Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics

Definitions

• the present invention is directed to novel substituted l-( ⁇ -alkyl-efhylamino)- lH-indazol-6-ols. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
• IOP intraocular pressure
• glaucoma The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve.
• the several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease.
• Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma.
• Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP.
• Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
• Patent 5,571 ,833 discloses tryptamine derivatives that are 5-HT 2 agonists for the treatment of portal hypertension and migraine.
• U.S. Patent 5,874,477 discloses a method for treating malaria using 5-HT 2A/ c agonists.
• U.S. Patent 5,902,815 discloses the use of 5-HT 2A agonists to prevent adverse effects of NMDA receptor hypo- function.
• Published International Patent Application No. WO98/30548 discloses that selected 1-ethylamino-lH-indazoles substituted at ring positions 4-, 5-, 6-, or 7- have selective affinity for the 5- ⁇ T 2 c receptor and thereby have utility in the treatment of central nervous system diseases.
• WO00/ 12481 and WO00/17170 disclose yet other 1-ethylamino-lH-indazoles that have selective affinity for the 5- ⁇ T 2 c receptor and thereby have utility in the treatment of disorders of the central nervous system.
• Published International Patent Application No. WO98/31354A2 discloses 5-HT 2B agonists for the treatment of depression and other CNS conditions.
• WO00/35922 discloses certain pyrazino[l ,2-a]quinoxaline derivatives as 5-HT 2 c agonists for the treatment of obsessive-compulsive disorder, depression, eating disorders, and other disorders involving the CNS.
• Agonist response at the 5-HT 2A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT c receptor possible [Psychopharmacology, Vol. 121 :357, 1995].
• the present invention is directed to novel substituted 1 -( ⁇ -alkyl-ethylamino)- lH-indazol-6-ols. It has been determined that these novel compounds have a high affinity for and function as agonists at the serotonergic 5- ⁇ T receptor, and are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma.
• IOP intraocular pressure
• a phenolic moiety e.g. a hydroxyl group at indazole ring position six, such compounds can be particularly sensitive to oxidation reactions well known to occur with phenolic compounds in general, including hydroxytiyptamines [J. Phys. Chem. 103, 8606 (1999), Chem. Res.
• ester, carbamate, or carbonate derivatives do not themselves possess a high affinity for the above mentioned receptors, they do have utility in the treatment of glaucoma since suitably protected phenols can be cleaved in vivo either by chemical hydrolysis or through the action of tissue esterases, thereby delivering the desired therapeutic agent, that is, the desired novel 6-hydroxy-indazole compounds of the present invention.
• the concept of utilizing such derivatized phenolic compounds as chemical delivery agents is well known in the art [Drugs Pharm. Sci. 53, 221 (1992), Pharm. Res., 168 (1984)]. Summary of the Invention
• the present invention is directed to new and known derivatives of 1- (ethylamino)-lH-indazole that can be used to lower and control IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma in warm-blooded animals, including man.
• the compounds are formulated in pharmaceutical compositions suitable for topical delivery to the eye.
• R 1 to R 4 are independently chosen from hydrogen, halogen, Cj- alkyl, trifluoromethyl, O-W, C ⁇ - 6 alkylthio, C]- 6 alkylsulfoxyl, C ⁇ - 6 alkylsulfonyl, or cyano;
• R 5 can be hydrogen, C ⁇ - 6 alkyl, or halogen, trifluoromethyl, cyano, NR 10 R n ;
• R 6 and R 7 are independently chosen from hydrogen, C ⁇ alkyl or R 6 , R 7 and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R 7 and
• R 8 together can be (C ⁇ 2 ) m to form a saturated heterocycle
• R 8 and R 9 are independently chosen from hydrogen or R and R 11 are independently chosen from hydrogen or C ⁇ alkyl, or R 10 , R 1 ' and the nitrogen atom to which they are attached can form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
• R to R cannot simultaneously be hydrogen
• R 6 and R 7 cannot both be hydrogen;
• Y and Z are independently chosen from hydrogen, C ⁇ - 10 alkyl or Y and Z can together form a lower alkyl chain of (CH 2 ) m ; m is 2 - 4; n is 1 or 2; and pharmaceutically acceptable salts and solvates of the compounds of Formula I.
• R 1 to R 4 are independently chosen from hydrogen, halogen, C ⁇ . 6 alkyl, trifluoromethyl, O-W, C]_ alkylthio, Ci- ⁇ alkylsulfoxyl, C ⁇ - alkylsulfonyl, or cyano;
• R 5 can be halogen, trifluoromethyl, cyano, NR 10 R ⁇ ;
• R 6 and R 7 are independently chosen from hydrogen, or R 6 , R 7 and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore, R 7 and
• R together can be (CH ) m to form a saturated heterocycle
• R 8 and R 9 are independently chosen from hydrogen or Ci ⁇ alkyl
• R 10 and R 11 are independently chosen from hydrogen or or R 10 , R n and the nitrogen atom to which they are attached can form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
• R 1 to R 4 cannot simultaneously be hydrogen
• R 6 and R 7 cannot both be hydrogen
• 6 alkyl (which can be substituted with halogen, hydroxyl, CO 2 C ⁇ - alkyl, CON(C ⁇ - 4 alkyl) 2 ,
• Y and Z are independently chosen from hydrogen, CM O alkyl or Y and Z can together form a lower alkyl chain of (CH ) m ; m is 3 or 4; n is 1 or 2; and pharmaceutically acceptable salts and solvates of the compounds of Formula I.
• Preferred compounds are:
• R and R are independently chosen from hydrogen, halogen, C ⁇ - 6 alkyl, trifluoromethyl, O-W, C ealkylthio, C ⁇ - 6 alkylsulfoxyl, C ⁇ - 6 alkylsulfonyl, or cyano;
• R 3 and R 4 are independently chosen from hydrogen, halogen, C ⁇ - 6 alkyl, trifluoromethyl, or cyano;
• R 5 can be hydrogen, C ⁇ - alkyl, halogen, trifluoromethyl, or d ⁇ alkoxy;
• R 6 and R 7 are independently chosen from hydrogen or C ⁇ - alkyl, or R 6 , R 7 and the carbon atom to which they are attached can form a cyclopropyl ring, or furthermore,
• R 7 and R 8 together can be (CH 2 ) m to form a saturated heterocycle
• R 8 and R 9 are independently chosen from hydrogen or d ⁇ alkyl
• R 1 to R 4 cannot simultaneously be hydrogen
• R 6 and R 7 cannot both be hydrogen;
• Y and Z are independently chosen from hydrogen, C ⁇ - ⁇ 0 alkyl or Y and Z can together form a lower alkyl chain of (CH 2 ) m ; m is 3; n is 1 or 2;
• R 1 , R 3 , and R 4 are independently chosen from hydrogen, halogen, C ⁇ - 6 alkyl, trifluoromethyl, or cyano;
• R 2 is chosen from O-W;
• R 5 can be hydrogen, d- 6 alkyl, halogen, trifluoromethyl, or R 6 is hydrogen and R 7 is methyl;
• R 8 and R 9 are independently chosen from hydrogen or d ⁇ alkyl;
• n is 1 or 2;
• R 1 , R 3 , and R 4 are independently chosen from hydrogen or halogen;
• R 2 is O-W;
• R 5 is hydrogen or C ⁇ . 6 alkyl
• R 6 is hydrogen and R 7 is methyl
• R and R are hydrogen; W is hydrogen, Cj- 4 alkyl; It is recognized that compounds of Formula I can contain one or more chiral centers. This invention contemplates all enantiomers, diastereomers and, mixtures thereof.
• the total number of carbon atoms in a substituent group is indicated by the C,-, prefix where the numbers i and j define the number of carbon atoms; this definition includes straight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups.
• a substituent may be present either singly or multiply when incorporated into the indicated structural unit.
• the substituent halogen which means 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.
• the compounds of Formula I can be prepared by processes analogous to those known in the art.
• the preparation of compounds of Formula I wherein R 2 is OH and R 1 and R 3 -R 5 are as defined above can be prepared from the appropriate C-protected substituted-indazol-6-ol (1), suitable O-protective groups are e.g. methyl or benzyl, and can be prepared by methods well known in the art and described in Scheme 1 [U.S. Patent 5,494,928 (1997), WO98/30548 (1998)].
• Alkylation of indazole 1 with the desired epoxide, e.g. propylene oxide provides the intermediate alcohol 2.
• the indazoles 1 can be prepared by conducting suitable functional group transformations on indazoles that are commercially available or that can be prepared according to literature procedures, generally starting from either the desired alkoxy-2- aminophenyl ketone (5), or the suitably substituted alkoxy-2-fluorophenyl ketone (6), depending on availability of suitable precursors (Scheme 2) [J. Heterocycl. Chem. 35, 895 (1998); J. Med. Chem. 40, 2706 (1997); Comp. Heterocycl. Chem. O, Vol. 3, 1
• indazoles 1 can be prepared from other indazoles 1 by direct substitution or by selective functional group transformations well known to the art.
• indazole derivatives of interest for use as starting materials for the preparation of compounds 10 can be prepared by methods described above and in Scheme 1.
• the compounds of this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
• the compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye.
• the compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
• Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
• the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
• the ophthalmic solution may contain an agent to increase viscosity, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
• Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
• the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
• Sterile ophthalmic gel formulations may 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 the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
• the compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8.
• the compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.25% to 2% by weight.
• 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
• the compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, ⁇ -blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), ⁇ i antagonists (e.g.
• ⁇ -blockers e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol
• carbonic anhydrase inhibitors e.g., brinzolamide and dorzolamide
• ⁇ i antagonists e.g.
• ⁇ 2 agonists e.g., iopidine and brimonidine
• miotics e.g., pilocarpine and epinephrine
• prostaglandin analogs e.g., latanoprost, travaprost, unoprostone, and compounds set forth in U.S. Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444, "hypotensive lipids" (e.g., lumigan and compounds set forth in 5,352,708)
• neuroprotectants e.g., compounds from U.S. Patent No. 4,690,931 , particularly eliprodil and R-eliprodil, as set forth in a pending application U.S.S.N. 06/203350, and appropriate compounds from WO94/13275, including memantine.
• [ 125 I]DOI to brain 5-HT 2 receptors is determined as described below with minor modification of the literature procedure [Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat or human cerebral cortex homogenates (400 ⁇ l) dispersed in 50 niM TrisHCl buffer (pH 7.4) are incubated with [ 125 I]DOI (80 pM final) in the absence or presence of methiothepin (10 ⁇ M final) to define total and non-specific binding, respectively, in a total volume of 0.5 ml.
• the assay mixture is incubated for 1 hour at 23 °C in polypropylene tubes and the assays terminated by rapid vacuum filtration over Whatman GF/B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cold buffer.
• Test compounds (at different concentrations) are substituted for methiothepin. Filter-bound radioactivity is determined by scintillation spectrometry on a beta counter.
• the data are analyzed using a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the compound affinity parameter.
• the concentration of the compound needed to inhibit the [ 125 I]DOI binding by 50% of the maximum is termed the IC 0 value.
• a compound is considered to possess high affinity for the 5-HT 2 receptor if the
• IC 50 value is less than 50 nM.
• the relative agonist activity of serotonergic compounds at the 5-HT 2 receptor can be determined in vitro using the ability of the compounds to stimulate the production of [ 3 H]inositol phosphates in [ 3 H]myo-inositol-labeled A7r5 rat vascular smooth muscle cells by their ability to activate the enzyme phospholipase C.
• These cells are grown in culture plates, maintained in a humidified atmosphere of 5% CO 2 and 95% air and fed semi-weekly with Dulbecco's modified Eagle medium (DMEM) containing 4.5 g/1 glucose and supplemented with 2mM glutamine, 10 ⁇ g/ml gentamicin, and 10% fetal bovine serum.
• DMEM Dulbecco's modified Eagle medium
• the A7r5 cells are cultured in 24-well plates as previously [J. Pharmacol. Expt. Ther., 286, 411 (1998)]. Confluent cells are exposed for 24-30 hrs to 1.5 ⁇ Ci [ 3 H]-myo-inositol (18.3 Ci/mmol) in 0.5 ml of serum-free medium. Cells are then rinsed once with DMEM/F-12 containing 10 mM LiCl prior to incubation with the test agent (or solvent as the control) in 1.0 ml of the same medium for 1 hr at 37°C, after which the medium is aspirated and 1 ml of cold 0.1 M formic acid added to stop the reaction.
• Serotonin (5-HT) is used as a positive control (standard) agonist compound and the efficacy of test compounds is compared to that of 5-HT (set at 100%).
• the concentration of the compound needed to stimulate the production of [ 3 H]-IPs by 50% of the maximum response is termed the EC 50 value.
• Compounds are considered potent agonists if their EC 50 values in this functional assay are ⁇ 1 ⁇ M and are considered full agonists if their efficacy is > 80% of that of 5-HT.
• Step A 6-Methoxy-3-methyI-l/_ r -indazole
• 2-fluoro-4-methoxyacetophenone (1.90 g, 11.3 mmol) in ethanol (20 ml) was added hydrazine hydrate (1.4 ml, 45.0 mmol) and heated at reflux temperature for 6 h.
• This mixture was evaporated to a residue and ethyl ene glycol (10 ml) was added.
• the mixture was heated at 150 °C for 18 h, cooled to room temperature, diluted with water (50 ml), and extracted with dichloromethane (3 x 60 ml).
• Step B l-(6-Methoxy-3-methyl-indazol-l-yl)-propan-2-one
• sodium hydride 60% in oil, 0.41 g, 10.2 mmol
• chloroacetone 0.79 ml, 10.2 mmol
• the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (10 ml) and extracted with ethyl acetate (3 x 65 ml).
• Step C l-(6-Methoxy-3-methyl-indazol-l-yl)-propan-2-ol
• Sodium borohydride (0.21 g, 5.5 mmol) was added to a solution of the product from Step B (1.2 g, 5.5 mmol) in MeOH (10 ml) at room temperature. After stirring for 2 h at room temperature the solvent was evaporated and a saturated aqueous solution of ammonium chloride (10 rnL) was added to the residue; this mixture was extracted with ethyl acetate (3 x 50 mL).
• Step D l-(2-Azido-propyl)-6-methoxy-3-methyI-li/-indazole
• dichloromethane 10 ml
• triethylamine 0.55 ml, 3.9 mmol
• methanesulfonyl chloride 0.31 ml, 3.9 mmol
• ether 50 ml
• water 50 ml
• Step E 2-(6-Methoxy-3-methyl-indazol-l-yl)-l-methylethylamine fumarate
• a solution of the product from Step D (0.50 g, 2.0 mmol) in methanol at room temperature was added palladium-on-carbon (10%, 0.10 g). This suspension was stirred for 18 h under an atmosphere of hydrogen. The reaction mixture was filtered through a filter aid and the filtrate evaporated to a residue (0.43 g, 96%) which was converted to the fumaric acid salt and crystallized from methanol/ether to give a colorless solid (0.27 g): mp 150-152 °C; MS (ES) m/z 191 (M + ). Analysis.
• Step A l-(4-Benzyloxy-2-fluoro-phenyl)-ethanone
• Step A A solution of the product from Step A (7.4 g, 30.3 mmol) in ethanol (20 mL) was treated as described for Example 1, Step A to give a colorless solid (6.1 g, 69%): MS(ES) m/z 239 (M + ).
• Step C l-(6-Benzy!oxy-3-methyl-indazol-l-yl)-propan-2-one
• Step D l-(6-Benzyloxy-3-methyl-indazol-l-yI)-propan-2-ol
• Step E l-(2-Azido-propyl)-6-benzyloxy-3-methyl-lH-indazole
• Step F l-(2-Aminopropyl)-3-methyI-l//-indazol-6-ol fumarate
• Step A 2,2-Dimethyl-propionic acid l/f-indazol- ⁇ -yl ester
• Step B 2,2-Dimethyl-propionic acid l-(2-oxo-propyl)-l/ -indazoI-6-yl ester
• Step C 2,2-Dimethyl-propionic acid l-(2-hydroxy-propyI)-l//-indazol-6-yl ester
• Step D 2,2-Dimethyl-propionic acid l-(2-azido-propyl)-l//-indazol-6-yl ester
• Step E 2,2-Dimethyl-propionic acid l-(2-aminopropyl)-l//-indazol-6-yl ester fumarate
• Step A [2-(6-Hydroxy-indazol-l-yl)-l-methyl-ethyl]-carbamic acid benzyl ester To a solution of l-(2-aminopropyl)-indazol-6-ol (0.46 g, 2.4 mmol) in THF
• Step B [2-(6-Methoxy-indazol-l-yl)-l-methyl-ethyl]-carbamic acid benzyl ester
• Step D [2-(3-Chloro-6-methoxy-indazol-l-yl)-l-methyl-ethyl]-carbamic acid benzyl ester
• Step E 2-(3-Chloro-6-methoxy-indazol-l-yI)-l-methyl-ethylamine

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Citations (5)

• 2000
  • 2000-11-14 EP EP00978628A patent/EP1268438A1/en not_active Withdrawn
  • 2000-11-14 JP JP2001568912A patent/JP2003528085A/ja not_active Withdrawn
  • 2000-11-14 CN CN00819346A patent/CN1450994A/zh active Pending
  • 2000-11-14 MX MXPA02008547A patent/MXPA02008547A/es unknown
  • 2000-11-14 AU AU2001216072A patent/AU2001216072A1/en not_active Abandoned
  • 2000-11-14 PL PL00358481A patent/PL358481A1/xx not_active Application Discontinuation
  • 2000-11-14 WO PCT/US2000/031247 patent/WO2001070702A1/en not_active Application Discontinuation
  • 2000-11-14 CA CA002402403A patent/CA2402403A1/en not_active Abandoned
  • 2000-11-14 KR KR1020027011867A patent/KR20030065304A/ko not_active Application Discontinuation
  • 2000-11-14 BR BR0017157-3A patent/BR0017157A/pt not_active IP Right Cessation
  • 2000-11-27 TW TW089125127A patent/TWI221839B/zh not_active IP Right Cessation
  • 2000-12-01 AR ARP000106394A patent/AR032138A1/es not_active Application Discontinuation
  • 2000-12-03 GC GCP20001082 patent/GC0000155A/xx active
• 2002
  • 2002-08-27 ZA ZA200206851A patent/ZA200206851B/en unknown

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