HK1241269A1

HK1241269A1 - Combinations of prostaglandins and nitric oxide donors

Info

Publication number: HK1241269A1
Application number: HK18100619.1A
Authority: HK
Inventors: Nicoletta Almirante; Laura Storoni; Elena Bastia; Francesco Impagnatiello
Original assignee: Nicox S.A.
Priority date: 2014-11-19
Filing date: 2015-11-17
Publication date: 2018-06-08

Description

Combination of prostanoids and nitric oxide donor

Technical Field

The present invention relates to a composition comprising a nitric oxide releasing isomannide derivative and prostaglandin F_2αAnd the like. More specifically, the present invention discloses methods for reducing glaucomaOr other intraocular pressure associated with ocular diseases.

Background

Glaucoma, including both hypertensive and normotensive glaucoma, is an ocular disease in which the visual field is gradually lost due to irreversible damage to the optic nerve, which if treated improperly may lead to blindness or significant loss of vision.

Glaucoma treatment of the prior art includes lowering intraocular pressure by administering drugs that reduce aqueous humor production or increase fluid drainage in the eye, such as beta adrenergic blockers, alpha-agonists, cholinergic agents, carbonic anhydrase inhibitors, and prostaglandin analogs.

Among these drugs, prostaglandin analogs help to drain aqueous humor from the episclera, thereby lowering intraocular pressure, and are therefore commonly used in the treatment of glaucoma. However, prostaglandin analogs such as bimatoprost, latanoprost, travoprost, tafluprost and unoprostone isopropyl (unoprostone isopropyl) may produce ocular side effects such as eye irritation, conjunctival hyperkalemia, iritis, uveitis, macular edema and increased iris pigmentation (Martindale, thirty-third edition, page 1445) in therapeutically effective amounts.

In the treatment of glaucoma and ocular hypertension, drugs having an intraocular pressure-lowering effect may be used in combination to enhance the intraocular pressure-lowering effect. For example, EP 0286903 discloses the use of a combination of a prostaglandin and a beta-adrenergic blocker, and US2013/0116254 discloses the use of a combination of the intraocular blood lowering drugs bimatoprost, brimonidine and timolol.

Further, WO 2013/060673, WO2014/170264 and WO2014/063923 disclose the use of quinone based nitric oxide donors alone and in combination with prostaglandin analogues for the treatment of glaucoma and intraocular pressure. Quinone based nitric oxide donors for ophthalmic use are disclosed. However, this patent application does not provide evidence for the effects of the combined use of quinone based nitric oxide donors and prostaglandin analogues.

EP 2238143B discloses nitric oxide releasing isohexene (isohexide) derivatives. These compounds have been disclosed as useful in the treatment of cardiovascular disease, hypertension, inflammation, pain, respiratory disease, vascular disease, renal disease and other pathological conditions, including glaucoma and ocular hypertension. However, the patent does not provide evidence for the effect of the combination of nitric oxide releasing isohexene derivatives and prostaglandin analogues.

US 7,816,399 discloses the use of a mixture of latanoprost and a Nitric Oxide (NO) donor in the treatment or prevention of ocular hypertension or glaucoma.

The patent discloses that the combination of latanoprost with niproplol or sodium nitroprusside increases the effect of reducing eye tension compared to the compounds used individually.

Disclosure of Invention

The inventors have unexpectedly found that nitric oxide releasing isomannide derivatives and prostaglandin F, relative to either of the two compounds administered separately at the same dose, respectively_2αCombination administration of the analogs can result in a greater reduction in intraocular pressure and a longer reduction in intraocular pressure.

Nitric oxide releasing isomannide derivatives and prostaglandin F_2αThe synergistic effect on intraocular pressure reduction following combination administration of the analogs enables reduction of prostaglandin F_2αThe analog dosage, thereby reducing or eliminating the side effects typically associated with topical application of prostaglandin analogs.

Thus, these combinations are useful as therapeutic agents for the treatment of glaucoma and ocular hypertension by lowering intraocular pressure.

Accordingly, the present invention provides effective ophthalmic compositions for the treatment and/or prevention of glaucoma and ocular hypertension with reduced side effects, thereby improving patient compliance.

The present invention relates to a composition comprising:

(i) a nitric oxide releasing isomannide derivative of the following formula (I) or a stereoisomer thereof:

wherein:

x is-CO-or-COO-;

y is

-straight or branched C₁-C₁₀Alkyl chain, 1 or 2-ONO₂Is substituted, or

-C₁-C₆Alkylene oxy-C₁-C₅Alkyl, in which the alkyl group is substituted by 1 or 2-ONO₂And (4) substituting the group.

(ii) Prostaglandin F_2αThe analogue is selected from latanoprost, bimatoprost, travoprost, tafluprost or unoprostone isopropyl ester, preferably prostaglandin F_2αThe analog is travoprost or bimatoprost.

A preferred embodiment of the present invention provides a composition comprising:

(i) nitric oxide releasing isomannide derivatives of formula (I) selected from:

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 4- (nitrooxy) butanoate (Compound (1))

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 6- (nitrooxy) hexanoate (Compound (2))

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 5, 6-di (nitrooxy) hexanoate (Compound (3))

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 3- (2, 3-di (nitrooxy) propoxy) propionate (Compound (4))

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 4, 5-di (nitrooxy) hexanoate (Compound (5))

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 4- (nitrooxy) butyl carbonate (Compound (6))

-4, 5-bis (nitrooxy) hexyl (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-ylcarbonate (Compound (7))

-5, 6-bis (nitrooxy) hexyl (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-ylcarbonate (Compound (8))

-2- (2, 3-bis (nitrooxy) propoxy) ethyl (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-ylcarbonate (Compound (9))

-3, 3-dimethyl-5, 6-di (nitrooxy) hexyl (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-ylcarbonate (Compound (10))

- (3R,3aR,6R,6aR) -6-Hydroxyhexahydrofuro [3,2-b ] furan-3-yl 6- (nitrooxy) hexyl carbonate (Compound (11))

- (S) - ((3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl) 5, 6-di (nitrooxy) hexanoate (Compound (12))

And a stereoisomer thereof, and a process for the preparation of,

(ii) prostate glandElemental F_2αThe analog is selected from latanoprost, bimatoprost, travoprost, tafluprost and unoprostone isopropyl.

Another embodiment of the present invention provides a composition comprising:

(i) nitric oxide releasing isomannide derivatives of formula (I) selected from:

And stereoisomers thereof

(ii) Prostaglandin F_2αThe analog is travoprost or bimatoprost.

Another embodiment of the present invention provides a composition comprising:

(i) nitric oxide releasing isomannide derivatives of formula (I) are

And

(ii) prostaglandin F_2αAn analog selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, and unoprostone isopropyl ester.

Another embodiment of the present invention provides a composition comprising:

(i) nitric oxide releasing isomannide derivatives of formula (I) are

And

(ii) prostaglandin F_2αThe analog is travoprost.

Another embodiment of the present invention provides a composition comprising:

(i) nitric oxide releasing isomannide derivatives of formula (I) are

And

(ii) prostaglandin F_2αThe analog is bimatoprost.

Nitric oxide releasing isomannide derivatives of formula (I) and prostaglandin F_2αThe weight ratio of the analogs is generally 1:1 to 10000:1, preferably 5:1 to 1000: 1.

The present invention also provides a nitric oxide releasing isomannide derivative comprising formula (I) as defined above and prostaglandin F_2αAnalog compositions for treating glaucoma, ocular hypertension and for lowering intraocular pressure associated with ocular disorders.

Another embodiment of the present invention provides an ophthalmic pharmaceutical formulation comprising at least one nitric oxide releasing isomannide derivative of formula (I) as defined above, prostaglandin F_2αAn analogue and at least one ophthalmic excipient.

Ophthalmic excipients may include, for example, buffers, tonicity agents, chelating agents, viscosity enhancing agents, solubilizing agents, surfactants, antioxidants, preservatives, or ophthalmic carriers.

The ophthalmic pharmaceutical preparation of the present invention may be in the form of a solution, a suspension, an emulsion, a dispersion, a topical eye drop or a gel tear.

Typically, the ophthalmic pharmaceutical formulations of the present invention comprise a compound of formula (I) in an amount of about 0.001 to about 10 weight percent (w/v%) and prostaglandin F in an amount of about 0.0001 to about 0.2 w/v%_2αAnd the like.

The nitric oxide-releasing isomannide derivatives of formula (I) are preferably used in amounts of about 0.005 to about 2.0 w/v%, with amounts of about 0.01 to about 0.5 w/v% being particularly preferred. Prostaglandin F is preferably used_2αThe amount of analog is between about 0.0001 and about 0.1 w/v%, depending on the potency of the prostaglandin.

Nitric oxide releasing isomannide derivatives of formula (I) and prostaglandin F of the present invention_2αThe combination of analogs can be prepared as a dosage form comprising the effective amounts of the various compounds in admixture with each other in suitable mixing ratios; or as a kit comprising an effective amount of each compound for each administration, either simultaneously or separately at certain intervals.

Nitric oxide releasing isomannide derivatives of formula (I) are described in EP 2238143B; the patent discloses the structure, preparation and physical properties of these compounds.

Prostaglandin F for use in compositions of the invention_2αAnalogs are known as drugs for the treatment of glaucoma and are:

latanoprost is 5-heptenoic acid, 7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- [ (3R) -3-hydroxy-5-phenylpentyl ] cyclopentyl ] -, 1-methylethyl ester, (5Z) -;

bimatoprost is 5-heptenamide, 7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- [ (1E,3S) -3-hydroxy-5-phenyl-1-penten-1-yl ] cyclopentyl ] -N-ethyl-, (5Z) -;

travoprost is 5-heptenoic acid, 7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- [ (1E,3R) -3-hydroxy-4- [3- (trifluoromethyl) phenoxy ] -1-buten-1-yl ] cyclopentyl ] -, 1-methylethyl ester, (5Z) -;

tafluprost is 5-heptenoic acid, 7- [ (1R,2R,3R,5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -3, 5-dihydroxycyclopentyl ] -, 1-methylethyl ester, (5Z) -;

unoprostone isopropyl ester is 5-heptenoic acid, 7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- (3-oxodecyl) cyclopentyl ] -, 1-methylethyl ester, (5Z) -.

Latanoprost, bimatoprost, travoprost, tafluprost or unoprostone isopropyl ester are all commercially available.

Detailed Description

Examples

Example 1

Activity for lowering intraocular pressure (IOP) in normotensive New Zealand White (NZW) rabbits

The activity of a combination of compound (12) (0.1%) and travoprost (0.004%) on the reduction of intraocular pressure (IOP) was evaluated in normotensive rabbits.

Adult male NZW rabbits weighing 1.8-2.0 kg were used in the experiment.

Barometer 30CLASSIC was used before (basal) and at different time points (30, 60, 120, 180, 240 and 300 minutes)^TMIOP was measured. Travoprost (0.004%) or vehicle (5% polymeric) was topically administered 5 minutes before compound (12) (0.1%) or vehicle (same as described below) was administered as eye drops into a conjunctival bag (conjuctiva pocket)Oxyethylenated castor oil (creppphor) -EL; 0.3% DMSO; PBS solution of BAC 0.2mg/ml pH 6.0). Eyes were randomly assigned to different treatment groups. Prior to each tonometric set, a drop of 0.4% tetracaine hydrochloride (Novesine, Sandoz) was applied to each eye.

Results as shown in the table, the intraocular pressure lowering activity of the combination of compound (12) and travoprost was expressed as changes in IOP (30, 60, 120 and 300 minutes after topical administration) relative to vehicle and relative to basal IOP (mean ± standard error).

The combination of compound (12) (0.1%) and travoprost (0.004%) resulted in increased IOP lowering activity compared to compound (12) (0.1%) or travoprost (0.004%) administered alone. Furthermore, the time-limit of action of the combination is prolonged compared to the administration of compound (12) alone (0.1%) or travoprost alone (0.004%).

The above results indicate that the combination of the nitric oxide releasing isomannide derivative of formula (I) and prostaglandin F_2αThe analog may result in an increased intraocular pressure-reducing effect and an increased duration of intraocular pressure-reducing effect. The ocular pressure lowering effect is greater than simple addition, particularly for a longer duration.

Example 2

Activity for lowering intraocular pressure (IOP) of New Zealand White (NZW) rabbits with ocular hypertension

The intraocular pressure (IOP) lowering activity of compound (12) (0.3%) in combination with travoprost (0.004%) was evaluated in ocular hypertension rabbits.

Adult male NZW rabbits weighing 1.8-2.0 Kg were used in the experiment.

0.1ml of hypertonic saline (5%) was injected into the NZW rabbitIn the vitreous humor of the eye. At various time points (30, 60, 120 and 240 minutes) after hypertonic saline injection and before topical administration (basal), the use of the Tono-Pen AVIAIOP was measured.

Travoprost (0.004%) or vehicle (5% cremophor EL-EL; 0.3% DMSO; 0.2mg/ml BAC in PBS at pH 6.0) was topically administered 15 minutes prior to hypertonic saline injection.

Immediately after hypertonic saline injection, compound (12) (0.3%) or vehicle (5% cremophor EL-EL; 0.3% DMSO; 0.2mg/ml BAC in PBS at pH 6.0) was administered topically. The eyes were randomly assigned to different treatment groups.

Immediately prior to each tonometry, a drop of 0.4% tetracaine hydrochloride (Novesine, Sandoz) was applied to each eye.

Table 2 lists travoprost, compound (12), and the lowering effect of compound (12) in combination with travoprost on intraocular pressure (30, 60, 120, and 300 minutes after topical administration).

The results reported in table 2 are expressed as the change in IOP from vehicle and from basal IOP (30, 60, 120 and 300 minutes after topical administration) (mean ± standard error).

The results show that the combination of compound (12) and travoprost is capable of increasing activity on IOP reduction compared to compound (12) or travoprostone administered alone, and that the combination of compound (12) and travoprost is capable of inducing an enhanced and sustained intraocular pressure reduction effect at a longer time point.

Claims

1. A composition, comprising:

wherein:

x is-CO-or-COO-;

y is

-straight or branched C₁-C₁₀Alkyl chain, 1 or 2-ONO₂Substitution; or

-C₁-C₆Alkylene oxy-C₁-C₅Alkyl, in which the alkyl group is substituted by 1 or 2-ONO₂And (4) substitution.

(ii) A prostaglandin F2 alpha analog selected from latanoprost, bimatoprost, travoprost, tafluprost or unoprostone isopropyl ester.

2. The composition of claim 1, wherein said prostaglandin F2 alpha analog is travoprost or bimatoprost.

3. The composition of claim 1 or 2, wherein

(i) Nitric oxide releasing isomannide derivatives of formula (I) are selected from:

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 4- (nitrooxy) butanoate (compound (1)),

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 6- (nitrooxy) hexanoate (Compound (2)),

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 5, 6-di (nitrooxy) hexanoate (Compound (3)),

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 3- (2, 3-di (nitrooxy) propoxy) propionate (compound (4)),

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 4, 5-di (nitrooxy) hexanoate (Compound (5)),

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 4- (nitrooxy) butyl carbonate (Compound (6)),

-4, 5-di (nitrooxy) hexyl (3R,3aR,6R,6aR) -6- [3,2-b ] furan-3-yl carbonate (compound (7)),

-2- (2, 3-bis (nitrooxy) propoxy) ethyl (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-ylcarbonate (Compound (9)),

-3, 3-dimethyl-5, 6-di (nitrooxy) hexyl (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-ylcarbonate (Compound (10)),

- (3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl 6- (nitrooxy) hexyl carbonate (Compound (11)),

- (S) - ((3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl) 5, 6-di (nitrooxy) hexanoate (Compound (12)),

and stereoisomers thereof.

4. The composition of claim 1, wherein:

(i) the nitric oxide-releasing isomannide derivative of formula (I) is- (S) - ((3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl) 5, 6-di (nitrooxy) hexanoate (compound (12)).

5. The composition of claim 1, wherein:

(i) the nitric oxide-releasing isomannide derivative of formula (I) is- (S) - ((3R,3aR,6R,6aR) -6-hydroxyhexahydrofuro [3,2-b ] furan-3-yl) 5, 6-di (nitrooxy) hexanoate (Compound (12)),

(ii) the prostaglandin F_2αThe analog is travoprost.

6. The composition of claim 1, wherein:

(ii) selected prostaglandin F_2αThe analog is bimatoprost.

7. The composition of any one of claims 1-6, wherein the nitric oxide releasing isomannide derivative of formula (I) is in combination with prostaglandin F_2αLikeThe weight ratio of the materials is 1: 1-10000: 1.

8. The composition of claim 7, wherein the nitric oxide releasing isomannide derivative of formula (I) is in combination with prostaglandin F_2αThe weight ratio of the analogues is 5: 1-1000: 1.

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

10. The composition of any one of claims 1-8 for use in the treatment of glaucoma and ocular hypertension.

11. The composition of any one of claims 1 to 8 for use in reducing intraocular pressure associated with an ocular disease.

12. An ophthalmic pharmaceutical formulation comprising the composition of any one of claims 1-8 and at least one ophthalmic excipient.

13. A kit, the kit comprising: nitric oxide releasing isomannide derivatives of formula (I) according to claim 1 and prostaglandin F according to claim 1_2αThe like, for the simultaneous or separate administration of the compounds at certain time intervals.