Classifications

• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • 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
  • A61P27/14—Decongestants or antiallergics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to a novel drug for the treatment of allergic eye disease effective for the treatment of allergic conjunctivitis, vernal catarrh, vernal conjunctivitis, etc. More particularly, the present invention relates to a drug for the treatment of an allergic eye disease containing a 3-anilino-2-cycloalkenone derivative having a phosphodiesterase (PDE) IV (hereinafter sometimes abbreviated as “PDE IV” in this description) inhibitory activity, or a stereoisomer or optical isomer thereof, a salt thereof, or a hydrate or solvate thereof.
• PDE phosphodiesterase
• Allergic conjunctivitis is caused by the binding of antigens such as pollen, house dust with mast cells through antibodies (IgE).
• the mast cells activated by the antigens release chemical mediators such as histamines to thereby cause conjunctival injection, progression of vascular permeability and infiltration of leukocytes (eosinophils and neutrophils) and, in severe cases, to lead to tissue disorders (Abelson, M. B. et al., Surv Ophthalmol 38, p. 115-132, 1993).
• antihistamines and sodium cromoglicate cannot be expected to act to suppress the activation of free neutrophils and eosinophils, while adrenocortical steroids have the risk of causing side effects such as glaucoma, cataracts, infection, and therefore, there are limits to their use (Friedlaender M. H., Ann Allergy Asthma & Immunol . 75, p. 212-222, 1995).
• a phosphodiesterase (PDE) IV inhibitor is expected to inhibit the CAMP hydrolyzing enzyme PDE IV present relatively commonly in inflammatory cells and raise the cAMP concentration in the cells so as to suppress the activation of the inflammatory cells, whereby an antiinflammatory activity is exhibited (Torphy, T. J. et al., Drug News Perspect , 6, p. 203-214, 1993, Torphy T. J. and Undem B. J., Thorax 46, p. 512-523, 1991).
• PDE phosphodiesterase
• an agent for the treatment of an allergic eye disease particularly preferably an allergic conjunctivitis treatment agent, comprising a 3-anilino-2-cycloalkenone derivative having the formula (I):
• R 1 is an unsubstituted or substituted C 1 to C 8 alkyl group provided that an unsubstituted methyl group is excluded, a C 3 to C 7 cycloalkyl group, a C 6 to C 10 bicycloalkyl group, a 3-tetrahydrofuryl group or an indanyl group
• R 2 is a C 1 to C 4 alkyl group
• R 3 is a hydrogen atom, an unsubstituted or substituted C 1 to C 5 alkyl group, a C 3 to C 7 cycloalkyl group or an acyl group
• R 4 is a hydrogen atom, an unsubstituted or substituted C 1 to C 5 alkyl group, a halogen atom, a group having the formula (II):
• R 9 and R 10 are independently a C 1 to C 5 alkyl group, or a group having the formula (III):
• n is an integer of 2 to 6, provided that one CH 2 group may be substituted with one hetero atom selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom
• R 5 , R 6 , R 7 and R 8 are independently a hydrogen atom, an unsubstituted or substituted C 1 to C 5 alkyl group or an unsubstituted or substituted phenyl group
• X is —(CR 11 R 12 ) n —, wherein R 11 and R 12 are independently a hydrogen atom, an unsubstituted or substituted C 1 to C 5 alkyl group, or an unsubstituted or substituted phenyl group, and n is an integer of 0 to 2, wherein, when n is 0, the carbonyl carbon atom adjacent to X and the other carbon atom are directly bonded to form a 5-member ring or —NR 13 — wherein R 13 is a hydrogen atom or an unsubstituted or substituted C 1 to
• the agent for the treatment of allergic eye disease of the present invention contains one of the 3-anilino-2-cycloalkenone derivative of the above general formula (I), the stereoisomer or optical isomer thereof, the pharmacologically acceptable salt thereof, or the hydrate or solvate thereof.
• a C 1 to C 8 straight chain or branched chain alkyl group e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2-ethylbutyl, n-heptyl, n-octyl, etc.
• substituent group e.g., halogen atom; hydroxy group; nitro group; cyano group; amino group; carboxyl group; aryl groups such as phenyl, tolyl, naphthyl; aromatic heterocyclic group such as pyridyl, thiazolyl, thienyl, furyl, quinolyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group, etc.).
• substituent group e.g., halogen atom; hydroxy group; nitro group; cyano group; amino group; carboxyl group; aryl groups such as phenyl, tolyl, naphthyl; aromatic heterocyclic group such as pyridyl, thiazolyl, thienyl, furyl, quinolyl;
• C 1 to C 8 alkyl group having a substituent group for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-methylcyclopropyl-methyl, 1-phenylcyclopropylmethyl, benzyl, phenethyl, 4-fluorophenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 2-indanylmethyl, 2-1-naphthyl)ethyl, 2-(2-pyridyl)ethyl, 2-(4-methyl-5-thiazolyl)ethyl, 2-(benzyloxy)ethyl, 2-(phenethyloxy)e
• a C 3 to C 7 cycloalkyl group e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
• C 6 to C 10 bicycloalkyl group e.g., (1RS,2RS,4SR)bicyclo [2,2,1]hept-2-yl, (1R,2R,4S)bicyclo[2,2,1]hept-2-yl, (1S,2S,4R)bicyclo[2,2,1]hept-2-yl, etc.] 3-tetrahydrofuryl group, or indanyl group may be mentioned.
• R 1 preferably a C 4 to C 6 alkyl group; C 4 to C 7 cycloalkyl group; C 6 to C 8 bicycloalkyl group; C 1 to C 5 alkyl group having as a substituent group a phenyl group, naphthyl group, indanyl group, or an unsubstituted or substituted C 3 to C 7 cycloalkyl group; 3-tetrahydrofuryl group, or indanyl group may be mentioned.
• cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, 2-(2-indanyl)ethyl, (1RS,2RS,4SR)bicyclo [2,2,1]hept-2-yl, (1R,2R,4S)bicyclo[2,2,1]hept-2-yl, (1S,2S,4R)bicyclo[2,2,1]hept-2-yl, or 2-indanyl may be mentioned.
• a C 1 to C 4 straight chain or branched chain alkyl group e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc.
• methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc. may be mentioned, preferably methyl or ethyl may be mentioned, more preferably methyl may be mentioned.
• R 3 of the compound of the above formula (I) a hydrogen atom, a C 1 to C 5 straight chain or branched chain alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, etc.) may be mentioned.
• substituent group e.g., halogen atom; hydroxy group; nitro group; cyano group; amino group; carboxyl group; cycloalkyl group; haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group; phenyl, tolyl, naphthyl, or other aryl group; aromatic heterocyclic group containing at least one hetero atom selected from the group consisting of an oxygen atom, nitrogen atom, and sulfur atom (pyridyl, thiazolyl, furyl, thienyl, quinolyl, etc.), etc.)
• a substituent group e.g., halogen atom; hydroxy group; nitro group; cyano group; amino group; carboxyl group; cycloalkyl group; haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group; phenyl, tolyl, naphthyl, or other
• R 3 a C 3 to C 7 cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or acyl group (formyl, acetyl, propionyl, benzoyl, etc.) may be mentioned.
• R 3 preferably a hydrogen atom; C 1 to C 5 alkyl group; C 3 to C 7 cycloalkyl group; or C 1, to C 2 alkyl group having as a substituent group an aryl group or aromatic heterocyclic group containing at least one hetero atom selected from an oxygen atom, nitrogen atom, and sulfur atom may be mentioned. More preferably a hydrogen atom, methyl, propyl, pentyl, cyclopentyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, benzyl, 2-quinolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, or acetyl may be mentioned.
• R 4 of the compound of the above formula (I) a hydrogen atom or C 1 to C 5 straight chain or branched chain alkyl group (methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, etc.) may be mentioned.
• a substituent group halogen atom; hydroxy group; nitro group; cyano group; amino group; carboxyl group; cycloalkyl group; haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group; aryl groups such as phenyl, tolyl, naphthyl; aromatic heterocyclic group containing at least one hetero atom selected from an oxygen atom, nitrogen atom and sulfur atom (e.g., pyridyl, thiazolyl, furyl, thienyl, quinolyl, etc.), etc.).
• a halogen atom chlorine atom, bromine atom, iodine atom, etc.
• a C 1 to C 5 straight chain or branched chain alkyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, etc.
• a C 1 to C 5 straight chain or branched chain alkyl group e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, etc.
• 1-azetidinylmethyl, 1-pyrrolidinylmethyl, 1-piperidylmethyl, 1-homo-piperidylmethyl, 1-piperazinylmethyl, morpholinomethyl, etc. may be mentioned.
• n of the above formula (III) is an integer of 2 to 6. Further, one CH 2 group may be substituted with one hetero atom selected from an oxygen atom, nitrogen atom and sulfur atom.
• R 4 preferably a hydrogen atom, halogen atom, C 1 to C 3 alkyl group, dimethylaminomethyl, morpholinomethyl, or benzyl may be mentioned.
• R 5 , R 6 , R 7 and R 8 of the above formula (I) a hydrogen atom, C 1 to C 5 straight chain or branched chain alkyl group (methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, etc.), phenyl group, etc. may be independently mentioned.
• the C 1 to C 5 alkyl group and phenyl group may also have a substituent group (e.g., halogen atom; hydroxy group; nitro group; cyano group; amino group; carboxyl group; alkyl group; cycloalkyl group; haloalkyl group; carbamoyl group; alkoxy group; alkylcarbonyl group; aryl groups such as phenyl, tolyl, naphthyl; aromatic heterocyclic group containing at least one hetero atom selected from an oxygen atom, nitrogen atom, and sulfur atom (e.g., pyridyl, thiazolyl, furyl, thienyl, quinolyl, etc.), etc.)
• a hydrogen atom or methyl may be preferably mentioned.
• R 11 and R 12 are independently a hydrogen atom,
• alkyl group having a substituent group examples include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, pyridylmethyl, furylmethyl, and thiazolylmethyl may be mentioned.
• X preferably, —(CR 11 R 12 ) n — where n is 0 or 1, wherein, when n is 1, R 11 and R 12 preferably are independently a hydrogen atom or methyl group or —NR 13 — wherein R 13 is a hydrogen atom, C 1 to C 3 alkyl group or benzyl group may be mentioned.
• the 3-anilino-2-cycloalkenone derivative of the above formula (I) may be produced by the method described in, for example, Japanese Unexamined Patent Publication (Kokai) No. 11-189577.
• the 3-anilino-2-cycloalkenone derivative of the above formula (I) has asymmetric carbon atoms and, therefore, has optical isomers.
• These optically pure compounds are obtained by dividing the racemate produced by the method described in the above publication into the optical isomers using high pressure liquid chromatography (HPLC). By recrystallizing the obtained optical isomers when needed, further higher purity optical isomers can be obtained.
• These optical isomers are also considered to be included in the content of the agent for the treatment of the allergic eye disease of the present invention.
• the salts of the compound of the above formula (I) and the stereoisomer or optical isomer thereof are also included in the content of the agent for the treatment of the allergic eye disease of the present invention.
• pharmacologically acceptable salts are preferable.
• inorganic acid salts such as hydrochlorate, hydrobromate, hydroiodate, phosphate
• organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartarate, benzoate, methanesulfonate, p-toluenesulfonate may be mentioned.
• the agent for the treatment of allergic eye disease of the present invention may also include hydrates or solvates of the 3-anilino-2-cycloalkenone derivative of the above formula (I), its stereoisomer or optical isomer, or their salts.
• the solvent of the solvate methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chloroform, etc. may be mentioned.
• the agent for the treatment of allergic eye disease of the present invention may be produced by preparing the 3-anilino-2-cycloalkenone derivative of the above formula (I), its stereoisomer or optical isomer, their pharmaceutically allowable salts, or their hydrates or solvates, alone or mixed with a pharmacologically acceptable vehicle, into a suitable unit form of administration.
• the composition thereof is determined depending upon the solubility of the compound, the chemical properties, route of administration, the plan of administration, etc.
• an eye drop, eye ointment, etc. or, in the case of systemic administration, tablets, granules, a dispersion, capsules, a liquid, injection, etc. may be mentioned.
• the agent for the treatment of allergic eye disease of the present invention is preferably used in the form of an eye drop.
• the agent for the treatment of allergic eye disease of the present invention is produced by any method known to persons skilled in the art, using the 3-anilino-2-cycloalkenone derivative of the above formula (I), its optical isomer, their pharmacologically acceptable salts, or their hydrates or solvates and a pharmacologially acceptable vehicle.
• additives usually used when making a preparation such as a suitable binder, lubricant, disintegrant, preservative, buffer, thickener, solution adjuvant, chelating agent, stabilizer, pH adjuster, or isotonic agent.
• excipients such as lactose, crystalline cellulose, glucose, corn starch, sucrose, sorbitol, erythritol; disintegrants such as calcium carboxymethylcellulose, hydroxypropylcellulose; lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, hydrogenated oil, or another gloss agent, hermectants such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylalcohol, gelatin, gum arabic, and also when needed a surfactant, flavoring agents, etc. may be used to prepare the desired form of administration.
• excipients such as lactose, crystalline cellulose, glucose, corn starch, sucrose, sorbitol, erythritol
• disintegrants such as calcium carboxymethylcellulose, hydroxypropylcellulose
• lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol, hydrogenated oil,
• a dilvents such as water, ethanol, glycerin, propyleneglycol, polyethyleneglycol, agar agar, gum tragacanth may be used, when needed, solution adjuvants (e.g., polyvinylpyrrolidone, polyoxyethylene hydrogenated castor oil, polyethylene glycol, Polysorbate 80, polyoxyethylene monostearate, etc.), preservative (chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetylpyridium chloride, phenethyl alcohol, p-oxybenzoate esters, benzethonium chloride, etc.), buffer (borate buffer, phosphate buffer, carbonate buffer, acetate buffer, citrate buffer, etc.), stabilizer (sodium edetate, sodium hydrogensulfite, etc.), pH adjuster (sodium hydroxide, potassium hydroxide, sodium carbonate,
• solution adjuvants e.g., polyviny
• the compound of the above formula (I) usable in the present invention is usually used at a concentration of 0.01 to 3.0 w/v % in the case of an eye drop and is usually used at a concentration of 0.01 to 10.0 w/v % in the case of an eye ointment.
• the dosage in the case of oral administration, is generally 0.01 to 1000 mg per day, preferably 0.01 to 100 mg per day, but the dosage is more preferably adjusted according to age, condition, symptoms, existence of co-administration, etc.
• the clinical usage and dosage of the agent for the treatment of allergic eye disease of the present invention changes depending on the age, condition, symptoms, etc., but in the case of an eye drop, usually one to two drops are applied from one to six times a day. In the case of an eye ointment, usually a suitable quantity is applied to the conjunctival sac one to two times a day. In the case of oral administration, the dosage is ingested once a day or divided into several times. Further, in the case of an injection, it is injected once a day or divided into several times.
• (+)-isomer retention time 103 to 121 min, column temperature 40° C.
• Wistar rats (CLEA Japan) were used.
• the rats were sensitized by intraperitoneal administration of ovalbumin (OA, made by Sigma) in an amount of 100 ⁇ g and 10 mg of aluminum hydroxide (Alum, made by Pierce Co.) suspended in 1 mL of physiological saline.
• Allergic conjunctivitis was induced using rats after 3 weeks from the date of sensitization by dropping into the eyes of 10 ⁇ g OA solution prepared by physiological saline to a concentration of 30 mg/mL.
• the medicine was suspended at a concentration of 1.0 w/v % in physiological saline and dropped into the eyes 10 minutes before OA challenge to induce conjunctivitis (as a positive control drug, diphenhydramine suspended in a concentration of 0.3 w/v % in physiological saline was dropped in the eyes 10 minutes before OA challenge to induce conjunctivitis).
• Control group presensitized rats in whose eyes physiological saline is dropped 10 minutes before using OA to induce conjunctivitis
• Untreated group unsensitized rats in whose eyes physiological saline is dropped.
• Inhibition rate (%) 100 ⁇ (test substance group ⁇ untreated group/(control group ⁇ untreated group) ⁇ 100
• Table I shows the results when using for the test substance 3-[3-cyclopentyloxy-4-methoxy-N-(2-naphthylmethyl)anilino]-2-cyclopenten-1-one (compound 1), 3-[3-[(1RS,2RS,4SR)-bicyclo[2,2,1]hept-2-yloxy]-4-methoxyanilino]-2-methyl-2-cyclopenten-1-one (compound 2), 3-[3-[(1RS,2RS,4SR)-bicyclo[2,2,1]hept-2-yloxy]-4-methoxyanilino]-2-ethyl-2-cyclopenten-1-one (compound 3), ( ⁇ )-3-[3-[(1R,2R,4S)-bicyclo[2,2,1]hept-2-yloxy]-4-methoxyanilino]-2-methyl-2-cyclopenten-1-one (compound 4), and (+)-3-[3-[(1S)-bic
• the agent for the treatment of allergic eye disease of the present invention contains a compound having an activity different from that of existing the agent for the treatment of allergic eye disease (PDE IV inhibitory activity), whereby, a good effect of alleviating allergic conjunctivitis can be obtained and therefore is extremely useful as a new type agent for the treatment of allergic eye disease.
• PDE IV inhibitory activity an activity different from that of existing the agent for the treatment of allergic eye disease

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• 2002
  • 2002-07-08 EP EP02743854A patent/EP1410795B1/en not_active Expired - Lifetime
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