Compositions for the treatment of glaucoma and ocular hypertension

Abstract

The present invention relates to ophthalmic compositions comprising a nitric oxide-releasing phosphodiesterase type 5 inhibitor (NO-PDE5 inhibitor) and a prostaglandin analog, and the use of these ophthalmic compositions for the treatment of all forms of glaucoma or ocular hypertension, as well as ophthalmic diseases or conditions associated with elevated intraocular pressure. The NO-PDE5 inhibitor is the following compound: [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl]pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (Compound (1)), [(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 (1A)) or 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (compound (2)). The prostaglandin analog is selected from latanoprost, bimatoprost, travoprost, or tafluprost.

Description

Technical Field

[0001] The present invention relates to an ophthalmic composition comprising a combination of a nitric oxide-releasing phosphodiesterase type 5 inhibitor (NO-PDE5 inhibitor) and a prostaglandin analog, and a method of treating any form of glaucoma or ocular hypertension, and an eye disease or ocular condition associated with elevated intraocular pressure using such a composition. The NO-PDE5 inhibitor is a compound selected from the following compounds: [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (Compound (1)); [(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 (1A)); 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (Compound (2)) selected from: The prostaglandin analog is selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0002] [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (Compound (1)) has the following formula

Chemical formula

[0003] [(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 (1A)) has the following formula

Chemical formula

[0004] 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (Compound (2)) has the following formula

Chemical formula

[0005] Glaucoma is a disease characterized by progressive optic nerve damage and ultimately complete loss of vision. Since there is a good correlation between intraocular pressure control and prevention / reduction of glaucomatous damage in patients with primary open-angle glaucoma (POAG), several therapeutic agents have been developed to lower intraocular pressure (Weinreb Robert N. et al. JAMA. 2014 May 14; 311(18): 1901-1911).

[0006] It is known that increased intraocular pressure can be at least partially controlled by administering a drug that increases the outflow of aqueous humor from the eye, such as a prostaglandin analog (i.e., latanoprost or bimatoprost, travoprost or tafluprost), or a drug that reduces the production of aqueous humor, including beta blockers (i.e., timolol, betaxolol, levobunolol) and carbonic anhydrase inhibitors (i.e., acetazolamide, dorzolamide, brinzolamide).

[0007] Currently, prostaglandin analogs are the first-choice treatment for most glaucoma patients. These drugs are very effective and only require once-daily administration, making them an ideal choice as a single-drug treatment regimen. However, in many cases, prostaglandin analogs are insufficient to achieve a sufficient reduction in IOP compared to the starting baseline value.

[0008] Furthermore, several clinical trials have shown that a reduced IOP is associated with a reduction in the progressive risk of vision loss of approximately 10% to 20% per mmHg (Heijl et al. Arch Ophthalmol. (2002) 120: 1268-1279; Heijl The Lancet (2015) 385: 1264-1266).

[0009] Recently, fixed-dose combinations of various prostaglandin analogs with timolol have been introduced to the market; these include Xalacom, a fixed-dose combination of latanoprost and timolol; DuoTrav, a combination of travoprost and timolol; and Ganfort, which combines bimatoprost with timolol.

[0010] These fixed-dose combinations provide better intraocular pressure control through complementary modes of action; indeed, while prostaglandin analogs are outflow facilitators, timolol reduces the production of aqueous humor within the eye.

[0011] However, fixed combination agents containing timolol as one of the active ingredients pose inherent limitations associated with the use of this particular class of drugs; for example, timolol, a beta blocker, is contraindicated in patients suffering from asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, impotence, depression, confusion, and memory loss.

[0012] Very recently, another fixed combination agent containing latanoprost and netarsudil, a Rho kinase inhibitor, was approved by the FDA (Rocklatan). European Patent No. 1459743 discloses a Rho kinase inhibitor as a therapeutic agent for reducing IOP in patients with open-angle glaucoma or ocular hypertension based on a new mechanism of action. Specifically, the Rho kinase inhibitor appears to increase the outflow of aqueous humor from the trabecular meshwork outflow pathway. Clin. Invest. (2014) 4(5), 391 - 393. However, despite its IOP-lowering profile, the Rho kinase inhibitor has raised some safety concerns including conjunctival hyperemia. Therefore, the tolerability of the latanoprost-netarsudil combination agent is important for its commercial success.

[0013] It is known that side effects of topical hypotensive treatment for glaucoma, such as conjunctival hyperemia, ocular discomfort, and itching, are the main causes of non-adherence in glaucoma patients.

[0014] U.S. Published Patent Application No. 2014 / 0018350 discloses the combination of tafluprost and isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate, a selective EP2 receptor agonist. The experimental results showed that the intraocular pressure was further reduced 6 hours after administration of the two compounds in combination compared to each compound administered alone. However, the tolerability of this combination agent is not described in U.S. Published Patent Application No. 2014 / 0018350.

[0015] U.S. Patent No. 7,816,399 discloses that administration of latanoprost in combination with nipradilol has a greater intraocular pressure (IOP) lowering effect than administration of a single drug.

[0016] Nipradilol is an alpha-beta blocker and has the effect of donating nitric oxide. Therefore, when nipradilol is added to latanoprost, it can bring about a further IOP lowering effect through multiple mechanisms, namely: a decrease in aqueous humor formation through beta-blocking activity, and an increase in aqueous humor outflow through blockade of alpha-adrenergic receptors and / or an increase in nitric oxide signaling.

[0017] International Publication No. WO 2015 / 007552 discloses a composition containing a 4-nitrooxybutane-1-ol alkyl ester as a nitric oxide donor and a prostaglandin analogue, which is useful for controlling elevated intraocular pressure associated with glaucoma or other diseases or conditions causing ocular hypertension. International Publication No. WO 2015 / 007552 does not provide experimental results related to the IOP lowering activity of the disclosed formulations.

[0018] European Patent No. 3220905 discloses a composition containing a nitric oxide-releasing isomannide derivative and a prostaglandin F2α analogue; data obtained in normal and ocular hypertensive rabbits indicate that these formulations have an enhanced and sustained IOP lowering effect compared to the compounds administered alone.

[0019] Vyzulta (latanoprostene bunod) is a nitric oxide-donating latanoprost in which a nitric oxide-donating molecule (butanediol mononitrate) is covalently bonded to the prostaglandin backbone via an ester linkage. Vyzulta is metabolized into two parts, latanoprost acid and butanediol mononitrate, and is further processed to release nitric oxide.

[0020] Published results from the VOYAGER trial in the Phase 2 dose range showed that latanoprostene bunod (0.024%) produced a greater reduction in mean IOP (a 9.0 mmHg reduction in mean diurnal IOP) compared to latanoprost (0.005%) (a 7.77 mmHg reduction in mean diurnal IOP). Weinreb RN, et al. Br J Ophthalmol 2015;99:6:738-45.

[0021] Several studies have shown that at the cellular level, nitric oxide binds to the soluble guanylate cyclase enzyme (sGC), increasing the production of cyclic guanosine monophosphate (cGMP) in the trabecular meshwork and Schlemm's canal tissue. Cyclic GMP then activates a series of mechanisms that promote conventional aqueous humor outflow and reduce intraocular pressure (Cavet et al., Invest Ophthalmol Vis Sci. 2014, 5005-5015).

[0022] International Patent Application No. PCT / EP / 2019 / 070597 discloses a novel class of nitric oxide-releasing phosphodiesterase type 5 inhibitors (NO-PDE5 inhibitors) having intraocular pressure-lowering activity and a good tolerance profile. International Patent Application No. PCT / EP / 2019 / 070597 does not provide results related to the intraocular pressure-lowering activity of formulations containing NO-PDE5 inhibitors and other drugs that lower IOP.

[0023] International Publication Nos. WO 2017 / 085056 and WO 2018 / 215433 disclose dual pharmacologic nitric oxide-donating PDE5 inhibitors that are effective in the treatment of various diseases where disruption of cGMP balance occurs and / or PDE inhibition is considered beneficial, particularly in the treatment of diabetic patients, and glaucoma is specifically cited as a preferred disease.

[0024] International Publication No. WO 2017 / 085056 discloses the results of in vitro studies showing that these nitric oxide-releasing PDE5 inhibitors can activate soluble guanylate cyclase and have greater PDE5 inhibitory activity than the known PDE5 inhibitor sildenafil. However, neither of these references provides any experimental data related to the intraocular pressure-lowering activity of these nitric oxide-releasing PDE5 inhibitors.

[0025] Despite the availability of effective drugs, new treatments for elevated intraocular pressure and glaucoma continue to be of interest for more effective management of these diseases and pathological conditions.

[0026] The present invention relates to another ophthalmic composition capable of reducing elevated intraocular pressure in patients having glaucoma or elevated intraocular pressure, and methods of using these compositions to reduce intraocular pressure.

[0027] [(2S)-1-(4-{[(3-Chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate, [(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, 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate, an NO-PDE5 inhibitor selected from the group consisting of these compounds, and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost, the ophthalmic composition of the present invention can effectively reduce elevated intraocular pressure. The complementary modes of action of the two active ingredients should result in a reliable and sustained reduction of IOP. This, combined with good tolerance, makes these compositions a viable option for the treatment of glaucoma and ocular hypertension. Good tolerance can also be expected to improve patient adherence to this treatment strategy.

[0028] Accordingly, the present invention provides another ophthalmic composition for reducing intraocular pressure, which is useful for preventing or treating glaucoma, ocular hypertension and eye diseases and pathological conditions associated with elevated intraocular pressure.

[0029] The present invention relates to i) the following: [(2S)-1-(4-{[(3-Chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (Compound (1)) or a pharmaceutically acceptable salt thereof, [(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 (1A)) or a pharmaceutically acceptable salt thereof, or 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (Compound (2)) or a pharmaceutically acceptable salt thereof A nitric oxide-releasing phosphodiesterase type 5 inhibitor selected from ii) A prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost To provide an ophthalmic composition comprising

[0030] The nitric oxide-releasing phosphodiesterase type 5 inhibitor used in the present invention includes salts of the NO-PDE5 inhibitor free base with acids acceptable to the eye (including citric acid, oxalic acid, malic acid, tartaric acid, succinic acid, acetic acid, propionic acid, lactic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid or benzenesulfonic acid).

[0031] Some examples of pharmaceutically acceptable salts of [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (Compound (1)) are the following compounds: 2-hydroxypropane-1,2,3-tricarboxylic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1); (2E)-But-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1); (2Z)-But-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) is as follows.

[0032] [(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 (1A)) examples of pharmaceutically acceptable salts are 2-hydroxypropane-1,2,3-tricarboxylic acid [(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 (1 / 1) is as follows.

[0033] Some examples of preferred pharmaceutically acceptable salts of 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (Compound (2)) are the following compounds: 2-Hydroxypropane-1,2,3-tricarboxylic 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (1 / 1); 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate hydrogen chloride (1 / 2) is as follows.

[0034] A preferred prostaglandin analog for use in the present invention is latanoprost.

[0035] Another preferred embodiment of the present invention provides an ophthalmic composition comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, and latanoprost.

[0036] Another embodiment of the present invention provides an ophthalmic composition comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, and bimatoprost.

[0037] Another embodiment of the present invention provides an ophthalmic composition comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, and travoprost.

[0038] Another embodiment of the present invention provides an ophthalmic composition comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, and tafluprost.

[0039] Another preferred embodiment of the present invention provides an ophthalmic composition comprising [(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 or a pharmaceutically acceptable salt thereof, and latanoprost.

[0040] Another preferred embodiment of the present invention provides an ophthalmic composition comprising [(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 or a pharmaceutically acceptable salt thereof, and bimatoprost.

[0041] Another embodiment of the present invention provides an ophthalmic composition comprising [(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 or a pharmaceutically acceptable salt thereof, and travoprost.

[0042] Another embodiment of the present invention provides an ophthalmic composition comprising [(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 or a pharmaceutically acceptable salt thereof, and tafluprost.

[0043] Another preferred embodiment of the present invention provides an ophthalmic composition comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, and latanoprost.

[0044] Another preferred embodiment of the present invention provides an ophthalmic composition comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, and bimatoprost.

[0045] Another embodiment of the present invention provides an ophthalmic composition comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, and travoprost.

[0046] Another embodiment of the present invention provides an ophthalmic composition comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, and tafluprost.

[0047] Another embodiment of the present invention provides an ophthalmic composition comprising 2-hydroxypropane-1,2,3-tricarboxylic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1), and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0048] Another embodiment of the present invention provides an ophthalmic composition comprising 2-hydroxypropane-1,2,3-tricarboxylic acid [(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 (1 / 1), and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0049] Another preferred embodiment of the present invention provides an ophthalmic composition comprising 2-hydroxypropane-1,2,3-tricarboxylic 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (1 / 1) and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0050] Another embodiment of the present invention provides an ophthalmic composition comprising (2E)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0051] Another embodiment of the present invention provides an ophthalmic composition comprising (2Z)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0052] Another embodiment of the present invention provides an ophthalmic composition comprising 2-hydroxypropane-1,2,3-tricarboxylic 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (1 / 1), and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0053] Another embodiment of the present invention provides an ophthalmic composition comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate hydrochloride (1 / 2), and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0054] The above prostaglandin analogs are commercially available: latanoprost (chemical name: propan-2-yl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hepta-5-enoate); bimatoprost (chemical name: (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenylpenta-1-enyl]cyclopentyl]-N-ethylhepta-5-enamide); travaprost (chemical name: propan-2-yl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-1-enyl]cyclopentyl]hepta-5-enoate); tafluprost (chemical name is propan-2-yl (Z)-7-[(1R,2R,3R,5S)-2-[(E)-3,3-difluoro-4-phenoxybut-1-enyl]-3,5-dihydroxycyclopentyl]hepta-5-enoate).

[0055] The [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, the [(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 or a pharmaceutically acceptable salt thereof, or the 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof can generally be administered once to several times a day within the range of 3.0 μg / eye to 600 μg / eye per day.

[0056] Regarding prostaglandin analogs, in the case of latanoprost, a dosage in the range of 0.15 μg / eye to 15 μg / eye per day is generally used; in the case of bimatoprost, a dosage in the range of 0.30 μg / eye to 90 μg / eye per day is generally used; in the case of travoprost, a dosage in the range of 0.12 μg / eye to 12 μg / eye per day is generally used; and in the case of tafluprost, a dosage in the range of 0.045 μg / eye to 4.4 μg / eye per day is generally used.

[0057] The dosage of the nitric oxide-releasing phosphodiesterase type 5 inhibitor or prostaglandin analog can be appropriately increased or decreased according to the age and symptoms of the patient, etc.

[0058] Regarding the mode of administration, the NO-PDE5 inhibitor and prostaglandin analog can be formulated into a single preparation and administered as a mixture, or the NO-PDE5 inhibitor and prostaglandin analog can be formulated into separate dosage forms as a kit for administering the individual compounds simultaneously or separately.

[0059] Another embodiment of the present invention provides an ophthalmic composition for use in the treatment of glaucoma, ocular hypertension, or a disease or condition associated with elevated intraocular pressure, comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, and a prostaglandin analog selected from latanoprost, bimatoprost, travoprost, or tafluprost.

[0060] Another embodiment of the present invention provides an ophthalmic composition for use in a method of reducing intraocular pressure in the pathophysiology of normal tension glaucoma, comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0061] Another embodiment of the present invention provides an ophthalmic composition for use in a method of treating glaucoma, ocular hypertension, or a disease or disorder associated with elevated intraocular pressure, comprising [(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 or a pharmaceutically acceptable salt thereof, and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0062] Another embodiment of the present invention provides an ophthalmic composition for use in a method of reducing intraocular pressure in the pathophysiology of normal tension glaucoma, comprising [(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 or a pharmaceutically acceptable salt thereof, and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0063] Another embodiment of the present invention provides an ophthalmic composition for use in a method of treating glaucoma, ocular hypertension, or a disease or condition associated with elevated intraocular pressure, comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0064] Another embodiment of the present invention provides an ophthalmic composition for use in a method of reducing intraocular pressure in the condition of normal tension glaucoma, comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, and a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0065] Glaucoma in the present invention includes primary open-angle glaucoma, normal tension glaucoma, aqueous humor overproduction glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, mixed glaucoma, corticosteroid glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma, plateau iris syndrome and drug-induced ocular hypertension.

[0066] In the present invention, diseases or conditions associated with elevated intraocular pressure include, for example, drug-induced elevated intraocular pressure (i.e., steroid and anti-VEGF-induced elevated IOP) that occurs during the treatment of retinopathy including retinopathy of prematurity, retinal vein occlusion or diabetic macular edema or age-related macular degeneration.

[0067] The present invention also relates to a method for treating and controlling ocular hypertension associated with glaucoma, or a method for treating a disease or condition associated with ocular hypertension or elevated intraocular pressure. The method includes topically applying a therapeutically effective amount of the composition according to the present invention to the eye of a patient. Another such method includes topically applying, separately or sequentially, a therapeutically effective amount of compound (1) or compound (1A) or compound (2) or a pharmaceutically acceptable salt thereof to the eye of a patient simultaneously with the application of a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0068] The present invention also relates to a method for reducing intraocular pressure in a patient having normal tension glaucoma. The method includes applying a therapeutically effective amount of the composition according to the present invention to the affected eye of the patient. Alternatively, the method includes topically applying, separately or sequentially, a therapeutically effective amount of compound (1) or compound (1A) or compound (2) or a pharmaceutically acceptable salt thereof to the affected eye of the patient simultaneously with the application of a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost.

[0069] The frequency and amount of such administration are determined by a clinician based on various clinical factors.

[0070] Another embodiment of the present invention provides an ophthalmic pharmaceutical preparation comprising [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a salt thereof, a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost, and at least a pharmaceutically acceptable excipient and / or vehicle.

[0071] Another embodiment of the present invention provides an ophthalmic pharmaceutical preparation comprising [(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 or a pharmaceutically acceptable salt thereof, a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost, and at least a pharmaceutically acceptable excipient and / or vehicle.

[0072] Another embodiment of the present invention provides an ophthalmic pharmaceutical preparation comprising 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof, a prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost, and at least a pharmaceutically acceptable excipient and / or vehicle.

[0073] [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, or [(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 or a pharmaceutically acceptable salt thereof, or 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a salt thereof, and a prostaglandin analogue, and at least a pharmaceutically acceptable excipient and / or vehicle, an ophthalmic pharmaceutical preparation can be prepared according to a known method.

[0074] In the ophthalmic pharmaceutical preparation of the present invention, the compound (1) or the compound (1A) or the compound (2) or a pharmaceutically acceptable salt thereof and the prostaglandin analogue may be combined in a single unit dosage form or in two separate unit dosage forms.

[0075] Another embodiment of the present invention is i) as follows: [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof, [(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 or a pharmaceutically acceptable salt thereof, or 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate or a pharmaceutically acceptable salt thereof A nitric oxide-releasing phosphodiesterase type 5 inhibitor selected from ii) A prostaglandin analogue selected from latanoprost, bimatoprost, travoprost or tafluprost Provided is a kit for the simultaneous or separate administration of a nitric oxide-releasing phosphodiesterase type 5 inhibitor and a prostaglandin analogue, comprising

[0076] Experimental section Example 1 Synthesis of [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (Compound 1)

[0077] To a solution of avanafil (1.00 g, 2.07 mmol) in dry dichloromethane (15 mL) were added 4-dimethylaminopyridine (DMAP) (252 mg, 2.07 mmol), dicyclohexylcarbodiimide (DCC) (512 mg, 2.48 mmol) and 6-(nitrooxy)hexanoic acid (440 mg, 2.48 mmol).

[0078] The mixture was stirred at room temperature overnight and then diluted with dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with dichloromethane. 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, 70:30 - 40:60).

[0079] The residue was taken up in dichloromethane and the solution was washed with a saturated aqueous solution of NaHCO3. The aqueous layer was then extracted twice with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 1.23 g of the desired product (yield: 93.0%). 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.81 (m, 1H), 8.75 (d, J = 4.9 Hz, 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 = 7.1 Hz, 2H), 2.09 - 1.73 (m, 4H), 1.66 - 1.52 (m, 4H), 1.32 (dt, J = 5.2, 7.5 Hz, 2H)

[0080] Example 2 Synthesis of [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) of 2-hydroxypropane-1,2,3-tricarboxylic acid (Formula 1a)

Chemical formula

[0081] A solution containing [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (100 mg, 0.155 mmol) and methanol (1.5 mL) prepared as described in Example 1 was added with citric acid monohydrate (33 mg, 0.155 mmol). The mixture was stirred at room temperature for 10 minutes and then concentrated, and the solid was washed with methyl tert-butyl ether (MTBE). The solid was filtered and dried under reduced pressure to give 125 mg of the desired product (crude yield: 96.6%). 1 H NMR (600 MHz, DMSO-d6) δ 12.39 - 12.36 (m, 3H), 9.19 (s, 1H), 8.80 (m, 1H), 8.75 (d, J = 4.9 Hz, 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 = 15.4 Hz, 2H), 2.65 (d, J = 15.4 Hz, 2H), 2.32 (m, 2H), 2.05 - 1.80 (m, 4H), 1.47 - 1.08 (m, 4H), 1.32 (q, 2H)

[0082] Example 3 Synthesis of (2E)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) (Formula 1b)

Chemical Structure

[0083] A solution containing [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (100 mg, 0.155 mmol) and methanol (1.5 mL) prepared as described in Example 1 was added with fumaric acid (18 mg, 0.155 mmol). The mixture was stirred at room temperature for 10 minutes and then concentrated, and the solid was washed with methyl tert-butyl ether. The solid was filtered and dried under reduced pressure to give 103 mg (yield: 87%) of (2E)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate. 1 H NMR (600 MHz, DMSO-d6) δ 13.13 (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)

[0084] Example 4 Synthesis of (2Z)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) (Formula 1c)

Chemical formula

[0085] A solution containing [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (100 mg, 0.155 mmol) and methanol (1.5 mL) was added to maleic acid (18 mg, 0.155 mmol). The mixture was stirred at room temperature for 10 minutes and then concentrated, and the solid was washed with methyl tert-butyl ether. The solid was filtered and dried under reduced pressure to give 113 mg (yield: 96%) of [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate maleate. 1 H NMR (600 MHz, DMSO-d6) δ 12.35 (m, 2H), 9.18 (m, 1H), 8.77 (m, 3H), 8.54 (s, 1H), 7.38 (m, 2H), 7.22 (m, 1H), 7.04 (m, 1H), 6.33 (s, 2H), 4.55 (m, 6H), 4.20 (m, 2H), 3.98 (m, 1H), 3.80 (s, 3H), 3.49 (m, 2H), 2.31 (m, 2H), 1.92 (m, 4H), 1.56 (m, 4H), 1.32 (m, 2H)

[0086] Example 5 Synthesis of [(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 (1A))

[0087] Synthesis of 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate Step 1: Synthesis of (S)-4-(allyloxymethyl)-2,2-dimethyl-1,3-dioxolane

[0088] NaH (60%) (3.4 g; 85.54 mmol) was suspended in dry THF (140 mL) together with S(+)-1,2-isopropylidene glycerol (5.65 g; 42.75 mmol) and 15-crown-5 (0.9 g; 4.28 mmol).

[0089] 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 h, then saturated NH4Cl solution (100 mL) was added dropwise at 0 °C, and then the mixture was extracted with Et2O (3 × 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 apparatus, SNAP 100 column, isocratic elution, Et2O / cyclohexane 1:9) to give the title compound ((S)-4-(allyloxymethyl)-2,2-dimethyl-1,3-dioxolane 5.8 g (yield: 78.5%)). 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)

[0090] Step 2: Synthesis of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol A solution of (S)-4-(allyloxymethyl)-2,2-dimethyl-1,3-dioxolane (2.0 g, 10.64 mmol) cooled to 0 °C and stirred in dry THF (180 mL) was added dropwise with 9-borabicyclo[3.3.1]nonane (9BBN) 0.5 M (241.8 mL, 121 mmol). The reaction was stirred at 0 °C for 30 minutes and then stirred overnight at room temperature. The reaction mixture was cooled to 0 °C, and 2 N NaOH (84 mL) was added together with 30% H2O2 (58 mL). The mixture was diluted with Et2O (100 mL) and 1 N NaOH (100 mL). The two phases were separated, and the aqueous layer was extracted with Et2O (3 × 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 apparatus, SNAP 100 column, ethyl acetate in cyclohexane, (30% - 80%), column volume (c.v.) 10) to give the title compound ((S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol) 6.4 g (yield: 100%). 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)

[0091] Step 3: Synthesis of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoic acid A solution of (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-1-ol (2.03 g, 10.51 mmol) cooled to 0 °C in acetone (50 mL) was added with saturated NaHCO3 solution (56 mL), NaBr (0.45 g, 4.37 mmol) and 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) (0.34 g, 2.17 mmol). Next, trichloroisocyanuric acid (4.91 g, 21.12 mmol) was added little by little. The mixture was allowed to reach room temperature and stirred for 3 h. Then, the mixture was cooled to 0 °C and isopropanol (20 mL) was slowly added. The mixture was stirred at 0 °C for 30 min. The formation of a white solid was observed. The precipitate was filtered off and the solvent was concentrated. 2N NaOH was added to the residue (pH = 12) and the aqueous solution was washed twice with ethyl acetate. 1N HCl was added to the aqueous phase until pH 2 - 3 was reached and extracted with ethyl acetate (5 × 50 mL). The combined organic phases were dried over Na2SO4 and then 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). 1 HNMR (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)

[0092] Step 4: Synthesis of (S)-4-nitrophenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoate (S)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)propanoic acid (0.82 g, 4.02 mmol), dicyclohexylcarbodiimide (DCC) (0.83 mg, 4.02 mmol) and 4-dimethylaminopyridine (DMAP) (0.1 g, 0.80 mmol) in dichloromethane (15 mL) were added portionwise with 4-nitrophenol (0.56 g, 4.02 mmol). The mixture was stirred overnight at room temperature, then the precipitate was filtered off and the solvent was evaporated. The residue was purified by flash chromatography (Biotage SP4 apparatus, 5% - 50% ethyl acetate in cyclohexane, column volume (CV) 12) to give the title compound ((S)-4-nitrophenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propanoate) 0.97 g (yield: 74%). 1 H 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)

[0093] Step 5: Synthesis of (R)-4-nitrophenyl 3-(2,3-dihydroxypropoxy)propanoate To a solution of stirred (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 h. Next, ethyl acetate (5 mL) and H2O (5 mL) were added, and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound ((R)-4-nitrophenyl 3-(2,3-dihydroxypropoxy)propanoate 0.89 g, which was used in the next step without further purification.

[0094] Step 6: Synthesis of 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate To a solution of acetic anhydride (0.76 mL, 8.07 mmol) in dichloromethane (5 mL) was added fuming nitric acid (0.38 mL, 9.32 mmol) dropwise at -40 °C. Next, a solution of (R)-4-nitrophenyl 3-(2,3-dihydroxypropoxy)propanoate (0.89 g, 3.11 mmol) in dichloromethane (7 mL) was added dropwise. The mixture was allowed to reach 0 °C and stirred for 4 h. Then, the mixture was poured into ice and NaHCO3 was added little by little. The two phases were separated, and the aqueous phase was washed twice with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated to give 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate 0.56 g (yield over two steps: 38%). 1 H 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)

[0095] Synthesis of [(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

[0096] To a solution of avanafil (160 mg, 0.331 mmol) and 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (82 mg, 0.218 mmol) in dry dichloromethane (1.5 mL) was added 4-dimethylaminopyridine (DMAP) (40 mg, 0.327 mmol).

[0097] The mixture was stirred at room temperature over the weekend and then diluted with dichloromethane and water. The two phases were separated and the aqueous phase was extracted twice with dichloromethane. 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, 85:15 - 55:45).

[0098] After purification, saturated solutions of dichloromethane and NaHCO3 were added to the residue. The two phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give the product 227 mg (yield: 95.0%). 11H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 6.0 Hz, 1H), 8.78 (m, 3H), 8.75 (d, J = 4.9 Hz, 1H), 8.53 (s, 1H), 7.38 (t, J = 4.9 Hz, 1H), 7.34 - 7.16 (m, 1H), 7.05 (t, J = 9.4 Hz, 1H), 5.55 (m, 1H), 4.89 (d, J = 12.9 Hz, 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 = 6.1 Hz, 2H), 1.92 (m, 4H)

[0099] Example 6 Preparation of [(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 (1 / 1) (Formula (1A.a)) [Chemical Formula]

[0100] To a solution of [(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 (227 mg, 0.315 mmol), prepared as described in Example 5, in methanol (2 mL) was added citric acid monohydrate (66 mg, 0.315 mmol). The mixture was stirred at room temperature for 10 minutes and then concentrated, and the residue was washed with diethyl ether. The solid was filtered and dried under reduced pressure to give the title product 280 mg (crude yield: 97.4%). 1 1H NMR (600 MHz, DMSO-d6) δ 12.35 (s, 3H), 9.18 (s, 1H), 8.77 (m, 3H), 8.55 (m, 1H), 7.46 - 7.33 (m, 2H), 7.34 - 7.17 (m, 1H), 7.06 (dd, J = 16.6, 8.3 Hz, 1H), 5.55 (s, 1H), 4.81 (m, 4H), 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 = 15.4 Hz, 2H), 2.65 (d, J = 15.4 Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 1.92 (m, 4H)

[0101] Example 7 Synthesis of 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (Compound (2))

[0102] Milodenafil (500 mg, 0.940 mmol) prepared as described in Example 5 and 4-nitrophenyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (423 mg, 1.128 mmol) in dry dichloromethane (5 mL) were added 4-dimethylaminopyridine (DMAP) (115 mg, 0.940 mmol).

[0103] The mixture was stirred at room temperature for 48 hours and then diluted with dichloromethane and water. The two phases were separated and the aqueous phase was extracted twice with dichloromethane. 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, 70:30 - 20:80).

[0104] After purification, dichloromethane and a saturated solution of NaHCO3 were added to the residue. The two phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 540 mg (yield: 75.0%) of 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.31 (s, 1H), 5.50-5.56 (m, 1H), 4.88 (dd, J = 12.8, 3.0 Hz, 1H), 4.72 (dd, J = 12.8, 6.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.00-4.15 (m, 4H), 3.60-3.75 (m, 4H), 2.89 (br s, 4H), 2.51-2.60 (m, 10H), 1.58-1.79 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H), 0.96 (br t, J = 7.4 Hz, 3H), 0.92 ppm (t, J = 7.3 Hz, 3H)

[0105] Example 8 Synthesis of 2-hydroxypropane-1,2,3-tricarboxylic 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (1 / 1) (Formula (2a))

Chemical formula

[0106] 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate (295 mg, 0.384 mmol) was redissolved in methanol (1.5 mL), and citric acid monohydrate (81 mg, 0.384 mmol) was added. The mixture was stirred at room temperature for 10 minutes and then concentrated, and the solid was washed with diethyl ether. The solid was filtered and dried under reduced pressure to give 361 mg of the title compound (crude yield: 98%). 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (bs, 3H), 11.67 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.8, 2.5 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.31 (s, 1H), 5.53 (m, J = 10.3, 6.7, 3.9 Hz, 1H), 4.88 (dd, J = 12.8, 3.0 Hz, 1H), 4.72 (dd, J = 12.9, 6.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.10 (dt, J = 11.4, 6.0 Hz, 4H), 3.77 - 3.58 (m, 4H), 2.90 (s, 4H), 2.75 (d, J = 15.4 Hz, 2H), 2.65 (d, J = 15.4 Hz, 2H), 2.61 - 2.52 (m, 10H), 1.80 - 1.58 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H), 0.97 (t, 3H), 0.94 (t, 3H)

[0107] Example 9 Synthesis of 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 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate hydrochloride (1 / 2) (Formula (2b))

Chem.

Claims

1. i) The following: [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof A nitric oxide-releasing phosphodiesterase type 5 inhibitor selected from, and ii) A prostaglandin analogue selected from latanoprost An ophthalmic composition comprising.

2. The pharmaceutically acceptable salt of the nitric oxide-releasing phosphodiesterase type 5 inhibitor is the following: 2-hydroxypropane-1,2,3-tricarboxylic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1), or (2E)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1), or (2Z)-but-2-enedioic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate (1 / 1) The composition according to claim 1, selected from.

3. The ophthalmic composition according to claim 1 or 2, for use as a medicament.

4. The ophthalmic composition according to claim 1 or 2, for use in a method of treating glaucoma, ocular hypertension, or a disease or condition associated with elevated intraocular pressure.

5. The ophthalmic composition for use according to claim 4, wherein the condition associated with elevated intraocular pressure is drug-induced elevated intraocular pressure that occurs during the treatment of retinopathy including retinopathy of prematurity, retinal vein occlusion, or diabetic macular edema or age-related macular degeneration.

6. The ophthalmic composition according to claim 1 or 2, for use in the treatment of normal-tension glaucoma.

7. The ophthalmic composition for use according to any one of claims 4 to 6, wherein the nitric oxide-releasing phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt thereof is applied to the eye simultaneously with, separately from, or sequentially to the application of the prostaglandin analog to the eye.

8. An ophthalmic pharmaceutical preparation comprising the composition according to claim 1 or 2, and at least a pharmaceutically acceptable excipient and / or vehicle.

9. i) The following: [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 6-(nitrooxy)hexanoate or a pharmaceutically acceptable salt thereof A nitric oxide-releasing phosphodiesterase type 5 inhibitor selected from; and ii) A prostaglandin analog selected from latanoprost A kit for the simultaneous or separate administration of the nitric oxide-releasing phosphodiesterase type 5 inhibitor and the prostaglandin analog, comprising

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