Allergan, Inc.

Allergan Sales, Inc.

Pfizer Corporation

Elizabeth WoldeMussie

Guadalupe Ruiz

Joseph S Adorante

Larry Allen Wheeler

Ronald K Lai

Arlene E Gwon

Daniel W Gil

Roger F Steinert

Kara L Kopper

Channing R Beals

Hovhannes John Gukasyan

Jingwen Ma

Alison M Moore

Inhibitors of Janus kinase-3 ('Jak3') are useful for treating dry eye disorders and other disorders requiring the wetting of the eye. Jak3 inhibitors useful for treating eye disorders include the compound 3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile.

Pharmaceutical compositions and methods of treating dry eye disorders

The present invention provides a method of providing neuroprotection to a mammal comprising administering to said mammal suffering from or at risk of suffering a noxious action on its nerve cells an effective amount of a compound of formula I to inhibit or prevent nerve cell injury or death wherein the 2-imidazolin-2-ylamino group is in either the 5- or 6-position of the quinoxaline nucleus; x, y and z are in any of the remaining 5-, 6-, 7- or 8-positions and are selected from hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; and R is an optional substituent in either the 2- or 3-position of the quinoxaline nucleus and may be hydrogen, lower alkyl or lower alkoxy, or pharmaceutically acceptable salts thereof and mixtures thereof. Such noxious action may result from ischemia, e.g. spinal ischemia.

Methods for treating retinal diseases

Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular neural injury

A method for increasing or decreasing parasympathetic/cholinergic/ciliary tonic contraction in order to restore the resting portion of the eye and allow normal positive and negative accommodation includes administering to a myopic or hyperopic presbyope.

Cholinergic agents in the treatment of presbyopia

A method for increasing or decreasing parasympathetic/cholinergic/ciliary tonic contraction in order to restore the resting portion of the eye and allow normal positive and negative accommodation includes administering to a presbyopic subject an effective amount of a muscarinic agent.

The present invention provides a method of providing neuroprotection to a mammal comprising administering to said mammal suffering from or at risk of suffering a noxious action on its nerve cells an effective amount of a compound of formula I to inhibit or prevent nerve cell injury or death

The present invention provides a method of protecting the optic or retinal nerve cells of a mammal comprising administering to said mammal suffering from or at risk of suffering a noxious action on said nerve cells an effective amount of a compound of formula I to inhibit or prevent nerve cell injury or death

Method of using (2-imidazolin-2-ylamino) quinoxoalines in treating neural injury

Ophthalmic compositions and a method are disclosed for treating glaucoma and/or ocular hypertension in the mammalian eye by topically administering to the mammalian eye the ophthalmic composition of the invention which contains as the active ingredient one or more gamma aminobutyric acid agonist compounds. Examples of gamma aminobutyric acid agonists utilized in the ophthalmic composition and method of treatment are: gamma aminobutyric acid (GABA), 5-(aminomethyl)-3(2H)-isoxazolone (muscimol), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and a pharmaceutically acceptable salt of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, piperidine-4-sulfonic acid and a pharmaceutically acceptable salt of piperidine-4-sulfonic acid, 3-(2H)-isothiazolone, 5-(aminomethyl) (thiomuscimol), 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (diazepam), 7-chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-b enzodiazaepin-2-one (flurazepam) and a pharmaceutically acceptable salt of 7-chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro and 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-amine 4-oxide (chlordiazepoxide) and a pharmaceutically acceptable salt of 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-amine 4-oxide.

Method for reducing intraocular pressure in the mammalian eye by

Pharmaceutical compositions and a method are disclosed for treating glaucoma and/or ocular hypertension in the mammalian eye by administering to the mammalian eye the pharmaceutical composition of the invention which contains, as the active ingredient, one or more compounds having potassium channel blocking activity. Examples of potassium channel blockers utilized in the pharmaceutical composition and method of treatment are quinine, tremogenic indole alkaloids, such as Penitrem A and paspalicine, and insect toxins such as charybdotoxin and iberiotoxin.

Pharmaceutical compositions and a method are disclosed for treating glaucoma and/or ocular hypertension in the mammalian eye by administering to the mammalian eye the pharmaceutical composition of the invention which contains as the active ingredient one or more compounds having calcium chelating activity. Examples of calcium chelating agents utilized in the pharmaceutical composition and method of treatment are: ##STR1## and lower alkyl and alkoxyalkyl esters thereof.

Pharmaceutical compositions and a method are disclosed for providing neuroprotective effect to the mammalian eye by administering to the mammalian eye the pharmaceutical composition of the invention which contains, as the active ingredient, one or more compounds having chloride channel blocking activity. Examples of chloride channel blockers utilized in the pharmaceutical composition and method of treatment are: ##STR1## wherein R is hydrogen or a pharmaceutically-acceptable cation, e.g. an alkali or alkaline earth metal, or a quaternary amine; or R represents a ester-forming moiety, e.g. a lower alkyl radical, having up to six carbon 20 atoms, that may be derived from a lower alkanol.

Method for providing a neuroprotective effect to the mammalian eye by

A method according to which neuroprotection is conferred upon ocular nerve cells by administration of a drug of formula I to the optic nerve and/or retina of a mammal within a period prior to or following an insult to ocular nerve cells but prior to cell death ##STR1## wherein the 2-imidazolin-2-ylamino group may be in either the 5- or 6-position of the quinoxaline nucleus; x, y and z may be in any of the remaining 5-, 6-, 7- or 8-positions and are selected from hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl; and R is an optional substitutent in either the 2- or 3-position of the quinoxaline nucleus and may be hydrogen, lower alkyl or lower alkoxy is disclosed.

Method of using (2-imidazolin-2-ylamino) quinoxalines in treating ocular

Pharmaceutical compositions and a method are disclosed for treating glaucoma and/or ocular hypertension in the mammalian eye by administering to the mammalian eye the pharmaceutical composition of the invention which contains as the active ingredient one or more muscarinic antagonist compounds. Examples of muscarinic antagonists utilized in the pharmaceutical composition and method of treatment are: 10H-thieno(3,4-b)(1,5)benzodiazepin-10-one 4,9-dihydro-3-methyl-4-((4-methyl-1-piperazinyl)acetyl) (telenzepine); 5,11-dihydro-11�4'-methyl-1'-piperazinyl)-acetyl!-6H-pyrido�2,3-b!�1,4!ben zodiazepin-6-one (pirenzepine); racemic 11-��2-(Diethylamino)methyl!-1-piperidinyl!-acetyl!-5,11-dihydro-6H-pyrido �2,3-b!�1,4!benzodiazepin-6-one (AF-DX 116); dextrorotatory 11-��2-(Diethylamino)methyl!-1-piperidinyl!-acetyl!-5,11-dihydro-6H-pyrido �2,3-b!�1,4! benzodiazepin-6-one (AF-DX 250); an ophthalmically acceptable salt of 4-diphenylacetoxy-1,1-dimethyl piperidine (4-DAMP); .alpha.-cyclohexyl, -.alpha.-phenyl-1-piperidinepropanol (trihexyphenidyl); cyclohexanemethanol, .alpha.-phenyl, .alpha.-�3-(1-piperidinyl)-1-propynyl (hexbutinol); 6H-pyrido�2,3-b!�1,4!benzodiazepin-6-one, 11-��4-�4-(diethylamino)butyl!-1-piperidinyl!acetyl!-5,11-dihydro (AQ-RA 741); 11-H-pyrido�2,3-b!�1,4!benzodiazepine-11-carboxamide, N-�2-�2-�(dipropylamino)methyl!-1-piperidinyl!ethyl!-5-, 6-dihydro-6-oxo, monomethanesulfonate (AF-DX 384); 1,8-octanediamine, N,N'-bis�6-��2-methoxyphenyl)methyl!amino!hexyl!-tetrahydrochloride (methoctramine) and naphto�2,3-c!furan-1(3H)-one, 4-2-(1,6-dimethyl-2-piperidinyl)ethenyl!decahydro-3-methyl-, �3S-�3 .alpha., 3a .alpha., 4 .beta.�1E,2(2R*,6S*)!,4a .beta., 8a .alpha., 9a .alpha.!!(himbacine).

Pharmaceutical compositions and a method are disclosed for treating glaucoma and/or ocular hypertension in the mammalian eye by administering to the mammalian eye the pharmaceutical composition of the invention which contains, as the active ingredient, one or more compounds having chloride channel blocking activity. Examples of chloride channel blockers utilized in the pharmaceutical composition and method of treatment are: ##STR1## wherein R is hydrogen or a pharmaceutically-acceptable cation, e.g. an alkali or alkaline earth metal, or a quaternary amine; or R represents a ester-forming moiety, e.g. a lower alkyl radical, having up to six carbon atoms, that may be derived from a lower alkanol.

The present invention provides a method for identifying a compound having muscarinic agonist activity that will lower intraocular pressure without causing miosis which comprises measuring the activity of the compound at the m.sub.3 and m.sub.5 muscarinic receptors and determining from the activity measurement a compound having at least twice the agonist activity at the m.sub.5 receptor as compared to the m.sub.3 receptor. Preferably, the method of measuring said muscarinic agonist activity comprises eliciting phosphoinositide hydrolysis in CHO-K1 cells stably expressing the m.sub.3 and m.sub.5 muscarinic receptor subtypes. The present invention also provides a method of lowering the intraocular pressure in a mammal which comprises administering to said mammal a compound that has been determined to have at least twice the agonist activity at the m.sub.5 receptor as compared to the m.sub.3 receptor.

Growing community of inventors

Laguna Niguel, CA, United States of America

Elizabeth WoldeMussie