| Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof -> Monitor Keywords |
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  Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereofUSPTO Application #: 20060205709Title: Preventive/remedy for retinal nerve diseases containing alkyl ether derivatives or salts thereof Abstract: or its salt: wherein R1 and R2 represent each a substituent such as hydrogen, halogeno or alkyl; R3 represents alkylamino, amino or hydroxyl; the ring A represents a 5- or 6-membered aromatic heterocycle or a benzene ring; m and n are each an integer of from 1 to 6; and p is an integer of from 1 to 3; shows an effect of protecting retinal nerve cells and, therefore, is useful as a preventive and/or a remedy for retinal nerve diseases such as glaucoma, diabetic retinopathy, retinal artery obstruction, retinal venous obstruction, macular degeneration and retinopathy of prematurity.
An alkyl ether derivative represented by the following general formula [1] (end of abstract)
Agent: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C. - Alexandria, VA, US Inventors: Tatsuo Kimura, Noboru Iwakami, Akihito Saitoh USPTO Applicaton #: 20060205709 - Class: 514210190 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Four-membered And Includes At Least One Ring Nitrogen, Additional Hetero Ring Attached Directly Or Indirectly To The Four-membered Hetero Ring By Nonionic Bonding The Patent Description & Claims data below is from USPTO Patent Application 20060205709. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to a preventive and/or remedy for retinal nerve diseases, which comprise a novel alkyl ether derivative or a salt thereof as an active ingredient. BACKGROUND ART [0002] The retina acting as a photoreceptive tissue is located at the inner surface of the wall of eyeball. When pathologic lesion occurs on the retina, eyesight fails, sometimes resulting in blindness. Such retina is broadly divided into sensory retina and retinal pigment epithelium. Such sensory retina is divided into 9 layers, and comprises visual cells as first neuron, bipolar cells as second neuron, ganglion cells as third neuron, and other cells (Hyojun Ganka Gaku, 7.sup.th edition, pp. 103-107, Igaku-Shoin Ltd., 1998). [0003] Various retinal diseases are developed depending on the causes of diseases or onset forms. Examples of a disease affecting the retinal nerve may include glaucoma, diabetic retinopathy, retinal artery obstruction, retinal venous obstruction, macular degeneration, and retinopathy of prematurity. [0004] It has been considered that the cell death of retinal nerve cells is deeply associated with dysfunction of the retinal nerve. Factors, which contribute the cell death of refinal nerve cells, may include apoptosis, neurotoxicity caused by glutamic acid, the absence of a neurotrophic factor, the abnormality of mitochondria, caspase activation, nitric oxide, and autoimmunity (Atarashii Ganka, 19(7), 903-912, 2002). For example, from the viewpoint of suppression of the cell death with an excitatory neurotransmitter such as glutamic acid, compounds having antagonistic action to N-methyl-D-aspartic acid have been studied (JP-A-8-506807; Scrip No. 2229, p. 13, 1997; Scrip No. 2307, p. 10, 1998). [0005] As stated above, various factors are associated with the cell death of retinal nerve cells. Other than compounds having antagonistic action to N-methyl-D-aspartic acid, compounds useful as remedies for diseases such as glaucoma, diabetic retinopathy, retinal artery obstruction, retinal venous obstruction, macular degeneration, and retinopathy of prematurity, are required. DISCLOSURE OF THE INVENTION [0006] The present inventors have found that an alkyl ether derivative represented by the general formula [1] described below or a salt thereof shows the effect of protecting retinal nerve cells, and thus that it is useful as a preventive and/or remedy for retinal nerve diseases, thereby completing the present invention. [0007] In the formula, R.sup.1 and R.sup.2, which may be the same or different, each represent one or more groups selected from a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, alkenyl, alkenyloxy, amino, alkylsulfonyl, arylsulfonyl, carbamoyl or heterocyclic group, a protected or unprotected amino, hydroxyl or carboxyl group, a nitro group and an oxo group; R.sup.3 represents a substituted or unsubstituted alkylamino group or a protected or unprotected amino or hydroxyl group; the ring A represents a 5- or 6-membered aromatic heterocyclic ring or a benzene ring; m and n each represent an integer between 1 and 6; and p represents an integer between 1 and 3. BEST MODE FOR CARRYING OUT THE INVENTION [0008] The present invention will be described in detail below. [0009] In the present specification, the terms have the following means, unless otherwise specified. [0010] The term "halogen atom" is used to mean a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; the term "alkyl group" is used to mean a linear or branched C.sub.1-12 alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, or octyl group; the term "lower alkyl group" is used to mean a linear or branched C.sub.1-6 alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl group; the term "alkenyl group" is used to mean a C.sub.2-12 alkenyl group such as a vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, or octenyl group; the term "lower alkenyl group" is used to mean a C.sub.2-6 alkenyl group such as a vinyl, propenyl, butenyl, pentenyl, or hexenyl group; the term "alkynyl group" is used to mean a C.sub.2-6 alkynyl group such as an ethynyl, 2-propynyl, or 2-butynyl group; the term "cycloalkyl group" is used to mean a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; the term "alkoxy group" is used to mean a linear or branched C.sub.1-12 alkyloxy group such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy group; the term "lower alkoxy group" is used to mean a linear or branched C.sub.1-6 alkyloxy group such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, or hexyloxy group; the term "alkenyloxy group" is used to mean a C.sub.2-12 alkenyloxy group such as a vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, or octenyloxy group; the term "lower alkenyloxy group" is used to mean a C.sub.2-6 alkenyloxy group such as a vinyloxy, propenyloxy, butenyloxy, pentenyloxy, or hexenyloxy group; the term "alkylthio group" is used to mean a C.sub.1-12 alkylthio group such as a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, or octylthio group; the term "lower alkylthio group" is used to mean a C.sub.1-6 alkylthio group such as a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, or hexylthio group; the term "aryl group" is used to mean a phenyl group, naphthyl group, indanyl group, or indenyl group; the term "aryloxy group" is used to mean a phenyloxy, naphthyloxy, indanyloxy, or indenyloxy group; the term "aralkyl group" is used to mean an ar C.sub.1-6 alkyl group such as a benzyl, diphenylmethyl, trityl, or phenethyl group; the term "arylthio group" is used to mean a phenylthio, naphthylthio, indanylthio, or indenylthio group; the term "acyl group" is used to mean a formyl group, a C.sub.2-12 alkanoyl group such as acetyl, isovaleryl, propionyl, or pivaloyl, an aralkylcarbonyl group such as benzylcarbonyl, or an aroyl group such as benzoyl or naphthoyl; the term "alkylsulfonyl group" is used to mean a C.sub.1-12 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, or octylsulfonyl; the term "lower alkylsulfonyl group" is used to mean a C.sub.1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, or pentylsulfonyl; the term "arylsulfonyl group" is used to mean a phenylsulfonyl, p-toluenesulfonyl, or naphthylsulfonyl group; the term "lower alkylsulfonyloxy group" is used to mean a C.sub.1-6 alkylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, or pentylsulfonyloxy; the term "arylsulfonyloxy group" is used to mean a phenylsulfonyloxy, p-toluenesulfonyloxy, or naphthylsulfonyloxy group; the term "alkylamino group" is used to mean a mono- or di-C.sub.1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, diisopropylamino, or dibutylamino; the term "monoalkylamino group" is used to mean a mono-C.sub.1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, or butylamino; the term "dialkylamino group" is used to mean a di-C.sub.1-6 alkylamino group such as dimethylamino, diethylamino, diisopropylamino, or dibutylamino; the term "heterocyclic group" is used to mean a heterocyclic group including a 5- or 6-membered ring, condensed ring, or crosslinked ring, containing at least one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, such as pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolizinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2,3-a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodioxanyl, or 1,4-benzodioxanyl group; and the term "cyclic amino group" is used to mean a cyclic amino group including a 5-, 6-, or 7-membered ring, condensed ring, or crosslinked ring, which contains at least one nitrogen atom as a heteroatom that forms the above ring, and may further contain at least one oxygen atom or sulfur atom, such as pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or imidazolidinyl. [0011] A 5- or 6-membered aromatic heterocyclic ring as the ring A may be a heterocyclic ring containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom as a heteroatom forming the above ring. Examples may include 5- or 6-membered aromatic heterocyclic rings such as triazine, pyridazine, pyrimidine, pyrazine, pyridine, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, isoxazole, isothiazole, pyrazole, or pyran. [0012] Substituents for an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, an alkenyl group, an alkenyloxy group, an amino group, an alkylsulfonyl group, an arylsulfonyl group, a carbamoyl group, and a heterocyclic group in R.sup.1 and R.sup.2, and an alkylamino group in R.sup.3, may include a halogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a lower alkoxy group, an aryloxy group, a lower alkylthio group, an arylthio group, a lower alkenyl group, a lower alkylsulfonyl group, an arylsulfonyl group, an alkylamino group, an amino group that may be protected, a hydroxyl group that may be protected, a carboxyl group that may be protected, an acyl group, and a heterocyclic group. [0013] Protecting groups for a carboxyl group may include all groups that can be used as common protecting groups for a carboxyl group. Examples of such a protecting group may include: a lower alkyl group such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl, or tert-butyl; an aryl group such as phenyl or naphthyl; an ar lower alkyl group such as benzyl, diphenylmethyl, trityl, 4-nitrobenzyl, 4-methoxybenzyl, or bis(4-methoxyphenyl)methyl; an acyl-lower alkyl group such as acetylmethyl, benzoylmethyl, 4-nitrobenzoylmethyl, 4-bromobenzoylmethyl, or 4-methanesulfonylbenzoylmethyl; an oxygen-containing heterocyclic group such as 2-tetrahydropyranyl or 2-teterahydrofuranyl; a halogeno-lower alkyl group such as 2,2,2-trichloroethyl; a lower alkylsilyl-lower alkyl group such as 2-(trimethylsilyl)ethyl; an acyloxy-lower alkyl group such as acetoxymethyl, propionyloxymethyl, or pivaloyloxymethyl; a nitrogen-containing heterocyclic ring-lower alkyl group such as phthalimidomethyl or succinimidomethyl; a cycloalkyl group such as cyclohexyl; a lower alkoxy-lower alkyl group such as methoxymethyl, methoxyethoxymethyl, or 2-(trimethylsilyl)ethoxymethyl; an ar-lower alkoxy-lower alkyl group such as benzyloxymethyl; a lower alkylthio-lower alkyl group such as methylthiomethyl or 2-methylthioethyl; an arylthio-lower alkyl group such as phenylthiomethyl; a lower alkenyl group such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, or allyl; and a substituted silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, or tert-butylmethoxyphenylsilyl. [0014] Protecting groups for a hydroxyl group may include all groups that can be used as common protecting groups for a hydroxyl group. Examples of such a protecting group may include: alkoxy and alkylthio-carbonyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, or S-benzylthiocarbonyl; an acyl group such as acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, or benzoyl; a lower alkyl group such as methyl, tert-butyl, 2,2,2-trichloroethyl, or 2-trimethylsilylethyl; a lower alkenyl group such as allyl; a lower alkynyl group such as propargyl; an ar-lower alkyl group such as benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, or trityl; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, or tetrahydrothiopyranyl; lower alkoxy- and lower alkylthio-lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, or 1-methyl-1-methoxyethyl; lower alkyl- and aryl-sulfonyl groups such as methanesulfonyl or p-toluenesulfonyl; and a substituted silyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, or tert-butylmethoxyphenylsilyl. [0015] Protecting groups for an amino group may include all groups that can be used as common protecting groups for an amino group. Examples of such a protecting group may include: an alkoxycarbonyl group such as methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, tert-butoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1-adamantyloxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, diphenylmethoxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, or 8-quinolyloxycarbonyl; an acyl group such as (mono-, di-, tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, phthaloyl, succinyl, alanyl, or leucyl; an ar lower alkyl group such as benzyl, diphenyl, methyl, or trityl; an arylthio group such as 2-nitrophenylthio or 2,4-dinitrophenylthio; an alkyl- or aryl-sulfonyl group such as methanesulfonyl or p-toluenesulfonyl; a di-lower alkylamino-lower alkylidene group such as N,N-dimethylaminomethylene; an ar-lower alkylidene group such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, or 2-hydroxy-1-naphthylmethylene; a nitrogen-containing heterocyclic alkylidene group such as 3-hydroxy-4-pyridylmethylene; a cycloalkylidene group such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, or 3,3-dimethyl-5-oxycyclohexylidene; a diaryl- or diar-lower alkylphosphoryl group such as diphenylphosphoryl or dibenzylphosphoryl; an oxygen-containing heterocyclic alkyl group such as 5-methyl-2-oxo-2H-1,3-dioxole-4-yl-methyl; and a substituted silyl group such as trimethylsilyl. [0016] A salt of the compound represented by the general formula [1] may include salts in commonly known basic groups such as an amino group or acidic groups such as a hydroxyl or carboxyl group. [0017] Examples of such salts in basic groups may include: salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, or sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, or trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, or naphthalenesulfonic acid. [0018] Examples of salts in acidic groups may include: salts with alkaline metals such as sodium or potassium; salts with alkaline-earth metals such as calcium or magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-p-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. [0019] Among the aforementioned salts, pharmacologically acceptable salts are preferable. [0020] When isomers (for example, optical isomers, geometric isomers, and tautomers) are present in the alkyl ether derivative represented by the general formula [1] or a salt thereof, the present invention includes all these isomers, and further includes hydrates, solvates, and all crystal forms. Continue reading... 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