Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to various pyranoindazoles. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and for treating glaucoma.
• IOP intraocular pressure
• the disease state refe ⁇ ed to as glaucoma is characterized by a permanent loss of visual function due to i ⁇ eversible damage to the optic nerve.
• the several mo ⁇ hologically 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 occu ⁇ ed; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated.
• Drag 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. There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
• Serotonergic 5-HT A agonists have been reported as being neuroprotective in animal models and many of these agents have been evaluated for the treatment of acute stroke among other indications.
• This class of compounds has been mentioned for the treatment of glaucoma (lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.) and EP 0771563A2 (Mano, et al.).
• Osbome, et al. (Ophthalmologica, Vol. 210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT) (a 5-HT 1A agonist) reduces IOP in rabbits. Wang, et al. (Current Eye Research, Vol.
• 5-HT 1A antagonists are disclosed as being useful for the treatment of glaucoma (elevated IOP) (e.g., WO 92/0338, McLees).
• DeSai, et al. WO 97/35579
• Macor, et al. U.S. 5,578,612
• 5-HT 1B D E F agonists are 5-HT 1B D E F agonists.
• U.S. Patent No. 5,494,928 relates to certain 2-(indol-l-yl)-ethylamine derivatives that are 5-HT 2C agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders.
• U.S. Patent No. 5,571,833 relates to tryptamine derivatives that are 5-HT 2 agonists for the treatment of portal hypertension and migraine.
• U.S. Patent No. 5,874,477 relates to a method for treating malaria using 5-HT 2A/2C agonists.
• U.S. Patent No. 5,902,815 relates to the use of 5-HT 2A agonists to prevent adverse effects of NMDA receptor hypo-function.
• WO 98/31354 relates to 5-HT 2B agonists for the treatment of depression and other CNS conditions.
• WO 00/12475 relates to indoline derivatives and WO 00/12510 and WO 00/44753 relate to certain indole derivatives as 5-HT 2B and 5-HT 2C receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity.
• WO 00/35922 relates to certain pyrazino[l,2-a]quinoxaline derivates as 5-HT 2C agonists for the treatment of obsessive compulsive disorder, depression, eating disorders, and other disorders involving the CNS.
• WO 00/77002 and WO 00/77010 relate to certain substituted tetracyclic pyrido[4,3-b]indoles as 5-HT 2C agonists with utility for the treatment of central nervous system disorders including obesity, anxiety, depression, sleep disorders, cephalic pain, and social phobias among others.
• 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 2C receptor possible [Psychopharmacology, Vol. 121:357, 1995].
• U.S. Patent Nos. 5,561,150 and 5,646,173 relate to certain tricyclic pyrazole derivative compounds which are identified as being 5- ⁇ T 2C agonists for the treatment of CNS diseases and are primarily directed to lipophilic analogs that have a high probability of entering the brain.
• WO 98/56768 relates to tricyclic 5-HT 2C agonists for the treatment of CNS diseases. All the patents and publications mentioned above and throughout are inco ⁇ orated in their entirety by reference herein.
• 5-Hyroxytryptamine does not cross the blood-brain ba ⁇ ier and enter the brain.
• the administration of 5-hydroxy- tryptophan can be employed.
• the transport of 5-hydroxy-tryptophan into the brain readily occurs, and once in the brain 5-hydroxy-tryptophan is rapidly decarboxylated to provide serotonin.
• a feature of the present invention is to provide novel compounds which are 5-HT 2
• Another feature of the present invention is to provide compounds which have increased chemical stability and which are useful in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.
• Another feature of the present invention is to provide compounds which provide a desired level of therapeutic activity in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.
• the present invention relates to a compound having the Formula I:
• R 1 and R 2 are independently chosen from hydrogen or an alkyl
• R 3 and R 4 are independently chosen from hydrogen or an alkyl group, such as C,. 4 alkyl or; R 3 and R 4 and the carbon atom to which they are attached can form a cycloalkyl ring, or furthermore,
• R 2 and R 3 together can be (CH 2 ) m to form a saturated heterocycle
• R 5 is chosen from hydrogen, halogen, an alkyl group, such as C,_ 6 alkyl or C,_ 4 alkyl substituted by halogen;
• R 6 and R 7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as
• C,. 4 alkylthio an alkyl such as C,. 4 alkyl, or a substituted alkyl such as C alkyl substituted by halogen;
• NR 10 R OR 12 , CO 2 R 13 , or CONR 14 R 15 , and further R 8 and R 9 can be chosen from Z-
• 6-membered heterocyclic ring which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;
• R 13 is hydrogen, C,, 6 alkyl, C,_ 6 alkyl substituted by hydroxyl, C M alkoxy, or halide;
• R 14 and R 15 are independently chosen from hydrogen, hydroxyl, C alkoxy, C ⁇ alkyl,
• C 2 _ 6 alkyl substituted by hydroxyl, C alkoxy, halide, or R 14 and R 15 can be combined to form a saturated heterocyclic ring selected from py ⁇ olidine, piperidine, piperazine, or mo ⁇ holine;
• B is either a single or a double bond, wherein when B is a double bond, R 8 and R 9 are selected from hydrogen, an alkyl group, such as C,_ 4 alkyl, or a substituted alkyl group, such as a C alkyl substituted by halogen, hydroxyl, or NR I0 R"; when A is (CH 2 ) n and n is 0, R 8 is chosen from CO 2 R 13 , C,_ 6 alkyl substituted with OR 12 ,
• NR'°R", CO 2 R 13 or CONR 14 R 15 and R 9 is selected from hydrogen or C, .2 alkyl and B is a single bond;
• X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.
• R 1 and R 2 are independently chosen from hydrogen or an alkyl group, such as C ⁇ alkyl;
• R 3 and R 4 are independently chosen from hydrogen or an alkyl group, such as C alkyl or;
• R 3 and R 4 and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., cyclopropyl ring), or furthermore,
• R 2 and R 3 together can be (CH 2 ) m to form a saturated heterocycle;
• R 5 is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as
• R 6 and R 7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as
• NR 10 R OR 12 , CO 2 R 13 , or CONR 14 R 15 , and further R 8 and R 9 can be chosen from Z-
• R 10 and R 11 are independently chosen from hydrogen, an alkyl group such as C ⁇ alkyl,
• R 13 is hydrogen, C,_ 6 alkyl, C,. 6 alkyl substituted by hydroxyl, C M alkoxy, or halide;
• R 14 and R 15 are independently chosen from hydrogen, hydroxyl, C M alkoxy, C, .6 alkyl, C ⁇ alkyl substituted by hydroxyl, C M alkoxy, halide, or R 14 and R 15 can be combined to form a saturated heterocyclic ring selected from py ⁇ olidine, piperidine, piperazine, or mo ⁇ holine;
• B is either a single or a double bond, wherein when B is a double bond, R 8 and R 9 are selected from hydrogen, an alkyl group, such as C ⁇ alkyl, or a substituted alkyl group, such as a C,_ 4 alkyl substituted by halogen, hydroxyl, or NR 10 R' ' ; when A is (CH 2 ) n and n is 0, R 8 is chosen from C,. 2 alkyl substituted by hydroxyl or OR 12 and R 9 is selected from hydrogen or C,. 2 alkyl and B is a single bond;
• X and Y are either N or C, wherein X and Y are different from each other; and the dashed
• the present invention further relates to pharmaceutical compositions containing at least one compound of Formula I.
• the present invention further relates to methods to lower and/or control normal or elevated intraocular pressure by administering an effective amount of a composition containing a compound having Formula I as described above.
• the present invention also relates to a method for treating glaucoma which involves administering an effective amount of a composition containing a compound having Formula
• the present invention relates to a variety of compounds which are useful according to the present invention. These compounds are generally represented by the following
• R 1 and R 2 are independently chosen from hydrogen or an alkyl group, such as C,_ 4 alkyl;
• R 3 and R 4 are independently chosen from hydrogen or an alkyl group, such as C alkyl or;
• R 3 and R 4 and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., cyclopropyl ring), or furthermore,
• R 2 and R 3 together can be (CH 2 ) m to form a saturated heterocycle
• R 5 is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as
• R 6 and R 7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as C,_ 4 alkylthio, an alkyl such as C alkyl, or a substituted alkyl such as C M alkyl substituted by halogen;
• R 10 and R 1 ' are independently chosen from hydrogen, an alkyl group such as C,_ 4 alkyl,
• R 13 is hydrogen, C,. 6 alkyl, C,. 6 alkyl substituted by hydroxyl, C alkoxy, or halide;
• R 14 and R 15 are independently chosen from hydrogen, hydroxyl, C ⁇ lkoxy, C h alky 1,
• C 2 . 6 alkyl substituted by hydroxyl, C alkoxy, halide, or R 14 and R 15 can be combined to form a saturated heterocyclic ring selected from py ⁇ olidine, piperidine, piperazine, or mo ⁇ holine;
• B is either a single or a double bond, wherein when B is a double bond, R 8 and R 9 are selected from hydrogen, an alkyl group, such as C,_ 4 alkyl, or a substituted alkyl group, such as a C,. 4 alkyl substituted by halogen, hydroxyl, or NR 10 R"; when A is (CH 2 ) n and n is 0, R 8 is chosen from CO 2 R 13 , C,. 6 alkyl substituted with OR 12 ,
• NR 10 R U , CO 2 R 13 or CONR 14 R 15 and R 9 is selected from hydrogen or C, .2 alkyl and B is a single bond;
• P l-2; X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.
• R 1 and R 2 are independently chosen from hydrogen or an alkyl group, such as C,_ 4 alkyl;
• R 3 and R 4 are independently chosen from hydrogen or an alkyl group, such as C,. 4 alkyl or; R 3 and R 4 and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., cyclopropyl ring), or furthermore,
• R 2 and R 3 together can be (CH 2 ) m to form a saturated heterocycle
• R 5 is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as
• R 6 and R 7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as
• NR 10 R OR 12 , CO 2 R 13 , or CONR 14 R 15 , and further R 8 and R 9 can be chosen from Z-
• R 13 is hydrogen, C,. 6 alkyl, C-.galkyl substituted by hydroxyl, C,_ 4 alkoxy, or halide;
• R 14 and R 15 are independently chosen from hydrogen, hydroxyl, C alkoxy, C ⁇ alkyl,
• C, .6 alkyl substituted by hydroxyl, C M alkoxy, halide, or R 14 and R 15 can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or mo ⁇ holine;
• B is either a single or a double bond, wherein when B is a double bond, R 8 and R 9 are selected from hydrogen, an alkyl group, such as C,. 4 alkyl, or a substituted alkyl group, such as a C, .4 alkyl substituted by halogen, hydroxyl, or NR 10 R";
• R 8 is chosen from C,. 2 alkyl substituted by hydroxyl or OR 12 and R 9 is selected from hydrogen or C, .2 alkyl and B is a single bond;
• X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond;
• R 1 and R 2 are independently chosen from hydrogen or C M alkyl
• R 3 and R 4 are independently chosen from hydrogen, C alkyl, or R 2 and R 3 together can be
• R 5 is chosen from hydrogen, halogen, or C,. 6 alkyl; R 6 and R 7 are independently chosen from hydrogen, halogen, cyano, C, ⁇ alkylthio, C, .
• R 8 and R 9 are chosen from hydrogen, hydroxyl, C,_ 6 alkyl, C M alkoxy, NR'°R", or C, .6 alkyl substituted with halogen, hydroxyl, or NR 10 R";
• A is (CH 2 ) n or CHC,. 4 alkyl; B is either a single or double bond, wherein when B is a double bond, R 8 and R 9 are selected from hydrogen, C,. 4 alkyl, or C M alkyl substituted by halogen, hydroxy, or
• X and Y are either N or C, wherein X and Y are different; and the dashed bonds denote a suitably appointed single and double bond;
• R 1 and R 2 are independently chosen from hydrogen or C, .4 alkyl;
• R 3 is C,. 2 alkyl, or R 2 and R 3 together can be (CH 2 ) 3 to form py ⁇ olidine;
• R 4 is hydrogen
• R 5 is chosen from hydrogen or C M alkyl
• R 6 and R 7 are independently chosen from hydrogen, halogen, or C,. 4 alkyl;
• R 8 and R 9 are independently chosen from hydrogen, hydroxyl, C,_ 6 alkoxy, NR I0 R", or C,. 6 alkyl substituted with hydroxyl or NR 10 R";
• R 11 together can complete a saturated 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S;
• A is (CH 2 ) n ;
• B is a single bond;
• n l;
• X is C and Y is N; and the dashed bonds denote a suitably appointed single and double bond.
• Representative examples of preferred compounds of Formula I are: 1 -(2-Aminopropyl)- 1 ,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
• Certain compounds of Formula I can contain one or more chiral centers.
• the present 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 inco ⁇ orated into the indicated structural unit.
• the substituent halogen which means fluorine
• the compounds of Formula I can be prepared by using one of several synthetic procedures.
• l-(2-aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ols can be prepared from an appropriately protected l-(6-hydroxyindazol-l-yl)-propan-2-ol 1 as outlined in Scheme 1.
• Pg denotes a suitable protective group to assure that a particular atom is not modified during the indicated chemical reaction.
• Other compounds of Formula I can be prepared from 12 through selected functional group transformations well known in the art. For example, initial protection of the primary amine group followed by activation of the hydroxyl group by formation of a sulfonate ester, e.g. methanesulfonyl, and subsequent reaction with a desired nucleophile such as alkylamines, dialkylamines, aryl or alkylthiols, and the like, will provide compounds 14 of Formula I.
• a sulfonate ester e.g. methanesulfonyl
• a desired nucleophile such as alkylamines, dialkylamines, aryl or alkylthiols, and the like
• a suitable oxidizing agent for example, a hypervalent iodine reagent, such as o-iodoxybenzoic acid [J Org Chem 60, 7272 (1995)]
• a hypervalent iodine reagent such as o-iodoxybenzoic acid [J Org Chem 60, 7272 (1995)]
• o-iodoxybenzoic acid J Org Chem 60, 7272 (1995)
• ketone 16 can be functionalized to provide yet other compounds of Formula I, such as 17, via reductive alkylation, and 15, via Grignard addition.
• compounds of Formula I can be prepared from appropriately substituted 5-propargyloxy-indazoles (19) via initial Claisen rea ⁇ angement reactions
• l-(hydroxyalkyl)-indazoles of interest for the preparation of compounds of Formula I can be prepared as outlined in Scheme 6 and in co-pending U.S. Patent Application No. 60/295,427, inco ⁇ orated in its entirety by reference herein.
• Nitrosation to provide 33 followed by reductive cyclization provides the l-(hydroxyalkyl)-indazoles 34.
• Intermediate pyranoindazoles 34 can also be prepared by alkylation of the appropriate O-protected 6-hydroxy-indazole (35), where suitable O-protective groups .ire e.g. methyl or benzyl, by methods well known in the art and described in Scheme 7 [U.S. Patent 5,494,928 (1997), WO98/30548 (1998)], with the desired epoxide, e.g. propylene oxide.
• reaction of indazoles 36 with the activated alaninol 39 provides 40, which following deprotection gives compounds 38 of Formula I as shown in Scheme 9.
• Replacement of 39 in Scheme 9 with, for example, an activated sulfonate ester, or the co ⁇ esponding halide, or N-protected (e.g. with t-butyloxycarbonyl, benzyloxycarbonyl) pyrrolidin-3 -methanol would, following removal of the amine protective group, provide yet another compound of Formula I.
• replacement of 39 in Scheme 9 with an activated sulfonate ester of N-(2 -hydroxy- l,l-dimethyl-ethyl)-phthalimide [J. Amer. Chem.
• Certain desirable substituted l,7,8,9-tetrahydro-pyrano[2,3-g]indazoles can be prepared from the appropriately substituted lH-indazol-6-ol (41), as described in the synthetic sequence outlined in Scheme 10.
• Alkylation of indazoles 41 with allyliodide followed by treatment under Claisen rea ⁇ angement conditions provides 43.
• Protection of the hydroxyl group from further reaction by conversion to, for example an ester such as acetyl, and similar inco ⁇ oration of a protective group on the nitrogen atom, for example by reaction with a suitable isocyanide to give a ureide, provides the desired allyl indazole 45.
• Formula I can be accomplished by the application of functional group transformations well known in the art.
• the desired pyrano[3,2-e]indazol-3-ethylamines, such as 49, 51 and 52 (Scheme 11) of Formula I can be prepared from the appropriately substituted 3-(2-hydroxypropyl)-lH- indazol-5-ol 48 by the methods described in Schemes 1-5 and as described in International Patent Application No. PCT/US00/31143, inco ⁇ orated in its entirety by reference herein.
• Certain desirable substituted 7,8-dihydro-furano[2,3-g]indazoles of Formula I can be prepared from the appropriately substituted lH-indazol-6-ol (53), as described in the synthetic sequence outlined in Scheme 12. Additionally, the application of standard functional group transformations well known to the art, for example by modification of compound 60, can give yet other compounds of Formula I.
• the compounds of the present invention can be used to lower and control IOP including IOP associated with normotension glaucoma, ocular hypertension, and glaucoma in warm blooded animals including humans. Since the treatment of glaucoma is preferably with compounds that do not enter the CNS, relatively polar compounds that are 5-HT 2 agonists are of particular interest.
• the compounds are preferably formulated in pharmaceutical compositions which are preferably suitable for topical delivery to the eye of the patient.
• the compounds of this invention can be inco ⁇ orated into various types of pharmaceutical compositions, such as ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
• ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
• the compounds are preferably inco ⁇ orated into topical ophthalmic formulations for delivery to the eye.
• the compounds may be combined with ophthalmologically acceptable preservatives, 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, polyvinylpy ⁇ olidone, 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 inco ⁇ orated.
• 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), ⁇ , antagonists (e.g., nipradolol), ⁇ 2 agonists (e.g.
• ⁇ -blockers e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol
• carbonic anhydrase inhibitors e.g., brinzolamide and dorzolamide
• ⁇ antagonists
• ⁇ 2 agonists e.g.
• miotics e.g., piloca ⁇ ine 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), and 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.
• alkyl group can be straight-chain, branched or cyclic and the like.
• Halogen includes Cl, Br, F, or I.
• Alkoxy is understood as an alkyl group bonded through an oxygen atom.
• the compounds of the present invention preferably function as 5-HT 2 agonists and preferably do not enter the CNS.
• Compounds having the ability to be a 5-HT 2 agonist are beneficial for controlling IOP as well as the treatment of glaucoma as shown in International Published Patent Application No. WO 00/16761, inco ⁇ orated in its entirety by reference herein.
• the compounds of the present invention preferably provide increased chemical stability and preferably achieve the desired level of therapeutic activity which includes a lowering or controlling of IOP.
• the compounds of the present invention can be used in controlling or lowering IOP in warm blooded animals including humans. Preferably, an effective amount of the compound is administered to the patient such that the IOP is controlled or lowered to acceptable levels. Furthermore, the compounds of the present invention can be used to treat glaucoma in warm blooded animals, including humans, by administering an effective amount of the compound to a patient in need of such treatment to treat the glaucoma. Examples of suitable pharmaceutical acceptable amounts of the compounds of the present invention include those amounts shown in the Examples.
• Another embodiment of the present invention is a method to block or bind to serotonin receptors comprising administering an effective amount of at least one compound of the present invention to a patient using an amount effective to block or bind to serotonin receptors, such as, but not limited to, the dosage levels described herein.
• cerebral cortex homogenates 400 ⁇ L dispersed in 50 mM TrisHCl buffer (pH 7.4) are
• the assay mixture is incubated for 1 hour at 23 °C in polypropylene tubes and the assays
• IC 50 or K value
• Confluent cell monolayers were trypsinized, pelleted, and re-suspended in normal media. Cells were seeded in a 50 ⁇ L volume at a density of 20,000 cells / well in a black wall, 96-well tissue culture plate and grown for 2 days.
• test compounds were stored at 25 ⁇ M in 50% DMSO/50% Ethanol solvent. Compounds were diluted 1:50 in 20% DMSO/20% Ethanol. For "hit" screening, compounds were further diluted 1 : 10 in FLIPR buffer and tested at a final concentration of
• the compound plate and cell plate were placed in the FLIPR instrument.
• a signal test was performed to check the basal fluorescence signal from the dye-loaded cells and the uniformity of the signal across the plate.
• the basal fluorescence was adjusted between 8000-12000 counts by modifying the exposure time, the camera F-stop, or the laser power.
• Instrument settings for a typical assay were the following: laser power 0.3-0.6 W, camera F-stop F/2, and exposure time
• Step A 6-Allyloxy-lH-indazole
• a solution of lH-indazol-6-ol (20.0 g, 150 mmol) in acetone (450 mL) was added pulverized potassium carbonate (22.4 g, 162 mmol), cesium carbonate (2.00 g, 5.7 mmol), and allyl iodide (14.63 mL, 160 mmol) and the mixture was sti ⁇ ed for 18 h at ambient temperature.
• Additional potassium carbonate (5.00 g, 36 mmol) and allyl iodide (1.4 mL, 15 mmol) were added and the mixture was sti ⁇ ed for 2 h followed filtration.
• Step C Acetic acid l-ethylcarbamoyl-7-oxiranylmethyl-lH-indazol-6-yl ester
• Step F l,7,8,9-Tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step A (6-Benzyloxy-indol-l-yl)-propan-2-ol
• Step B N-(5-Benzyloxy-2-formylphenyl)-N-(2-hydroxypropyl)-formamide A solution of the product from Step A (172 g) in 1.5 L of dichloromethane was cooled
• Step C 4-Benzyloxy-2-(2-hydroxy-propylamino)benzaldehyde An ice-cooled solution of the product from Step B (298 g, 0.95 mol) in THF (3 L) was treated with 1 M aqueous sodium hydroxide (1.95 L, 1.9 mol) keeping the temperature
• Step D l-(6-benzyloxy-indazol-l-yl)-propan-2-ol
• Step C The product of Step C (202.7 g, 0.71 mol) was treated as described for Steps C and D of Preparation 3. After the nitrosamine intermediate had been converted to a mixture of the desired indazole product and unreacted starting material (5:1), sodium nitrite (29.5 g, 0.43 mol) was added to renitrosate the starting material. Zinc dust (84 g, 1.28 mol) was then added in portions with cooling as described. When the starting material was consumed, the reaction mixture was worked up as described and combined with the product from another batch that started with 176 g of the product of Step C. The combined crude products were purified by chromatography (Biotage Kiloprep-250) to give a solid (226 g, 60%): 99% purity by HPLC.
• the filter-aide was washed with 10 L of 4:1 ether- ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane.
• the organic washes were extracted with water (5 L) and the aqueous phase was extracted with 25% ethyl acetate- hexane (4 x 2 L).
• the combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 3 L and allowed to stand for 48 h.
• the precipitated solid was collected by filtration, washed with hexane, and vacuum-dried to provide the desired product in two crops (619 g and 86 g).
• Step B N-[2-(3-Hydroxybutyl)-4-methoxyphenyl]-2,2-dimethylpropionamide
• Step C (R)-2-(3-Hydroxybutyl)-4-methoxyphenylammonium chloride
• Step B l-[2-(tert-Butyldimethyl-silanyloxy)-propyl]-lH-indazol-6-ol
• Step C 7-Bromo-l-[2-(tert-butyldimethyl-silanyloxy)-propyl]-lH-indazol-6-ol
• N-bromosuccinimide 3.49 g, 19.6 mmol
• the mixture was poured into a saturated aqueous solution of sodium bisulfite (300 mL) and extracted with EtOAc (3 x 100 mL). The combined extracts were dried (MgSO 4 ) and evaporated to a residue (6.39 g).
• Step F 7-Bromo-6-[3-bromo-2-(l-ethoxyethoxy)-propoxy]-l-[2-(tert-butyldimethyl- silanyloxy)-propyl]-lH-indazole
• Step H l-(2-Azidopropyl)-8-(l-ethoxyethoxy)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazole
• methanesulfonic anhydride (0.71 g, 4.05 mmol).
• the mixture was sti ⁇ ed for 20 min and sodium azide (2.11 g, 32.4 mmol) was added ' along with DMSO (20 mL).
• Step H To a mixture of the product from Step H (0.40 g, 1.1 mmol) in THF (60 mL) was added 1 N HCl (26 mL). After sti ⁇ ing for 40 min a saturated solution of sodium bicarbonate (150 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined extracts were dried and evaporated to a residue, which was purified by chromatography (silica, 50% EtOAc/hexane) to give an oil (0.29 g, 92%): LC/MS (+APCI) m/z 374 (M+H).
• Step J l-(2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol hydrochloride
• Step B l-[(S)-2-(tert-Butyldimethyl-silanyloxy)-propyl]-lH-indazol-6-ol
• Step A A mixture of the product from Step A (5.44 g, 13.7 mmol) and palladium-on-carbon (10%), 0.50 g) in methanol (200 mL) was sti ⁇ ed under an atmosphere of hydrogen for 18 h, filtered and evaporated to give an off-white solid (3.80 g, 90%): mp 171-172°C.
• Step C 7-Bromo- 1 - [(S)-2-(tert-butyldimethyl-silanyloxy)-propyl] - 1 H-indazol-6-ol
• Step D 7-Bromo-l-[(S)-2-(tert-butyldimethyl-silanyloxy)-propyl]-6-oxiranylmethoxy-lH- indazole
• Step E l-Bromo-3-[7-bromo-l-[(S)-2-(tert-butyl-dimethyl-silanyloxy)-propyl]-lH- indazol-6-yloxy]-propan-2-ol
• Step F 7-Bromo-6-[3-bromo-2-(l-ethoxyethoxy)-propoxy]-l-[(S)-2-(tert-butyldimethyl-
• Step G (S)-l-[8-(l-Ethoxyethoxy)-8,9-dihydro-7H-pyrano[2,3-g]indazol-l-yl]-propan-2- ol
• Step ⁇ l-((R)-2-Azidopropyl)-8-(l-ethoxyethoxy)-l ,7,8,9-tetrahydro-pyrano[2,3- g] indazole To a solution of the product from Step G (0.35 g, 1.09 mmol) and triethylamine
• Step I l-((R)-2-Azidopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step J l-((R)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol hydrochloride
• This compound was synthesized by following the procedure described in Example 2, Step I but using l-((S)-2-azidopropyl)-8-(l-ethoxyethoxy)-l,7,8,9-tetrahydro- pyrano [2,3 -g] indazole, which was prepared from (S)-l-(6-benzyloxyindazol-l-yl)-propan- 2-ol instead of (R)-l-(6-benzyloxyindazol-l-yl)-propan-2-ol as described: oil (0.45 g,
• Step B l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step J l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step C (R)-l-[(R)-2-(tert-Butyl-dimethyl-silanyloxy)-propyl]-l,7,8,9-tetrahydro- pyrano[2,3-g]indazol-8-ol
• 9-BBN 0.5 M in THF, 13 mL, 6.4 mmol
• the solution was heated at 70°C for 2 h, cooled to ambient temperature and the reaction was quenched with methanol (5 mL) and hydrogen peroxide (30%), 5 mL).
• Triethylamine (0.1 mL) was added and the mixture was evaporated to a residue, which was purified by chromatography (10% to 35% ethyl acetate in hexane) to give the desired azido-alcohol as a solid (0.27 g, 99%): LCMS (+APCI) m/z 274 (M+H).
• Step E (R)-l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step B (S)-l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step A (S)-8-Azido-l-((R)-2-azido-propyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazole
• Step A a solution of the S,8S-diastereomer of Example 5, Step A (0.44 g, 1.61 mmol) and triethylamine (0.90 mL, 6.44 mmol) in anhydrous THF (50 mL) at 0°C was added methanesulfonic anhydride (0.56 g, 3.22 mmol); this mixture was sti ⁇ ed for 30 min, the ice bath was removed, and the mixture was sti ⁇ ed for an additional 20 min.
• Step A Benzyl (S)-2-(6-hydroxy-lH-indazol-l-yl)-l-methylethylcarbamate
• Step B Benzyl (S)-l-Methyl-2-(6-prop-2-ynyloxy-indazol-l-yl)-ethylcarbamate
• Step C Benzyl (S)-l-Methyl-2-(7H-pyrano[2,3-g]indazol-l-yl)-ethylcarbamate
• the product from Step B (2.37 g, 6.53 mmol) was heated in mesitylene (40 mL) in a
• Step D Benzyl (S)-2-((8R*,9S*)-8,9-Dihydroxy-8,9-dihydro-7H-pyrano[2,3-g]indazol-l- yl)- 1 -methyl-ethylcarbamate
• Step A (R)-l-(7H-Pyrano[2,3-g]indazol-l-yl)-propan-2-ol
• Step B (0.26 g, 0.76 mmol) and tetrabutylammonium fluoride (1 M, 1.52 mmol) in THF (3 mL) was sti ⁇ ed at ambient temperature for 4 h.
• the reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (10 mL) and this mixture was extracted with ethyl acetate (3 x 5 mL).
• Step C (S)-2-(8,9-Dihydro-7H-pyrano[2,3-g]indazol-l-yl)-l-methyl-ethylamine dihydrochloride A solution of the product from Step B in methanol was treated as described in
• Example 2 Step J to give a yellowish solid (0.07 g, 77%): mp >120°C; LC/MS (+APCI) m/z 232 (M+ ⁇ ). The free base form was obtained as a colorless solid: mp 95-98°C; [ ⁇ ] D -66.7° (c 0.445, T ⁇ F). Analysis. Calculated for C 13 ⁇ 17 N 3 O: C, 67.51; H, 7.41 ; N, 18.17.
• Step B To a solution of the product from Example 8, Step B (0.10 g, 0.39 mmol) in dry THF (20 ml) at 0°C was added a solution of lithium aluminum hydride (0.39 mL, 1.56 mmol of a 1 M solution in THF) and the mixture was allowed to warm to room temperature (1 h) with sti ⁇ ing. Aqueous potassium hydroxide (2 M, 0.02 mL) was added to the reaction mixture and the solids that formed were removed by filtration. The filtrate was evaporated to a yellow oil (0.05 g, 56%): LC/MS (+APCI) m/z 230. Analysis.
• Step A Benzyl (S)-2-(8-Bromo-9-hydroxy-8,9-dihydro-7 ⁇ -pyrano[2,3-g]indazol-l-yl)-l-
• Step C 9-Amino-l-((S)-2-amino-propyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• the product from step B (0.26 g, 0.30 mmol) and Pd/C (10%, 0.026 g) were mixed with methanol (5 mL) and placed under a hydrogen atmosphere for 18 h. The mixture was filtered and evaporated to give a yellowish solid (0.155 g, 96%): mp 84-88°C; LC/MS (+APCI) m/z 263 (M+H).
• Example 12 l-((S)-2-Amino-propyl)-9-methoxy-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-oI
• Step A Benzyl (S)-2-(8-hydroxy-9-methoxy-8,9-dihydro-7H-pyrano[2,3-g]indazol-l-yl)-
• Step A To a solution of the product from Example 11, Step A (0.46 g, 1.12 mmol) in tetrahydrofuran (50 mL) was added 2 N sodium hydroxide (6 mL). After sti ⁇ ing for 10 min, methanol (10 mL) was added and the mixture sti ⁇ ed for 1 h followed by evaporation to a residue, which was mixed with water (50 mL) and extracted with ethyl acetate (3 x 50 mL).
• Step B l-((S)-2-Amino-propyl)-9-methoxy-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol
• Step C To a solution of the product from Example 4, Step C (1.76 g, 4.86 mmol) in anhydrous DMF (20 mL) at 0 °C and under nitrogen was added sodium hydride (0.39 g, 9.72 mmol, 2.0 equiv, 60% in mineral oil). After 20 minutes t-butyl bromoacetate (1.61 g, 1.33 mL, 8.26 mmol, 1.7 equiv.) was added and the ice bath removed. The reaction mixture was sti ⁇ ed at ambient temperature for 2 h, a saturated aqueous solution of sodium bicarbonate (100 mL) was added, and the mixture extracted with ethyl acetate. The extract was dried
• Step B [(R)-l-((R)-2-Hydroxypropyl)-l,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]- acetic acid tert-butyl ester
• a mixture of the product from step A (2.60 g, 4.41 mmol) and a solution of tetrabutylammonium fluoride (1 M, 1.52 mmol) in THF (3 mL) was sti ⁇ ed at ambient temperature overnight, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate.
• Step C [(R)-l-((S)-2-Azidopropyl)-l,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]- acetic acid tert-butyl ester
• Step D 2-[(R)-l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]- ethanol dihydrochloride
• a 1 M solution of lithium aluminum hydride in THF 2.0 mL, 2.6 mmol.
• the mixture was sti ⁇ ed for 1 h and cooled followed by the addition of methanol and 2 N HCl.
• the volatiles were evaporated and the residue was purified by reversed phase HPLC (gradient, 0% to 50% acetonitrile in water).
• Step A 2-[(R)- 1 -[(R)-2-(tert-Butyldimethyl-silanyloxy)-propyl]- 1 ,7,8,9-tetrahydro- pyrano [2,3 -g] indazol-8 -y loxy] -ethanol
• Step A To a cooled (0 °C) solution of the product from Example 13, Step A (1.76 g, 3.70 mmol) in anhydrous THF (30 mL) under nitrogen was added an 1 M solution of lithium aluminum hydride in THF (3.70 mL, 3.70 mmol). The reaction mixture was sti ⁇ ed for 0.5 h, cooled on ice, and a saturated aqueous solution of sodium bicarbonate (100 mL) was added.
• Step C N-[2-[(R)-l-[(R)-2-(tert-Butyldimethyl-silanyloxy)-pro ⁇ yl]-l,7,8,9-tetrahydro- pyrano[2,3-g]indazol-8-yloxy]ethyl]-acetamide
• Step D N-[2-[(R)-l-((R)-2-Hydroxypropyl)-l ,7,8,9-tetrahydropyrano[2,3-g]indazol-8- y loxy] -ethyl] -acetamide
• Step E N-[2-[(R)-l-((S)-2-Azidopropyl)-l,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]- ethyl] -acetamide
• Step F N-[2-[(R)-l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8- yloxy]-ethyl]acetamide
• step E A mixture of the product from step E (0.20 g, 0.56 mmol) and palladium-on-carbon (10%, 0.02 g) in methanol (20 mL) was placed under an atmosphere of hydrogen and sti ⁇ ed overnight. The mixture was filtered, evaporated, and treated with 2 N HCl in ethanol.
• Step A Methyl [(R)-l-[(R)-2-(tert-Butyldimethyl-silanyloxy)-propyl]-l,7,8,9-tetrahydro- pyrano[2,3-g]indazol-8-yloxy]acetate
• Step B 2-[(R)- 1 -[(R)-2-(tert-Butyldimethylsilanyloxy)-propyl]- 1 ,7,8,9-tetrahydro- pyrano[2,3-g]indazol-8-yloxy]acetamide
• Step B The product from Step B (0.44g, 1.05 mol) was dissolved in THF (20 mL) and a solution of tetrabutylammonium fluoride in THF (1 M, 2.1 mL, 2.1 mmol) was added; this mixture was sti ⁇ ed for 2 h at room temperature. A saturated aqueous solution of sodium bicarbonate (100 mL) was added and the mixture was saturated with sodium chloride and extracted with ethyl acetate (2 x 100 mL).
• Step F 2-[(R)-l-((S)-2-Aminopropyl)-l,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]- acetamide
• Step B (R)-l-(5-Prop-2-ynyloxy-lH-indazol-3-yl)propan-2-ol
• potassium carbonate (1.62 g, 11.7 mmol)
• propargyl bromide 80% in toluene, 1.74 g, 1.30 mL, 11.7 mmol.
• the mixture was heated at 75 °C for 2 hours under nitrogen, evaporated to dryness, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate.
• Step C 3-[(R)-2-(tert-Butyldimethylsilanyloxy)propyl]-5-prop-2-ynyloxy-lH-indazole
• t-butyldimethylsilyl chloride 1.23 g, 8.15 mmol
• imidazole 0.74 g, 10.9 mmol
• DMAP 0.1 g
• Step D l-[(R)-2-(tert-Butyldimethylsilanloxy)propyl]-3,7-dihydro-pyrano[3,2-e]indazole
• mesitylene 8 mL
• the vial was heated at 210 ° C for 1 hour, cooled to ambient temperature and chromatographed on silica (gradient, 2% to 15% ethyl acetate in hexane) to give an oil (1.31 g, 79%): LC/MS (+APCI) m/z 345
• Step F (S)-l-(2-Azidopropyl)-3,7-dihydropyrano[3,2-e]indazole
• Step G (S)-l-Methyl-2-(3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-l-yl)-ethylamine dihydrochloride A mixture of the product from Step F (0.09 g) and palladium-on-carbon (10%, 0.01 g)
• the mixture was purified by a reverse phase HPLC (gradient, acetonitrile/water, 0%> to
• Step A [1 -[(R)-2-(tert-Butyldimethylsilanyloxy)propyl]-7-hydroxymethyl- lH-indazol-6- yloxy] acetic acid tert-butyl ester
• Step B [1 -[(R)-2-(tert-Butyldimethylsilanyloxy)propyl]-7-chloromethyl- 1 H-indazol-6- yloxy] acetic acid tert-butyl ester
• thionyl chloride 0.68 g, 9.27 mmol
• sti ⁇ ing was continued for 20 min.
• Step C l-[(R)-2-(tert-Butyldimethylsilanyloxy)propyl]-7,8-dihydro-lH- furo[2,3-
• Step E l-[(S)-2-Azidopropyl]-7,8-dihydro-lH-furo[2,3-g]indazol-7-carboxylic acid tert- butyl ester
• Step F [l-((S)-2-Aminopropyl)-7,8-dihydro-lH-furo[2,3-g]indazol-7-yl]-methanol
• Step B l-[(S)-2-Aminopropyl]-7,8-dihydro-lH-furo[2,3-g]indazol-7-carboxylic acid ethyl
• topical ophthalmic formulations are useful according to the present invention administered 1-4 times per day according to the discretion of a skilled clinician.

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