EP1079763A2 - Composes a affinite pour le recepteur de 5ht 7? serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central - Google Patents

Composes a affinite pour le recepteur de 5ht 7? serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central

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Publication number
EP1079763A2
EP1079763A2 EP99922894A EP99922894A EP1079763A2 EP 1079763 A2 EP1079763 A2 EP 1079763A2 EP 99922894 A EP99922894 A EP 99922894A EP 99922894 A EP99922894 A EP 99922894A EP 1079763 A2 EP1079763 A2 EP 1079763A2
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European Patent Office
Prior art keywords
alkyl
substituted optionally
substituted
unsubstituted
halogen
Prior art date
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Withdrawn
Application number
EP99922894A
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German (de)
English (en)
Inventor
Jesse A. May
Thomas R. Dean
Najam A. Sharif
Hwang-Hsing Chen
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Alcon Vision LLC
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Alcon Laboratories Inc
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Publication of EP1079763A2 publication Critical patent/EP1079763A2/fr
Withdrawn legal-status Critical Current

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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.

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Abstract

L'invention concerne des composés possédant une affinité à l'égard du récepteur de 5HT7 (dont certains sont nouveaux), utiles pour abaisser la tension intra-oculaire, pour améliorer l'écoulement sanguin vers la tête du nerf optique et la rétine, pour apporter une protection neurologique et traiter des maladies de la rétine. Ces composés sont également utiles pour traiter les troubles du sommeil, la dépression ainsi que d'autres troubles psychiatriques tels que la schizophrénie, l'anxiété, les troubles obsessifs impulsifs, les troubles du rythme circadien, ainsi que l'hypertension d'origine centrale ou périphérique. L'invention concerne encore des compositions et des procédés destinés à l'emploi de ces composés.
EP99922894A 1998-05-19 1999-05-10 Composes a affinite pour le recepteur de 5ht 7? serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central Withdrawn EP1079763A2 (fr)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US8598998P 1998-05-19 1998-05-19
US8600698P 1998-05-19 1998-05-19
US8600298P 1998-05-19 1998-05-19
US8600598P 1998-05-19 1998-05-19
US85989P 1998-05-19
US86006P 1998-05-19
US86005P 1998-05-19
US86002P 1998-05-19
PCT/US1999/010179 WO1999059499A2 (fr) 1998-05-19 1999-05-10 Composes a affinite pour le recepteur de 5ht7 serotoninergique, destines au traitement de troubles oculaires et du systeme nerveux central

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EP (1) EP1079763A2 (fr)
JP (1) JP2002515408A (fr)
CN (1) CN1301161A (fr)
AU (1) AU3978899A (fr)
BR (1) BR9910590A (fr)
CA (1) CA2332505A1 (fr)
WO (1) WO1999059499A2 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6960579B1 (en) 1998-05-19 2005-11-01 Alcon Manufacturing, Ltd. Serotonergic 5HT7 receptor compounds for treating ocular and CNS disorders
GB9828004D0 (en) * 1998-12-18 1999-02-10 Smithkline Beecham Plc Use
WO2000069437A1 (fr) 1999-05-18 2000-11-23 Synaptic Pharmaceutical Corporation Utilisation d'agonistes ou d'antagonistes vis-a-vis du recepteur 5-ht7 pour traiter les troubles de la vessie
AU2001219180B2 (en) * 2000-03-17 2005-04-07 Alcon, Inc. 5-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
WO2001070702A1 (fr) * 2000-03-17 2001-09-27 Alcon, Inc. Derives de 6-hydroxy-indazole destines au traitement du glaucome
US6630469B2 (en) 2000-05-09 2003-10-07 Bristol-Myers Squibb Company 5-HT7 receptor antagonists
TW593302B (en) 2001-12-20 2004-06-21 Alcon Inc Novel benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma
JP2006511556A (ja) 2002-12-13 2006-04-06 アルコン，インコーポレイテッド 新規のベンゾピラン類似体及び緑内障の治療のためのそれらの使用
WO2005058911A2 (fr) 2003-12-15 2005-06-30 Alcon, Inc. [1,4]oxazino[2,3-g]indazoles substitues pour traiter le glaucome
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
US7425572B2 (en) 2004-12-08 2008-09-16 Alcon, Inc. Use of dioxindoindazoles and dioxoloindazoles for treating glaucoma

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880134A (en) * 1996-03-20 1999-03-09 Eli Lilly And Company Method for using ergoline compounds to effect physiological and pathological functions at the 5-HT7 receptor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9959499A2 *

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JP2002515408A (ja) 2002-05-28
WO1999059499A2 (fr) 1999-11-25
BR9910590A (pt) 2001-01-23
CA2332505A1 (fr) 1999-11-25
WO1999059499A3 (fr) 2000-03-16
CN1301161A (zh) 2001-06-27
AU3978899A (en) 1999-12-06

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