LV12793B - Imidazole1,5-AU-pyrido-3,2-ECpyrazinone as a medicinal product - Google Patents

Abstract

The invention relates to the use of imidazo[1,5-a]-pyrido[3,2-e]-pyrazinones of formula (1) as inhibitors for phosphodiesterase 5 for the therapy of erectile dysfunction (impotence). The invention also relates to the use of imidazo[1,5-a]-pyrido[3,2-e]-pyrazinones of formula (1) as dual inhibitors of phosphodiesterase 3 and of phosphodiesterase 5 for the therapy of heart failure, pulmonic hypertonia and vascular diseases which are accompanied by insufficient blood supply. The invention further relates to a method for making the same.

Claims (27)

INVENTION FORMULA A process for the preparation of imidazo [1,5-a] -pyrido [3,2-e] -pyrazinone of formula (1) H (1), where A-denotes О or NH, R ¹ , R, R ³ may be the same or different and may represent a hydrogen atom as well -C ₈ - alkyl, straight or branched chain, optionally substituted one or more times by -OH, -SH, -NH _2, -NHCj ₆ -alkyl, -N (Ci .6 alkyl) _2, -NHC ₆ ... 14-aryl, -N (C ₆ -C 14) aryl ₂ , -N (Ci ₆ alkyl) (C _6. I4-aryl), -NO _2, -CN, -COOH, -COOC 5- alkyl, - (C = O) Ci ... 5- alkyl, -F, -Cl, -Br, -I, -Ο-Ci-6 alkyl, -OC ₆ ... 14 -aryl, -S-Ci ₆ alkyl, -SC ₆ .14-aryl, -OSO ₂ -Ci.6-alkyl, -OSO ₂ C ₆ ... 14- aryl, mono-, bi- or tricyclic saturated or mono- or several unsaturated carbocyclic connection with the third ..14 ring members, mono-, bi- or tricyclic saturated or mono- or poly-unsaturated heterocyclic compounds with 5 to 15 ring members and 1 to 6 heteroatoms, preferably N, О and S, C ₂ .8-alkenyl, singly or repeatedly unsaturated, straight-chain or branched, optionally one or more substituted with -ОН, -SH, -NH _2, -NHCj 6 -alkyl, -N (C ₆ -alkyl _t ) _2, -NHC ₆ [4-aryl, -N (C ₆ i4-aryl) _2, -N (C | ..6 alkyl) (C6 14 aryl), -NO _2, -CN, -COOH, -COOC 5-alkyl, - (C = O) C 1 5 -alkyl, -F, -Cl, -Br, -I, -Ο-Ci-6 alkyl, -OC _6th 14-aryl, -SC ₆ -alkyl, -SC ₆ 6-14 -aryl, -2-OSO ₂ -C 1-6 alkyl, -OSO ₂ -C ₆ . 14-aryl, mono-, bi- or tricyclic saturated or singly or multiply unsaturated carbocyclic compounds with 3 to 14 ring members, mono-, bi- or tricyclic saturated or monounsaturated heterocyclic compounds with 5 to 15 ring members and 1-6 heteroatoms, with N, О and S being preferred, C ₂ .g-alkynyl, mono- or several unsaturated, straight-chain or branched, optionally one or more substituted with -ОН, -SH, -NH _2, -NHC ... 6 -alkyl, -N (Ci, ₆ alkyl) _2, -NHC ₆ ... 14 -aryl, -N (C ₆ .i4-aryl) _2, -N (Ci ... 6 -alkyl) (C ₆ .. u -aryl) - NO ₂ , -CN, -COOH, -COOCi. -5-alkyl, - (C = O) C 1-5 -alkyl, -F, -Cl, Br, -I, -O-C 1-6 -alkyl, -OC 6-14 aryl, -S-C _{1 6-} alkyl, -S-Cb ... 14-aryl, -OSO2-C1. _6- alkyl, -OSO2-C6-14 aryl, mono-, bi- or tricyclic saturated or singly or multiply unsaturated carbocyclic compounds with 3 to 14 ring members, mono-, bi- or tricyclic saturated or mono- a polyunsaturated heterocyclic compound having 5 to 15 ring members and 1 to 6 heteroatoms, preferably N, O, and S, -mono, -bi- or tricyclic saturated or mono- or poly-unsaturated carbocyclic compounds with 3 to 14 ring members, optionally substituted one or more times with -OH, -SH, -NH ₂ , -NHCi-b-alkyl, - N (C _"6 -alkyl) _2, -NHC ₆ .. 14 -aryl, -N (C ₆ ... i4-aryl) _2, -N (Ci .. ₆ alkyl) (C ₆ ..i4- aryl), -NO ₂ , -CN, -COOH, -COOC 1-5 alkyl, - (C = O) Cl. 5-alkyl, -F, -Cl, -Br, -I, -Ο-Ci ... б-alkyl, -OC ₆ 14-aryl, -S-Ci ... 6 -alkyl, -S-Сб. 14-aryl, -OSO ₂ -C _1-6 alkyl, -OSO ₂ -C 6-14 aryl, -mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocyclic compounds having 5 to 15 ring members; and 1 to 6 heteroatoms, preferably N, О and S, optionally substituted one or more times with -O, -SH, -NH ₂ , -NHC 1-6 alkyl, -N (C 1-6) alkyl) _2, -NHC ₆ ... 14 -aryl, -N (C ₆ ... i4-aryl) _2, -N (Cj. ₆ alkyl) (C ₆ i4-aryl), -NO _2, -CN, -COOH, -COOC .5-alkyl, - (C = O) Ci ... 5-alkyl, -F , -Cl, -Br, -I, -Ο-Ci..6-alkyl, -OC ₆ .14-aryl, -S-Ci-6 alkyl, -SC _6th -I-aryl, -OSO ₂ -C 1-6 alkyl, -OSO ₂ -C 6-14 aryl, characterized in that the 3-aminopyridines of formula (2) are identical with A, R ¹ , R ² and R ³ meanings (2) In an organic solvent reacts with cyanate in the presence of an acid to form ureas of formula (3) having the same meaning as A, R ¹ , R ² and R ³ R (3). Which is then heated in an organic solvent to cyclize to the compounds of the invention of formula (1). A process for the preparation of compounds of formula (1) according to formula (1). (3), particular preference is given to using alkyl cyanates to provide intermediates of formula (3). A process for the preparation of compounds of formula (1) according to claim 1 or 2, with particular preference being given to the use of protic solvents for the preparation of intermediates of formula (3). Process for the preparation of compounds of formula (1) according to claim 1, 2 or 3, with particular preference for the preparation of intermediates of formula (3) in the presence of mineral acid. A process for preparing the compounds of formula (1) according to any one of claims 1 to 4, with particular preference for the preparation of intermediates of formula (3) in the presence of concentrated mineral acid which may be mixed with a protic solvent according to claim 3. A process for the preparation of compounds of formula (1) according to any one of claims 1-5. is particularly preferred for the cyclization of urea according to formula (3) using solvents having a boiling point> 80 ° C. A process for preparing a compound of formula (1) according to any one of claims 1-6. is particularly preferred for urea cyclization according to formula (3), particularly advantageous using solvents having a boiling point> 100 ° C. A process for the preparation of compounds of formula (1) according to any one of claims 1 to 7, with particular preference for the cyclization of urea according to formula (3) using a reaction temperature of> 80 ° C. A process for the preparation of compounds of formula (1) according to any one of claims 1 to 8, with particular preference for the cyclization of urea according to formula (3), particularly advantageous using a reaction temperature of> 100 ° C. Use of compounds of formula (1) according to claim 1 as therapeutically active substances for the treatment of erectile dysfunction (impotence). Use of the salts of the physiologically compatible compounds of formula (1) according to claim 10, characterized in that the bases are neutralized with inorganic and organic acids by the appropriate neutralization of acids with inorganic and organic bases, respectively by quaternization of amines to quaternary ammonium salts as therapeutic agents. for the treatment of erectile dysfunction (impotence). Use of compounds of formula (1) according to claims 10 and 11 with asymmetric carbon atoms in the D-form, L-form and DL-mixture, as well as the compound of formula (1) according to claim 10 or 11 A compound having several asymmetric carbon atoms for the manufacture of a towel for the treatment of erectile dysfunction (impotence). Use of the compounds of formula (1) according to claim 10, 11 or 12, in particular the following: 8-methoxy-3-methyl-1-propylimidazo [1,5-a] -pyrido [3,2-e] -pyrazinone; 8-methoxy-imidazo [1,5-a] -pyrido [3,2-e] -pyrazinone; 8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 8-methoxy-1-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 8-methoxy-1-propylimidazo [1,5-a] -pyrido [3,2-e] -pyrazinone; 1-ethyl-8-hydroxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 1-ethyl-8- (3-hydroxypropoxy) -3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-3-methyl-8- (2-oxopropoxy) -imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-3-methyl- (2-pyridylmethoxy) -imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 8-methoxy-1-phenylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 8-methoxy-3-phenylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone. Medicaments containing one or more compounds according to claims 10 to 12 in parallel with conventional physiologically compatible carriers and / or diluents, respectively adjuvants. 15. A process for the preparation of a medicament according to claim 14, wherein the one or more compounds according to claim 10, 11 or 12 together with the pharmaceutical carriers and / or diluents or excipients used are processed into pharmaceutical preparations. or in therapeutically useful forms. Use of compounds of general formula (1) according to 10, 11 or 12 and / or a pharmaceutical preparation according to 14 or 15 alone or in combination with one another or in combination with carriers and / or diluents or other excipients. Use of compounds according to claim 10, 11 or 12 as therapeutic active substances for the manufacture of a medicament for the treatment of erectile dysfunction (impotence) according to claim 14 or 16, with particular preference for oral, parenteral, buccaler or sublingual use. Use of the compounds according to claim 10, 11 or 12 as veterinary therapeutic agents for the prophylaxis and treatment of erectile dysfunction (impotence) in male mammals. 19. Use of imidazo [1,5-a] -pyrido [3,2-e] -pyrazinone according to formula (1) where Α-replaces О or NH, 1 о R, R may be the same or different and may represent a hydrogen atom as well -Ci ... 5-alkyl, unbranched or branched, optionally substituted once or more with -O, -SH, -NH 2, -NO 2, -CN, -COOH, -F, -Cl, -Br, -I, -S-C 1-6 alkyl, -S-C _1-6 alkyl, and R ³ can mean a hydrogen atom as well Phosphite 5-alkyl, straight or branched chain, optionally substituted one or more times by -OH, -SH, -NH _2, -NO _2, -CN, -COOH, -F, -Cl, -Br, -I, - Ο-Ci. 6-alkyl, -S-C 1-6 -alkyl, or phenyl as therapeutic active substances for the treatment of congestive heart failure, pulmonary hypertension and vascular disorders. The use of physiologically compatible salts in the compounds of formula (1) according to claim 19, characterized by the neutralization of bases with inorganic or organic acids, respectively, by the quaternization of tertiary amines in ammonium salts, as therapeutic agents for the preparation of therapeutic agents. for the treatment of heart failure, pulmonary hypertension and vascular disease, which occurs in association with impaired bleeding. Use of the compounds of formula (1) according to claim 19 or 20 with asymmetric carbon atoms in the D-form, the L-form, in the DL mixture as well as in the case of the compounds of formula (1) according to claim 19 or 20. Use of mixtures of diastereomeric forms with several asymmetric carbon atoms as therapeutic active substances for the manufacture of a medicament for the treatment of cardiac insufficiency, pulmonary hypertension and vascular disease accompanied by impaired bleeding. Compounds of formula (1) according to claims 19, 20. or 12, using one of the following compounds, in particular: 8-methoxy-3-methyl-1-propylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 8-methoxy-imidazo [1,5-a] -pyrido [3,2-e] -pyrazinone; 8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 8-methoxy-1-methylimidazol-1,5-a] -pyrido [3,2-e] -pyrazinone; 8-methoxy-1-propylimidazol-1,5-a] -pyrido [3,2-e] -pyrazinone; 1-ethyl-8-hydroxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 8-benzylamino-1-ethyl-3-methylimidazol-1,5-a] pyrido [3,2-e] -pyrazinone; 1-ethyl-8- (3-hydroxypropoxy) -3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone. Use of a compound of formula (1) according to claim 19, 20, 21 or 22 as a therapeutically active substance for the manufacture of a medicament for the treatment of heart failure, pulmonary hypertension and vascular disease, which is accompanied by the reduced bleeding characteristic. the fact that these compounds inhibit phosphodiesterase 3 and phosphodiesterase 5 in two ways, simultaneously and equally potently, resulting in a positive inotropic effect on the heart combined with decompensating dilation of the arterial blood vessels under the influence of the same active substance. 24. Medicaments comprising one or more compounds according to claim 19, 20, 21 or 22, in parallel with conventional physiologically compatible carriers and / or diluents, respectively, excipients. A process for the preparation of a medicament according to claim 25, characterized in that one or more compounds according to claim 19, 20, 21 or 22 are used in the pharmaceutical preparations, respectively, with the applicable pharmaceutical carriers and / or diluents. or in a therapeutically useful form. Use of compounds of general formula (1) according to claim 19, 20, 21 or 22 and / or of a pharmaceutical product according to claim 23 or 24, alone or in combination with carriers and / or diluents or other excipients. Use of a compound according to claim 19, 20, 21 or 22 as therapeutic active ingredients for the manufacture of a medicament for the treatment of cardiac insufficiency, pulmonary hypertension and vascular hyporesponsiveness, particularly suitable for oral, intravenous, intramuscular, subcutaneous , parenteral, buccal or sublingual use.