MXPA02008825A - 5 hydroxy indazole derivatives for treating glaucoma. - Google Patents

Abstract

3 (2 aminoethyl) 1H indazol 5 ols useful for treating elevated intraocular pressure and glaucoma are disclosed.

Description

5-HYDROXY DERIVATIVES INDAZOL FOR GLAUCOMA TREATMENT The present invention is directed to the substituted 3- (2-aminoethyl) -lH-indazole-5-ols, some of which are novel, for the reduction and control of normal or elevated intraocular pressure (IOP) and glaucoma treatment. .

BACKGROUND OF THE INVENTION The disease state known as glaucoma is characterized by a permanent loss of visual function due to irreversible damage of the optic nerve. The different types of glaucoma are characterized morphologically or functionally, usually by elevated IOP, which is considered causally related to the pathological course of the disease. Ocular hypertension is a condition where intraocular pressure is elevated but no apparent loss of visual function has occurred; it is considered that such patients are at a high risk for the eventual development of visual loss associated with glaucoma. Some patients with glaucomatous field loss have relatively low intraocular pressure. These patients with normotension glaucoma or also called low tension glaucoma also benefit from agents that decrease and control IOP. If the 7 glaucoma or ocular hypertension is detected at an early stage and treated promptly with medications that effectively reduce elevated intraocular pressure; visual loss or progressive deterioration can usually be improved. Medications that have proven to be effective in reducing intraocular pressure include agents that decrease the production of aqueous humor and agents that increase the ease of spill. These treatments are usually administered by one or two possible rare, topically (direct application to the eye) or orally.

There are some individuals who do not respond well when treated with certain existing glaucoma treatments. Therefore, other topical therapeutic agents that control IOP are necessary.

It was found that serotonergic compounds possessing agonist activity towards 5-HT2 receptors effectively decrease and control elevated and normal ICP and are useful for the treatment of glaucoma, see the co-pending application of the same transferee, PCT / OS99 / 19883 . Compounds that act as agonists towards 5-HT2 receptors are also known and have shown a variety of utilities, mainly for disorders or conditions associated with the central nervous system (CNS). US Patent No. 5,494,928 discloses certain 2- (indol-1-yl) -ethylamine derivatives which are 5-HT 2c agonists for the treatment of obsessive-compulsive disorders and other personality disorders derived from the CNS. US Patent No. 5,571,833 discloses tryptamine derivatives that are 5-HT 2 agonists for the treatment of portal hypertension and migraine. US Patent No. 5,874,477 discloses a method for treating malaria using 5-H 2A / 2C agonists. US Patent No. 5,902,815 discloses the use of 5-HT 2A agonists to prevent adverse effects of hypofunction of the NMDA receptor. WO 98 / 31354A2 discloses 5-HT2B agonists for the treatment of depression and other CNS conditions. The agonist response to the 5-HT2A receptor is reported to be the primary activity responsible for hallucinogenic activity with some minor involvement of the possible 5-HT2C receptor [Psychopharmacology, vol. 121: 357, 1995].

The present invention is directed to substituted 3- (2-aminoethyl) -lH-indazole-5-ols, some of which are novel. It was believed that these compounds could have a high affinity for and function as agonists towards serotonergic 5-H 2 receptors, and could therefore be useful for decreasing and controlling high or normal intraocular pressure (IOP) and for glaucoma treatment. When a phenolic fraction is included in this substitution, for example, a hydroxyl group on the indazole ring at position five, such compounds may be particularly sensitive to the well-known oxidation reactions that occur with phenolic compounds in general, which include the related hydroxytryptamines [J. Phys. Chem. 103, 8606 (1999), Chem. Res. Toxicol. 11, 639 (1998), J. Org. Chem. 52, 2817 (1987), J. Pharm. Sci. 77, 911 (1988)], which are of particular relevance in the present application. The protection of such hydroxy-substituted phenols against oxidation can be achieved by derivatization of the aryl hydroxy group to provide a suitable ester, carbamate or carbonate. Although the ester, carbamate or carbonate derivative itself does not possess a high affinity for the above-mentioned receptors, these have no utility in the treatment of glaucoma, since adequately protected phenols can be divided in vivo either by chemical hydrolysis or by of the action of tissue esterase. Such a disruption could release the desired therapeutic agent, i.e., the desired novel 5-hydroxy-indazole compounds of the present invention. The concept of using such derived phenolic compounds as chemical release agents is well known in the art [Drugs Pharm. Sci. 53, 221 (1992), Pharm. Res., 168 (1984)].

The chemical synthesis of 3- (2-dimethylamino-ethyl) -1H-indazol-5-ol has been reported without comment on the utility of the compound [J. Amer. Chem. Soc. 79, 5242 (1957); J. Amer. Chem. Soc. 80, 965 (1958)].

The chemical synthesis of 1- (2-aminopropyl) -lH-indazol-6-ol and other variants of ring substitution has been reported in published International Patent Application No. O 98/30548 (1998). The utility cited for the compounds of this application is to treat diseases of the central nervous system such as sexual disorders, genital insufficiency, disorders of appetite regulation, anxiety, depression and sleep disorders. The ophthalmic use noted in this application is not contemplated. Published International Patent Application No. WO 00/12482 (2000) discloses certain 1- (indazol-3-yl) -2-propylamine derivatives which are 5-HT 2 agonists for the treatment of central nervous system disorders.

SUMMARY OF THE INVENTION The present invention is directed to the 3- (2-aminoethyl) -lH-indazol-5-ol derivatives, some of which are novel, which can be used to decrease and control the IOP associated with glaucoma of normal tension, ocular hypertension and glaucoma in warm-blooded animals, including man. The compounds are formulated in pharmaceutical compositions suitable for topical release in the eye.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds that are useful according to the present invention are represented by the following Formula I.

FORMULA I wherein G is selected from hydrogen, halogen or C 1 -C 4 alkyl; R is hydrogen, C1-C4 alkyl, C (= 0) W, or P (= 0) (OX) (OY); 1 2 R and R are hydrogen; 3 R and R are independently selected from hydrogen, C1-C alkyl or R3, R4 and the carbon atom to which they are attached can form a cyclopropyl ring, or 2 3 furthermore R and R together can be (CH2) m to form a saturated heterocycle; 2 3 1 when R and R are part of a heterocycle, R may be hydrogen or C1-C alkyl; R5 can be hydrogen or C1-C4 alkyl; when R, R1, R2, R5 and G are all hydrogen, R3 and R4 can not both be hydrogen; W is Ci-C6 alkyl, NR6R7, N (R6) CH2 (CH2) nC (= 0) N (R) (R8), OC-CI-C6 alkyl, Ci-Cg alkyl (which may be substituted with halogen, hydroxyl, CC ^ C 1 -C 4 alkyl, CON (C 1 -C 4 alkyl) 2, C (= NH) NH 2, KC (= NH) NH 2, NH 2), C 2 -C alkenyl (substituted by phenyl, substituted or substituted with one or more of C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen); 6 7 8 R, R, R are independently chosen from hydrogen or Ci-C4 alkyl; X and Y are independently chosen from hydrogen, C1-C10 alkyl, or X and Y can together form a lower alkyl chain of (CH2) m; m is 2-4; n is 1 or 2; and the pharmaceutically acceptable salts and solvates of the compounds of Formula I.

Compounds that are novel and that are useful in accordance with the present invention can be defined as follows: G is chosen from hydrogen, halogen or C1-C4 alkyl; R is C (= 0) W or P (= 0) (OX) (OY); 1 2 R and R are hydrogen; 3 4 R, R and the carbon atom to which they are attached can form a cyclopropyl ring, or in addition, R and R together can be (CH) m to form a saturated heterocycle; 2 3 1 when R and R are part of a heterocycle, R may be hydrogen or Ci-C4 alkyl; R5 can be hydrogen or Ci-C4 alkyl; W is Ci-C6 alkyl, NR6R7, N (R6) CH £ (CH2) n (= 0) N (R7) (R8), 0 (Ci-Ce alkyl) r alkyl of ?? -? ^, ( which may be substituted with halogen, hydroxyl, CC ^ C 1 -C 4 alkyl, CON (C 1 -C 4 alkyl) 2 / C (= NH) NH 2, HC (= NH) NH 2, NH 2), C 2 -C 4 alkenyl ( substituted by phenyl, unsubstituted or substituted by one or more of C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen); 6 7 | 8 R, R, R are independently chosen from hydrogen or Ci-C4 alkyl; X and Y are independently chosen from hydrogen, C1-C10 alkyl or X and Y together can form a lower alkyl chain of (CH2) m; m is 2-4; n is 1 or 2.

The preferred compounds are: G is chosen from hydrogen, halogen or C1-C4 alkyl; R is hydrogen, C (= 0) W or P (= 0) (OX) (OY); 1 2 R and R are hydrogen; R 4 and R are independently chosen from hydrogen, C -C 4 alkyl, or R 3, R 4 and the carbon atom to which they are attached can form a cyclopropyl ring; R5 can be hydrogen or C1-C4 alkyl; W is Ci-C6 alkyl, NR6R? , N (R6) CH2 (CH2) nC (= 0) N (R7) (R8), Ci-C6 alkyl (which may be substituted with halogen, hydroxyl, C02C1-C4alkyl, CON (Ci-C4 alkyl) ) 2, C (= NH) NH 2, HC (= NH) NH 2, NH 2), C 2 -C 4 alkenyl (substituted by phenyl, unsubstituted or substituted by one or more of C 1 -C 4 alkyl, C 1 -C 4 alkoxy or halogen); 6 7 8 R, R, R are independently chosen from hydrogen or C1-C alkyl; X and Y are independently chosen from hydrogen, C -C10 alkyl or X and Y together can form a lower alkyl chain of (CH2) m; m is 2 or 3; n is 1 or 2.

The most preferred compounds are: G are chosen from hydrogen, halogen or Ci-C4 alkyl; R is hydrogen or C (= 0) W; 1 2 R and R are hydrogen; R3 is hydrogen and R4 is methyl or R3, R4 and the carbon atom to which they are attached form a cyclopropyl ring; 5 R is hydrogen; W is Ci-C6 alkyl, Ci-Cs alkyl (which may be substituted by halogen, hydroxyl, CON (Ci-C4 alkyl) 2, C (= NH ') NH2).

Representative examples of the novel, preferred compounds of the formula I are: 3- (2-aminopropyl) -lH-indazol-5-ol; 3- (2-aminopropyl) -l-methyl-lly-indazol-5-ol; 3- (5-methoxy-lH-indazol-3-yl) -1-methyl-ethylamine; 3- (2-aminopropyl) -6-fluoro-lfl-indazol-5-ol; 3- (2-aminopropyl) -7-methyl-li-indazol-5-ol; 3- (2-aminopropyl) -6-fluoro-l-methyl-lH-indazol-5-ol; 3- (2-Aminopropyl) -lH-indazol-5-yl ester of 2-methyl-propionic acid; Ester 3- (2-aminopropyl) -lfl-indazol-5-yl of 2,2-dimethyl-propionic acid; 3- (2-aminopropyl) -lι-indazole-5-yl ester of cyclopropanecarboxylic acid; 3- (2-Aminopropyl) -lH-indazol-5-yl ester of N, N-diethyl-succinamic acid.

It is recognized that the compounds of Formula I may contain one or more chiral centers. This invention contemplates all the enantiomers, diastereomers and mixtures thereof.

In the above definitions, the total number of carbon atoms in a substituent group is indicated by the prefix Ci_j, where the numbers i and j define the number of carbon atoms. This definition includes linear chains, branched chains and cyclic alkyl or alkyl (cyclic alkyl) groups.

It is important to recognize that a substituent can be present individually or multiple when incorporated into the indicated structural unit. For example, the halogen substituent, meaning fluorine, chlorine, bromine or iodine, would indicate that the unit to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.

SYNTHESIS The compounds of Formula I can be prepared using one of several synthetic methods. For example, the condensation of the appropriate substituted indazole-3-carboxaldehyde (1) (1), which can be prepared from the corresponding indazole by known methods [J. Med. Chem. 38, 2331 (1995)], with the appropriate nitroalkane the corresponding nitroalkene (2) is obtained, which can be reduced with, for example LiAlH4, and if desired dealkylated with, for example boron tribromide, to provide the desired compound 3 of Formula I.

SCHEME 1 Another procedure for preparing the compounds of Formula I is summarized in Scheme 2. The 2-fluoro-acetophenone (4) appropriately substituted, obtained or prepared by the known procedures, for example, from Tetrahedron 50, 1179 (1994), can reacting with the desired aldehyde, such as acetaldehyde, in the presence of a strong base, for example lithium diisopropylamide, to give the aryl β-hydroxyalkyl ketone (5) [Synth. Commun. 10, 851 (1980)], which can be reacted with anhydrous hydrazine by the known methods to provide substituted 6-indazole [J. Med. Chem. 37, 2721 (1994)]. The conversion of the secondary alcohol fraction from 6 to the desired primary amine can be effected using the well-known sequence involving initial activation by formation of a sulfonated ester followed by displacement of this ester by reaction with sodium azide, and finally the reduction of the azide with the concomitant separation of any phenol protecting group, for example benzyl, to provide the desired amine (3). Otherwise, compound 4 can be reacted with an aldehyde, for example acetaldehyde, under acidic conditions to provide the chalcone intermediate, for example 7 [J. Chem. Soc, 2403 (1953)] (Scheme 3). The addition of a suitable protective amine, for example benzylamine, in the double bond of 7 gives the desired amino ketone 8 [Chem. Pharm. Bull. 22, 1348 (1974)] which, when treated with hydrazine, provides indazole 9 substituted [J. Med. Chem. 37, 2721 (1994)]; separation of the protecting groups by hydrogenolysis provides the desired compound 3.

?? Still another method for preparing the compounds of Formula I, but starting with the acid (5-benzyloxy-ltf-indazol-3-yl) -acetic acid (10) [J. Amer. Chem. Soc. 79, 5246 (1959)] as the starting material, is summarized in Scheme 4. The reaction of 10 with acetic anhydride in the presence of the appropriate base under Dakin-West conditions [Chem. Soc. Rev., 17, 91 (1988)] provides intermediate 11 which by reaction with 0-methyl-hydroxylamine provides oxime 12. Reduction of 12, for example, with borane, will provide the desired compound 13 of Formula I [Eur. J. Med. Chem. 27, 595 (1992), Tetrahedron, 29, 223 (1988)].

SCHEME 4 10 11 The compounds of Formula I, wherein R is C (= 0) W, can be prepared by reaction of the appropriate indazole 3, or preferably a suitable amino-protected intermediate, for example 14 (Scheme 5) with the desired activated acid derivative , as an acid halide or active ester, or the like, to provide ester 15. Separation of the N-protecting group from intermediate 15 provides the desired compound 16 of Formula I.

SCHEME 5 The compounds of this invention, Formula I, can be incorporated into different types of ophthalmic formulations for release into the eye (eg, topically, intra-chamber or by means of an implant). The compounds are preferably incorporated in topical ophthalmic formulations for release into the eye. The compounds can be combined with preservatives acceptable for the use of the enzyme, surfactants, viscosity improvers, penetration enhancers, buffers, sodium chloride and water to form a sterile, aqueous ophthalmic solution or suspension. Formulations of ophthalmic solutions can be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer. In addition, the ophthalmic solution may include an acceptable surfactant for ophthalmological use, in order to aid in the dissolution of the compound. In addition, the ophthalmic solution may contain an agent for increasing the viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone or the like, to improve the retention of the formulation in the conjunctive sac. Also gelling agents can be used, including, but not limited to, gelano gum and xanthan. To prepare the sterile ophthalmic oily formulations, the active ingredient is with a preservative in a suitable vehicle, such as mineral oil, lanolin or white petrolatum. Sterile, ophthalmic gel formulations can be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-974 or the like, according to published formulations for similar ophthalmic preparations; preservatives and tonicity agents can be incorporated.

The compounds are preferably formulated as suspensions or topical ophthalmic solutions, with a pH of about 5 to 8. The compounds should normally be contained in these formulations in an amount of 0.01% up to 5% by weight, preferably in an amount of 0.25% up to 2% by weight. % in weigh. In this way, for topical presentation of up to 2 drops of this formulation could be delivered to the surface of the eye of one up to 4 times per day according to the criteria of the expert clinician.

It is also possible to use the compounds in combination with other agents to treat glaucoma, such as, but not limited to, β-blockers (for example, timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors ( for example, brinzolamide and dorzolamide), antagonists to (for example, nipradolol), agonists a.2 (for example, iopidin and brimonidine), miotics (for example pilocarpine and epinephrine), prostaglandin analogues (for example, latanoprost, travaprost, unoprostone and compounds disclosed in US Patent Nos. 5,889,052; 5,296,504; 5,422,368 and 5,151,444"hypotensive lipids" (e.g., lumigan and compounds reported at 5,352,708), and neuroprotective (e.g., compounds of U.S. Patent No. 4,690,931, in particular eliprodil and R-eliprodil, as stated in a pending application USSB 06 / 203350, and appropriate compounds of W094 / 13275, including memantine.

Preferred compounds of Formula I are described in Examples 1 and 2. The most preferred compounds are in Example 1. Examples of anticipated formulations are provided which are suitable for the delivery of this compound to the eye.

EXAMPLE 1 3- (2-aminopropyl) -lH-indazol-5-ol hydrochloride Step A: 1- [5-benzyloxy-3- (2-oxo-propyl) -indazol-1-yl] -ethanone A mixture of (5-benzyloxy-llydazol-3-yl) -acetic acid (2 g, 7.08 mmol) and sodium acetate (0.99 g, 12 mmol) in acetic anhydride (6 mL) was stirred at 130 ° C. for 3 h. After cooling, water (15 mL) and ethyl acetate (15 mL) were added to the reaction mixture. The aqueous layer was separated and extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with NaHCC > 3 saturated aqueous (2 x 20 mL) and saturated aqueous NaCl (20 mL), dried (MgSO 4), and evaporated to a residue, which was purified by chromatography (silica, 15% ethyl acetate in hexane) to give a solid. yellow (0.48 g): 1H NMR (CD3OD) d 8.35-8.30 (m, 1H), 7.48-7.23 (m, 6H), 7.04-7.02 (m, 2H), 5.11 (s, 2H), 4.02 (s, 2H), 2.77 (s, 3K), 2.27 (s, 3H); 13C NMR (CDCI3) 5 203.64 (C), 170.47 (C), 156.20 (C), 145.04 (C), 136.52 (C), 128.64 (CH), 128.31 (CH), 127.60 (CH), 120.51 (CH) , 116.74 (CH), 102.26 (CH), 70.68 (CH2), 42.76 (CH2), 29.59 (CH3), MS (APC1) m / z 323 (M + H) +.

Step B: 1- [5-benzyloxy-3- (2-hydroxypropyl) -indazol-1-yl] -ethanone To a solution of the product from Step A (0.13 g, 0.4 mmol) in methanol (8 mL) was added NaBH 4 (0.016 g, 0.4 mmol) and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous solution of NH 4 Cl (20 mL) and ethyl acetate (20 mL) was added to the reaction mixture. The aqueous layer was separated and extracted with ethyl acetate (3 x 15 mL). The combined extracts were washed with a saturated aqueous solution of NaCl (2 x 15 mL), dried (MgSO 4) and evaporated to give an oil (0.12 g). MS (APCl) m / z 325 (M + H) +.

Step C: 1- [3- (2-azido-propyl) -5-benzyloxy-indazol-1-yl] -ethanone A solution of the product from Step B (0.12 g, 0.37 mmol) and methanesulfonyl chloride (0.04 mL, 0.48 mmol) in CH 2 Cl 2 (5 mL) under nitrogen was cooled to 0 ° C and triethylamine (0.07 mL, 0.48 mmol) was added. . The resulting mixture was stirred at 0 ° C for 10 minutes followed by the addition of a saturated aqueous solution of NH 4 Cl (20 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 5 mL). The combined extracts were washed with saturated aqueous NaCl solution (2 x 15 mL), dried (gS04) and evaporated to a residue which was dissolved in DMF (3 mL). Sodium azide (0.08 g, 1.2 mmol) was added and the mixture was stirred until 70 CC for 18 hours. After cooling, water (20 mL) and ether (20 mL) were added and the aqueous layer was separated and further extracted with ether (3 x 20 mL). The combined extracts were washed with saturated aqueous NaCl solution (3 x 15 mL), dried (MgSO 4) and evaporated to a residue which was purified by chromatography (silica, 10% ethyl acetate in hexane) to give a yellow oil. (0.12 g). MS (ES) m / z 350 (M + H) +.

Step D: 3- (2-aminopropyl) -lH-indazol-5-ol hydrochloride A solution of the product from Step C (0.12 g, 0.34 mmol) in methanol (20 mL) was stirred under a hydrogen atmosphere (35 psi) in the presence of 10% palladium on carbon (0.12 g) for 18 h. The catalyst was separated by filtration and the filtrate evaporated to a residue, which was purified by chromatography to give an oil. Treatment of the oil with a 1N HC1 solution in ethanol yielded the hydrochloride salt as a colorless semi-solid (0.013 g): H NMR (CD3OD) d 7.34-7.30 (m, 1H), 7.05-6.98 (m, 2H ), 7.04-7.02 (m, 2H), 3.68-3.58 (m, 1H), 3.19-3.05 (m, 2H), 1.19-1.16 (d, J = 6 Hz, 3H), MS (ES) m / z 192 (M + H) +. The treatment of the oil prepared by this process with fumaric acid gave the fumarate salt as a gray solid; p.f. 227-230 ° C. Analysis: Calculated for C10H13N3O · C4H404 · 0.3 H20: C, 53.77; H, 5.63; N, 13.43. Found: C, 53.83; H, 5.85; N, 13.34.

EXAMPLE 2 3- (2-aminopropyl) -l-methyl-lH-indazol-5-ol fumarate Step A. 1- (5-benzyloxy-lH-indazol-3-yl) -propan-2-one A solution of the product from Step 1 of Example 1 (2.0 g, 6.2 mmol) and sodium hydroxide (0.3 g, 7.5 mmol) in a mixture of methanol (15 mL) and water (15 mL) was stirred for 18 h at room temperature . The reaction mixture was extracted with ethyl acetate (4 x 30 mL) and the combined extracts were washed with brine, dried (MgSO 4) and evaporated to a residue which was purified by chromatography (silica, ethyl acetate / hexane, 1: 1) to give a syrup (1.5 g): ESI / MS m / z 281 (M + H) +.

Step B. 1- (5-benzyloxy-l-methyl-lH-indazol-3-yl) propan-2-one To a solution of the product from Step A (1.2 g, 4.28 mmol) in DMF (10 mL) were added. iodomethane (0.53 mL, 8.6 mmol) and potassium carbonate (1.2 g, 8.6 mmol); this mixture was stirred for 16 h at 70 ° C. Then water (15 mL) and ethyl acetate (15 mL) were added to the reaction mixture, the aqueous layer was separated and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine, dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, ethyl acetate / hexane, 1: 1) to give a viscous oil (0.06 g): APC1 / LCMS m / z 295 (M + H) +.

Step C. Fumara or 3- (2-aminopropyl) -l-methyl-lH-indazol-5-ol The product of Step B (0.3 g, 0.1 mmol) was treated in the same manner as described in Example 1 from Steps B to D to give an oil that was converted to the fumarate salt (0.071 g): m.p. 136 ~ 139 ° C; LCMS m / z 206 (M + H) +. Analysis. Calculated for C 10 H 15 N 3 O · C 4 H 4 O 4 · 0.1 H 20: C, 55.76; H, 5.98; N, 13.00 Found: C, 55.53; H, 6.11; N, 13.22.

EXAMPLE 3 2- (2-aminopropyl) -lfi-indazol-5-yl ester of 2-methyl-propionic acid Step A: 3- (2- (9-fluorenylmethoxycarbonylamino) ropil) -lH-indazol-5-ol To a mixture of dioxane and water (4: 1, 10 mL) was added 3- (2-aminopropyl) -lH-indazol-5-ol (0.10 g, 0.36 mmol), 9-fluorenylmethoxycarbonyl chloride (0.13 g, 0.54 g). mmol) and sodium bicarbonate (0.9 g, 0.54 mmol). The reaction mixture was poured into dilute sodium bicarbonate and the resulting mixture was extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated to a residue that was purified by chromatography.

Step B: Ester 3- (2- (9-fluorenylmethoxycarbonylamino) propyl) -lH-indazol-5-yl of 2-methyl-propionic acid To a solution of 3- (2- (9-fluorenylmethoxycarbonylamino) propyl) -lH-indazol-5-ol (0.17 g, 0.41 mmol) and diisopropylethylamine (0.06 g, 0.50 mmol), in methylene chloride (10 μL) cooled to 0 ° C 2-methylpropionyl chloride (0.05 g, 0.5 mmol) is added followed by 4-dimethylaminopyridine (0.05 g, 0.40 mmol). The reaction was allowed to warm to room temperature and then stirred at room temperature. The reaction mixture was added to dilute aqueous sodium bicarbonate and extracted with ether. The combined ether extracts were washed, dried (MgSC > 4) and concentrated. The residue was purified by chromatography.

Step C: Ester 3- (2-aminopropyl) -lH-indazol-5-yl of 2-methyl-propionic acid A solution of the 2- (methyl-propionic acid) 3- (2- (9-fluorenylmethoxycarbonylamino) propyl) -lif-indazole-5-yl ester (0.16 g, 0.33 mmol) in a mixture of piperidine and dimethylformamide 1: 4 (2.5 mL) is stirred at room temperature. The reaction mixture is poured into dilute aqueous sodium bicarbonate and the resulting mixture is extracted first with ethyl acetate and then with methylene chloride. The combined organic extracts are dried (MgSC) and concentrated. The residue is purified by chromatography.

The receptor binding agonist activity according to this invention can be determined using the following methods.

METHOD 1 Assay of binding to the 5H 2 receptor To determine the affinities of serotonergic compounds towards 5HT2 receptors, their ability to compete for radioligand agonist binding 125 [I] DOI towards 5HT receptors? of the brain is determined as described below with minor modifications of the literature of origin [Neuropharmacology, 26, 1803 (1987)]. Aliquots of post-mortem rat or human brain cut homogenate (400 μ? _ Dispersed in 50 mM Tris HC1 buffer (pH 7.4) are 125 incubate with [I] DOI (final 80 pM) in the absence or presence of methiothepin (10 μ final) to define the total and non-specific binding, respectively, in a total volume of 0.5 mL. The test mixture is incubated for one hour at 23 ° C in polypropylene tubes and the tests are terminated by rapid vacuum filtration on Whatman GF / B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cooled buffer. The test compounds (in different concentrations) are replaced by methiothepin. The radioactivity bound to the filter is determined by scintillation spectrometry in a beta counter. The data were analyzed using a calculation program with iterative curve fitting, not linear [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the affinity parameter of the compound. The concentration of the compound needed to inhibit the binding of [125I] DOI at 50% of the maximum is called the IC50 or the K ± value.

METHOD 2 Functional assay of 5-HT2: Test of replacement of the phosphoniositide (PI) The relative agonist activity of the serotonergic compounds at the 5HT2 receptor can be determined in vivo using the property of the compounds to stimulate the production of [H] inositol phosphates in rat vascular smooth muscle cells A7r5 3 labeled with [H] myo -mositol for its ability to activate the phospholipase C enzyme. These cells were grown in culture dishes, kept in a humid atmosphere with 5% CO2 and 95% air and weekly semi-fed with Dulbecco's Modified Eagle Medium (DMEM) which it contained 4.5 g / L of glucose and supplemented with 2 mM glutamine, 10 μg / mL of gentamicin and 10% of fetal bovine serum. For the purpose of carrying out the PI phosphoinositide change experiments, the A7r5 cells are cultured as in the above in dishes with 24 wells [J. Pharmacol. Expt. Ther., 286, 411 (1988)]. The confluent cells are exposed for 24-30 hours at 1.5 μ? [HJmyo-inositol (18.3 Ci / mmol) in 0.5 mL of medium without serum. The cells are then rinsed once with D EM / F-12 with a 10 mM LiCl content before incubation with the test agent (or solvent as control) in 1.0 mL of the same medium for one hour at 37 ° C. , after which the medium is aspirated and 1 mL of 0.1M formic acid cold is added to stop the reaction. The chromatographic separation of [H] -inositol 3 phosphates ([H] -IPs) on an AG-1-X8 column is performed as previously described [J. Pharmacol. Expt. Ther. 286r 411 (1988)] with sequential washes with ¾0 and 50 mM ammonium format, followed by elution of the total fraction [H] -IP with 1.2 M ammonium format containing 0.1 M formic acid. Eluate (4 mL ) is collected, mixed with 15 mL of scintillation fluid and the 3 [H] -IP total is determined by scintillation account in a beta counter. The concentration-response data are analyzed by the sigmoidal adjustment function of Origin Scientific Graphics software (Microcal Software, Northampton,?) To determine the potency (EC50 value) and efficacy (Emax) of the agonist. Serotonin (5HT) is used as a positive control agonist compound (standard) and the efficacy of the test compounds is compared with 5HT (defined as 100%). The concentration of the 3 compound needed to stimulate the production of [H] -IP for 50% of the maximum response is defined as the EC50 value.

The above procedures were used to generate the data shown in Table 1.

TABLE 1 Function and binding data to the 5HT2 receptor Compound IC8, nM EC50, nM Efficiency ftrrxr%) 3- (2- 2.5 1,210 97 aminopropyl) -lif-indazol-5-ol hydrochloride 3- (2-aminopropyl) - - 778 97 l-methyl-lly-indazol-5-ol fumarate EXAMPLE 4 Ingredients Quantity (% by weight) Fumarate of 3- (2-aminopropyl) -1-methyl- 0.01-2% lfí-indazol-5-ol Hydroxypropyl methylcellulose 0.5% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (edetate disodium) 0.01 % Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / hydrochloric acid For pH adjustment Purified water q.s. up to 100% EXAMPLE 5 Ingredients Quantity (% by weight) 3- (2-aminopropyl) -lH-indazol-5-ol 0.01-2% Methylcellulose 4.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% Disodium EDTA (edetatc disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / hydrochloric acid For pH adjustment Purified water q.s. up to 100% EXAMPLE 6 EXAMPLE 7 Ingredients Quantity (% by weight) Ester 3- (2-aminopropyl) -lH-indazol-5- 0.01-2% ol of 2-methyl-propoionic acid White petrolatum and mineral oil and oily consistency lanolin Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride 0.5% EDTA disodium (edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide / hydrochloric acid For pH adjustment

Claims (1)

1. CLAIMS The use of a compound of the formula: FORMULA I I wherein G is selected from hydrogen, halogen or algayl of C! -C4; R is hydrogen, Ci-C ^ alkyl (= 0), or P (= 0) (OX) (OY), R1 and R2 are hydrogen; R 4 and R are independently chosen from hydrogen, C 3- C 4 alkyl or R, R and the carbon atom to which they are attached can form a cyclopropyl ring, or 2 3 furthermore R and R together can be (CH2) m to form a saturated heterocycle; when R and R are part of a heterocycle, R can be hydrogen or Ci-C4 alkyl; R can be hydrogen or C 1 -C alkyl; when R, R1, R2, R5 and G are all hydrogen, R3 and R4 can not both be hydrogen; W is Ci-C6 alkyl, NR6R7, N (R6) CH2 (CH2) nC (= 0) N (R7) (R8), OC-Ci-Cg alkyl, C ^ -Cg alkyl (substituted with halogen, hydroxyl, C02C1-C4alkyl, CO (Ci-C4 alkyl) 2 / C (= NH) NH2, HC (= NH) NH2, H2), C2-C4 alkenyl (substituted by phenyl, unsubstituted or substituted by one or more of C1-C4 alkyl, C-C4 alkoxy or halogen); R6, R7, R8 are independently chosen from hydrogen or Ci-C4 alkyl; X and Y are independently chosen from hydrogen, C1-C10 alkyl, or X and Y can together form a lower alkyl chain of (CH2) m; m is 2-4; n is 1 or 2; and pharmaceutically acceptable salts and solvates of the compounds for the preparation of a medicament for reducing and controlling normal or elevated intraocular pressure. 2. The use of a compound according to claim 1, wherein in formula I: G is chosen from hydrogen, halogen or Ci-C alkyl; R is C (= 0) W or P (= 0) (OX) (OY), 1 2 R and R are hydrogen; R3, R4 and the carbon atom to which they are attached can form a cyclopropyl ring, or in addition, R and R together can be (CH2) m to form a saturated heterocycle; 2 3 1 when R and R are part of a heterocycle, R may be hydrogen or Ci-C4 alkyl; R can be hydrogen or Ci-C4 alkyl W is alkyl of CL-C6, NR6R7, N (R6) CH2 (CH2) nC (= 0) N (R7) (R8), 0 (Ci-Cg alkyl), Ci-Ce alkyl (substituted with halogen, hydroxyl, C02C1-C4alkyl, CON (Ci-C4 alkyl) 2r C (= NH) NH2r HC (= NH) NH2, NH2), C2-C4 alkenyl (substituted by phenyl, unsubstituted or substituted by one or more than C1-C4 alkyl, C1-C4 alkoxy or halogen); R6, R7, R8 are independently chosen from hydrogen or C1-C4 alkyl; X and Y are independently chosen from hydrogen, Ci-C] _o alkyl or X and Y together can form a lower alkyl chain of (CH2) m; m is 2-4; n is 1 or 23. The use of a compound according to claim 1, wherein in formula I: G is chosen from hydrogen, halogen or C 1 -C 4 alkyl is hydrogen, C (= 0) W or P (= 0) (OX) (OY), 1 2 R and R are hydrogen; R3 and R4 are independently chosen from hydrogen, C1-C4 alkyl, or R3, R4 and the carbon atom to which they are attached can form a cyclopropyl ring; R can be hydrogen or Ci-C4 alkyl; W is Ci-C6 alkyl, NR6R7, N (R6) CH2 (CH2) nC (= 0) N (R7) (R8), Cx-Cg alkyl (substituted with halogen, hydroxyl, C02C1-C4 alkyl, CO (C 1 -C 4 alkyl) 2, C (= NH) NH 2, HC (= NH) NH 2, NH 2), C 2 -C 4 alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of C 1 -C 4 alkyl , C1-C4 alkoxy or halogen); 6 7 8 R, R, R are independently chosen from hydrogen or C 1 -C 4 alkyl; X and Y are independently chosen from hydrogen, C1-C10 alkyl or X and Y together can form a lower alkyl chain of (CH2) m; m is 2 or 3; n is 1 or 2. 4. The use of a compound according to claim 1, wherein in formula I: G are chosen from hydrogen, halogen or Ci-C4 alkyl; hydrogen or C (= 0) W; 1 2 R and R are hydrogen; R3 is hydrogen and R4 is methyl or R3, R4 and the carbon atom to which they are attached form a cyclopropyl ring; R5 is hydrogen; W is Ci-Cg alkyl or Ci-C6 alkyl (substituted with halogen, hydroxyl, CON (Ci-C4 alkyl) 2, C (= NH) NH2). 5. The use of a compound according to claim 1, wherein the compound is selected from: 3- (2-aminopropyl) -lfi-indazol-5-ol; 3- (2-aminopropyl) -l-methyl-lff-indazol-5-ol; 3- (5-methoxy-lH-indazol-3-yl) -1-methyl-ethylamine; 3- (2-aminopropyl) -6-fluoro-lf-indazol-5-ol; 3- (2-aminopropyl) -7-methyl-lly-indazol-5-ol; 3- (2-aminopropyl) -6-fluoro-l-methyl-lly-indazol-5-ol; Ester 3- (2-aminopropyl) -lff-indazol-5-ylico of 2-methyl-pro-ionic acid Ester 3- (2-aminopropyl) -lH-indazol-5-yl of 2,2-dimeti-1-propionic acid; 3- (2-Aminopropyl) -lH-indazol-5-yl ester of cyclopropanecarboxylic acid; 3- (2-Aminopropyl) -lH-indazol-5-yl ester of N, N-diethyl-succinamic acid. 6. A compound of the formula: wherein G is selected from hydrogen, halogen or C] __ C4 alkyl; R is hydrogen, C1-C alkyl, C (= 0) W or P (= 0) (OX) (OY), 1 2 R and R are hydrogen; R ~ and R4 and the carbon atom to which they are attached can form a cyclopropyl ring, or in addition R and R together can be (CH2) m to form a saturated heterocycle; and R 4 is hydrogen and Ci-C alkyl; 2 3 1 when R and R are part of a heterocycle, R can be hydrogen or Ci-C alkyl; R3 may be hydrogen or Ci-C4 alkyl; W is C 1 -Ce alkyl, NR 6 R 7, N (R 5) CH 2 (CH 2) n C (= 0) N (R 7) (R 8), OC-CI alkyl C 1, C 1 -C 6 alkyl (substituted with halogen, hydroxyl, C02alkyl Ci-C4f CO (alkyl) Ci-C4) 2, C (= NH) NH2, HC (= NH) NH2, NH2), C2-C4 alkenyl (substituted by phenyl, unsubstituted or substituted by one or more of C1-C4 alkyl, alkoxy of C1-C4 or halogen); R6, R7, R8 are independently chosen from hydrogen or C1-C4 alkyl; X and Y are independently chosen from hydrogen, Ci-Cior alkyl or X and Y can together form a lower alkyl chain of (CR ^ n-; m is 2-4; n is 1 or 2. 7. A compound of the formula: wherein G is selected from hydrogen, halogen or 1-C4 alkyl; R C (= 0) W or P (= 0) (OX) (OY), R1 and R2 are hydrogenated; R3 and R4 are independently chosen from hydrogen, C1-C4 alkyl or R3, R4 and the carbon atom to which they are attached can form a cyclopropyl ring; R can be hydrogen or C1-C4 alkyl; W is Ci-C6 alkyl, NR6R7, N (R5) CH2 (CH2) nC (= 0) N (R7) (R8), CX-C6 alkyl (substituted with halogen, hydroxyl, C02C1-C4 alkyl, CO (Cx-C4 alkyl) 2, C (= NH) NH2, HC (= NH) NH2, NH2), C2-C4 alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of Ci-Cj alkyl , C1-C4 alkoxy or halogen); R 6, R 7, R 8 are independently selected from hydrogen or C 1 -C alkyl X and Y are independently chosen from hydrogen, alkyl? - ??? or X and Y can together form a lower alkyl chain of (CH2) m; m is 2 or 3; n is 1 or 2. 8. The compound of claim 1, wherein: G is selected from hydrogen, halogen or Ci-C4 alkyl; R is C (= 0) W; 1 2 R and R are hydrogen; 3, 4 3 4 R is hydrogen and R is methyl or R, R and the carbon atom to which they are attached can form a cyclopropyl ring; R is hydrogen; is alkyl of C] _-Cg, alkyl-Cg (substituted with halogen, hydroxyl, CON (C 1 -C 4 alkyl) 2, C (= NH) NH 2. 9. The compound according to claim 6, wherein G is selected from hydrogen, halogen or alkyl of R C (= 0) W or P (= 0) (OX) (OY), 1 2 R and R are hydrogen; R, R and the carbon atom to which they are attached can form a cyclopropyl ring, or in addition, R2 and R3 together can be (CH2) m to form a saturated heterocycle; when R 2 and R 3 are part of a heterocycle, R 1 may be hydrogen or C 1 -C 4 alkyl R may be hydrogen or C 1 -C 4 alkyl; W is Ci-C6 alkyl, NR6R7, N (R6) CH2 (CH2) nC (= 0) N (R7) (R8), 0-Ci-C6 alkyl, Ci-Cg alkyl (substituted with halogen, hydroxyl , C02alkyl of C] _- C4, CON (alkyl) Ci-C) 2, C (= NH) NH 2, HC (= NH) NH 2, NH 2), C 2 -C 4 alkenyl (substituted by phenyl, unsubstituted or substituted with one or more of C 1 -C 4 alkyl, alkoxy C1-C4 or halogen); 6 7 8 R, R, R are independently chosen from hydrogen or Ci-Cn alkyl; X and Y are independently chosen from hydrogen, alkyl of. Ci-CiOf or X and Y together can form a lower alkyl chain of (CH2) m; m is 2-4; n is 1 or 2. 10. A compound selected from the group consisting of: 3- (2-aminopropyl) -lily-indazol-5-ol; 3- (2-aminopropyl) -l-methyl-líT-indazol-5-ol; 3- (2-aminopropyl) -6-fluoro-lfl-indazol-5-ol; 3- (2-aminopropii) -7-methyl-lff-indaz-5-ol; 3- (2-aminopropyl) -6-fluoro-l-methyl-lH-indazol-5-ol; 3- (2-aminopropyl) -lfl-indazyl-5-yl ester of 2-methyl-propionic acid; 3- (2-aminopropyl) -lff-indazol-5-yl ester of 2,2-dimethyl-propionic acid; 3- (2-Aminopropyl) -lif-indazol-5-yl ester of cyclopropanecarboxylic acid; 3- (2-Aminopropyl) -lH-indazo-1-5-yl ester of N, N-diethyl-succinamic acid. 11. The use of a compound according to any of claims 1-5 in combination with one or more agents for treating glaucoma, selected from the group consisting of: β-blockers, carbonic anhydrase inhibitors, ai antagonists, agonists < ¾, miotics, prostaglandin analogs, hypotensive and neuroprotective lipids. 12. The use of a compound according to any of claims 1-5 in combination with one or more of the following: thymol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol, brinzolamide, dorzolamide, nipradolol, idopin, brimonidine, pilocarpine, epinephrine, latanoprost, travaprost, unoprostone, iumigan, eliprodii and R-eliprodil. The composition for reducing and controlling normal or elevated intraocular pressure containing a pharmaceutically effective amount of a compound as used in any of claims 1-5 and a carrier or diluent acceptable for pharmaceutical use. 14. The composition according to claim 13 further contains one or more other agents for treating glaucoma. 14. The composition according to claim 14, wherein the other agent is selected from the group consisting of β-blockers, carbonic anhydrase inhibitors, α2-agonist antagonists, miotics, prostaglandin analogs, hypotensive and neuroprotective lipids.