
| Number | Name | Date | Kind |
|---|---|---|---|
| 7056937 | Grant et al. | Jun 2006 | B2 |
| 7105172 | Bolla | Sep 2006 | B1 |
| Number | Date | Country |
|---|---|---|
| WO 03106428 | Dec 2003 | WO |
| WO 2004054584 | Jul 2004 | WO |
| WO 2004083173 | Sep 2004 | WO |
| WO 2007003411 | Jan 2007 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20060100219 A1 | May 2006 | US |
