Dual mode of action soluble guanylate cyclase activators and phosphodiesterase inhibitors and uses thereof

The present invention relates to pharmaceutically useful compounds, in particular to compounds which are activators of the enzyme soluble guanylate cyclase (sGC) and at the same time inhibit cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), in particular type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE5). The compounds of the present invention have utility in a variety of therapeutic areas, including male erectile dysfunction (MED), priapism, female sexual dysfunction, Alzheimer's disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), priapism, hair loss, cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes, and in particular for pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction, wound healing, in particular chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer.

RELATED ART

Phosphodiesterases (PDEs) are enzymes that catalyzes the hydrolysis and thus the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and thereby regulates intracellular levels of second messengers. Inhibition of PDEs leads to increasing intracellular concentrations of endogenous cAMP/cGMP. Therefore, inhibition of PDE can mediate a variety of physiological mechanisms at different cell and organ levels.

Phosphodiesterase type 5 (PDE5) hydrolyses cyclic guanylate monophosphate (cGMP) specifically to 5′ GMP. The selective inhibition of PDE5 has been validated as a relevant approach and strategies directed to promote inhibition of PDE5 activity have been applied as therapeutic tools, in particular, in neuronal and cardiovascular conditions. Moreover, the introduction of PDE5 inhibitors has revolutionized the treatment of male erectile dysfunction (MED) (Dobhal T, Kaur S, Prakash Sharma O, Hari Kumar S L, Critical Review in Pharmaceutical Sciences (2012) 1(3):13-27; Palit V, Eardley I, Nature Reviews Urology (2010) 7(11):603-609). Several PDE5 inhibitors are on the market and are characterized particularly for MED or pulmonary hypertension (PH), in particular pulmonary artery hypertension (PAH) (Papapetropoulos A, Hobbs A J, Topouzis S, British Journal of Pharmacology (2015) 172:1397-1414; Monica F Z, Murad F, Bian K, OA Biochemistry (2014) March 11; 2(1):3; Beedimani R S, Kalmath B, Int J Pharm Bio Sci (2014) 5(2): 530-539; Wronski S, Cent European J Urol (2014) 67: 314-318; and references cited therein). Most prominent examples of PDE5 inhibitors are Sildenafil, Tadalafil, Vardenafil and Mirodenafil which have been described among others, for example, in WO 99/24433, WO 01/60825, EP 995′751 and WO 2011/075655.

Beside the success of the known PDE5 inhibitors, there is still a need for further and in particular more effective drugs and their pharmaceutical compositions for use in the therapeutic treatment or prophylaxis of diseases associated with a disturbed cGMP balance. Moreover, and in general, there is still a need for compounds and their pharmaceutical compositions being beneficial for use in the therapeutic treatment or prophylaxis of diseases associated with a disturbed cGMP balance.

Endothelial dysfunction leads to an imbalance of vasodilator and vasoconstrictor mediators shifted towards the latter. One key mechanism remains impaired endothelial NO generation and associated, reduced activation of soluble guanylyl cyclase (sGC) in adjacent smooth muscle cells. Strategies to increase disturbed cGMP levels by enhancing cGMP in vascular smooth muscle by improving cGMP synthesis and inhibiting its degradation have been described. Examples are combinations of sGC stimulators or activators in combination with PDE5 inhibitors, for example WO 2010/081647 or US2002/0182162. Compounds however, which stimulate sGC and inhibit PDE5 at the same time however have not been described.

SUMMARY OF THE INVENTION

We have surprisingly found that the compounds of the present invention are dual-pharmacology NO-releasing PDE5 inhibitors believed to release NO in addition to its PDE5 inhibition in a more than additive, thus, synergistic fashion. We have further surprisingly found that the compounds of the present invention are highly bound to plasma proteins when they reach blood circulation. Such strongly bound compounds cannot exhibit their biological activity, making them especially prone to local application and local action. The synergistic increase of cGMP results in highly potent vasodilatation, angiogenesis and inhibition of endothelial dysfunction (see FIG. 1). Thus, the dual-pharmacology NO-releasing PDE5 inhibitors of the present invention are expected to be especially beneficial in treating disorders where NO production is diminished such as in conditions of endothelial dysfunction. Furthermore, the inventive dual-pharmacology NO-releasing PDE5 inhibitors are further believed to be highly beneficial for the treatment of diabetic patients.

Moreover, we have surprisingly found that the compounds of the present invention show even a significantly higher efficacy to elevate intracellular cGMP. as compared to known PDE5 inhibitors such as sildenafil or mirodenafil. In addition we discovered a very high plasma protein binding with several compounds of the invention, making them especially prone to local applications and local actions. As a consequence, the novel pyrrolo pyrimidone compounds of the present invention are useful in the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance.

Due to the potent and selective PDE5 inhibition in combination with stimulation of soluble guanylate cyclase exhibited by compounds of the present invention, cGMP levels are elevated, which in turn can give rise to beneficial vasodilatory, anti-vasospastic, anti-platelet, natriuretic and diuretic activities. Furthermore, the dual-pharmacology NO-releasing PDE5 inhibitors allows the release of nitric oxide for activating the soluble guanylate cyclase as well as the PDE5 inhibition in a more than additive fashion. Thus, the compounds of the present invention have utility in variety of therapeutic areas where a disturbed cGMP balance occurred and/or PDE5 inhibition is thought to be beneficial. Some of the preferred therapeutic areas are pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction, wound healing, in particular chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud's, male erectile dysfunction, Alzheimer's disease, livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, diabetes, hair loss, skin aging, vascular aging, pulmonary artery hypertension and chronic heart failure. The compounds of the invention are especially suited for local drug application as depicted in FIG. 2.

Thus, in a first aspect, the present invention provides for a compound of formula I

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or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

at least one of R₁, R₂, R₃, R₄, or R₅independently of each other comprises at least one ONO₂or ONO moiety, and wherein preferably said R₁, R₂, R₃, R₄, and R₅comprise together at least two moieties selected from ONO₂or ONO moieties;

R₁is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl, C₁-C₃alkoxy, ONO, ONO₂;

R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C(O)N(R₆)OR₇, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂, CR₈═N—ONO₂, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, OH, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂or CR₈═N—ONO₂;

R₃is C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl;

R₄is C₁-C₆alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl;

R₅is H, SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;

R₆is H or C₁-C₃alkyl;

R₇is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C₁-C₃alkyl, F;

R₈is H, CH₃or C₂H₅;

R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl;

R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C₁-C₃alkyl;

R₁₂is C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl;

R₁₃and R₁₄are each independently H or C₁-C₆alkyl optionally substituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy, C₃-C₆cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R₁₅;

R₁₅is C₁-C₆alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with a tetrazole moiety which is optionally substituted with C₁-C₃alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen;

R₁₆is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, NR₁₇R₁₈, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C₁-C₄alkyl;

R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;

R₁₉is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂; C₃-C₆cycloalkyl.

In a further aspect, the present invention provides for a pharmaceutical composition comprising at least one of the inventive compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient, adjuvant, or carrier.

In another aspect, the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal, preferably in a human, wherein preferably said disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary artery hypertension; livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, stable, unstable and variant (Prinzmetal) angina; hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or a disease characterized by disorders of gut motility like irritable bowel syndrome, liver fibrosis, Alzheimer's disease and chronic heart failure.

In another aspect, the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or in a non-human mammal, preferably in a human, wherein said disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary artery hypertension; livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, stable, unstable and variant (Prinzmetal) angina; hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, Idiopathic pulmonary fibrosis (IPF), peyronic's disease, glaucoma or a disease characterized by disorders of gut motility like irritable bowel syndrome, liver fibrosis, Alzheimer's disease and chronic heart failure, wherein preferably said disease is selected from pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer.

Further aspects and embodiments of the present invention will be become apparent as this description continues.

DESCRIPTION OF THE FIGURES

FIG. 1: PDE5 inhibition and activation of soluble guanylate cyclase from one molecule

FIG. 2: Dual-pharmacology NO-releasing PDE5 inhibitors addressing disturbed cGMP balance in diseases with disturbed cGMP balance

FIG. 3: Concentration dependent measurements of cyclic guanosine 3′-5′-monophosphate (cGMP) in human pulmonary artery smooth muscle cells (hPASMC) incubated in presence of the compounds of the inventions or the reference PDE5 inhibitor sildenafil and mirodenafil.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

We have surprisingly found that the compounds of the present invention are dual-pharmacology NO-releasing PDE5 inhibitors believed to release NO in addition to its PDE5 inhibition resulting in a more than additive stimulation of intracellular cGMP elevation. Moreover, the compounds of the present invention show even a significantly higher efficacy to stimulate cGMP as compared to known single pharmacology PDE5 inhibitors such as sildenafil or mirodenafil. Furthermore, the compounds of the present invention are highly bound to plasma proteins when they reach blood circulation making them especially prone to local application and local action.

Thus, in a first aspect, the present invention provides for a compound of formula I,

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or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

at least one of R₁, R₂, R₃, R₄, or R₅independently of each other comprises at least one ONO₂or ONO moiety, and wherein preferably said R₁, R₂, R₃, R₄, and R₅comprise together at least two moieties selected from ONO₂or ONO moieties;

R₁is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl, C₁-C₃alkoxy, ONO, ONO₂;

R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C(O)N(R₆)OR₇, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂, CR₈═N—ONO₂, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, OH, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂or CR₈═N—ONO₂;

R₃is C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl;

R₄is C₁-C₆alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl;

R₅is H, SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;

R₆is H or C₁-C₃alkyl;

R₇is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C₁-C₃alkyl, F;

R₈is H, CH₃or C₂H₅;

R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C₁-C₃alkyl;

R₁₂is C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl;

R₁₃and R₁₄are each independently H or C₁-C₆alkyl optionally substituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy, C₃-C₆cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R₁₅;

R₁₅is C₁-C₆alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with a tetrazole moiety which is optionally substituted with C₁-C₃alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen;

R₁₆is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, NR₁₇R₁₈, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C₁-C₄alkyl;

R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;

R₁₉is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂; C₃-C₆cycloalkyl.

Thus, in a further aspect, the present invention provides for a compound of formula I

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wherein

at least one of R₁, R₂, R₃, R₄, or R₅independently of each other comprises at least one ONO₂or ONO moiety, and wherein preferably said R₁, R₂, R₃, R₄, and R₅comprise together at least two moieties selected from ONO₂or ONO moieties;

R₁is C₁-C₃alkyl optionally substituted with F, C₃-C₆cycloalkyl, C₁-C₃alkoxy, ONO, ONO₂;

R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C(O)N(R₆)OR₇, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂, CR₈═N—ONO₂, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, OH, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂or CR₈═N—ONO₂;

R₃is C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl; C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl;

R₄is C₁-C₆alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl;

R₅is H, SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄;

R₆is H or C₁-C₃alkyl;

R₇is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ring, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C₁-C₃alkyl, F;

R₈is H, CH₃or C₂H;

R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C₁-C₃alkyl;

R₁₂is C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl;

R₁₃and R₁₄are each independently H or C₁-C₆alkyl optionally substituted with F, OH, ONO, ONO₂, COOH, C₁-C₃alkoxy, C₃-C₆cycloalkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R₁₅;

R₁₅is C₁-C₆alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉, or with a tetrazole moiety which is optionally substituted with C₁-C₃alkyl; or a heteroaryl ring which is optionally substituted with F, wherein the at least one heteroatom of said heteroaryl ring is nitrogen;

R₁₆is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, NR₁₇R₁₈, or with a heteroaryl ring, wherein the at least one heteroatom of said heteroaryl ring is nitrogen, and wherein preferably said heteroaryl ring is selected from pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole, wherein nitrogen atom is directly bound to C₁-C₄alkyl;

R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;

R₁₉is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂; C₃-C₆cycloalkyl.

The term “alkyl”, as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having typically and preferably from one to six carbon atoms (e.g., (C_1-6alkyl), and which typically is attached to the rest of the molecule by a single bond. Whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range. For example, “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated. Typical alkyl groups include, but are not limited to methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl. Examples of an alkoxy include methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neo-pentoxy, n-hexoxy.

The term “alkylene”, as used herein, refers to a straight or branched hydrocarbon chain bi-radical derived from alkyl, as defined herein, wherein one hydrogen of said alkyl is cleaved off generating the second radical of said alkylene. Examples of alkylene are, by way of illustration, —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—, or —CH(CH₂CH₃)—.

Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically and preferably in mono-cyclic form, and preferably contains 3 to 8 carbon atoms, more preferably 3 to 7 carbon atoms. Examples of monocyclic cycloalkyl moieties include cyclopropyl, cyclobutyl and cyclohexyl.

Each alkenyl moiety either alone or as part of a larger moiety such as alkenyloxy or alkenylene is a straight or branched chain and is preferably C₂-C₆alkenyl, more preferably C₂-C₄alkenyl. Each moiety can be of either the (E)- or (Z)-configuration. Examples include vinyl and allyl. A compound of the present invention comprising an alkenyl moiety thus may include, if applicable, either said compound with said alkenyl moiety in its (E)-configuration, said compound with said alkenyl moiety in its (Z)-configuration and mixtures thereof in any ratio.

Each alkynyl moiety either alone or as part of a larger moiety such as alkynyloxy is a straight or branched chain and is preferably C₂-C₆alkynyl, more preferably C₂-C₄alkynyl. Examples are ethynyl and propargyl.

The term “ONO2” refers to the nitrate moiety *—O—NO₂as described herein, wherein the * indicates the attachment to the parent structure and rest of the molecule. Preferably, said ONO2 is a terminal ONO2 substituent.

The term “ONO” refers to the nitrite moiety *—O—NO as described herein, wherein the * indicates the attachment to the parent structure and rest of the molecule. Preferably, said ONO is a terminal ONO substituent.

The term “alkoxy” refers to the group —O-alkyl, including typically from 1 to 6 carbon atoms of a straight, branched configuration and combinations thereof attached to the parent structure through an oxygen, also referred to as C_1-6alkoxy or O—C_1-6alkyl. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. As described herein, alkoxy may include further substitutents such as halogen atoms leading to haloalkoxy moieties.

Halogen is fluorine, chlorine, bromine, or iodine.

Each haloalkyl moiety either alone or as part of a larger moiety such as haloalkoxy is an alkyl moiety substituted by one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.

The term “heterocyclic ring” refers to a saturated or partially unsaturated carbocyclic ring containing one to four heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples are aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, tetrahydrofurane, dioxane, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and further preferred are aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane.

The term “heteroaryl” refers to an aromatic ring system containing at least one heteroatom, and preferably up to three heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Heteroaryl rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples are include pyrrolidine, piperidine, piperazine, morpholine, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, isothiazole, thiazole, tetrazole, furane, and thiophenyl, and further preferred are pyrrolidine, piperidine, piperazine, morpholine, pyrrole, and imidazole.

Where a moiety is said to be optionally substituted, preferably there are optionally 1-5 substituents, more preferably optionally 1-3 substituents, again more preferably optionally 1 or 2 substituents. Where a moiety is said to be optionally substituted, and where there are more than one substituents for said optional substitution of said moiety, said more than one substituents can either be the same or different.

Certain compounds of formula I of the present invention may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio. The compounds of the invention also include all tautomeric forms of the compounds of formula I. The compounds of formula I may also be solvated, especially hydrated, which are also included in the compounds of formula I. Solvation and hydration may take place during the preparation process.

As a consequence, the compounds of the present invention and, thus, the compounds of formula I include stereoisomers, geometric isomers and tautomers. Furthermore, the compounds of the present invention and, thus, the compounds of formula I include solvates or hydrates, pharmaceutically acceptable salts, and solvates or hydrates of the salts thereof.

Compounds of formula I of the present invention include pharmaceutically acceptable salts of said compounds. In particular, the term “pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the present invention, in particular acid addition salts. Exemplary salts include, but are not limited to, salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or salts of organic acids, such as methane-sulfonic acid, p-toluenesulfonic acid, lactic acid, malic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further examples of pharmacologically acceptable salts of the compounds of formula I are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts. Further examples of pharmaceutically acceptable salts of the compounds of formula I include the hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogen phosphate, nitrate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, benzenesulphonate, p-toluenesulphonate or the like.

A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.

In a preferred embodiment of the present invention, said compound of formula I comprises exactly one ONO₂moiety. In another preferred embodiment of the present invention, said compound of formula I comprises exactly one ONO moiety. In a preferred embodiment of the present invention, said compound of formula I comprises at least two moieties selected from ONO₂or ONO moieties. In another preferred embodiment of the present invention, said compound of formula I comprises exactly two ONO₂or two ONO moieties. In another preferred embodiment of the present invention, said compound of formula I comprises exactly one ONO₂moiety and one ONO moiety. In another preferred embodiment of the present invention, said compound of formula I comprises at least three moieties selected from ONO₂or ONO moieties. In another preferred embodiment of the present invention, said compound of formula I comprises exactly three ONO₂or three ONO moieties. In another preferred embodiment of the present invention, said compound of formula I comprises exactly three moieties selected from ONO₂or ONO moieties.

In a preferred embodiment of the present invention, R₁is C₁-C₃alkyl substituted with ONO₂. In a further preferred embodiment of the present invention, R₁is C₁-C₃alkyl. In a further preferred embodiment, R₁is CH₃or C₂H₅, In a further very preferred embodiment, R₁is CH₃. In a further very preferred embodiment, R₁is C₂H.

In a further preferred embodiment, said R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, C(O)N(R₆)OR₇, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂, CR₈═N—ONO₂, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, OH, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂or CR₈═N—ONO₂;

In a further preferred embodiment, R₇is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ring selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C₁-C₃alkyl, F. In a further preferred embodiment, R₇is H, C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkyl substituted with phenyl, benzyl or a heterocyclic ring selected from pyrollidine, piperidine, morpholine, piperazine, homopiperazine, wherein said phenyl, benzyl or said heterocyclic ring are independently optionally substituted by C₁-C₃alkyl.

In a further preferred embodiment, said R₉is H, C₁-C₃alkyl substituted with OH, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl. In a further preferred embodiment, said R₉is H, C₁-C₃alkyl substituted with OH, CN, COOH, COOC₁-C₃alkyl, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇.

In a further preferred embodiment, said R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C₁-C₃alkyl. In a further preferred embodiment, said R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, CN, COOH, COOC₁-C₃, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl, C(O)N(R₆)OR₇, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)OC₁-C₃alkyl, OC₁-C₃alkylene-C(O)N(R₆)OR₇, S(O_0-2)C₁-C₃alkyl; or together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein preferably said heterocyclic ring is selected from pyrollidine, piperidine, morpholine, piperazine and homopiperazine, wherein said heterocyclic ring is optionally substituted with C₁-C₃alkyl.

In a further preferred embodiment, said R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; C(O)OH, C(O)OC₁-C₃alkyl, CHO, CN, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂, CR₈═N—ONO₂, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, CHO, CN, OH, OC(O)H, OC₁-C₃alkylene-C(O)OH, OC₁-C₃alkylene-C(O)N(R₆)OR₇, OC(O)—C₁-C₃alkyl, C(O)OC₁-C₃alkyl, C(O)N(R₆)OR₇, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, CR₈═NR₁₂or CR₈═N—ONO₂, wherein preferably said R₆and R₈are independently of each other H or CH₃.

In a further preferred embodiment, said R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; CHO, CN, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, CHO, CN, OH, OC(O)H, C(O)OC₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, or CR₈═N—ONO₂, wherein R₆and R₈are independently of each other H or CH₃; R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl; R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said R₂is H, CHO, CN, C₁-C₃alkoxy, C₁-C₃alkoxy optionally substituted with ONO₂; CR₈═N—OR₉, preferably (E)-CR₈═N—OR₉, wherein said R₈is H or CH₃, preferably wherein said R₈is H, and wherein said R₉is H or C₁-C₃alkyl optionally substituted with OH or C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, OC(O)H, OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said R₂is H, CHO, CN, C₁-C₃alkoxy, C₁-C₃alkoxy optionally substituted with ONO₂; CH═N—OR₉, preferably (E)-CH═N—OR₉, wherein R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, OC(O)H, OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said R₂is H, CHO, C₁-C₃alkoxy, C₁-C₃alkoxy optionally substituted with ONO₂; CH═N—OR₉, preferably (E)-CH═N—OR₉, wherein R₉is H, C₁-C₃alkyl optionally substituted with ONO₂.

In a further very preferred embodiment, said R₂is H.

In a further very preferred embodiment, said R₂is CHO.

In a further very preferred embodiment, said R₂is C₁-C₃alkoxy. In a further very preferred embodiment, said R₂is C₁-C₃alkoxy optionally substituted with ONO₂.

In a further very preferred embodiment, said R₂is methoxy (CH₂OH) or ethoxy (C₂H₅OH).

In a further very preferred embodiment, said R₂is methoxy.

In a further very preferred embodiment, said R₂is CH═N—OR₉, preferably (E)-CH═N—OR₉, wherein R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, COOC₁-C₃alkyl, OC(O)H, OC(O)—C₁-C₃alkyl.

In a further very preferred embodiment, said R₂is CH═N—OR₉, preferably (E)-CH═N—OR₉, wherein R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO₂.

In a further very preferred embodiment, said R₂is CH═N—OR₉, preferably (E)-CH═N—OR₉, wherein R₉is H, C₁-C₃alkyl optionally substituted with ONO₂.

In a further very preferred embodiment, said R₂is CH═N—OR₉, preferably (E)-CH═N—OR₉, wherein R₉is H.

In another preferred embodiment, R₃is C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂, C₁-C₃alkoxy; C₂-C₄alkenyl. In another preferred embodiment, R₃is C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl. In a further preferred embodiment, R₃is C₂-C₃alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₂-C₄alkenyl. In a further preferred embodiment, R₃is C₁-C₄alkyl optionally substituted with ONO, ONO₂or C₃-C₅cycloalkyl. In a further preferred embodiment, R₃is C₁-C₄alkyl optionally substituted with ONO₂or C₃-C₅cycloalkyl. In a further preferred embodiment, R₃is C₁-C₄alkyl optionally substituted with ONO₂. In a further preferred embodiment, R₃is C₁-C₄alkyl, very preferably R₃is C₂-C₃alkyl. In a very preferred embodiment, R₃is n-propyl.

In another preferred embodiment, R₄is C₁-C₄alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₆alkoxy, F, ONO, ONO₂; C₂-C₄alkenyl. In a further preferred embodiment, R₄is C₁-C₄alkyl optionally substituted with ONO, ONO₂, C₁-C₆alkoxy, or C₃-C₅cycloalkyl. In a further preferred embodiment, R₄is C₁-C₄alkyl optionally substituted with ONO, ONO₂or C₁-C₆alkoxy. In a further preferred embodiment, R₄is C₁-C₄alkyl optionally substituted with ONO₂or C₁-C₆alkoxy. In a further preferred embodiment, R₄is C₁-C₄alkyl substituted with ONO₂. In a further preferred embodiment, R₄is C₂-C₃alkyl substituted with ONO₂. In a further preferred embodiment, R₄is ethyl or n-propyl. In a further very preferred embodiment, R₄is ethyl. In a further very preferred embodiment, R₄is n-propyl.

In a further preferred embodiment, said R₁is C₁-C₃alkyl; R₃is C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂, C₁-C₃alkoxy, C₃-C₆cycloalkyl, C₂-C₄alkenyl; and R₄is C₁-C₄alkyl optionally substituted with C₃-C₆cycloalkyl, C₁-C₃alkoxy, F, ONO, ONO₂; C₂-C₄alkenyl.

In a further preferred embodiment, said R₁is CH₃or C₂H₅, preferably R₁is CH₃; R₃is C₁-C₄alkyl optionally substituted with ONO₂or C₃-C₅cycloalkyl, preferably R₃is n-propyl; and R₄is C₁-C₄alkyl optionally substituted with ONO₂or C₃-C₅cycloalkyl, preferably R₄is ethyl or n-propyl.

In a further preferred embodiment, said R₅is SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄. In a further preferred embodiment, said R₁₃and R₁₄together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo-[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R₁₅; R₁₅is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂; R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂, preferably R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO₂; R₁₉is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂, preferably R₁₉is C₁-C₄alkyl optionally substituted with ONO₂.

In a further preferred embodiment, said R₅is SO₂NR₁₃R₁₄, NHSO₂NR₁₃R₁₄; said R₁₃and R₁₄together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is selected from aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo-[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, wherein said heterocyclic ring is optionally substituted with R₁₅; said R₁₅is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂; said R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂; said R₁₉is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

In a further preferred embodiment, said R₅is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄are each independently H or together with the nitrogen atom to which they are attached form a mono-cyclic ring selected from imidazol, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine optionally substituted with R₁₅; said R₁₅is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂; said R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂; said R₁₉is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

In a further preferred embodiment, said R₅is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄together with the nitrogen atom to which they are attached form a mono-cyclic ring selected from imidazol, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine optionally substituted with R₁₅; said R₁₅is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆is H, or C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂; said R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂; said R₁₉is C₁-C₄alkyl optionally substituted with ONO, ONO₂.

In a further preferred embodiment, said R₅is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄together with the nitrogen atom to which they are attached form a mono-cyclic ring selected from imidazol, aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine optionally substituted with R₁₅; said R₁₅is C₁-C₄alkyl optionally substituted with halogen, OH, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆is H, or C₁-C₄alkyl optionally substituted with OH, ONO₂; said R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO₂; said R₁₉is C₁-C₄alkyl optionally substituted with ONO₂.

In a further preferred embodiment, said R₅is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄together with the nitrogen atom to which they are attached form a mono-cyclic ring selected from imidazol, pyrrolidine, piperidine, morpholine, piperazine and homopiperazine optionally substituted with R₁₅; said R₁₅is C₁-C₄alkyl optionally substituted with OH, ONO₂, C₁-C₃alkoxy, COOR₁₆, NR₁₇R₁₈, C═NR₁₉; R₁₆is H, or C₁-C₄alkyl optionally substituted with OH, ONO₂; said R₁₇and R₁₈are each independently H or C₁-C₄alkyl optionally substituted with ONO₂; said R₁₉is C₁-C₄alkyl optionally substituted with ONO₂.

In a further very preferred embodiment, said R₅is SO₂NR₁₃R₁₄, wherein R₁₃and R₁₄together with the nitrogen atom to which they are attached form a mono-cyclic ring selected from piperidine, and piperazine optionally substituted with R₁₅; said R₁₅is C₁-C₄alkyl optionally substituted with OH, ONO or ONO.

In a further very preferred embodiment, said compound of formula I is a compound of formula I*, or pharmaceutically acceptable salt, solvate or hydrate thereof;

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wherein R₁, R₂, R₃, and R₄, are as defined herein; and wherein X is CR₂₁or N; and wherein at least one of R₁, R₂, R₃, R₄, R₂₀or R₂₁independently of each other comprises at least one ONO₂or ONO moiety, and wherein preferably said R₁, R₂, R₃, R₄, R₂₀and R₂₁comprise together at least two moieties selected from ONO₂or ONO moieties;

R₂₀is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₂₅, NR₂₆R₂₇, C═NR₂₈;

R₂₁is H or C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₂₅, NR₂₆R₂₇, C═NR₂₈;

R₂₅is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂;

R₂₆and R₂₇are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;

R₂₈is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

In a further very preferred embodiment, said R₂₀or R₂₁independently of each other comprises at least one ONO₂or ONO moiety. In a further very preferred embodiment, said R₂₀or said R₂₁comprises exactly one ONO₂moiety. In a further very preferred embodiment, said R₂₀comprises exactly one ONO₂moiety. In a further very preferred embodiment, said R₂₁comprises exactly one ONO₂moiety. In a further very preferred embodiment, said R₂₀and said R₂₁comprise together at least two moieties selected from ONO₂or ONO moieties. In a further very preferred embodiment, said R₂₀and said R₂₁comprise together exactly two moieties selected from ONO₂or ONO moieties. In a further very preferred embodiment, said R₂₀and said R₂₁comprise together exactly two moieties, one ONO₂moiety and one ONO moiety. In a further very preferred embodiment, said R₂₀comprises exactly two ONO₂moieties. In a further very preferred embodiment, said R₂₀comprises exactly two ONO moieties. In a further very preferred embodiment, said R₂₀and said R₂₁each comprises exactly one moiety selected from ONO₂or ONO. In a further very preferred embodiment, said R₂₀and said R₂₁each comprises exactly one ONO₂moiety. In a further very preferred embodiment, said R₂₀and said R₂₁comprise together at least three moieties selected from ONO₂or ONO moieties. In a further very preferred embodiment, said R₂₀and said R₂₁comprise together exactly three ONO₂or three ONO moieties. In a further very preferred embodiment, said R₂₀and said R₂₁comprise together exactly three moieties selected from ONO₂or ONO moieties. In a further very preferred embodiment, said R₂₀comprises exactly three ONO moieties. In a very preferred embodiment, said R₂₁is H.

In a further very preferred embodiment, said compound of formula I is a compound of formula I*, or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of R₁, R₂, R₃, R₄, or R₂₀independently of each other comprises at least one ONO₂or ONO moiety, and wherein preferably said R₁, R₂, R₃, R₄, and R₂₀comprise together at least two moieties selected from ONO₂or ONO moieties;

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wherein R₁, R₂, R₃, and R₄, are as defined herein; and wherein X is CH or N;

R₂₀is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₂₅, NR₂₆R₂₇, C═NR₂₈;

R₂₅is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂;

R₂₆and R₂₇are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;

R₂₈is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

In a further very preferred embodiment, said compound of formula I is a compound of formula I**, or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein at least one of R₁, R₂, R₃, R₄, R₂₂, R₂₃or R₂₄independently of each other comprises at least one ONO₂or ONO moiety, and wherein preferably said R₁, R₂, R₃, R₄, R₂₂, R₂₃and R₂₄comprise together at least two moieties selected from ONO₂or ONO moieties;

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wherein R₁, R₂, R₃, and R₄, are as defined herein;

R₂₂is H or C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₂₅, NR₂₆R₂₇, C═NR₂₈;

R₂₃and R₂₄are each independently C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, C₁-C₃haloalkoxy, COOR₂₅, NR₂₆R₂₇, C═NR₂₈;

R₂₅is H, or C₁-C₄alkyl optionally substituted with F, OH, ONO, ONO₂;

R₂₆and R₂₇are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂;

R₂₈is C₁-C₄alkyl optionally substituted with F, ONO, ONO₂.

In a further very preferred embodiment, said R₂₂, R₂₃or R₂₄independently of each other comprises at least one ONO₂or ONO moiety. In a further very preferred embodiment, said R₂₂, R₂₃and R₂₄comprise together at least two moieties selected from ONO₂or ONO moieties. In a further very preferred embodiment, said R₂₂, R₂₃and R₂₄comprise together exactly two moieties selected from ONO₂or ONO moieties. In a further very preferred embodiment, said R₂₃and said R₂₄comprise together exactly two ONO₂or two ONO moieties. In a further very preferred embodiment, said R₂₃and said R₂₄comprise together exactly one ONO₂moiety and one ONO moiety. In a further very preferred embodiment, said R₂₃and said R₂₄comprise exactly one ONO₂moiety. In a further very preferred embodiment, said R₂₃and said R₂₄comprise exactly one ONO moiety.

In a further very preferred embodiment, said compound of formula I is a compound of formula I*, wherein R₁is C₁-C₃alkyl; and

R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; CHO, CN, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, CHO, CN, OH, OC(O)H, C(O)OC₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, or CR₈═N—ONO₂, wherein R₆and R₈are independently of each other H or CH₃; R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl; R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl;

R₃is C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂, C₁-C₃alkoxy;

R₄is C₁-C₄alkyl optionally substituted with C₁-C₃alkoxy, F, ONO, ONO₂;

R₂₀is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₂₅, NR₂₆R₂₇; wherein R₂₅is H, or C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂;

R₂₆and R₂₇are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂.

In a further very preferred embodiment, said compound of formula I is a compound of formula I*, wherein R₁is C₁-C₃alkyl; and

R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; CHO, CN, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, CHO, CN, OH, OC(O)H, C(O)OC₁-C₃alkyl, CR₈═N—OR₉, CR₈═N—NR₁₀R₁₁, or CR₈═N—ONO₂, wherein R₆and R₈are independently of each other H or CH₃; R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl; R₁₀and R₁₁are each independently H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂, CN, COOH, C₁-C₃alkoxy, OC(O)H, OC(O)—C₁-C₃alkyl;

R₃is C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂, C₁-C₃alkoxy;

R₄is C₁-C₄alkyl optionally substituted with C₁-C₃alkoxy, F, ONO, ONO₂;

R₂₀is C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₂₅, NR₂₆R₂₇; wherein R₂₅is H, or C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂;

R₂₁is H or C₁-C₄alkyl optionally substituted with halogen, OH, ONO, ONO₂, C₁-C₃alkoxy, COOR₂₅, NR₂₆R₂₇; wherein R₂₅is H, or C₁-C₄alkyl optionally substituted with OH, ONO, ONO₂;

R₂₆and R₂₇are each independently H or C₁-C₄alkyl optionally substituted with ONO, ONO₂.

In a further very preferred embodiment, said compound of formula I is a compound of formula I*, wherein R₁is C₁-C₂alkyl;

R₂is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂; CHO, CR₈═N—OR₉, C₁-C₃alkoxy; C₁-C₃alkylene-Y, wherein Y is ONO, ONO₂, CN, or CR₈═N—OR₉, wherein R₈is H or CH₃; R₉is H, C₁-C₃alkyl optionally substituted with OH, ONO, ONO₂;