Nitric oxide releasing type 5 phosphodiesterase inhibitors

Abstract

The present invention relates to a nitric oxide releasing type 5 phosphodiesterase (PDE5) inhibitor of formula (I) or (Ib) or (II), or a stereoisomer or a pharmaceutically acceptable salt thereof, which is useful in the treatment of ocular conditions associated with elevated intraocular pressure, such as ocular hypertension, glaucoma or retinopathy. The invention further relates to 3-[(2S)-2, 3-bis (nitrooxy) propoxy] propionic acid and 6-(nitrooxy) hexanoic acid for use in the treatment of ocular conditions associated with elevated intraocular pressure, such as ocular hypertension, glaucoma or retinopathy. # imgabs0 #

Description

[0001] This application is a divisional application. The application number of the original application is 201980052271.2, the application date is July 31, 2019, the earliest priority date is August 6, 2018, and the name of the invention is "Nitric oxide-releasing type 5 phosphodiesterase inhibitor". Technical Field

[0002] The present invention relates to inhibitors of nitric oxide releasing phosphodiesterase type 5 (PDE5). The present invention further provides compositions and methods for treating ocular conditions associated with elevated intraocular pressure, such as ocular hypertension and glaucoma. Background Art

[0003] Glaucoma is a progressive disease that can lead to optic nerve damage and eventual complete loss of vision. Due to the good correlation between intraocular pressure control and prevention / reduction of glaucomatous damage in POAG (Primary Open-Angle Glaucoma) patients, several therapeutic agents have been developed to treat high intraocular pressure (Heijl A. et al., Arch Ophthalmol. 2002; 120: 1268-1279; Garway Heath et al., The Lancet 2015; 385: 1295-1304; Heijl A. The Lancet 2015; 385: 1264-1266).

[0004] It is known that increased intraocular pressure can be at least partially controlled by administering drugs that increase the outflow of aqueous humor from the eye, such as prostaglandin analogs (such as latanoprost or bimatoprost), or that decrease the production of aqueous humor within the eye, such as beta-blockers (such as timolol, betaxolol, levobunolol) and carbonic anhydrase inhibitors (such as acetazolamide, dorzolamide or brinzolamide).

[0005] Unfortunately, many drugs routinely used to treat ocular hypertension have a variety of side effects. For example, prostaglandin therapy can cause eye irritation and congestion of varying severity and duration. Beta-blockers exhibit severe pulmonary side effects, depression, fatigue, mental confusion, impotence, hair loss, heart failure, and bradycardia. Side effects associated with carbonic anhydrase inhibitors include fatigue, anorexia, depression, paresthesia, and serum electrolyte abnormalities.

[0006] Nitric oxide (NO) is known to play an important role in many physiological processes; specifically in the eye, nitric oxide plays an important role in physiological intraocular pressure regulation by promoting the outflow of aqueous humor from the trabecular meshwork and Schlemm's canal (Cavet et al., Invest Ophthalmol Vis Sci. 2014, 5005-5015).

[0007] Several studies have shown that NO donors reduce intraocular pressure by increasing the outflow of aqueous humor from the trabecular meshwork and Schreiber's canal.

[0008] At the cellular level, nitric oxide binds to soluble guanylate cyclase (sGC) and increases the production of cyclic guanosine monophosphate (cGMP) in the trabecular meshwork and Schreiber's canal tissues, where its activation promotes a series of mechanisms that promote regular aqueous humor drainage and ultimately reduce intraocular pressure (Cavet et al., Invest Ophthalmol Vis Sci. 2014, 5005-5015).

[0009] For example, US Pat. No. 4,590,207 discloses an ophthalmic solution containing isosorbide mononitrate as an active ingredient for treating and / or preventing ocular hypertension and glaucoma.

[0010] EP 2 993 172 B1 discloses nitric oxide-releasing carnosine analogs for the treatment and / or prevention of glaucoma and ocular hypertension. Results of studies in animal models show that nitric oxide-releasing carnosine analogs have a higher IOP lowering effect than isosorbide mononitrate (5-ISMN) and the IOP lowering effect lasts for up to about 2 hours after topical application.

[0011] WO 2014 / 063923 discloses a nitric oxide donor compound having a quinone structure and use thereof in treating and / or preventing glaucoma and ocular hypertension.

[0012] In general, however, NO donor compounds that do not require activation by endogenous enzymes typically release nitric oxide rapidly; as a result of the rapid release rate of nitric oxide, it is difficult to deliver sufficient amounts of NO to target tissues for extended periods of time.

[0013] One possible approach to provide sustained efficacy would require multiple administrations of NO donor compounds; however, this treatment approach exposes patients to a potentially higher propensity for side effects compared to a single ocular dosing regimen. Excessive NO can cause undesirable effects, including oxidative stress and biosynthesis of inflammatory markers (Colasanti & Suzuki, Trends Pharmacol Sci. 2000 21: 249-252).

[0014] Another possible approach to provide sustained activity over time is to reduce the degradation of cyclic guanosine monophosphate (cGMP) by utilizing phosphodiesterase type 5 (PDE5) inhibitors.

[0015] Prior art suggests the use of a combination of a type 5 cyclic phosphodiesterase (PDE5) inhibitor and a nitric oxide (NO) donor to treat glaucoma or ocular hypertension; for example, US2002 / 0168424 discloses a topical drug for treating glaucoma, comprising a mixture of a nitric oxide (NO) donor such as nitrovasodilators minoxidil, nitroglycerin, L-arginine, isosorbide dinitrate or nitroprusside, and a type 5 phosphodiesterase (PDE5) inhibitor such as sildenafil citrate. The combination improves blood circulation to the optic nerve and has an ocular hypotensive activity.

[0016] US2002 / 0168424 does not disclose any experimental data related to the intraocular pressure lowering activity of the combination and it does not suggest effective doses of the individual compounds used.

[0017] WO 2017 / 085056 discloses dual pharmacological NO-releasing PDE5 inhibitors which can be used to treat various diseases in which a disturbance of cGMP balance occurs and / or PDE inhibition is believed to be beneficial, in particular for treating diabetic patients; glaucoma is cited in a list of preferred diseases.

[0018] In dual pharmacological NO-releasing PDE5 inhibitors, the nitric oxide precursor is a nitroxy group (ONO2) directly bonded to the hydroxyl group (nitrate) of the PDE5 inhibitor molecule.

[0019] WO 2017 / 085056 discloses in vitro studies on rat aortic rings, showing that NO-releasing PDE5 inhibitors can activate soluble guanylate cyclase and have higher PDE5 inhibitory activity than the known PDE5 inhibitor sildenafil. However, WO 2017 / 085056 does not disclose any experimental data related to the intraocular pressure-lowering activity of NO-releasing PDE5 inhibitors.

[0020] Regarding phosphodiesterase type 5 (PDE5) inhibitors, the prior art also proposes potential therapeutic uses of such compounds in the treatment of glaucoma, for example:

[0021] US 4,975,428 discloses the use of the PDE inhibitor bemarinone as an agent for reducing intraocular pressure.

[0022] WO 01 / 60825 discloses a series of pyrazolo[4,3-d]pyrimidin-7-one derivatives as PDE5 inhibitors; glaucoma is mentioned as one of the potential therapeutic uses of the compounds.

[0023] EP 0 463 756 discloses a series of pyrazolo[4,3-d]pyrimidin-7-one derivatives as PDE5 inhibitors as antianginal agents; glaucoma is mentioned among several potential therapeutic uses of the compounds.

[0024] EP 1 074 258 discloses a method for treating glaucomatous optic neuropathy associated with chronic glaucoma, chronic (idiopathic) open-angle glaucoma and macular (dry) degeneration by systemic (oral or parenteral) administration of a PDE5 inhibitor, in particular sildenafil citrate.

[0025] Therefore, there remains a continuing need for compounds for the therapeutic treatment of ocular diseases associated with elevated intraocular pressure. Summary of the invention

[0026] The present invention provides novel nitric oxide-releasing phosphodiesterase type 5 (NO-PDE5) inhibitors, wherein the nitric oxide precursor is a NO-releasing molecule (NO donor) linked to the PDE5 inhibitor via an enzymatically cleavable bond.

[0027] The nitric oxide releasing phosphodiesterase type 5 (NO-PDE5) inhibitors of the present invention are shown by the greater E observed for NO-PDE5 and NO-donor, respectively. max (defined as the maximum intraocular reduction effect at a given dose) and E 480min (IOP-reduction at the last analyzed time point), both compared with PDE5 and NO-donors, exhibiting better efficacy and longer duration. Therefore, it is expected that the nitric oxide releasing phosphodiesterase type 5 (NO-PDE5) inhibitors of the present invention provide alternative treatments for various diseases and conditions requiring reduction of intraocular pressure, such as glaucoma, ocular hypertension and other conditions associated with elevated ocular pressure.

[0028] The present invention provides a compound of formula (I) or a stereoisomer or salt thereof:

[0029]

[0030] in:

[0031] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0032] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ]p -(CH-ONO2) q -CH2-ONO2

[0033] in:

[0034] y is 1 or 0;

[0035] p is 1 or 0;

[0036] q is 1 or 0;

[0037] m is an integer in the range of 1 to 10; preferably m is 1 to 6;

[0038] n is an integer in the range of 1 to 6; preferably n is 1 or 2;

[0039] R2 is ethyl or n-propyl;

[0040] R3 is methyl or ethyl;

[0041] Provided that when R2 is ethyl, R3 is methyl, or when R2 is n-propyl, R3 is ethyl.

[0042] When y=0, R1 is preferably selected from:

[0043]

[0044] When y=1, R1 is preferably selected from:

[0045]

[0046] Another embodiment of the present invention provides a compound of formula (I) as defined above, its stereoisomers or salts, wherein: R1 is the residue of a nitric oxide releasing molecule of the formula:

[0047] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0048] in:

[0049] y is 1 or 0;

[0050] p is 1 or 0;

[0051] q is 1 or 0;

[0052] m is an integer in the range of 1 to 10; preferably m is 1 to 6;

[0053] n is an integer in the range of 1 to 6; preferably n is 1 or 2;

[0054] R2 is n-propyl, and R3 is ethyl.

[0055] When y=0, R1 is preferably selected from:

[0056]

[0057] When y=1, R1 is preferably selected from:

[0058]

[0059] Another embodiment of the present invention provides a compound of formula (I) as defined above, its stereoisomers or salts, wherein: R2 is n-propyl, and R3 is ethyl;

[0060] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0061] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0062] y=0, and R1 is selected from:

[0063]

[0064]

[0065] Another embodiment of the present invention provides a compound of formula (I) as defined above, its stereoisomers or salts, wherein: R2 is n-propyl, and R3 is ethyl;

[0066] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0067] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0068] y=1 and R1 is selected from:

[0069]

[0070] Another embodiment of the present invention provides a compound of formula (I) as defined above, its stereoisomers or salts, wherein: R1 is the residue of a nitric oxide releasing molecule of the formula:

[0071] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0072] in:

[0073] y is 1 or 0;

[0074] p is 1 or 0;

[0075] q is 1 or 0;

[0076] m is an integer in the range of 1 to 10; preferably m is 1 to 6;

[0077] n is an integer in the range of 1 to 6; preferably n is 1 or 2;

[0078] R2 is ethyl, and R3 is methyl.

[0079] When y=0, R1 is preferably selected from:

[0080]

[0081] When y=1, R1 is preferably selected from:

[0082]

[0083] Another embodiment of the present invention provides a compound of formula (I) as defined above, its stereoisomers or salts, wherein: R2 is ethyl, and R3 is methyl;

[0084] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0085] y=0, and R1 is selected from:

[0086]

[0087]

[0088] Another embodiment of the present invention provides a compound of formula (I) as defined above, its stereoisomers or salts, wherein: R2 is ethyl, and R3 is methyl;

[0089] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0090] y=1, and R1 is selected from:

[0091]

[0092] Another embodiment of the present invention provides a compound of formula (II) or a stereoisomer or salt thereof

[0093]

[0094] wherein R1 is the residue of a nitric oxide releasing molecule of the formula:

[0095] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0096] in:

[0097] y is 1 or 0;

[0098] p is 1 or 0;

[0099] q is 1 or 0;

[0100] m is an integer in the range of 1 to 10; preferably m is 1 to 6;

[0101] n is an integer in the range of 1 to 6; preferably n is 1 or 2;

[0102] When y=0, R1 is preferably selected from:

[0103]

[0104] When y=1, R1 is preferably selected from:

[0105]

[0106] Another embodiment of the present invention provides a compound of formula (II) as defined above, its stereoisomers or salts, wherein R1 is the residue of a nitric oxide releasing molecule of the formula:

[0107] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0108] in:

[0109] y=0 and R1 is selected from:

[0110]

[0111] Another embodiment of the present invention provides a compound of formula (II) as defined above, its stereoisomers or salts, wherein R1 is the residue of a nitric oxide releasing molecule of the formula:

[0112] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0113] in:

[0114] y=1, and R1 is selected from:

[0115]

[0116] Another embodiment of the present invention provides a stereoisomer or salt of a compound of formula (Ib) having the formula

[0117] in:

[0118] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0119] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0120] in:

[0121] y is 1 or 0;

[0122] p is 1 or 0;

[0123] q is 1 or 0;

[0124] m is an integer in the range of 1 to 10; preferably m is 1 to 6;

[0125] n is an integer in the range of 1 to 6; preferably n is 1 or 2;

[0126] R2 is ethyl or n-propyl;

[0127] R3 is methyl or ethyl;

[0128] Provided that when R2 is ethyl, then R3 is methyl; when R2 is n-propyl, then R3 is ethyl; and provided that when R2 is ethyl and R3 is methyl, y is 0, p and q are 0, then m is not 2.

[0129] When y is 0, preferred compounds of formula (Ib) are those wherein R1 is selected from the group consisting of formula (IIIa)-(IIIh):

[0130] When y is 1, preferred compounds of formula (Ib) are those wherein R1 is selected from the group consisting of formula (IVa)-(IVh):

[0131]

[0132] Another embodiment of the present invention provides a compound of formula (Ib) as defined above, wherein R1, y, p, q, m and n are as defined above, R2 is ethyl, and R3 is methyl, or a stereoisomer or salt thereof.

[0133] Another embodiment of the present invention provides a compound of formula (Ib) or a stereoisomer or salt thereof

[0134]

[0135] in:

[0136] R1 is the residue of a nitric oxide releasing molecule of the formula:

[0137] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0138] in:

[0139] y is 1;

[0140] p is 1 or 0;

[0141] q is 1 or 0;

[0142] m is an integer in the range of 1 to 10; preferably m is 1 to 6;

[0143] n is an integer in the range of 1 to 6; preferably n is 1 or 2;

[0144] R2 is ethyl or n-propyl;

[0145] R3 is methyl or ethyl;

[0146] Provided that when R2 is ethyl, then R3 is methyl; and when R2 is n-propyl, then R3 is ethyl.

[0147] Another embodiment of the present invention provides a compound of formula (Ib) as defined above, its stereoisomers or salts, wherein p, q, m, n are as defined above, R2 is ethyl, R3 is methyl, and R1 is selected from the groups of formula (IIIa)-(IIIh) as defined above.

[0148] Another embodiment of the present invention provides a compound of formula (Ib) as defined above, its stereoisomers or salts, wherein p, q, m, n are as defined above, R2 is ethyl, R3 is methyl, and R1 is selected from the groups of formula (IVa)-(IVb) as defined above.

[0149] Another embodiment of the present invention provides a compound of formula (Ib) as defined above, wherein R1, y, p, q, m and n are as defined above, R2 is n-propyl and R3 is ethyl, or a stereoisomer or salt thereof.

[0150] Another embodiment of the present invention provides a compound of formula (Ib) as defined above, or a stereoisomer or salt thereof, wherein p, q, m, n are as defined above, R2 is n-propyl, R3 is ethyl, and R1 is selected from a group of formula (IIIa)-(IIIh) as defined above.

[0151] Another embodiment of the present invention provides a compound of formula (Ib) as defined above, its stereoisomers or salts, wherein p, q, m, n are as defined above, R2 is n-propyl, R3 is ethyl, and R1 is selected from the groups of formula (IVa)-(IVh) as defined above.

[0152] Another embodiment of the present invention provides a compound of formula (I) or (Ib) or a stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from:

[0153] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 3-[2,3-bis(nitrooxy)propoxy]propanoate (Compound (1))

[0154]

[0155] 2-(2-(Nitrooxy)ethoxy)acetic acid 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl ester (Compound (2))

[0156]

[0157] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 5,6-bis(nitrooxy)hexanoate (Compound (3))

[0158]

[0159] 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexanoate (Compound (4))

[0160]

[0161]

[0162] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexyl carbonate (Compound (5))

[0163]

[0164] Carbonate 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 5,6-bis(nitrooxy)hexyl ester (Compound (6))

[0165]

[0166] 2-{4-[4-ethoxy-3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-1H-pyrrolo[3,2-d]pyrimidin-2-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 5,6-bis(nitrooxy)hexanoate (Compound (7))

[0167]

[0168] 2-{4-[4-ethoxy-3-(5-methyl-4-oxo-7-propyl-4,5-dihydro-1H-pyrrolo[3,2-d]pyrimidin-2-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 6-(nitrooxy)hexanoate (Compound (8))

[0169]

[0170] 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 5,6-bis(nitrooxy)hexanoate (Compound (7b))

[0171]

[0172] 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 6-(nitrooxy)hexanoate (Compound (8b))

[0173]

[0174] 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 3-[2,3-bis(nitrooxy)propoxy]propanoate (Compound 15)

[0175]

[0176] Another embodiment of the present invention provides a compound of formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is selected from:

[0177] 6-(Nitrooxy)hexanoic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester (Compound (9))

[0178]

[0179] [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 5,6-bis(nitrooxy)hexanoate (Compound (10))

[0180]

[0181] 2-(2-(Nitrooxy)ethoxy)acetic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester (Compound (11))

[0182]

[0183] 3-[2,3-bis(nitrooxy)propoxy]propanoic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl ester (Compound (12))

[0184]

[0185] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexyl carbonate (Compound (13))

[0186]

[0187] ((S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl carbonate 5,6-bis(nitrooxy)hexyl ester (Compound (14))

[0188]

[0189] Another embodiment of the present invention provides a compound of formula (I), (Ib) or (II) selected from:

[0190] (5S)-[(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 5,6-bis(nitrooxy)hexanoate (compound (10)-(5S));

[0191] [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (compound (12)-(2S));

[0192] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate 2-hydroxypropane-1,2,3-tricarboxylate ((Compound (9)-citrate);

[0193] (S)-((S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl (5S)-5,6-bis(nitrooxy)hexanoate 2-hydroxypropane-1,2,3-tricarboxylate ((Compound (10)-(5S) citrate);

[0194] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 2-(2-(nitrooxy)ethoxy)acetate 2-hydroxypropane-1,2,3-tricarboxylate ((Compound (11) citrate);

[0195] ((S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 3-((S)-2,3-bis(nitrooxy)propoxy)propanoate 2-hydroxypropane-1,2,3-tricarboxylate ((Compound (12)-(2S) citrate);

[0196] (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 3-[2,3-bis(nitrooxy)propoxy]propanoate citrate (Compound (1)-(2S) citrate);

[0197] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexanoate citrate (compound (4) citrate);

[0198] 2-Hydroxypropane-1,2,3-tricarboxylic acid [2-(nitrooxy)ethoxy]acetic acid 2-{4-[3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxybenzene-1-sulfonyl]piperazin-1-yl}ethyl ester (compound (2) citrate);

[0199] (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 5,6-bis(nitrooxy)hexanoate citrate (Compound (3)-(5S) citrate);

[0200] (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 3-(2,3-bis(nitrooxy)propoxy)propanoate dihydrochloride (Compound (1)-(2S) HCl salt);

[0201] ((S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl (S)-5,6-bis(nitrooxy)hexyl carbonate (compound (14)-(5S));

[0202] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexyl carbonate 2-hydroxypropane-1,2,3-tricarboxylate ((Compound (13) citrate);

[0203] (S)-2-(4-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl (S)-5,6-bis(nitrooxy)hexanoate (compound (7b)-(5S));

[0204] (S)-2-(4-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl 3-(2,3-bis(nitrooxy)propoxy)propanoate (compound (15), (S) isomer);

[0205] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate fumarate (compound (9) fumarate);

[0206] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate maleate (Compound (9) maleate).

[0207] Another embodiment of the present invention provides a compound of formula (I), or formula (Ib), or formula (II) or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition associated with elevated intraocular pressure. The disease or condition is preferably selected from ocular hypertension or glaucoma, including open-angle glaucoma, normal-tension glaucoma, pigmentary glaucoma, pseudoexfoliative glaucoma, or drug-induced glaucoma.

[0208] Another embodiment of the present invention provides a compound of formula (I), (Ib), or (II) or a pharmaceutically acceptable salt thereof for use in a method for treating retinopathy including retinopathy of prematurity, retinal vein occlusion, or diabetic macular edema.

[0209] Another embodiment of the present invention provides an ophthalmic pharmaceutical composition comprising a compound of formula (I), (Ib), or (II) or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and / or carrier. The ophthalmic pharmaceutical composition is in the form of a solution, suspension, gel, cream or emulsion.

[0210] Certain specific compounds of the present invention may be converted into acid salts. Thus, the compounds of the present invention may exist as salts. Examples of such salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; or organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic acid, and the like.

[0211] Included within the scope of the present invention are the individual mirror image isomers of the compounds of Formula (I), Formula (II), or Formula (Ib), as well as their diastereoisomers, racemic and non-racemic mixtures.

[0212] Another embodiment of the present invention relates to a composition comprising a compound of formula (I), or formula (Ib), or formula (II) and at least one other active agent selected from the following drug classes:

[0213] β-adrenergic antagonists, wherein the β-adrenergic antagonists are selected from: carteolol, levobunolol, metipranolol or timolol;

[0214] Prostaglandin analogs, wherein the prostaglandin analogs are selected from: latanoprost, travoprost, tafluprost or bimatoprost or their respective NO donor derivatives;

[0215] Adrenergic agonists Adrenergic agonists, wherein the adrenergic agonist is selected from: epinephrine borate, epinephrine hydrochloride, dipivefrin or apraclonidine;

[0216] A carbonic anhydrase inhibitor, wherein the carbonic anhydrase inhibitor is selected from acetazolamide, dichlorphenamide, methazolamide, brinzolamide or dorzolamide;

[0217] A cholinergic agonist, wherein the cholinergic agonist is selected from: carbachol, pilocarpine hydrochloride, pilocarpine nitrate or pilocarpine;

[0218] A steroid, wherein the steroid is selected from the group consisting of fluocinolone, fluticasone propionate, triamcinolone or dexamethasone;

[0219] A cholinesterase inhibitor, wherein the cholinesterase inhibitor is selected from: demecarium, echothiophate or physostigmine;

[0220] A soluble guanylate cyclase activator (sCG activator), preferably, the sCG activator is a compound disclosed in WO 2016 / 001875, more preferably, the sCG activator is (+)-1-(6-(3-((4-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (MGV-354) disclosed in WO 2016 / 001875;

[0221] Rho-kinase inhibitors, including Netarsudil, Ripasudil, Fasudil, Verosudil, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride (Y-27632) disclosed in US2012 / 0288428, or (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide (Y-39383);

[0222] sGC activator cinaciguat.

[0223] The above-mentioned composition comprising a compound of formula (I) or a compound of formula (Ib) or a compound of formula (II) and at least another active agent selected from β-adrenergic antagonists, prostaglandin analogs, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids, cholinesterase inhibitors, soluble guanylate cyclase activators or Rho-kinase inhibitors can be prepared as a dosage form containing the two active compounds in a suitable mixing ratio, or prepared as a kit for simultaneous or separate administration of the two active compounds, wherein the two active compounds are prepared in separate dosage forms.

[0224] Another embodiment of the present invention provides a composition which is a kit comprising a topical ophthalmic dosage form and another topical ophthalmic dosage form, wherein the topical ophthalmic dosage form comprises a compound of formula (I) or a compound of formula (Ib) or a compound of formula (II) or a salt thereof, and the other topical ophthalmic dosage form comprises an active agent selected from the following drug classes: prostaglandin analogs, β-adrenergic antagonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids, cholinesterase inhibitors, soluble guanylate cyclase activators or Rho-kinase inhibitors or sGC activator cinaciguat.

[0225] Another embodiment provides a composition comprising a compound of formula (I), or a compound of formula (Ib), or a compound of formula (II) and at least another active agent reported above for use in a method for treating a disease or condition associated with elevated intraocular pressure. Preferably, the disease or condition is selected from ocular hypertension or glaucoma including open-angle glaucoma, normal-tension glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma or drug-induced glaucoma.

[0226] Another embodiment provides the use of a composition comprising a compound of formula (I), or a compound of formula (Ib), or a compound of formula (II) and at least another active agent reported above for use in a method for treating retinopathy including retinopathy of prematurity, retinal vein occlusion or diabetic macular edema.

[0227] In compositions for topical administration, the concentration of the compound of the present invention is generally 0.0001% to 3% (w / v) or 0.003% to 3% (w / v), preferably, 0.03% to 2% (w / v), and most preferably, 0.3% to 1% (w / v).

[0228] Another embodiment of the present invention provides 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid (compound (IIIg)-OH) or 6-(nitrooxy)hexanoic acid (compound (IIIa)-OH) for use as an intraocular pressure reducing agent for treating an ocular disease or condition associated with elevated intraocular pressure.

[0229] Another embodiment of the present invention provides 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoic acid (compound (IIIg)-OH) or 6-(nitrooxy)hexanoic acid (compound (IIIa)-OH) for use in a method for treating retinal diseases including retinopathy of prematurity, retinal vein occlusion or diabetic macular edema.

[0230] Another embodiment of the present invention provides an ophthalmic composition comprising compound 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid ((IIIg)-OH) or compound 6-(nitrooxy)hexanoic acid ((IIIa)-OH) and at least one pharmaceutically acceptable excipient and / or carrier.

[0231] Another embodiment of the present invention provides an ophthalmic composition comprising compound 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid ((IIIg)-OH) or compound 6-(nitrooxy)hexanoic acid ((IIIa)-OH) and at least one other active agent selected from the following drug classes: β-adrenergic antagonists, prostaglandin analogs, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids, cholinesterase inhibitors, soluble guanylate cyclase activators, Rho-kinase inhibitors or cinaciguat.

[0232] The composition can be prepared in one dosage form comprising the two active compounds in an appropriate mixing ratio or as a kit for simultaneous or separate administration of the two active compounds prepared in separate dosage forms.

[0233] Universal synthesis

[0234] Compounds of formula (I) and formula (II)

[0235]

[0236] in:

[0237] R1=-C(O)-(O-CH2) y (CH2)m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0238] y=0,

[0239] p is 1 or 0,

[0240] q is 1 or 0,

[0241] m is an integer in the range of 1 to 10; preferably m is 1 to 6,

[0242] n is an integer in the range of 1 to 6; preferably n is 1 or 2,

[0243] R2 is n-propyl and R3 is ethyl, or R2 is ethyl and R3 is methyl, the compound of formula A1, A2 or A3 can be prepared by:

[0244]

[0245] With the compound of formula B1 to prepare

[0246] HO-C(O)-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0247] B1

[0248] wherein p, q, m and n are as previously defined; the reaction is carried out in an aprotic polar / nonpolar solvent such as THF, DMF or CH2Cl2, in the presence of a coupling reagent such as N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), in the presence of varying amounts of DMAP at temperatures ranging from -0°C to 80°C.

[0249] Alternatively, the compound of formula (I) can be prepared by reacting a compound of formula A1, A2 or A3 with a compound of formula B2:

[0250] XC(O)-(CH2) m -[O-(CH2) n ] p -(CH-ONO2)q -CH2-ONO2

[0251] B2

[0252] wherein p, q, m and n are as previously defined, and X is -Cl, p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy;

[0253] When X = -Cl, the reaction is carried out in the presence of a base such as DMAP, pyridine or triethylamine or K2CO3, Cs2CO3, in an aprotic / non-polar solvent such as THF, DMF or CH2Cl2 at a temperature ranging from -20°C to 60°C.

[0254] When X is selected from p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy, the reaction is carried out in an aprotic polar / non-polar solvent such as THF, DMF or CH2Cl2 in the presence of DMAP with or without a catalyst such as scandium triflate at a temperature ranging from 0°C to 80°C.

[0255] Compound A1 is known in the literature as mirodenafil. Compounds A1 and A2 are disclosed in US 6,962,911.

[0256] Compound A3 is known in the literature as avanafil, and its synthesis is disclosed in US Pat. No. 6,656,935.

[0257] Compounds of formula B2 are generally prepared from compounds B1 by methods known in the literature.

[0258] Compound B1 is known in the art or can be prepared from known compounds by known methods: for example, compound B1 can be prepared from the corresponding alcohol of formula B3

[0259] HO-CH2-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0260] B3

[0261] wherein m, n, p and q are as defined above, prepared by oxidation using known reagents such as 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) or ruthenium(IV) oxide / sodium periodate.

[0262] Synthesis examples of compound (B1) are described in WO2009 / 098113 or WO2016 / 155906.

[0263] Compounds of formula (I) and formula (II),

[0264]

[0265] in:

[0266] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0267] y=1,

[0268] p is 1 or 0,

[0269] q is 1 or 0,

[0270] m is an integer in the range of 1 to 10; preferably m is 1 to 6,

[0271] n is an integer in the range of 1 to 6; preferably n is 1 or 2,

[0272] R2 is n-propyl and R3 is ethyl, or R2 is ethyl and R3 is methyl, which can be generally prepared by making a compound of formula A4, A5 or A6

[0273]

[0274] and one or more equivalents of a compound of formula B3 to prepare

[0275] HO-CH2-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0276] B3

[0277] wherein p, q and n are as defined previously; in the presence of an organic or inorganic base such as DMAP, TEA, DIPEA, with or without a catalyst such as Sc(OTf)3, in an aprotic polar / non-polar solvent such as THF, DMF CH2Cl-2, at a temperature in the range of -20°C to 100°C, according to methods well known in the literature.

[0278] Compounds of formula A4, A5 and A6 are prepared from compounds A1, A2 and A3, respectively, by methods known in the art.

[0279] Alternatively, compounds (I) and (II) can be prepared by reacting compound A1, A2 or A3 with a compound of formula B4 according to methods well known in the literature.

[0280] pNO2-C6H4-C(O)-O-CH2-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0281] B4

[0282] wherein p, q and n are as defined previously; in the presence of an organic or inorganic base such as DMAP, TEA, DIPEA, with or without a catalyst such as Sc(OTf)3, in an aprotic polar / non-polar solvent such as THF, DMF CH2Cl-2, at a temperature ranging from -20°C to 100°C.

[0283] Compounds of formula B4 are readily prepared from compound B3 by methods known in the art.

[0284] Compound of formula (Ib)

[0285]

[0286] in:

[0287] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0288] y=0,

[0289] p is 1 or 0,

[0290] q is 1 or 0,

[0291] m is an integer ranging from 1 to 10;

[0292] n is an integer ranging from 1 to 6;

[0293] R2 is n-propyl and R3 is ethyl, or R2 is ethyl and R3 is methyl, the compound of formula A1b, A2b

[0294]

[0295] With the compound of formula B1 to prepare

[0296] HO-C(O)-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0297] B1

[0298] wherein p, q, m and n are as defined previously; the reaction is carried out in an aprotic polar / nonpolar solvent such as THF, DMF or CH2Cl2, in the presence of a coupling reagent such as N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), in the presence of varying amounts of DMAP at temperatures ranging from -0°C to 80°C.

[0299] Alternatively, the compound of formula (Ib) can be prepared by reacting a compound of formula A1b or A2b with a compound of formula B2:

[0300] XC(O)-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0301] B2

[0302] wherein p, q, m and n are as previously defined, and X is -Cl, p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy;

[0303] When X = -Cl, the reaction is carried out in the presence of a base such as DMAP, pyridine or triethylamine or K2CO3, Cs2CO3 in an aprotic / non-polar solvent such as THF, DMF or CH2Cl2 at a temperature ranging from -20°C to 60°C.

[0304] When X is selected from p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy, the reaction is carried out in an aprotic polar / non-polar solvent such as THF, DMF or CH2Cl2 in the presence of DMAP with or without a catalyst such as scandium triflate at a temperature ranging from 0°C to 80°C.

[0305] Compounds A1b and A2b are disclosed in EP 0 463 756. A2b is known as lodenafil.

[0306] Compounds of the formula B2 are known from the literature or can generally be prepared from compounds B1 by methods known from the literature.

[0307] Compound B1 is known in the prior art or can be prepared from known compounds by known methods: for example, compound B1 can be prepared from the corresponding alcohol of formula B3

[0308] HO-CH2-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0309] B3

[0310] wherein m, n, p and q are as defined above, by oxidation using known reagents such as 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) or ruthenium(IV) oxide / sodium periodate.

[0311] Synthesis examples of compound (B1) are described in WO2009 / 098113 or WO2016 / 155906.

[0312] Compound of formula (Ib)

[0313]

[0314] in:

[0315] R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0316] y=1,

[0317] p is 1 or 0,

[0318] q is 1 or 0,

[0319] m is an integer ranging from 1 to 10;

[0320] n is an integer ranging from 1 to 6;

[0321] R2 is n-propyl and R3 is ethyl (A5b), or R2 is ethyl and R3 is methyl (A4b), which can be generally prepared by making a compound of formula A4b or A5b

[0322]

[0323] and one or more equivalents of a compound of formula B3 to prepare

[0324] HO-CH2-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0325] B3

[0326] wherein m, p, q and n are as defined previously; in the presence of an organic or inorganic base such as DMAP, TEA, DIPEA, with or without a catalyst such as Sc(OTf)3 in an aprotic polar / non-polar solvent such as THF, DMF CH2Cl-2 at a temperature in the range of -20°C to 100°C, according to methods well known in the literature.

[0327] Compounds of formula A4b and A5b are prepared from compounds A2b and A1b, respectively, by methods known in the art.

[0328] Alternatively, compound (Ib) can be prepared by reacting compound A1b or A2b with a compound of formula B4 according to methods well known in the literature.

[0329] pNO2-C6H4-C(O)-O-CH2-(CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2

[0330] B4

[0331] wherein m, p, q and n are as defined previously; in the presence of an organic or inorganic base such as DMAP, TEA, DIPEA, with or without a catalyst such as Sc(OTf)3 in an aprotic polar / non-polar solvent such as THF, DMF CH2Cl-2 at a temperature ranging from -20°C to 100°C.

[0332] Compounds of formula B4 are prepared from compound B3 by methods known in the art.

[0333] Glossary

[0334] ACN: Acetonitrile

[0335] AC2O: Acetic anhydride

[0336] DCC: dicyclohexylcarbodiimide

[0337] DCM: dichloromethane

[0338] DIPEA: N,N-diisopropylethylamine

[0339] DMF: N,N-dimethylformamide

[0340] DMSO: dimethyl sulfoxide

[0341] DMAP: 4-dimethylaminopyridine

[0342] EtOAc: Ethyl acetate

[0343] Et2O: ethyl ether

[0344] EtOH: ethanol

[0345] iPrOH: isopropyl alcohol

[0346] NBS: N-bromosuccinimide

[0347] MTBE: Methyl tert-butyl ether

[0348] TEA: triethylamine

[0349] TEMPO: 2,2,6,6-tetramethylpiperidin-1-oxyl

[0350] THF: Tetrahydrofuran

[0351] PhP3: triphenylphosphine

[0352] Example 1

[0353] 6-(Nitrooxy)hexanoic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester (Compound (9))

[0354]

[0355] To a solution of avanafil (1.00 g, 2.07 mmol) in anhydrous DCM (15 ml) were added DMAP (252 mg, 2.07 mmol), DCC (512 mg, 2.48 mmol) and 6-(nitrooxy)hexanoic acid (440 mg, 2.48 mmol).

[0356] The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous layer was extracted twice with DCM. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.1% formic acid, from 70:30 to 40:60).

[0357] The residue was dissolved in DCM and the solution was washed with a saturated aqueous solution of NaHCO3. The aqueous layer was then extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 1.23 g of the desired product (Compound (9)) (yield: 93.0%).

[0358] 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 1H), 8.81 (m, 1H), 8.75 (d, J = 4.9Hz, 2H), 8.54 (m, 1H), 7.50-7.14 (m, 3H), 7.06 (s, 1H), 4.54 (m, 4H), 4.37 -3.90(m,3H),3.81(s,3H),3.59-3.39(m,4H),2.32(t,J=7.1Hz,2H),2.09-1.73(m,4H),1.66-1.52(m,4H),1.32(dt,J=5.2,7.5Hz,2H).

[0359] Example 2

[0360] (5S)-5,6-bis(nitrooxy)hexanoic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl ester (Compound (10)-(5S)-isomer)

[0361]

[0362] To a solution of avanafil (120 mg, 0.248 mmol) in anhydrous DCM (1.5 ml) were added DMAP (30 mg, 0.248 mmol), DCC (56 mg, 0.273 mmol) and (5S)-5,6-bis(nitrooxy)hexanoic acid (65 mg, 0.273 mmol).

[0363] The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% formic acid, from 70:30 to 40:60).

[0364] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 165 mg of the desired product (compound (10)-(5S)-isomer) (yield: 94.5%).

[0365] 1 H NMR(400MHz, DMSO-d6)δ9.16(t,J=6.0Hz,1H),8.79(m,1H),8.75(d,J=4.9Hz,2H), 8.54(s,1H),7.38(t,J=4.9Hz,1H),7.34-7.23(m,1H),7.19(d,J=7.4Hz,1H),7.05 (t,J=9.8Hz,1H),5.41(m,1H),4.91(m,1H),4.71(m,1H),4.54(m,4H),4.16(m,3H) ,3.98(s,3H),3.50(m,2H),2.38(t,J=6.7Hz,2H),1.92(m,4H),1.79-1.51(m,4H).

[0366] Example 3

[0367] 2-(2-(Nitrooxy)ethoxy)acetic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester (Compound (11))

[0368]

[0369] To a solution of avanafil (160 mg, 0.331 mmol) in anhydrous DCM (1.5 ml) were added DMAP (40 mg, 0.327 mmol), DCC (82 mg, 0.397 mmol) and 2-(2-(nitrooxy)ethoxy)acetic acid (82 mg, 0.497 mmol).

[0370] The mixture was stirred at room temperature over the weekend and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% formic acid, from 90:10 to 65:35).

[0371] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 109 mg of the desired product (compound (11)) (yield: 52%).

[0372] 1 H NMR (400MHz, DMSO-d6) δ9.16(t,J=6.0Hz,1H),8.79(s,1H),8.75(d,J=4.9Hz,2H),8.54(s,1H),7.38(t,J=4.9Hz,1H),7.24(m,1H),7.06 (s,1H),4.70(m,2H),4.54(m,4H),4.26(dd,J=10.5,3.4Hz,1H),4.18(s,2H),3.80(s,3H),3.78(m,2H),3.50(m,2H),2.02-1.79(m,4H).

[0373] Example 4

[0374] 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl ester (Compound (12)-(2S)-isomer)

[0375]

[0376] To a solution of avanafil (160 mg, 0.331 mmol) and 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (82 mg, 0.497 mmol) in anhydrous DCM (1.5 ml) was added DMAP (40 mg, 0.327 mmol).

[0377] The mixture was stirred at room temperature over the weekend and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% formic acid, from 85:15 to 55:45).

[0378] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 227 mg of the desired product (compound (12)-(2S)-isomer) (yield: 95.0%).

[0379] 1 H NMR(400MHz,DMSO-d6)δ9.16(t,J=6.0Hz,1H),8.78(s,1H),8.75(d,J=4.9Hz,1H ),8.53(s,1H),7.38(t,J=4.9Hz,1H),7.34-7.16(m,1H),7.05(t,J=9.4Hz,1H),5 .55(q,1H),4.89(d,J=12.9Hz,1H),4.75(m,1H),4.54(m,4H),4.41-3.93(m,3H), 3.80(s,3H),3.78-3.63(m,4H),3.51(m,2H),2.57(t,J=6.1Hz,2H),1.92(m,4H).

[0380] Synthesis of 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate

[0381] Step 1: Synthesis of (S)-4-(allyloxymethyl)-2,2-dimethyl-1,3-dioxolane

[0382] NaH (60%) (3.4 g; 85.54 mmol) was suspended in anhydrous THF (140 ml) together with S(+)-1,2-isopropylideneglycerol (5.65 g; 42.75 mmol) and 15-crown-5 (0.9 g; 4.28 mmol).

[0383] The mixture was cooled to 0°C and allyl bromide (7.2 ml; 85.54 mmol) was added dropwise. The suspension was stirred at room temperature for 6 hours, then a saturated solution of NH4Cl (100 ml) was added dropwise at 0°C and the mixture was then extracted with Et2O (3X 100 ml). The combined organic layers were washed once with brine and carefully concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4 instrument, SNAP 100 column, isocratic elution Et2O / cyclohexane 1:9) to give 5.8 g (yield 78.5%) of the title compound ((S)-4-(allyloxymethyl)-2,2-dimethyl-1,3-dioxolane).

[0384] 1 H NMR (300 MHz, CHLOROFORM-d) δ 6.00-5.78 (m, 1H), 5.35-5.13 (m, 2H), 4.35-4.21 (m, 1H), 4.11-3.98 (m, 3H), 3.73 (m, 1H), 3.57-3.40 (m, 2H), 1.51-1.32 (m, 6H).

[0385] Step 2: Synthesis of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol

[0386] To a stirred solution of (S)-4-(allyloxymethyl)-2,2-dimethyl-1,3-dioxolane (2.0 g, 10.64 mmol) in anhydrous THF (180 ml) cooled at 0°C was added 9BBN 0.5M (241.8 ml, 121 mmol) dropwise. The reaction was stirred at 0°C for 30 minutes and at room temperature overnight. The reaction mixture was cooled at 0°C and NaOH 2N (84 ml) was added along with H2O2 30% (58 ml). The mixture was diluted with Et2O (100 ml) and NaOH 1N (100 ml). The two phases were separated and the aqueous layer was extracted with Et2O (3X 120 ml). The combined organic layers were washed once with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4 instrument, SNAP 100 column, EtOAC in cyclohexane from 30% to 80% in 10 c.v.) to give 6.4 g (yield: 100%) of the title compound ((S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol).

[0387] 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.35-4.20 (m, 1H), 4.11-4.01 (m, 1H), 3.85-3.63 (m, 5H), 3.58-3.46 (m, 2H), 1.97-1.80 (m, 2H), 1.45 (s, 3H), 1.38 (s, 3H).

[0388] Step 3: Synthesis of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoic acid

[0389] To a solution of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol (2.03 g; 10.51 mmol) in acetone (50 ml) cooled at 0°C was added a saturated solution of NaHCO3 (56 ml), NaBr (0.45 g, 4.20 mmol) and TEMPO (0.34 g, 2.10 mmol). Trichloroisocyanuric acid (4.91 g, 21.02 mmol) was then added in portions. The mixture was allowed to reach room temperature and stirred for 3 hours. The mixture was then cooled at 0°C and isopropanol (20 ml) was slowly added. The mixture was stirred at 0°C for 30 minutes. The formation of a white solid was observed. The precipitate was filtered off and the solvent was concentrated. NaOH2N was added to the residue (pH=12) and the aqueous solution was washed twice with EtOAc. HCl 1N was added to the aqueous phase until pH 2-3 and extracted with EtOAc (5 x 50 ml). The combined organic phases were dried over Na2SO4 and evaporated to give 0.82 g (yield: 38%) of the title compound ((S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoic acid).

[0390] 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.34-4.16 (m, 1H), 4.11-3.97 (m, 1H), 3.85-3.68 (m, 3H), 3.63-3.42 (m, 2H), 2.74-2.55 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H).

[0391] Step 4: Synthesis of (S)-4-nitrophenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoate

[0392] To a solution of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoic acid (0.82 g, 4.02 mmol), DCC (0.83 mg, 4.02 mmol) and DMAP (0.1 g, 0.80 mmol) in DCM (15 ml) was added 4-nitrophenol (0.56 g; 4.02 mmol) in portions. The mixture was stirred at room temperature overnight, then the precipitate was filtered off and the solvent was evaporated. The residue was purified by flash chromatography (Biotage SP4 instrument, EtOAc in cyclohexane from 5% to 50% in 12 CV) to give 0.97 g of the title compound ((S)-4-nitrophenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoate) (yield: 74%).

[0393] 1H NMR (300 MHz, CHLOROFORM-d) δ 8.33-8.21 (m, 2H), 7.37-7.20 (m, 2H), 4.37-4.20 (m, 1H), 4.09-4.00 (m, 1H), 3.96-3.84 (m, 2H), 3.80-3.66 (m, 1H), 3.63-3.47 (m, 2H), 2.96-2.78 (m, 2H), 1.42 (s, 3H), 1.36 (s, 3H).

[0394] Step 5: Synthesis of (R)-4-nitrophenyl 3-(2,3-dihydroxypropoxy)propanoate

[0395] To a stirred solution of (S)-4-nitrophenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoate (0.97 g, 2.97 mmol) in THF (10 ml) was added HCl 3N (2 ml), and the solution was stirred at room temperature for 4 hours. EtOAc (5 ml) and H2O (5 ml) were then added, and the two phases were separated. The aqueous phase was extracted with EtOAc (2x5 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.89 g of the title compound ((R)-4-nitrophenyl 3-(2,3-dihydroxypropoxy)propanoate), which was used in the next step without further purification.

[0396] Step 6: Synthesis of 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate

[0397] To a solution of Ac2O (0.76 ml, 8.07 mmol) in DCM (5 ml) was added fuming HNO3 (0.38 ml, 9.32 mmol) dropwise at -40°C. A solution of (R)-4-nitrophenyl 3-(2,3-dihydroxypropoxy)propanoate (0.89 g, 3.11 mmol) in DCM (7 ml) was then added dropwise. The mixture was allowed to reach 0°C and stirred for 4 hours. The mixture was then poured into ice and NaHCO3 was added in portions. The two phases were separated and the aqueous phase was washed twice with DCM. The combined organic phases were dried over Na2SO4 and concentrated to give 0.56 g of the title compound (4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate) (yield for two steps: 38%).

[0398] 1H NMR (300 MHz, CHLOROFORM-d) δ 8.35-8.22 (m, 2H), 7.35-7.22 (m, 2H), 5.48-5.34 (m, 1H), 4.88-4.73 (m, 1H), 4.73-4.56 (m, 1H), 3.94-3.85 (m, 2H), 3.85-3.77 (m, 2H), 2.88 (t, 2H).

[0399] Synthesis of 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid (Compound (IIIg)-OH)

[0400] A solution of 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (step 6) (500 mg, 1.33 mmol) in 5 ml of a 1 / 1 (v / v) mixture of EtOH / THF was cooled to 0° C. Then 1.33 ml (2.66 mmol) of 2N NaOH solution was added dropwise to the stirred solution over 45 min.

[0401] The mixture was allowed to stand under stirring for 1 hour. The organic solvent was then removed in vacuo and EtOAc (25 ml) and water (25 ml) were added. The organic phase was removed and the pH of the aqueous phase was set to 1 using HCl 2N. The aqueous phase was extracted with DCM (2x15 ml), dried over sodium sulfate, and evaporated in vacuo.

[0402] The crude product was purified on a 4 g 25μ C18 cartridge using a gradient of (ACN) / (H2O+0.1% HCOOH) from 5 / 95 to 30 / 70 in 30 min.

[0403] The eluted fractions containing clean products were pooled and lyophilized to give 210 mg of the title compound (clear oil of 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid) (yield 61%).

[0404] 1 H NMR(400MHz,DMSO-d-6)δppm 2.43-2.48(m,2H),3.61-3.78(m,4H),4.76(dd,J=12.89,6.54Hz,1H),4.92(dd,J=12.89,2.93Hz,1H),5.54-5.59(m,1H),12.23(br s,1H).

[0405] Example 5

[0406] 6-(Nitrooxy)hexanoic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester 2-hydroxypropane-1,2,3-tricarboxylate ((Compound (9) citrate)

[0407]

[0408] To a solution of compound (9) (100 mg, 0.155 mmol) prepared as described in Example 1 in methanol (1.5 ml) was added citric acid monohydrate (33 mg, 0.155 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid washed with MTBE. The solid was filtered and dried under reduced pressure to give 125 mg of the desired product (compound (9) citrate) (crude yield: 96.6%).

[0409] 1 H NMR(600MHz,DMSO-d-6)δ12.39-12.36(m,3H),9.19(s,1H),8.80(m,1H),8.75(d ,J=4.9Hz,2H),8.53(m,1H),7.42-7.15(m,3H),7.06(m,1H),4.65-4.38(m,6H),4 .37-4.11(m,3H),3.80(s,3H),3.59-3.39(m,2H),2.75(d,J=15.4Hz,2H),2.65(d ,J=15.4Hz,2H),2.32(m,2H),2.05-1.80(m,4H),1.47-1.08(m,4H),1.32(q,2H).

[0410] Example 6

[0411] (5S)-5,6-bis(nitrooxy)hexanoic acid ((S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester 2-hydroxypropane-1,2,3-tricarboxylate (Compound (10)-(5S)-isomer, citrate)

[0412]

[0413] To a solution of compound (10)-(5S)-isomer (165 mg, 0.234 mmol) prepared as described in Example 2 in methanol (1.5 ml) was added citric acid monohydrate (49 mg, 0.233 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the residue washed with ether. The solid was filtered and dried under reduced pressure to give 205 mg of the desired product (compound (10)-(5S)-isomer-citrate salt) (crude yield: 97.8%).

[0414] 1 H NMR(600MHz,DMSO-d-6)δ12.37(s,3H),9.18(s,1H),8.85-8.70(m,3H),8.53(m,1H),7. 42-7.36(m,2H),7.34-7.15(m,1H),7.10-7.01(m,1H),5.41(m,1H),4.91(d,J=12.4Hz, 1H),4.70(m,1H),4.63-4.42(m,4H),4.38-3.92(m,3H),3.81(s,3H),3.51(m,2H),2.75 (d,J=15.4Hz,2H),2.66(d,J=15.4Hz,2H),2.38(m,2H),1.92(m,4H),1.79-1.58(m,4H).

[0415] Example 7

[0416] 2-(2-(Nitrooxy)ethoxy)acetic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester 2-hydroxypropane-1,2,3-tricarboxylate (Compound (11) citrate)

[0417]

[0418] To a solution of compound 11 (109 mg, 0.173 mmol) prepared as described in Example 3 in methanol (1.0 ml) was added citric acid monohydrate (36 mg, 0.171 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the residue was washed with ether. The solid was filtered and dried under reduced pressure to give 139 mg of the desired product (compound (11) citrate) (crude yield: 97.6%).

[0419] 1H NMR(600MHz,DMSO-d-6)δ12.36(s,3H),9.18(s,1H),8.85-8.72(m,3H),8. 53(m,1H),7.41-7.35(m,2H),7.34-7.15(m,1H),7.06(m,1H),4.70-4.64(m ,2H),4.62-4.46(m,4H),4.40-3.99(m,5H),3.80(s,3H),3.78(m,2H),3.58 -3.43(m,2H),2.75(d,J=15.4Hz,2H),2.66(d,J=15.4Hz,2H),1.93(m,4H).

[0420] Example 8

[0421] 3-((S)-2,3-bis(nitrooxy)propoxy)propanoic acid ((S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester 2-hydroxypropane-1,2,3-tricarboxylate (Compound (12)-(2S)-isomer, citrate)

[0422]

[0423] To a solution of compound 12, (2S)-isomer (227 mg, 0.315 mmol) prepared as described in Example 4 in methanol (2 ml) was added citric acid monohydrate (66 mg, 0.315 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the residue washed with ether. The solid was filtered and dried under reduced pressure to give 280 mg of the desired product (compound (12)-(2S)-isomer, citrate) (crude yield: 97.4%).

[0424] 1 H NMR(600MHz,DMSO-d-6)δ12.35(s,3H),9.18(s,1H),8.77(m,2H),8.55(m,1H),7.46- 7.33(m,1H),7.34-7.17(m,1H),7.06(dd,J=16.6,8.3Hz,1H),5.55(s,1H),4.81(m,4 H),4.63-4.42(m,4H),4.38-3.96(m,3H),3.81(s,3H),3.71(m,2H),3.57-3.42(m,2H ), 2.75 (d, J = 15.4Hz, 2H), 2.65 (d, J = 15.4Hz, 2H), 2.57 (t, J = 5.9Hz, 2H), 1.92 (m, 4H).

[0425] Example 9

[0426] 3-[2,3-bis(nitrooxy)propoxy]propanoic acid (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl ester citrate (Compound (1)-(2S)-isomer, citrate)

[0427]

[0428] To a solution of milonafil (500 mg, 0.940 mmol) and 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (see Example 4) (423 mg, 1.128 mmol) in anhydrous DCM (5 ml) was added DMAP (115 mg, 0.940 mmol).

[0429] The mixture was stirred at room temperature for 48 hours, then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% formic acid, from 70:30 to 20:80).

[0430] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 540 mg of (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 3-(3-nitro-2-(nitrooxy)propoxy)propanoate (compound (1), yield: 75.0%).

[0431] Compound (1) (295 mg, 0.384 mmol) was redissolved in methanol (1.5 ml), and monohydrated citric acid (81 mg, 0.384 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid was washed with ether. The solid was filtered and dried under reduced pressure to obtain 361 mg of the title compound (compound (1)-(2S)-isomer, citrate) (crude yield: 98%).

[0432] 1H NMR (400MHz, DMSO-d-6) δ2.30(bs,1H),7.89(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.5Hz,1H),7.38(d,J=8.9Hz,1 H),7.31(s,1H),5.53m,J=10.3,6.7,3.9Hz,1H),4.88(dd,J=12.8,3.0Hz,1H),4.72(dd,J=12.9,6.5Hz,1H),4 .37(q,J=7.1Hz,2H),4.10(dt,J=11.4,6.0Hz,4H),3.77-3.58(m,4H),2.90(s,4H),2.75(d,J=15.4Hz,2H),2. 65(d,J=15.4Hz,2H),2.61-2.52(m,10H),1.80-1.58(m,4H),1.36(t,J=7.1Hz,3H),0.97(t,3H),0.94(t,3H).

[0433] Example 10

[0434] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexanoate citrate (compound (4) citrate);

[0435]

[0436] To a solution of milonafil (500 mg, 0.940 mmol) in anhydrous DCM (5 ml) were added DMAP (115 mg, 0.940 mmol), DCC (233 mg, 1.128 mmol) and 6-(nitrooxy)hexanoic acid (200 mg, 1.128 mmol).

[0437] The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous layer was extracted twice with DCM. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.1% formic acid, from 70:30 to 20:80).

[0438] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 450 mg of 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexanoate (compound (4), yield: 69.0%).

[0439] To a solution of compound (4) (200 mg, 0.290 mmol) in methanol (1.5 ml) was added citric acid monohydrate (61 mg, 0.290 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid was washed with ether. The solid was filtered and dried under reduced pressure to obtain 253 mg of the title compound (compound (4) citrate) (yield 98.8%).

[0440] 1 H NMR (400MHz, DMSO-d-6) δ11.67(s,1H),7.90(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.5Hz,1H),7.38(d ,J=8.9Hz,1H),7.31(s,1H),4.47-4.32(m,4H),4.09(dt,J=11.3,6.0Hz,4H),2.90(s,4H),2.75(d ,J=15.4Hz,2H),2.65(d,J=15.4Hz,2H),2.55(ddd,J=11.8,8.4,4.7Hz,8H),2.26(t,J=7.3Hz,2H) ,1.81-1.69(m,2H),1.69-1.55(m,4H),1.50(m,2H),1.39-1.33(m,3H),1.29(q,2H),0.94(m,6H).

[0441] Embodiment 11

[0442] 2-Hydroxypropane-1,2,3-tricarboxylic acid [2-(nitrooxy)ethoxy]acetic acid 2-{4-[3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxybenzene-1-sulfonyl]piperazin-1-yl}ethyl ester (Compound (2) citrate)

[0443]

[0444] To a solution of milonafil (500 mg, 0.940 mmol) in anhydrous DCM (5 ml) were added DMAP (115 mg, 0.940 mmol), DCC (233 mg, 1.128 mmol) and [2-(nitrooxy)ethoxy]acetic acid (186 mg, 1.128 mmol).

[0445] The mixture was stirred at room temperature for 48 hours, then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.1% formic acid, from 70:30 to 40:60).

[0446] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 338 mg of [2-(nitrooxy)ethoxy]acetic acid 2-{4-[3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxybenzene-1-sulfonyl]piperazin-1-yl}ethyl ester (compound (2), yield: 53.0%).

[0447] To a solution of compound (2) (172 mg, 0.253 mmol) in methanol (1.5 ml) was added citric acid monohydrate (53 mg, 0.276 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid was washed with ether. The solid was filtered and dried under reduced pressure to obtain 220 mg of the title compound (compound (2) citrate) (crude yield: 99.8%).

[0448] 1 H NMR (400MHz, DMSO-d-6) δ11.68 (s, 1H), 7.90 (t, J = 5.8Hz, 1H), 7.80 (m, 1H), 7.38 (d,J=8.9Hz,1H),7.31(s,1H),4.67-4.59(m,2H),4.45-4.27(m,2H),4.20-4.04( m,6H),3.78-3.71(q,2H),2.90(s,4H),2.75(t,J=15.4Hz,2H),2.65(t,J=15.4H z, 2H), 2.61-2.52 (m, 8H), 1.81-1.55 (m, 4H), 1.36 (t, J = 7.1Hz, 3H), 0.94 (t, 6H).

[0449] Example 12

[0450] 5,6-Bis(nitrooxy)hexanoic acid (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl ester citrate (Compound (3)-(5S) isomer, citrate)

[0451]

[0452] To a solution of milonafil (500 mg, 0.940 mmol) in anhydrous DCM (5 ml) were added DMAP (115 mg, 0.940 mmol), DCC (233 mg, 1.128 mmol) and (5S)-5,6-bis(nitrooxy)hexanoic acid (270 mg, 1.128 mmol).

[0453] The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.1% formic acid, from 70:30 to 40:60).

[0454] After purification, a saturated solution of DCM and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 550 mg of (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazine-1-yl)ethyl 5,6-bis(nitro)hexanoate (compound (3), yield: 77.8%).

[0455] To a solution of compound (3) (207 mg, 0.275 mmol) in methanol (1.5 ml) was added citric acid monohydrate (58 mg, 0.302 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid was washed with ether. The solid was filtered and dried under reduced pressure to obtain 254 mg of the title compound (compound (3)-(5S) isomer, citrate) (yield: 97.8%).

[0456] 1H NMR (400MHz, DMSO-d-6) δ11.67(s,1H),7.89(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.5Hz,1H),7.38(d,J =8.9Hz,1H),7.31(s,1H),5.38(m,J=13.1,5.9,2.6Hz,1H),4.89(dd,J=12.9,2.6Hz,2H),4.70(m,2H ),4.37(q,J=7.1Hz,2H),4.09(dt,J=11.3,6.0Hz,4H),2.90(s,4H),2.75(t,2H),2.65(d,J=15.4Hz, 2H), 2.61-2.52(m,8H), 2.32(t,J=7.1Hz,2H), 1.82-1.55(m,8H), 1.36(t,J=7.1Hz,3H), 0.94(t,6H).

[0457] Embodiment 13

[0458] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexyl carbonate (Compound (5))

[0459]

[0460] Step 1: 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl (4-nitrophenyl) carbonate

[0461] To a solution of milonafil (290 mg, 0.545 mmol) in anhydrous DCM (5 ml) was added 4-nitrophenyl chloroformate (121 mg, 0.600 mmol) and DMAP (74 mg, 0.600 mmol). The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (cyclohexane: EtOAc: MeOH 5:5:0.1%). The eluted fractions were then collected and dried under reduced pressure to give 310 mg of the title compound (2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl carbonate (4-nitrophenyl) carbonate) (yield: 81.7%) as a colorless oil.

[0462] Step 2: 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl 6-(nitrooxy)hexyl carbonate

[0463] To a solution of 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl (4-nitrophenyl) carbonate (150 mg, 0.21 mmol) in anhydrous DCM (1 ml) was added DMAP (30 mg, 0.24 mmol) and 6-hydroxyhexyl nitrate (39 mg, 0.24 mmol). The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.1% formic acid, from 90:10 to 20:80). After purification, a saturated solution of dichloromethane and NaHCO3 was added to the residue. The two phases were separated, and the aqueous phase was extracted twice with DCM. The eluted fractions were then collected and dried under reduced pressure to obtain 150 mg of the title compound (Compound (5)) (yield: 97%) as a viscous oil.

[0464] 1 H NMR (600MHz, DMSO-d-6) δ11.65(s,1H),7.89(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.4Hz,1H),7.38(d,J=8.9Hz,1H),7.3 1(s,1H),4.47(t,J=6.6Hz,2H),4.37(q,J=7.1Hz,2H),4.13(t,J=5.9Hz,2H),4.00(t,J=6.6Hz,2H),2.88(t,2H),2.60 -2.51(m,8H),1.79-1.70(m,2H),1.68-1.57(m,4H),1.56-1.48(m,2H),1.36(t ,J=7.2Hz,3H),1.33-1.22(m,4H),0.97(t,J=7.4Hz,3H),0.92(t,J=7.3Hz,3H).

[0465] Embodiment 14

[0466] Carbonate (S)-5,6-bis(nitrooxy)hexyl 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl ester (Compound (6))

[0467]

[0468] To a solution of 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl (4-nitrophenyl) carbonate (200 mg, 0.29 mmol)) prepared as described in Example 13, Step 1 in anhydrous DCM (2 ml) was added DMAP (39 mg, 0.32 mmol) and dinitro 6-hydroxyhexane-1,2-diyl ester (72 mg, 0.32 mmol).

[0469] The mixture was stirred at room temperature overnight, then diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted twice with DCM. The combined organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.1% formic acid, from 85:15 to 20:80). After purification, a saturated solution of dichloromethane and NaHCO3 was added to the residue. The two phases were separated, and the aqueous phase was extracted twice with DCM. The eluted fractions were then collected and dried under reduced pressure to obtain 150mg of the desired product (compound (6)) (yield: 73.5%) of viscous oil.

[0470] 1 H NMR (400MHz, DMSO-d-6) δ11.66(s,1H),7.88(d,J=2.4Hz,1H),7.80(dd,J=8.8,2.5Hz,1 H),7.38(d,J=8.9Hz,1H),7.31(s,1H),5.38(dt,J=6.2,4.3Hz,1H),4.90(dd,J=12.9,2 .6Hz,1H),4.67(dd,J=12.9,6.1Hz,1H),4.37(q,J=7.2Hz,2H),4.20-3.96(m,6H),2.75 (m,6H),2.62-2.51(m,8H),1.82-1.52(m,8H),1.46-1.29(m,3H),0.94(t,J=7.4Hz,6H).

[0471] Embodiment 15

[0472] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexyl carbonate (Compound (13))

[0473]

[0474] Step 1: (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)-5-((pyrimidin-2-ylmethyl)carbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl (4-nitrophenyl) carbonate

[0475] To a solution of avanafil (500 mg, 1.033 mmol) in anhydrous DCM (10 ml) was added 4-nitrophenyl chloroformate (416 mg, 2.066 mmol) and pyridine (184 μL, 2.346 mmol). The mixture was stirred at room temperature for 2 hours and then diluted with DCM and water. The two phases were separated and the aqueous layer was extracted twice with DCM to give 1.02 g of the desired product ((S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)-5-((pyrimidin-2-ylmethyl)carbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl (4-nitrophenyl) carbonate).

[0476] Step 2: (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexyl carbonate

[0477] To a solution of (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)-5-((pyrimidin-2-ylmethyl)carbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl (4-nitrophenyl) carbonate (1.02 g, 1.57 mmol) in anhydrous DCM (20 ml) was added DMAP (211 mg, 1.73 mmol) and 6-hydroxyhexyl nitrate (282 mg, 1.73 mmol). The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / iPrOH from 100:0 to 90:10). The eluted fractions were then collected and dried under reduced pressure to give 405 mg of the title compound (compound (13)) (yield: 38%) as a viscous oil.

[0478] 1H NMR (600MHz, DMSO-d-6) δ9.17(t,J=6.0Hz,1H),8.79(m,1H),8.75(d,J=4.9Hz,2H),8.55(m,1H),7.45-7.15(m,3H),7.04(d,J=8.3Hz,1 H),4.61-4.43(m,6H),4.29(m,3H),4.05(t,J=6.4Hz,2H),3.81(s,3H),3.56-3.42(m,2H),2.05-1.80(m,4H),1.60(m,4H),1.32(t,4H).

[0479] Example 16

[0480] 3-(2,3-bis(nitrooxy)propoxy)propanoic acid (S)-2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl ester dihydrochloride (Compound (1)-(2S) dihydrochloride)

[0481]

[0482] To a solution of compound (1) (72 mg, 0.094 mmol) obtained in Example 9 in methanol (1.0 ml) was added HCl 3M methanol solution (63 μL, 0.188 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid was washed with Et2O. The solid was filtered and dried under reduced pressure to obtain 68 mg of the title compound (compound (1)-(2S) dihydrochloride) (yield: 86%).

[0483] 1 H NMR(600MHz,DMSO-d-6)δ11.73(s,1H),11.05(s,1H),8.07-7.76(m,2H),7.42(d,J=8.7Hz,1H) ,7.32(s,1H),5.59-5.52(m,1H),4.90(dd,J=12.8,2.8Hz,1H),4.75(dd,J=12.8,6.5Hz,1H),4 .38(q,J=7.1Hz,3H),4.14(t,J=6.3Hz,2H),3.77-3.66(m,6H),2.60-2.49(m,14H),1.80-1.72 (m,2H),1.69-1.60(m,2H),1.36(t,J=7.2Hz,3H),0.97(t,J=7.4Hz,3H),0.93(t,J=7.3Hz,3H).

[0484] Embodiment 17

[0485] (S)-1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl carbonate (S)-5,6-bis(nitrooxy)hexyl carbonate (Compound (14)-(5S) isomer)

[0486]

[0487] To a solution of (S)-(1-(4-((3-chloro-4-methoxybenzyl)amino)-5-((pyrimidin-2-ylmethyl)carbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl (4-nitrophenyl) carbonate (prepared as described in Example 15, Step 1) (758 mg, 1.167 mmol) in anhydrous DCM (10 ml) was added DMAP (157 mg, 1.284 mmol) and (2S)-6-hydroxyhexane-1,2-diyl dinitrate (288 mg, 1.284 mmol).

[0488] The mixture was stirred at room temperature overnight, then diluted with DCM and water. The two phases were separated, and the aqueous layer was extracted twice with DCM. The combined organic phase was dried over MgSO4, and concentrated under reduced pressure. By flash chromatography (DCM / iPrOH from 100:0 to 90:10) and then by reverse phase chromatography (H2O / CH3CN, from 100:0 to 0:100) purification of residue, 334 mg of the desired product (compound (14)-(5S) isomer) (yield: 39%) of sticky solid was obtained.

[0489] 1 H NMR(600MHz,DMSO-d-6)δ9.17(d,J=5.5Hz,1H),8.79(m,1H),8.75(d,J=4.9Hz,2 H),8.55(s,1H),7.44-7.16(m,3H),7.04(d,J=7.7Hz,1H),5.41(m,1H),4.92(d,J =12.8Hz,1H),4.69(dd,J=12.7,6.0Hz,1H),4.64-4.42(m,4H),4.39-4.14(m,3H ),4.06(m,2H),3.81(m,3H),3.49(m,2H),1.92(m,4H),1.66(m,4H),1.42(m,2H).

[0490] Embodiment 18

[0491] (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexyl carbonate 2-hydroxypropane-1,2,3-tricarboxylate (Compound (13) citrate)

[0492]

[0493] To a solution of (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexyl carbonate (compound (13), prepared as described in Example 15) (218 mg, 0.324 mmol) in methanol (1.0 ml) was added citric acid monohydrate (68 mg, 0.324 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid washed with MTBE. The solid was filtered and dried under reduced pressure to give 265 mg of the desired product (compound (13) citrate) (crude yield: 94.5%).

[0494] 1 H NMR(400MHz, DMSO-d-6)δ9.19(t,J=5.8Hz,1H),8.80(m,1H),8.75(d,J=4.9Hz,2H), 8.54(m,1H),7.38(t,J=4.9Hz,1H),7.35-7.15(m,2H),7.06(s,1H),4.64-4.43(m,6 H),4.29(m,3H),4.05(t,J=6.5Hz,2H),3.81(s,3H),3.49(t,J=7.1Hz,2H),2.76(d, J=15.4Hz,2H),2.65(d,J=15.4Hz,2H),2.06-1.81(m,4H),1.61(m,4H),1.33(m,4H).

[0495] Embodiment 19

[0496] 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 6-(nitrooxy)hexanoate (Compound (8b))

[0497]

[0498] To a solution of lodenafil (400 mg, 0.793 mmol) in anhydrous DCM (5 ml) were added DMAP (97 mg, 0.793 mmol), DCC (196 mg, 0.951 mmol) and 6-(nitrooxy)hexanoic acid (168 mg, 0.951 mmol).

[0499] The mixture was stirred at room temperature overnight, then diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted twice with DCM. The organic phase merged was dried over MgSO4, and concentrated under reduced pressure. Residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% formic acid, from 90:10 to 20:80). After purification, dichloromethane and NaHCO3 saturated solution were added to residue. The two phases were separated, and the aqueous phase was extracted twice with DCM. The organic phase merged was dried over MgSO4, and concentrated under reduced pressure to obtain 150mg of the desired product (compound (8b)) (yield: 69.0%).

[0500] 1 H NMR (400MHz, DMSO-d-6) δ12.17(s,1H),7.81(m,2H),7.36(d,J=8.7Hz,1H),4.43(t,J= 6.6Hz,2H),4.19(q,J=6.9Hz,2H),4.14(s,3H),4.03(t,J=5.7Hz,2H),2.86(bs,4H),2 .75(t,J=7.5Hz,2H),2.58-2.37(m,5H),2.23(t,J=7.3Hz,2H),1.72(dd,J=14.9,7.4H z,2H),1.63-1.53(m,2H),1.53-1.40(m,2H),1.35-1.20(m,6H),0.92(t,J=7.4Hz,3H).

[0501] Embodiment 20

[0502] (S)-2-(4-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl 5,6-bis(nitrooxy)hexanoate (Compound (7b)-(5S)) isomer)

[0503]

[0504] To a solution of rodenafil (400 mg, 0.793 mmol) in anhydrous DCM (5 ml) was added DMAP (97 mg, 0.793 mmol), DCC (196 mg, 0.951 mmol) and (5S)-5,6-bis(nitrooxy)hexanoic acid (226 mg, 0.951 mmol). The mixture was stirred at room temperature overnight and then diluted with DCM and water. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% formic acid, from 85:15 to 10:90). After purification, a saturated solution of dichloromethane and NaHCO3 was added to the residue. The two phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 150 mg of the desired product (compound (7b)-(5S)) isomer) (yield: 78.0%).

[0505] 1 H NMR (400MHz, DMSO-d-6) δ12.17 (s, 1H), δ7.85-7.76 (m, 2H), 7.36 (d, J = 8.7Hz, 1H), 5.36 (m, J=6.0,3.4Hz,1H),4.87(dd,J=12.9,2.6Hz,1H),4.65(dd,J=12.9,5.9Hz,1H),4.26-4.12( m,5H),4.02(t,J=5.7Hz,2H),2.87(bs,4H),2.75(t,J=7.6Hz,2H),2.59-2.41(m,3H),2.30 (t,J=7.1Hz,2H),2.08(s,2H),1.78-1.33(m,7H),1.32(t,J=6.9Hz,3H),0.92(t,J=7.4H).

[0506] Example 21 - (Comparative Example) - PDE5 Inhibitor Nitrate

[0507] 2-(4-(3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenylsulfonyl)piperazin-1-yl)ethyl nitrate

[0508]

[0509] The nitrate ester of milonafil was prepared from milonafil according to the method described in WO 2017 / 085056 (Example 29): the hydroxyl group of milonafil was first converted to the corresponding bromide using a known method (PPh3 / NBS) and then nitrated with silver nitrate in acetonitrile.

[0510] 1 H NMR (600 MHz, chloroform-d) δ ppm 10.71 (br s,1H),7.80(dd,J=8.65,2.49Hz,1H),7.15(d,J=8.80Hz,1H),5.30(s,1H ),4.41-4.55(m,5H),4.25(t,J=6.45Hz,3H),3.11(brs,5H),2.72(t,J=7. 48Hz,4H),2.53-2.69(m,5H),2.00-2.09(m,3H),1.74(sxt,J=7.39Hz,4H ), 1.48 (t, J = 7.19Hz, 5H), 1.20 (t, J = 7.33Hz, 5H), 1.00 (t, J = 7.33Hz, 5H).

[0511] Embodiment 22

[0512] Intraocular pressure (IOP) lowering effects in non-human primates with laser-induced ocular hypertension

[0513] In this study, the efficacy of the compound of formula (Ia) - compound (1)-(2S)-citrate (disclosed in Example 9), the NO-donor 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid ((IIIg)-OH), and a reference PDE5 inhibitor (milonafil) in reducing intraocular pressure was evaluated in laser-induced ocular hypertension non-human primates.

[0514] Experimental Procedure

[0515] Compound (1)-(2S)-citrate (0.48 μmol / eye equals 1.59% w / v, 30 μL), milonafil (0.48 μmol / eye equals 1% w / v, 30 μL), NO-donor ((IIIg)-OH=3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid; 1.17 μmol / eye equals 1% w / v, 30 μL) or vehicle (phosphate buffer pH 6, cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v) were applied in a masked manner to non-human primates with laser-induced ocular hypertension. The contralateral eye was not treated.

[0516] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatonometer (Model 30 TMReichert, Depew, NY, USA) measured intraocular pressure at selected time points. One drop of proparacaine HCl 0.13% was topically applied to the eye before each intraocular pressure measurement.

[0517] result

[0518] Data are reported as mean ± SEM for n = 13. Efficacy (E) as change in IOP relative to baseline and vehicle values ​​was calculated using the following equation: (IOP 药物 -IOP 基线药物 )-(IOP 媒介物 -IOP 基线媒介物 The reported values ​​refer to the maximum IOP change (E max ) and the IOP lowering effect detected at 300 minutes after administration (E 300min ).

[0519] The results showed that the nitric oxide-releasing type 5 phosphodiesterase inhibitor of the present invention (compound (1)-(2S)-citrate) exhibited a higher maximum intraocular pressure lowering effect (E- max ) and a longer duration. It should be noted that the NO-donor (IIIg-OH) was administered at a 2.4-fold higher dose than the compound of the present invention ((1)-(2S)-citrate).

[0520]

[0521] Embodiment 23

[0522] Intraocular pressure (IOP) lowering effects in non-human primates with laser-induced ocular hypertension

[0523] In separate experiments, the compound of formula (II), compound (9)-citrate (disclosed in Example 5), and the NO-donor 6-(nitrooxy)hexanoic acid) ((IIIa)-OH) were evaluated for their efficacy in reducing intraocular pressure in laser-induced ocular hypertension non-human primates.

[0524] Experimental Procedure

[0525] Compound (9)-citrate (0.79 μmol / eye equals 2.2% w / v, 30 μL) or NO-donor ((IIIa)-OH=6-(nitrooxy)hexanoic acid (0.79 μmol / eye equals 0.47% w / v, 30 μL) or vehicle (phosphate buffer pH 6, Cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v) were administered to non-human primates with laser-induced ocular hypertension. The contralateral eye was not treated.

[0526] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatic tonometer (Model 30 TM Intraocular pressure was measured by RT-PCR (Reichert, Depew, NY, USA). One drop of proparacaine HCl 0.13% was topically applied to the eye before each intraocular pressure measurement.

[0527] result

[0528] Efficacy (E) was calculated as the change in IOP relative to baseline and vehicle values ​​using the following equation: (IOP 药物 -IOP 基线药物 )-(IOP 溶媒 -IOP 基线溶媒 ), where IOP values ​​were measured at 30, 60, 180, 300 and 480 minutes after administration.

[0529] The results reported in Table 2 show that the nitric oxide-releasing type 5 phosphodiesterase inhibitor of the present invention (compound (9)-citrate) exhibited a higher maximum intraocular pressure lowering efficacy (compared to E of -5.2±1.0 mmHg at 60 min for compound (IIIa)-OH). max Compared with compound (9)-citrate, the E of -6.0±2.1 at 480 min max ) and a longer duration (compared to E of -2.7±1.5 mmHg for compound (IIIa)-OH 480 The E of compound (9)-citrate at the same time point was -6.0±2.1 mmHg. 480 ).

[0530]

[0531]

[0532] Data reported are mean ± SEM of three independent experiments performed on n = 8 eyes each for compound 6-(nitrooxy)hexanoic acid ((IIIa)-OH) and mean ± SEM of one experiment performed on n = 8 eyes for compound (9)-citrate.

[0533] Embodiment 24

[0534] Intraocular pressure (IOP) lowering effect in normotensive New Zealand white rabbits

[0535] In this study, the efficacy of the NO-donor compound 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid ((IIIg)-OH) (disclosed in Example 4) and a reference PDE5 inhibitor (milonafil) in lowering intraocular pressure was evaluated in normotensive New Zealand white rabbits.

[0536] Experimental Procedure

[0537] Vehicle (phosphate buffer pH 6.0, Cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v), 0.5 μmol / eye equal to 0.63% w / v milonafil (50 μL dose), 0.5 μmol / eye equal to 0.26% w / v compound (IIIg-OH) (50 μL dose) alone, or 0.5 μmol / eye equal to 0.26% w / v compound (IIIg-OH) (50 μL dose) co-administered topically (50 μL) to New Zealand male white (NZW) rabbits.

[0538] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatic tonometer (Model 30 TM Intraocular pressure was measured by RT-PCR (Reichert, Depew, NY, USA). One drop of NOVESINA 0.4% (available from Thea Pharma) was topically applied to the eye before each intraocular pressure measurement.

[0539] result

[0540] Data are presented as mean ± SEM of n = 6-9. Efficacy (E) was calculated as the change in intraocular pressure (IOP) relative to baseline and vehicle values ​​using the following equation:

[0541] (IOP 药物 -IOP 基线药物 )-(IOP 溶媒 -IOP 基线溶媒 )

[0542] IOP values ​​were measured at the time of maximum effect and 300 minutes after administration.

[0543] The results reported in Table 3 show that the combined instillation of milonafil (reference PDE5 inhibitor) and the compound (3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid ((IIIg)-OH) did not show any improvement in the intraocular pressure lowering effect compared to the instillation of each compound alone; in fact, the efficacy of milonafil (E max ) is comparable to the efficacy of combined instillation of milonafil and compound (IIIg)-OH.

[0544]

[0545] Embodiment 25

[0546] Intraocular pressure (IOP) lowering effect in normotensive New Zealand white rabbits

[0547] In this study, the efficacy of the compounds of the present invention (1)-(2S)-citrate (disclosed in Example 9), which is a NO-releasing derivative of milonafil, and milonafil nitrate (in which the nitrooxy group (ONO2) is directly bonded to the hydroxyl group of the milonafil molecule) (PDE5-nitrate disclosed in Comparative Example 21) in lowering intraocular pressure was evaluated in normotensive New Zealand white rabbits.

[0548] Experimental Procedure

[0549] Vehicle (phosphate buffer pH 6.0, Cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v), 0.5 μmol / eye equal to 1% w / v (1)-(2S)-citrate (50 μL dose), 0.5 μmol / eye equal to 0.6% w / v PDE5 nitrate (50 μL dose) were topically applied (50 μL) to New Zealand white male (NZW) rabbits.

[0550] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatic tonometer (Model 30 TM Intraocular pressure was measured by RT-PCR (Reichert, Depew, NY, USA). One drop of NOVESINA 0.4% (available from Thea Pharma) was topically applied to the eye before each intraocular pressure measurement.

[0551] result

[0552] Data are presented as mean ± SEM of n = 6-9. Efficacy (E) as change in intraocular pressure (IOP) relative to baseline and vehicle values ​​was calculated as follows:

[0553] (IOP 药物 -IOP 基线药物 )-(IOP 溶媒 -IOP 基线溶媒 )

[0554] IOP values ​​were measured at 30, 60, and 180 minutes after administration.

[0555] The results reported in Table 4 show that the nitric oxide-releasing type 5 phosphodiesterase inhibitor of the present invention (compound (1)-(2S)-citrate) exhibits a higher intraocular pressure lowering efficacy than the corresponding PDE5 nitrate (comparison of E max Corresponding E to PDE5 nitrate max ) and longer duration (comparing the IOP change at 180 min for compound (1)-(2S)-citrate with the IOP change at 180 min for PDE5 nitrate).

[0556]

[0557] Embodiment 26

[0558] Intraocular pressure (IOP) lowering effects in non-human primates with laser-induced ocular hypertension

[0559] In this experiment, the compound of formula (II), Compound (9)-fumarate salt (disclosed in Example 29), was evaluated for its efficacy in reducing intraocular pressure in laser-induced ocular hypertension non-human primates.

[0560] Experimental Procedure

[0561] Compound (9)-fumarate (2.0% w / v, 30 μL) or vehicle (phosphate buffer pH 6, Cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v) was administered to non-human primates with laser-induced ocular hypertension. The contralateral eye was not treated.

[0562] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatic tonometer (Model 30 TM Intraocular pressure was measured by RT-PCR (Reichert, Depew, NY, USA). One drop of proparacaine HCl 0.13% was topically applied to the eye before each intraocular pressure measurement.

[0563] result

[0564] Efficacy (E) was calculated as the change in IOP relative to baseline and vehicle values ​​using the following equation: (IOP 药物 -IOP 基线药物 )-(IOP 溶媒 -IOP 基线溶媒 ), where IOP values ​​were measured at 30, 60, 300, 480 and 1440 minutes after administration.

[0565] The results reported in Table 5 show that compound (9)-fumarate exhibited the greatest IOP-lowering efficacy at 300 minutes, with an E of -4.1 ± 2.7 mmHg. max In addition, the IOP lowering effect of compound (9)-fumarate lasted for 24 hours after administration, at which time the IOP change was still -2.8±2.0 mmHg.

[0566]

[0567] Data reported are mean ± SEM of one experiment performed on n = 8 eyes.

[0568] Embodiment 27

[0569] Intraocular pressure (IOP) lowering effects in non-human primates with laser-induced ocular hypertension

[0570] In this study, the efficacy of compound (I)-(2S)-citrate (disclosed in Example 9), the NO-donor 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid (compound (IIIg)-OH, disclosed in Example 4), a reference PDE5 inhibitor (milonafil), and milonafil and NO-donor 3-[(2S)-2,3-bis(nitrooxy)propoxy]propionic acid administered in combination in reducing intraocular pressure was evaluated in non-human primates with laser-induced ocular hypertension.

[0571] Experimental Procedure

[0572] Compound (1)-(2S)-citrate (0.31 μmol / eye equals 1.0% w / v, 30 μL), milonafil (0.31 μmol / eye equals 0.63% w / v, 30 μL), (IIIg)-OH (0.31 μmol / eye equals 0.26%% w / v, 30 μL), milonafil concomitantly with (IIIg)-OH, or vehicle (phosphate buffer pH 6, Cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v) were administered in a masked manner to non-human primates with laser-induced ocular hypertension. The contralateral eye was not treated.

[0573] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatic tonometer (Model 30 TM Reichert, Depew, NY, USA) measured intraocular pressure at selected time points. One drop of proparacaine HCl 0.13% was topically applied to the eye before each intraocular pressure measurement.

[0574] result

[0575] Data are reported as mean ± SEM for n = 13. Efficacy (E) was calculated as the change in IOP relative to baseline and vehicle values ​​using the following equation: (IOP 药物 -IOP 基线药物 )-(IOP 溶媒 -IOP 基线溶媒 The reported values ​​refer to the maximum IOP change (E max ) and the IOP lowering effect (E 300min ).

[0576] The results reported in Table 6 show that the nitric oxide-releasing type 5 phosphodiesterase inhibitor of the present invention (compound (1)-(2S)-citrate) exhibited a higher intraocular pressure lowering effect than an equimolar dose of a NO-donor ((IIIg)-OH), milonafil, or a combination of milonafil and a NO-donor at most of the analyzed time points. .

[0577]

[0578] Embodiment 28

[0579] (S)-2-(4-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl 3-(2,3-bis(nitrooxy)propoxy)propanoate (Compound (15), (S) isomer)

[0580]

[0581] To a solution of lodenafil (400 mg, 0.794 mmol) and 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (see Example 4) (226 mg, 0.951 mmol) in anhydrous DCM (5 ml) was added DMAP (97 mg, 0.794 mmol).

[0582] The mixture was stirred at room temperature over the weekend, then diluted with DCM and water. The two phases were separated, and the aqueous phase was extracted twice with DCM. The organic phase merged was dried over MgSO4, and concentrated under reduced pressure. Residue was purified by reverse phase chromatography (H2O / CH3CN containing 0.01% FA, from 80:20 to 20:80). After purification, dichloromethane and NaHCO3 saturated solution were added to residue. The two phases were separated, and the aqueous phase was extracted twice with DCM. The organic phase merged was dried over MgSO4, and concentrated under reduced pressure to obtain 170mg of the desired product (compound (15), (S) isomer) (yield: 30.0%).

[0583] 1 H NMR(600MHz,dmso)δ12.19(s,1H),7.83(dt,J=8.7,2.4Hz,2H),7.38(d,J=8.8Hz,1 H),5.53(m,1H),4.88(dd,J=12.8,3.0Hz,1H),4.72(dd,J=12.8,6.5Hz,1H),4.21(q ,2H),4.16(s,3H),4.06(t,2H),3.77-3.59(m,4H),2.89(bs,4H),2.77(t,2H),2.55 (m, 8H), 1.74 (dd, J = 14.9, 7.4Hz, 2H), 1.33 (t, J = 6.9Hz, 3H), 0.94 (t, J = 7.4Hz, 3H).

[0584] Embodiment 29

[0585] 6-(Nitrooxy)hexanoic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester fumarate (Compound (9) fumarate)

[0586]

[0587] To a solution of compound (9) (100 mg, 0.155 mmol) prepared as described in Example 1 in methanol (1.5 ml) was added fumaric acid (18 mg, 0.155 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid washed with MTBE. The solid was filtered and dried under reduced pressure to give 103 mg of (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate fumarate (compound (9) fumarate, yield: 87%).

[0588] 1 H NMR(600MHz,DMSO-d-6)δ13.13(m,2H),9.17(m,1H),8.76(m,3H),8.54(m,1H),7.38(m,1H),7.24(m,2H),7.04(m,1H),6.63(s,2H), 4.52(m,5H),4.20(m,2H),3.81(s,3H),3.52(m,2H),3.32(m,2H),2.31(m,2H),1.92(m,4H),1.64(m,2H),1.50(m,2H),1.32(m,2H).

[0589] Embodiment 30

[0590] 6-(Nitrooxy)hexanoic acid (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl ester maleate (Compound (9) maleate)

[0591]

[0592] To a solution of compound (9) (100 mg, 0.155 mmol) prepared as described in Example 1 in methanol (1.5 ml) was added maleic acid (18 mg, 0.155 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated and the solid washed with MTBE. The solid was filtered and dried under reduced pressure to give 113 mg of (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate 2-maleate (compound (9) maleate, yield: 96%).

[0593] 1 H NMR(600MHz,DMSO-d-6)δ12.35(m,3H),9.18(m,1H),8.77(m,3H),8.54(s,1H),7.38(m,2H),7.22(m,1H),7.04(m,1H),4.55(m,6H), 4.20(m,3H),3.98(m,1H),3.80(s,3H),3.49(m,2H),2.75(m,2H),2.65(m,2H),2.31(m,2H),1.92(m,4H),1.56(m,4H),1.32(m,2H).

[0594] Embodiment 31

[0595] Intraocular pressure (IOP) lowering effect in normotensive New Zealand white rabbits

[0596] In this study, the efficacy of the compound of the invention (12)-(2S)-citrate (disclosed in Example 8) in reducing intraocular pressure was evaluated in normotensive New Zealand White rabbits.

[0597] Experimental Procedure

[0598] Vehicle (phosphate buffer pH 6.0, Cremophor EL 5% w / v, DMSO 0.3% w / v, benzalkonium chloride 0.02% w / v) or 1% concentration of (12)-(2S)-citrate was topically applied (50 μL) to New Zealand white male (NZW) rabbits.

[0599] Before (baseline) and at selected time points after ocular administration, intraocular pressure was measured using a pneumatic tonometer (Model 30 TM Intraocular pressure was measured by RT-PCR (Reichert, Depew, NY, USA). One drop of NOVESINA 0.4% (available from Thea Pharma) was topically applied to the eye before each intraocular pressure measurement.

[0600] result

[0601] Data are presented as mean ± SEM for n = 9. Efficacy (E) as change in intraocular pressure (IOP) relative to baseline and vehicle values ​​was calculated as follows: (IOP 药物 -IOP 基线药物 )-(IOP 溶媒 -IOP 基线溶媒 ). IOP values ​​were measured at 30, 60 and 120 minutes after administration.

[0602] The results reported in Table 7 show that the nitric oxide releasing type 5 phosphodiesterase inhibitor of the present invention (Compound (12)-(2S)-citrate) effectively lowered IOP at various time points after administration.

[0603]

Claims

1. A compound of formula (Ib) or its isomer or pharmaceutically acceptable salt, wherein the compound has the following formula in: R1 is the residue of a nitric oxide releasing molecule of the formula: R1=-C(O)-(O-CH2) y (CH2) m -[O-(CH2) n ] p -(CH-ONO2) q -CH2-ONO2 in: y is 1 or 0; p is 1 or 0; q is 1 or 0; m is an integer ranging from 1 to 10; n is an integer ranging from 1 to 6; R2 is ethyl or n-propyl; R3 is methyl or ethyl; Provided that when R2 is ethyl, then R3 is methyl; when R2 is n-propyl, then R3 is ethyl; and Provided that when R2 is ethyl, and R3 is methyl, y is 0, p and q are 0, then m is not 2.

2. The compound of claim 1, wherein R1 is selected from the group consisting of formula (IIIa)-(IIIh):

3. The compound of claim 1, wherein R1 is selected from the group consisting of formula (IVa)-(IVh):

4. The compound of claim 1, wherein R2 is ethyl and R3 is methyl, or R2 is n-propyl and R3 is ethyl.

5. The compound according to claim 2 or 3, wherein R2 is ethyl, and R3 is methyl.

6. The compound according to claim 2 or 3, wherein R2 is n-propyl, and R3 is ethyl.

7. The compound of claim 1, wherein y is 1.

8. The compound of claim 1, selected from: 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 5,6-bis(nitrooxy)hexanoate (compound (7b)); (S)-2-(4-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl (S)-5,6-bis(nitrooxy)hexanoate (compound (7b)-(5S)); 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 6-(nitrooxy)hexanoate (Compound (8b)); 2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl]piperazin-1-yl}ethyl 3-[2,3-bis(nitrooxy)propoxy]propanoate (Compound 15); (S)-2-(4-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperazin-1-yl)ethyl 3-(2,3-bis(nitrooxy)propoxy)propanoate (Compound (15), (S) isomer).

9. A compound according to any one of claims 1 to 8 for use as a medicament.

10. A compound as claimed in any one of claims 1 to 8 for use in a method of treating a disease or condition associated with increased intraocular pressure.

11. The compound used as claimed in claim 10, wherein The disease or condition is selected from the group consisting of ocular hypertension, glaucoma, open-angle glaucoma, normal-tension glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, and drug-induced glaucoma.

12. A compound according to any one of claims 1 to 8 for use in a method of treating a retinopathy including retinopathy of prematurity, retinal vein occlusion or diabetic macular oedema.

13. An ophthalmic pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

14. A composition comprising a compound according to any one of claims 1 to 8 and at least one other active agent selected from the following drug classes: beta-adrenergic antagonists, prostaglandin analogs, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids, cholinesterase inhibitors, soluble guanylate cyclase activators, Rho-kinase inhibitors or cinaciguat.

15. The composition of claim 14 in the form of a kit comprising a dosage form comprising a compound according to any one of claims 1 to 8 and a dosage form comprising another active agent selected from the following drug classes: beta-adrenergic antagonists, prostaglandin analogs, adrenergic agonists, carbonic anhydrase inhibitors, cholinergic agonists, steroids and cholinesterase inhibitors, soluble guanylate cyclase activators, Rho-kinase inhibitors or cinaciguat.

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