Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics

Definitions

• This invention relates to a method for lowering intraocular pressure, treating ocular hypertension, and treating glaucoma, by administering indole analogues and pharmaceutical compositions.
• Glaucoma is a slowly progressive blinding disease usually associated with chronic elevation of intraocular pressure (IOP). Sufficiently high and persistent intraocular pressure is believed to result in damage to the optic disc at the juncture of the optic nerve and retina, resulting in degeneration of retinal ganglion cells and blindness characteristic of glaucoma.
• IOP elevation also known as ocular hypertension
• a fraction of patients with typical visual field loss associated with glaucoma do not show abnormal elevated IOP levels (known as low-tension or normal-tension glaucoma).
• Glaucoma is primarily classified as open-angle, closed-angle, or congenital, and further classified as primary and secondary. Glaucoma is treated with a variety of pharmacological and surgical approaches, h cases where glaucoma is associated with ocular hypertension, pharmacological treatment comprises adrenergic agonists (epinephrine, dipevefrin, apraclonidine), cholinergic agonists (pilocarpine), beta blockers (betaxolol, levobunolol, timolol), carbonic anhydrase inhibitors (acetazolamide) or more recently, prostaglandin analogues (latanoprost, LumiganTM) and alpha adrenergic agonists (brimonidine).
• adrenergic agonists epinephrine, dipevefrin, apraclonidine
• cholinergic agonists pilocarpine
• Anticholinergic agents reduce intraocular pressure in primary glaucoma, reducing the resistance to outflow of the aqueous humor outflow.
• Anticholmesterase inhibitors have been used to manage primary and certain forms of secondary glaucoma, such as aphakic glaucoma following cataract extraction.
• Acute congestive (narrow angle) glaucoma is nearly always a medical emergency in which the drugs are essential in controlling the acute attacks, but long-range management is usually based predominantly on surgery (peripheral or complete iridectomy).
• chronic simple (wide-angle) glaucoma has a gradual, insidious onset and is not generally amenable to surgical improvement; and control of intraocular pressure depends upon permanent therapy.
• Acute congestive glaucoma may be precipitated by the injudicious use of a mydriatic agent in patients over 40 years, or by a variety of factors that can cause pupillary dilatation or engorgement of intraocular vessels.
• Signs and symptoms include marked ocular inflammation, a semidilated pupil, severe pain, and nausea.
• the therapeutic objective is to reduce the intraocular pressure to the normal level for the duration of the attack.
• An anticholmesterase agent is instilled into the conjunctival sac in combination with a parasympathomimetic agent for greatest effectiveness.
• a commonly used combination consists of a solution of physostigmine and salicylate, 0.5%, plus pilocarpine nitrate, 4%.
• Adjunctive therapy includes the intravenous administration of a carbonic anhydrase inhibitor such as acetozolamide to reduce the secretion of aqueous humor, or of an osmotic agent such as mannitol or glycerin to induce intraocular dehydration.
• a carbonic anhydrase inhibitor such as acetozolamide
• an osmotic agent such as mannitol or glycerin to induce intraocular dehydration.
• the long-acting organophosphorus compounds are not indicated in narrow-angle glaucoma because of vascular engorgement and increase in the angle block.
• Treatment of chronic simple glaucoma and secondary glaucoma includes: (1) parasympathomimetic agents (e.g. pilocarpine nitrate, 0.5 to 0.6 %); (2) anticholmesterase agents that are short-acting (e.g.
• beta-adrenergic antagonists such as timolol maleate, a long- acting agent that is administered at 12-hour intervals, does not directly affect pupillary aperture, but reduces production of aqueous humor (Boger, et al, Am. J. Opthalmol.
• sympathomimetic agents e.g. epinephrine, 0.25 to 2%, phenylephrine, 10%
• They reduce intraocular pressure by decreasing secretion of the aqueous humor, and prevent engorgement of the small blood vessels.
• the cholinergic agonists and cholinesterase inhibitors block accommodation, they induce transient blurring of far vision, usually after administration of relatively high doses over shorter duration.
• the response diminishes due to a diminished number of acetylcholine receptors.
• the use of long-acting anticholmesterase agents is associated with a greater risk of developing lenticular opacities and untoward autonomic effects.
• DFP organophosphorus agent
• An organophosphorus agent, DFP has the longest duration of action and is extremely potent when applied locally; solutions in peanut or sesame oil require installation from once daily to once weekly, and may control intraocular pressure in severe cases that are resistant to other drugs. Because the oily vehicle is unpleasant to most patients, DFP has been replaced by echothiophate.
• Treatment of glaucoma with potent, long-acting anticholmesterase agents (including demecarium, echothiophate, and isoflurophate) for 6 months or longer is associated with a high risk of developing cataracts.
• pilocarpine Treatment with pilocarpine (4%) alone or in combination with physostigmine (0.2%)) one to five times daily was found to cause no higher incidence of the development of lenticular opacities that appeared spontaneously in untreated patients in comparable age groups (Axelsson, Acta Opthalmol. (Kbh., Suppl. 102, 1-37 (1969)).
• pilocarpine and other short-acting miotic drugs can be used to control intraocular tension. If ineffective, the hazards of cataract development must be balanced against those of increased intraocular pressure before resorting to the use the potent, long-acting anticholmesterase agents.
• patients should be examined for the appearance of lenticular opacities at intervals of 6 months or less.
• glaucoma including an A 3 subtype adenosine receptor antagonist, a calmodulin antagonist, and an antiestrogen (WO 00/03741); an oligonucleotide which maybe substituted, or modified in its phosphate, sugar, or base so as to decrease intraocular pressure (U.S. Patent No. 5,545,626); a class of pyrazine, pyrimidine, and pyridazine derivatives, substituted by a non-aromatic azabicyclic ring system and optionally by up to two further substituents (U.S. Patent No.
• Latanaprost (Xalatan ® ) is a prostanoid agonist that is believed to reduce IOP by increasing the uveoscleral outflow of aqueous humor.
• Latanoprost is an isopropyl ester prodrug, and is hydrolyzed by esterases in the cornea to the biologically active acid.
• Xalatan ® is prescribed for once-daily dosing and is shown to be equivalently effective as twice-daily dosing of 0.5% timolol.
• Xalatan ® may gradually change eye color by increasing the amount of brown pigment in the iris. This long-term effect on the iris is unknown.
• Eyelid skin darkening has also been reported in associated with the use of Xalatan ® .
• Xalatan ® may gradually increase the length, thickness, pigmentation, and number of eyelashes.
• Macular edema including cystoid macular edema, has been reported during treatment with Xalatan ® . These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. ((Ophthalmic PDR, 315-316 (2001).)
• Melatonin is a neurohormone secreted primarily by the pineal gland and also in small amounts, by the retina. Melatonin production follows a circadian rhythm with levels increasing during the night. Melatonin is known to regulate many aspects of circadian rhythm, such as the processing of periodic information.
• melatonin membrane receptors classified into three types, MTi (previously known as mel la ), MT 2 (previously known as meli or ML and MT 3 (previously known as ML 2 ), and anti-oxidative protection against oxidative injury through radical scavenger activity. Similar to muscarinic and purinergic receptors, MTi and MT receptors belong to the superfamily of putative seven transmembrane domain G-protein coupled receptors. Both MTi and MT 2 receptors have been cloned and are negatively coupled to adenylate cyclase via a pertussis toxin-sensitive G-protein.
• MT 3 has not been cloned and seems to be coupled to phospholipase C.
• MT ⁇ receptors mediate rat caudal artery vasoconstriction and inhibition of neuronal firing associated with somnogenic effects
• MT 2 receptors mediate rat caudal artery vasodilatation and phase advancement of circadian rhythms.
• the MT 3 receptor has been characterized using the high affinity ligand, 5-(methoxycarbonyl- amino)-N-acetyltryptamine (5-MCA-NAT), also known as GR 135531 (Molinari, et al, European J. Pharmacol. 301, 159-168 (1996)) although no physiological activity was reported.
• 5-MCA-NAT 5-(methoxycarbonyl- amino)-N-acetyltryptamine
• melatonin in regulating intraocular pressure (IOP) is unclear, and previous work has shown that melatonin can increase or decrease IOP, depending on the species and time during circadian rhythm that the IOP is measured. (Chiou and
• Patent No. 4,803,218 discloses a method of treating hypertension in an animal by administering a pharmaceutical composition comprising a [3-(aminoalkyl)-lH-indol-5- yl]urea compound and a pharmaceutically-acceptable carrier. This patent also teaches methods of making N-[3-(2-Aminoethyl)-lH-indol-5-yl]urea and related analogues. U.S. Patent Nos.
• 5,633,276, 6,040,451, 5,948,804 and 6,159,998 disclose methods of using substituted 5-(2-imidazolin-2-ylamino)indole compounds for lowering intraocular pressure, presbyopia, treating migraine, hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis, ischemic pain, spasticity, diarrhea, nasal decongestion, and urinary incontinence.
• U.S. Patent No. 6,004,991, 6,140,372, 59,998,461, and 6,071,946 disclose methods of treating complaints associated with melatonin disorders. Methods of syntheses of substituted indole derivatives disclosed in the above-mentioned patents are incorporated herein by reference.
• PCT International Application WO 96/25397 discloses indole derivatives active at cannabinoid receptors and their use for lowering intraocular pressure and treating glaucoma.
• PCT International Application WO 96/11685 discloses indole derivatives for the treatment of glaucoma and other disorders. The indole derivatives disclosed in the above two PCT applications are different from those of the present invention.
• agents commonly used to treat glaucoma may cause adverse side effects, such as the development of cataracts.
• agents that are both safe and effective in treating glaucoma are both safe and effective in treating glaucoma.
• Disclosed herein is a novel method of reducing intraocular pressure by administering compounds of Formulae I, EL, in, and IV, which possess a core indole or melatonin-type chemical structure.
• the present invention provides a method of using such compounds for reducing intraocular pressure with increased duration and/or magnitude of action compared to melatonin.
• a preferred compound is 5-(methoxycarbonylamino)-N-acetyltryptamine (MCA-NAT), also known as GR 135531, (Molinari, et al, Eur. J. Pharmacol. 301, 159- 168 ( 1996)), a high affinity ligand with specificity for the MT 3 receptor.
• MCA-NAT 5-(methoxycarbonylamino)-N-acetyltryptamine
• the present invention provides a method of reducing intraocular pressure and treating disorders associated with intraocular pressure such as ocular hypertension and glaucoma.
• the method comprises the step of administering to a subject in need thereof an indole derivative in an amount effective to reduce intraocular pressure.
• the indole derivatives of Formulae I, JJ, HI, and IN have a prolonged duration of action and/or increased efficacy in reducing intraocular pressure.
• FIGURES Figure 1 shows the effect of melatonin on IOP in New Zealand white rabbits during a six hour timecourse.
• Figure 2 illustrates the effect of an equivalent amount of 5-MCA-NAT , during 10 hours.
• Figure 3 compares the dose-response of 5-MCA-NAT and melatonin for lowering IOP.
• Figure 4 illustrates reversal of the IOP-lowering effect of 5-MCA-NAT and melatonin by the melatonin receptor antagonist luzindole.
• the present invention provides a method of treating disorders associated with increased intraocular pressure.
• the method comprises administering an effective dose of an indole derivative of Formulae I, It, HJ, and TV, with or without therapeutic and adjuvant agents commonly used to treat or manage increased intraocular pressure.
• Applicants have unexpectedly found that application of such compounds brings about a significant and sustained reduction of intraocular pressure.
• An effective dose will be the amount of such compound necessary to elicit the reduction of intraocular pressure.
• the present invention further provides a novel approach for reducing intraocular pressure associated with ocular hypertensive disorders, and thus can be useful in the prevention, management and treatment of ocular hypertension.
• the method of the present invention is useful for the management and/or treatment of primary glaucoma, which consists of two types: narrow angle or acute congestive and wide angle or chronic simple glaucoma. Yet another embodiment of the present invention is the management of secondary glaucoma.
• the method of the present invention is useful to enhance the effects of therapeutic agents and adjunctive agents used to treat and manage the different types of glaucoma.
• Therapeutic agents used to treat narrow angle or acute congestive glaucoma include, for example, physostigmine salicylate and pilocarpine nitrate.
• Adjunctive therapy used in the management of narrow angle glaucoma includes, for example, the intravenous administration of a carbonic anhydrase inhibitor such as acetozolamide to reduce the secretion of aqueous humor, or of an osmotic agent such as mannitol or glycerin to induce intraocular dehydration.
• Therapeutic agents used to manage wide angle or chronic simple glaucoma and secondary glaucoma include, for example, parasympathomimetic agents, such as pilocarpine nitrate, short-acting anticholmesterase agents such as physostigmine salicylate, long acting anticholinesterase inhibitors such as demecarium bromide, echothiophate iodide, isofluorophate, beta-adrenergic antagonists, such as timolol maleate, and sympathomimetic agents, such as epinephrine and phenylephrine.
• parasympathomimetic agents such as pilocarpine nitrate
• short-acting anticholmesterase agents such as physostigmine salicylate
• long acting anticholinesterase inhibitors such as demecarium bromide, echothiophate iodide, isofluorophate
• beta-adrenergic antagonists such as ti
• prostaglandin analogues (latanoprost (Xalatan), LumiganTM), alpha adrenergic agonists (brimonidine), and Rescula, which reduces intraocular pressure by an unknown mechanism, have been used to manage cases where glaucoma is associated with ocular hypertension.
• High doses may be required for some therapeutic agents to achieve levels to effectuate the target response, but may often be associated with a greater frequency of dose-related adverse effects.
• combined use of the compounds of the present invention with agents commonly used to treat glaucoma allows the use of relatively lower doses of such agents resulting in a lower frequency of adverse side effects associated with long-term administration of such therapeutic agents.
• another indication of the compounds in this invention is to reduce adverse side effects of drugs used to treat glaucoma, such as the development of cataracts with long-acting anticholinesterase agents including demecarium, echothiophate, and isoflurophate.
• the present invention provides a method of using indole derivatives of Formulae I, ⁇ , IJJ, and IN with increased duration and/or magnitude of action in reducing intraocular pressure.
• Ri and R 2 are each independently H, (un)substiruted linear-, branched- or cyclo- alkyl, -alkenyl, -alkynyl, -aryl, -aralkyl, -aralkenyl, -aralkynyl, R 6 (CO)-, F, OR 5 ; either Ri or R 2 can be R 6 R 7 N(CO)-; or optionally, Ri and R 2 when taken together can represent oxo; or a (un)substituted carbocycle or heterocycle of 4, 5, 6, or 7 members;
• R 6 and R 7 are independently H, (un)substituted linear-, branched- or cyclo-alkyl, - alkenyl, -alkynyl, -aryl, -aralkyl, -aralkenyl, -aralkynyl or heterocyclic ring; or when optionally taken together, NR 6 R can represent a (un)substituted ring of 3,
• R 8 (un)substituted linear-, branched- or cyclo-alkyl, -alkenyl, -alkynyl, -aryl, - aralkyl, -aralkenyl, -aralkynyl, heterocyclic ring or CF 3 -;
• R H, (un)substituted linear-, branched- or cyclo-alkyl, -alkenyl, -alkynyl, -aryl, - aralkyl, -aralkenyl, -aralkynyl; or optionally taken together, R 6 and R 9 can represent a ring of 5, 6, or 7 members;
• X! O, S, NR 9 , -CF2-, -CH2-, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or absent;
• Z 2 and Z 3 are independently R 6 R 7 N(CO , R 6 (CO)-, R 8 O(CO)-, R 8 S(O) 2 -, R 8 OS(O) 2 -, R 6 R 7 NS(O) 2 -;
• A halogen, NO 2 , CN or R 5 -X ! -;
• D 2 H, (un)substituted linear-, branched- or cyclo-alkyl, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl;
• Enantiomers, diastereomers, cis/trans isomers, pharmaceutically useful salts, and mixtures thereof are included in this invention.
• a preferred compound useful for this invention is 5-(methoxycarbonylamino)-N- acetyltryptamine (MCA-NAT), also known as GR 135531.
• Z 2 and Z 3 are independently NR 6 R 7 (CO)-, R 6 (CO)-, R 8 O(CO)- 5 R 8 S(O) 2 -, R 8 OS(O) 2 -, NR 6 R 7 S(O) 2 -; or optionally, each unit Z 2 -N-R ⁇ o, and Z 3 -N-R 10 can independently represent a ring of 4-7 members; and Di of Formula I is now H.
• Di is defined as in the broad embodiment, or optionally Di may form a ring with
• D 2 H, (un)substituted linear-, branched- or cyclo-alkyl, halogen, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl;
• R 5 Ci- C 4 alkyl, acetyl, formyl or CF 3 ;
• R 6 H, Ci- C 4 alkyl, or CF 3 ;
• R 6 cannot be CH 3 .
• alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl means said group may or may not be substituted with a radical chosen from the same group or from halogen, nitrogen, oxygen, phosphorus or sulfur.
• alkyl, alkenyl, alkynyl refer to such radicals containing from 1 to 9 carbon members.
• aralkyl, aralkenyl, aralkynyl refer to groups with groups according to the parent definition comprised of both radicals.
• cyclo without further specification, refers to an (un)substituted ring of from 3-7 members.
• heterocyclic means a ring containing one or more non-carbon atoms and any or no degrees of unsaturation.
• aralkenyl describes an aryl group attached to an alkenyl radical.
• This invention provides a method of using a formulation of a pharmaceutical composition comprising indole derivatives (such as melatonergic analogues) of Formulae I-IN and a pharmaceutically acceptable carrier, for use in reducing intraocular pressure and thereby treating glaucoma.
• the compounds of the present invention also encompass their non-toxic pharmaceutically acceptable salts, such as, but not limited to, chlorides, sulfates, and acetates, as well as sodium, ammonium and pyridinium.
• Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
• the present invention also encompasses prodrugs of the compounds disclosed herein.
• the pharmaceutical utility of compounds of this invention are indicated by the changes in IOP as measured by means of a TOPONEN contact tonometer supplied by Xomed (Jacksonville, Florida, USA).
• the efficacy of these compounds is reflected in their ability to activate melatonin receptors to effectuate the target response.
• the target response is the reduction in intraocular pressure associated with glaucoma.
• the effective dose will depend on characteristics of the individual patient, activity of the specific compound employed, mode of administration, and characteristics of the disease or disorder, and can be determined by those skilled in the art. Dosage and/or concentration levels of the order of from about 10 " M to about 10 "
• M preferably in the range from about 10 " ⁇ M to about 10 "4 M, more preferably from about 10 "10 to about 10 "5 M.
• the compounds of the present invention may be administered by any means known to those skilled in the art for treatment of eye diseases.
• the indole derivatives are administered in a sterile preparation comprising the active compound or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable vehicle or carrier therefor.
• the active compounds disclosed herein may be administered to the eyes of a patient by any suitable means, but are preferably administered as a liquid or gel suspension of the active compound in the form of drops of liquid, liquid washes, sprays, ointments, or gel.
• the active compounds may be applied to the eye via liposomes or other carriers such as cyclodextrins.
• the active compounds may be infused into the tear film via a pump-catheter system.
• Another embodiment of the present invention involves the active compound contained within a continuous or selective-release device, for example, membranes such as, but not limited to, those employed in the OcusertTM System (Alza Corp., Palo Alto, CA).
• the active compounds can be contained within, carried by, or attached to contact lenses, that are placed on the eye.
• Another embodiment of the present invention involves the active compound contained within a swab or sponge that can be applied to the ocular surface.
• Another embodiment of the present invention involves the active compound contained within a liquid spray that can be applied to the ocular surface.
• Another embodiment of the present invention involves an injection of the active compound directly into the lachrymal tissues or onto the eye surface, or intravitreal injection.
• the topical solution containing the active compound may also contain a physiologically compatible vehicle, as those skilled in the ophthalmic art can select using conventional criteria.
• the vehicles may be selected from the known ophthalmic vehicles which include, but are not limited to, saline and aqueous electrolyte solutions, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.
• water polyethers such as polyethylene glycol
• polyvinyls such as polyvinyl alcohol and povidone
• cellulose derivatives such as methylcellulose and hydroxy
• respirable particles comprised of the active compound, which the subject inhales.
• the active compound would be absorbed into the bloodstream via the lungs or contact the ocular tissues via the nasolacrimal ducts, and subsequently contact the intraocular cells in a pharmaceutically effective amount.
• the respirable particles may be liquid or solid, with a particle size sufficiently small to pass through the mouth and larynx upon inhalation; in general, particles ranging from about 1 to 10 microns, but more preferably 1-5 microns, in size are considered respirable.
• Liquid pharmaceutical compositions of the active compound for producing a nasal spray or nasal or eye drops may be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free water or sterile saline by techniques known to those skilled in the art.
• compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
• Oxalyl chloride (19.2 rnmol) is added dropwise to a suspension of 5-nitroindole (6.2 mmol) and phthalimide (0.4 g) in ether (30 mL) and the mixture stirred 48 h at 24 °C.
• the reaction vessel is then equipped with a Dewar condenser, chilled to 0 °C, and anhydrous ammonia bubbled through the mixture during 1.5 h. The gas and solvent are removed in vacuo. The resulting yellow solid is triturated with water, filtered, and the retentate washed with toluene.
• Example 2 The product from Example 2 (0.05 mmol) is taken into ethanol (3 mL) and hydrogenated 6 h at 3 atmospheres of H 2 pressure over a catalytic amount of 10%> Pd C. The catalyst is removed by filtration through Celite and the solvent removed in vacuo, affording the title compound. This product is somewhat air sensitive and is used immediately for subsequent reactions.
• silica gel TLC 5% methanol-chloroform eluent
• the mixture is evaporated to dryness and maintained at a vacuum of ⁇ 0.1 rnrnHg at least 2 h. It is then dissolved in a small amount of methanol, and purified by reverse-phase HPLC with a gradient of water to methanol.
• Example 3 The product from Example 3 is dissolved in acetic acid-water (1:2, 3 mL) and sodium cyanate (2 mmol) added. This is stirred until a brownish gum is precipitated. The mixture is extracted with chloroform (3 x 30 mL), and the organic extracts washed with saturated sodium bicarbonate, dried with magnesium sulfate and the solvent evaporated in vacuo. The resulting product is purified by reverse-phase HPLC as above.
• N-[2-(5-Methoxycarbonylamino-lH-indol-3-yl)-ethyl]-succinamic acid Triethylamine (12 mmol), DMAP (0.6 mmol), and succinic anhydride (9 mmol) are added to a solution of 5-nitrotryptamine (6 mmol) in dichloromethane (25 mL). The mixture is stirred 4 h, the solvent removed in vacuo, and the residue chromatographed on silica gel using 10% methanol-chloroform with 1% acetic acid as eluent. The product is then hydrogenated and transformed to the carbamic acid methyl ester as in the previous examples. Purified product is obtained by reverse-phase HPLC as above.
• Example 16 N-[3-(2-Acetylamino-ethyl)-lH-indol-5-yl]-acetamide
• the product from Example 1 (0.05 mmol) is taken into ethanol (3 mL) and hydrogenated overnight at 3 atmospheres of H 2 pressure with a catalytic amount of 10%> Pd/C.
• the catalyst is removed by filtration through Celite and the solvent removed in vacuo.
• Acetylation with pyridine/acetic anhydride as above produces the title compound.
• Example 17 f 3-(2-Acetylamino-ethyl)-2-bromo-l H-indol-5-ylJ -carbamic acid methyl ester
• a solution of 5-methoxycarbonylamino-N-acetyltryptamine (0.05 mmol) in acetic acid (0.5 mL) is treated with N-bromosuccinimide (0.05 mmol) 3.5 h at 25 °C.
• the solution is next neutralized with 50% sodium hydroxide solution and extracted with ethyl acetate.
• the organic extract is evaporated and the purified product obtained following chromatography on silica gel with 2% methanol-chloroform as eluent.
• Example 19 (l-Oxo-2,3,4,9-tetrahydro-lH- ⁇ -carbolin-6-yl)-carbamic acid methyl ester A sample of 6-Nifro-2,3,4,9-tefrahydro-/ ⁇ carbolin-l-one (0.05 mmol) is transformed to the title compound by hydrogenation and conversion to the carbamic acid methyl ester as in the previous examples.
• This product (2 mmol) is dissolved in ether (40 mL), oxalyl chloride (8 mmol) added dropwise and the mixture stirred 8 h at 24 °C.
• the reaction vessel is then equipped with a Dewar condenser, chilled to 0 °C, and anhydrous ammonia bubbled through the mixture during 1.5 h. The gas and solvent are removed in vacuo.
• the resulting solid is dissolved in ethyl acetate, extracted with brine, and the ethyl acetate phase dried with magnesium sulfate and evaporated.
• the material is dissolved in THF (15 mL) and treated with borane-THF (3 mL of 1 M solution) 16 h at 25 °C.
• reaction is neutralized with sodium bicarbonate and extracted with ethyl acetate.
• ethyl acetate extract is next dried in vacuo, redissolved in ethanol (10 mL) and refluxed in the presence of cesium fluoride (380 mg) and sodium carbonate (350 mg).
• cesium fluoride 380 mg
• sodium carbonate 350 mg.
• the mixture is filtered through Celite, evaporated and the residue chromatographed on silica gel using chloroform-methanol-ammonia (9:1:0.1) as eluent affording 2-[4-(l-methoxy-ethyl)-l- methyl-lH-indol-3-yl]-ethylamine.
• N- ⁇ 2-[4-(l- methoxy-ethyl)-l-methyl-5-nitro-lH-indol-3-yl]-ethyl ⁇ -acetamide is isolated by chromatography on silica gel using ethyl acetate-hexane as eluent, and finally transformaed into the title compound by hydrogenation and formation of the methyl carbamate as described in previous examples.
• IOP Ion intraocular pressure
• the non-specific melatonin antagonist luzindole was added 30 min before the application of either melatonin or 5- MCA-NAT at a dose of 100 ⁇ g/10 uL or 342 nM.
• the maximal effect was observed after 2 hour and persisted during 10 hours ( Figure 2).
• the maximum response to 5-MCA- NAT was statistically significantly greater than that due to melatonin.
• the IC 50 values for melatonin and 5-MCA-NAT were 363 + 23.0 ng/10 ⁇ L and 423 ⁇ 30 ng/ ⁇ L, respectively which are equivalent to doses of 1.6 + 0.1 nmol and 1.8 + 0.1 nmol, respectively ( Figure 3). These values are not significantly different from each other.

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