PDE5 Inhibitors for Use in the Treatment of Anterior Ischemic Optic Neuropathy - Patent application

Abstract

The present invention relates to the use 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 for the treatment of anterior ischemic optic neuropathy. The compound improves ocular blood flow and also improves visual field and visual acuity in patients. [(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 has the following formula (I): TIFF2025505847000008.tif50161 It is a nitric oxide-releasing phosphodiesterase type 5 inhibitor.

Description

[Technical field]

[0001] The present invention relates to the topical ophthalmic use 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 for the treatment of anterior ischemic optic neuropathy; [(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 improves perfusion to the optic nerve, thereby resulting in improved visual function. [Background technology]

[0002] Anterior ischemic optic neuropathy (AION) is a condition that affects mostly older people and is characterized by dysfunction of the optic nerve and retina, often leading to a significant loss of vision. There are two types of AION: arteritic and non-arteritic. Arteritic (AAION) is associated with giant cell arteritis, which is described as inflammation of large blood vessels that affects the inner lining of the arteries, leading to swelling of the vessels and reduced blood flow (resulting in ischemia of the optic nerve and retina).

[0003] In the more common non-arteritic form (NAION), the reduced blood flow causing damage to the optic nerve and retina is not related to local vascular pathological processes (e.g., inflammation, coagulation) but rather depends on cardiovascular risk factors including diabetes, vasospasm and impaired autoregulation, nocturnal hypotension, and sleep apnea.

[0004] In both forms of AION, vision loss is usually permanent but may be partially self-limited within the first few weeks or months after diagnosis.

[0005] Currently, there is no unique established treatment strategy for AION. Oral corticosteroids are sometimes used for AION. However, the systemic side effects of corticosteroids greatly hinder their efficacy, limiting their use. Off-label use of intravitreal corticosteroids has also been proposed and used. Dexamethasone and other corticosteroids administered by intravitreal injection / implant have fewer systemic side effects, but both result in a steady increase in intraocular pressure. In addition, cataract formation has been reported after intraocular administration of corticosteroids. Finally, it has been reported that corticosteroid treatment may cause vasoconstriction and vasospasm, thereby exacerbating the ischemic damage observed in patients with AION. Anti-VEGF therapy has been shown to suppress inflammation and reduce edema in the eye; however, these compounds may exacerbate ocular vascular dysfunction, resulting in further reduction of ocular perfusion.

[0006] US 6,462,066 describes cytoplasmic Ca 2+ The present invention discloses a method for treating or preventing neurological disorders, including ischemic optic neuropathy, by administering a compound that reduces the concentration of and inhibits intracellular calcium-mediated neuronal damage caused by reperfusion injury, the compound being selected from dantrolene, aminodantroline, azumolene, cyclopiazonic acid, or 2,5-di(tert-butyl)-1,4-benzohydroquinone.

[0007] US 10,159,669 discloses the ophthalmic use of topical or intravitreal administration of Mdivi-1 and Nutlin-3, alone or in combination, for the treatment of ischemic optic neuropathy. This document discloses that Nutlin-3 inhibits apoptosis by inhibiting Bax and Bak in the apoptotic pathway, Mdivi-1 regulates apoptosis by regulating mitochondrial fission or fusion, and that the combination of these drugs blocks the interaction of Bax / Bak and Drpl on the mitochondrial surface as a key step in the apoptotic pathway in various ophthalmic diseases including glaucoma, ischemic optic neuropathy, hereditary optic neuropathy, and retinal artery / vein occlusion.

[0008] EP 0 968 716 discloses that the systemic calcium antagonist nicardipine increases retinal and choroidal blood flow and inhibits vasoconstriction caused by ET-1, one of the biological vasoconstrictors in the eye, without increasing intraocular pressure. This literature suggests that nicardipine may be suitable for treating eye diseases associated with inadequate retinal blood flow, including ischemic optic neuropathy.

[0009] Patent applications US 2002 / 0119974 and US 2006 / 0014754 disclose that oral administration of cyclic guanosine 3',5'-monophosphate phosphodiesterase type 5 (PDE5 inhibitors) of the pyrazolo[4,3-d]pyrimidin-7-one class, particularly Sildenafil, can be used to prevent or treat eye diseases or disorders, including optic neuropathy, such as ischemic optic neuropathy and glaucomatous optic neuropathy. These documents disclose that administration of PDE5 inhibitors increases cGMP levels, which in turn increases blood flow to the optic nerve and retina. However, these documents do not provide experimental results.

[0010] Patent application US 2002 / 0168424 discloses the use of a topical eye drop mixture of a nitric oxide (NO) donor and a specific phosphodiesterase type 5 (PDE5 inhibitor) sildenafil citrate for the treatment of glaucoma or ocular hypertension, which act synergistically to reduce intraocular pressure. The authors also state that the trabecular meshwork (TM) and Schlemm's canal (SC) will relax to facilitate drainage of aqueous humor (AH), resulting in increased blood circulation to the optic nerve. However, there is no discussion or experimental proof of how these two effects are interrelated. This aspect is particularly important because the two effects occur via two independent target tissues: TM / SC versus blood vessels.

[0011] Neurobiology of Disease 121 (2019) 65-75 discloses that the PDE5 inhibitor tadalafil prevented IOP-induced retinal ganglion cell (RGC) degeneration in two mouse models of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), respectively. The results of an in vitro study showed that the RGC neuroprotective effect was independent of IOP and promoted by increased cGMP bioavailability, which resulted in improved RGC survival through modulation of pro- and anti-apoptotic pathways. Although the literature seems to suggest that RGC neuroprotection may be mediated by an additional effect of tadalafil on retinal vascular function, no experimental data have been reported showing possible effects of tadalafil on the retinal vasculature.

[0012] WO 2021 / 245192 discloses NO-releasing PDE5 inhibitors and their potential therapeutic use, inter alia, in the treatment of ocular diseases such as glaucoma, diabetic retinopathy, macular degeneration, including age-related macular degeneration, and degenerative ocular diseases associated with microangiopathy. The reported experimental data show that NO-releasing PDE5 inhibitors enhanced the accumulation of cGMP, possibly by activating soluble guanylate cyclase (cGC) and inhibiting its degradation via PDE5 inhibition. The data and the cell line used (trabecular meshwork cells) are consistent with the activity of this class of compounds on aqueous humor drainage and intraocular pressure reduction, but the efficacy of these compounds on other targets in different tissue compartments, such as blood vessels responsible for ocular blood flow regulation, is not disclosed.

[0013] British J Ophthalmology 83 (1999) 162-167 examines the effects of the NO donor isosorbide mononitrate (ISMN) on blood flow near the optic nerve head and choroid after systemic administration. The authors conclude that under these experimental conditions, ISMN increases blood flow near the optic nerve head without altering the choroidal compartment. The results of this study do not suggest that the ocular effects of systemic ISMN administration can be reproduced by topical ocular application of ISMN; the availability of ISMN and its conversion to active nitric oxide may not be equivalent to that observed after systemic treatment.

[0014] [(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 of formula (1) is a nitric oxide donating derivative of avanafil, a phosphodiesterase type 5 inhibitor.

[0015] [ka]

[0016] [(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 is also referred to herein as Compound (I).

[0017] Compound (I) is disclosed in WO 2020 / 030489 regarding NO-donating PDE5 inhibitors and their effect of reducing intraocular pressure. This document discloses the use of NO-donating PDE5 inhibitors for the treatment of eye diseases associated with elevated intraocular pressure, such as ocular hypertension and glaucoma, and for the treatment of retinopathies, such as retinopathy of prematurity, retinal vein occlusion, and diabetic macular edema. WO 2020 / 030489 does not disclose or suggest the effect of NO-donating PDE5 inhibitors on ischemic damage to the optic disc and retina, or specifically on diseases such as AION.

[0018] Journal of Ocular Pharmacology and Therapeutics, Vol. 37, 4, 215-2022, 2021, discloses that topical administration of NCX 1741, the citrate salt of Compound (I), reduces IOP in a non-human primate model of elevated intraocular pressure. This effect is caused by the combined activity of NO, which induces cGMP formation, and Avanafil, which inhibits its degradation in target tissues.

[0019] WO 2021 / 156275 discloses the use 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 in combination with a prostaglandin analogue to reduce elevated intraocular pressure. The therapeutic use of this combination is based on the complementary mode of action of the two compounds; the prostaglandin analogue reduces IOP by draining aqueous humor through the uveoscleral pathway, and the NO-donating PDE5 inhibitor induces aqueous humor drainage through the trabecular meshwork upon release of nitric oxide. This document also does not disclose or suggest the effect of NO-donating PDE5 inhibitors on markers related to ischemic damage of the optic nerve head and retina, especially for diseases such as AION.

[0020] Currently, there are no approved therapies to specifically treat anterior ischemic optic neuropathy; only off-label treatments are available. Summary of the Invention

[0021] The inventors discovered that compound (I) reduced the ophthalmic artery resistive index (OA-RI) and increased photoreceptor activity in a rabbit model of optic nerve ischemia / reperfusion injury induced by sub-Tenon injection of endothelin-1 (ET-1). Resistive index (RI) is a widely used measure of resistance to arterial blood flow; elevated ophthalmic artery RI indicates increased peripheral resistance or vasospasm, which may lead to reduced blood flow to the optic nerve and retina. ET-1 is a potent vasoconstrictor released from endothelial cells. Elevated ET-1 levels are associated with impaired ocular circulation, reduced optic nerve head blood flow, and reduced visual function. Experimental data show that compound (I) can improve ocular perfusion and retinal function, and thus compound (I) may be an effective therapeutic approach for treating anterior ischemic optic neuropathy, a disease associated with reduced or insufficient perfusion of the optic nerve head.

[0022] The present invention relates to a method of treating anterior ischemic optic neuropathy comprising administering [(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 (I)).

[0023] One embodiment of the invention provides [(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 for use in the treatment of anterior ischemic optic neuropathy in a patient in need thereof, whereby [(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 is administered to the eye.

[0024] Another embodiment of the invention provides [(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 for use in the treatment of non-arteritic anterior ischemic optic neuropathy (NAION) in a patient in need thereof, wherein 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 is administered to the eye.

[0025] Another embodiment of the present invention provides [(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 for use in the treatment of arteritic anterior ischemic optic neuropathy (AAION) in a patient in need thereof, where 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 is administered to the eye.

[0026] Compound (I) may be administered topically to the eye or by subconjunctival injection, preferably Compound (I) is applied topically to the eye.

[0027] Another embodiment of the invention provides [(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 for use in the treatment of anterior ischemic optic neuropathy in a patient in need thereof, wherein 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 is applied topically to the eye.

[0028] Another embodiment of the invention provides [(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 for use in the treatment of anterior ischemic optic neuropathy in a patient in need thereof, wherein 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 is administered by subconjunctival injection.

[0029] Another embodiment of the invention provides [(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 for use in the treatment of anterior ischemic optic neuropathy in a patient in need thereof, where [(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 is administered to the eye and the patient is receiving concomitant therapy with corticosteroids.

[0030] The method of treating anterior ischemic optic neuropathy of the present invention has several advantages: i) it is safer than oral, intravenous or intravitreal treatment with corticosteroids or anti-VEGF, as it reduces the disadvantage of encountering systemic side effects or severe adverse events due to repeated intravitreal injections, such as endophthalmitis, retinal detachment, ocular inflammation and bleeding; ii) it is non-invasive and does not require additional surgical intervention, as Compound (I) can be self-administered by patients as topical eye drops (eyewash); and iii) it is expected that this treatment strategy will improve patient compliance.

[0031] Furthermore, the ability of Compound (I) to lower intraocular pressure may gradually reverse the changes in intraocular pressure as a result of ischemia / reperfusion injury, thereby further reducing the risk of progression of AION, as well as counteracting the increase in intraocular pressure caused by corticosteroids currently used off-label in the treatment of AION.

[0032] Treatment of anterior ischemic optic neuropathy includes treatment of patients with signs or symptoms of acute arteritic and non-arteritic ischemic optic neuropathy, as well as treatment of patients after the disease has already been diagnosed to maintain or improve vision or visual fields and prevent further vision loss.

[0033] [(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 is typically administered to a person in need of treatment for the treatment of anterior ischemic optic neuropathy in an amount ranging from 5 μg / eye (0.01%, 50 μL / eye) to 5000 μg / eye (10%, 50 μL / eye), preferably in an amount ranging from 50 μg / eye (0.1%, 50 μL / eye) to 1000 μg / eye (2%, 50 μL / eye), and most preferably in an amount of 250 μg / eye (0.5%, 50 μL / eye) and 1000 μg / eye (2%, 50 μL / eye).

[0034] Compound (I) is administered as a pharmaceutical composition adapted for topical administration to the eye, or in the form of a subconjunctival injection into the eye in which Compound (I) is combined with a suitable ophthalmic vehicle.

[0035] Pharmaceutical compositions adapted for topical administration to the eye include eye drops (solutions or suspensions) or eye ointments.

[0036] Thus, the present invention also provides an ophthalmic composition comprising Compound (I) and a pharma- ceutically acceptable vehicle for use in the treatment of anterior ischemic optic nerve atrophy.

[0037] The topical ophthalmic dosage form can be prepared by mixing pharma- ceutically acceptable excipients and vehicles that are usually required for normal formulations and processing them according to conventional methods. For example, pharma- ceutically acceptable excipients used in eye drops include buffers, isotonicity agents, preservatives, surfactants, water-soluble polymers, etc. The pH of the eye drops is usually set to about 3-7, preferably 4-6. Example 1

[0038] These experiments were performed to determine the effects of 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 (Compound (I)) on ocular vascular reactivity and retinal function after topical administration in a rabbit model of optic nerve ischemia / reperfusion injury induced by sub-Tenon injection of endothelin-1 (ET-1). [(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 can be synthesized as described in Example 1 of WO 2020 / 030489.

[0039] Methods and Procedures Adult male New Zealand White (NZW) rabbits weighing 1.5-2.0 kg were used. All animals received topical administration of Compound (I) (1% w / w) or vehicle (Kolliphor® EL 5.0% w / w, Myrj™ S40 3.0% w / w, Kollisolv® PEG400 2.8% w / w, H3BO3 0.19% w / w, Na2HPO4·7H2O 0.51% w / w, EDTA 0.10% w / w, BAK 0.01% w / w, HCl 0.5N pH 6.6, purified water 100 g) twice daily for 4 consecutive weeks starting 2 weeks after the first dose of endothelin-1 (ET-1). Ischemia / reperfusion injury was induced in each animal by sub-Tenon injection (twice a week for 6 weeks) of 200 μL of 250 nM ET-1 dissolved in water using a lacrimal cannula under anesthesia with intramuscularly injected ketamine and xylazine. Ophthalmic Artery Resistive Index (OA-RI) measurements were performed using Echo Color Doppler before ET-1 treatment (baseline, time 0) and then weekly until the end of the study. Ophthalmic Artery Pourcelot Resistive Index (OA-RI) was calculated using the following formula: ((OA-PSV)-(OA-EDV)) / (OA-PSV), where (OA-PSV) and (OA-EDV) refer to Ophthalmic Artery Peak Systolic Velocity and Ophthalmic Artery End Diastolic Velocity, respectively. Electroretinogram (ERG) recordings were performed under topical anesthesia. Eyes were dilated with topical application of tropicamide 1% and, if necessary, dark-adapted for at least 2 hours before ERG recording. ERG recordings were performed using standard contact lens corneal electrodes. Specifically, dark-adapted 0.01 ERGs (predominantly rod-based responses), dark-adapted 3.0 ERGs (mixed rod / cone responses), and light-adapted 3.0 ERGs (predominantly cone-based responses) were recorded. Measurements were performed before the first dose of ET-1 (baseline, time 0), at the end of week 2 (before the first dose of vehicle or Compound (I) on the first day), and at the end of week 6.

[0040] result Ophthalmic artery resistance index (OA-RI) The resistive index (RI) is a measure of the resistance to arterial blood flow, and elevated RI indicates increased peripheral resistance or vasospasm. The OA-RI before endothelin-1 (ET-1) administration was 0.35±0.09 and 0.40±0.08 in animals randomized to vehicle or compound (I) treatment, respectively (Table 1). ET-1 administered twice weekly for 2 weeks increased the OA-RI. In vehicle-treated animals, the OA-RI continued to increase over the next 4 weeks. In animals treated with compound (I), the OA-RI showed a decrease (0.43±0.09 and 0.43±0.04 at weeks 4 and 6, respectively) (Table 1), which may be the result of a compensatory effect of compound (I) on the effect of ET-1. Data are presented as mean±SD.

[0041] [Table 1]

[0042] Electroretinogram (ERG) ERG is a test that quantitatively measures central retinal function. ET-1 treatment resulted in a decrease in retinal function 2 weeks after ET-1 injection, however eyes treated with Compound (I) for 4 weeks showed less impairment in ERG wave amplitude than vehicle-treated eyes.

[0043] [Table 2]

[0044] In summary, the results show that compound (I) improves ocular vascular reactivity, i.e., ophthalmic artery resistive index (OA-RI), and retinal function, i.e., ERG, upon repeated topical ocular administration in a well-defined model of optic nerve ischemia / reperfusion injury induced by sub-Tenon injection of ET-1 in rabbits. These data provide evidence that ocular perfusion and retinal cell physiology are improved following administration of Compound (I), which may ultimately reverse optic nerve degeneration and retinal cell dysfunction as a result of repeated ischemic lesions. Example 2

[0045] This study evaluated the ocular hemodynamic effects of repeated topical ocular administration of Compound (I) compared with the desnitro derivative of Compound (I), Compound (Ia), administered at equimolar doses in rabbits with endothelin-1 (ET-1)-induced ischemia / reperfusion injury of the optic nerve head and retina.

[0046] Test items: - 6-(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 (compound (I))

[0047] [ka]

[0048] - 6-hydroxyhexanoic acid [(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl (compound (Ia))

[0049] [ka]

[0050] Methods: ET-1 was injected adjacent to the optic nerve head twice weekly for 6 weeks. Animals received Compound (I) (1% twice daily, 6 days per week), Compound (Ia) (0.93%, equimolar to 1% of Compound (I)) or vehicle from the third week until the end of ET-1 treatment. Functional endpoint was ophthalmic artery resistive index (OA-RI) measured using echo color Doppler.

[0051] Results and Conclusions The results are reported in Table 3 and show that: ET-1 increased OA-RI over time. Treatment with compound (I) restored baseline OA-RI by week 6. Conversely, compound (Ia) (the desnitro derivative) administered at equimolar amounts to compound (I) had no effect. Compound (I) improves ocular perfusion following ET-1-induced ischemia / reperfusion injury of the optic nerve head and retina. These effects appear to be largely NO-dependent, as compound (Ia), lacking the NO-donor moiety, showed only marginal activity. These data indicate that compound (I) has potential for the treatment of anterior ischemic optic neuropathy, where increased angiogenesis and vascular permeability are key pathophysiological features of disease progression.

[0052] [Table 3]

Claims

1. A pharmaceutical composition 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 for use in the treatment of anterior ischemic optic neuropathy in a patient in need thereof, wherein 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 is administered topically to the eye or by subconjunctival injection.

2. 2. A pharmaceutical 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 for use in the treatment of claim 1, wherein the anterior ischemic optic neuropathy is non-arteritic anterior ischemic optic neuropathy.

3. 2. A pharmaceutical 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 for use in the treatment of claim 1, wherein the anterior ischemic optic neuropathy is arteritic anterior ischemic optic neuropathy.

4. The pharmaceutical 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 for use in the treatment of any one of claims 1 to 3, wherein 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 is administered as an ophthalmic pharmaceutical composition.

5. 4. A pharmaceutical 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 for use in the treatment of any one of claims 1 to 3, wherein the patient is receiving concomitant therapy with corticosteroids.

6. 1. Use 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 for the manufacture of a medicament for the treatment of anterior ischemic optic neuropathy, wherein the medicament is administered topically to the eye or by subconjunctival injection.

7. An ophthalmic composition for use in treating anterior ischemic optic neuropathy, 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 and a pharmaceutically acceptable vehicle, the composition being administered topically to the eye or by subconjunctival injection.