Ophthalmic compositions containing a nitric oxide donor

Abstract

The present invention relates to compositions comprising a 4-nitrooxybutan-1-ol alkyl ester as nitric oxide donor. More specifically, the invention relates to compositions comprising 4-nitrooxybutan-1-ol alkyl ester as a nitric oxide donor and an ophthalmic drug, useful in controlling elevated intraocular pressure associated with glaucoma or ocular hypertension associated with other diseases or conditions. The invention is also directed to methods of controlling intraocular pressure utilizing said compositions.

Claims

1. A compositions comprising (A) a nitric oxide donor of formula (I) or stereoisomers thereof:
RC(O)O(CH.sub.2).sub.4ONO.sub.2 (I) wherein R is a linear or branched (C.sub.3-C.sub.5)-alkyl chain, and (B) an ophthalmic drug selected from one of the following groups: alpha adrenergic agonists, beta blockers, carbonic anhydrase inhibitors, prostaglandin analogs, cholinergic agonists, non-steroidal anti-inflammatory and steroidal anti-inflammatory drugs.

2. A composition according to claim 1 wherein the nitric oxide donor of formula (I) is
CH.sub.3(CH.sub.2).sub.2C(O)O(CH.sub.2).sub.4ONO.sub.2 (Ia).

3. A composition according to claim 2 wherein the ophthalmic drug is selected from bimatoprost, latanoprost, travoprost, tafluprost, unoprostone isopropyl, apraclonidine, bromonidine, timolol, levobunolol, dorzolamide or brinzolamide.

4. A composition according to claim 1 wherein the carbonic anhydrase inhibitor is selected from dorzolamide, brinzolamide.

5. A composition according to claim 1 wherein the beta blocker selected from timolol, carteolol, betaxolol, levobunolol or metipranolol.

6. A composition according to claim 1 wherein the alpha-adrenergic agonist is selected from brimonidine, apraclonidine, epinephrine or dipivefrin.

7. A composition according to claim 1 wherein the prostaglandin analogue is selected from bimatoprost, latanoprost, travoprost, unoprostone isopropyl or tafluprost.

8. A composition according to claim 1 wherein the cholinergic agonist selected from pilocarpin, carbacol or echothiophate.

9. A composition according to claim 1 wherein the non-steroidal anti-inflammatory drug is selected from bromfenac, flurbiprofen, naproxen or ketoprofen.

10. A composition according to claim 1 wherein the steroidal anti-inflammatory drug is selected from dexamethsone, fluocinolone acetonide, triamcinolone acetonide, budesonide or prednisolone.

11. Pharmaceutical formulation comprising a composition according to claim 1 and at least an ophthalmically acceptable excipient.

12. A pharmaceutical formulation comprising a nitric oxide donor of formula (I) or stereoisomers thereof:
RC(O)O(CH.sub.2).sub.4ONO.sub.2 (I) wherein R is a linear or branched (C.sub.3-C.sub.5)-alkyl chain, and at least an ophthalmically acceptable excipient and/or ophthalmically acceptable vehicle.

13. Pharmaceutical formulation comprising the nitric oxide donor of formula (Ia) and at least an ophthalmically acceptable excipient and/or ophthalmically acceptable vehicle.

14. A method of treating elevated intraocular pressure associated with glaucoma comprising administering to an eye of a subject in need thereof a composition according to claim 1.

15. A method of treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma, neovascular glaucoma, and/or ocular hypertension comprising administering to an eye of a subject in need thereof a composition according to claim 1.

16. A method of treating high intraocular pressure resulting from orbital edema, ischemia, intraocular inflammation, and/or pupillary block comprising administering to an eye of a subject in need thereof a composition according to claim 1.

17. A method of treating age related macular degeneration, diabetic retinopathy, retinal vein occlusion, macular degeneration, inflammatory retinal disease, and/or uveitis comprising administering to an eye of a subject in need thereof a composition according to claim 9.

18. A method of treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma, neovascular glaucoma, and/or ocular hypertension comprising administering to an eye of a subject in need thereof a nitric oxide donor of formula (Ia)
CH.sub.3(CH.sub.2).sub.2C(O)O(CH.sub.2).sub.4ONO.sub.2 (Ia).

19. A method of treating high intraocular pressure resulting from orbital edema, ischemia intraocular inflammation, and/or pupillary block comprising administering to an eye of a subject in need thereof a nitric oxide donor of formula (Ia)
CH.sub.3(CH.sub.2).sub.2C(O)O(CH.sub.2).sub.4ONO.sub.2 (Ia).

20. A method of treating age related macular degeneration, diabetic retinopathy, retinal vein occlusion, macular degeneration, inflammatory retinal disease, and/or uveitis comprising administering to an eye of a subject in need thereof a nitric oxide donor of formula (Ia)
CH.sub.3(CH.sub.2).sub.2C(O)O(CH.sub.2).sub.4ONO.sub.2 (Ia).

Description

EXAMPLE 1

Preparation of 4-Nitrooxybutan-1-Ol Butyrate (Compound (Ia))

Step a) Preparation of 1,4-Butandiol Monobutyrate

(1) Toluenesulfonic acid monohydrate (2.12 g, 11.1 mmol), butyric acid (368 mL, 4.00 mol) 1,4-butanediol (1067 mL, 12.00 mol) and n-octane (750 mL) were mixed in a 2.5 L reaction vessel and the resulting emulsion was stirred vigorously at reflux for 1 h during which the water formed was removed by azeotropic distillation of the n-octane-water azeotrope. The mixture was allowed to cool to room temperature and the octane-layer was separated from the butanediol-layer containing the product and the latter phase was extracted four times with petrol ether 80/110 (300 mL for each extraction). The so obtained butanediol-layer was extracted three times with dichloromethane (500 mL for each extraction) and after phase separation the dichloromethane-layers were combined and washed four times with water (200 mL for each extraction). Removal of the dichloromethane by distillation and drying of the residue using a jacket temperature of 70 C. gave 499 g (78%) of the title compound having a chromatographic purity of 99.1% (gas chromatography) and a water content of 0.27%. This was used without further treatment in the synthesis of 4-nitrooxybutan-1-ol butyrate.

Step b) Preparation of 4-Nitrooxybutan-1-Ol Butyrate (Compound (Ia))

(2) Sulfuric acid (96%, 285 mL, 5.13 mol) and dichloromethane (100 mL) were mixed and the mixture was cooled with stirring to 15 C. Nitric acid (98-99%, 2.9 mL, 0.069 mol) was added to the mixture with stirring. Another portion of nitric acid (98-99%, 26.0 mL, 0.618 mol) was then added in parallel with the above obtained 1,4-butandiol monobutyrate (103 mL, 0.624 mol) at such a rate that the inner temperature was maintained below 5 C. which took 90 min. An inner temperature of +5 C. must not be exceeded for stability reasons. Directly after the addition was finished the entire crude mixture was poured into a mixture of ice and water (2.25 kg) with efficient stirring keeping the inner temperature below +5 C. Stirring was switched off and the phases were allowed to separate. The dichloromethane-layer was saved and the aqueous layer was extracted with dichloromethane (400 mL). Phase separation was followed by washing of the combined dichloromethane-layers with 8% aqueous sodium bicarbonate solution (150 mL) and water (150 mL-portions) to pH 7-8. Removal of the dichloromethane by vacuum distillation at a jacket temperature below +40 C. (important for thermal safety reasons) gave 98.5 g (73% yield) of the title compound as a pale yellow oil. The purity according to GC was 95%.

(3) .sup.1H NMR (CDCl.sub.3) 4.50 (t, J=6 Hz, 2H), 4.13 (t, J=6 Hz, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.72-1.92 (m, 4H), 1.67 (sext, J=7.4 Hz, 2H), 4.50 (t, J=7.4 Hz, 3H);

(4) .sup.13C NMR (CDCl.sub.3) 173.9, 73.1, 63.6, 36.4, 25.3, 24.0, 18.8, 14.0;

(5) IR 1732 (CO), 1623, 1278 cm.sup.1.

EXAMPLE 2

Intraocular Pressure (IOP) Lowering Activity in Hypertonic Saline-Induced IOP Increase in Rabbits

(6) The Intraocular pressure (TOP) lowering activity of compound (Ia) (Example 1) was assessed in an animal model of elevated IOP.

(7) Adults male New Zealand White rabbits weighting 1.8-2.0 Kg were used in the experiments.

(8) IOP was measured using a Tono-Pen XL prior to hypertonic saline injection (basal) and at 30, 60, 120 and 240 min thereafter. Vehicle (5% cremophor-EL; 0.3% DMSO; 0.2 mg/ml bac in PBS pH 6.0,) or compound (Ia) dissolved in the vehicle at different concentrations (0.1%, 0.3% and 1%) was instilled as eye drops immediately after hypertonic saline injection. Eyes were randomly assigned to different treatment groups. Vehicle or compound (Ia) was directly instilled into the conjunctiva pocket at the desired doses. One drop of 0.4% oxybuprocaine hydrochloride (Novesine, Sandoz) was instilled in each eye immediately before each set of pressure measurements.

(9) Results are reported in Table in which the ocular hypotensive activity of compound (Ia) at different is expressed as IOP change (at 60 and 120 minutes following topical administration) versus vehicle and versus IOP at basal before hypertonic saline injection.

(10) TABLE-US-00001 IOP change Treatment 60 min 120 min Compound (Ia) 1% 21.1 4.5 15.1 2.3 Compound (Ia) 0.3% 16.5 3.8 9 2.1 Compound (Ia) 0.1% 10.3 0.3 5 1.8