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WO1999064011A1 - Medicaments - Google Patents

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Publication number
WO1999064011A1
WO1999064011A1 PCT/JP1999/003137 JP9903137W WO9964011A1 WO 1999064011 A1 WO1999064011 A1 WO 1999064011A1 JP 9903137 W JP9903137 W JP 9903137W WO 9964011 A1 WO9964011 A1 WO 9964011A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
salt
general formula
compound
isoquinoline derivative
Prior art date
Application number
PCT/JP1999/003137
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyoshi Hidaka
Manabu Takagi
Takushi Matsuzaki
Original Assignee
Hiroyoshi Hidaka
Manabu Takagi
Takushi Matsuzaki
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hiroyoshi Hidaka, Manabu Takagi, Takushi Matsuzaki filed Critical Hiroyoshi Hidaka
Publication of WO1999064011A1 publication Critical patent/WO1999064011A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • 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
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

  • the present invention relates to a medicament containing an isoquinoline derivative as an active ingredient.
  • Bronchial asthma is a chronic inflammatory disease of the respiratory tract, with persistent inflammation of the respiratory tract and frequent attacks of airway asphyxia.
  • the primary etiology of bronchial asthma is the type I allergic response to antigenic stimulation, but asthma attacks can also be triggered by external stimuli (eg, infection, exercise, smoke, cold, stress).
  • Bronchial asthma involves many cells, especially mast cells, eosinophils and T lymphocytes.
  • Steroidal anti-inflammatory drugs especially inhaled steroid drugs, are the basic drug treatment.
  • oral antiallergic agents are used. These drugs are used as prophylactic / maintenance drugs (controllers) to reduce respiratory tract inflammation and reduce seizures.
  • Bronchodilators such as theophylline have been used as remedies for acute attacks (Releiva-1).
  • Long-acting bronchodilators such as sustained-release aminophylline preparations, are used as prophylactic / maintenance drugs because they can easily maintain optimal blood levels.
  • Substance P is one of the neuropeptides, the oldest and smoothest It was isolated from the intestinal tract in 1931 as a substance with muscle contractile activity, and in 1971 its structure was determined as a peptide consisting of 11 amino acids.
  • Substance P is widely distributed in the central and peripheral nervous systems, functions as a pain transmitter from the periphery to the center, and regulates the transmission system of dopamine and adrenaline in the brain. In the periphery, it is widely involved in immunity and inflammation as a regulator of macrophage dysm- piocyte activation and site force in (IL-1, TNF, IL-6). Furthermore, involvement in bronchial asthma has been suggested.
  • substance P and neurokinin A from nerve terminals distributed to smooth muscle, capillaries, and glands, causing inflammatory symptoms such as increased vascular permeability, plasma leakage, and glandular stimulation. Therefore, if the activity of substance P is inhibited, it can be used for treating asthma.
  • Asthma attacks are due in part to abnormal contraction of tracheal smooth muscle cells.
  • compounds that inhibit smooth muscle contraction may be potential therapeutics for asthma.
  • Smooth muscle contraction ⁇ Relaxation is regulated by increasing or decreasing intracellular Ca ion concentration.
  • the mechanism that enhances the sensitivity of muscle fibers to Ca ions also regulates the contraction and relaxation of smooth muscle.
  • Rho one of the low molecular weight GTP-binding proteins, is activated by signals from various cell membrane receptors. Activated Rho functions as a molecular switch for various cellular phenomena such as smooth muscle contraction, cell motility, cell adhesion, cell morphology change, and cell proliferation via the actomyosin system. It has been revealed. Therefore, by inhibiting Rho kinase (Rho-associate dkinase), which is considered to be present downstream of the Rho-mediated signaling pathway, Rho inhibits the response of various cellular phenomena caused by Rho, and It is thought to be a therapeutic drug for the diseases involved.
  • Rho-associate dkinase Rho-associate dkinase
  • Rho kinase is a protein phosphatase activated by Rho that acts on intracellular signal transduction. Rho kinase is present in cells, and when activated, smooth muscle contracts. Specific inhibition of this enzyme selectively inhibits G-protein (guanine-nucleotide binding regulatory protein) -mediated increase in Ca ion sensitivity and decreases intracellular Ca ion sensitivity, resulting in smooth muscle relaxation. I do.
  • Rho kinase has been shown to selectively act on Ca-sensitivity, a mechanism of contraction that is independent of intracellular Ca concentration (Natur e 389 (1997): 990-994 j 0 Therefore, compounds that inhibit Rho kinase are promising as new therapeutic agents for asthma and hypertension, which exert their effects by reducing Ca ion sensitivity.
  • Rho kinase is present not only in smooth muscle but also in cancer cells It is said that activation activates stress fibers and adhesion molecules. Therefore, if Rho kinase is inhibited, cell motility can be controlled, and it may be used as a therapeutic agent for autoimmune diseases or as a cancer cell metastasis inhibitor.
  • An object of the present invention is to provide a novel agent for preventing or treating asthma.
  • an isoquinoline derivative represented by the following general formula [I] has an excellent substance P antagonistic activity, co DOO Lin D 4 antagonism has a Rho kinase inhibitory action and smooth muscle relaxant action, find a useful this in the prevention or treatment of asthma, the present invention has been completed.
  • R 2 represents hydrogen, hydroxy or halogen.
  • R 3 represents hydrogen, alkyl or amidino.
  • ⁇ A represents an optionally substituted 5- to 11-membered cyclic amino. Such a cyclic amino may be bridged between any two carbons at any position.
  • An antagonist and a Rho kinase inhibitor An antagonist and a Rho kinase inhibitor.
  • a feature of the present invention is that the 4-position of the isoquinoline skeleton has an alkyl or aryl group.
  • the “prophylactic or therapeutic agent for asthma” in the present invention refers to a drug which has an action as a controller or a releaser, or has both actions, and is useful for the prevention or treatment of asthma.
  • “Smooth muscle relaxant” refers to a drug that suppresses abnormal contraction of smooth muscle. “Antiallergic agent” refers to a drug that suppresses a type I, II, II, or IV allergic reaction.
  • Subject P antagonist refers to a drug that is effective in ameliorating the symptoms of various diseases caused by substance P by suppressing a disorder induced by the activity of substance P.
  • Roy co preparative Lin D 4 antagonist refers Ri by the suppressing disorders more induced activity of Roy co preparative Lin D 4, the symptoms of various diseases caused by Roy co Application Benefits E down D 4 Refers to drugs that are effective in improving.
  • Rho kinase inhibitors are defined as physiological disorders or diseases involving Rho kinase (eg, asthma, peripheral circulatory disorders, retinopathy, hypertension, inflammation, immune diseases, autoimmune diseases, cancer, AIDS, bacterial It refers to the prevention or treatment of gastrointestinal infections, arteriosclerosis, osteoporosis, pathological diseases of cerebral dysfunction, fertilization and biological phenomena such as implantation of fertilized eggs. P99 / 03137
  • alkyl in the present invention is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopopenol pinole, n-butynole, and isobutynole. , Sec-butinole, tert-butinole, ⁇ -pentyl, isopentyl, n-hexyl, isohexinole. Of these, alkyl having 1 to 4 carbon atoms is preferable, and methyl is particularly preferable.
  • alkenyl is a straight-chain or branched-chain one having 2 to 6 carbon atoms, for example, vinyl, arylene, isopropenyl, 2-metharyl, 2-butenyl, 3- Butul can be mentioned. Of these, anorecanyl having 2 to 4 carbon atoms is preferred.
  • alkynyl a straight-chain or branched-chain one having 2 to 6 carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butyninole, 2-butenyl, 3-butynyl, 3-Methyl-2-butynyl can be mentioned. Among them, alkynyl having 2 to 4 carbon atoms is preferable.
  • Alkoxy refers to a straight or branched chain having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t ert—butoxy.
  • Halogen includes chlorine, fluorine, bromine, and iodine. Of these, fluorine is preferred.
  • ring A examples include a saturated 5- to 11-membered monocyclic or bridged ring containing two nitrogen atoms as a ring-forming heteroatom.
  • Nonan-3-yl, 3,6-diazabicyclo [3.2.1] octane-3-yl, 2,5-diazabicyclo [2.2.1] heptane-2-yl or 2,5-diazabicyclo [2.2.2] octane Tan-2-yl can be mentioned.
  • Such ring A may have 1 to 4 identical or different substituents at any position selected from the group consisting of anolequinole, halogen, phenyl and aminoanorexyl. Examples of the alkyl portion of the aminoalkyl include the aforementioned alkyl.
  • R 1 alkyl having 1 to 4 carbon atoms and halogen are preferable, and methyl and fluorine are particularly preferable.
  • R 2 and R 3 hydrogen is preferable.
  • hexahydro-1H-1,4-dazepine-1-yl is preferable, and in particular, 2- or 7-methylhexahydrid-1H-1, 4-dazepine_1-yl is preferable. More preferred.
  • Salts of the isoquinoline derivatives of the general formula [I] include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid and acetic acid. Tartaric acid, lactic acid, cunic acid, fumaric acid, maleic acid, konnoic acid, methansnoleonic acid, ethansnoleonic acid, benzenesnolefonic acid, tonoreensnolefonic acid, naphthalenesnolefonic acid, camphorsnolefonic acid, etc. Organic acid salts can be mentioned.
  • isoquinoline derivatives of the general formula [I] have an asymmetric carbon and may have optical isomers. Each of these isomers and mixtures thereof are included in the present invention.
  • the isoquinoline derivative of the general formula [I] has a leukotriene D 4 antagonistic action, a substance P antagonistic action, and a Rho kinase inhibitory action, Since it inhibits abnormal contraction of smooth muscle cells, it is useful as a prophylactic or therapeutic agent for bronchial asthma.
  • the isoquinoline derivative of the general formula [I] When the isoquinoline derivative of the general formula [1] is administered as a medicament, the isoquinoline derivative of the general formula [I] may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier. For example, it is administered to mammals including humans as a pharmaceutical composition containing 0.1% to 99.5%, preferably 0.5% to 90%.
  • the carrier one or more solid, semi-solid or liquid diluents, fillers, and other prescription auxiliaries are used.
  • the pharmaceutical compositions are preferably administered in dosage unit forms.
  • the pharmaceutical composition of the present invention can be administered orally, intraosseously, topically (such as transdermally), or rectally. Of course, they are administered in dosage forms suitable for these administration methods. Of these, oral administration or inhalation administration is preferred.
  • the dosage as a prophylactic or therapeutic agent for asthma or other diseases should be adjusted in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc.
  • the amount of the active ingredient of the present invention for an adult is, in the case of oral administration, in the range of l to l, 000 tng / adult per day, preferably in the range of 10 to 100 mgZ adult. .
  • the range is 0.1 to 100 mgZ adult, preferably 1 to 30 mg_ adult per day.
  • lower doses may be sufficient, and conversely, higher doses may be required. It can also be divided into two or three divided doses.
  • solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms
  • the powder is produced by making the compound of the general formula [I] into appropriate fine particles. Powders are prepared by mixing the compound of general formula [I] with a suitable finely divided and then with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
  • Force capsules are prepared by first filling powdered powders, powders or granules as described in the section on tablets, as described above, into a capsule shell such as a gelatin capsule. It is manufactured by this. Lubricants and glidants, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed with the powdered form, The filling operation can be performed later.
  • Disintegrants and solubilizers such as urenoboximetinoresenorelose, canoleboximetinoresenorelose kanoresum, low substituted hydroxypropinoresenorelose, cross-force noremelose sodium, carboxy
  • urenoboximetinoresenorelose canoleboximetinoresenorelose kanoresum
  • low substituted hydroxypropinoresenorelose low substituted hydroxypropinoresenorelose
  • cross-force noremelose sodium carboxy
  • carboxy methyl starch sodium, calcium carbonate, sodium carbonate
  • a fine powder of the compound of the general formula (I) is suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and this is wrapped in gelatin sheet to form a soft capsule.
  • Can be. Tablets are made by adding an excipient to form a powder mixture, granulating or slugging, then adding a disintegrating or lubricating agent and compressing.
  • Powder mixtures can be obtained by mixing appropriately powdered substances with the diluents and bases mentioned above and, if necessary, binding agents (eg, carboxymethyl cellulose Ream, methinoresenorelose, 3- hydroxy hydroxif pinoremetinoresenorelose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), dissolution retardant (eg, paraffin), resorbent (eg, A quaternary salt or an adsorbent (eg, bentonite, kaolin, dicalcium phosphate) may also be used in combination.
  • binding agents eg, carboxymethyl cellulose Ream, methinoresenorelose, 3- hydroxy hydroxif pinoremetinoresenorelose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
  • dissolution retardant eg, paraffin
  • resorbent eg, A quaternary salt or an adsorbent (eg, bentonite, kaolin
  • the powder mixture can be first moistened with a binder, for example, syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules.
  • a binder for example, syrup, starch paste, gum arabic, cellulose solution or polymer solution
  • the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearate, talc, mineral oil or the like as a lubricant.
  • the lubricated mixture is then tableted.
  • the uncoated tablets thus produced can be coated with a film coating or sugar coating.
  • the compound of the general formula [I] may be directly compressed after being mixed with a fluid inert carrier without going through the steps of granulation and slag formation as described above.
  • Transparent or translucent protective coatings consisting of a shellac hermetic coating, coatings of sugar or polymeric materials, and polishing coatings made of wax may also be used.
  • Other oral dosage forms such as solutions, syrups and elixirs can also be presented in dosage unit form so that a given quantity contains a fixed amount of the drug.
  • Syrup is produced by dissolving the compound of the general formula [I] in an appropriate aqueous flavor solution, and elixir is produced by using a non-toxic alcoholic carrier.
  • the suspension is
  • dosage unit formulations for oral administration may be microencapsulated.
  • the formulation can also provide an extended period of action or sustained release by coating or embedding in a polymer wax or the like.
  • inhalants for parenteral administration, inhalants, injections, suppositories and the like can be used. It can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension form.
  • a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection for example, a solution or suspension form.
  • a certain amount of the compound is suspended or dissolved in a non-toxic liquid carrier compatible with the purpose of injection, such as an aqueous or oily medium, and the suspension or solution is then sterilized.
  • a non-toxic liquid carrier compatible with the purpose of injection, such as an aqueous or oily medium
  • Non-toxic salts or salt solutions may be added to make the injection solution isotonic.
  • a stabilizer, a preservative, an emulsifier and the like can be used in combination.
  • a compound of the general formula [I] may be used as a low-melting, water-soluble or insoluble solid, for example, polyethylene glycol, cocoa butter, semi-synthetic fat (for example, Witepzol, registered trademark) Higher esters (eg, myristyl palmitate) and suppositories produced by dissolving or suspending them in a mixture thereof can be used.
  • the test included hexahydro-1 7-methyl-1_ (4-methyl-5-isoquinolinin sulfonyl) -1H-1,4-diazepine hydrochloride (Compound 1) as the test drug, and (S) — (-)-Hexahydro 7-methyl-1- (4-methyl-5-isoquinolinin sulfonyl)-1H-1,4-diazepine hydrochloride '(Compound 2), Hexahydro-1 2 -Methyl-1- (4-methyl-5-isoquinolinosulfonyl) -1H-1,4-diazepine hydrochloride (compound 3), (S)-(+)-hexahydro-2-methyl Tyl-1- (4-methyl-5-isoquinolinin sulfonyl) -1H-1,4-dazepine hydrochloride (compound 4), (R)-(-)-hexahydro — 2-methyl-1 -(
  • the ileum was removed from a guinea pig and a section specimen was prepared.
  • the specimen was suspended by adding the load of lg Magnus bath satisfies the Krebs solution (32 ° C, 95% 0 2 + 5% C0 2, pH 7 ⁇ 4) were recorded contraction of the specimen. Atre pin (0.35 ⁇ ) was co-present in the Krebs solution.
  • the specimen was thoroughly washed.
  • Substance ⁇ ⁇ (3 ⁇ ) is injected again in the presence of the test drug, and the substance in the absence of the test drug is injected.
  • test was performed according to the method of Holroyde et al. (Eur. J. Pharmacol. 1983, 90, 251-255).
  • the ileum was removed from a guinea pig and a section specimen was prepared.
  • the specimen was prepared.
  • Rho kinase inhibitory action
  • composition of the Atsushi system is as follows.
  • MgCl 2 5mM
  • EDTA linM EGTA ImM
  • DTT 1mM DTT 1mM
  • Substrate (S6-peptide) 40 ⁇
  • GST-RhoK-cat 26pg hot ATP 100 ⁇ M (0.2 ⁇ Ci) .
  • the reaction solution was prepared by removing the substrate and ATP from the eluate.
  • the substrate and radioactive ATP were added to the system and reacted at 30 ° C for 10 minutes.
  • the reaction solution was spotted on a P81 filter (manufactured by Whatman), washed with a 75 mM phosphoric acid solution, and radioactivity was measured. Table 1 shows the results.
  • Control compound 1.5 As is clear from Table 1, the Rho kinase inhibitory activity of the isoquinoline derivative of the general formula (II) was much higher by 7.5 to 100 times than that of the control compound, fasudil hydrochloride. . And its activity is professional CT / JP99 / 03137
  • PKA tin kinase A
  • PLC protein kinase C
  • MLCK myosin light chain kinase
  • the trachea was removed from the guinea pig and a section specimen was prepared.
  • the specimen was prepared.
  • a Magnus bath filled with Krebs solution (37. C, 95% 0 2 + 5% C 0 2 pH 7.4) was suspended under a load of lg, and the generated tension of the sample was recorded. After the tension of the specimen became stable, the test drug (30 ⁇ M) was injected into the Magnus bath. The relaxation effect of the test drug was studied with the relaxation caused by 1.6 ⁇ e epinephrine as 100%. As a result, Compound 6 exhibited a relaxing action of 30 to 94%.
  • granules for tableting are manufactured by a wet granulation method using an aqueous polyvinyl alcohol solution as a binder. After mixing magnesium stearate with this, it is molded into 180 mg per tablet using a tableting machine to make internal tablets.
  • 220 capsules are filled into hard capsules using a force capsule filling machine to obtain hard capsules.
  • the isoquinoline derivative of the general formula [I] is an advantageous agent for preventing or treating asthma.
  • the isoquinoline derivative represented by the general formula [I] inhibits the contraction of vascular smooth muscle, and is therefore useful as a hypotensive agent for treating malignant or severe hypertension. It also improves microcirculation and is therefore useful as a therapeutic agent for glaucoma.
  • Rho kinase inhibitory activity By having excellent selective Rho kinase inhibitory activity, it can suppress the activation of stress fibers and adhesion molecules, control the movement of cancer cells, and act as a cancer cell metastasis inhibitor. Or for autoimmune diseases.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des agents pour prévenir ou traiter l'asthme, contenant comme principe actif des dérivés d'isoquinoléine de formule générale (I) ou des sels desdits dérivés. Dans la formule, R1 représente alkyle, alcényle, alcoxy, hydroxy, cyano ou halogéno; R2 représente hydrogène, hydroxy ou halogéno; R3 représente hydrogène, alkyle ou amidino; et A représente amino cyclique comprenant cinq à onze chaînons, éventuellement substitué, pouvant être ponté entre deux atomes de carbone quelconques constituant l'amino cyclique.
PCT/JP1999/003137 1998-06-11 1999-06-11 Medicaments WO1999064011A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/163223 1998-06-11
JP16322398A JP4212149B2 (ja) 1998-06-11 1998-06-11 医薬

Publications (1)

Publication Number Publication Date
WO1999064011A1 true WO1999064011A1 (fr) 1999-12-16

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WO2000057914A1 (fr) * 1999-03-25 2000-10-05 Santen Pharmaceutical Co., Ltd. Agents permettant d'abaisser la tension oculaire
WO2005035506A1 (fr) 2003-10-15 2005-04-21 Ube Industries, Ltd. Nouveau derive d'indazole
JP2006348028A (ja) * 2005-05-19 2006-12-28 Kowa Co 緑内障予防又は治療剤
WO2007026664A1 (fr) * 2005-08-30 2007-03-08 Asahi Kasei Pharma Corporation Composé sulfonamide
JP2007084474A (ja) * 2005-09-21 2007-04-05 Kowa Co 点眼用組成物
WO2007142323A1 (fr) 2006-06-08 2007-12-13 Ube Industries, Ltd. Nouveau dérivé d'indazole ayant une structure cyclique spiro dans une chaîne latérale
WO2008105058A1 (fr) * 2007-02-27 2008-09-04 Asahi Kasei Pharma Corporation Sulfamides
WO2008105442A1 (fr) 2007-02-28 2008-09-04 Asahi Kasei Pharma Corporation Dérivé de sulfonamide
CN101087613B (zh) * 2004-12-23 2010-08-18 兴和株式会社 青光眼的预防或治疗剂
EP2314299A1 (fr) 2002-08-29 2011-04-27 Santen Pharmaceutical Co., Ltd Traitement contre le glaucome a base d'inhibiteurs de rho kinase et de prostaglandines
US8232292B2 (en) 2007-07-02 2012-07-31 Asahi Kasei Pharma Corporation Sulfonamide compound and crystal thereof
JP2012193213A (ja) * 2005-05-19 2012-10-11 Kowa Co 緑内障予防又は治療剤
EP2628482A1 (fr) 2012-02-17 2013-08-21 Academisch Medisch Centrum Inhibiteurs du rho kinase pour l'utilisation dans le traitement du neuroblastome
US10034885B2 (en) 2014-09-24 2018-07-31 Kowa Company, Ltd. Corneal thickness modulating agent
WO2019124488A1 (fr) 2017-12-21 2019-06-27 参天製薬株式会社 MÉDICAMENT COMPRENANT UNE COMBINAISON DE SEPETAPROST ET D'INHIBITEUR DE LA Rho-KINASE
WO2020047229A1 (fr) 2018-08-29 2020-03-05 University Of Massachusetts Inhibition de protéines kinases pour traiter la maladie de friedreich
WO2022150676A1 (fr) 2021-01-11 2022-07-14 Incyte Corporation Polythérapie comprenant un inhibiteur de la voie jak et un inhibiteur de rock
US11739326B2 (en) 2017-11-14 2023-08-29 Massachusetts Eye And Ear Infirmary RUNX1 inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition

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DE10226943A1 (de) * 2002-06-17 2004-01-08 Bayer Ag Phenylaminopyrimidine und ihre Verwendung
US20060142270A1 (en) * 2004-12-23 2006-06-29 Kowa Co., Ltd. Preventing or treating agent for glaucoma
JP2006290827A (ja) * 2005-04-13 2006-10-26 Kowa Co 緑内障予防又は治療剤
ATE423779T1 (de) 2005-04-25 2009-03-15 Western Therapeutics Inst Inc Hochselektiver rho-kinase-inhibitor
EP1902731B1 (fr) * 2005-06-21 2013-04-10 Kowa Company, Ltd. Agent prophylactique ou remède pour le glaucome
DK1905452T3 (da) 2005-07-12 2013-07-01 Kowa Co Middel til forebyggelse eller behandling af glaukom
JP2007153891A (ja) * 2005-11-30 2007-06-21 Kowa Co 慢性進行性腎障害の抑制のための医薬
WO2012105674A1 (fr) 2011-02-04 2012-08-09 興和株式会社 Pharmacothérapie pour la prévention ou le traitement du glaucome
JP2013035802A (ja) * 2011-08-10 2013-02-21 D Western Therapeutics Institute Inc 緑内障又は高眼圧症の予防又は治療剤
TWI629985B (zh) 2013-04-24 2018-07-21 國立大學法人九州大學 眼底疾患治療劑
PL3199160T3 (pl) 2014-09-25 2020-07-27 Kowa Company, Ltd. Kompozycja wodna
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US8227480B2 (en) 2006-06-08 2012-07-24 Ube Industries, Ltd. Indazole derivative having spiro ring structure in side chain
WO2008105058A1 (fr) * 2007-02-27 2008-09-04 Asahi Kasei Pharma Corporation Sulfamides
US8415372B2 (en) 2007-02-27 2013-04-09 Asahi Kasei Pharma Corporation Sulfonamide compound
WO2008105442A1 (fr) 2007-02-28 2008-09-04 Asahi Kasei Pharma Corporation Dérivé de sulfonamide
US7964613B2 (en) 2007-02-28 2011-06-21 Asahi Kasei Pharma Corporation Sulfonamide compound
JP5313125B2 (ja) * 2007-02-28 2013-10-09 旭化成ファーマ株式会社 スルホンアミド誘導体
US8232292B2 (en) 2007-07-02 2012-07-31 Asahi Kasei Pharma Corporation Sulfonamide compound and crystal thereof
US8664243B2 (en) 2007-07-02 2014-03-04 Asahi Kasei Pharma Corporation Sulfonamide compound and crystal thereof
EP2628482A1 (fr) 2012-02-17 2013-08-21 Academisch Medisch Centrum Inhibiteurs du rho kinase pour l'utilisation dans le traitement du neuroblastome
US10034885B2 (en) 2014-09-24 2018-07-31 Kowa Company, Ltd. Corneal thickness modulating agent
US11739326B2 (en) 2017-11-14 2023-08-29 Massachusetts Eye And Ear Infirmary RUNX1 inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition
WO2019124488A1 (fr) 2017-12-21 2019-06-27 参天製薬株式会社 MÉDICAMENT COMPRENANT UNE COMBINAISON DE SEPETAPROST ET D'INHIBITEUR DE LA Rho-KINASE
EP4338751A2 (fr) 2017-12-21 2024-03-20 Santen Pharmaceutical Co., Ltd. Médicament comprenant une combinaison de sépiétart et d'inhibiteur de protéine kinase contenant une superhélice associée à rho
WO2020047229A1 (fr) 2018-08-29 2020-03-05 University Of Massachusetts Inhibition de protéines kinases pour traiter la maladie de friedreich
US12281308B2 (en) 2018-08-29 2025-04-22 University Of Massachusetts Inhibition of protein kinases to treat Friedreich ataxia
WO2022150676A1 (fr) 2021-01-11 2022-07-14 Incyte Corporation Polythérapie comprenant un inhibiteur de la voie jak et un inhibiteur de rock
US11918581B2 (en) 2021-01-11 2024-03-05 Incyte Corporation Combination therapy comprising JAK pathway inhibitor and rock inhibitor

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