MXPA00005853A - Use of 3-benzoyl-phenylacetic acids, esters, or amides for treatment of glc1a glaucoma - Google Patents

Abstract

Compositions of 3-benzoylphenylacetic acid derivatives for treating GLC1A glaucoma and methods for their use are disclosed.

Description

USE OF O. AMIDAS ESTERS OF 3-BENZOYL-PHENYLACTIC ACID FOR THE TREATMENT OF GLAÜCOMA GLC1A.

This invention is directed towards the use of certain non-steroidal cyclooxygenase inhibitors for treating glaucoma or ocular hypertension resulting from the altered expression of the GLC1A gene (from the GLC1A aguí or lg glaucoma) in an individual.

Background of the Invention Glaucomas are a heterogeneous group of optic neuropathies characterized by the widening of the optic nerve head, thinning of the fibrous layer of the retinoic nerve due to loss of retinoic ganglion cells, and specific patonomonic changes in the visual field.

Elevated intraocular pressure (IOP) is a very important risk factor for the development of the most common forms of glaucoma (Sommer A, et al., "" Relatioship Between Intraocular Pressure and Primary Open Angle Glaucoma Among White and Black Americans " , Arch. Ophthalmol., 109: 1090-1095 (1991).) REF 120928 A family history of glaucoma is also an important risk factor for the development of glaucoma, it seems that a significant portion of glaucoma is inherited (or at least the risk for the development of glaucoma is inherited) aungue it is often difficult to clearly establish hereditary patterns for most glaucomas because the disease occurs late in life and the clinical manifestations of the disease progress slowly. Of these problems, a number of families with inherited form of glaucoma have been identified and these families have been used to represent a variety of glaucoma genes (Sheffield, et al., Gentic Lankage of Familial Open Angle Glaucoma to Chromosome Iq2l-q31", Nature Genetics, 4: 47-50 (1993), Sarfarazi, et al," "" Asignment of a Locus (GLC3A) for Primary Congenital Glaucoma (Buphthalmos) to 2p21 and Evidence for Genetic Heterogeneity ", Genomics, 30: 171-177 (1995); Akarsu, and collaborators, "A Second Locus (GLC3B) for Primary Congenital Glaucoma (Buphthalmos) Maps to the lp36 Region ", Human Molecular Genetics, 5 (8): 1199-1203 (1996); Stoilova, et al., "Localization of a Locus (GLC1B) for Adult-Onset Primary Open Angle Glaucoma to the 2nd Region", Genomics, 36: 142-150 (1996); Wirtz et al., "Mapping Gene for Adult-Onset Primary Open- ng Glaucoma to Chromoso e 3q", Am. J. Hum. Genet., 60: 296-304 (1997); Andersen, and collaborators, "- ^ A Gene Responsible for the Pigment Dispersion Syndrome Maps to Chromosome 7g35-g36", Arch. Ophthalmol. , 115: 384-388 (1997). The first glaucoma gene represented (GLC1A) was from a large family with inherited autosomal dominant juvenile glaucoma (JG) This disease is characterized by an early onset of the disease (at the age from adolescence to the beginning of the 20s), relatively high lOPs, and general resistance to conventional pharmacological therapy for IOP attenuation. The GLC1A gene was represented by positional cloning and Ig22-g25 chromosome binding analysis (Sheffield et al., Id, and a number of other groups have confirmed lg localization of this juvenile glaucoma gene (Richards, et al., " Mapping of a Gene for Autosomal Dominant Juvenile- Onset Open-Angle Glaucoma to Chromosome lg, "Am. J. Hum. Genet., 54: 62-70 (1994); Morissette, et al.," "Common Gene for Juvenile and Adult - Onset Primary Open-Angle Glaucoma Confined on Chromosome Ig ", Am. J.

Hum. Genet , 56: 1431-1442 (1995); iggs, and collaborators, "" Genetic Linkage of Autosomal Dominant Juvenile Glaucoma to Ig21-g31 in Three Affected Pedigrees, "Genomics, 21: 299-303 (1994); Meyer et al.," Age-Dependent Penetrance and Mapping of the Locus for Juvenile and Early-Onset Open-Angle Glaucoma on Chromosome lg (GLC1A) in a French Family ", Hum. Genet., 98: 567-571 (1996); Graff, et al.," Confirmation of Linkage to lq2l-3l in a Danish Autosomal Dominant Juvenile-Onset Glaucoma Family and Evidence of Genetic Heterogeneity, "Hum. Genet., 96: 285-289 (1995) .Glaucoma due to the GLC1A gene is often referred to as glaucoma lq.

The GLC1A gene was identified as encoding a 57 kD protein expressed in the trabecular (TM) system (Stone, et al., "Identification of a Gene That Causes Primary Open Angle Glaucoma", Science, 275: 668-670 (1997 The expression of the GLC1A gene, and the encoded protein TM, is upregulated by glaucocorticoids (Polansky, et al., "" In Vitro Correlates of Glucscorticoid Effects on Intraocular Pressure ", Glaucoma Update IV (1991), and Polansky, et al. "Cellular Pharmacology and Molecular Biology of the Trabecular Meshwork Inducible Glucocorticoid Reeponse Gene Product", Ophthalmologica, 211: 126-139 (1997) This TM protein is also known as TIGR (glucocorticoid-inducible trabecular system response) (Polansky, Id) The glucocorticoid induction of this protein has been suggested to be involved in the generation of ocular hypertension and glucocorticoid-induced glaucoma (Polansky, Id). The GLC1A gene is expressed in other ocular tissues such as the ciliary epithelium (Ortego, et al., "Cloning and Characterization of Substracted cDNAs from a Human Ciliary Body Library Encoding TIGR, a Protein Involved in Juvenile Open Angle Glaucoma with Homology to Myosin and Olfatomedin", FEBS Letters, 413: 349-353 (1997) and the retina (Rabota, et al., "A Novel Myosin-like Protein (Myocilin) Expressed in the Connecting Cilium of the Photoreceptor; Molecular Cloning, Tissue Expression, and Chromosomal Mapping ", Geno ics, 41: 360-369 (1997) .The gene is mentioned by several names including GLC1A (Sheffield, supra; Sunden, et al.," "Fine Mapping of theAutosomal Dominant Juvenile Open Angle Glaucoma (GLC1A) Region and Evaluation of Candidate Genes '', Genome Research, 6: 862- 869 (1996), Stone, et al, supra, TIGR (Polansky ssupra, Ortego, supra, and myocillin (kubota, supra ), GLC1A mutations are not only responsible for juvenile glaucoma, but also a significant subpopulation of primary open-angle glaucoma that occurs in adults (Stone, et al., supra; Adam, et al., "Recurrent Mutations in a Single Exon Encoding the Evolutionarily Conserved Olfatomedin- Homology Domain of TIGR in Familial Open-Angle Glaucoma, "Human Molecular Genetics, 6 (12): 2091-2097 (1997) .The glaucsma lg gene (GLC1A, TIGR) is the theme of Nguyen, and collaborators, US Patent No. 5, 606,043, registered on February 25, 1997.

Several patent applications have exposed the use of non-steroidal cyclooxygenase inhibitors to treat intraocular pressure (WO 95/17178) through the action of the compounds on cells of the trabecular system (WO 96/40103 and WO 96/40102). At least some of the beneficial effects of nonsteroidal cyclooxygenase inhibitors are attributed to the inhibition of miocillin expression (or TIGR) which is the product of the GLC1A gene.

It is known that the cells of the trabecular system have glucocorticoid receptors and that the glucocorticoid that binds to these receptors causes a change in the expression of the gene of the cells of the trabecular system. Well-known manifestations of this change include a reorganization of the cytoskeleton (Wilson, et al., "Dexamethasone Induced Ultrastructural Changes in Cultured Human Trabecular Meshwork Cells, Curr. Eye Res., 12: 783-793 (1993), and Clark et al.," Glucocorticoid. -Induced Formation of Cross-Linked Actin Networks in Cultured Human Trabecular Meshwork Cells, Invest Ophthalmol, Sci., 35: 281-294 (1994)) and increased deposition of extracellular matrix material in cells of the trabecular system. As a result, the trabecular system becomes "obstructed" and facilitates performing one of its most critical functions, which is to serve as an access to the flow of aqueous humor from the anterior chamber of the eye. When the aqueous humor leaves the eye via the diminished trabecular system, the intraocular pressure of the eye rises. If this state of elevated intraocular pressure is maintained or occurs frequently, the head of the optic nerve can be damaged resulting in loss of visual field. The loss of the visual field is the distinctive symptom associated with glaucoma.

In summary, the GLClA gene product can lead to the development of ocular hypertension and glaucoma in one of two ways: (1) mutations in GLClA are responsible for many forms of juvenile glaucoma and a subpopulation of adults who present POAG or (2) exposure of some individuals to glucocorticoids leads to increased expression of GLClA in the TM which causes resistance to the outflow of increased aqueous humor and the development of ocular hypertension. The precise mechanism responsible for the effects of GLClA on IOP are currently unknown.

Brief Description of the Invention Certain non-spheroidal cyclooxygenase inhibitors and their pharmaceutical formulations are useful for treating GLClA glaucoma. The invention is also directed to methods for controlling glaucoma GLClA using non-steroidal cyclooxygenase inhibitors.

According to one aspect, the present invention provides a method of treating GLClA glaucoma said method comprising administering a pharmaceutically effective amount of a compound of the structure: R = H, C? _4 unbranched or branched alkyl, CF3 or MR Y = OR 'or NR "R' R 'H (except when Y = OR'), Ci-or unbranched or branched alkyl, unsubstituted or substituted aryl (substituted as defined by X below), unsubstituted or substituted heterocycle (substituted as defined for X below) , - (CH2) nZ (CH2) n, or A n = 2-6 n '= 1-6 Z = none, O, C = 0, OC (= 0), C (= 0) O, C (= 0) NR3, n = 0-2 R '3 _H, C? -6 branched or unbranched alkyl, substituted or unsubstituted aryl (substituted as defined for X below) or unsubstituted or substituted heterocycle (substituted as defined for X subsequently) A = H, OH, unsubstituted or substituted aryl (substituted as defined for X subsequently), unsubstituted or substituted heterocycle (substituted as defined for X subsequently), or - (CH2) n OR3 R "= H, OH or OR ' X and X 'independently = H, F, Cl, Br, I, OR', CN, OH, S (0) nR, CF3, Rq or N02 R = C6-6 unbranched or branched alkyl m = 0-5 m '= 0-5 W = 0 or H.

According to another aspect, the present invention provides the use of a compound of the structure: R = H, C 1 -4 unbranched or branched alkyl, CF 3 or SR4 Y = OR 'or NR "R' R '= H (except when Y = OR'), unbranched or branched alkyl d, unsubstituted or substituted aryl (substituted as defined below for X), unsubstituted or substituted heterocycle (substituted as defined for X subsequently ), n = 2-6 n '1- 6 Z = nothing, O, C = 0, OC (= 0), C (= 0) 0, C (= 0) NR °, NR3C (= 0), S (0) n2, CHOR3 or NR3 n2 = 0 R3 = H, unbranched or branched C6-6 alkyl, unsubstituted or substituted aryl (substituted as defined for X below) or unsubstituted or substituted heterocycle (substituted as defined for X below) A = H, OH, unsubstituted or substituted aryl (substituted as defined for X subsequently), or - (CH2) nOR3 R "= H, OH or OR 'X and X' independently = H, F, Cl, Br, I, OR ', CN, OH, S (0) n2R4, CF3, R4 or N02 R4 = unbranched or branched alkyl C6-6 m = 0- m '0- 5 W = 0 or H in the manufacture of a drug for the treatment of glaucoma GLClA.

Brief Description of the Drawings Figure 1 shows concentrations of nepafenac in eye tissue of rabbits following a single topical dose. Figure 2 shows the concentration of nepafenac calculated from the data of figure 1. Description of the Preferred Modalities Agents that alter the expression of GLClA in the glaucomatous eye are expected to attenuate the IOP and thereby prevent or inhibit glaucomatous optic neuropathy which is driven by elevated IOP. Glucocorticoids on regulate the expression of GLClA in the TM of certain individuals. There have been several reports of elevated levels of natural cortisol glucocorticoid in the aqueous humor and plasma of patients with glaucoma (Schwartz, et al., Supra).; Rozsival, et al., Supra. In addition, certain mutations in GLClA can alter the expression of GLClA in TM tissue of patients with glaucoma lq. Unexpectedly, it has been found that certain non-steroidal cyclooxygenase inhibitors inhibit the expression of GLClA in cultured human TM cells and attenuate elevated IOP in certain animal models of ocular hypertension. Nonsteroidal cyclooxygenase inhibitors act to prevent the expression of GLClA and the subsequent development of ocular hypertension.

Many non-steroidal cyclooxygenase inhibitors do not easily penetrate the cornea on topical administration and, therefore, do not reach therapeutic concentrations in the target tissue, the trabecular system.

A series of compounds set forth in the commonly assigned Patent with no. 5,475,034, which exhibits nonsteroidal nonsteroidal anti-inflammatory activity, exhibits superior penetration into the cornea, which leads to improved ocular bioavailability. The concentration estimated in the anterior chamber that follows topical ocular administration of 0. 3% of nepafenac in rabbits is 24 μM (see figure 1). This concentration, achieved using a simple formulation without penetration enhancers, is in excess of the parent compounds of C0X1 and COXII IC50S. This improved bioavailability provides a significant advantage and is unexpectedly on other non-steroidal anti-inflammatory drugs as well as amides derived from non-steroidal anti-inflammatory drugs. The compounds set forth in the '034 patent, the content of which is incorporated herein by reference, are esters and amides derived from 3- benzoylphenylacetic acid.

The compounds set out in the patent x034 have the following structure: R = H, C 1 -4 unbranched or branched alkyl, CF 3 or SR 4 Y = OR 'or NR "R' R '= H (except when Y = OR'), unbranched or branched C? _? 0 alkyl, unsubstituted or substituted aryl (substituted as defined for X below), unsubstituted or substituted heterocycle (substituted as defined for X below), - (CH2) nZ (CH2) n, or A n = 2- n '= 1- Z = nothing, O, C = 0, OC (= 0), C (= 0) 0, C (= 0) NR3, NR3C (= 0), S (0) n2 , CHOR3 or NR3 nz = 0- 2 R = H, unbranched or branched Ci- 6 alkyl, unsubstituted or substituted aryl (substituted as defined for X below) or unsubstituted or substituted heterocycle (substituted as defined for X subsequently) A = H, OH, unsubstituted or substituted aryl (substituted as defined for X subsequently), unsubstituted or substituted heterocycle (substituted as defined for X subsequently), or - (CH2) n0R3 R "= H, OH or OR ' X and X 'independently = H, F, Cl, Br, I, OR', CN, OH, S (0) nR% CF3, R * or N0 R4 = unbranched or branched Ci-β alkyl m = 0-5 m '= O- 5 W = O or H.

Preferred compounds for use in the present invention are those of formula I wherein: R = H or Ci- 2 alkyl Y = NR'R ' R '= H, unbranched or branched alkyl d- 6, (CH2) nZ (CH2) n, or A Z = nothing, 0, CHOR3 or NR3 RJ = H A = H, OH, unsubstituted or substituted aryl (substituted as defined for X subsequently) X and X 'independently = H, F, Cl, Br, CN, CF3, OR', SR4 or R4 R 'H R4 C4-4 unbranched or branched alkyl m = 0- 2 m '= 0- 2 W = H n = 2- n ' The most preferred compounds for use in the present invention are 2-amino-3- (4-fluorobenzoyl) -phenylacetamide; 2-amino-3-benzoyl-phenylacetamide (nepafenac); and 2-amino-3- (4-chlorobenzoyl) -phenylacetamide.

For the preferred compound, nepafenac, W = H, R = H, Y = NH2, X * = H, X = H, m = 3 and m '= 5.

The compounds are administered topically in the eye at a concentration of 0.001% - 1% (weight / volume), preferably 0.05% - 0.5% (weight / volume) one to three times per day according to the discretion of the skilled physician.

The following examples are illustrative of formulations which may be used in accordance with the present invention, but are not limiting. "" Active agent "means one or more compounds described by the structure and definitions set forth above.

Example 1 Active agent 0.01 - 0.5 Polysorbate 80 0.01% Benzalkonium Chloride 0.01% + 10% excess Disodium EDTA 0.1 Monobasic sodium phosphate 0.03 Dibasic sodium phosphate 0.1 Sodium Chloride c.b.p. 290-300 mOsm / Kg pH adjustment with NaOH and / or HCl pH 4.2 - 7.4 Water c.b.p. 100 2 Active agent 0.01 0.5 Hydroxypropyl Methylcellulose 0.5 Polysorbate 80 0.01 Benzalkonium Chloride 0.01 + 5 in Excess Disodium EDTA 0.01% Dibasic sodium phosphate 0.2% Sodium Chloride c.b.p. 290-300 mOsm / Kg PH adjustment with NaOH and / or HCl pH 4.2 - 7.4 Water c.b.p. 100 It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following:

Claims (5)

1. A method of treating GLClA glaucoma which is characterized in that it comprises administering a pharmaceutically effective amount of a compound of the structure: R = H, C? - unbranched or branched alkyl, CF3 or SR4 Y = OR 'or NR "R' R '= H (except when Y = OR'), unbranched or branched C? _4 alkyl, unsubstituted or substituted aryl (substituted as defined for X below), unsubstituted or substituted heterocycle (substituted as defined for X) subsequently), - (CH2) nZ (CH2) n, or A n = 2- n '= 1- 6 Z = nothing, O, C = 0, OC (= 0), C (= 0) O, C (= 0) NR3, NR3C (= 0), S (O) n2, CHOR3 or NR3 n O- 2 R3 = H, C1-branched or branched alkyl, unsubstituted or substituted aryl (substituted as defined for X below) or unsubstituted or substituted heterocycle (substituted as defined for X below) A = H, OH, unsubstituted or substituted aryl (substituted as defined for X subsequently), unsubstituted or substituted heterocycle (substituted as defined for X subsequently), or - (CH2) nOR3 R "= H, OH, or 0R ' X and X 'independently = H, F, Cl, Br, I, OR', CN, OH, S (0) n2R4, CF3, R4 or N02 R = C6-6 unbranched or branched alkyl m = O- 5 m '= O- 5 W = O or H.

2. A method according to claim 1, characterized in that: W = H, R = H, Y-NH2, X '= H, X = H, m = 3, and m' = 5.

3. Use of a compound of the structure: R = H, C 1 -4 unbranched or branched alkyl, CF 3 or SR 4 Y = OR 'or NR "R R' = H (except when Y = OR '), unbranched or branched Ci-io alkyl, unsubstituted or substituted aryl (substituted as defined for X below), unsubstituted or substituted heterocycle (substituted as defined for X later), - (CH2) nZ (CH2) n, or A n = 2- n '= 1- Z = nothing, O, C = 0, OC (= 0), C (= 0) 0, C (= 0) NR3, NR3C (= 0), S (0) n2, CHOR3 or NR3"0- 2 R = H, unbranched or branched C 1 e alkyl, unsubstituted or substituted aryl (substituted as defined for X below) or unsubstituted or substituted heterocycle (substituted as defined for X subsequently) A = H, OH, unsubstituted or substituted aryl [substituted as defined for X subsequently), unsubstituted or substituted heterocycle (substituted as defined for X subsequently), or - (CH2) n0R3 R "= H, OH or OR ' X and X 'independently = H, F, Cl, Br, I, OR', CN, OH, S (0) n2R4, CF3, R4 or ¥ SOz R4 = unbranched or branched Ci-? Alkyl m = 0-5 m '= 0- 5 W = O or H, in the manufacture of a drug for the treatment of glaucoma GLClA.

4. The use according to claim 3, which is characterized by W = H, R = H, Y = NH2, X '= H, X = H, m = 3, and m' = 5.