DE10003323A1 - 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. [Image] R 11-4C alkyl; R 21-4C alkyl or 3-8C cycloalkyl; R 3H or 1-4C alkyl; R 4, R 5H, alkoxy, 1-6C alkoxy, OH or 1-8C alkyl (optionally substituted by 1-3 of OH, alkoxy, tetrahydrofuran-2-yl, morpholino, pyrrolidino or NR 6R 7; or phenyl or phenoxy (themselves optionally substituted by halo, OH, 1-6C alkoxy, 1-6C alkyl or SO 2NR 8R 9)); or R 4H or Me; and R 41,1-dioxo-tetrahydro-3-thienyl, 2-oxo-perhydroazepin-3-yl or phenyl (optionally substituted by 1-3 of halo, COMe, alkoxy, cyclopentyloxy, NR 10R 11or CH 2P(O)(OR 12)(OR 13)); or NR 4R 5piperidino substituted by R 14and R 15, 4-(R 16)-piperazino or morpholino; R 6-R 9, R 12, R 13H or alkyl; R 10, R 11H or 1-4C alkyl; R 14, R 5H, OH or 1-4C alkyl (optionally substituted by OH); or R 14H; and R 155,6-dihydro-1,4,2-dioxazin-3-yl or CR 14R 15C=NOMe; R 16H, 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). ACTIVITY : Hypotensive; antianginal; antiarrhythmic; vasotropic; cardiant; thrombolytic; anticoagulant; cerebroprotective; nootropic; neuroprotective; cytostatic; uropathic; antiinflammatory. No biological data given. MECHANISM OF ACTION : Cyclic guanosine monophosphate (cGMP)-metabolizing phosphodiesterase (PDE) inhibitor; PDE I inhibitor, PDE II inhibitor, and PDE V inhibitor.

Description

The present invention relates to new imidazo [1,3,5] triazinones, processes for their Production and their use as medicaments, 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. About a biological Effect is not 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 literature references were mostly prepared as guanine or guanosine analogs and are therefore usually _{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. An inhibitory effect against phosphodiesterases is not described for any of the compounds described.

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

An increase in the cGMP concentration can lead to beneficial, anti-aggregatory, antithrombotic, antiproliferative, antivasospastic, vasodilating, result in natriuretic and diuretic effects. It can be 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 the erection. Hence there are such Compounds suitable for the treatment of erectile dysfunction.

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 with up to 4 carbon atoms,
R ^{2 stands} for straight-chain or branched alkyl with up to 4 carbon atoms or for (C ₃ -C ₈ ) -cycloalkyl,
R ^{3 represents} hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) -alkoxy, hydroxy or (C ₁ -C ₈ ) -alkyl, optionally up to 3 times, identically or differently, through Hydroxy, (C ₁ -C ₆ ) -alkoxy or radicals of the formulas

or -NR ⁶ R ⁷
is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and / or in turn (C ₁ -C ₈ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally substituted one to three times, identically or differently, 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, which is optionally up to 3 times, identical or different, by halogen, acetyl, (C ₁ -C ₆ ) -alkoxy or by radicals of the formulas

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )
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 to which they are attached are radicals of the formulas

form,
wherein
R ¹⁴ and R ^{15 are} identical or different and are 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 denotes hydrogen or (C ₁ -C ₆ ) -alkyl which is optionally substituted by hydroxy, or
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 of the invention can be in stereoisomeric forms, which either like image and mirror image (enantiomers), or not like image and Mirror image (diastereomers) behave, exist. The invention relates to both Enantiomers or diastereomers or their respective mixtures. The Racemfor Men, like the diastereomers, can be converted into the stereoisomers in a known manner separate uniform components.

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

Physiologically acceptable salts can be salts of the compounds according to the invention Chemicals 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 carboxylic 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 naphthalene disulfone acid.

Physiologically harmless salts can also be metal or ammonium salts be compounds according to the invention. Particularly preferred are, for. B. Sodium, Potassium, magnesium or calcium salts, as well as ammonium salts that 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 represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may be mentioned as preferred: 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 having 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 having 1 to 3 carbon atoms is particularly preferred.

Halogen generally stands for 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 Series S, O and / or N stands, for example, for pyridyl, pyrimidyl, pyridazinyl, Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl are preferred, Pyrimidyl, pyridazinyl, furyl and thienyl.

Preference is given to compounds of the general formula (I) according to the invention,
in which
R ^{1 represents} methyl or ethyl,
R ^{2 represents} straight-chain or branched alkyl with up to 3 carbon atoms or (C ₃ -C ₆ ) -cycloalkyl,
R ^{3 represents} straight-chain or branched alkyl with up to 3 carbon atoms,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₄ ) -alkoxy, hydroxy or (C ₁ -C ₇ ) -alkyl, optionally up to 3 times, identical or different, through Hydroxy, (C ₁ -C ₄ ) -alkoxy or radicals of the formulas

or -NR ⁶ R ⁷
is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or methyl,
and / or in turn (C ₁ -C ₇ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally substituted one to three times, identically or differently, 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 NH _2,
or
R ^{4 represents} hydrogen or methyl
and
R ⁵ for residues of the formulas

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

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )
is substituted,
wherein
R ¹⁰ and R ^{13 are} identical or different and are hydrogen or methyl,
R ¹² and R ^{13 are} identical or different and are hydrogen or methyl,
or
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are radicals of the formulas

form,
wherein
R ¹⁴ and R ^{15 are} identical or different and are hydroxy, hydrogen or (C ₁ -C ₃ ) -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 denotes 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.

Particular preference is given to compounds of the general formula (I) according to the invention,
in which
R ^{1 represents} methyl or ethyl,
R ^{2 represents} n-propyl or cyclopentyl,
R ^{3 represents} methyl, ethyl or n-propyl,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₃ ) -alkoxy, hydroxy or (C ₁ -C ₆ ) -alkyl, optionally up to 3 times, identical or different, through Hydroxy, (C ₁ -C ₃ ) -alkoxy or radicals of the formulas

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

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

-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )
is substituted,
wherein
R ¹⁰ and R ^{11 are} identical 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 to which they are attached are radicals of the formulas

form,
wherein
R ¹⁴ and R ^{15 are} identical or different and are hydroxy, hydrogen or a radical of the formula - (CH ₂ ) ₂ -OH,
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 denotes 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:

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention has been found in which compounds of the general formula (II)

in which
R ¹ , R ² and R ^{3 have} the meaning given above,
initially by reaction with chlorosulfonic acid (ClSO ₃ H), if appropriate 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 method according to the invention can be exemplified by the following equation:

The usual organic solvents are suitable as solvents for the individual steps Solvents that do not change under the reaction conditions. These include 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 ethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the solvents mentioned turn around.

The reaction temperatures can generally be within a relatively wide range vary. Generally one works in a range from -20 ° C to 200 ° C, preferably from 0 ° C to 70 ° C.

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

The reactions can, for example, in a temperature range from 0 ° C to Room temperature and normal pressure take place.

The compounds of the general formula (II) are new and can be prepared by adding compounds of the 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 system NaO ₂ H ₅ / C ₂ H ₅ OH a reaction with compounds of the general formula (VIII)

in which
R ^{3 has} 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 hexamethyldisilazane (HMDS) and chlorotrimethylsilane (TMSCl).

The usual organic solvents are suitable as solvents for the individual steps Solvents that do not change under the reaction conditions. These include 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 ethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the solvents mentioned turn around.

The reaction temperatures can generally be within a relatively wide range vary. Generally one works in a range from -20 ° C to 200 ° C, preferably from 0 ° C to 70 ° C.

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

The reactions can, for example, in a temperature range from 0 ° C to Room temperature and normal pressure take place.

The compounds of the 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 known or can be prepared by customary methods.

Some of the compounds of the general formula (IX) are new and can be according to usual methods are produced.

The compounds of the general formula (I) according to the invention do not show any 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 the phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, enable in connection with the selective inhibitors according to the invention, a selective addressing of the various processes regulated by cGMP.

In addition, the compounds according to the invention increase the effect of Substan zen, such as EDRF (Endothelium derived relaxing factor), ANP (atrial natriuretic peptide), nitrovasodilators and all other substances that act on a types 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. Disorders Related to cGMP regulated processes (in English mostly simply as' cGMP-related diseases'). These include cardiovascular diseases, diseases of the Genitourinary system as well as cerebrovascular diseases.

The term "cardiovascular diseases" as used herein Invention fall diseases such as high blood pressure, neural Hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, Arrhythmias, thromboembolic diseases and ischemias such as myocardial infarction, Stroke, transitory and ischemic attacks, angina pectoris, peripheral Circulatory disorders, prevention of restenoses after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angio plasties (PTCA) and bypass.

Furthermore, the compounds of the general formula (I) according to the invention can are also of importance 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 prostatic hypertrophy, incontinence as well especially for the treatment of erectile dysfunction and female sexual Dysfunction.

Phosphodiesterase (PDE) activity

The cGMP stimulable PDE II, the cGMP-inhibitable PDE III and the cAMP-specific PDE IV were isolated from either porcine or bovine heart 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 pig 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 mixture of 100 μl in 20 mM Tris / HCl buffer pH 7.5 containing 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 approx. 50% of the substrate is converted during the incubation time of 30 minutes. In order to test the cGMP-stimulable PDE II, ³ HcAMP is used ^{as substrate and 10 -6} mol / l unlabelled cGMP is added to the batch. In order ^{to test the Ca 2+} -calmodulin-dependent PDE I, 1 µM CaCl ₂ and 0.1 µM calmodulin are added to the reaction mixture. The reaction is stopped by adding 100 μl of acetonitrile containing 1 mM cAMP and 1 mM AMP. 100 μl of the reaction mixture are separated by means of HPLC and the cleavage products are quantitatively determined "online" using a flow scintillation counter. 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 for testing. 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 PDE II, ^{10 -6} M cGMP being added to the reaction mixture to activate the enzyme. To measure PDE I, 10 ^-7 M calmodulin and 1 μM CaCl ₂ were added to the reaction mixture. The PDE V was ^{measured with the [3} H] cGMP SPA assay.

Basically, one or more phosphodiesterases of this type are inhibited to an increase in the cGMP concentration. This makes the connections interesting for all therapies in which an increase in the cGMP concentration is considered beneficial can be accepted.

The study of cardiovascular effects were on normotensive and on SH rats and dogs. The substances were administered intravenously or orally applied.

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

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

The formulations are prepared, for example, by stretching the active ingredient substances with solvents and / or carriers, if necessary using of emulsifiers and / or dispersants, where z. B. in the case of use of water as a diluent, optionally organic solvents as Co-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.

For human use, oral administration is generally used Dosages from 0.001 to 50 mg / kg, preferably 0.01 mg / kg-20 mg / kg, are administered. In the case of parenteral administration, such as B. via mucous membranes nasal, buccal, inhalative, is a dosage of 0.001 mg / kg-0.5 mg / kg makes sense.

Nevertheless, it may be necessary to deviate from the stated amounts soft, depending on the body weight or the type of applicator pathway, the 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 the above mentioned minimum amount, while in other cases the mentioned upper limit must be exceeded. In the case of the application of larger amounts it may be advisable to distribute these in several individual doses over the day.

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

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

I. E. 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".

Manufacture of the preliminary stages

Example I.

Ethyl 2-acetylamino-2-cyanopentanoate

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 acetamidocyanoacetate 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 refluxed 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 ethyl 2-acetylamino-2-cyanopentanoate 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, 1H.

Example II

2-ethoxy-benzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed overnight 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-D ₆ ): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, German, 2H.

Example III

2-ethoxy-benzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene and the The suspension is cooled to 0 ° C. 200 ml of a 2 M solution of Trimethylaluminum in hexane are added dropwise and the mixture up to completed gas evolution stirred at room temperature. After adding 29.44 g (200 mmol) 2-ethoxybenzonitrile (Example II) is the reaction mixture over Stirred overnight at 80 ° C (bath).

The cooled reaction mixture is added with ice cooling to a suspension of 100 g of silica gel and 950 ml of chloroform and the mixture is stirred for 30 minutes at room temperature. 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 colorless solid are obtained.
200 MHz ¹ H-NMR (DMSO-D ₆ ): 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-dihydro-pyrimidin-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 ethyl 2-acetylamino-2-cyanopentanoate (Example I) in 800 ml of ethanol and refluxed for 4 hours. The solvent is removed in vacuo, the residue is taken up in dichloromethane, the organic phase is shaken with water and sodium chloride solution, dried over sodium sulfate and the solvent is removed in vacuo. Chromatographic purification (dichloromethane / methanol) gives 11.57 g (21%) 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-α] [1,3,5] triazin-4-one

To a solution of 11.57 g (35 mmol) N- [6-Amino-2- (2-ethoxyphenyl) -4-oxo-5-propyl-4,5-dihydro-pyriminin-5-yl] -acetamide (Example IV ) in 500 ml of pyridine are added 11.41 g (105 mmol) of chlorotrimethylsilane and the reaction mixture is stirred for 20 minutes at room temperature. After adding 16.96 g (105 mmol) of hexamethyldisilazane, the reaction mixture is refluxed 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, 1H.

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 and dried over magnesium sulfate and the solvent is removed in vacuo. 2.15 g (99%) of 4-ethoxy-3- (6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo [1,5-α] [1,3,5] triazine 2-yl) benzene sulfonic acid chloride.
200 MHz ¹ H-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, 1H.

Example VII

Ethyl 2-acetylamino-2-cyano-2-cyclopentylethanoate

125 g of ethyl acetamidocyanoacetate (734.6 mmol) are added at room temperature to a solution of 17.74 g of sodium (771.3 mmol) in 1.2 l of ethanol. 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 concentrated on a rotary evaporator. It is taken up in dichloromethane, washed twice with water, dried over magnesium sulfate and concentrated. The crystalline residue is stirred with ether and filtered off with suction.
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, 3H); 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 ethyl 2-acetylamino-2-cyano-2-cyclopentylethanoate in 120 ml of ethanol and stirred under reflux for 5 h. It 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, 12H); 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 stirred at room temperature for 20 min. After adding 2.8 ml (13.5 mmol) of hexamethyldisilazane, the mixture is stirred under reflux overnight. It is evaporated to dryness, the residue is taken up in 80 ml of methanol and stirred for 45 min at room temperature. 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, 3H); 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-imidazol [1,5-a] [1,3,5] triazin-2-yl) -benzenesulfonic acid chloride

To 0.66 ml (9.9 mmol) of ice-cold 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 at room temperature overnight before it is 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, 3H); 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 (brs, 1H).

Manufacture of the active ingredients

example 1

2- {2-Ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-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) -benzenesulphonic acid chloride (Example VI) in 5 ml of dichloromethane are added 86 mg (0.66 mmol) of hydroxyethylpiperazine and the reaction mixture is stirred for 16 hours at room temperature. After purification by chromatography (dichloromethane / methanol = 95: 5), 63 mg (57%) 2- {2-ethoxy- 5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} - 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-piperazine-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 are added 73 mg (0.73 mmol) of N-methylpiperazine and the reaction mixture is stirred for 2 hours at room temperature. After purification by chromatography (dichloromethane / methanol = 95: 5), 110 mg (95%) of 2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -6-methyl-8- are obtained 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-piperazine-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) benzene sulfonic acid chloride (Example VI) in 5 ml dichloromethane are added 83 mg (0.73 mmol) N-ethylpiperazine and the reaction mixture is stirred for 2 hours at room temperature. After purification by chromatography (dichloromethane / methanol = 95: 5), 104 mg (87%) of 2- [2-ethoxy- 5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -6-methyl-8- are obtained propyl-3H-imidazo [1,5-a] [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 are added 143 mg (0.73 mmol) of N- (3,4-dimethoxyphenylethyl) -N-methylamine and the reaction mixture is stirred for 2 hours at room temperature. After purification by chromatography (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-dihydro-imidazo [1,5-α] [1,3,5] triazin-2-yl) benzene sulfonamide

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) benzene sulfonic acid chloride (Example VI) in 5 ml of dichloromethane is added 55 mg (0.73 mmol) of 2-methoxyethylamine and the reaction mixture is stirred for 2 hours at room temperature. After purification by chromatography (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-hydroxypiperidine-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 purification by chromatography (dichloromethane / methanol = 95: 5), 100 mg (87%) of 2- [2-ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) -phenyl] -6-methyl-8- are obtained 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-Hydroxyethyl-piperazinyl) - [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) 4-ethoxy-3- (8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazole [1,5-α] [1,3,5] triazine-2- yl) -benzenesulfonic acid chloride (Example X) are placed in 7 ml of dichloromethane. 116.2 mg (0.89 mmol) of N-hydroxyethylpiperazine are added and the mixture is stirred at room temperature overnight. Purification is carried out by flash chromatography with a) cyclohexane / ethyl acetate 1: 1 and b) dichloromethane / methanol 95: 5.
Yield: 151.4 mg (94.3% of theory)
R _f 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 (br.s, 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 (brs, 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) 4-ethoxy-3- (8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazole [1,5-α] [1,3,5] triazine-2- yl) -benzenesulfonic acid chloride (Example X) are placed in 7 ml of dichloromethane. 174.3 mg (0.89 mmol) of N-methylhomoveratrylamine are added and the mixture is stirred at room temperature overnight. Purify by flash chromatography with cyclohexane / ethyl acetate 1: 1.
Yield: 144.5 g (81.5% of theory)
R _f 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 (brs, 1H).

The sulfonamides listed in Tables 1 and 2 below were by means of 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 HPLC, their Characterizations made by LC-MS measurement. The one in the column% The numerical value given (HPLC) indicates the content of the molar peak characterized end product. Standard provision A was applied to Amines with acidic functionalities, standard specification B for amines with neutral Functionalities, standard regulation C for amines with additional basic ones Functionalities.

For compounds that are listed in the following Tables 1 and 2 and the optically show a free nitrogen valence, these are basically as -NH radicals to understand.

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 added 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). The product is obtained after the filtrate has been concentrated in vacuo.

Standard regulation B Implementation of amines with neutral functionalities

First, 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 by the synthesizer. After 24 hours, 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 , mobile phase: ethyl acetate). The filtrate is concentrated in vacuo.

Standard regulation C Implementation of amines with basic functionalities

First, 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 by 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. The product is obtained after the filtrate has been concentrated in vacuo.

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

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 with up to 4 carbon atoms,
R ^{2 stands} for straight-chain or branched alkyl with up to 4 carbon atoms or for (C ₃ -C ₈ ) -cycloalkyl,
R ^{3 represents} hydrogen or straight-chain or branched alkyl with up to 4 carbon atoms,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) -alkoxy, hydroxy or (C ₁ -C ₈ ) -alkyl, optionally up to 3 times, identically or differently, through Hydroxy, (C ₁ -C ₆ ) -alkoxy or radicals of the formulas
or -NR ⁶ R ⁷
is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or (C ₁ -C ₆ ) -alkyl,
and / or in turn (C ₁ -C ₈ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally substituted one to three times, identically or differently, 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, which is optionally up to 3 times, identical or different, by halogen, acetyl, (C ₁ -C ₆ ) -alkoxy or by radicals of the formulas
-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )
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 to which they are attached are radicals of the formulas
form,
wherein
R ¹⁴ and R ^{15 are} identical or different and are 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 denotes hydrogen or (C ₁ -C ₆ ) -alkyl which is optionally substituted by hydroxy, or
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 with up to 3 carbon atoms or (C ₃ -C ₆ ) -cycloalkyl,
R ^{3 represents} straight-chain or branched alkyl with up to 3 carbon atoms,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₄ ) -alkoxy, hydroxy or (C ₁ -C ₇ ) -alkyl, optionally up to 3 times, identical or different, through Hydroxy, (C ₁ -C ₄ ) -alkoxy or radicals of the formulas
or -NR ⁶ R ⁷
is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or methyl,
and / or in turn (C ₁ -C ₇ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally substituted one to three times, identically or differently, 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 NH _2,
or
R ^{4 represents} hydrogen or methyl
and
R ⁵ for residues of the formulas
stands
or
represents phenyl, which is optionally up to 3 times, identical or different, by fluorine, chlorine, acetyl, (C ₁ -C ₄ ) -alkoxy or by radicals of the formulas
-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )
is substituted,
wherein
R ¹⁰ and R ^{11 are} identical or different and are hydrogen or methyl,
R ¹² and R ^{13 are} identical or different and are hydrogen or methyl,
or
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are radicals of the formulas
form,
wherein
R ¹⁴ and R ^{15 are} identical or different and are hydroxy, hydrogen or (C ₁ -C ₃ ) -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 denotes 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. 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 represents} n-propyl or cyclopentyl,
R ^{3 represents} methyl, ethyl or n-propyl,
R ⁴ and R ^{5 are} identical or different and represent hydrogen, (C ₁ -C ₃ ) -alkoxy, hydroxy or (C ₁ -C ₆ ) -alkyl, optionally up to 3 times, identical or different, through Hydroxy, (C ₁ -C ₃ ) -alkoxy or radicals of the formulas
or -NR ⁶ R ⁷
is substituted,
wherein
R ⁶ and R ^{7 are} identical or different and are hydrogen or methyl,
and / or in turn (C ₁ -C ₆ ) -alkyl is optionally substituted by phenyl or phenoxy, which in turn is optionally substituted one to three times, identically or differently, by fluorine, hydroxy, methoxy or by a radical of the formula -SO ₂ NH ₂ are,
or
R ^{4 represents} hydrogen or methyl
and
R ⁵ for residues of the formulas
stands
or
stands for phenyl, which is optionally up to 3 times, identical or different, by fluorine, acetyl, methoxy or by radicals of the formulas
-NR ¹⁰ R ¹¹ or -CH ₂ -P (O) (OR ¹² ) (OR ¹³ )
is substituted,
wherein
R ¹⁰ and R ^{11 are} identical 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 to which they are attached are radicals of the formulas
form,
wherein
R ¹⁴ and R ^{15 are} identical or different and are hydroxy, hydrogen or a radical of the formula - (CH ₂ ) ₂ -OH,
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 denotes 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. Process for the preparation of imidazo [1,3,5] triazinones according to Claims 1 to 4, characterized in that one
Compounds of the general formula (II)
in which
R ¹ , R ² and R ^{3 have} the meaning given above,
initially by reaction with chlorosulfonic acid (ClSO ₃ H), if appropriate 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 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 the general formula (I) according to any 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 related diseases with cGMP regulated processes are ('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, as well as 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, neural hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, Arrhythmias, thromboembolic diseases and ischemias such as Myocardial infarction, stroke, transitory 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 the genitourinary system such as prostatic 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 the pharmaceutical composition is administered intravenously or orally. 14. Use of the compounds of the general formula (I) according to one of the Claims 1 to 4 for the manufacture of drugs or pharmaceuticals Compositions for the prophylaxis and / or treatment of diseases. 15. Use according to claim 14 for the production of a medicament or a pharmaceutical composition for prophylaxis and / or Treatment of disorders related to cGMP regulated Processes ('cGMP-related diseases'). 16. Use according to claim 14 or 15 for the production of a medicament or a pharmaceutical composition for prophylaxis and / or Treatment of cardiovascular diseases, diseases of the Genitourinary system as well as cerebrovascular diseases. 17. Use according to any one of claims 14 to 16 for the production of a Drug or pharmaceutical composition for prophylaxis and / or treatment of cardiovascular diseases such as Hypertension, neural hypertension, stable and unstable angina, peripheral and cardiac vascular diseases, arrhythmias, thromboembolic Diseases and ischemias such as myocardial infarction, stroke, transitory and ischemic attacks, angina pectoris, peripheral circulatory disorders, Prevention of restenoses after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angio plasties (PTCA) and bypass. 18. Use according to any one of claims 14 to 16 for the production of a Drug or 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 any one of claims 14 to 16 for the production of a Drug or 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 any one of claims 14 to 19, characterized in that that the drugs or compositions are intravenous or oral be applied.