EP1776120A1

EP1776120A1 - Novel uses of 2-phenyl-substituted imidazotriazinone derivatives

Info

Publication number: EP1776120A1
Application number: EP05764196A
Authority: EP
Inventors: Helmut Haning
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2004-08-06
Filing date: 2005-07-23
Publication date: 2007-04-25
Also published as: KR20070041613A; CN101035539A; BRPI0514123A; MA28811B1; ECSP077224A; US20070299088A1; JP2008509101A; IL181164A0; AU2005270446A1; NO20071231L; RU2007108078A; WO2006015715A1; MX2007001275A; CA2575907A1; DE102004038328A1

Abstract

The invention relates to the use of PDE 5 inhibitors, and especially of known 2-phenyl-substituted imidazotriazinone derivatives for producing medicaments for the treatment of symptoms that can be treated by increasing cGMP levels in certain tissues, such as acute myocardial infarction and damage caused by reperfusion, various symptoms in the female and male reproductive system and urogenital tract, gastrointestinal diseases, damage caused by diabetes, and liver failure.

Description

Uses of 2-phenyl-siibstitiiierten imidazotriazinone derivatives

The present invention relates to the use of PDE 5 inhibitors in general and ins¬ particular of known 2-phenyl-substituted imidazotriazinone derivatives for the preparation of medicaments for the treatment of diseases that are treatable by increasing cGMP levels in certain tissues, such as for example, acute myocardial infarction and reperfusion damage, - various clinical pictures of the female and male reproductive system and genitourinary tract, gastrointestinal diseases, diabetes damage and kidney failure.

The cyclic nucleotide cGMP (cyclic guanosine monophosphate) is one of the most important intracellular messengers and is metabolised by certain phosphodiesterases (PDEs), in particular the isoenzyme PDE 5 [Drugs Fut. 26, 153-162 (2001)]. PDE 5 is found mainly in vascular smooth muscle cell tissue, less in the kidney, lung and platelets. Due to their vasorelaxing effect PDE 5 inhibitors are proposed for the treatment of angina and hypertension, but mainly for the treatment of erectile dysfunction.

WO 99/24433 describes 2-phenyl-substituted imidazotriazinones, their cGMP-PDE-inhibiting action and their use for the treatment of vascular diseases, in particular for the treatment of erectile dysfunction. In WO 02/089808 and WO 03/011262, uses of 2-phenyl-substituted imidazotriazinones are disclosed.

At present 11 phosphodiesterases with different specificity towards the cyclic nucleotides cAMP and cGMP are described in the literature [cf. Fawcett et al., Proc. Nat. Acad. Be. 97 (7), 3072-3077 (2000)]. Cyclic guanosine-3 ', 5'-monophosphate-rnetabolisierende Phos¬ phosphodiesterases (cGMP-PDEs) are the PDE 1, 2, 5, 6, 9, 10 and 11. The mentioned, according to the invention used 2-phenyl-substituted imidazotriazinones are potent inhibitors of phosphodiesterase 5. The differentiated expression of phosphodiesterases in various cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with selective inhibitors allow a selective increase of cGMP concentration in specific cells, tissues and organs and thereby allow the addressing of various processes regulated by cGMP so that PDE 5 inhibitors are therapeutically applicable in a number of conditions that may be affected by the increase in cGMP levels.

In this case, preference is given to those PDE 5 inhibitors which inhibit PDE 5 with an IC ₅₀ value of less than 1 μM, preferably of less than 0.1 μM, in the test listed below. Preferably, the PDE 5 inhibitors used according to the invention are also selective to cAMP-PDEs, in particular to PDE 4. Particularly preferred is an at least 10-fold stronger inhibition of PDE 5.

Compounds having an inhibitory effect on cGMP-PDEs are described, for example, in the following documents: EP-AO 201 188, EP-A-0 214 708, EP-A 0 293 063 ^' , EP-A-0 319 050, EP-A-

0 347 027, EP-A-0 347 146, EP-A-0 349 239, EP-A-0 351 058, EP-A-0 352 960, EP-A-0 371 731,

EP-A-0 395 328, EP-A-0 400 799, EP-A-0 428 268, EP-A-0 442 204, EP-A-0 463 756, EP-A-0 526

004, EP-A-0 579 496, EP-A-0 607 439, EP-A-0 640 599, EP-A-0 669 324, EP-A-0 686 625, EP-A-

07 / 22,936, US 4,060,615, US 5,294,612, WO 91/19717, WO 94/19351, WO 94/22855, WO 96/32379, WO 97/03070, JP-A-05222000 (CAPLUS 1994, 191719).

Compounds having an inhibitory effect on the cGMP-specific PDE (corresponding to PDE 5) are described, for example, in the following documents: EP-AO 636 626, EP-AO 668280, EP-A 722 937, EP-A 722 943, EP-A 722 944 EP-A-0 758 653, EP-A-995 750, EP-A-995 751, EP-A-0 092 719, WO 94/28902, WO 95/19978, WO 96/16657, WO 96/28159, WO 96/28429, WO 98/49166, WO 99/24433, WO 99/67244, WO 00/78767, WO 01/12608, WO 01/18004, WO 01/19369, WO 01/19802, WO 01/21620, WO 01/27105, J Med. Chem. 39, 1635-1644 (1996), J. Med. Chem. 43, 1257-1263 (2000), Dmgs Fut. 26, 153-162 (2001).

Reference is expressly made to the disclosure of these documents, in particular to the compounds disclosed therein.

One aspect of the present invention relates to the use of compounds of the general formula (I)

in which

R ^{1 is} methyl or ethyl,

R ^{2 is} ethyl or propyl, R ³ and R ^{4 are} identical or different and represent a straight-chain or branched alkyl chain having up to 5 carbon atoms, which is optionally substituted identically or differently by hydroxy or methoxy up to two times,

or

R ³ and R ⁴ together with the nitrogen atom, a piperidinyl, morpholinyl, Thiomorpholinyl- ring or a radical of the formula

form,

worm

R ⁶ denotes hydrogen, formyl, acyl or alkoxycarbonyl having in each case up to 3 carbon atoms,

or

straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally mono- to disubstituted, identical or different, by hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by groups of the formulas - (CO) _r NR ⁷ R ⁸ or

-P (O) (OR ⁹ XOR ¹⁰ ) is substituted,

wherein

f is a number 0 or 1,

R ⁷ and R ^{8 are} identical or different and denote hydrogen or methyl,

R ⁹ and R ^{10 are the} same or different and denote hydrogen, methyl or ethyl,

or

R ⁶ denotes cyclopentyl,

and the heterocycles formed together with the nitrogen atom listed under R ³ and R ⁴ , where appropriate, one to two times, identical or different, optionally also geminal, - A - by hydroxy, formyl, carboxyl, acyl or alkoxycarbonyl with up to 2x1 3 carbon atoms or groups of the formulas -P (O) (OR ⁿ ) (OR ¹² ) or - (CO) _r NR ¹³ R ¹⁴ substitu¬ are

wherein

R ¹¹ and R ^{12 are the} same or different and denote hydrogen, methyl or ethyl,

i is a number 0 or 1,

and

R ¹³ and R ^{14 are the} same or different and denote hydrogen or methyl,

and / or the heterocycles listed together with the nitrogen atom listed under R ³ and R ⁴ are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms, which may optionally be mono- to disubstituted, identical or different Substituted hydroxy, carboxyl or by a radical of the formula -P (O) OR ¹⁵ OR ¹⁶ ,

wherein

R ¹⁵ and R ^{16 are the} same or different and denote hydrogen, methyl or ethyl,

and / or the heterocycles listed together with the nitrogen atom listed under R ³ and R ⁴ are optionally substituted by N-linked piperidinyl or pyrrolidinyl,

and

R ^{5 is} ethoxy or propoxy,

and their salts and solvates and the solvates of the salts,

for the treatment of cardiac ischemia, for the achievement or improvement of a preconditioning effect, for the treatment of acute myocardial infarction and reperfusion injury, especially after a myocardial infarction, for the treatment of male infertility, Raynaud's syndrome, Claudicatio intermittens, Peyronie's disease, for the treatment of fibrotic diseases, arteriosclerosis, sperm motility, depression, leukemia (eg, chronic lymphocytic leukemia), priapism, platelet adhesion and aggregation in renal ischemia Support and promotion of liver regeneration after surgical liver resection or in liver cancer, to inhibit the contraction of the esophagus muscles (eg in nutcracker esophagus or esophagospasm), for the treatment of achalasia, premature labor, female infertility and dysmenorrhea, for the treatment of liver diseases such as cirrhosis , portal hypertension, for the treatment of lupus, hypertensive systemic lupus erythematosus, scleroderma, for the treatment of multiple sclerosis, rheumatoid arthritis, allergy, autoimmune diseases, osteoporosis, cachexia, polycystic ovarian syndrome, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic cataract, hyperlipidemia and dyslipidemia, for growth promotion and survival improvement of oocytes, zygotes, embryos or fetuses, for weight increase in premature birth, to increase milk production in mammals, especially in humans, for the treatment of migraine, incontinence, acute and chronic renal failure, glomerular disease, nephritis, tubulointerstitial diseases, glomuleropathy, hair loss, pancreatitis, amnesia, disorders of consciousness, autism, Speech disorders, Lennox syndrome and epilepsy.

Depending on their structure, the compounds used according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the use of the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents can be isolated in a known manner.

If the compounds used according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds used according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the compounds used according to the invention.

Physiologically acceptable salts of the compounds used according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic acids , Citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds used according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16C Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates are those forms of the compounds used according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention. Hydrates can be prepared, for example, by crystallizing the compound in question from water or an aqueous solvent.

In addition, the present invention also includes prodrugs of the compounds used in the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body to the compounds used according to the invention (for example metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

An acyl radical having 1 to 3 carbon atoms in the context of the invention is, for example, formyl, acetyl or propionyl.

A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms in the context of the invention is, for example, methoxy, ethoxy, n-propoxy or isopropoxy.

An alkoxycarbonyl radical having 1 to 3 carbon atoms in the context of the invention is, for example, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

A straight-chain or branched alkyl radical having 1 to 5 or 1 to 3 carbon atoms in the context of the invention is, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl or n-pentyl. Straight-chain or branched alkyl radicals having 1 to 4 or 1 to 3 carbon atoms are preferred.

Another embodiment of the invention relates to the use according to the invention of compounds of the general formula (I) in which the radicals R ⁵ and -SO ₂ NR ³ R ⁴ in the para position each other on the phenyl ring and R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} each as defined above.

A further embodiment of the invention relates to the use according to the invention of compounds of the general formula (Ia)

in which R ¹ , R ² , R ³ , R ⁴ and R ^{s are} each as defined above,

and their salts and solvates and the solvates of the salts.

The use according to the invention of the following compounds is preferred:

2- [2-Ethoxy-5- (4-methylpiperazine-l-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-fJ [1,2,4] triazin-4-one ;

2- [2-Ethoxy-5- (4-hydroxyethyl-piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3 H -imidazo [5,1-f] - [1,2,4] triazin-4-one;

2- [2-Ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-fl [l, 2,4] -triazin-4-one ;

2- [2-Ethoxy-5- (4-hydroxymethyl-piperidin-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-fj- [1,2,4] triazin-4-one ;

242-ethoxy-5- (3-hydroxypyrrolidm-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-fJ [1,2,4] triazin-4-one;

4-ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5,7-dimethyl-4-oxo-3,4-dihydro-imidazo [5, l-fJ [l, 2,4] - triazin-2-yl) benzenesulfonamide;

N, N-diethyl-4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydro-imidazo [5, l-fJ [l, 2,4] triazin-2-yl) -benzol- sulfonamide; 2- [2-Ethoxy-5- (4- (2-pyrimidinyl) -piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-iniidazo [5, lf] - [1, 2,4 ] triazin-4-one;

2- [2-ethoxy-5- (morpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one;

2- [2-Ethoxy-5- (1,4-dioxa-6-azaspiro [4.4] nonane-6-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5, l-f] [l , 2,4] triazin-4-one;

N, N-bis (2-methoxyethyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5, lf] [l, 2,4] -triazine-2 yl) benzenesulfonamide;

N- (3-Isoxazolyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5, lf] [l, 2,4] triazin-2-yl) benzenesulfonamide ;

2- [2-ethoxy-5- (2-tert-butoxycarbonylaminomethylmorpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5, lf] [l, 2,4] triazine-4 one;

2- [2-Ethoxy-5- (4-phenyl-piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3 H -imidazo [5,1-f] [1,2,4] triazin-4-one;

2- [2-Ethoxy-5- (3-hydroxy-3-methoxymethyl-pyrrolidine-1-sulfonyl) -phenyl] -5,7-dimeth-yl-3H-imidazo [5, lf] [l, 2,4] triazine -4-one;

2- [2-Ethoxy-5- (4-methylpiperazine-l-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine-4 one;

2- [2-Ethoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] - [1,2,4] triazine 4-one lactate;

2- [2-Ethoxy-5- (4-methylpiperazine-l-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf | - [l, 2,4] triazine-4 on hydrochloride;

2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1f [1, 2,4] -triazine-4 one;

2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-fl [l, 2,4] -triazine-4 -one hydrochloride;

2- [2-Ethoxy-5- (4-methyl-1-amino-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-iridazo [5, lf] [l, 2, 4] triazin-4-one; 2- [2-Ethoxy-5- (4-hydroxyethyl-1-amino-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1-f] [1, 2 , 4] triazin-4-one;

N, N-bis-hydroxyethylaminoethyl-4-ethoxy-3 - (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] - [1,2,4] triazine-2 -yl) benzolsulfonarnid;

2- [2-Ethoxy-5- (4-dimethoxy-phosphorylmethyl-piperazm-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1-f] [1,2,4] triazine -4-one;

2- [2-Ethoxy-5- (4-diethoxy-phosphorylmethyl-piperidine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1-f] [1,2,4] triazine -4-one;

2- [2-Ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine-4 one;

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -splienyl} -5-methyl-7-propyl-3H-imidazo [5, 1-f] [1, 2,4] triazin-4-one;

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, lf] [l, 2, 4] triazine-4-one hydrochloride;

2- {2-Ethoxy-5- [4- (3-hydroxypropyl) -piperazm-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, 1-f] [1, 2 , 4] triazin-4-one;

N-Allyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] - [l, 2,4 ] triazin-2-yl) benzenesulfonamide;

N-ethyl-4-ethoxy-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] - [1, 2 , 4] triazin-2-yl) benzenesulfonamide;

N, N-diethyl-4-ethoxy-3 - (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, 1-f] [1, 2,4] triazine-2-one yl) - benzenesulfonamide;

N- (2-methoxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) -4 - ethoxybenzenesulfonamide;

N- (2-N, N-dimethylethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazm-2- yl) -4-ethoxy-benzenesulfonamide;

N- [3- (1-morpholino) propyl] -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazm-2 yl) -4-ethoxy-benzenesulfonamide; N- {3- [1- (4-Methyl) piperazino] -propyl} -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, l-fI- [l , 2,4] triazin-2 ~ yl) -4-ethoxy-benzenesulfonamide;

2- {2-Ethoxy-5 - [4- (2-methoxyethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, lf] [l, 2, 4] triazin-4-one;

2- {2-Ethoxy-5- [4- (2-N, N-dimethyl-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, 1 - f] [l, 2,4] triazin-4-one;

2- {2-Ethoxy-5- [4- (3-N, N-dimethyl-propyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, 1 - f] [1, 2,4] triazin-4-one;

2- [2-Ethoxy-5- (4-dioxolano-piperidine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1-f] - [1, 2,4] triazin-4-one;

2- [2-Ethoxy-5- (4- (5-methyl-4-furoic-oxanecarbonyl) -piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, 1-f] [1, 2,4] triazine-4-one;

2- {2-Ethoxy-5- [4-acetyl-piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine 4-one;

2- {2-Ethoxy-5- [4-formylpiperazine-l-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine 4-one;

2- [2-Ethoxy-5- (3-butylsydnonimine) -l-sulfonyl) -phenyl] -5-meth-yl-7-propyl-3H-iniidazo [5, lf] - [l, 2,4] triazine -4-one;

5-Methyl-2- [5- (4-methylpiperazine-l-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine 4-one;

5-Methyl-2- [5- (4-methylpiperazine-l-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine 4-one hydrochloride;

2- [5- (4-hydroxypiperidine-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf] - [l, 2,4] triazine-4 one;

2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazine 4-one;

2- {5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -2-propoxyphenyl} -5-niethyl-7-propyl-3H-imidazo [5, 1-f] [1, 2 , 4] triazin-4-one; N- (l, l-dioxo-tetrahydro-lλ ⁶ -thiophene-3-yl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, l-f] [ 1, 2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid amide;

N- (2-Dimethyl-aminoethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, l-fI- [1, 2,4] triazine) 2-yl) -4-propoxy-benzenesulfonamide;

3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, l-fl [l, 2,4] triazm-2-yl) -N- (3-moφholm-4 -yl-propyl) -4-propoxybenzenesulfonic acid amide;

N, N-bis (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazm-2- yl) -4-propoxy-benzenesulfonamide;

N-CS-hydroxybenzyl-S-CS-methyl-oxo -propyl-S 1 -dihydro-iinidazo-SJ-fluoro-1-triazmyl-4-propoxybenzenesulfonic acid amide;

N-ethyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazine-2- yl) -4-propoxy-benzenesulfonamide;

N- (3-ethoxypropyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-fj [1,2,4] triazin-2-yl) - 4-propoxybenzenesulfonic acid amide;

2- [5- (4-hydroxypiperidm-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl-3H-imidazo [5,1- ^] - [1,2,4] triazine 4-one;

3 - (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f] [1,2,4] triazin-2-yl) -4-propoxy-N-pyridine 4-yl-benzenesulfonic acid amide;

N ^ diethyl-S-CS-methyl ^ -oxo ^ -propyl-S ^ _-dihydro-l-j imidazofS fltl ltriazm ^^ ^ -y ^^ - propoxy benzenesulfonamide;

l- [3- (5-methyl-4-oxo-7-ρropyl-3,4-dihydro-imidazo [5, l-fj [l, 2,4] triazin-2-yl) -4-proρoxy-benzene - sulfonyl] -piperidine-4-carboxylic acid;

5-Methyl-2- [5- (morpliolm-4-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5, l- / l [l, 2,4] -triazine-4 one;

N- (2-hydroxyethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] -triazine-2 yl) -4-propoxy-benzenesulfonamide;

N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) -4 - propoxy-N-propyl-benzenesulfonamide; N- [2- (3,4-Dimethoxyphenyl) -ethyl] -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, 1-f] [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid amide;

N-allyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-f] [1,2,4] triazine 2-yl) -4-propoxybenzolsulfonsäureamid;

N-allyl-N-cyclopentyl-S-CS-methyl ^ -oxo-T-propyl-S ^ -dihydro-imidazot SJ-fltl ^^ ltriazine ^ -yl) -4-propoxybenzenesulfonic acid amide;

N-allyl-N-ethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) -4 - propoxybenzenesulfonic acid amide;

2- [2-Ethoxy-4-methoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf] [l, 2,4] triazin-4-one;

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -4-methoxy-pb.enyl} -5-methyl-7-propyl-3H-imidazo [5,1] f] [1, 2,4] triazin-4-one;

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -2-methoxy-5 - (5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, 1-f] [ 1, 2,4] triazin-2-yl) -benzenesulfonic acid amide;

4-Ethoxy-N- (4-ethoxyphenyl) -2-metb.oxy-5- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] - [l, 2 , 4] triazin-2-yl) -benzolsulfonsäureamid;

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1f] [1,2,4] triazine -2-yl) benzenesulfonamide;

N- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) -4 ethoxybenzenesulfonic acid amide;

N, N-bis (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-fl [l, 2,4] triazm-2-yl ) -4-ethoxybenzolsulfonsäureamid;

2- [5- (4-hydroxypiperidino-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7-propyl-3H-imidazo [5, 1-f] [1, 2,4] -triazine-4 one;

2- [5- (4-hydroxymethylpiperidin-1-sulfonyl) -2-ethoxy-phenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazine-4 -one;

2- {2-Ethoxy-5 - [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -phenyl} -5-ethyl-7-propyl-3H-imidazo [5, lf] [l, 2, 4] triazin-4-one; 2- [2-Ethoxy-5 - (4-methyl-piperazin-1-sulfonyl) -phenyl] -5-ethyl-7-propyl-3H-imidazo [5, 1-f] [1,2,4] -triazine 4-one;

2- [2-Ethoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5-ethyl-7-propyl-3H-imidazo [5, lf] [l, 2,4] -triazine-4 on hydrochloride;

3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) -N- (3-moφliolm-4- yl-propyl) -4-ethoxybenzenesulfonic acid amide;

N- (2-Ηydroxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, lf] [l, 2,4] triazin-2-yl) -4 ethoxy-N-propyl-benzenesulfonic acid amide;

2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazole [5, 1-f] - [1, 2,4] triazine-4-one hydrochloride trihydrate;

2- [2-Ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf | - [l, 2,4] triazine 4-one dihydrochloride.

Especially preferred compounds are listed in Table A:

Table A:

The compounds of the formulas (I) and (Ia) and Table A used according to the invention and their preparation are described in WO 99/24433. The disclosure of WO 99/24433 is expressly incorporated by reference.

A further embodiment of the invention relates to the use of the compounds of the general formulas (T) and (Ia) for the preparation of a medicament for the treatment of cardiac ischemia, for achieving or improving a preconditioning effect, for the treatment of an acute myocardial infarction and for reperfusion damage, especially after a myocardial infarction, for the treatment of male infertility, Raynaud's syndrome, Claudicatio intermittens, Peyronie's disease, for the treatment of fϊbrotic diseases, atherosclerosis, for the improvement of sperm motility, for the treatment of depression, leukemia (eg lymphocytic leukemia), for the treatment of priapism, for the treatment of platelet adhesion and aggregation in renal ischemia, for the promotion and promotion of liver regeneration after surgical liver resection or in liver cancer, for the inhibition of Contraction of the esophageal musculature (eg in nutcracker esophagus or esophagospasm), for the treatment of achalasia, preterm labor, female infertility and dysmenorrhoea, for the treatment of liver diseases such as cirrhosis, portal hypertension, for the treatment of lupus, hypertensive systemic lupus erythematosus, scleroderma for the treatment of multiple sclerosis, rheumatoid arthritis, allergy, autoimmune diseases, osteoporosis, cachexia, polycystic ovarian syndrome, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic cataract, Hyperlipidaemia and dyslipidemia, to promote growth and survival of oocytes, zygotes, embryos or fetuses, to increase weight in preterm birth, to increase milk production in mammals, especially in humans, to treat migraine, inco ntinence, acute and chronic renal failure, glomerular disease, nephritis, tubulointerstitial diseases, glomerulopathy, hair loss, pancreatitis, amnesia, disorders of consciousness, autism, speech disorders, Lennox syndrome and epilepsy.

The compounds used according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.

For these routes of administration, the compounds used according to the invention can be administered in suitable administration forms.

For the oral administration, according to the state of the art, functioning fast and / or modified delivery forms which contain the compounds used in accordance with the invention in crystalline and / or amorphized and / or dissolved form, such as eg Tablets (non-coated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound used according to the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (For example, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Iarzhalationsarzneiformen (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures ), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral and intravenous administration. Intravenous administration is particularly preferred for the treatment of acute myocardial infarction and reperfusion damage, for example; Intravenous administration can also take place creeping in here.

The compounds used according to the invention can be converted into the stated forms of application. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Carrier materials (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example Antioxi - Dantien such as ascorbic acid), dyes (eg, inorganic pigments such as example, iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one of the compounds used in the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

In general, it has been found to be beneficial to administer parenterally administered amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 1 mg / kg of body weight to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.1 to 30 mg / kg and most preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior the active substance, method of preparation and time or interval to which the application is made. Thus, in some cases it may be sufficient to make do with less than the aforementioned Mindest¬ amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

Embodiment 1 is 2- [2-ethoxy-5 ~ (4-methyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5, lf] [l, 2,4] triazin-4-one; this compound is prepared according to Example 16 in WO 99/24433.

Embodiment 2 is 2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3Η-imidazole [5, 1-fj [l, 2,4 ] triazm-4-one hydrochloride trihydrate; This compound is prepared according to Example 336 in WO 99/24433.

The PDE or PDE 5 -inhibiting effect of the compounds used according to the invention can be determined as follows:

PDE 5 inhibition test

To test the inhibitory effect, the "phosphodiesterase [ ³ H] cGMP-SPA enzyme assay" from Amersham Life Science is used. The test is carried out according to the test protocol specified by the manufacturer. Human recombinant PDE 5 expressed in a bacculovirus system is used. The substance concentration is measured at which the reaction rate is reduced by 50%.

Exemplary embodiments 1 and 2 show IC 50 values of 0.6 and 0.7 nM in this test.

PDE inhibition assay

Recombinant PDE1C (GenBank / EMBL Accession Number: NM_005020, Loughney et al., J. BUA Chan., 1996, 271, 796-806), PDE2A (GenBank / EMBL Accession Number: NM_002599, Rosman et al., Gene 1997, 191, 89-95), PDE3B (GenBank / EMBL Accession Number: NM_000922, Miki et al., Genomics 1996, 36, 476-485), PDE4B (GenBank / EMBL Accession Number: NM_002600, Obernolte et al., Gene 1993, 129, 239-247), PDE5A (GenBank / EMBL Accession Number: NM_001083, Loughney et al., Gene 1998, 216, 139-147), PDE7B (GenBank / EMBL Accession Number: NMj) 18945, Hetman et al., Proc. Natl. Acad. Be. USA 2000, 91, A12A16), PDE8A (GenBank / EMBL Accession Number: AF_056490, Fisher et al., Biochem Biophys Res. Commun 1998, 246, 570-577), PDE9A (Fisher et al., Biol Chem. 1998, 273_ (25), 15559-15564), PDE10A (GenBank / EMBL Accession Number: NM_06661, Fujishige et al., J. Biol. Chem. 1999, 274_, 18438-45), PDELA (GenBank / EMBL Accession Number: NMJH6953, Fawcett et al., Proc Natl Acad., 2000, 9Σ, 3702-3707) were expressed in Sf9 cells using the pFASTBAC baculovirus expression system (GibcoBRL).

The test substances are dissolved in 100% DMSO to determine their in vitro effect on PDE9A and serially diluted. Typically, serial dilutions of 200 μM to 1.6 μM are prepared (resulting final concentrations in the assay: 4 μM to 0.032 μM). 2 μL each of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate, Wallac Inc., Atlanta, GA). Subsequently, 50 μl of a dilution of the above-described PDE9A preparation are added. The dilution of the PDE9A preparation is chosen such that during the later incubation less than 70% of the substrate is reacted (typical dilution: 1: 10,000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA, 0.2% BSA). The substrate, [8- ³ H] guanosine 3 ', 5-cyclic phosphate (1 μCi / μL, Amersham Pharmacia Biotech., Piscataway, NJ) is assayed 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA) to a concentration of 0.0005 μCi / μL. By adding 50 μL (0.025 μCi) of the diluted substrate, the enzyme reaction is finally started. The test mixtures are incubated for 60 min at room temperature and the reaction is stopped by addition of 25 μl of a PDE9A inhibitor dissolved in assay buffer (eg compound from Example 1 in WO 2004/026286, 10 μM final concentration). Immediately thereafter, 25 μl of a suspension containing 18 mg / ml of Yttrium Scintillation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ) is added. The microtiter plates are sealed with a foil and left for 60 min at room temperature. The plates are then measured for 30 seconds per well in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA). IC ₅₀ values are determined by plotting the concentration of the substance against the percent inhibition.

The in vzϊro-effect of test substances on recombinant PDE3B, PDE4B, PDE7B, PDE8A, PDE10A and PDEIlA is determined by the method described above for PDE9A test protocol with the following adaptations: As the substrate [5 ', 8- ³ H] adenosine 3', 5 Cyclic phosphates (1 μCi / μL; Amersham Pharmacia Biotech., Piscataway, NJ). The addition of an inhibitor solution to stop the reaction is not necessary. Instead, following the incubation of substrate and PDE, the addition of the Yttrium Scintillation Proximity Beads is continued as described above, thereby stopping the reaction. For the determination of a corresponding effect on recombinant PDE1C, PDE2A and PDE5A becomes the protocol Additionally adjusted as follows: In the case of PDE1C, calmodulin 10 ^"7 M and CaCk 3 mM are added to the reaction mixture PDE2A is stimulated by addition of cGMP 1 μM and tested with a BSA concentration of 0.01% substrate [5 ', 8- ³ H] adenosine 3', 5'-cyclic phosphate (1 uCi / ul; Amersham Pharmacia Biotech, Piscataway, NJ.), for PDE5A [8- ³ H] guanosine 3 ', 5'- cyclic phosphates (1 μCi / μL; Amersham Pharmacia Biotech., Piscataway, NJ).

Claims

claims

Use of PDE 5 inhibitors for the manufacture of a medicament for the treatment of cardiac ischemia, for the achievement or improvement of a preconditioning effect, for the treatment of acute myocardial infarction and reperfusion injury, especially after a myocardial infarction, for the treatment of male infertility, of Raynaud's

Syndrome, intermittent claudication, Peyronie's disease, for the treatment of febrotic diseases, arteriosclerosis, sperm motility, depression, leukemia (eg, chronic lymphocytic leukemia), priapism, treatment of prokapism Platelet adhesion and aggregation in renal ischemia, to support and promote liver regeneration following surgical liver resection or liver cancer, to inhibit esophageal muscle contraction (eg, nutcracker esophagus or esophageal spasm), to treat achalasia, preterm labor, female infertility, and dysfunction Menorrhea, for the treatment of liver diseases such as Liver cirrhosis, portal hypertension, for the treatment of lupus, hypertensive systemic lupus erythematosus, scleroderma, for the treatment of multiple sclerosis, rheumatoid arthritis, allergy, autoimmune diseases, osteoporosis, cachexia, polycystic ovarian syndrome, inflammatory bowel disease, e.g. Crohn's disease and ulcerative colitis, diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermatopathy, diabetic cataract, hyperlipidemia and dyslipidaemia

Promoting growth and survival of oocytes, zygotes, embryos or fetuses, increasing premature birth weight, increasing milk production in mammals, especially in humans, for the treatment of migraine, incontinence, acute and chronic renal failure, glomerular disease, nephritis, tubulo-interstitial Diseases, glomerulopathy, hair loss, pancreatitis, amnesia, consciousness disorders, autism, speech disorders, Lennox syndrome and epilepsy.

2. Use according to claim 1 of compounds of the formula (T)

in which

R ^{1 is} methyl or ethyl,

R ^{2 is} ethyl or propyl,

R ³ and R ^{4 are} identical or different and represent a straight-chain or branched alkyl chain having up to 5 carbon atoms, which is optionally monosubstituted by identical or different substituents by hydroxy or methoxy,

or

R ³ and R ⁴ together with the nitrogen atom, a piperidinyl, morpholinyl, thiomorpholinyl ring or a radical of the formula

form,

wherein

R ^{6 is} hydrogen, formyl, acyl or alkoxycarbonyl, each having up to 3 carbon atoms,

or

straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally mono- to disubstituted, identical or different, by hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms or by groups of the formulas - (CO) _r NR ⁷ R ⁸ or -P (O) (OR ⁹ ) (OR ¹⁰ ) is substituted,

wherein

f is a number 0 or 1,

R ⁷ and R ^{8 are} identical or different and denote hydrogen or methyl,

R ⁹ and R ^{10 are the} same or different and denote hydrogen, methyl or ethyl, or

R ⁶ denotes cyclopentyl,

and those listed under R ³ and R ⁴ , taken together with the nitrogen atom

Heterocycles optionally one to two times, identical or different, if appropriate also geminal, by hydroxy, formyl, carboxyl, acyl or alkoxycarbonyl having up to 3 carbon atoms or groups of the formulas

-P (O) (OR ^π ) (OR ¹² ) or - (CO) ₁ -NR ¹³ R ^{14 are} substituted,

wherein

i is a number 0 or 1,

and

R ¹³ and R ^{14 are the} same or different and denote hydrogen or methyl,

and / or the heterocycles formed together with the nitrogen atom listed under R ³ and R ⁴ are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms, optionally once or twice, identically or differently, by hydroxyl, carboxyl or by a rest of

Formula -P (O) OR ¹⁵ OR ^{16 is} substituted,

wherein

and

R ^{5 is} ethoxy or propoxy,

and their salts and solvates and the solvates of the salts.

3. Use according to claim 2 of compounds of the formula (Ia)

in which R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the meaning given in claim 2,

and their salts and solvates and the solvates of the salts.

Use according to claim 3 of compounds selected from the group having the following structures:

5. Use of the compounds according to claim 4 for the oral or intravenous treatment of acute myocardial infarction and reperfusion damage.