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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/14—Antitussive agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:

Definitions

• the present invention relates to an antitussive
• An object of the present invention is to provide an antitussive that can be used as an oral preparation.
• a compound having a completely different mechanism of action from conventional morphine codine and dextromethorphan that is, an S receptor antagonist has a strong antitussive action
• this 5-antagonist is expected to show a selective antitussive effect without showing drug dependence, psychiatric effects, or drug aversion.
• the present invention provides an antitussive comprising an S-antagonist or a pharmacologically acceptable salt thereof as an active ingredient.
• an antitussive having a completely different mechanism of action from conventional antitussives having serious side effects such as drug dependence, psychiatric effects, drug aversive effects, etc., having high activity and capable of oral administration is provided.
• Figure 1 shows the effect of Compound 1 (Naltriindole: NT) on capsaicin-induced cough.
• FIG. 2 is a graph showing the rate of cough suppression 15 minutes after administration of Compound 1.
• FIG. 3 is a graph showing the effect of compound 3 (BNTX) on capsaicin-induced cough.
• the antitussive of the present invention contains an S-antagonist or a pharmacologically acceptable salt thereof as an active ingredient.
• S-antagonists include, for example, the following general formula (I)
• R1 is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aryl having 6 to 12 carbons, carbon number?
• X represents alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, arylcarbonyloxy having 7 to 13 carbon atoms, or aralkyloxy having 7 to 13 carbon atoms, and X is
• R4 represents hydrogen, alkyl having 1 to 5 carbons or aralkyl having 7 to 13 carbons
• R5, RS, R? Separately represent hydrogen, fluorine, chlorine, bromine, nitro, carbon number 1 ⁇ 5 alkyl, C1-C5 alkoxy, isothiocyanato, iodine, trifluoromethyl, trifluoromethoxy, cyano, phenyl, C1-C3 hydroxyalkyl, SR8, SOR8, S 2R8 ,
• R5 and R6 are bonded to each other to obtain an alkylene having 3 to 6 carbon atoms (where hydrogen of the alkylene portion is Rii (Rii is alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, and 1 to 5 carbon atoms) of Arukanoiru, hydroxyalkyl of 1 to 5 carbon atoms, S R8, S OR8, S0 2 R8, (CH 2) m CO ⁇ R8,
• S, T, U, V is nitrogen or CH (provided that hydrogen is Ri 2 (R1 2 fluorine, chlorine, bromine, nitro, having 1 to 5 carbon atoms alkyl, C 1-5 alkoxy carbon, Isochi Oshianato, Iodine, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxyalkyl having 1 to 3 carbon atoms, S R8, S ⁇ R8, S ⁇ 2 R8, (CH 2 ) m C ⁇ 2 R8, S 0 2 N R9 Ro, CONR9 Ri. ,
• the compound of the above general formula (I) can be specifically represented by the following general formulas (la), (lb) and (Ic).
• Rl is preferably alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, aralkyl having 7 to 13 carbons, alkenyl, aryl, or furan-2-ylalkyl having 4 to 7 carbons.
• methyl, ethyl, propyl, cyclopropylmethyl, cyclobutylmethyl, benzyl, phenethyl, butenyl, aryl, and furan-2-ylmethyl are preferred.
• R 2 and R 3 are preferably hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms or aralkyloxy having 7 to 13 carbon atoms, particularly hydrogen, hydroxy, a Preference is given to ethoxy, methoxy, ethoxy, propoxy and benzyloxy.
• R 4 hydrogen and alkyl having 1 to 5 carbon atoms are preferable, and hydrogen and methyl are particularly preferable.
• Is hydrogen, halogen, nitro, alkyl having 1 to 5 carbon atoms, of 1-5 carbon atoms alkoxy, C0 2 R8 (R8 is alkyl of 1 to 5 carbon atoms) are preferred, especially hydrogen, fluorine, chlorine , Bromine, nitro, methyl, methoxy, methoxycarbonyl are preferred.
• R6 and R7 are preferably hydrogen, halogen, nitro, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, isothiocyanato, trifluoromethyl, trifluoromethoxy, cyano, phenyl, carbon having 1 to 5 carbon atoms.
• the compounds used in the present invention are specifically 17-aryl-16,7-didehydro-4,5 ⁇ -epoxy-13,14 ⁇ -dihydroxy-16,7 , 2 ', 3'-Indolomorphinan, 17-Cyclopropylmethyl-16,7-Didehydro-1,4,5-Epoxy-1-14-Hydroxy-3-Methoxy-1,6,7,2', 3'-Indolomorphinan, 17-allyl-6,7-didehydro_4,5 ⁇ -epoxy-14-4 ⁇ -hydroxy-1-3-methoxy-1-6,7,2 ', 3'-Indolomorphinan , 1 7-cyclopropylmethyl-6,7-didehydro-4,5
• Ri is Shikurofuropi Rumechiru
• R2 R3 Gahi Dorokishi
• R7 is hydrogen
• the compounds used in the present invention are specifically 17-aryl-1-6,7-didehydro-4,5 ⁇ -epoxy-13,14 / 9-dihydroxy-16- , 7 — —cyclohexeno 6, 7, 2 '3' -indolomorphinan, 17 7-cyclopropylmethyl-1,6,7-didehydro 4,5 a-epoxy-1 14 / 5—hydroxy-1 3— Methoxy 6 ', 7'-cyclohexeno 6,7,2'3--Indolomorphinan, 17-Aryl-6,7-didedraw 4,5 ⁇ -Epoxy-14 / S-hydroxy- 3-Methoxy 6 7'-cyclohexeno 6,7,2 '3'-Indolomorphinan, 17-Cyclopropylmethyl-6,7-didedraw 4,5 ⁇ -Epoxy-1,4 /?
• Ri is cyclopropylpyrmethyl
• R2 and R3 are hydroxy
• R4, R5, R6 and R7 are hydrogen compounds 4
• 17-cyclopropylmethyl-6,7-didehydro-1,4,5 ⁇ -epoxy-1,3,14 ⁇ dihydroxy-1,6,7,2 ', 3-quinolinomorphinan As specific examples of the compounds, 17-aryl-1,6,7-didehydro-14,5 ⁇ -epoxy-1,3,14 / 5-dihydroxy-6,7,2 ', 3'-ki Norinomorphinan, 17 7-Cyclopropylmethyl-6,7-didehydro-1,4,5 ⁇ -epoxy-14 4 ⁇ -Hydroxy-1-3-methoxy 6,7,2 ', 3'-Quinolinomorphinan, 17 —Aryl-1,6,7-didedraw 4,5 ⁇ -epoxy-1 4 ⁇ —hydroxy-1-3-methoxy-1,6,7,2 ′, 3 ′ —quinolinomol hinane, 17-cyclopropylmethyl- 6,7-didehydro 4,5 ⁇ -epoxy-1,
• the compound of the general formula U) used in the present invention can be prepared by a known method (PS Portoghese, Jed. Chem. Vol 31, No. 2, 281, 1988; PS Portoghese, J. Med. Chem. Vol 4, No. 4, 1292, 1991; PS Portoghese, J. Med. Chem. Vol 34, No. 5, 17, 1991).
• PS Portoghese Jed. Chem. Vol 31, No. 2, 281, 1988
• PS Portoghese J. Med. Chem. Vol 4, No. 4, 1292, 1991
• PS Portoghese J. Med. Chem. Vol 34, No. 5, 17, 1991
• the compound (I) is produced according to the following chemical reaction formula.
• the pharmacologically acceptable salt of the present invention includes inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, oxalate, and the like.
• Organic carboxylates such as mandelic, benzoate, phthalate, glutarate, fumarate, tartrate, malate, lactate, succinate, maleate, methanesulfonate, ethane Organic sulfonates such as sulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate and the like, among which hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonic acid Salts and the like are preferable, but are not limited thereto.
• a free base or a salt thereof may be used, or excipients such as a stabilizer, a buffer, a diluent, an isotonic agent, and a preservative may be appropriately mixed.
• excipients such as a stabilizer, a buffer, a diluent, an isotonic agent, and a preservative may be appropriately mixed.
• dosage forms include injections; oral preparations such as tablets, capsules, granules, powders, and suppositories; enteral administration using suppositories; or topical administration using ointments, creams, patches and the like. Injectable and oral preparations are preferred.
• the antitussive of the present invention preferably contains 0.001 to 90% by weight of the above active ingredient.
• the dose is determined appropriately according to the administration subject, administration method and symptoms.For injections, the dose is in the range of 1 g to 0.1 lg Z days, and for oral drugs, 10 // g to 1 g. It is a range of days, each of which can be administered once or in several divided doses.
• Methanesulfonate of the title compound was obtained in the same manner as in Reference Example 1 using naltrexone-13-methylether instead of naltrexone hydrochloride and phenylhydrazine instead of 5-hydrazinoquinoline (yield 76%).
• the measurement was performed by the plethysmograph method.
• the plethysmograph used in this study is a plastic cylinder with a diameter of 7.5 cm and a length of 15 cm, and is made up of a cylinder part to put the body of the rat and a cap part to cover from the head.
• An exhaust port was opened at the top of the cylinder so that it could be connected to a respiratory flow meter. Rubber and celluloid collars were attached to the neck to seal the inside of the cylinder.
• the cap was provided with an inlet and vent for capsaicin inhalation. Breathing was measured through the respiratory flow meter as the movement of the thorax accompanying the respiration of the rat in the cylinder as a change in volume in the cylinder.
• the rat's thorax moves violently, causing a temporary large volume change in the cylinder, which is measured separately from normal respiration through a respiratory flow meter. This number was measured to be the number of coughs.
• Cavsaicin (30 M) was inhaled in an artificial nebulizer using an ultrasonic nebulizer and sent through a silicone tube to the cap of the rat's head, and coughing was induced by inhalation.
• Artificial respiratory insufflation for capsaicin inhalation was performed at a rate of 30 ml per minute, 20 ml per dose.
• Capsaicin was inhaled for 5 minutes 15 minutes before drug application, and it was confirmed that coughing was induced during this period. Capsaicin was inhaled for 5 minutes at 15, 60, and 120 minutes after drug application, and the number of coughs induced during this period was measured. Antitussive effect before and after drug application From the number of coughs, the inhibition rate against the number of coughs before drug application was determined and evaluated. Inhibition rates were compared using a Mann hiteny U-test. Those with a difference of 5% or less were judged to be significant. Capsaicin was dissolved using 10% ethanol and 10% Tween 80 solution, and diluted with physiological saline. The drug was dissolved in saline. All drugs were applied intraperitoneally. Effect of Compound 1 (Naltriindole: NT I) on cough reflex
• FIG. 2 shows the dose-responsiveness of the cough suppression rate of Compound 1 at 15 minutes after administration.
• Compound II showed a dose-dependent cough-suppressing effect in the dose range of 0.0 SmgZkg to 1 mg kg.
• the antitussive effect of Compound II (l mg / kg) was almost the same as that of morphine (0.3 mg.kg).
• Fig. 1 represents the average soil S.E. of at least 5 cases in which the rate of suppression of the number of coughs was suppressed.
• ⁇ shows the results for the physiological saline administration group
• ⁇ shows the results for the compound ⁇ (1 mg / kg, i.p.) administration group.
• * indicates P ⁇ 0.05 for the saline administration group.
• each value shown in Fig. 2 represents the average soil S. E. of at least five cases in which the rate of suppression of the number of coughs was suppressed.
• NTI shows the result for compound II
• M ⁇ R shows the result for morphine.
• the figures in parentheses indicate the dose (mg / kg, i.p.). * Has the same meaning as in FIG.
• Example 2 According to a method similar to that of Example 1, the effect of the compound which is an S 1 -antagonist (benzylidenetrexone: BNTX) was observed.
• the results are shown in FIG.
• Each value shown in Fig. 3 represents the average soil SE of at least 5 cases in which the rate of suppression of the number of coughs was suppressed.
• ⁇ indicates the results for the saline administration group, and ⁇ indicates the compound 3 ( 3 mg / kg, i.p.) shows the results for the administration group.
• Capsaicin 60 M was inhaled in an artificial nebulizer using an ultrasonic nebulizer and sent to a cap on the rat's head through a silicon tube, and coughing was induced by inhalation. Artificial respiratory insufflation for capsaicin inhalation was performed as quickly as 70 m / min with a single dose of 10 m.
• Capsaicin was inhaled for 5 minutes 270 minutes before drug application, and it was confirmed that coughing was induced during this period. Thirty minutes after the drug application, capsaicin was inhaled for five minutes, and the number of coughs induced during this period was measured. The antitussive effect was evaluated by determining the rate of suppression of the number of coughs before drug application from the number of coughs before and after drug application. Capsaicin was dissolved in saline. Drugs were dissolved in 10% DMS / water and all applied intraperitoneally. The effect of the drug was expressed as the ED 5D value, which showed a 50% cough suppression rate. Test compound ED 5 o ( ⁇ g / kg)

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Emergency Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Pulmonology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Saccharide Compounds (AREA)
• Linear Motors (AREA)
• Fats And Perfumes (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=18349997

Family Applications (1)

Country Status (11)

Cited By (4)

Families Citing this family (5)

Citations (3)

Family Cites Families (3)

• 1993
  • 1993-12-22 CA CA002130457A patent/CA2130457A1/en not_active Abandoned
  • 1993-12-22 WO PCT/JP1993/001855 patent/WO1994014445A1/ja not_active Ceased
  • 1993-12-22 AT AT94903039T patent/ATE166229T1/de not_active IP Right Cessation
  • 1993-12-22 US US08/290,837 patent/US5714483A/en not_active Expired - Fee Related
  • 1993-12-22 KR KR1019940702877A patent/KR950700065A/ko not_active Abandoned
  • 1993-12-22 CN CN93119935A patent/CN1071117C/zh not_active Expired - Fee Related
  • 1993-12-22 AU AU57156/94A patent/AU674379B2/en not_active Ceased
  • 1993-12-22 DE DE69318710T patent/DE69318710T2/de not_active Expired - Fee Related
  • 1993-12-22 EP EP94903039A patent/EP0636371B1/en not_active Expired - Lifetime
• 1994
  • 1994-01-21 TW TW083100512A patent/TW366284B/zh active
  • 1994-08-19 NO NO943070A patent/NO307496B1/no not_active IP Right Cessation

Patent Citations (3)

Also Published As

Similar Documents

Legal Events