DE19962928A1 - New aminosulfonyl-substituted 3H-imidazo (1,5-a) (1,3,5) triazin-4-one derivatives, are phosphodiesterase inhibitors, useful for treating cardiovascular, cerebrovascular or urogenital disorders - Google Patents

Abstract

2-(2-Oxy-5-(amino-sulfonyl)-phenyl)-3H-imidazo (1,5-a) (1,3,5) triazin-4-ones (I), their salts, N-oxides or isomers are new. 2-(2-Oxy-5-(amino-sulfonyl)-phenyl)-3H-imidazo (1,5-a) (1,3,5) triazin-4-ones of formula (I), their salts, N-oxides or isomers are new. R1 = 1-4C alkyl; R2 = 1-4C alkyl or 3-8C cycloalkyl; R3 = H or 1-4C alkyl; R4, R5 = H, alkoxy, 1-6C alkoxy, OH or 1-8C alkyl (optionally substituted by 1-3 of OH, alkoxy, tetrahydrofuran-2-yl, morpholino, pyrrolidino or NR6R7; or phenyl or phenoxy (themselves optionally substituted by halo, OH, 1-6C alkoxy, 1-6C alkyl or SO2NR8R9)); or R4 = H or Me; and R4 = 1,1-dioxo-tetrahydro-3-thienyl, 2-oxo-perhydroazepin-3-yl or phenyl (optionally substituted by 1-3 of halo, COMe, alkoxy, cyclopentyloxy, NR10R11 or CH2P(O)(OR12)(OR13)); or NR4R5 = piperidino substituted by R14 and R15, 4-(R16)-piperazino or morpholino; R6-R9, R12, R13 = H or alkyl; R10, R11 = H or 1-4C alkyl; R14, R5 = H, OH or 1-4C alkyl (optionally substituted by OH); or R14 = H; and R15 = 5,6-dihydro-1,4,2-dioxazin-3-yl or CR14R15 = C=NOMe; R16 = H, 1-6C alkyl (optionally substituted by OH) or 5- or 6-membered aromatic heterocycle containing 1-3 of O, N and S as heteroatom(s); alkyl moieties have 1-6C unless specified otherwise. An Independent claim is included for the preparation of (I).

Description

The present invention relates to novel imidazo [1,3,5] triazinones, processes for their Production and their use as pharmaceuticals, in particular as inhibitors cGMP-metabolizing phosphodiesterases.

The synthesis of imidazo [1,3,5] triazinones is described in J. Org. Chem. (1979), 44 (10), 1740-2; in J. Org. Chem. (1979), 44 (22), 3835-9; in J. Org. Chem. (1981), 46 (18), 3681-5 and J. Chem. Res. Synop. (1994), (3), 96-7. No biological effects are reported. Imidazo [1,3,5] triazinones with antiviral and / or antitumor activity are described in Nucleosides Nucleotides (1987), 6 (4), 663-78; in Eur., J. Med. Chem. (1992), 27 (3), 259-66; in J. Heterocycl. Chem. (1993), 30 (5), 1341-9; in J. Med. Chem. (1995), 38 (18), 3558-68 and Biorg. Med. Chem. Lett. (1996), 6 (2), 185-8. The compounds mentioned in these references were mostly produced as guanine or guanosine analogs and are therefore generally substituted in the 2-position with -NH ₂ , -SH or -H. None of the compounds described contains a phenyl ring or a substituted phenyl ring in the 2-position. None of the described compounds has an inhibitory activity against phosphodiesterases.

The compounds according to the invention are potent inhibitors of cyclic Guanosine 3 ', 5'-monophophate metabolizing phosphodiesterases (eGMP -PDE's). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) is the phosphodiesterase isoenzyme PDE-I, PDE- II and PDE-V.

An increase in the eGMP concentration can lead to beneficial, anti-aggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilating, lead natriuretic and diuretic effects. It can be the short or Long-term modulation of vascular and cardiac inotropy, the heart rhythm and the affect cardiac conduction (J.C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100). The inhibition of  cGMP-PDE's can also increase erection. Therefore, there are Compounds suitable for erectile dysfunction treatment.

The present invention now relates to new imidazo [1,3,5] triazinones of the general formula (I),

in which
R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 represents} straight-chain or branched alkyl having up to 4 carbon atoms, or
represents (C ₃ -C ₆ ) cycloalkyl,
R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R ⁴ and R ^{5 are} identical or different and stand for hydrogen, (C ₁ -C ₆ ) alkoxy, hydroxy or for (C ₁ -C ₈ ) alkyl, optionally up to 3 times, identical or different, by Hydroxy, (C ₁ -C ₆ ) alkoxy or by residues of the formulas

is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and / or (C ₁ -C ₈ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by halogen, hydroxy, (C ₁ -C ₆ ) -alkoxy, (C ₁ - C ₆ ) -alkyl or are substituted by a radical of the formula -SO ₂ NR ⁸ R ⁹ ,
wherein
R ⁸ and R ^{9 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
or
R ^{4 represents} hydrogen or methyl,
and
R ⁵ for residues of the formulas

stands,
or
represents phenyl, optionally up to 3 times, identical or different, by halogen, acetyl, (C ₁ -C ₆ ) -alkoxy or by radicals of the formulas

is substituted,
wherein
R ¹⁰ and R ^{11 are} identical or different and are hydrogen or (C ₁ -C ₄ ) -alkyl,
R ¹² and R ^{13 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
or
R ⁴ and R ⁵ together with the nitrogen atom are residues of the formulas

form,
wherein
R ¹⁴ and R ^{15 are the} same or different and denote hydroxy, hydrogen or (C ₁ -C ₄ ) -alkyl, which is optionally substituted by hydroxy,
or
R ^{14 is} hydrogen, and
R ^{15 is} a radical of the formula

means
or
R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,
R ^{16 is} hydrogen or (C ₁ -C ₆ ) alkyl, which is optionally substituted by hydroxy, or
is a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means
and their salts, N-oxides and isomeric forms.

The compounds according to the invention can exist in stereoisomeric forms either like image and mirror image (enantiomers), or which are not like image and Mirror image (diastereomers) behave, exist. The invention relates to both Enantiomers or diastereomers or their respective mixtures. The Racemfor Like the diastereomers, they can be converted into the stereoisomer in a known manner separate uniform components.

The substances according to the invention can also be present as salts. As part of the Invention physiologically acceptable salts are preferred.  

Physiologically acceptable salts can be salts of the compound according to the invention with inorganic or organic acids. Salts are preferred with inorganic acids such as hydrochloric acid, hydrobromic acid, Phosphoric acid or sulfuric acid, or salts with organic carbon or Sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, Citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, Ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfone acid.

Physiologically acceptable salts can also be metal or ammonium salts compounds of the invention. Z are particularly preferred. B. sodium, Potassium, magnesium or calcium salts, as well as ammonium salts, which are derived are of ammonia, or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethyl aminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine

(C ₃ -C ₈ ) Cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl.

(C ₁ -C ₈ ) -alkyl, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₄ ) -alkyl stands for a straight-chain or branched alkyl radical with 1 to 8, 1 to 6 or 1 to 4 Carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms is particularly preferred.

(C ₁ -C ₆ ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred.

A straight-chain or branched alkoxy radical with 1 to 3 is particularly preferred Carbon atoms.

Halogen generally represents fluorine, chlorine, bromine and iodine. Fluorine is preferred, Chlorine and bromine. Fluorine and chlorine are particularly preferred.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Row S, O and / or N stands for example for pyridyl, pyrimidyl, pyridazinyl, Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preferred are pyridyl, Pyrimidyl, pyridazinyl, furyl and thienyl.

Preferred compounds of the general formula (I) according to the invention are those in which
R ^{1 represents} methyl or ethyl,
R ^{2 represents} straight-chain or branched alkyl having up to 3 carbon atoms, or
represents cyclopentyl,
R ^{3 represents} straight-chain or branched alkyl having up to 3 carbon atoms,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, (C ₁ -C ₄ ) alkoxy, hydroxy or (C ₁ -C ₇ ) alkyl, which may be up to 3 times the same or different Hydroxy, (C ₁ -C ₄ ) alkoxy or by residues of the formulas

is substituted,
wherein
R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,
and / or (C ₁ -C ₇ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, chlorine, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl or are substituted by a radical of the formula -SO ₂ NR ⁸ R ⁹ ,
wherein
R ⁸ and R ^{9 are} hydrogen,
or
R ^{4 represents} hydrogen or methyl,
and
R ⁵ for residues of the formulas

stands,
or
represents phenyl, optionally up to 3 times, identical or different, by fluorine, chlorine, acetyl, (C ₁ -C ₄ ) -alkoxy or by radicals of the formulas

is substituted,
wherein
R ¹⁰ and R ^{11 are the} same or different and are hydrogen or methyl,
R ¹² and R ^{13 are the} same or different and are hydrogen or methyl,
or
R ⁴ and R ⁵ together with the nitrogen atom are residues of the formulas

form,
wherein
R ¹⁴ and R ^{15 are} identical or different and denote hydroxy, hydrogen or (C ₁ -C ₃ ) -alkyl, which is optionally substituted by hydroxy,
or
R ¹⁴ means hydrogen,
and
R ^{15 is} a radical of the formula

means
or
R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,
R ^{16 is} hydrogen or (C ₁ -C ₅ ) alkyl, which is optionally substituted by hydroxy, or is pyridyl, pyrimidyl, furyl, pyrryl or thienyl
and their salts, N-oxides and isomeric forms.

Compounds of the general formula (I) according to the invention are particularly preferred
in which
R ^{1 represents} methyl or ethyl,
R ^{2 stands} for n-propyl or stands for cyclopentyl,
R ^{3 represents} methyl, ethyl or n-propyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, (C ₁ -C ₃ ) alkoxy, hydroxy or (C ₁ -C ₆ ) alkyl, which may be up to 3 times the same or different Hydroxy, (C ₁ -C ₃ ) alkoxy or by residues of the formulas

or -NR ⁶ R ⁷
is substituted,
wherein
R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,
and / or (C ₁ -C ₆ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, hydroxy, methoxy or by a radical of the formula -SO ₂ NR ⁸ R ⁹ are substituted,
wherein
R ⁸ and R ^{9 are} hydrogen,
or
R ^{4 represents} hydrogen or methyl,
and
R ⁵ for residues of the formulas

stands,
or
represents phenyl, optionally up to 3 times, identical or different, by fluorine, acetyl, methoxy or by radicals of the formulas

is substituted,
wherein
R ¹⁰ and R ^{11 are the} same or different and are hydrogen or methyl,
R ¹² and R ^{13 are} methyl,
or
R ⁴ and R ⁵ together with the nitrogen atom are residues of the formulas

form,
wherein
R ¹⁴ and R ^{15 are the} same or different and are hydroxyl, hydrogen or a radical of the formula - (CH ₂ ) ₂ -OH,
or
R ¹⁴ means hydrogen,
and
R ^{15 is} a radical of the formula

means
or
R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,
R ^{16 is} hydrogen, pyrimidyl or a radical of the formula - (CH ₂ ) ₂ -OH
and their salts, N-oxides and isomeric forms.

The following compounds according to the invention are very particularly preferred:

We have also found a process for preparing the compounds of the general formula (I) according to the invention, characterized in that compounds of the general formula (II)

in which
R ¹ , R ² and R ^{3 have} the meaning given above,
first by reaction with chlorosulfonic acid (ClSO ₃ H) in inert solvents, if appropriate in the presence of a base, into the compounds of the general formula (III)

in which
R ¹ , R ² and R ^{3 have} the meaning given above,
transferred and in a last step with amines of the general formula (IV)

HN-R ⁴ R ⁵ (IV)

in which
R ⁴ and R ^{5 have} the meaning given above,
implements.

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

The usual organic solvents are suitable as solvents for the individual steps Solvents that do not change under the reaction conditions. This includes preferably ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetra chloromethane, dichloroethane, trichlorethylene or chlorobenzene, or ethyl acetate, dime thylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to mix mixtures of the solvents mentioned turn. Ethanol is particularly preferred for the first step and ethanol for the second Step dichloroethane.

The reaction temperature can generally be varied within a substantial range become. In general, a range from -20 ° C. to 200 ° C. is preferred from 0 ° C to 70 ° C.

The process steps according to the invention are generally carried out at normal pressure carried out. However, it is also possible to operate at overpressure or underpressure lead (e.g. in a range of 0.5 to 5 bar).

The conversion to the compounds of general formula (V) takes place in one Temperature range from 0 ° C to room temperature and normal pressure.

The reaction with the amines of the general formula (VI) takes place in one of the chlorinated hydrocarbons listed above, preferably in dichloromethane.

The reaction temperature can generally be varied within a substantial range become. In general, a range from -20 ° C. to 200 ° C. is preferred from 0 ° C to room temperature.  

The reaction is generally carried out at normal pressure. It is also possible to perform at overpressure or underpressure (e.g. in a range of 0.5 to 5 bar).

The compounds of general formula (II) are new and can be prepared by using compounds of general formula (V)

in which
R ^{1 has} the meaning given above,
in the NaOC ₂ H ₅ / C ₂ H ₅ OH system with compounds of the general formula (VI)

R ² halogen (VI)

in which
R ^{2 has} the meaning given above;
to the compounds of the general formula (VII)

in which
R ¹ and R ^{2 have} the meaning given above,
implements
then also in the NaO ₂ H ₅ / C ₂ H ₅ OH system, a reaction with compounds of the general formula (VIII)

in which
R ^{3 have} the meaning given above,
to the compounds of the general formula (IX)

in which
R ¹ , R ² and R ^{3 have} the meaning given above,
performs,
and finally cyclized in inert solvents in the presence of HMDS and TMSCl.

The usual organic solvents are suitable as solvents for the individual steps Solvents that do not change under the reaction conditions. This includes preferably ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or Hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetra chloromethane, dichloroethane, trichlorethylene or chlorobenzene, or ethyl acetate, dime thylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to mix mixtures of the solvents mentioned turn. Ethanol is particularly preferred for the first step and ethanol for the second Step dichloroethane.

The reaction temperature can generally be varied within a substantial range become. In general, a range from -20 ° C. to 200 ° C. is preferred from 0 ° C to 70 ° C.

The process steps according to the invention are generally carried out at normal pressure carried out. However, it is also possible to operate at overpressure or underpressure lead (e.g. in a range of 0.5 to 5 bar).

The conversion to the compounds of general formula (V) takes place in one Temperature range from 0 ° C to room temperature and normal pressure.

The reaction with the amines of the general formula (VI) takes place in one of the chlorinated hydrocarbons listed above, preferably in dichloromethane.

The reaction temperature can generally be varied within a substantial range become. In general, a range from -20 ° C. to 200 ° C. is preferred from 0 ° C to room temperature.  

The reaction is generally carried out at normal pressure. It is also possible to perform at overpressure or underpressure (e.g. in a range of 0.5 to 5 bar).

The compounds of general formula (III) are new and can be as above described.

The compounds of the general formulas (IV), (V), (VI), (VII) and (VIII) are on is known or can be produced by customary methods.

The compounds of general formula (IX) are partly new and can be usual methods are produced.

The compounds of the general formula (I) according to the invention do not show one predictable, valuable pharmacological spectrum of action.

They inhibit either one or more of the c-GMP metabolizing phospho diesterases (PDE I, PDE II and PDE V). This leads to an increase in c-GMP. The differentiated expression of phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in conjunction with the selective inhibitors according to the invention enable a selective addressing of the various processes regulated by cGMP.

In addition, the compounds of the invention enhance the action of Substan zen, such as EDRF (Endothelium derived relaxing factor), ANP (atrial natriuretic peptide), of nitrovasodilators and all other substances acting on one other than phosphodiesterase inhibitors increase the cGMP concentration.

The compounds of the general formula (I) according to the invention are therefore suitable for the prophylaxis and / or treatment of diseases in which an increase in cGMP concentration is beneficial, d. H. Diseases related to  cGMP-regulated processes are usually simply called "cGMP-related diseases "). These include cardiovascular diseases, diseases of the Genitourinary and cerebrovascular diseases.

Under the term "cardiovascular diseases" in the sense of the present Invention diseases such as high blood pressure, neuronal fall Hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, Arrhythmias, thromboembolic disorders and ischemia such as myocardial infarction, Stroke, transistoric and ischemic attacks, angina pectoris, peripheral Circulatory disorders, prevention of restenosis after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angio plastic (PTCA) and bypass.

Furthermore, the compounds of the general formula (I) according to the invention also have significance for cerebrovascular diseases. Which includes for example cerebral ischemia, stroke, reperfusion damage, brain trauma, Edema, cerebral thrombosis, dementia and Alzheimer's disease.

The relaxing effect on smooth muscles makes them suitable for treatment of diseases of the genitourinary system such as prostate hypertrophy, incontinence as well especially for the treatment of erectile dysfunction and female sexual Dysfunction.

Activity of phosphorus diesterases (PDE's)

The cGMP stimulable PDE II, the cGMP-inhibitable PDE III and the cAMP-specific PDE IV were isolated from either pig or bovine myocardium. The Ca ²⁺ -calmodulin stimulable PDE I was isolated from pig aorta, pig brain or preferably from bovine aorta. The c-GMP specific PDE V was obtained from small intestine, pig aorta, human platelets and preferably from bovine aorta. The purification was carried out by anion exchange chromatography on MonoQ® Pharmacia essentially according to the method of M. Hoey and Miles D. Houslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al. Biochemical Pharmacology Vol. 35 1743-1751 (1986).

The enzyme activity is determined in a test batch of 100 μl in 20 mM Tris / HCl buffer pH 7.5 which contains 5 mM MgCl ₂ , 0.1 mg / ml bovine serum albumin and either 800 Bq ³ HcAMP or ³ HcGMP. The final concentration of the corresponding nucleotides is 10 ^-6 mol / l. The reaction is started by adding the enzyme, the amount of enzyme is such that approximately 50% of the substrate is converted during the incubation period of 30 minutes. In order to test the cGMP stimulable PDE II, ³ HcAMP is used as the substrate and 10 ^-6 mol / l unlabeled cGMP is added to the batch. To test the Ca ²⁺ -calmodulin-dependent PDE I, CaCl ₂ 1 µM and calmodulin 0.1 µM are added to the reaction mixture. The reaction is stopped by adding 100 μl of acetonitrile which contains 1 mM cAMP and 1 mM AMP. 100 ul of the reaction mixture are separated on the HPLC and the cleavage products are determined "online" with a flow scintillation counter quantitatively. The substance concentration at which the reaction rate is reduced by 50% is measured. In addition, the "Phosphodiesterase [ ³ H] cAMP-SPA enzyme assay" and the "Phosphodiesterase [ ³ H] cGMP-SPA enzyme assay" from Amersham Life Science were used. The test was carried out according to the test protocol specified by the manufacturer. The [ ³ H] cAMP SPA assay was used to determine the activity of the PDEII, 10 ^-6 M cGMP being added to the reaction mixture to activate the enzyme. For the measurement of the PDEI, Calmodulin 10 ^-7 M and CaCl ₂ 1 µM were added to the reaction mixture. The PDEV was measured with the [ ³ H] cGMP SPA assay.

Basically, inhibition of one or more phosphodiesterases of this type leads to an increase in the cGMP concentration. This makes the connections interesting sant for all therapies, in which an increase of the cGMP concentration as healing can be accepted.  

The study of cardiovascular effects was carried out on normotonic and SH- Rats and performed on dogs. The substances were administered intravenously or orally applied.

The investigation for erection-inducing effects was carried out on the awake rabbit [Naganuma H, Egashira T, Fuji J, Clinical and Experimental Phar macology and Physiology 20, 177-183 (1993)]. The substances were orally or applied parenterally.

The new active ingredients and their physiologically acceptable salts (e.g. Hydro chloride, maleinate or lactate) can be known in the usual form lations are transferred, such as tablets, coated tablets, pills, granules, aerosols, Syrups, emulsions, suspensions and solutions, using inert ones, not toxic, pharmaceutically suitable carriers or solvents. Here, the therapeutically active compound in a concentration of about 0.5 to 90% by weight of the total mixture is present, i.e. H. in amounts that are sufficient are in order to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients substances with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, z. B. in the case of use of water as a diluent, optionally organic solvents Auxiliary solvents can be used.

The application takes place in the usual way, preferably orally, transdermally or parenterally, e.g. B. perlingual, buccal, intravenous, nasal, rectal or inhalation.

Dosages are used for oral administration in humans from 0.001 to 50 mg / kg, preferably 0.01 mg / kg-20 mg / kg, makes sense administered. With parenteral administration, e.g. B. via mucous membranes nasally, buccally, inhalation, a dosage of 0.001 mg / kg-0.5 mg / kg is advisable.  

Nevertheless, it may be necessary to deviate from the quantities mentioned give way, depending on the body weight or the type of application path, from individual behavior towards the drug, the type of its formulation and the time or interval at which the administration he follows. So in some cases it may be sufficient with less than that above mentioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. In the case of application of larger quantities it may be advisable to distribute them in several single doses throughout the day.

The compounds of the invention are also for use in veterinary medicine suitable. For applications in veterinary medicine, the compounds or their non-toxic salts in a suitable formulation in accordance with the general veterinary practices. The veterinarian can the application and the dosage according to the type of animal to be treated.  

In the following production examples of the precursors and end products is in Structural formulas with one or more unsaturated valences on nitrogen or Oxygen atom to always add a hydrogen.

That is, Structures e.g. B. with a structural element "-N-" actually means "-NH" and Structures e.g. B. with a structural element with "-O" actually means "-OH".

Production of the preliminary stages

Example I

2-Acetylamino-2-cyanopentanoic acid ethyl ester

1.35 g of sodium (58.8 mmol) are dissolved in 200 ml of ethanol and the resulting solution is cooled to 0 ° C. 10 g (58.8 mmol) of ethyl acetamidocyanacetate are added. After a clear solution has formed, a solution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol is added dropwise and the reaction mixture is stirred at room temperature for 2 hours. A solution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol is again added and the reaction mixture is heated under reflux for 16 hours. The solvent is removed in vacuo, the residue is taken up in dichloromethane, washed with water and dried over magnesium sulfate. The solvent is removed in vacuo and the residue is stirred with petroleum ether. After suctioning off, 7.5 g (60%) of 2-acetylamino-2-cyanopentanoic acid ethyl ester are obtained.
200 MHz ¹ H NMR (CDCl ₃ ): 1.00, t, 3H; 1.36, t, 3H; 1.51, m, 2H; 2.08, m, 5H; 4.34, q, 2H; 6.45, s, broad, 1 H.

Example II

2-ethoxybenzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone. The solid is filtered off, the solvent is removed in vacuo and the residue is distilled in vacuo. 30.0 g (97%) of a colorless liquid are obtained.
200 MHz ¹ H NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, German, 2H; 7.51, German, 2H.

Example III

2-ethoxybenzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene and the suspension is cooled to 0 ° C. 200 ml of a 2M solution of trimethylaluminum in hexane are added dropwise and the mixture is stirred at room temperature until the evolution of gas has ended. After adding 29.44 g (200 mmol) of 2-ethoxybenzonitrile (Example II), the reaction mixture is stirred at 80 ° C. (bath) overnight.
The cooled reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of chloroform while cooling with ice, and the mixture is stirred at room temperature for 30 minutes. It is suctioned off and washed with the same amount of methanol. The mother liquor is evaporated, the residue obtained is stirred with a mixture of dichloromethane and methanol (9: 1), the solid is filtered off with suction and the mother liquor is evaporated. 30.4 g (76%) of a colorless solid are obtained.
200 MHz ¹ H NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H; 7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

Example IV

N- [6-Amino-2- (2-ethoxyphenyl) -4-oxo-5-propyl-4,5-dihydropyrimidin-5-yl] acetamide

33 g of 2-ethoxybenzamidine hydrochloride (Example III) are added to a solution of 3.97 g of sodium in 1300 ml of ethanol and the reaction mixture is stirred for 45 minutes at room temperature. The reaction mixture is filtered, the filtrate is added to a solution of 69.8 g (329 mmol) of 2-acetylamino-2-cyanopentanoic acid ethyl ester (Example I) in 800 ml of ethanol and the mixture is heated under reflux for 4 hours. The solvent is removed in vacuo, the residue is taken up in dichloromethane, the organic phase is shaken with water and brine, dried over sodium sulfate and the solvent is removed in vacuo.
Chromatographic purification (dichloromethane / methanol) gives 11.57 g (21%) of N- [6-amino-2- (2-ethoxyphenyl) -4-oxo-5-propyl-4,5-dihydro-pyriminin-5-yl] - acetamide.
200 MHz ¹ H NMR (CDCl ₃ ): 0.91, t, 3H; 1.41, m, 2H; 1.58, t, 3H; 2.07, m, 5H; 4.39, q, 2H; 7.08, m, 3H; 7.53, dt, 1H; 8.41, dd, 1H.

Example V

2- (2-ethoxyphenyl) -6-methyl-8-propyl-3H-imidazo [1,5-a] [1,3,5] triazin-4-one

To a solution of 11.57 g (35 mmol) of N- [6-amino-2- (2-ethoxyphenyl) -4-oxo-5-propyl-4,5-dihydro-pyriminin-5-yl] -acetamide (Example IV ) in 500 ml of pyridine, 11.41 g (105 mmol) of chlorotrimethylsilane are added and the reaction mixture is stirred for 20 minutes at room temperature. After the addition of 16.96 g (105 mmol) of hexamethyldisilazane, the reaction mixture is heated under reflux for 16 hours. The solvent is removed in vacuo, the residue is taken up in dichloromethane, extracted with water and 1N HCl, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is stirred with ether and the solid residue is purified by chromatography (cyclohexane / ethyl acetate). 1,655 g (15%) of solid are obtained.
200 MHz ¹ H NMR (CDCl ₃ ): 1.02, t, 3H; 1.61, t, 3H; 1.80, hex, 2H; 2.80, t, 2H; 2.88, s, 3H, 4.30, q, 2H; 7.05, d, 1H; 7.15, t, 1H; 7.58, dt, 1H; 8.39, dd, 1H; 10.35, s, broad, 1 H.

Example VI

4-Ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) benzenesulfonic acid chloride

1.64 g (5.25 mmol) of 2- (2-ethoxyphenyl) -6-methyl-8-propyl-3H-imidazo [1,5-α] [1,3,5] triazine-4 are added to 3.14 ml of chlorosulfonic acid while cooling with ice -on (Example VI) in portions. The reaction mixture is stirred at room temperature for 16 hours, diluted with dichloromethane and poured onto ice water. The organic phase is washed with water, dried over magnesium sulfate and the solvent removed in vacuo. 2.15 g (99%) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-a] [1,3,5] triazine 2-yl) - benzenesulfonic acid chloride.
200 MHz 1H NMR (CDCl ₃ ): 0.92, t, 3H; 1.34, t, 3H; 1.71, hex, 2H; 2.80, t, 2H; 2.96, s, 3H; 4.15, q, 2H; 7.12, d, 1H; 7.73, dd, 1H; 7.81, d, 1H; 12.5, s, broad, 1 H.

Example VII

2-Acetylamino-2-cyano-2-cyclopentylethanoic acid ethyl ester

To a solution of 17.74 g of sodium (771.3 mmol) in 1.2 l of ethanol is added 125 g of ethyl acetamidocyanacetate (734.6 mmol) at room temperature. After a clear solution has formed, 157.5 ml of cyclopentyl bromide (1.47 mol) are added dropwise. The mixture is stirred under reflux overnight, then evaporated. It is taken up in dichloromethane, washed twice with water, dried over magnesium sulfate and concentrated. The crystalline residue is stirred with ether and suction filtered.
Yield: 70.8 g (40.4% of theory)
MS (DCI, NH ₃ ): m / z (%) = 256 (M + H ₂ O) (100)
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.35 (t, 3 H); 1.55-1.82 (m, 7H); 1.91-2.03 (m, 1H); 2.06 (s, 3H); 2.37-2.50 (m, 1H); 4.31 (q, 2H); 6.79 (s, 1H).

Example VIII

N- [6-Amino-5-cyclopentyl-2- (2-ethoxyphenyl) -4-oxo-4,5-dihydropyrimidin-5-yl] acetamide

5.02 g (25 mmol) of 2-ethoxybenzamidine hydrochloride (Example III) are added to a solution of 0.6 g of sodium (26.25 mmol) in 80 ml of ethanol. After 45 min at room temperature, the resulting mixture is filtered into a solution of 11.91 g (50 mmol) of 2-acetylamino-2-cyano-2-cyclopentylethanoic acid ethyl ester in 120 ml of ethanol and stirred under reflux for 5 h. The mixture is then concentrated, the residue is taken up in dichloromethane, washed twice with water, dried and evaporated. The crude product is purified by column chromatography on silica gel with dichloromethane / methanol 9: 1.
Yield 545.4 mg (6.1% of theory)
MS (DCI, NH ₃ ): m / z (%) = 357 (M + H), (100)
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.45-1.90 (m, 12 H); 2.05 (s, 3H); 2.42-2.58 (m, 1H); 4.28 (q, 2H); 6.99-7.14 (m, 2H); 7.19 (s, 1H); 7.53 (dt, 1H); 8.87 (dd, 1H).

Example IX

8-Cyclopentyl-2- (2-ethoxyphenyl) -6-methyl-3H-imidazo [1,5-α] [1,3,5] triazin-4-one

1.6 g (4.5 mmol) of N- [6-amino-5-cyclopentyl-2- (2-ethoxyphenyl) -4-oxo-4,5-dihydropyrimidin-5-yl] acetamide (Example VIII) are dissolved in 64 ml of anhydrous pyridine submitted. 1.71 ml (13.5 mmol) of chlorotrimethylsilane are added dropwise and the mixture is subsequently stirred at room temperature for 20 min. After adding 2.8 ml (13.5 mmol) of hexamethyldisilazane, the mixture is stirred under reflux overnight. The mixture is evaporated to dryness, the residue is taken up in 80 ml of methanol and the mixture is stirred at room temperature for 45 min. It is evaporated and purified by flash chromatography with cyclohexane / ethyl acetate 1: 1.
Yield 727 mg (47.5% of theory)
MS (DCI, NH ₃ ): m / z (%) = 339 (M + H) (100)
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.60 (t, 3 H); 1.65-2.12 (m, 8H); 2.89 (s, 3H); 3.40 (qui, 1H); 4.29 (q, 2H); 7.0-7.18 (m, 2H); 7.49 (dt, 1H); 8.48 (dd, 1H); 10.31 (bs, 1H).

Example X

4-Ethoxy-3- (8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazole [1,5-α] [1,3,5] triazin-2-yl) benzenesulfonic acid chloride

To 0.66 ml (9.9 mmol) of ice-cooled chlorosulfonic acid, 372.3 mg (1.1 mmol) of 8-cyclopentyl-2- (2-ethoxyphenyl) -6-methyl-3H-imidazo [1,5-α] [1,3,5 ] triazin-4-one (Example IX) added in portions. The mixture is stirred overnight at room temperature before being diluted with dichloromethane and poured onto ice water. The organic phase is separated off. It is extracted again with dichloromethane, the organic phases are combined, dried and evaporated.
Yield 266.5 mg (55.5% of theory)
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.69 (t, 3 H); 1.70-2.14 (m, 8H); 3.49-3.51 (m, 1H); 4.45 (q, 2H); 7.24 (d, 1H); 8.11 (s, 1H); 9.04 (d, 1H); 9.89 (bs, 1H).

Manufacturing examples

example 1

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) piperazin-1-sulfonyl] phenyl} -6-methyl-8-propyl-3H-imidazo [1,5-α] [1 , 3,5] triazin-4-one

To a solution of 90 mg (0.22 mmol) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) -benzenesulfonic acid chloride (Example VI) in 5 ml of dichloromethane, 86 mg (0.66 mmol) of hydroxyethylpiperazine are added and the reaction mixture is stirred for 16 hours at room temperature. After chromatographic purification (dichloromethane / methanol = 95: 5), 63 mg (57%) of 2- {2-ethoxy-5- [4- (2-hydroxyethyl) piperazin-1-sulfonyl] phenyl} - are obtained. 6-methyl-8-propyl-3H-imidazo [1,5-α] [1,3,5] triazin-4-one.
400 MHz ¹ H NMR (CDCl ₃ ): 1.00, t, 3H; 1.65, t, 3H; 1.79, hex, 2H; 1.90, s, broad, 1H; 2.56, t, 2H; 2.63, m, 4H; 2.80, t, 2H; 2.87, s, 3H, 3.09, s, broad, 4H; 3.58, m, 2H; 4.39, q, 2H; 7.16, d, 1H; 7.82, dd, 1H; 8.70, d, 1H; 10.0, s, broad, 1H.

Example 2

2- [2-ethoxy-5- (4-methyl-piperazin-1-sulfonyl) phenyl] -6-methyl-8-propyl-3H-imidazo [1,5-α] [1,3,5] triazine -4-on

To a solution of 100 mg (0.24 mmol) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) benzenesulfonic acid chloride (Example VI) in 5 ml of dichloromethane, 73 mg (0.73 mmol) of N-methylpiperazine are added and the reaction mixture is stirred for 2 hours at room temperature. After chromatographic purification (dichloromethane / methanol = 95: 5), 110 mg (95%) of 2- [2-ethoxy-5- (4-methyl-piperazin-1-sulfonyl) phenyl] -6-methyl-8- propyl-3H-imidazo [1,5-α] [1,3,5] triazin-4-one.
200 MHz ¹ H NMR (CDCl ₃ ): 1.00, t, 3H; 1.65, t, 3H; 1.79, hex, 2H; 2.29, s, 3H; 2.50, m, 4H; 2.80, t, 2H; 2.89, s, 3H; 3.10, m, 4H; 4.37, q, 2H; 7.13, d, 1H; 7.83, dd, 1H; 8.71, dd, 1H; 10.0, s, broad, 1H.

Example 3

2- [2-ethoxy-5- (4-ethyl-piperazin-1-sulfonyl) phenyl] -6-methyl-8-propyl-3H-imidazo [1,5-α] [1,3,5] triazine -4-on

To a solution of 100 mg (0.24 mmol) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) -benzenesulfonic acid chloride (Example VI) in 5 ml of dichloromethane, 83 mg (0.73 mmol) of N-ethylpiperazine are added and the reaction mixture is stirred for 2 hours at room temperature. After chromatographic purification (diehlormethane / methanol = 95: 5), 104 mg (87%) of 2- [2-ethoxy-5- (4-ethyl-piperazin-1-sulfonyl) phenyl] -6-methyl-8- propyl-3H-imidazo [1,5-α] [1,3,5] triazin-4-one.
200 MHz ¹ H NMR (CDCl ₃ ): 1.00, t, 3H; 1.05, t, 3H; 1.65, t, 3H; 1.79, hex, 2H; 2.42, q, 2H; 2.54, m, 4H; 2.78, t, 2H; 2.87, s, 3H; 3.09, m, 4H; 4.37, q, 2H; 7.13, d, 1H; 7.83, dd, 1H; 8.71, dd, 1H; 10.0, s, broad, 1H.

Example 4

N- [2- (3,4-dimethoxyphenyl) ethyl] -4-ethoxy-N methyl-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1, 5-α] [1,3,5] triazin-2-yl) benzenesulfonamide

To a solution of 100 mg (0.24 mmol) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α) [1,3,5) triazin-2-yl) -benzenesulfonic acid chloride (Example VI) in 5 ml of dichloromethane, 143 mg (0.73 mmol) of N- (3,4-dimethoxyphenylethyl) -N-methylamine are added and the reaction mixture is stirred for 2 hours at room temperature. After chromatographic purification (dichloromethane / methanol = 95: 5), 138 mg (98%) of N- [2- (3,4-dimethoxyphenyl) ethyl) -4-ethoxy-N methyl-3- (6- methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) benzenesulfonamide.
200 MHz ¹ H NMR (CDCl ₃ ): 0.95, t, 3H; 1.62, t, 3H; 1.78, hex, 2H, 2.83, m, 10H; 3.31, t, 2H; 3.85, s, 6H; 4.35, q, 2H; 6.72, m, 3H; 7.09, d, 1H; 7.81, dd, 1H; 8.73, d, 1H; 10.0, s, broad, 1H.

Example 5

4-Ethoxy-N- (2-methoxy-ethyl) -3- (6-methyl-4-oxo-8-propyl-3,4-dihydroimidazo [1,5-α] [1,3,5] triazine -2-yl) benzenesulfonamide

To a solution of 100 mg (0.24 mmol) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) -benzenesulfonic acid chloride (Example VI) in 5 ml of dichloromethane, 55 mg (0.73 mmol) of 2-methoxyethylamine are added and the reaction mixture is stirred for 2 hours at room temperature. After chromatographic purification (dichloromethane / methanol = 95: 5) and stirring with diethyl ether, 64 mg (57%) of 4-ethoxy-N- (2-methoxy-ethyl) -3- (6-methyl-4-oxo-8) are obtained -propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) -benzenesulfonamide.
200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.65, t, 3H; 1.80, hex, 2H, 2.80, t, 2H; 2.88, s, 3H, 3.18, t, 2H; 3.30, s, 3H; 3.46, t, 2H; 4.38, q, 2H, 7.13, d, 1H, 7.95, dd, 1H, 8.85, d, 1H, 10.02, s, broad, 1H.

Example 6

2- [2-ethoxy-5- (4-hydroxy-piperidine-1-sulfonyl) phenyl] -6-methyl-8-propyl-3H-imidazo [1,5-α] [1,3,5] triazine -4-on

To a solution of 100 mg (0.24 mmol) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) -benzenesulfonic acid chloride (Example VI) in 5 ml of dichloromethane, 74 mg (0.73 mmol) of 4-hydroxypiperidine are added and the reaction mixture is stirred for 2 hours at room temperature. After chromatographic purification (dichloromethane / methanol = 95: 5), 100 mg (87%) of 2- [2-ethoxy- 5- (4-hydroxy-piperidine-1-sulfonyl) phenyl] -6-methyl-8- propyl-3H-imidazo [1,5-α] [1,3,5] triazin-4-one
200 MHz ¹ H NMR (CDCl ₃ ): 1.01, t, 3H; 1.65, m, 9H; 2H, 2.78, t, 2H; 2.88, s, 3H; 3.00, m 2H; 3.30, m, 2H; 3.83, s, 1H; 4.38, q, 2H, 7.15, d, 1H, 7.85, dd, 1H, 8.73, d, 1H, 10.02, s, broad, 1H.

Example 7

N- (N hydroxyethylpiperazinyl) - [4-ethoxy-3- (8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazole [1,5-α] [1,3,5] triazin-2-yl] benzenesulfonic acid amide

130 mg (0.3 mmol) of 4-ethoxy-3- (8-cyclopentyl-6-methyl-4-oxo-3,4-dihydroimidazole [1,5-α] [1,3,5] triazin-2-yl ) -Benzenesulfonic acid chloride (Example X) are placed in 7 ml dichloromethane. 116.2 mg (0.89 mmol) of N-hydroxyethylpiperazine are added and the mixture is stirred overnight at room temperature. It is purified by flash chromatography with a) cyclohexane / ethyl acetate 1: 1 and b) dichloromethane / methanol 95: 5.
Yield: 151.4 mg (94.3% of theory)
Rf value = 0.477, dichloromethane / methanol 95: 5
MS (DCI, NH ₃ ): m / z (%) = 531 (M + H) (100)
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.64 (t, 3H); 1.67-2.08 (m, 8H); 2.35 (bs, 1H); 2.55-2.69 (m, 6H); 2.87 (s, 3H); 3.08-3.13 (m, 4H); 3.40 (qui, 1H); 3.59 (bt, 2H); 4.38 (q, 2H); 7.18 (d, 1H); 7.83 (dd, 1H); 8.71 (d, 1H); 9.97 (bs, 1H).

Example 8

N- [2- (3,4-dimethoxyphenyl) ethyl methyl] -4-ethoxy-5- [8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazo [1.5 -α] [1,3,5] triazin-2-yl) benzenesulfonamide

130 mg (0.3 mmol) of 4-ethoxy-3- (8-cyclopentyl-6-methyl-4-oxo-3,4-dihydroimidazole [1,5-α] [1,3,5] triazin-2-yl ) -Benzenesulfonic acid chloride (Example X) are placed in 7 ml dichloromethane. 174.3 mg (0.89 mmol) of N-methylhomoveratrylamine are added and the mixture is stirred overnight at room temperature. It is purified by flash chromatography with cyclohexane / ethyl acetate 1: 1.
Yield: 144.5 g (81.5% of theory)
Rf value = 0.658, dichloromethane / methanol 95: 5
MS (DCI, NH ₃ ): m / z (%) = 596 (M + H) (100)
¹ H NMR (200 MHz, CDCl ₃ ): δ = 1.65 (t, 3H); 1.72-2.08 (m, 8H); 2.80-2.91 (m, 8H); 3.27-3.41 (m, 3H); 3.88 (s, 6H); 4.36 (q, 2H); 6.70-6.81 (m, 3H); 7.10 (d, 1H); 7.81 (dd, 1H); 8.74 (d, 1H); 9.98 (bs, 1H).

The sulfonamides listed in Tables 1 and 2 below were determined using automated parallel synthesis from the sulfonic acid chlorides Example VI (Table 1) or Example X (Table 2) and the corresponding amines according to one of the three following standard regulations.  

The purity of the end products was determined by means of HPLC, their Characterizations made by LC-MS measurement. The in the% column (HPLC) numerical value gives the content of the Molpeak characterized end product. Standard A was applied to Amines with acidic functionalities, standard regulation B for amines with neutral ones Functionalities, standard regulation C for amines with additional basic Functionalities.

Compounds that are listed in the following tables 1 and 2 and the optical Show a free nitrogen valence are basically to be understood as an -NH residue.

Standard regulation A Implementation of amines with acidic functionalities

First 0.05 mmol of amine, 0.042 mmol of sulfonic acid chloride and 0.10 mmol of Na ₂ CO ₃ are initially introduced and 0.5 ml of a mixture of THF / H ₂ O is pipetted in by hand. After 24 h at RT, 0.5 ml of 1 MH ₂ SO ₄ solution is added and the mixture is filtered through a two-phase cartridge (500 mg Extrelut (upper phase)) and 500 mg SiO ₂ , mobile phase ethyl acetate). After concentrating the filtrate in vacuo, the product is obtained.

Standard regulation B Implementation of amines with neutral functionalities

0.125 mmol of amine are initially introduced and 0.03 mmol of sulfonic acid chloride as a solution in 1,2-dichloroethane are pipetted in from the synthesizer. After 24 h, the mixture is mixed with 0.5 ml of 1 MH ₂ SO ₄ and filtered through a two-phase cartridge (500 mg Extrelut (upper phase) and 500 mg SiO ₂ , eluent: ethyl acetate). The filtrate is concentrated in vacuo.

Standard regulation C Implementation of amines with basic functionalities

0.05 mmol of amine are initially introduced and 0.038 mmol of sulfonic acid chloride as a solution in 1,2-dichloroethane and 0.05 mmol of triethylamine as a solution in 1,2-dichloroethane are pipetted in from the synthesizer. After 24 h, 3 ml of saturated NaHCO ₃ solution are first added and the reaction mixture is filtered through a two-phase cartridge. After concentrating the filtrate in vacuo, the product is obtained.

All reactions are followed by thin layer chromatography. In case of after 24 h at RT no complete conversion has taken place, the mixture is left on for a further 12 h Heated 60 ° C and then the experiment ended.  

Table 1

Table 2

Claims (20)

1. New imidazo [1,3,5] triazinones of the general formula (I)
in which
R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms,
R ^{2 represents} straight-chain or branched alkyl having up to 4 carbon atoms, or
represents (C ₃ -C ₆ ) cycloalkyl,
R ^{3 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R ⁴ and R ^{5 are} identical or different and stand for hydrogen, (C ₁ -C ₆ ) alkoxy, hydroxy or for (C ₁ -C ₈ ) alkyl, optionally up to 3 times, identical or different, by Hydroxy, (C ₁ -C ₆ ) alkoxy or by residues of the formulas
is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and / or (C ₁ -C ₈ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by halogen, hydroxy, (C ₁ -C ₆ ) -alkoxy, (C ₁ - C ₆ ) -alkyl or are substituted by a radical of the formula -SO ₂ NR ⁸ R ⁹ ,
wherein
R ⁸ and R ^{9 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
or
R ^{4 represents} hydrogen or methyl,
and
R ⁵ for residues of the formulas
stands, or stands for phenyl, optionally up to 3 times, identical or different, by halogen, acetyl, (C ₁ -C ₆ ) alkoxy or by radicals of the formulas
is substituted,
wherein
R ¹⁰ and R ^{11 are} identical or different and are hydrogen or (C ₁ -C ₄ ) -alkyl,
R ¹² and R ^{13 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
or
R ⁴ and R ⁵ together with the nitrogen atom are residues of the formulas
form,
wherein
R ¹⁴ and R ^{15 are} identical or different and denote hydroxy, hydrogen or (C ₁ -C ₄ ) -alkyl, which is optionally substituted by hydroxy,
or
R ¹⁴ means hydrogen,
and
R ^{15 is} a radical of the formula
means
or
R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,
R ^{16 is} hydrogen or (C ₁ -C ₆ ) alkyl, which is optionally substituted by hydroxy, or
is a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means
and their salts, N-oxides and isomeric forms. 2. New imidazo [1,3,5] triazinones of the general formula (I) according to claim 1,
in which
R ^{1 represents} methyl or ethyl,
R ^{2 represents} straight-chain or branched alkyl having up to 3 carbon atoms, or
represents cyclopentyl,
R ^{3 represents} straight-chain or branched alkyl having up to 3 carbon atoms,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, (C ₁ -C ₄ ) alkoxy, hydroxy or (C ₁ -C ₇ ) alkyl, which may be up to 3 times the same or different Hydroxy, (C ₁ -C ₄ ) alkoxy or by residues of the formulas
is substituted,
wherein
R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,
and / or (C ₁ -C ₇ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, chlorine, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl or are substituted by a radical of the formula -SO ₂ NR ⁸ R ⁹ ,
wherein
R ⁸ and R ^{9 are} hydrogen,
or
R ^{4 represents} hydrogen or methyl,
and
R ⁵ for residues of the formulas
stands,
or
represents phenyl, optionally up to 3 times, identical or different, by fluorine, chlorine, acetyl, (C ₁ -C ₄ ) -alkoxy or by radicals of the formulas
is substituted,
wherein
R ¹⁰ and R ^{11 are the} same or different and are hydrogen or methyl,
R ¹² and R ^{13 are the} same or different and are hydrogen or methyl,
or
R ⁴ and R ⁵ together with the nitrogen atom are residues of the formulas
form,
wherein
R ¹⁴ and R ^{15 are} identical or different and denote hydroxy, hydrogen or (C ₁ -C ₃ ) -alkyl, which is optionally substituted by hydroxy,
or
R ¹⁴ means hydrogen,
and
R ^{15 is} a radical of the formula
means
or
R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,
R ^{16 is} hydrogen or (C ₁ -C ₅ ) alkyl, which is optionally substituted by hydroxy, or
Pyridyl, pyrimidyl, furyl, pyrryl or thienyl means
and their salts, N-oxides and isomeric forms. 3. New imidazo [1,3,5] triazinones of the general formula (I) according to claim 1,
in which
R ^{1 represents} methyl or ethyl,
R ^{2 stands} for n-propyl or stands for cyclopentyl,
R ^{3 represents} methyl, ethyl or n-propyl,
R ⁴ and R ^{5 are the} same or different and represent hydrogen, (C ₁ -C ₃ ) alkoxy, hydroxy or (C ₁ -C ₆ ) alkyl, which may be up to 3 times the same or different Hydroxy, (C ₁ -C ₃ ) alkoxy or by residues of the formulas
is substituted,
wherein
R ⁶ and R ^{7 are the} same or different and are hydrogen or methyl,
and / or (C ₁ -C ₆ ) alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally one to three times, identical or different, by fluorine, hydroxy, methoxy or by a radical of the formula -SO ₂ NR ⁸ R ⁹ are substituted,
wherein
R ⁸ and R ^{9 are} hydrogen,
or
R ^{4 represents} hydrogen or methyl,
and
R ⁵ for residues of the formulas
stands,
or
represents phenyl, optionally up to 3 times, identical or different, by fluorine, acetyl, methoxy or by radicals of the formulas
is substituted,
wherein
R ¹⁰ and R ^{11 are the} same or different and are hydrogen or methyl,
R ¹² and R ^{13 are} methyl,
or
R ⁴ and R ⁵ together with the nitrogen atom are residues of the formulas
form,
wherein
R ¹⁴ and R ^{15 are the} same or different and are hydroxyl, hydrogen or a radical of the formula - (CH ₂ ) ₂ -OH,
or
R ¹⁴ means hydrogen,
and
R ^{15 is} a radical of the formula
means
or
R ¹⁴ and R ¹⁵ together form a radical of the formula = NO-CH ₃ ,
R ^{16 is} hydrogen, pyrimidyl or a radical of the formula - (CH ₂ ) ₂ -OH
and their salts, N-oxides and isomeric forms. 4. New imidazo [1,3,5] triazinones of the general formula (I) according to Claims 1 to 3 with the following structures:
5. A process for the preparation of imidazo [1,3,5] triazinones according to claims 1 to 4, characterized in that
Compounds of the general formula (II)
in which
R ¹ , R ² and R ^{3 have} the meaning given above,
first by reaction with chlorosulfonic acid (ClSO ₃ H) in inert solvents, if appropriate in the presence of a base, into the compounds of the general formula (III)
in which
R ¹ , R ² and R ^{3 have} the meaning given above,
transferred and in a last step with amines of the general formula (IV)
HN-R ⁴ R ⁵ (IV)
in which
R ⁴ and R ^{5 have} the meaning given above,
implements. 6. Compounds of the general formula (I) according to Claims 1 to 4 for Prophylaxis and / or treatment of diseases. 7. Medicament or pharmaceutical composition containing at least a compound of general formula (I) according to one of claims 1 to 4 and one or more pharmacologically acceptable auxiliary and Carriers. 8. Medicament or pharmaceutical composition according to claim 7 for Prophylaxis and / or treatment of diseases related with processes regulated by cGMP ("cGMP-related diseases"). 9. Medicament or pharmaceutical composition according to claim 7 or 8 for the prophylaxis and / or treatment of cardiovascular Diseases, diseases of the genitourinary system and cerebrovascular Diseases. 10. Medicament or pharmaceutical composition according to one of the Claims 7 to 9 for the prophylaxis and / or treatment of cardiovascular diseases such as high blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, Arrhythmias, thromboembolic disorders and ischemia such as Myocardial infarction, stroke, transistor and ischemic attacks, angina pectoris, peripheral circulatory disorders, prevention of restenosis after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA) and bypass.   11. Medicament or pharmaceutical composition according to one of the Claims 7 to 9 for the prophylaxis and / or treatment of cerebrovascular diseases such as cerebral ischemia, stroke, Reperfusion damage, brain trauma, edema, cerebral thrombosis, dementia and Alzheimer's disease. 12. Medicament or pharmaceutical composition according to one of the Claims 7 to 9 for the prophylaxis and / or treatment of diseases of the urogenital system such as prostate hypertrophy, incontinence as well especially erectile dysfunction and female sexual dysfunction. 13. Medicament or pharmaceutical composition according to one of the Claims 7 to 12, characterized in that the drug or pharmaceutical composition is administered intravenously or orally. 14. Use of the compounds of general formula (I) according to one of the Claims 1 to 4 for the manufacture of pharmaceuticals or pharmaceuticals Compositions for the prophylaxis and / or treatment of diseases. 15. Use according to claim 14 for the manufacture of a medicament or a pharmaceutical composition for prophylaxis and / or Treatment of diseases related to eGMP-regulated Processes stand ("cGMP-related diseases"). 16. Use according to claim 14 or 15 for the manufacture of a medicament or a pharmaceutical composition for prophylaxis and / or Treatment of cardiovascular diseases, diseases of the Genitourinary and cerebrovascular diseases. 17. Use according to one of claims 14 to 16 for the production of a Medicament or a pharmaceutical composition for prophylaxis and / or treatment of cardiovascular diseases such as  High blood pressure, neuronal hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, arrhythmias, thromboembolic Diseases and ischemia such as myocardial infarction, stroke, transistor and ischemic attacks, angina pectoris, peripheral circulatory disorders, Prevention of restenosis after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angio plastic (PTCA) and bypass. 18. Use according to one of claims 14 to 16 for the production of a Medicament or a pharmaceutical composition for prophylaxis and / or treatment of cerebrovascular diseases such as cerebral Ischemia, stroke, reperfusion damage, brain trauma, edema, cerebral Thrombosis, dementia and Alzheimer's disease. 19. Use according to one of claims 14 to 16 for the production of a Medicament or a pharmaceutical composition for prophylaxis and / or treatment of diseases of the genitourinary system such as prostate hypertrophy, incontinence and especially erectile dysfunction and female sexual dysfunction. 20. Use according to one of claims 14 to 19, characterized in that that the drug or composition is intravenous or oral be applied.