TWI221839B - 6-hydroxy-indazole derivatives for treating glaucoma - Google Patents

Abstract

Novel substituted 1-(alpha-alkyl-ethylamino)-1H-indazol-6-ols useful for lowering and controlling IOP and treating glaucoma are disclosed. A compound of the formula, wherein R1 to R4 are independently chosen from hydrogen, halogen, C1-6alkyl, trifluoromethyl, O-W, C1-6alkylthio, C1-6alkylsulfoxyl, C1-6alkylsulfonyl, or cyano; R5 can be halogen, trifluoromethyl, cyano, NR10R11; R6 and R7 are independently chosen from hydrogen, C1-4alkyl; R8 and R9 are independently chosen from hydrogen or C1-4alkyl; R10 and R11 are independently chosen from hydrogen or C1-4alkyl, or R10, R11 and the nitrogen atom to which they are attached can form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine; R1 to R4 cannot simultaneously be hydrogen; R6 and R7 cannot both be hydrogen; W is hydrogen, C1-4alkyl, or C(=O)X; X is C1-6alkyl, NR8R9, OC1-6alkyl, C2-4alkenyl; and pharmaceutically acceptable salts and solvates of the compounds.

Description

1221839 A7 V. Description of the invention (1) The present invention relates to a novel substitution of 1- (α-alkyl-ethylamine) -1-gas-indazole-6 alcohol. These novel compounds are used to reduce and control normal or elevated intraocular pressure and to treat glaucoma. Detailed description of the invention The condition of glaucoma is characterized by permanent loss of visual function due to irreversible damage to the optic nerve. Several types of glaucoma with different types and functions have the typical characteristic of Nannan intraocular pressure, which is thought to be occasionally related to the pathological pathology of the disease. IOP is a condition in which IOP is elevated but no significant loss of visual function occurs; these patients are considered to be likely to develop into a high-risk group of glaucoma-related vision loss. If glaucoma or high intraocular pressure is detected early and immediately treated with an agent that can effectively reduce the increase in intraocular pressure, the loss of visual function or progressive damage can be gradually improved. Medications that have proven effective in reducing intraocular pressure include agents that reduce the production of aqueous humor and agents that increase their outflow. These treatments are usually administered in one or two possible routes, either topically (directly to the eye) or orally. i Some individuals do not respond well to the use of some existing glaucoma treatments. Therefore, there is a need for other local therapeutic agents that can control intraocular pressure. It has been found that serotonin compounds with agonist activity at the 5- 发现 Τ2 receptor can effectively reduce and control normal and elevated intraocular pressure, and can effectively treat glaucoma. See co-owned co-examined patent application PCT / US99 / 19888. Compounds that act as agonists at the 5-HT2 receptor are known and have shown many different uses, primarily for abnormalities or conditions associated with the medial iliac nerve. U.S. Patent No. 5,494,928 discloses certain 2- (bendo-1) -ethylamine derivatives that can be used to treat compulsive sexual behavior. This paper is sized to the Chinese National Standard (CNS) A4 (21G x 297 g £ 1221839 A7) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (2) 5_HT2 receptor agonist for abnormalities and other personality disorders caused by the central nervous system. US Patent No. 5,571,833 discloses tryptamine derivatives, which can be used to treat 5-HT2 receptor agonist for portal hypertension and migraine. U.S. Patent No. 5,874,477 discloses a method for treating malaria using 5-11 d: ^ / 2 (: agonist. U.S. Patent No. 5,902,815 discloses the use of 5-HT2A agonists for prevention Harmful effects of insufficient NMDA receptor function. Published U.S. Patent No. WO98 / 30548 discloses the selective substitution of 1-ethylamine-1hydro-indazole at the 4-, 5-, 6-, or 7 · position of the ring It has selective affinity for 5-HT2 receptors and is therefore useful for / oral treatment of diseases of the central nervous system. Jnternatianol patent Application Nos. WOOO / 12481 and WQOO / 17170 also disclose other l-ethylamine-1 hydrogen- It has a selective affinity for the 5-HT2c receptor and is therefore useful for the treatment of central nervous system abnormalities. WO 00/35922 discloses certain pyrazino [l, 2-a] oxazine derivatives as 5-HT2C Agonists are used to treat obsessive-compulsive behavioral disorders, depression, eating disorders, and other disorders related to the central nervous system. Agonist responses at 5-HT2A receptors have been reported to be related to the main activity of hallucinogenic activity, compared with 5_ht2c receptors. Fewer associations [Psychopharmacology, v. 121: 357, 1995]. The present invention relates to novel substitutions of 1- (α-alkyl-ethylamine, hydrogen-indazol-6ol. It has been determined that these novel compounds are useful in The serotonin 5- ^ 1-butan-2 receptor has a high affinity and acts as an agonist, and therefore can be used to reduce and control normal or elevated intraocular pressure and to treat glaucoma. When a phenol moiety is included here instead, for example, A hydroxyl group at the 6th position of the indazole ring, these compounds can be particularly sensitive to the oxidation reactions known to often occur in phenol compounds (please read the precautions on the back and then fill out this page). Installation • ϋ ---- Order -----

I ^ 1 1 I Stupid _ This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1221839 A7 V. Description of the invention ('Including relevant mesotryptamine [j. PhyS. Chem. 103,8606 (1999),

Chem. Res. Toxico Ul, 639 (1998), J. Org. Chem. 52, 2817 (1987), J. Pharm. Sci. 77, 911 (1988)], which are particularly relevant to the present invention. Protecting these substitutions from oxidation can be achieved by derivatizing the aryl group to provide a suitable ester, carbamate or carbonate. Although these esters, carbamates or carbonate derivatives do not themselves have a high affinity for the aforementioned receptors, they are useful in the treatment of glaucoma, as properly protected phenols can be passed through the organism Chemically hydrolyzed or cleaved by the action of tissue esters. This cleavage produces the required therapeutic agent, that is, the novel 6-hydroxy-indazole compound required in this case. The concept of using these derived phenolic compounds as chemical carriers is known in the art [Drugs Pham. Sci. 53,221 (1992), Pharm. Res., 168 (1984)]. 'The brief description of the invention i The present invention is related to the novel and known ethylamine derivates and hydrogen derivatives which can be used to reduce and control glaucoma, high intraocular pressure, and warm-blooded animals, including humans, with normal intraocular pressure. Glaucoma. These compounds are manufactured with a pharmaceutical composition suitable for local use in the eye. Explanation of specific examples of trend A The compounds useful according to the present invention are shown in the following chemical formula. This paper size applies the Chinese National Standard (CNS) A4 specification ⑵ G χ 297 public love) 1221839 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _____B7____ V. Description of the invention (7) and (^ -6 alkyl, NR8R9, N (R8) CH2 (CH2) nC (= 0) NR8R9, OCb 6 alkyl, CV6 alkyl (which can be halogen, indyl, (: 02 (^ _ 4 alkyl, con (cv4 alkyl) 2, C ( = NH) NH2, NHC (= NH) NH2, NH2), [2.4 Alkenyl (can be substituted by phenyl, unsubstituted or substituted by one or more CV4 alkyl groups, Cw oxy or oxon); Y and Z are individually selected from hydrogen and alkyl, or γ and Z can form a lower alkyl chain (CH2) m together; m is 3; η is 1 or 2; more preferred compounds are: wherein R1, R3 and R4 can be selected from hydrogen, halogen, Cw alkyl, trifluoromethyl or cyano; R2 can be selected from 0-W; R5 can be hydrogen, CV6 alkyl, halogen, trifluoromethyl, or CV4. Oxygen · R6 is hydrogen and R7 is methyl; R8 and R9 are individually selected from hydrogen or C, _4 alkyl; W is hydrogen, CV4 alkyl or C (= 0) X; X is C, -6 alkyl , NR8R9 or N (R8) CH2 (CH2) nC (= 0) NR8R9; η is 1 or 2; The best compound is: where R1 , R3 and R4 are individually selected from hydrogen or halogen; R2 is 0-W; R5 is hydrogen or (V6 alkyl; R6 is hydrogen and R7 is methyl; This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the notes on the back before filling out this page) Packing --- I ---- Order ----- Hua 1221839 A7

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

R8 and R9 are hydrogen; W is hydrogen, cv4 alkyl; compounds of formula I are known to contain one or more chiral centers. The invention includes all of its enantiomers, diastereomers, and mixtures. In the above definition, the total number of carbon atoms in the substituent aci_j prefix indicates 'its number i and j are the number of carbon atoms; this definition includes a straight bond' branch, and a cyclic alkyl or (cycloalkyl) alkyl. It is important to note that when a substituent is incorporated into the indicated structural unit, it may exist alone or in a majority. For example, a substituted halogen, which represents fluorine, gas, bromine, or iodine, may indicate that the unit to which it is attached may be replaced by one or more halo atoms, which may be the same or different. The compound of formula I can be synthesized according to a similar method known in the art, ie, the compound of formula 1 is prepared, wherein R2 is OH and R1 and R-R are as defined above. The indazole alcohol may be substituted from the appropriate oxygen-protection. (1) Manufacturing, suitable oxygen-protecting groups are, for example, methyl or phenyl, and can be manufactured by methods known in the art as described in Figure 1 [US Patent 5,494,928 (1997), WQ98 / 30548 (1998 )]. Alkylation of salivary 1 with a desired epoxy such as propylene oxide provides the interproduct ethanol 2. Choice of 1 ± 'For some compounds, alkylation with chloroacetone 1 and reduction of the intermediate ketone with NaBH4 to give intermediate 2 are advantageous, for example.

This paper is a medium size specification (210- X 297 mm). ^ -------- Order --------- AWI — (Please read the precautions on the back before filling this page) Printed by Employee Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs Α7

Note-

Indazole 1 can be manufactured by performing appropriate functional group transformations on commercially available indazoles, or it can be manufactured according to procedures in the literature, usually starting with the desired alkoxy-2-amine phenone (5), Or appropriately substituted alkoxyphenone (6) 'end depending on the availability of appropriate precursors (Figure 2) 第 · Heterocycl. Chem. 35? 895 (1998); J. Med. Chem .40, 2706 (1997), Comp. Heterocycl. Chem. II, Vol. 3, 1 (1996)]. Some of these primers can also be manufactured from other indazoles by direct substitution or selective functional group conversion known in the art. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm). 12 items to be filled, please fill in this page.) ---- Order ---- 1221839

V. Invention Description (10 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2

6 Intermediate product 2 of Figure 2 can also be made from appropriately substituted oxy-2-fluoropanone, for example, 6 and 1-diamino-2-propanol [J. Amer · Chem · Soc · 76, 1283 (1954) Reaction in a similar procedure known in the art.] (^ Chem. 41, 5429 (1998)] Compound of formula I, wherein R2 is 0C (= 0) X Similar steps are known in the manufacturing. For example, when the substituted oc (= o) x is competitive with the aforementioned continuous reaction, the compounds can be manufactured in the steps described in Figures 1 and 2. Optionally And, preferably, a compound of the formula [wherein R2 is 0C (= 0) X. The intermediate product can be protected by an appropriate sigmadol 7 or preferably an appropriate amine group, such as 8 (third Figure) React with the desired active acid derivative, such as hydrazone or active ester, or the like, to produce, for example, vinegar 9. Removal of the nitrogen protecting group from the intermediate 9 can provide the desired compound 10 of formula I.- -------- Install -------- Order ---------.-(Please read the notes on the back before filling in this page)

-13-1221839 A7 ____B7 V. Description of Invention (11) Figure 3

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. An indazole derivative that is of interest as a starting material for the production of compound 10 can be produced by the method described above and in Figure 1. The compound of the invention, formula I, can be combined in different kinds of ophthalmic formulations for use in the eye (eg, topically, intraocularly, or via implantation). The compound is preferably incorporated into a topical ophthalmic formulation for use in the eye. The compound can be mixed with ophthalmically acceptable preservatives, surfactants, thickeners, penetration enhancers' buffers, sodium gas, and water to form an aqueous sterilized ophthalmic suspension or solution. Ophthalmic solutions can be formulated by dissolving a compound in a physiologically acceptable isotonic buffer. In addition, the ophthalmic solution may contain an ophthalmically acceptable surfactant to assist the dissolution of the compound. Furthermore, the ophthalmic solution may contain an agent that can increase viscosity, such as methylol fibers, hydroxyethyl fibers, hydroxypropylmethyl fibers, methyl fibers, polychlorinated birrol, or Analogs to increase the formula ----------- installed -------- order --------- • (Please read the note on the back first? Matters (Fill in this page again.) This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm). 14 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1221839 A7 -------- B7 V. Description of Invention (12) Stay in the conjunctival sac. Gels can also be used including, but not limited to, gellan gum and xanthan gum. To make a sterilized ophthalmic ointment formulation, the active ingredient is mixed with a preservative in a suitable carrier, such as mineral oil, liquid lanolin, or white paraffin. Sterile ophthalmic gel formulations can be made by suspending the active ingredient in a hydrophilic base, which is made from a blend such as carbolpol-974 or its analogues, according to published methods for preparing ophthalmic analogues; Preservatives and penetrants can be used in combination. The compound is preferably a topical ophthalmic suspension or solution formulation having a pH of about 5 to 8. The compound will normally make up from 0.01% to 50% by weight in these formulations, but the optimal amount is about 0.25% to 2% by weight. Therefore, according to the instructions of the skilled clinician, when these formulations are applied topically, they are applied 1 to 2 times a day, 1 to 2 drops at a time. The compound can also be used in combination with other agents for treating glaucoma, such as, but not limited to, -blockers (for example, timolol (tim〇1〇1), betaxolol, levobetaxolo, carteolol, levobunolol ), Naproxen (prOpran〇i〇i)), carbon dehydration inhibitors (such as 'brinzolamide and dorzolamide), ai-lead inhibitors (such as nipradolol)' α2 anti-antibodies (such as iopidine and brimonidine) Pupils (such as' pilocarpine and epinephrine), prostaglandin analogs (such as latanoprost, travaprost, unoprostone, and US Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444) Compounds), hypotonic fats (such as the compounds listed in lugigan and 5,352,708), and neuron protective agents (such as the compounds of uS · Patent No. 4,690,931, especially eliprodii and R- This paper applies the Chinese National Standard (CNS) A4 size (210 X 297 mm) 15 Pack -------- Order ----------· (Please read the precautions on the back before filling this page) 12 21839 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs 5. Description of Invention (13) eliprodil, as listed in the pending patent application USSN · 06/203350, and appropriate compounds in W094 / 13275 ' Including memantine). The following examples are provided as preparations for illustrative compounds, which are the subject matter of the present invention, but should not be construed to imply any limitation as to the scope of the patent for this application. Preferred compounds of formula I are illustrated in Examples 2, 5 and 7. Most preferred is the compound of Example 2. The proton nuclear magnetic resonance spectrum of each compound of these examples is consistent with its assigned structure. Method 1 5-H2 Receptor Bonding Analysis To determine the relative affinity of serotonin compounds at the 5_H2 receptor 'and its ability to compete with radiation-labeled [125I] DOI agonists for binding to the brain's 5_H2 receptor, it should be based on the literature The steps are slightly modified to measure. [Neuropharmacology, 26, 1803 (1987)]. A few drops of homogenate of the cerebral cortex (400 // 1) of Post mortem rat were dissolved in 1 ^ 11 (: 1 buffer (pH 7.4) in 5〇1111 ^ and in the absence or presence of methiothepin (10 # Μ final) [125I] DOI (80pM final) was used for incubation, and all and non-specific bonds were measured at a total volume of 0.5ml. The analysis mixture was incubated in a polypropylene tube at 23 ° C for 1 hour, and analyzed to use pre-soak Fast vacuum filtration was terminated in 0.3% polyethyleneimine Whatman GF / B glass fiber filter paper using ice-cold buffer. Test compounds (at different concentrations) were replaced with methiothepin. The filter paper was bonded Radioactivity is measured by a scintillator on a beta counter. The data is analyzed by a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 Mm) 16 ----------- install -------- order --------- Hua (please read the notes on the back before filling this page) Ministry of Economy Printed by the Intellectual Property Bureau's Consumer Cooperatives 1221839 A7 ___ B7 V. Description of Invention (14) 16,413 ( 1995)] to determine the affinity parameter of the compound. The concentration of the compound required to avoid [1251 shell 01 bonding up to 50% is defined as a value of 1 (: 5 (). The compound of the present invention has a high affinity for the 5-H2 receptor, if its ic5 () Value &lt; 50nM. Method 2 5-H2 functional analysis: Phosphoinositide (PI) conversion analysis of the relative agonist activity of the serotonin compound at the 5-H2 receptor, which can be used in a test tube Ability test to stimulate [3H] cyclohexanol phosphate in vascular smooth muscle cells labeled with [3H] myoinositol (A7r5 rat) to activate the enzyme phospholipid c. These cells grow in petri dishes, Maintain a humid climate with 5% CO2 and 95% air and twice a week with 4.5g / l glucose and 2mM glutamine, 10 / g / ml gentamicin, and 10% fetus Bovine serum was fed with Dulbecco's modified Eagle's medium (DMEM). For inositol phosphate (pi) conversion experiments, A7r5 cells were cultured in 24-well plates as previously described [J. Pharmacol, Expt. Ther., 286 , 411 (1998)]. Fusion cells exposed in 0.5 ml serotonin-free matrix 1.5 // Ci [3H] inositol (myo-inositol) (18 · 3 Ci / mmol) 24 to 30 hours. Then the cells were washed with 1 (0_ml) of the same substrate at 37 ° C for 1 hour with the test agent (or a solvent such as the control group), and then washed once with DMEM / F-12 containing 10 mM LiCl. The medium was vented and 1 ml of cold 0.1 M formic acid was added to stop the reaction. [3H &gt; Inositol Phosphate ([3H] -IPs) Chromatographic Separation Method on AG-1-X8 Column as previously described [J · Pharmacol · Expt · Ther · 286,411 (1998)] with water and 50mM Continuous washing with ammonium formate, followed by 1.2M formic acid containing 0.1M formic acid. The size of this paper is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm). 17 ----------- Order --- ------ (Please read the notes on the back before filling this page) 1221839 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (l5) Ammonium extraction of all [3H] -IPs. After the eluent (4 ml) was collected, it was mixed with 15 ml of scintillation liquid, and the total amount of [3H] _Ips was measured by a scintillation count on a beta counter. Concentration response data was analyzed using an S-shaped curve of Origin Scientific Graphics software (Microcal Software, Northampton, MA) with a function to measure its agonist capacity (EC5G value) and potency (Emax ·). Serotonin was used as a positive control (standard) agonist compound and the potency of the test compound was compared to that of 5-H2 (set to 100%). Can increase up to 5000 /. The concentration of compounds required for the production of [3H] -Ips is defined as the EC5G value. If its EC50 value is <2.5 // M in this functional analysis, the compound can be regarded as a potent agonist, and if its potency (Emax.)> 80% of 5-H2, it can be regarded as a full agonist. Use the above steps to generate the data shown in Table 1. Table 1. 5-H2 Bonding and Functional Information Compounds IC50, nM EC50, &quot; M potency (E_ ·) (Emax.,%) Α-methylserotonin 3.5 189 104 Example 1 3.1 578 71 Example 2 3.0 483 87 Example 4-243 73 Example 5 2.0 541 64 Example 6 2.2 1050 84 Example 1 6- (Methoxy-3-methylj inzolemethylethylamine fumarate step A 6-methoxy-3-methyl-1 hydrogen-bow | σ sitting in ethanol solution (20ml) of 2-fluoro-4 · methoxyketophenol (i.90g, U 3mm〇1) Add hydrazine hydrate (4, 4ml, 45 mm) and heat at reflux temperature for 6 hours. The mixture evaporates to produce a residue. Add ethylene glycol (iomi). The paper size applies Chinese national standards (CNS). ) A4 specification (210 X 297 public love) ------------- Order --------- ^ 9 (Please read the precautions on the back before filling this page) 18 A7

V. Description of the Invention (l6) (Please read the notes on the back before filling this page). The mixed solution was heated to 150 ° C for 18 hours, cooled to room temperature, diluted with water (50 ml) 'and extracted with one-shot methane (3 X 60 ml). The mixed extract was washed with brine (10 ml), dried (magnesium sulfate) and evaporated to a residue. It was recrystallized from ethyl acetate to give a solid (l lg, 59%): MS (ES) m / z 163 ( M +) 〇 Step B: 1- (6-methoxy-3-methyl-1-indazol-i) -propane-2-one at room temperature over the product from Step A (1.1 g, 6.7 mmol) To a solution of DMF (10 ml) was added sodium hydride (60% in oil, 0.4 ig, 10.2 mmol). Stir for 30 minutes, add gaseous acetone (0 79 ml, 102 mln), and heat the solution at 60 C for 5 hours. The reaction mixture was diluted with saturated gasified ammonium solution (100 μm) and extracted with ethyl acetate (3 × 65 ml). The mixed extract was washed with brine (10 mL) 'dried (magnesium sulfate), and evaporated to a residue which was purified by chromatography (silica, 20% to 30% ethyl acetate in hexanes) to yield An oil (1.3 g, 88%); MS (ES) m / z 219 (M +) 〇 Step C: 1- (6-methoxy-3-fluorenyl-hydroxyind-1) -propane-2-ol Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, a hydrogenated pendant (0.21 g, 5.5 mmol) was added to a solution of the product of Step B (1.2 g, 5.5 mmol) in MeOH (10 ml) at room temperature. After stirring at room temperature for 2 hours, the solution was evaporated and a saturated ammonium chloride solution (10 ml) was added; the mixture was extracted with ethyl acetate (3 x 50 ml). The mixed extract was washed with brine (10 ml), dried (magnesium sulfate), and evaporated to a residue which was purified by chromatography (Shi Xi, 20% to 30% in ethyl acetate). An oil was produced (0.68 g, 56%); MS (ES) m / z 221 (M +). Step D: 1- (2-Azidepropene) -6-methoxy-3 -methyl-1 hydrogen. Dichloromethane produced at step C (0.66 g, 3.0 mmol) at 0 ° C via σ. Kraft 19 This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) 1221839 A7

V. Description of the Invention (i7) (Please read the precautions on the back before filling this page) (10ml) Add dimethylamine (〇55ml, 39 betaine and methanesulfonyl chloride (0.31ml, 3.9mm) to the solution. l). After stirring for 30 minutes, diethyl ether (50 ml) &amp; water (50 ml) was added. The organic layer was separated and the aqueous layer was extracted with ether (2 x 50 ml). The mixed extract was washed with brine (30 ml) and dried (Magnesium sulfate), and evaporated. The mixture was heated to 70 C for 12 hours, poured into water, and extracted with ethyl scale (3 X 50 ml). The combined extract was washed with brine, dried (magnesium sulfate), and evaporated to a residue. Material, which was purified by chromatographic analysis (silicon, hexane to 10% ethyl acetate in hexane) to give an oil (0.5ig, 69%); MS (ES) m / z 246 (M +) 〇Step E: 2- (6-methoxy-3-methyl-hydroxyindylethylamine fumarate salt of the product of Step D (0.50 g, 2.0 mmol) at room temperature To the methanol solution was added palladium in carbon (10%, 0.10 g). The suspension was stirred under nitrogen for 18 hours. The reaction mixture was filtered through a filtration aid and the filtrate was evaporated to a residue ( .43 g, 96%) which can be converted to fumarate and crystallized from methanol / acetamidine to give a colorless solid (0.27 g): mp 150-152. MS; (ES) m / z 191 (M +). Analysis. Calculate c12H17N3O.1.0C4H4O4: 1.0 CH30H: C, 55.58; H, 6.86; N, 11.44. Found: C, 55.41 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; Η, 6.85; N, 11.37. Example 2 1- (2-Aminopropyl) -3 -methyl-1 hydrogen-sigma-6-ol fumarate Step A: 1- (4-phenoxy- 2-Gas-Phenyl) -Yigang will add acid chloroform (5.5g, 40.0mmol) and phenyl bromide (4.6ml, 3 8.9111111〇1) to 2-fluoro-4-mercaptan (5. (^ , 32.4111111〇1) of ethanol 20 This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm)! 221839

In the solution printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (50ml), the mixed solution was heated at reflux temperature for 16 hours. The reaction mixture was evaporated to give a residue to which 2N hydrochloric acid (100 ml) was added. The mixture was extracted with ether (3 x 60 ml) and the combined extracts were washed with brine (10 mL), dried (magnesium sulfate), and evaporated to a residue, which crystallized from ethyl acetate (7.4 g, 93%) ); MS (ES) m / z245 (M +). Step B: 6-phenoxy-3-methyl-1hydro-ind. A solution of the product of Step A (7.4 g, 20.3 mmol) in ethanol (20 mL) was treated according to the method described in Step A of Example 1 to give a colorless solid (61 g, 69%): MS (ES) m / z 239 (M +). Step C: 1- (6-phenoxy-3_methyl_indazolpropanone) DMF solution (10 ml) of the product (2.3 g, 9.7 mmol) obtained from step B, as described in step 1 of Example 1 Processed to produce a residue that was used without purification in the next step: MS (ES) m / z 295 (M +). Step D: 1 · (6-phenoxy-3-methyl-indazole-1 ). Propanol from MeOH (10 ml) of the product obtained in step C (3.3 g, 5.5 mmol) was treated according to the method described in step C of Example 1 to produce an oil (0 30 g, 10%); MS (ES ) m / z297 (M +). Step E: 1- (2-Azide-propyl) -6-phenoxyaspartyl "hydrogen, azole from the product obtained in step D (0.28 g, 0.95 mmol). The gas-fired solution (10ml) was processed in the order described in step 1 of Example 1 to produce an oil (0.16g, 52%); MS (ES) m / z322 (M +). Step F: 1- (2-amine The propyl) -3-amidino-1hydrobongo-6-alcohol fumarate product from step E (0.16 g, 0.50 mmol) in methanol was treated as described in step E of Example 1 to A kind of residue (0.10g, 97%) is produced. The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 21 ^ Packing -------- Order --------- (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1221839 A7 _ B7 V. Description of the invention (19), which can be converted into fumarate and crystallized from a methanol / ether mixture to produce a colorless solid (0.11 g): mp 166-168 ° c; MS (ES) m / z 206 (M + ). Analysis. Calculate Ci # ^ 1 ^ 0.1.8 (: 411404 :( :, 52.78: 1 ^ 5.40; N, 10.15. Found: C, 52.45; H, 5.53; N, 10.29. Example 3 2 1,2-Dimethyl-propionic acid 1- (2-aminopropyl) -1 hydrogen-indazole-6-ester fumarate Step A: 2,2-Difluorenyl-propionic acid-1 hydrogen -Indazole-6-ester in a dihydromethane solution (10ml) of 1hydro-indazole-6-ol (0.88g, 6.6mmol) at room temperature, and triethylamine (0.98ml, 7.0) was added mm〇1) and DMAP (0.05g), followed by the addition of trimethyl chloride (0.82ml, 6-6mmol). After stirring for 1 hour, the mixture was diluted with saturated ammonium chloride solution (20ml) and ethyl acetate was added. Ester extraction (3 X 50 ml). The combined extracts were washed with brine (10 ml), dried (magnesium sulfate), and evaporated to a residue, which was analyzed by chromatography. Purified (silicon, 10% to 20% ethyl acetate in hexanes) to produce an oil (1.1 g, 76%): 4 NMR (CDC13) 5 8.15 (d, J = 0.8 Hz, 1H), 8.01 ( s, lH), 7.75 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.01 and 6.96 (dd, J = 2.0 and 8.6 Hz, 1H), 1.59 (s, 9H); MS (ES ) m / z 219 (M +). Step B · 2,2-dimethyl-propionic acid 1- (2-oxo-propyl) -ihydro-indazole-6-ester solution of the product of Step A (1.5 g, 6.9 mmol) in DMF (10 ml) Processed as described in Step B of Example 1 to produce an oil (13g, 62%): 4 NMR (CDC13) 5 8.09 (d, J = 0.8 Hz, 1H), 7.99 (s, 1H), 7.90 (s , 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.01 and 6.96 (dd, J = 2.0 and 8.6 Hz, 1H), 4.64 (s, 2H), 2.21 (s, 3H), 1.56 ( s, 3H), this paper size applies to China National Standard (CNS) A4 specification (210 X 297 public love) 22 --------_-- installation -------- order ----- ---- (Please read the notes on the back before filling this page) 1221839 A7 ------- B7 V. Description of the invention (20) 1.27 (s, 6H); MS (ES) m / z 275 ( M +). Step c: A solution of 2,2-dimethyl-propionate hydrazine · propyl sulfonium · 6 · vinegar The methanol solution of the product obtained from step B (0.91g, 3.6 · 1) in accordance with the examples The process described in step 1 c was used to produce an oil (079 g 86%), which was used in the next reaction without purification. Lfi NMR (eDei ^ 5 7.99 (s, lH), 7.98 (s, 1H) , 7.60 (d, J = 8.6 HZ, 1H), 7 〇1 and 6.96 (dd, J = 2.0 and 8.6 Hz, 1H), 4.14-3.89 (m, 3H), 156 (s, 3H), 1.32 (s ， 9H) 〇 Step D: 2,2-dimethyl-propanoic acid azide, propyl hydrogen, indazole, 6 ιιια dichloromethane solution of the product obtained from step C (1.70 g, 6.2 mmol) (10ml) was treated according to the method described in step D of Example 1 to produce an oil (1.30g, 69%); MS (ES) m / z274 (M + -28). Step E · 2,2-monomethyl- Propionic acid 1- (2-aminopropyl) -1 nitrogen-π-sialo-6-methyl fumarate obtained from step D (1.25 g, 4.1 mmol) in methanol solution according to Example 1 step The process described in E is used to produce an oil (0.13 g, 88%), which can be treated with fumaric acid, and the resulting salts are in a mixture of methanol and ether Crystal to give a colorless solid: mp 180-1821: 屮 NMR (DMSO-d6) 5 8 · 37 (s, lH), 7_89 (s, lH), 7.82 (d, J = 8.6 Hz, 1H), 7 · 12 (d, J = 8.6 Hz, 1H), 6.45 (s, 2H), 4.18-4.01 (m, 2H), 3.5 (m, 1H), 1.50 (s, 9H), 1.30 (d, J = 6.6 Hz, 3H); MS (ES) m / 2: 276 (M +). Analysis. Calculate C15H21N302.1.2C4H404: C, 57.36; H, 6.27; N, 10.13. Found: C, 56.98; H, 6.57; N, 10 · 22. This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page). --- II --- Order--I-- -Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 23 ^ 21839 A7 R7 $, Description of Invention (21) Example 4 2- (6-methoxy-indazole-1) -1-methyl-ethylamine ( Please read the note on the back? Matters before filling out this page) Step A: p- (6-hydroxy-indazole-1) -1-methyl-ethyl] -phenyl carbamate at room temperature at 1- (2-Aminopropyl)-, sialo-6-ol (0-46 g, 2.4 mmol) in a THF solution (10.0 mL) was added a saturated sodium bicarbonate solution (2.0 ml) and propyl formate chloride (0.40 mL) . After stirring for 1 hour, the mixture was diluted with a 1N hydrogen acid solution (10 mL) and ammonium vaporized (10 mL) and extracted with ethyl acetate (3 × 50 mL). The mixed extract was washed with brine (10 mL), dried (magnesium sulfate), and evaporated to a residue, which was used in the next step without purification (0.75 g, 98%); MS (ES) m / z 236 (M +). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Step B: [2- (6-methoxy-indazole-1) -1-methyl-ethyl] -phenylcarbamate at step A at room temperature To a solution of the product (0.95 g, 3.19 mmol) in DMF (10 mL) was added carbonic acid shaving solution (1.26 g, 3.70 mmol) and methane iodine (0.40 mL, 3.70 mmol). After stirring for 3 hours, a saturated ammonium chloride solution (30 mL) was added and the mixture was extracted with ethyl acetate (3 X 65 mL). The combined extracts were washed with brine (10 mL), dried (magnesium sulfate) and evaporated to a residue, which was purified by chromatography (silica, 20% ethyl acetate in hexanes to 30% acetic acid in hexanes) Ethyl) to give a syrup (063g, 92%): MS (ES) m / z 340 (M +). Step C: 2- (6-methoxy · indazole-1) -1-fluorenyl-ethylamine at room temperature under nitrogen in a methanol solution of the product obtained from step B (0.68 g, 2.0 mmol) To this was added palladium / carbon (1 ()%, 0.10 g). The mixture was stirred under nitrogen for 20 hours and filtered through a filtration aid. The filtrate was mixed with the residues', which was purified by chromatographic analysis (crushed, 5% on dichloromethane paper) Applicable to China National Standard (CNS) A4 (210 X 297 mm) 24 1221839 A7 __B7 V. Invention Note (22) (Please read the notes on the back before filling this page) Burning methanol to 10% methanol in dichloromethane) to produce a syrup (0.40g, 97%). Treatment of the syrup with fumaric acid yields a residue 'which is recrystallized in methanol / ether to give a colorless solid: mp 151-152 C; MS (ES) m / z 206 (M +). analysis. Calculation (^ ηΗ15N30 · 1.0 C4H404 · 1.0 H20: C, 53.09; H, 6.24; N, 12.38. Found: C, 52.88; H, 6.31; N, 12.14. Example 5 2- (3- 气 -6 -Methoxymethoxy-ι) -fluorene-methyl-ethylamine Step A: 2-Hydrazine-4 "methoxy-benzoic acid 2-Ethylamino-4-methoxy-benzoic acid ( i5g, 73.7mmol) in water (75ml) was cooled to -5 ° C, and concentrated hydrochloric acid (150ml) was added after cooling to -5 ° C. To this solution was added 1 ^ 1 ^. 2 (5 43§ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 77.4 mmol) aqueous solution (50 ml); this solution should be added at a rate that can maintain the temperature of the reaction mixture between -5 ° and 0 ° C. Reaction The mixture was stirred for 10 minutes and to the clear solution was added a solution of stannous stannous (41.9 @, 221111111〇1) concentrated hydrochloric acid (15〇1111) which had been cooled to -20 ° C. The temperature of the reaction mixture was maintained during the addition Between -20. To -10 ° C, and then stir the mixture for 1.5 hours at -20 ° C. The solid formed was collected by filtration, rinsed with cold EtOH, and dried to give an off-white solid (l0. .8g): APCI / LCMS m / z 183 (M + H) +. Step B: 6-Methoxy_1hydro-indazol-3-ol product of step A (10.5 g, 48 mmol), water (250 ml) and concentrated hydrochloric acid (2.5 ml) were mixed The solution was refluxed for 30 minutes. The volume of the reaction mixture was reduced by evaporation (approximately 100ml) and the saturated sodium carbonate solution was slowly added to adjust the pH to 25 at room temperature. 1221839 A7

5. Description of the invention (23) Rounded to 7. The solid formed upon standing was collected and dried to give a gray solid (6.8g) ·· APCI / LCMS m / z 165 (M + H) + 〇 Step C · 3-Gas-6-methoxy · 1 Hydrogen In a solution of the product of step B (lg, 6.1 mmol) (0.5 ml, 6.1 mmol), oxychlorinate (0.9 ml, 9.2 mmol) was added, and the mixture was heated at 130 to 140 ° C for 5 minutes. hour. The reaction mixture was cooled to 70. Afterwards, it was poured into ice (100 g). After standing for 24 hours, the resulting solid was collected and dried to give a cream-colored solid (0.42 g): ES / LCMS m / z 181 (MH) + 〇 Step D: [2- (3- 气 -6- 甲Oxy-indazole-1) -1-methyl-ethylamine] -carbamic acid benzoic acid is aimed at the product of step C (0.18g, 1 mmol) and (2-bromo-1-methyl-ethyl) To a solution of phenyl carbamate (0.27 g, 1 mmol) in DMF (2 ml) was added potassium carbonate (0.17 g, 1.2 mmol), and the mixture was stirred at 75 ° C. for 18 hours. Ethyl acetate (20 ml) and water (20 ml) were added to the reaction mixture, and the aqueous layer was separated and extracted with ethyl acetate (3 X 20 ml). The mixed extract was rinsed with brine (30 mL), dried (magnesium sulfate) and evaporated to give a residue. Phase analysis and purification (silicon, hexane to 15% ethyl acetate in hexane) to produce a syrup ( 0.27g): APCI / LCMS m / z 374 (M + H) + 〇 Step E: 2- (3-Ga-6-methoxy-indazole-1) -1-methyl · ethylamine under nitrogen Next, a solution of the product of step D (0.15 g, 0.4 mmol) in 1,2-dichloromethane (4 ml) was added with borontribromo-dimethylsulfonate complex (2.4 mmol, 2,5 mL in 1,2- IN gas solution of methane gas), and the mixture was heated at 84 ° C for 3 hours. After cooling, a saturated sodium bicarbonate solution (5 ml) was added and the mixture was extracted with chloroform (3 X 10 ml). Bring the mixed extract to brine (10 mL). The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm). ---------- Order ---------- ^ 91 f Please read the notes on the back before filling in this page} Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 26 1221839 A7 B7 V. Description of the invention (24) Rinse, dry (magnesium sulfate), and purify by chromatography (C-18RP-HPLC, 5% acetonitrile / water to 70% acetonitrile / water containing 0.1% trifluoroacetic acid) to produce a residue (0.03 g) which can be converted to dihydrochloride: ESI / LCMS m / z 240 (M + H) +. Example 6 1- (2aminopropyl) -3-gas-1hydro-indazol-6-ol The solution of the product (0.1 g, 0.27 mmol) obtained from step D of Example 5 was as described in Example 5 Step E. Processed, but the reaction mixture was heated for 8 hours to produce a syrup (0.015 g), which was converted to the dihydrochloride salt; ESI / LCMS m / z226 (M + H) +. (Please read the precautions on the back before filling out this page) Example 7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Composition (wt%) 1- (2-Aminopropyl) -3-methyl-1 hydrogen- Indazole-6-alcohol fumarate 0.01-2% hydroxypropylmethyl fiber 0.5% sodium dihydrate (anhydrous) 0.2% sodium chloride 0.5% disodium EDTA (disodium ethylenediamine tetraacetate) ) 0.01% polyethoxy ether 80 0.05% benzyl ammonium chloride 0.01% sodium hydroxide / hydrochloric acid used to adjust the pH to 7.4 pure water to about 100% 27 This paper applies Chinese national standard (CNS) A4 Specification (210 X 297 mm) 1221839 A7B7 V. Description of the invention (25) Printed in Example 8 of the Intellectual Property Office of the Ministry of Economic Affairs and Consumer Cooperatives. Composition 8 (wt%) 1_ (2_aminopropyl) -3-methyl- 1 Hydrogen-indazole-6-alcohol fumarate 0.01-2% fluorene-based fibers 4.0% sodium dibasic phosphate (anhydrous) 0.2% sodium gasification 0.5% disodium EDTA (disodium ethylenediamine tetraacetate) 0.01% Polyethyl milk basis test 80 0.05% Benzonium chloride 0.01% Sodium hydroxide / hydrochloric acid is used to adjust the pH to 7.4 Pure water to about 100% Example 9 Composition (wt%) 1- (2 -Aminopropyl) -3-methyl-1hydro-ind -6-Alcohol fumarate 0.01-2% Guanhua bean gum 0.4-0.6% Sodium dibasic phosphate (anhydrous) 0.2%-Sodium gasification 0.5% disodium EDTA (disodium ethylenediamine tetraacetate) 0.01 % Polyethoxy ether 80 0.05% Phenyl ammonium chloride 0.01% Sodium hydroxide / hydrochloric acid is used to adjust the pH of pure water to about 100% (Please read the precautions on the back before filling this page) This paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 28 1221839 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs V. Description of Invention (26) Example 10

Ingredient Amount (wt%) 1- (2-Aminopropyl) -3-methyl-1hydro-triazole-6-ol fumarate 0.01-2% White paraffin, mineral oil and sheep fat ointment Consistency test sodium phosphate (anhydrous) 0.2% sodium chloride 0.5% disodium EDTA (disodium ethylenediamine tetraacetate) 0.01% polyethoxy ether 80 0.05% vaporized benzyl ammonium 0.01% sodium hydroxide / hydrogen Chloric acid is used to adjust the pH. -------- Order --------- (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 29

Claims (1)

1221839 AS B8 C8 D8 7. Application for profit-seeking scope No. 89125127 Patent application 'application for amendment of patent scope 1. A compound with the following chemical formula: R9 \ / N 93.05.07 (Please first print on the back of Mt5 by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics and Intellectual Property, where R1 to R4 are individually selected from hydrogen, halogen or Cw alkyl, trifluorofluorenyl, 0-W, Cw alkylthio, Cw is selected from alkyloxythio, sulfosulfanyl, or cyano; R5 may be il, trifluorofluorenyl, cyano, NR1GRn; R6 and R7 are individually selected from hydrogen and C3.4 alkyl; R8 and R9 is individually selected from hydrogen or Cw alkyl; R1G and R11 are individually selected from hydrogen or C] .4 alkyl, or R1G, Rn and the nitrogen atom they adsorb can form a saturated heterocyclic ring, which is selected from pyrrolidine , Piperidine, piperidine, or morpholine; R1 to R4 cannot be hydrogen at the same time; R6 and R7 cannot be both hydrogen; W is hydrogen, Cw alkyl, or C (= 0) X; X is C] -6 alkane , NR8R9, OC], alkyl, C2.4 alkenyl; and pharmaceutically acceptable salts and solvates of the compound. 2. The compound according to item 1 of the scope of patent application, wherein: 2Individually fill in this page from hydrogen, halogen, Cw alkyl, trifluorofluorenyl, OW) -30-1221839 (Please close the back of the note before cooking. Then fill out this page) I A3 B3 C3 D3 VI. Application Patent scope Cw group thio, Cw group oxythio, Cw group continuation, or cyano; R3 to and R4 are individually selected from hydrogen, halogen, Cw alkyl, trifluoromethyl or cyano R5 can be halogen or trifluorofluorenyl; R6 and R7 are individually selected from hydrogen and 4 alkyl; R8 and R9 are individually selected from hydrogen or Cw alkyl; R] to R4 cannot be hydrogen at the same time; R6 and R7 cannot be Both are hydrogen; W is hydrogen, C] .6 alkyl, or C (= 0) X; 'X is Cw alkyl, NR8R9, OCw alkyl, C2.4 alkenyl. 3. For example, the compound in the first item of the patent application range, where R], R3 and R4 are individually selected from hydrogen, halogen, Cw alkyl, trifluorofluorenyl or cyano; R2 can be selected from 0-W R5 can be halogen or trifluorofluorenyl; R6 is hydrogen and R7 is fluorenyl; RS &amp; R9 is individually selected from hydrogen or Cyalkyl; W is hydrogen, Cw alkyl or C (= 0) X; X is Cw alkyl, or NRSR9. 4. For example, the compounds in the scope of patent application No. 1 in which: R1, R3 and R4 are individually selected from hydrogen or halogen; R2 is 0-W; R5 is halogen or trifluorofluorenyl; (Please close 15 back first Please note this page before filling in this page) »----! Printed by the Consumer Property Cooperative of the Ministry of Intellectual Property Bureau 1221839 AS BS C8 D8 VI. The scope of patent application R6 is hydrogen and R7 is 曱 '; R8 and R9 Is hydrogen; W is hydrogen, Cw alkyl. 5. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of: 1- (2-aminopropyl) -3-chloro-1hydro-indazole-6-ol, and 2 -(3-chloro-6-methoxy-indazol-1-yl) -1-methyl-ethylamine. 6. · A local ophthalmic composition for reducing and controlling normal or elevated intraocular pressure and treating glaucoma, which includes a pharmacologically effective amount such as in the scope of patent application No. 1, 2, 3, 4 or 5 Item of compounds. (Please fill in this page with M'tsf's note first) Printed by the Consumer Consumption Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs; '4