WO1999059499A2 - Serotonergic 5ht7 receptor compounds for treating ocular and cns disorders - Google Patents

Serotonergic 5ht7 receptor compounds for treating ocular and cns disorders Download PDF

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Publication number
WO1999059499A2
WO1999059499A2 PCT/US1999/010179 US9910179W WO9959499A2 WO 1999059499 A2 WO1999059499 A2 WO 1999059499A2 US 9910179 W US9910179 W US 9910179W WO 9959499 A2 WO9959499 A2 WO 9959499A2
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alkyl
substituted optionally
substituted
unsubstituted
halogen
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PCT/US1999/010179
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French (fr)
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WO1999059499A3 (en
Inventor
Jesse A. May
Thomas R. Dean
Najam A. Sharif
Hwang-Hsing Chen
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Alcon Laboratories, Inc.
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Priority to AU39788/99A priority Critical patent/AU3978899A/en
Priority to EP99922894A priority patent/EP1079763A2/en
Priority to US09/674,403 priority patent/US6960579B1/en
Priority to JP2000549166A priority patent/JP2002515408A/en
Priority to BR9910590-0A priority patent/BR9910590A/en
Priority to CA002332505A priority patent/CA2332505A1/en
Publication of WO1999059499A2 publication Critical patent/WO1999059499A2/en
Publication of WO1999059499A3 publication Critical patent/WO1999059499A3/en
Priority to US11/100,918 priority patent/US7060704B2/en
Priority to US11/265,030 priority patent/US7285553B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention is directed to the use of compounds with serotonergic 5HT 7 receptor affinity (Compound) (some of which are novel), to improve blood flow to the optic nerve head and the retina, provide neuroprotection, lower intraocular pressure (IOP), and treat retinal diseases, such as, glaucoma, age related macular degeneration (ARMD), optic neuritis, ischemic disorders, diabetic retinopathy, and retinal edema.
  • Compounds are also useful for treating sleep disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension.
  • Serotonin (5-hydroxy tryptamine; 5HT) is an endogenous biogenic amine with a well defined neurotransmitter function in many tissues of the body including the eye [Zifa and Fillion, Pharmacol. Rev., 44:401-458, 1992; Hoyer et al., Pharmacol Rev., 46: 157-203, 1994; Tobin et al., J Neurosci., 8:3713-3721, 1988].
  • 5HT can interact with at least seven major 5HT receptors (5HTj - 5HT 7 ) and additional subtypes within these families to initiate intracellular biochemical events such as stimulation of second messengers (e.g. cAMP, inositol trisphosphate) eventually leading to the final biological response, for example, tissue contraction or hormone release, etc.
  • second messengers e.g. cAMP, inositol trisphosphate
  • Receptor subtypes within the 5HT ⁇ family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5HT 4 , 5HT 6 , and 5HT 7 receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5HT [Martin et al., supra].
  • the receptors in the 5HT 2 family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5HT.
  • PLC phospholipase C
  • the 5HT 3 receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al., supra].
  • the human and animal 5HT 7 receptor has only recently been cloned, expressed, and shown to be present in various brain areas and peripheral tissues [Eglen et al., Trend Pharmacol. Sci., 18:104-107, 1997]. Recent studies have shown there to be four splice variants of the 5HT 7 receptor [Heidmann et al, J Neurochem., 68:1372-1381, 1997]. It has been proposed that the 5HT 7 receptor may be involved in the pathophysiology of sleep disorders, depression, and other psychiatric disorders [Eglen et al., supra]. In the periphery, stimulation of 5HT 7 receptors results in relaxation of blood vessels and hence vasodilation [Eglen et al., supra].
  • Improving blood flow to the back of the eye, including the retina, the macula, and the optic nerve head is believed to be beneficial in the treatment of a number of retinal diseases, for example, glaucoma, ARMD, and diabetic retinopathy [Chiou, et al, J. Ocular Pharmacol. 9:13-24 (1993)].
  • 5HT binding sites have been shown to be functionally coupled to second messenger generation in rabbits [Tobin and Osborne, J. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci, supra].
  • human ICB these binding sites are characterized as 5HTIA and 5HT 2 receptors [Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993].
  • mRNAs for 5HT la and 5HT 7 receptors in the rabbit ICB have been reported [Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and Osborne and Chidlow, Ophthalmologica, 210:308-314, 1996].
  • the precise functions of these receptors in the eye are unknown, especially the 5HT 7 subtype(s).
  • 5HT or 5-carboxamidotryptamine (5-CT) topically applied to the rabbit eye raise intraocular pressure in the anterior chamber of the eye [Meyer-Bothling et al., Invest. Ophthalmol. Vis. Sci., 34:3035-3042, 1993].
  • 5HT 5-carboxamidotryptamine
  • topically applied 5HT lowers IOP [Krootila et al., J. Ocular Pharmacol, 3:279-290, 1987 (intracamerally 5HT raised IOP and caused breakdown of the blood-aqueous barrier)].
  • the 5HT uptake inhibitor, fiuoxetine (Prozac ® ) also raises IOP in human subjects upon oral administration [Costagliola et al., Br. J.
  • Methysergide lowered IOP in rabbits [Krootila, et al., Esp. Eye Res., supra].
  • Ketanserin (5HT 2A c antagonist), also with significant ⁇ l antagonist activity, lowers IOP in rabbits and man [Chan, et al., J. Ocular Pharmacol, 1 :137-147, 1985 and Costagliola, et al., Ex. Eye Res., 52:507-510, 1991].
  • Saprogrelate (5HT A antagonist) lowers IOP in rabbits and in man when dosed topically or orally [Mano, et al., Invest. Ophthal Vis.
  • EP 522226 and U.S. Patent No. 5,290,781 disclose the use of ketanserin and its derivatives for treating ocular hypertension.
  • U.S. Patent Nos. 5,290,781 and 5,106,555 discloses the use of certain 5HT 2 antagonists for lowering IOP.
  • U.S. Patent No. 5,652,272 discloses saprogrelate for reducing IOP.
  • U.S. Patent No. 5,538,974 discloses opthalmic compositions of certain 5HT antagonists for lowering IOP.
  • U.S. Patent No. 5,011,846 discloses certain 5HT 3 receptor antagonists for treating glaucoma.
  • WO 97/17345 discloses that particular compounds with 5HT 4 serotonergic receptor agonist or antagonist activity are useful for treating psychiatric, gastrointestinal, lower urinary, and cardiovascular disorders. The publication mentions the compounds may also be useful for glaucoma.
  • receptor(s) might be responsible for increasing blood flow and providing neuroprotection in the eye.
  • the present invention is directed to Compounds, some of which are novel, that have 5HT 7 receptor affinity, and the use of compounds with 5HT 7 receptor affinity to lower IOP, improve blood flow to the optic nerve head and the retina, provide neuroprotection, and control damage associated with diseases, such as, glaucoma, ARMD, optic neuritis, ischemic disorders, and retinal edema by functioning as neuroprotectants.
  • Compositions of the compounds are contemplated for such uses.
  • the Compounds are also useful for treating sleep disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension.
  • 5HT 7 receptors are present in the retina, choroid, and possibly the optic nerve head.
  • the Compounds' (preferrably Compounds that are agonists or partial agonists) ability to improve blood flow to the optic nerve head and the retina and other characteristics are believed to render them neuroprotective.
  • the novel Compounds disclosed herein are also useful for treating sleep disorders, depression, and other psychiatric disorders.
  • WO 97/48681 WO 97/49695; and WO 98/00400.
  • Specific Compounds include: LY-215840, SB-258719, and DR-4004.
  • Aryl signifies a fused phenyl or monocyclic heteroaromatic ring
  • R 1 is H, OH, OC ⁇ . 3 alkyl, C 1-3 alkyl, C 1-3 alkyl substituted optionally with OH, or OC 1-3 alkyl
  • R 3 , R 4 are independently H, C ⁇ -3 alkyl, C ⁇ -3 alkyl substituted optionally with OH or OC 1-3 alkyl;
  • R 5 , R 6 are independently H, C ⁇ an yl, C 2 .
  • R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C 1-3 alkyl, C 2-3 alkyl substituted optionally with OH or OC 1-3 alkyl;
  • R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, ⁇ 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C ⁇ - 3 alkyl, C ⁇ -3 alkyl substituted optionally with OH, OC 1-3 alkyl, phenyl which can be unsubstituted or substituted
  • Aryl signifies a fused phenyl or monocyclic heteroaromatic ring
  • R 3 & R 4 are independently H, C ⁇ .
  • R 5 , R 6 are independently H, C 1-3 alkyl, C 2-3 alkyl substituted optionally with OH, OC 1-3 alkyl, or R 5 and R 6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C ⁇ -3 alkyl, C 2-3 alkyl substituted optionally with OH or OC 1-3 alkyl;
  • R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, ⁇ 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from
  • R 3 & R 4 are independently H, C 1-3 alkyl, or C 1-3 alkyl substituted optionally with OH or
  • R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, ⁇ 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C 1-3 alkyl, C ⁇ -3 alkyl substituted optionally with OH, OC ⁇ -3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1-3 alkyl, or C 1-3 alkyl, or substituted on nitrogen with or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC ⁇ -3 alkyl, or C ⁇ - 3 alkyl; R 9 is phenyl or
  • R 3 & R 4 are independently H, Ct. 3 alkyl, or C 1-3 alkyl substituted optionally with OH or OC 1-3 alkyl;
  • R 7 , R 8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, ⁇ 3 -piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C ⁇ -3 alkyl, C 1-3 alkyl substituted optionally with OH, OC ⁇ -3 alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1-3 alkyl, or C 1-3 alkyl, or substituted on nitrogen with C 1-4 alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF 3 , OC 1-3 alkyl, or R 1 is C 1-3 alkyl, phenyl or a mono
  • the compounds of the present invention can be prepared using chemical synthesis procedures herein described.
  • the preferred method for preparing compounds of Formula I is illustrated in Scheme I.
  • the thiazine alcohols 1 which can be prepared by methods described in U.S.Patents 5,344,929 and 5,470,973, or inJ. Org. Chem. 31, 162 (1966), can be selectively alkylated on the nitrogen atom at position two with, for example, a dihaloalkane using procedures known to the art to give 2, where X is a halogen atom such as chlorine, bromine, or iodine.
  • Compounds 2 can be treated with amines by known procedures to provide compounds of Formula I (3) where R 1 is hydroxyl, further these alcohols 3 can be treated with an alkylhalide to effect alkylation on oxygen to provide the ethers, R 1 is alkoxy.
  • 2 can be dehydrated by using methods described in U.S. Patent 5,538,966 to give compounds 4 which can be further reacted with amines to give compounds of Formula I where R 1 is hydrogen and the thiazine ring contains a double bond (5).
  • heteroaromatic ring refers to thiophene, furan, pyrrole, pyridine, pyrimidine, pyridazine and pyrazine.
  • the Compounds can be administered systemically or locally to the eye (e.g., topically, intracamerally, or via an implant).
  • the Compounds are preferrably 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. Further, 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-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be inco ⁇ orated.
  • the Compounds can be formulated for systemic (e.g. oral, IN., I.M., subcutaneous) delivery according to methods known to one skilled in the art. For systemic delivery the Compounds are delivered at concentrations of 0.005 - 1000 mg. per dose, preferrably 0.05 - 20.0, most preferrably 0.2 - 5 mg. per dose. The Compounds will be dosed 1-4 times per day according to the discretion of a skilled clinician.
  • 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 .01% to 5% by weight, but preferably in an amount of .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 routine discretion of a skilled clinician.
  • the preferred Compounds are those set forth in Examples 1, 1.1, 1.2, 1.6, 1.8, 2.3, 2.7, 2.10, 2.1, 2.4, 3, 3.1, 3.11, 3.5, and 3.10.
  • Step 2 The product from Step 1 (10.6 g, 28.3 mmol) was dissolved in tetrahydrofuran (anhydrous, 400 mL) and treated with triethyl amine (9.88 mL, 70.9 mmol) and methane sulfonic anhydride (9.86 g, 56.6 mmol) at room temperature and stirred for one hour. The suspension was concentrated and taken up in dimethylformamide (anhydrous, 120 mL). This mixture was heated at 160° for 45 min. The reaction mixture was poured into ice water (300 ml) and extracted with dichloromethane (300 mL).
  • Step 3 A solution of 4-(2H-benzimidazo-2-oxo-l-yl)piperidine (0.30 mmol) in DMF (1.6 mL, anhydrous) and triethyl amine (0.5 mL) was treated with the product of Step 2 (0.103 g, 0.29 mmol) and stirred at 70° for 20 hours and then at room temperature for two days. The reaction mixture was diluted with ethyl acetate (3 mL) and water (4 mL). Saturated sodium bicarbonate (1 mL) was added and the layers were mixed followed by removal of the aqueous layer.
  • Step 1 To a solution of indoline (4.00 g, 33.6 mmol) in 100 mL of acetone at 0 ° C was added 3-chloropropanesulfonyl chloride (5.95 g, 33.6 mmol) with stirring. A solid precipitated from the solution. Diisopropylethylamine (4.33 g, 33.6 mmol) was added in two portions and the reaction mixture became a homogenous solution. The mixture was stirred for 30 min, warmed to ambient temperature, and evaporated to dryness. The crude mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2 x 100 mL). Chromatography on silica (10% to 25% ethyl acetate/hexane) gave an oil which solidified on standing (7.68 g, 77%, mp 53-53 ° C ).
  • Step 2 A mixture of the product of Step 1 (200 mg, 0.77 mmol) and 0.5 M solution of 4- methylpiperidine (4 mL, 2.0 mmol) was heated at 35 ° C for 60 h. The reaction mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2 x 10 mL). The extracts were dried and evaporated to dryness. The crude product was filtered though a short silica column and treated with a 1.0 M solution of hydrogen chloride gas in ether. The solid was filtered and dried to give the hydrochloride salt (220 mg, 80 %): MS(ES) 323 (M+H).
  • Step 1 To a solution ofp-anisidine (6.00 g, 48.7 mmol) and triethylamine (5.91 g, 58.4 mmol) in methylene chloride (200 mL) at 0 C was added propylsulfonyl chloride (7.64 g, 53.6 mmol) with stirring under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with a saturated aqueous solution of sodium bicarbonate (100 mL), water, and dried over magnesium sulfate.
  • Step 2 To the product of Step 1 (3.50 g, 15.3 mmol) in anhydrous dimethylformamide (80 mL) at 0°C was added sodium hydride (60 % suspension in mineral oil, 0.672 g, 16.8 mmol) under a nitrogen atmosphere. The suspension was stirred for 30 min and 1 ,3-dibromopropane (9.27 g, 45.9 mmol) was added over 1 min. The reaction was stirred for 3 h, mixed with a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried and evaporated to dryness.
  • sodium hydride 60 % suspension in mineral oil, 0.672 g, 16.8 mmol
  • 1 ,3-dibromopropane 9.27 g, 45.9 mmol
  • Step 3 To a solution of the product of Step 2 (0.175 g, 0.50 mmol) in anhydrous dimethylformamide (1 mL) was added a 0.5 M solution of l-(3-chlorophenyl)piperazine in dimethylformamide (1.1 mL, 0.55 mmol) and triethylamine (0.20 mL); this mixture was heated at 60 C for 18 h.
  • Step 3 with the appropriate amine, the following compounds were prepared.
  • the 1H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure.
  • topical ophthalmic formulations are useful according to the present invention administered 1-4 times per day according to the discretion of a skilled clinician.
  • Tablet 0.2 - 5 mg. of 5HT
  • Compound with inactive ingredients such as comstarch, lactose, colloidal silicon dioxide, microcrystalline cellulose, and magnesium sterate can be formulated according to procedures known to those skilled in the art of tablet formulation.

Abstract

Compounds with 5HT7 receptor affinity (some of which are novel) useful for lowering IOP, improving blood flow to the optic nerve head and the retina, providing neuroprotection, and treating retinal diseases are disclosed. The Compounds are also useful for treating sleep disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension. Compositions and methods for their use are also disclosed.

Description

SEROTONERGIC 5HT7 RECEPTOR COMPOUNDS FOR TREATING OCULAR AND CNS DISORDERS
The present invention is directed to the use of compounds with serotonergic 5HT7 receptor affinity (Compound) (some of which are novel), to improve blood flow to the optic nerve head and the retina, provide neuroprotection, lower intraocular pressure (IOP), and treat retinal diseases, such as, glaucoma, age related macular degeneration (ARMD), optic neuritis, ischemic disorders, diabetic retinopathy, and retinal edema. The Compounds are also useful for treating sleep disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension.
Background of the Invention
Serotonin (5-hydroxy tryptamine; 5HT) is an endogenous biogenic amine with a well defined neurotransmitter function in many tissues of the body including the eye [Zifa and Fillion, Pharmacol. Rev., 44:401-458, 1992; Hoyer et al., Pharmacol Rev., 46: 157-203, 1994; Tobin et al., J Neurosci., 8:3713-3721, 1988].
5HT can interact with at least seven major 5HT receptors (5HTj - 5HT7) and additional subtypes within these families to initiate intracellular biochemical events such as stimulation of second messengers (e.g. cAMP, inositol trisphosphate) eventually leading to the final biological response, for example, tissue contraction or hormone release, etc. [Hoyer et al., supra; Martin et al., Trends Pharmacol. Sci., 19:2-4, 1998]. Receptor subtypes within the 5HTι family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5HT4, 5HT6, and 5HT7 receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5HT [Martin et al., supra]. The receptors in the 5HT2 family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5HT. The 5HT3 receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al., supra]. The human and animal 5HT7 receptor has only recently been cloned, expressed, and shown to be present in various brain areas and peripheral tissues [Eglen et al., Trend Pharmacol. Sci., 18:104-107, 1997]. Recent studies have shown there to be four splice variants of the 5HT7 receptor [Heidmann et al, J Neurochem., 68:1372-1381, 1997]. It has been proposed that the 5HT7 receptor may be involved in the pathophysiology of sleep disorders, depression, and other psychiatric disorders [Eglen et al., supra]. In the periphery, stimulation of 5HT7 receptors results in relaxation of blood vessels and hence vasodilation [Eglen et al., supra]. Improving blood flow to the back of the eye, including the retina, the macula, and the optic nerve head is believed to be beneficial in the treatment of a number of retinal diseases, for example, glaucoma, ARMD, and diabetic retinopathy [Chiou, et al, J. Ocular Pharmacol. 9:13-24 (1993)].
Serotonergic nerves innervate the eye [Tobin et al., J. Neurosci., 8:3713-3721, 1988] and 5HT has been found in the aqueous humor of human eyes [Martin et al., Ophthalmol, 95:1221-1226, 1988]. In addition, receptor binding sites for [3H]5HT have been demonstrated and pharmacologically characterized in the iris-ciliary body (ICB) of rabbits [Mallorga and Sugrue, Curr. Eye Res., 6:527-532, 1987 and Chidlow et al., Invest. Ophthalmol. Vis. Sci., 36:2238-2245, 1995]. These 5HT binding sites have been shown to be functionally coupled to second messenger generation in rabbits [Tobin and Osborne, J. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci, supra]. In the human ICB these binding sites are characterized as 5HTIA and 5HT2 receptors [Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993]. In addition, the presence of mRNAs for 5HTla and 5HT7 receptors in the rabbit ICB have been reported [Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and Osborne and Chidlow, Ophthalmologica, 210:308-314, 1996]. The precise functions of these receptors in the eye are unknown, especially the 5HT7 subtype(s).
5HT or 5-carboxamidotryptamine (5-CT) topically applied to the rabbit eye raise intraocular pressure in the anterior chamber of the eye [Meyer-Bothling et al., Invest. Ophthalmol. Vis. Sci., 34:3035-3042, 1993]. By contrast, it has been shown that topically applied 5HT lowers IOP [Krootila et al., J. Ocular Pharmacol, 3:279-290, 1987 (intracamerally 5HT raised IOP and caused breakdown of the blood-aqueous barrier)]. In addition, the 5HT uptake inhibitor, fiuoxetine (Prozac®), also raises IOP in human subjects upon oral administration [Costagliola et al., Br. J. Ophthalmol, 80:678, 1996] and may cause glaucoma [Ahmad, Ann. Pharmacother., 25:436, 1992]. However, the 5HT receptor subtype(s) involved in the IOP-elevating effects of 5HT, 5-CT and fluoxetine are unknown.
Studies conducted in rabbits with 8-hydroxy DP AT and MKC-242 (5HT1A agonists) have shown these compounds lower IOP [Osborne and Chidlow, Ophthalmologica, 210:308-319, 1996, and EP 0771563-A2]. In addition, 5-methylurapidil (5HT1A agonist) lowered IOP in glaucomatous monkeys [Wang, et al., Curr. Eye Res., 16:679-775, 1997]. Both MKC-242 and 5-methylurapidil are relatively potent αl receptor antagonists (αl antagonists are known to lower IOP in rabbits, monkeys, and man). The mechanism of action for lowering IOP by 5-methylurapidil has been attributed to its αl antagonist activity and not its 5HT1A agonist activity [Wang, et al., Invest. Ophthal. Vis. Sci., 39(Suppl):2236- 488, 1998]. U.S. Patent No. 5,693,654, discloses 5HTi receptor agonists for lowering IOP. WO92/20333 discloses certain 5HT1A agonists for the treatment of glaucoma.
Methysergide (5HT2 antagonist) lowered IOP in rabbits [Krootila, et al., Esp. Eye Res., supra]. Ketanserin (5HT2A c antagonist), also with significant αl antagonist activity, lowers IOP in rabbits and man [Chan, et al., J. Ocular Pharmacol, 1 :137-147, 1985 and Costagliola, et al., Ex. Eye Res., 52:507-510, 1991]. Saprogrelate (5HT A antagonist) lowers IOP in rabbits and in man when dosed topically or orally [Mano, et al., Invest. Ophthal Vis.
Sci., 36(Supρl):3322-309, 1995, and Takenaka, et al, Invest Ophthal. Vis. Sci., 36(Suppl):3390-377, 1995]. EP 522226 and U.S. Patent No. 5,290,781 disclose the use of ketanserin and its derivatives for treating ocular hypertension. U.S. Patent Nos. 5,290,781 and 5,106,555 discloses the use of certain 5HT2 antagonists for lowering IOP. U.S. Patent No. 5,652,272 discloses saprogrelate for reducing IOP. U.S. Patent No. 5,538,974 discloses opthalmic compositions of certain 5HT antagonists for lowering IOP.
U.S. Patent No. 5,011,846 discloses certain 5HT3 receptor antagonists for treating glaucoma. WO 97/17345 discloses that particular compounds with 5HT4 serotonergic receptor agonist or antagonist activity are useful for treating psychiatric, gastrointestinal, lower urinary, and cardiovascular disorders. The publication mentions the compounds may also be useful for glaucoma.
As evidenced by the previous discussion, it is not clear which serotonergic receptor activity is responsible for lowering IOP. Moreover, a number of these compounds are known to have activity at other receptors which are known to be involved in lowering IOP.
Furthermore, it has not been cleared which receptor(s) might be responsible for increasing blood flow and providing neuroprotection in the eye.
Summary of the Invention
The present invention is directed to Compounds, some of which are novel, that have 5HT7 receptor affinity, and the use of compounds with 5HT7 receptor affinity to lower IOP, improve blood flow to the optic nerve head and the retina, provide neuroprotection, and control damage associated with diseases, such as, glaucoma, ARMD, optic neuritis, ischemic disorders, and retinal edema by functioning as neuroprotectants. Compositions of the compounds are contemplated for such uses. The Compounds are also useful for treating sleep disorders, depression, and other psychiatric disorders, such as, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension.
Detailed Description Preferred Embodiments
It has been unexpectedly discovered that 5HT7 receptors are present in the retina, choroid, and possibly the optic nerve head. Furthermore, sertonergic Compounds which possess a relatively high affinity (Kj = 0.01 - 200nM) for 5HT7 receptors effectively lower elevated IOP. It is believed that these Compounds can improve blood flow, and provide neuroprotection to the optic nerve head and the retina. The Compounds' (preferrably Compounds that are agonists or partial agonists) ability to improve blood flow to the optic nerve head and the retina and other characteristics are believed to render them neuroprotective. The novel Compounds disclosed herein are also useful for treating sleep disorders, depression, and other psychiatric disorders.
Compounds found in the following applications are useful according to the present invention and are incorporated herein by reference: EP 738513-Al; WO 97/29097;
WO 97/48681; WO 97/49695; and WO 98/00400. Specific Compounds include: LY-215840, SB-258719, and DR-4004.
The following novel Compounds and their pharmaceutically acceptable salts and solvates are useful for treating persons with the diseases and disorders previously described.
Formula I
Figure imgf000007_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, OH, OCι.3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH, or OC1-3alkyl; R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-3alkyl substituted optionally with OH, or OC].3alkyl; R3, R4 are independently H, Cι-3alkyl, Cι-3alkyl substituted optionally with OH or OC1-3alkyl; R5, R6 are independently H, C^an yl, C2.3alkyl substituted optionally with OH, OC1-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cι-3alkyl, Cι-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3a.kyl, or C1-3alkyl, or substituted on nitrogen with
Figure imgf000008_0001
or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2.
Formula II
Figure imgf000008_0002
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, Cι-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC1-3alkyl, S(=O)rnC1-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2.5alkyl substituted optionally with OH, OC1-3alkyl, S(=O)mC1.3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCι.3alkyl, S(=O)mC1-3alkyl, halogen, CF3, S(=O)2
NR5R6; or C3.5alkenyl substituted optionally with OH, OCι-3alkyl, or S(=O)mC1- 3alkyl; R2 is H, halogen, d_3alkyl, S(=O)mC1.3alkyl, S(=O)2 NR5R6, or d-3alkyl substituted optionally with OH, or OC1-3alkyl; R3 & R4 are independently H, Cι.3alkyl, or C1-3alkyl substituted optionally with OH or OC1-3alkyl; R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with OH, OC1-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Cι-3alkyl, C2-3alkyl substituted optionally with OH or OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, Cι-3alkyl substituted optionally with OH, OCι-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or C1-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl; n is 2 to 4; m is 0, 1 or 2.
Formula III
Figure imgf000009_0001
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally with OH or
OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, Cι-3alkyl substituted optionally with OH, OCι-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on nitrogen with
Figure imgf000009_0002
or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or Cι-3alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OC1-4alkyl; R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4.
Formula IV
Figure imgf000010_0001
R3 & R4 are independently H, Ct.3alkyl, or C1-3alkyl substituted optionally with OH or OC1-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incorporated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, morpholine or thiomorpholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cι-3alkyl, C1-3alkyl substituted optionally with OH, OCι-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or
Figure imgf000010_0002
R1 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OC alkyl; R12 is C alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or 1 ,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4. The compounds of the present invention can be prepared using chemical synthesis procedures herein described. The preferred method for preparing compounds of Formula I is illustrated in Scheme I. For example, the thiazine alcohols 1, which can be prepared by methods described in U.S.Patents 5,344,929 and 5,470,973, or inJ. Org. Chem. 31, 162 (1966), can be selectively alkylated on the nitrogen atom at position two with, for example, a dihaloalkane using procedures known to the art to give 2, where X is a halogen atom such as chlorine, bromine, or iodine. Compounds 2 can be treated with amines by known procedures to provide compounds of Formula I (3) where R1 is hydroxyl, further these alcohols 3 can be treated with an alkylhalide to effect alkylation on oxygen to provide the ethers, R1 is alkoxy. Alternately, 2 can be dehydrated by using methods described in U.S. Patent 5,538,966 to give compounds 4 which can be further reacted with amines to give compounds of Formula I where R1 is hydrogen and the thiazine ring contains a double bond (5).
Scheme I
Figure imgf000011_0001
Ms,0/DBN
Figure imgf000011_0002
Procedures for preparing compounds of Formula II are illustrated in Scheme II. For example, the 3-hydroxymethyl thiazine compounds 7 can be prepared from the esters 6 by methods described in U.S. Patent 5,538,966 [Equation (a)]. Further, compounds 7 can be aminated using a variety of well known procedures, such as initial activation of the hydroxyl group by forming a sulfonate ester, followed by reaction of this intermediate with the desired primary or secondary amine to give compounds 8 of Formula II where R3 and R4 are hydrogen and n is 1 [Equation (b)]. Additionally, using 7 as an intermediate with which to initiate a suitable homologation sequence, compounds of Formula II wherein R3 and R4 are hydrogen and n is 2 or 3 can be prepared; an example of such a homologation sequence employing 7 is illustrated in Equations (c) and (d), respectively.
Scheme II
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000013_0001
11
L MgtTHF
2. Ethylene Oxide
1. MS;,OtTEA
2. Amine
Figure imgf000013_0002
Figure imgf000013_0003
13 12
The preparation of compounds of Formula III can be readily accomplished by procedures herein described. For example, reaction of the desired amine 14 with the appropriate haloalkylsulfonyl chloride 15 in an inert solvent in the presence of a suitable base [see e.g., J. Med. Chem. 40, 3217 (1997)] to give the haloalkylsulfonamide intermediate 16. Subsequent reaction of 16 with the appropriate primary or secondary amine employing known procedures, provides compounds 17 of Formula III.
Scheme III
Figure imgf000013_0004
The preparation of compounds of Formula IV can be readily accomplished by procedures herein described. For example, reaction of the desired primary amine 18 with the appropriate sulfonyl chloride in an inert solvent in the presence of a suitable base provides the intermediate secondary sulfonamide 19 which can be alkylated by known procedures with the appropriately substituted alkyldibromide to give the haloalkylsulfonamide intermediate 20. Subsequent reaction of 20 with the appropriate primary or secondary amine employing well known procedures provides compounds 21 of Formula IV.
Scheme IV
Figure imgf000014_0001
It is evident that some of the Compounds of Formula I - IV will include asymmetric atoms, all enantiomers and diastereomers are contemplated.
The term heteroaromatic ring refers to thiophene, furan, pyrrole, pyridine, pyrimidine, pyridazine and pyrazine.
The Compounds can be administered systemically or locally to the eye (e.g., topically, intracamerally, or via an implant). The Compounds are preferrably 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. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound. Furthermore, 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. In order to prepare sterile ophthalmic ointment formulations, 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-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incoφorated. The Compounds can be formulated for systemic (e.g. oral, IN., I.M., subcutaneous) delivery according to methods known to one skilled in the art. For systemic delivery the Compounds are delivered at concentrations of 0.005 - 1000 mg. per dose, preferrably 0.05 - 20.0, most preferrably 0.2 - 5 mg. per dose. The Compounds will be dosed 1-4 times per day according to the discretion of a skilled clinician.
For ophthalmic medications 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 .01% to 5% by weight, but preferably in an amount of .25% to 2% by weight. Thus, for topical presentation 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 routine discretion of a skilled clinician. The preferred Compounds are those set forth in Examples 1, 1.1, 1.2, 1.6, 1.8, 2.3, 2.7, 2.10, 2.1, 2.4, 3, 3.1, 3.11, 3.5, and 3.10. Example 1
6-Chloro-2-[4-[4-(2H-benzimidazo-2-oxo-l-yl)piperidin-l-yl]butyl]- 2H-thieno[3,2-e]-l,2-thiazine 1,1-dioxide Ηydrochloride
Figure imgf000016_0001
Step 1. A solution 6-chloro-3,4-dihydro-2H-thieno [3 ,2-e]-l,2-thiazine-4-ol 1,1-dioxide
(9.0 g, 37.6 mmol) in dimethylformamide (200 mL, anhydrous) and sodium hydride (60% in oil, 1.66 g, 41.5 mmol) was reacted with 1 ,4-dibromobutane at 0°. The reaction was stirred in an ice bath for 30 min and then it was allowed to warm to room temperature and stir for three days. The mixture was poured into ice water (400 mL) and extracted with diethyl ether (2 x 200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL) and then were dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel flash chromatography with hexane/ethyl acetate (7:3) to give 6-chloro- 3,4-dihydro-2-(4-bromobutyl)-2H-thieno[3,2-e]-l,2-thiazine-4-ol 1,1-dioxide as a colorless oil (10.62 g, 75%); the Η NMR was consistent with the structure.
Step 2. The product from Step 1 (10.6 g, 28.3 mmol) was dissolved in tetrahydrofuran (anhydrous, 400 mL) and treated with triethyl amine (9.88 mL, 70.9 mmol) and methane sulfonic anhydride (9.86 g, 56.6 mmol) at room temperature and stirred for one hour. The suspension was concentrated and taken up in dimethylformamide (anhydrous, 120 mL). This mixture was heated at 160° for 45 min. The reaction mixture was poured into ice water (300 ml) and extracted with dichloromethane (300 mL). The organic layer was washed with water (2 x 200 mL), dried over magnesium sulfate and evaporated to a brown oil. After silica flash chromatography with hexane/ethyl acetate 6-chloro-2-(4-bromobutyl)-2H-thieno[3,2-e]-l,2- thiazine 1,1-dioxide was obtained as a yellow oil (4.97 g, 49%); the 1H NMR. was consistent with the structure.
Step 3. A solution of 4-(2H-benzimidazo-2-oxo-l-yl)piperidine (0.30 mmol) in DMF (1.6 mL, anhydrous) and triethyl amine (0.5 mL) was treated with the product of Step 2 (0.103 g, 0.29 mmol) and stirred at 70° for 20 hours and then at room temperature for two days. The reaction mixture was diluted with ethyl acetate (3 mL) and water (4 mL). Saturated sodium bicarbonate (1 mL) was added and the layers were mixed followed by removal of the aqueous layer. The organic layer was washed with water (6 mL) and evaporated to give a residue that was dissolved in ethanol and treated with 1 N hydrochloric acid in ether. After evaporation the desired product was obtained as a white solid (69.2 mg, 45%): 1H NMR and MS (M + H 493) were consistent with the structure.
By following the procedures of Example 1, but replacing 4-(2H-benzimidazo-2-oxo-l- yl)piperidine in Step 3 with the appropriate amine, the following compounds were prepared.
The 1H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure.
1. 6-Chloro-2- [4-(4-phenylpiperazin- 1 -yl)butyl] -2H-thieno [3 ,2-e] - 1 ,2-thiazine 1 , 1 -dioxide hydrochloride;
2. 6-Chloro-2-[4-[4-(2-fluorophenyl)piρerazin- 1 -yl]butyl]-2H-thieno[3,2-e]- 1 ,2-thiazine 1,1- dioxide hydrochloride;
3. 6-Chloro-2-[4-[4-hydroxy-4-(4-chlorophenyl)piperidin-l-yl]butyl]-2H-thieno[3,2-e]-l,2- thiazine 1,1-dioxide hydrochloride; 4. 6-Chloro-2-[4-[4-hydroxypiperidin-l-yl]butyl]-2H-thieno[3,2-e]-l,2-thiazine 1,1-dioxide hydrochloride.
By following the procedures of Example 1, but replacing the 1,4-dibromobutane in Step 1 with 1,3-dibromopentane and 4-(2H-benzimidazo-2-oxo-l-yl)piperidine in Step 3 with the appropriate amine, the following compounds were prepared. The 1H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure.
5. 6-Chloro-2-[3-[4-phenylpiperazin-l -yl]propyl]-2H-thieno[3,2-e]-l ,2-thiazine 1 , 1 -dioxide hydrochloride; 6. 6-Chloro-2-[3-[4-(3-trifluoromethylphenyl)piperazin-l-yl]propyl]-2H-thieno[3,2-e]-l,2- thiazine 1,1-dioxide hydrochloride; 7. 6-Chloro-2-[3-[4-(2-fluorophenyl)piperazin-l-yl]propyl]-2H-thieno[3,2-e]-l,2-thiazine 1,1-dioxide hydrochloride;
8. 6-Chloro-2-[3-[4-(2H-benzimidazol-2-oxo)piperidin-l-yl]propyl]-2H-thieno[3,2-e]-l,2- thiazine 1,1-dioxide hydrochloride.
Example 2 3-(4-Methylpiperidin-l-yl)propylsulfonyl-2,3-dihydro-lH-indole Hydrochloride
Figure imgf000018_0001
Step 1. To a solution of indoline (4.00 g, 33.6 mmol) in 100 mL of acetone at 0°C was added 3-chloropropanesulfonyl chloride (5.95 g, 33.6 mmol) with stirring. A solid precipitated from the solution. Diisopropylethylamine (4.33 g, 33.6 mmol) was added in two portions and the reaction mixture became a homogenous solution. The mixture was stirred for 30 min, warmed to ambient temperature, and evaporated to dryness. The crude mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2 x 100 mL). Chromatography on silica (10% to 25% ethyl acetate/hexane) gave an oil which solidified on standing (7.68 g, 77%, mp 53-53 °C ).
Step 2. A mixture of the product of Step 1 (200 mg, 0.77 mmol) and 0.5 M solution of 4- methylpiperidine (4 mL, 2.0 mmol) was heated at 35 °C for 60 h. The reaction mixture was combined with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2 x 10 mL). The extracts were dried and evaporated to dryness. The crude product was filtered though a short silica column and treated with a 1.0 M solution of hydrogen chloride gas in ether. The solid was filtered and dried to give the hydrochloride salt (220 mg, 80 %): MS(ES) 323 (M+H).
By following the procedures of Example 2, but replacing 4-methylpiperidine in Step 2 with the appropriate amine, the following compounds were prepared. The 1H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure. 1. 3-[4-(3-Chlorophenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole;
2. 3-(3-Methylpiperidin-l-yl)propylsulfonyl-2,3-dihydro-lH-indole;
3. 3-(l,2,3,4-Tetrahydroisoquinolin-2-yl)propylsulfonyl-2,3-dihydro-lH-indole; 4. 3-[4-(3-Trifluoromethylphenyl)piperazin- 1 -yl]propylsulfonyl-2,3-dihydro- 1 H-indole;
5. 3 -(4-Phenylpiperazin- 1 -yl)propylsulfonyl-2,3-dihydro- 1 H-indole;
6. 3-[4-(2-Fluorophenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole;
7. 3-[4-(2-Methoxyphenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole;
8. 3-[4-(4-Methoxyphenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole; 9. 3-[4-(2-Chlorophenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole.
By following the procedures of Example 2, but replacing the indoline in Step 1 with N- methylaniline and the 4-methylpiperidine in Step 2 with the appropriate amine, the following compounds were prepared. The Η ΝMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure.
10. 3-(l ,2,3,4-Tetrahydroisoquinolin-2-yl)-N-methyl-N-phenyl-propylsulfonamide;
11. N-Methyl-N-phenyl-3-[4-(3-trifluoromethylphenyl)piperazin- 1 -yl]propylsulfonamide;
12. N-Methyl-N-phenyl-3-(4-phenylpiperazin- 1 -yl)propylsulfonamide; 13. 3-[4-(2-Fluorophenyl)piperazin-l-yl]- N-methyl-N-phenyl-propylsulfonamide;
14. N-Methyl-3-[4-(2-methoxyphenyl)piperazin-l-yl]-N-phenyl-propylsulfonamide;
15. 3 - [4-(2-Chlorophenyl)piperazin- 1 -yl] - N-methyl-N-phenyl-propylsulfonamide
By following the procedures of Example 2, but replacing the 3-chloropropanesulfonyl chloride in Step 1 with 2-chloroethanesulfonyl chloride and the 4-methylpiperidine in Step 2 with 3-methylpiperidine, the following compound was prepared. The 1H ΝMR spectrum and the mass spectrum for this compound were consistent with the assigned structure.
16. 2-(3-Methylpiperidin- 1 -yl)ethylsulfonyl-2,3-dihydro- 1 H-indole. Example 3
N-[3-[4-(3-Chlorophenyl)piperazin-l-yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide Hydrochloride
Figure imgf000020_0001
Step 1. To a solution ofp-anisidine (6.00 g, 48.7 mmol) and triethylamine (5.91 g, 58.4 mmol) in methylene chloride (200 mL) at 0 C was added propylsulfonyl chloride (7.64 g, 53.6 mmol) with stirring under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was washed with a saturated aqueous solution of sodium bicarbonate (100 mL), water, and dried over magnesium sulfate. The organic layer was evaporated to give an oil that was mixed with a solution of hexane and ethyl acetate (3: 1) to afford a crystalline solid (7.97 g). The mother liquid was chromatographed on silica (hexane/ethyl acetate, 4: 1) to give a solid (2.27 g, 92%): mp 72°C; MS(-ES) 228 (M-H).
Step 2. To the product of Step 1 (3.50 g, 15.3 mmol) in anhydrous dimethylformamide (80 mL) at 0°C was added sodium hydride (60 % suspension in mineral oil, 0.672 g, 16.8 mmol) under a nitrogen atmosphere. The suspension was stirred for 30 min and 1 ,3-dibromopropane (9.27 g, 45.9 mmol) was added over 1 min. The reaction was stirred for 3 h, mixed with a saturated aqueous solution of sodium bicarbonate (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried and evaporated to dryness.
Chromatography on silica (20% ethyl acetate in hexane) gave a colorless oil (4.33 g, 81%): MS(+ES) 352 (M+H).
Step 3. To a solution of the product of Step 2 (0.175 g, 0.50 mmol) in anhydrous dimethylformamide (1 mL) was added a 0.5 M solution of l-(3-chlorophenyl)piperazine in dimethylformamide (1.1 mL, 0.55 mmol) and triethylamine (0.20 mL); this mixture was heated at 60 C for 18 h. The cooled reaction mixture was extracted with ethyl acetate (2 x 1 mL) and the combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried and evaporated to an oil which was treated with a 1.0 M solution of hydrogen chloride gas in ether to give the corresponding salt (0.11 g, 44%): MS(ES) 466 (M+).
By following the procedures of Example 3, but replacing l-(3-chlorophenyl)piperazine in
Step 3 with the appropriate amine, the following compounds were prepared. The 1H NMR spectrum and the mass spectrum for each of these compounds were consistent with the assigned structure.
1. N-[3-(l ,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]-N-(4-methoxyphenyl)- propanesulfonamide;
2. N-[3-(3-Hydroxymethylpiperidin-l-yl)propyl]-N-(4-methoxyphenyl)-propanesulfonamide;
3. N-(4-Methoxyphenyl)-N-[3-(morpholin-4-yl)propyl]-propanesulfonamide;
4. N-(4-Methoxyphenyl)-N-[3-(2-methylpiperidin- 1 -yl)propyl]-propanesulfonamide; 5. N-[3-[4-(3-Chlorophenyl)piperazin-l-yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide;
6. N-(4-Methoxyphenyl)-N-[3-[4-(3-trifluoromethylphenyl)piperazin- 1 -yl]propyl]- propanesulfonamide;
7. N-[3-(4-phenylpiperazin- 1 -yl)propyl]-N-(4-methoxyphenyl)-propanesulfonamide; 8. N-[3-[4-(2-Fluorophenyl)piperazin- 1 -yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide;
9. N- [3 - [4-(4-Methoxyphenyl)piperazin- 1 -yljpropyl] -N-(4-methoxyphenyl)- propanesulfonamide;
10. N-[3-[4-(2-Methoxyphenyl)piperazin- 1 -yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide;
11. N-[3-[4-(2-Chlorophenyl)piperazin- 1 -yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide;
12. N-[3-[4-(2H-Benzimidazo-2-oxo- 1 -yl)piperidin- 1 -yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide.
By following the procedures of Example 3, but replacing the 1,3-dibromopropane in Step 2 with 1 ,4-dibromobutane and the l-(3-chlorophenyl)piperazine in Step 3 with 1,2,3,4- tetrahydroisoquinoline, the following compound was prepared. The Η NMR spectrum and the mass spectrum for this compound were consistent with the assigned structure.
13. N-[4-(l,2,3,4-Tetrahydroisoquinolin-2-yl)butyl]-N-(4-methoxyphenyl)- methanesulfonamide.
The following topical ophthalmic formulations are useful according to the present invention administered 1-4 times per day according to the discretion of a skilled clinician.
EXAMPLE 4
Figure imgf000022_0001
EXAMPLE 5
Figure imgf000023_0001
EXAMPLE 7
Figure imgf000024_0001
EXAMPLE 9
Figure imgf000025_0001
EXAMPLE 11
Figure imgf000026_0001
EXAMPLE 12
Formulation for Oral Administration
Tablet: 0.2 - 5 mg. of 5HT Compound with inactive ingredients such as comstarch, lactose, colloidal silicon dioxide, microcrystalline cellulose, and magnesium sterate can be formulated according to procedures known to those skilled in the art of tablet formulation.

Claims

We Claim:
1. A compound of the formula:
Figure imgf000027_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, OH, OC1-3alkyl, C╬╣-3alkyl, d.3alkyl substituted optionally with OH, or Od.3alkyl;
R2 is H, halogen, d_3alkyl, CONR5R6, S(=O)mCι-3alkyl, S(=O)2 NR5R6 , d.3alkyl substituted optionally with OH, or Od.3alkyl; R3, R4 are independently H, C1-3alkyl, Cι-3alkyl substituted optionally with OH or OCι-3alkyl; R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with OH, OC1-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1- alkyl, C2-3alkyl substituted optionally with OH or OCι-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, Cι-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with d^alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or C1-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
2. A compound of the formula:
Figure imgf000028_0001
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, d-salkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC1-3alkyl, S(=O)md.3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl substituted optionally with OH, OC╬╣-3alkyl, S(=O)mC1- alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, Od.3alkyl, S(=O)mC1-3alkyl, halogen, CF3, S(=O)2 NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)mC1- 3alkyl; R2 is H, halogen, C1-3alkyl, S(=O)md.3alkyl, S(=O)2 NR5R6, or C1-3alkyl substituted optionally with OH, or OC╬╣-3alkyl; R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally with OH or
OC1-3alkyl; R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with OH, OCι-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Cι-3alkyl, C2.3alkyl substituted optionally with OH or OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ -piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cι-3alkyl, C1-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or Cι-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or Cι-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
3. A compound of the formula:
Figure imgf000029_0001
R3 & R4 are independently H, d-3alkyl, or C1-3alkyl substituted optionally with OH or
OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cι-3alkyl, Cι-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or C1-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1.3alkyl, or C)-3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C1-4 alkyl, halogen, OC^a-kyl; R10 is or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
4. A Compound of the formula:
Figure imgf000030_0001
R3 & R4 are independently H, d-3alkyl, or C1-3alkyl substituted optionally with OH or
OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cι-3alkyl, C1-3alkyl substituted optionally with OH, OCι. alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1- alkyl, or C1-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or C1-3alkyl;
R11 is d-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen,
Figure imgf000030_0002
R12 is C1-4alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or 1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
5. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000031_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OCι-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH, or OCι-3alkyl; R2 is H, halogen, Cι-3alkyl, CONR5R6, S(=O)mCι-3alkyl, S(=O)2 NR5R6 , C1-3alkyl substituted optionally with OH, or OC1-3alkyl; R3, R4 are independently H, d-3alkyl, C1-3alkyl substituted optionally with OH or OC1-3alkyl; R5, R6 are independently H, Cι-3alkyl, C2.3alkyl substituted optionally with OH, OC1-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OCι-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or Cι-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
6. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000032_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, d.salkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH,
OC1-3alkyl, S(=O)md.3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC1-3alkyl, S(=O)mC1.3alkyl, halogen, CF3, S(=O)2 NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)mC╬╣-
3alkyl; R2 is H, halogen, C1-3alkyl, S(=O)mC1-3alkyl, S(=O)2 NR5R6, or C1-3alkyl substituted optionally with OH, or OC1-3alkyl; R3 & R4 are independently H, C1-3alkyl, or C╬╣-3alkyl substituted optionally with OH or OC1-3alkyl;
R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with OH, OC1- alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1-3alkyl, C2.3alkyl substituted optionally with OH or OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ -piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or d.3alkyl, or substituted on nitrogen with d^alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
7. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000033_0001
R3 & R4 are independently H, C1-3alkyl, or Cι-3alkyl substituted optionally with OH or OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cι-3alkyl, Cι-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or C1-3alkyl, or substituted on nitrogen with C alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or d.3alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OC1- alkyl;
R10 is C alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
8. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000034_0001
R3 & R4 are independently H, C1-3alkyl, or C1-3alkyl substituted optionally with OH or
Od-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or C1- alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or Cι-3alkyl; R11 is C1-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CMalkyl, halogen, OCM lkyl; R12 is CMalkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l ,2-thiazine, or 9 1 1
1 ,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
9. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000035_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, OH, OC1-3alkyl, C1-3alkyl, C1-3alkyl substituted optionally with OH, or OC1-3alkyl;
R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , C1-3alkyl substituted optionally with OH, or Od.3alkyl; R3, R4 are independently H, Ci alkyl, C1-3alkyl substituted optionally with OH or OCι-3alkyl; R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with OH, OCι-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1-3alkyl, C2-3alkyl substituted optionally with OH or OC!-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted optionally with OH, OCι-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
10. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000036_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, C1-5alkyl, C3-5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, Od.3alkyl, S(0)md-3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2.5alkyl substituted optionally with OH, OC^alkyl, S(=O)mC1-3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, S(=O)2
NR5R6; or C3-5alkenyl substituted optionally with OH, OC1-3alkyl, or S(=O)md. 3alkyl; R2 is H, halogen, C1-3alkyl, S(=O)raC1-3alkyl, S(=O)2 NR5R6, or C╬╣-3alkyl substituted optionally with OH, or OC╬╣.3alkyl; R3 & R4 are independently H, C1-3alkyl, or C╬╣.3alkyl substituted optionally with OH or OC1-3alkyl; R5, R6 are independently H, d-3alkyl, C2-3alkyl substituted optionally with OH, OCj-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1-3alkyl, C -3alkyl substituted optionally with OH or OC╬╣-3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, Cι-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or Cj-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or C1-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
11. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000037_0001
R3 & R4 are independently H, C╬╣-3alkyl, or C1-3alkyl substituted optionally with OH or
Od.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, Cj.3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or C1-3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or Cj.3alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OC1-4alkyl; R10 is C1-4alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
12. A method for improving blood flow to the optic nerve head and the retina which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000038_0001
R3 & R4 are independently H, C1-3alkyl, or C]-3alkyl substituted optionally with OH or
OCι-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1-3alkyl, C1-3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1-3alkyl, or substituted on nitrogen with C lko y or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3a.kyl, or d-salkyl; R11 is d.3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OC1-4alkyl; R12 is CMalkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l ,2-thiazine, or
19 1 1
1 ,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
13. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000039_0001
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, OCι-3alkyl, Cι-3alkyl, C1-3alkyl substituted optionally with OH, or Od.3alkyl; R2 is H, halogen, C1-3alkyl, CONR5R6, S(=O)mC1-3alkyl, S(=O)2 NR5R6 , CI-3alkyl substituted optionally with OH, or OCι-3alkyl; R3, R4 are independently H, C1-3alkyl, C1-3alkyl substituted optionally with OH or OCι-3alkyl; R5, R6 are independently H, C1-3alkyl, C2-3alkyl substituted optionally with OH, OCj-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with C1.3a.kyl, C .3alkyl substituted optionally with OH or OCι.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from
Figure imgf000039_0002
d alkyl substituted optionally with OH, Od.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or C╬╣-3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1.3a.kyl, or Cj.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
14. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000040_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, d-5alkyl, C3.5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OCi.3alkyl, S(=O)md_3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl substituted optionally with OH, OC╬╣-3alkyl, S(=O)mC╬╣-3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC1-3alkyl, S(=O)mC1-3alkyl, halogen, CF3, S(=O)2 NR5R6; or C3.5alkenyl substituted optionally with OH, OC^alkyl, or S(=O)md. 3alkyl; R2 is H, halogen, d_3alkyl, S(=O)md.3alkyl, S(=O)2 NR5R6, or d.3alkyl substituted optionally with OH, or OC╬╣-3alkyl;
R3 & R4 are independently H, C╬╣-3alkyl, or C].3alkyl substituted optionally with OH or
Od.3a.kyl; R5, R6 are independently H, d^alkyl, C2.3alkyl substituted optionally with OH, Od.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Cι.3alkyl, doalkyl substituted optionally with OH or OC1.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1.3a.kyl, d.3alkyl substituted optionally with OH, OCι.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1.3a.kyl, or CMalkyl, or substituted on nitrogen with d-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or Cι.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
15. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000041_0001
R3 & R4 are independently H, d.3alkyl, or CMalkyl substituted optionally with OH or
OCι-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1.3a.kyl, C1-3alkyl substituted optionally with OH, OCι.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with d-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3a.kyl, or C1.3a.kyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OCMalkyl; R10 is CMalkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
16. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising an effective amount of a compound of the formula:
Figure imgf000042_0001
R3 & R4 are independently H, CMalkyl, or C╬╣.3alkyl substituted optionally with OH or
Od.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl;
R11 is d-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OCMalkyl; R12 is or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or 1 ,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
17. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000043_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, OH, OC╬╣.3alkyl, C╬╣.3alkyl, d.3alkyl substituted optionally with OH, or Od.3alkyl;
R2 is H, halogen, C1.3alkyl, CONR5R6, S(=O)md.3alkyl, S(=O)2 NR5R6 , d.3alkyl substituted optionally with OH, or Od-3alkyl; R3, R4 are independently H, d.3alkyl, Cι.3alkyl substituted optionally with OH or Od.3alkyl; R5, R6 are independently H, d.3alkyl, C2.3alkyl substituted optionally with OH, Od.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d-3alkyl, C2.3alkyl substituted optionally with OH or Od-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from CMalkyl, Cι.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
18. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000044_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, d.5alkyl, C3. alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH,
OC╬╣.3alkyl, S(=O)md_3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2-5alkyl substituted optionally with OH, Od.3alkyl, S(=O)mC1.3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC╬╣.3alkyl, S(=O)mC╬╣.3alkyl, halogen, CF3, S(=O)2 NR5R6; or C3.5alkenyl substituted optionally with OH, Od.3alkyl, or S(=O)md.
3alkyl; R2 is H, halogen, d.3alkyl, S(=O)mC╬╣.3alkyl, S(=O)2 NR5R6, or C,.3alkyl substituted optionally with OH, or Od.3a.kyl; R3 & R4 are independently H, d.3alkyl, or Cj.3alkyl substituted optionally with OH or Od_3alkyl;
R5, R6 are independently H, CMalkyl, C2.3alkyl substituted optionally with OH, Od.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d^alkyl, C2.3alkyl substituted optionally with OH or OCι.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ -piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or d.3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or C1.3a.kyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
19. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000045_0001
R3 & R4 are independently H, d.3alkyl, or d.3alkyl substituted optionally with OH or OCι.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ -piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from Cj.3alkyl, d.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or
Figure imgf000045_0002
or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3a.kyl, or d-3alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OCMalkyl;
R10 is Ci^alkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
20. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000046_0001
R3 & R4 are independently H, d.3alkyl, or C╬╣-3alkyl substituted optionally with OH or
OCι.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, CMalkyl substituted optionally with OH, Od.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or d^alkyl; R11 is Cj.3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OCMalkyl; R12 is CMalkyl or a fused bicyclic heteroaromatic ring such as thieno [3 ,2-e]-l ,2-thiazine, or
1 1 1
1 ,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
21. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000047_0001
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, Od.3alkyl, C╬╣.3alkyl, d.3alkyl substituted optionally with OH, or OC1-3alkyl; R2 is H, halogen, d.3alkyl, CONR5R6, S(=O)mC╬╣.3alkyl, S(=O)2 NR5R6 , d.3alkyl substituted optionally with OH, or Od.3alkyl; R3, R4 are independently H, CMalkyl, d-3alkyl substituted optionally with OH or OC╬╣-3alkyl;
R5, R6 are independently H, d-3alkyl, C2.3alkyl substituted optionally with OH, OC1-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d.3alkyl, C2.3alkyl substituted optionally with OH or Od-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, Cι-3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCj.3alkyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
22. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000048_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, C╬╣-5alkyl, C3.5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC╬╣.3alkyl, S(=O)md.3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2.5alkyl substituted optionally with OH, Od.3alkyl, S(=O)mC1.3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC╬╣.3alkyl, S(=O)mC╬╣.3alkyl, halogen, CF3, S(=O)2 NR5R6; or C3.5alkenyl substituted optionally with OH, Od_3alkyl, or S(=O)mC╬╣. 3alkyl; R2 is H, halogen, CMalkyl, S(=O)md.3alkyl, S(=O)2 NR5R6, or d.3alkyl substituted optionally with OH, or OC╬╣.3alkyl;
R3 & R4 are independently H, d.3alkyl, or C].3alkyl substituted optionally with OH or
OCι.3alkyl; R5, R6 are independently H, d^alkyl, C2.3alkyl substituted optionally with OH, OC1.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d-3alkyl, C2-3alkyl substituted optionally with OH or OCι- alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d^alkyl, d.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC].3alkyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
23. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000049_0001
R3 & R4 are independently H, C╬╣-3alkyl, or C╬╣.3alkyl substituted optionally with OH or Od.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, OCι-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or d.3alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OCMalkyl;
R10 is CMalkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
24. A composition for improving blood flow to the optic nerve head and the retina comprising a pharmaceutically effective amount of a Compound of the formula:
Figure imgf000050_0001
R3 & R4 are independently H, d.3alkyl, or d.3alkyl substituted optionally with OH or OCi.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, Cι.3alkyl substituted optionally with OH, OC1.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od alkyl, or d.3alkyl; R11 is d.3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OCMalkyl; R12 is CMalkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or 1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
25. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000051_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, OH, OC╬╣.3alkyl,
Figure imgf000051_0002
d.3alkyl substituted optionally with OH, or OCι.3alkyl; R2 is H, halogen, d.3alkyl, CONR5R6, S(=O)md.3alkyl, S(=O)2 NR5R6 , d.3alkyl substituted optionally with OH, or Od-3alkyl; R3, R4 are independently H, Cι-3alkyl, d.3alkyl substituted optionally with OH or OCι.3alkyl; R5, R6 are independently H, Cι.3alkyl, C2.3alkyl substituted optionally with OH, Od.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Cι.3alkyl, C2.3alkyl substituted optionally with OH or OCι-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or d.3alkyl, or substituted on nitrogen with
Figure imgf000051_0003
or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or C╬╣.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
26. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000052_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, d.5alkyl, d-salkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, Od.3alkyl, S(=O)md.3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2.5alkyl substituted optionally with OH, OC╬╣-3alkyl, S(=O)mC╬╣.3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, Od-3alkyl, S(=O)md.3alkyl, halogen, CF3, S(=O)2
NR5R6; or C3.5alkenyl substituted optionally with OH, Od.3alkyl, or S(=O)md- 3alkyl; R2 is H, halogen, C╬╣-3alkyl, S(=O)md.3alkyl, S(=O)2 NR5R6, or d.3alkyl substituted optionally with OH, or OC╬╣-3alkyl; R3 & R4 are independently H, d.3alkyl, or d.3alkyl substituted optionally with OH or
Od.3alkyl; R5, R6 are independently H, d.3alkyl, C2.3alkyl substituted optionally with OH, Od.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d.3alkyl, CMalkyl substituted optionally with OH or Od.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, Cι.3alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or d-3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1.3a.kyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
27. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000053_0001
R3 & R4 are independently H, d.3a.kyl, or d.3alkyl substituted optionally with OH or
Od.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, CMalkyl substituted optionally with OH, OC1.3a.kyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or C1-3alkyl, or substituted on nitrogen with d^alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3a.kyl, or d^alkyl;
R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM lkyl, halogen, OC1-4alkyl; R10 is CMalkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
28. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000054_0001
R3 & R4 are independently H, d-3alkyl, or C╬╣.3alkyl substituted optionally with OH or OC╬╣.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCj.3alkyl, or Cι.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or Cι-3alkyl; Ru is d-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OC1-4alkyl; R12 is CMalkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or
19 1 1
1 ,2-benzothiazine, or R can be joined to R to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
29. A method for improving blood flow to the optic nerve head or the retina which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT7 receptor affinity.
30. A composition for improving blood flow to the optic nerve head or the retina comprising a pharmaceutically effective amount of a compound with 5HT receptor affinity.
31. A method for providing neuroprotection to the optic nerve head or the retina which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT7 receptor affinity.
32. A composition for providing neuroprotection to the optic nerve head or the retina comprising a pharmaceutically effective amount of a compound with 5HT receptor affinity.
33. A method for treating retinal diseases which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT7 receptor affinity.
34. The method of Claim 1 wherein the retinal disease is selected from the group consisting of glaucoma, age related macular degeneration, optic neuritis, ischemic disorders, and retinal edema.
35. A composition for treating retinal diseases comprising a pharmaceutically effective amount of a compound with 5HT receptor affinity.
36. The composition of Claim 35 wherein the retinal diseases are selected from the group consisting of glaucoma, age related macular degeneration, optic neuritis, ischemic disorders, diabetic retinopathy, and retinal edema.
37. A method for lowering IOP which comprises administering to a person in need thereof, a composition comprising a pharmaceutically effective amount of a compound with 5HT7 receptor affinity.
38. A composition for lowering IOP comprising a pharmaceutically effective amount of a compound with 5HT receptor affinity.
39. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, circadian rhythm disorders, and centrally and peripherally mediated hypertension, which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000056_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring;
R1 is H, OH, Od.3alkyl, d.3alkyl, Cι.3alkyl substituted optionally with OH, or Od.3alkyl; R2 is H, halogen, d.3alkyl, CONR5R6, S(=O)md.3alkyl, S(=O)2 NR5R6 , d.3alkyl substituted optionally with OH, or Od-3alkyl; R3, R4 are independently H, Cι-3alkyl, d.3alkyl substituted optionally with OH or OC].3alkyl; R5, R6 are independently H, d.3alkyl, C2.3alkyl substituted optionally with OH, OCj.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with Cι-3alkyl, C .3alkyl substituted optionally with OH or OC1-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, Od.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC^alkyl, or C1.3a.kyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
40. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythem disorders, and centrally and peripherally mediated hypertension which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000057_0001
Wherein the dashed bond represents a single or double bond;
Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, Ci-salkyl, d-salkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, Od.salkyl, S(=O)mC╬╣.3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2.5alkyl substituted optionally with OH, Od-3alkyl, S(=O)mC1.3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC╬╣.3alkyl, S(=O)mC1.3alkyl, halogen, CF3, S(=O)2 NR5R6; or C3.5alkenyl substituted optionally with OH, Od.3alkyl, or S(=O)mC╬╣. 3alkyl; R2 is H, halogen, CMalkyl, S(=O)mC╬╣.3alkyl, S(=O)2 NR5R6, or d.3alkyl substituted optionally with OH, or OC╬╣.3alkyl; R3 & R4 are independently H, C╬╣.3alkyl, or d^alkyl substituted optionally with OH or
Od.3alkyl; R5, R6 are independently H, C1.3a.kyl, C2.3alkyl substituted optionally with OH, OCj.3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d.3alkyl, d^alkyl substituted optionally with OH or Od.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, OCι.3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC].3alkyl, or C1-3alkyl, or substituted on nitrogen with C1-4alkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC1-3alkyl, or C1.3a.kyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates.
41. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, obsessive compulsive disorders, circadian rhythm disorders, and centrally and peripherally mediated hypertension which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000058_0001
R3 & R4 are independently H, C╬╣-3alkyl, or C╬╣.3alkyl substituted optionally with OH or Od.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ -piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, OCι-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od_3alkyl, or d.3alkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or CMalkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with C alkyl, halogen, OC alkyl; R10 is CMalkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
42. A method for treating persons suffering from a sleeping disorder, depression, schizophrenia, anxiety, obsessive compulsive disorder, circadian rhythm disorders, and centrally and peripherally mediated hypertension which comprises, administering a composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000059_0001
R3 & R4 are independently H, C1.3a.kyl, or C1.3a.kyl substituted optionally with OH or
Od.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ -piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from C1.3a.kyl, d alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or C1.3a.kyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or C1.3a.kyl; R11 is d.3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM lkyl, halogen, OC alkyl; R12 is or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or 1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates.
43. A composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000060_0001
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, OH, OCι.3alkyl, C1.3a.kyl, d.3alkyl substituted optionally with OH, or OCMalkyl; R2 is H, halogen, d.3alkyl, CONR5R6, S(=O)md.3alkyl, S(=O)2 NR5R6 , d.3alkyl substituted optionally with OH, or OCι.3alkyl; R3, R4 are independently H, Cι.3alkyl, d.3alkyl substituted optionally with OH or OCι.3alkyl; R5, R6 are independently H, d.3alkyl, C2.3alkyl substituted optionally with OH, OCMalkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d.3alkyl, C2-3alkyl substituted optionally with OH or Od-3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, Cι.3alkyl substituted optionally with OH, Od^alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC).3alkyl, or Cj.3alkyl, or substituted on nitrogen with
Figure imgf000061_0001
or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OC╬╣-3alkyl, or d-3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.
44. A composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000061_0002
Wherein the dashed bond represents a single or double bond; Aryl signifies a fused phenyl or monocyclic heteroaromatic ring; R1 is H, d.5alkyl, C .5alkenyl, an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, Od.3alkyl, S(=O)md.3alkyl, halogen, CF3, or S(=O)2 NR5R6; or C2.5alkyl substituted optionally with OH, Od-3alkyl, S(=O)mC1.3alkyl or an aromatic ring such as phenyl, thienyl, pyridyl, and imidazoyl which is either unsubstituted or substituted optionally with OH, OC1-3alkyl, S(=O)mC╬╣.3alkyl, halogen, CF3, S(=O)2
NR5R6; or C3.5alkenyl substituted optionally with OH, Od.3alkyl, or S(=O)md. 3alkyl; R2 is H, halogen, d_3alkyl, S(=O)md.3alkyl, S(=O)2 NR5R6, or CMalkyl substituted optionally with OH, or OC╬╣-3alkyl; R3 & R4 are independently H, CMalkyl, or C╬╣-3alkyl substituted optionally with OH or Od.3alkyl; R5, R6 are independently H,
Figure imgf000061_0003
C2.3alkyl substituted optionally with OH, Od-3alkyl, or R5 and R6 can be joined together with saturated carbon atoms to form a 5 or 6 membered ring and said carbon atoms can be either unsubstituted or substituted optionally with d.3alkyl, C2.3alkyl substituted optionally with OH or OCj.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, Cj.3alkyl substituted optionally with OH, OC1-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3alkyl, or CMalkyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od-3alkyl, or d.3alkyl; n is 2 to 4; m is 0, 1 or 2 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.
45. A composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000062_0001
R3 & R4 are independently H, d.3alkyl, or d-3alkyl substituted optionally with OH or Od.3alkyl; R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d^alkyl substituted optionally with OH, Od-3alkyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι.3alkyl, or d.3alkyl, or substituted on nitrogen with CM lkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι_3alkyl, or Cι-3alkyl; R9 is phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OCMalkyl; R10 is CMalkyl, or R10 can be joined to R9 to form a fused bicyclic ring system such as indoline; n is 2 to 4 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.
46. A composition comprising a pharmaceutically effective amount of a compound of the formula:
Figure imgf000063_0001
R3 & R4 are independently H, d.3alkyl, or CMalkyl substituted optionally with OH or Od.3alkyl;
R7, R8 are together with the nitrogen atom to which they are attached incoφorated into a heterocyclic ring of 5 to 8 atoms which may include a second heteroatom selected from N, O, S, such as pyrrolidine, piperidine, Δ3-piperidein, piperazine, moφholine or thiomoφholine which can be unsubstituted or substituted on carbon with one or more substituents optionally selected from d.3alkyl, d.3alkyl substituted optionally with OH, OC1.3a.kyl, phenyl which can be unsubstituted or substituted optionally with halogen, CF3, OCι-3alkyl, or C1.3a.kyl, or substituted on nitrogen with CMalkoxy or phenyl which can be unsubstituted or substituted optionally with halogen, CF3, Od.3a.kyl, or C1.3a.kyl; R11 is d-3alkyl, phenyl or a monocyclic heteroaromatic ring which can be unsubstituted or substituted with CM alkyl, halogen, OCMalkyl; R12 is C alkyl or a fused bicyclic heteroaromatic ring such as thieno[3,2-e]-l,2-thiazine, or 1,2-benzothiazine, or R12 can be joined to R11 to form a fused bicyclic ring system such as 2,3-dihydro-benzo[c]isoxazole; n is 2 to 4 and any pharmaceutically acceptable salts and solvates in a pharmaceutically acceptable carrier.
47. The Compound of Claim 1 selected from the group consisting of: 6-Chloro-2-[4-[4-(2H-benzimidazo-2-oxo- 1 -yl)piperidin- 1 -yl]butyl]-2H-thieno[3,2-e]- 1 ,2- thiazine 1,1-dioxide;
6-Chloro-2-[4-(4-phenylpiperazin- 1 -yl)butyl]-2H-thieno[3,2-e]- 1 ,2-thiazine 1 , 1 -dioxide; 6-Chloro-2-[4-[4-(2-fluorophenyl)piperazin-l-yl]butyl]-2H-thieno[3,2-e]-l,2-thiazine 1,1- dioxide; 6-Chloro-2-[3-[4-(3-trifluoromethylphenyl)piperazin-l-yl]propyl]-2H-thieno[3,2-e]-l,2- thiazine 1,1-dioxide;
6-Chloro-2-[3-[4-(2H-benzimidazol-2-oxo)piperidin-l-yl]propyl]-2H-thieno[3,2-e]-l,2- thiazine 1,1-dioxide.
48. The Compound of Claim 3 selected from the group consisting of: 3-[4-(3-Chlorophenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole;
3-(l,2,3,4-Tetrahydroisoquinolin-2-yl)propylsulfonyl-2,3-dihydro-lH-indole; 3-[4-(3-Trifluoromethylphenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole; 3-[4-(2-Methoxyphenyl)piperazin-l-yl]propylsulfonyl-2,3-dihydro-lH-indole; 3-(l,2,3,4-Tetrahydroisoquinolin-2-yl)-N-methyl-N-phenyl-propylsulfonamide;
49. The Compound of Claim 4 selected from the group consisting of:
N- [3 - [4-(3 -Chlorophenyl)piperazin- 1 -yljpropyl] -N-(4-methoxyphenyl)-propanesulfonamide; N-[3-(l,2,3,4-Tetrahydroisoquinolin-2-yl)propyl]-N-(4-methoxyphenyl)-propanesulfonamide; N- [3 - [4-(3 -Chlorophenyl)piperazin- 1 -yl]propyl] -N-(4-methoxyphenyl)-propanesulfonamide; N-[3-[4-(2-Methoxyphenyl)piperazin-l-yl]propyl]-N-(4-methoxyphenyl)- propanesulfonamide; N-[3-[4-(2-Chlorophenyl)piperazin-l-yl]propyl]-N-(4-methoxyphenyl)-propanesulfonamide.
PCT/US1999/010179 1998-05-19 1999-05-10 Serotonergic 5ht7 receptor compounds for treating ocular and cns disorders WO1999059499A2 (en)

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EP99922894A EP1079763A2 (en) 1998-05-19 1999-05-10 Serotonergic 5ht 7? receptor compounds for treating ocular and cns disorders
US09/674,403 US6960579B1 (en) 1998-05-19 1999-05-10 Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
JP2000549166A JP2002515408A (en) 1998-05-19 1999-05-10 Serotonergic 5HT7 receptor compounds for the treatment of ocular and central nervous system disorders
BR9910590-0A BR9910590A (en) 1998-05-19 1999-05-10 Compound, process to decrease iop, to improve blood flow to the end of the optic nerve and the retina, and to treat retinal diseases, compositions to decrease iop, to improve blood flow to the end of the optic nerve and the retina, and to treating retinal diseases, process and composition to provide neuroprotection to the end of the optic nerve or the retina, and, process to treat people suffering from sleep disorders, depression, schizophrenia, anxiety, circadian rhythmic disorders and centrally and peripherally mediated hypertension
CA002332505A CA2332505A1 (en) 1998-05-19 1999-05-10 Serotonergic 5ht7 receptor compounds for treating ocular and cns disorders
US11/100,918 US7060704B2 (en) 1998-05-19 2005-04-07 Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
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US6440988B1 (en) 1999-05-18 2002-08-27 Synaptic Pharmaceutical Corporation Use of agonists or antagonists of the 5-HT7 receptor to treat disorders of the bladder
US6630469B2 (en) 2000-05-09 2003-10-07 Bristol-Myers Squibb Company 5-HT7 receptor antagonists
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
US6989445B2 (en) 2003-12-15 2006-01-24 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7005443B1 (en) 2000-03-17 2006-02-28 Alcon, Inc. 5-Hydroxy indazole derivatives for treating glaucoma
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US7208512B2 (en) 2001-12-20 2007-04-24 Alcon, Inc. Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
US7396856B2 (en) 2002-12-13 2008-07-08 Alcon, Inc. Benzopyran analogs and their use for the treatment of glaucoma
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7285553B2 (en) 1998-05-19 2007-10-23 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
US7060704B2 (en) 1998-05-19 2006-06-13 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
WO2000037082A1 (en) * 1998-12-18 2000-06-29 Smithkline Beecham P.L.C. Use of 5-ht7 receptor antagonists for treating neuronal degeneration resulting from ischemic events
US6440988B1 (en) 1999-05-18 2002-08-27 Synaptic Pharmaceutical Corporation Use of agonists or antagonists of the 5-HT7 receptor to treat disorders of the bladder
WO2001070702A1 (en) * 2000-03-17 2001-09-27 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
US6956036B1 (en) 2000-03-17 2005-10-18 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
US7005443B1 (en) 2000-03-17 2006-02-28 Alcon, Inc. 5-Hydroxy indazole derivatives for treating glaucoma
WO2001070701A1 (en) * 2000-03-17 2001-09-27 Alcon, Inc. 5-hydroxy indazole derivatives for treating glaucoma
US6630469B2 (en) 2000-05-09 2003-10-07 Bristol-Myers Squibb Company 5-HT7 receptor antagonists
US7208512B2 (en) 2001-12-20 2007-04-24 Alcon, Inc. Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
US7396856B2 (en) 2002-12-13 2008-07-08 Alcon, Inc. Benzopyran analogs and their use for the treatment of glaucoma
US6989445B2 (en) 2003-12-15 2006-01-24 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7268131B2 (en) 2003-12-15 2007-09-11 Alcon, Inc. Substituted [1,4]oxazino[2,3-g]indazoles for the treatment of glaucoma
US7129257B1 (en) 2003-12-15 2006-10-31 Alcon, Inc. Pyrazolo[3,4- e]benzoxazoles for the treatment of glaucoma
US7338972B1 (en) 2003-12-15 2008-03-04 Alcon, Inc. Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma
US7439262B1 (en) 2003-12-15 2008-10-21 Alcon, Inc. Substituted 1-alkylamino-1-H-indazoles for the treatment of glaucoma
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma

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