WO2002024250A1 - Inhibiteur de la no synthetase inductible (inos) utilise pour le traitement ou la prevention de la myopie - Google Patents

Inhibiteur de la no synthetase inductible (inos) utilise pour le traitement ou la prevention de la myopie Download PDF

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Publication number
WO2002024250A1
WO2002024250A1 PCT/CN2000/000284 CN0000284W WO0224250A1 WO 2002024250 A1 WO2002024250 A1 WO 2002024250A1 CN 0000284 W CN0000284 W CN 0000284W WO 0224250 A1 WO0224250 A1 WO 0224250A1
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group
optionally substituted
compound
salt
oxide
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PCT/CN2000/000284
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English (en)
Chinese (zh)
Inventor
George C. Y. Chiou
Tricia T. S. Cheng
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Yong Guang Pharmaceutical Co., Ltd.
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Priority to CN00815738A priority Critical patent/CN1399547A/zh
Priority to AU2000275033A priority patent/AU2000275033A1/en
Priority to PCT/CN2000/000284 priority patent/WO2002024250A1/fr
Publication of WO2002024250A1 publication Critical patent/WO2002024250A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • 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
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • iNOS inhibitor for treating or preventing myopia
  • the present invention relates to a semicarbazide derivative, a preparation method thereof, a pharmaceutical composition containing the compound, and a use of the semicarbazide derivative in the preparation of a medicament for treating or preventing myopia and a method for treating or preventing myopia.
  • Myopia is a common visual condition or disease. Although the etiology of myopia can be attributed to a variety of factors, including genetics, environment, and weak light, it can be attributed to a common factor, namely the extension of the central axis of the eyeball, and the eye Clear due to the inappropriate refractive power or the combination of the two. (Chen, WC et al., Myopia Updates II. Lin L. et al., Ed. Pp. 39-42, Springer, New York (1998)). Myopia can cause retinopathy when severe, and age-related speckle degeneration (AMD) And cataracts.
  • AMD age-related speckle degeneration
  • Contraction of the ciliary muscle is mediated by several types of receptors, including muscarinic receptors, prostaglandin receptors and endothelin receptors (Erickson-Larry, K. et al., Invest. Ophthalmol. Vis. Sci 32: 492-495 (1991)).
  • Ciliary muscle relaxation is regulated by two independent mechanisms: cAMP-dependent mechanisms, which include ⁇ -adrenergic and prostaglandin receptor-regulated relaxation, and cAMP- Independent mechanism (Goh, Y., et al., Invest. Ophthalmol. Vis. Sci.
  • Another cause of myopia is due to cell necrosis due to scleral lesions at the base of the eye, such as inflammation, resulting in softening or reduced hardness of the sclera.
  • the sclera deforms such as protruding backwards, which causes the eye axis to become longer and causes myopia. .
  • NO nitric oxide
  • Isoform NOS includes neuronal NOS (nNOS) or brain NOS (bNOS) in the central nervous system and peripheral nervous system, and endothelial NOS (eNOS or ecNOS) in neurons and non-neuronal cells.
  • nNOS and eNOS produce NO shortly after being activated by calcium / calmodulin to produce different biological responses.
  • Immune NOS (1N0S) is the third isoform NOS induced by lipopolysaccharide and certain cytokines (such as interleukin-1, interleukin-6, tumor necrosis factor and interferon ⁇ ). They produce large amounts of NO for a period of time, causing pathophysiological responses (Szabo, C. et al., Nitric Oxide, Biochemistry, Molecular Biology, and Therapeutic Implication. Ignarro, L. and Murad, F., pp. 113-153, Academic Press, New York (1995))
  • NO will be further oxidized to N0 2 —, nitrite, peroxy nitrite (0N00—) and free And interact with thiols, iron-sulfur centers of various enzymes, cytochrome oxidase, glycolytic enzymes, liver cells, macrophages, calmodulin, etc., as a result, the biological functions of the cells are changed, and DNA is damaged And cause apoptosis, neurotoxicity, ophthalmic nerve degradation and many ophthalmic diseases.
  • iNOS is only induced by lipopolysaccharides, endotoxins, and cytokines under pathophysiological conditions (such as inflammation).
  • the rate-limiting step for NO production from iNOS is the availability of L-arginine, which is recycled by arginine succinate synthetase, which is simultaneously induced when iNOS is induced.
  • the induction of iNOS also triggered the membrane-carrying system of L-arginine to enhance the utilization of iNOS by L-arginine, resulting in a large amount of NO.
  • NO has been linked to eye diseases such as glaucoma (Nathanson, J. A. J. Pharmacol. Exp. Ther. 956-965 (1992)), but the relationship between NO and myopia has not yet been shown.
  • the present inventors have unexpectedly discovered that oversupply of NO and oversupply of NO can occur in ocular tissues, which respectively cause the above-mentioned dysfunction of the eye and cause diseases such as the occurrence of myopia. Therefore, ocular dysfunction and diseases, especially the prevention or treatment of myopia, can be made up by reducing the deficiency of NO, or by inhibiting iNOS activity or inhibiting induction to reduce the oversupply of NO.
  • iNOS activity or inhibiting induction to reduce the oversupply of NO.
  • semicarbazone derivatives are known as 2-phenyl-5-(4-phenyl-1 -methylthiourea amino)-3 (2H)-pyridone (Kihara, Yoshito et al. , Synthesis (1990), (11), 1020-1030 (1990)) (hereinafter referred to as Compound 3) have been applied to many inflammations including eye diseases.
  • Such agents are not only effective in treating ophthalmitis in ophthalmology, but also for controlling wound healing after refractive keratotomy and laser keratomileusis (LASIK) (Schwade, N. Chiou, GCY, J. Ocular Pharmacol. Ther. 11: 113-134 (1995)).
  • an effective preventive or therapeutic drug for myopia is provided.
  • the semicarbazide derivative can reduce the excessively high NO concentration in the eye by inhibiting iNOS, inhibit the protrusion of the central sclera and Elongation of the axis of the eye to achieve the effect of preventing or treating myopia, and without pupil dilation and other side effects of parasympathetic nerves, thus completing the present invention.
  • a first aspect of the present invention relates to a method for the prevention and treatment of myopia, which comprises administering a therapeutically effective amount of a semicarbazide derivative to a patient.
  • Another aspect of the present invention relates to the use of a semicarbazide derivative in the manufacture of a medicament for preventing or preventing myopia.
  • Another aspect of the present invention relates to a semicarbazide derivative as a pharmaceutically active substance shield, and another aspect of the present invention relates to a novel semicarbazide derivative.
  • Another aspect of the present invention relates to a method for preparing a novel semicarbazide derivative.
  • Still another aspect of the present invention relates to a pharmaceutical composition containing a pharmaceutically active semicarbazide derivative as an active ingredient.
  • the present invention relates to a commercial kit comprising a therapeutically effective amount of a semicarbazide derivative or composition, and a medicinal compound or composition recorded in the treatment or prevention of myopia or should be used Information about the compound or composition.
  • the present invention is as follows.
  • R1 represents hydrogen, optionally substituted CI_C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;
  • X represents 0 or S atom
  • A represents a 5- to 10-membered monocyclic or polycyclic heterocyclic ring containing 1-4 identical or different atoms escaping from N, 0 and S;
  • a and B may be optionally substituted by a group selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, amino, lower alkylamino, and oxygen. Substituted, thio, halogen, aryl, aralkyl, aromatic heterocyclyl, non-aromatic heterocyclyl, carboxyl, lower alkoxycarbonyl, hydroxyl, sulfo, nitro, acyl, nitroso, cyano, Azide.
  • R1 is preferably hydrogen, optionally substituted CI-C6 alkyl, more preferably C1-C3 alkyl substituted, most preferably methyl, ethyl;
  • B is preferably a phenyl group or a naphthyl group optionally substituted with a halogen, a lower alkyl group, and more preferably a benzyl group optionally substituted with a halogen;
  • A is preferably an optionally substituted 5-6 membered monocyclic heterocycle containing 1 to 3 identical or dissimilar heteroatoms selected from N, 0, and S, and said optional substituent is selected from the group consisting of: hydrogen , Lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, amino, lower alkylamino, oxo, thio, element, aryl, aralkyl, aromatic heterocyclic group, Non-aromatic heterocyclyl, carboxyl, lower alkoxycarbonyl, hydroxyl, sulfo, nitro, acyl, nitroso, cyano, azido; more preferably optionally substituted pyranyl, furanyl, thienyl , Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furoxanyl, pyridyl, piperidinyl, pyr
  • Rl, X, ⁇ and ⁇ are the same as in the above (1);
  • preferred compounds are the same as in (1) above.
  • Rl represents an optionally substituted CI- C 6 alkyl, optionally substituted C 2 -C6 alkenyl, optionally substituted C2- C6 alkynyl;
  • X represents 0 or S atom
  • A represents a 5-10 membered monocyclic or polycyclic heterocyclic ring containing 1-4 identical or different atoms selected from N, 0 and S;
  • a and B may be optionally substituted by a group selected from the group consisting of: hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, amino, lower alkylamino, Oxo, thio, halogen, aryl, aralkyl, aromatic heterocyclyl, non-aromatic heterocyclyl, carboxyl, lower alkoxycarbonyl, hydroxyl, sulfo, nitro, acyl, nitroso, cyano , Azide.
  • a group selected from the group consisting of: hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, amino, lower alkylamino, Oxo, thio, halogen, aryl, aralkyl, aromatic heterocyclyl, non-aromatic heterocyclyl, carboxyl, lower alkoxycarbonyl, hydroxyl, sulfo,
  • R1 is preferably an optionally substituted C1-C3 alkyl group, more preferably a methyl group or an ethyl group;
  • Youyi is optionally substituted with phenyl, lower alkyl, or naphthyl, more preferably phenyl optionally substituted with halogen;
  • A is preferably an optionally substituted 5- to 6-membered monocyclic heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from N, 0, and S, and the optional substituent is selected from the group consisting of: Hydrogen, lower alkyl, lower alkenyl, lower block, lower alkoxy, lower alkenyloxy, amino, lower alkylamino, oxo, thio, halogen, aryl, aralkyl, aromatic heterocyclic group , Non-aromatic heterocyclic group, carboxyl group, lower alkoxycarbonyl group, hydroxyl group, sulfo group, nitro group, cyano group, nitroso group, cyano group, and azide group; more preferably an optionally substituted pyranyl group, furanyl group, Thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, furox
  • B-NCS Formula III In the formula, B is the same as described in (3) above.
  • the reaction is preferably performed in the presence of an inert solvent.
  • the pharmaceutical composition may further contain an anticholinergic agent, and the anticholinergic agent is preferably atropine.
  • a method for preventing or treating myopia comprising administering to a patient a therapeutically effective amount of the compound of the above (1), its N-oxide, its salt, its lipid, and its solvate or a pharmaceutical composition containing it .
  • a commercial kit comprising the compound of (1) above or a pharmaceutical composition containing the same, and it is recorded that the pharmaceutical compound or composition can be used or should be used in the treatment or prevention of myopia. Information on the composition.
  • Figure 1 illustrates iNOS-induced inhibition of iNOS induced by interleukin-1 ⁇ and the compound of Example 2
  • myopia in the present invention include curvature myopia, malignant myopia, progressive myopia, proactive myopia, simple myopia, median myopia, and high myopia and low myopia classified by the degree of myopia.
  • the classification of true myopia and pseudo myopia from the stage of myopia also includes related diseases caused by myopia, such as retinopathy, age-related speckle degeneration (AMD), and cataracts.
  • AMD age-related speckle degeneration
  • the semicarbazide derivative of the general formula (I) of the present invention is a novel anti-inflammatory agent as an interleukin-1 blocker.
  • the inventors have unexpectedly found that it can effectively treat or prevent myopia. Its mechanism of action may be related to blocking the induction of iNOS by interleukin-1 Relatedly, this blocking effect can continuously eliminate the production of excessive NO for a long time, and as a result, it is effective for preventing or treating myopia caused by excessive NO supply.
  • CI-C6 alkyl in the definition of R1 refers to a straight or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl Base, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2, 2 -Dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C1-C3 alkyl is preferred, for example methyl, ethyl, propyl, isopropyl and the like are preferred. More preferred are methyl and ethyl.
  • Such a CI-C6 alkyl group may also be substituted with the following groups, for example, lower alkenyl (such as vinyl, butenyl, and propenyl C2-C6 alkenyl, etc.), cycloalkyl (such as cyclopropyl, C3-C7 cycloalkyl, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), aryl (such as C6-C10 aryl such as phenyl, naphthyl, etc.), the aryl is optionally further substituted by hydroxy, methyl C1-C4 alkyl such as alkyl, ethyl, CI-C4 alkoxy substituted such as methoxy,
  • heteroatoms such as 1 to 4 nitrogen atoms, oxygen atoms, sulfur atoms, etc.
  • non-aromatic heterocyclic groups such as ethylene oxide, azetidinyl, oxetanyl, thietyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiaha 4- to 6-membered non-aromatic containing 1 to 3 nitrogen atoms, oxygen atoms, sulfur atoms, and other heteroatoms such as methyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl Heterocyclyl, etc.), amino, mono- or di-lower alkylamino (e.g.
  • methylamino Mono- or di-C1-C6 alkylamino groups such as ethylamino, dimethylamino, etc.
  • tri-lower alkylammonium groups such as trimethylammonium, triethylammonium, tripropylammonium, etc. tri-CI-C6 alkylammonium groups Etc.
  • amidino acyl (such as formyl, acetyl, propionyl, etc.
  • CI-C6 alkylacyl carbamoyl, mono- or di-lower alkylcarbamoyl (eg, methylcarbamoyl, ethyl Carbamoyl, dimethylcarbamoyl, mono- or di-C6-C6 alkylcarbamoyl, etc.), sulfamoyl, mono- or di-lower alkylsulfamoyl (eg, methylsulfamoyl, ethylsulfamoyl Mono- or di-CI-C6 alkylsulfamoyl groups such as acyl, dimethylsulfamoyl, etc.), carboxyl, lower alkoxycarbonyl groups (eg, CI-C6 alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl ), Hydroxyl, lower alkoxy (for example, CI-C6 alkoxy, such as methoxy,
  • C2-C6 Alkenyloxy, etc. cycloalkoxy (for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyl C3-C7 cycloalkoxy, such as cycloheptyloxy, etc.), aralkyloxy (eg, C7-C10 aralkyloxy, such as benzyloxy, phenethyloxy, etc.), aryloxy (eg, phenoxy C6-C10 aryloxy groups such as naphthyloxy, naphthyloxy, etc.), mercapto groups, lower alkylthio groups (for example, CI-C6 alkylthio groups such as methylthio, ethylthio groups, etc.), aralkyloxythio groups (For example, C7-C10 aralkylthio, such as benzylthio, phenethoxythio), arylthio (for example
  • C2-C6 alkenyl means a linear or branched alkenyl group containing 2 to 6 carbon atoms, and can be vinyl, allyl, propenyl, butenyl, pentenyl, hexadecyl Alkenyl, etc. These groups are optionally substituted with the same substituents as those described above for the lower alkyl group.
  • C2-C6 alkynyl means a straight or branched alkynyl group containing 2 to 6 carbon atoms, and examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. These groups are optionally substituted with the same substituents as those described above for the lower alkyl group.
  • the "monocyclic or polycyclic heterocyclic ring" in A refers to a 5-10 membered aromatic and non-aromatic monocyclic or polycyclic heterocyclic ring containing 1 to 4 identical or different atoms selected from N, 0 and S. Ring two.
  • aromatic monocyclic ring include pyran, furan, thiophene, pyrrole, pyrazole, pyrazole, triazole, oxazole, isoxazole, furazine, pyridine, pyrimidine, pyridazine, pyrazine, Triazine, oxazine, thiazole, isothiazole, etc.
  • non-aromatic monocyclic ring examples include pyrrolidine, thiazolidine, oxazolidine, imidazolidine, thiazoline, oxazoline, imidazoline, piperazine, morpholine, thiomorpholine, and oxaline Diazoline, dioxane, etc.
  • examples include benzothiophene, indole, benzothiazole, benzofuran, benzimidazole and the like.
  • a benzene ring, a pyrene ring, and a pyrazine ring are condensed on the aromatic monocyclic ring. , Pyridyl ring, pyrimidine ring and the like.
  • a 5- to 6-membered aromatic or non-aromatic single heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from N, 0, and S is preferred.
  • the group represented by A may be optionally substituted by: for example, hydrogen, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary CI-C6 straight or branched alkyl such as butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, etc., lower alkenyl (such as vinyl C2-C6 straight or branched alkenyl, such as propenyl, butenyl, etc.), lower alkynyl (eg Such as ethynyl, propynyl, butynyl and other C2-C6 straight or branched chain alkynyl, etc.), lower alkoxy (for example, methoxy, ethoxy and other CI-C6 alkoxy
  • aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1, 2, 3- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furoxanyl, 1,2,3-thiadiazolyl, 1,2,4-thia Diazolyl, 1,3,4- Diazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyridyl, triazinyl, etc.
  • aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
  • ethylene oxide azetidinyl, oxetanyl, thietyl, pyrrolidin, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl , Morpholinyl, thiomorpholinyl, piperazinyl, etc.
  • the number of the substituents is preferably 1-3, and when there are any substituents, they may be the same or different.
  • substituents of A are lower alkyl, oxo, thio, thiol, carboxyl, hydroxyl, and phenyl. More preferred are lower alkyl, oxo, thio, hydroxy, phenyl. Optimal examples include CI-C3 alkyl, oxo, hydroxyl, and phenyl groups such as methyl, ethyl, propyl, and isopropyl.
  • substituents of A are lower alkyl, oxo, thio, halogen, carboxyl, and hydroxyl. More preferred are lower alkyl, oxo, thio, and hydroxyl. Most preferred are CI-C3 alkyl, oxo, and hydroxyl groups such as methyl, ethyl, propyl, and isopropyl.
  • aromatic ring represented by B refers to a C6-C10 aryl group such as a phenyl group, a naphthyl group, and the like, preferably a benzyl group.
  • the group represented by B may be optionally substituted by, for example, hydrogen, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary CI-C6 straight or branched alkyl such as butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, etc., lower alkenyl (such as vinyl C2-C6 straight or straight alkenyl, such as propenyl, butenyl, etc., lower alkynyl (such as ethynyl, propynyl, butynyl, etc.
  • lower alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter
  • C2-C6 straight or straight chain alkynyl, etc. Lower alkoxy (for example, CI-C6 alkoxy, such as methoxy, ethoxy, etc.), lower alkoxy (for example, C2-C6 alkoxy, such as allyloxy, 2-butenoxy, etc.) Group, etc.), amino, lower alkylamino (such as methylamino, ethylamino, dimethylamino, mono- or di-CI-C6 alkylamino, etc., such as trimethylammonium, triethylammonium, tripropylammonium, etc.
  • Lower alkoxy for example, CI-C6 alkoxy, such as methoxy, ethoxy, etc.
  • lower alkoxy for example, C2-C6 alkoxy, such as allyloxy, 2-butenoxy, etc.
  • amino, lower alkylamino such as methylamino, ethylamino, dimethylamino, mono
  • non-aromatic heterocyclic groups such as ethylene oxide, azetidinyl, oxetanyl, thietane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene 4- to 6-membered non-aromatic groups containing 1 to 3 nitrogen atoms, oxygen atoms, sulfur atoms, and other heteroatoms such as methyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl Heterocyclyl, etc.), carboxyl, lower alkoxycarbonyl (for example, CI
  • the preferred substituents of B are ion, lower alkyl, more preferably element, and most preferably chlorine.
  • high myopia refers to myopia above 500 degrees, preferably myopia above 600 degrees, and "low myopia” refers to myopia below 500 degrees.
  • the term "compounds of the present invention” and equivalent expressions thereof include compounds of the general formula (I) in (1), (2), and (3) above, and when the context allows, This expression includes its N-oxides, the compound and its N-oxide salts, and esters and their solvates, such as hydrates.
  • “Compounds of the invention” also include their prodrugs.
  • a “prodrug” refers to a compound that can be metabolized (eg, hydrolyzed) in vivo to a compound of formula (I), including its N-oxide. For example, an ester of a compound of formula (I) containing a hydroxyl group can be converted into the parent molecule in vivo by hydrolysis.
  • Esters of compounds of formula (I) containing carboxyl groups can also be converted into the parent molecule in vivo by hydrolysis.
  • hydrolysis For clarity, special circumstances are sometimes indicated in the text when the context allows, but these are merely illustrative and not intended. Exclude other situations.
  • Bioelectronic isosteric acid refers to a group with chemical and physical similarities that can produce biological properties substantially similar to carboxyl groups (see Lipinski, Annual Reports in Medicinal Chemistry), 1986, 21 , Page 283), suitable bioelectronic isosteric acids include: sulfo, phosphono, alkylsulfonylcarbamoyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-formyl Oxycarbamoyl, or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl.
  • esters of compounds of formula (I) containing hydroxyl groups are, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate Acid ester, propionate, succinate, fumarate, maleate, methylene-di- ⁇ -hydroxynaphthoate, 2, 5-dihydroxybenzoate, hydroxyethylsulfonate Acid esters, di-p-toluoyl tartrate, mesylate, ethanesulfonate, benzylsulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • a base addition salt may be formed.
  • the bases which can be used in the preparation of the base addition salt preferably include those A base that can form a pharmaceutically acceptable salt when mixed with a free acid, which refers to a salt whose cation is non-toxic to the patient at the dosage of the salt, so that the beneficial inhibitory effect of the free base is not affected Interference from side effects caused by cations.
  • the pharmaceutically acceptable salts within the scope of the present invention include salts derived from alkali metal and alkaline earth metal salts, including salts prepared from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide , Lithium hydroxide, magnesium hydroxide, hydroxide, ammonia, ethylenediamine, N-methyl-glucosamine, lysine, arginine, ornithine, choline, N, N, -dibenzyl Ethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide, etc. .
  • Certain compounds of the invention are basic, and these compounds can be used in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acids useful in the preparation of acid addition salts preferably include those which can form a pharmaceutically acceptable salt when mixed with a free base.
  • the pharmaceutically acceptable salt refers to a salt whose anion is non-toxic to the patient at the dosage of the salt administered Thus, the beneficial inhibitory effect of free base is not disturbed by side effects caused by anions.
  • the pharmaceutically acceptable salts within the scope of the present invention include salts made from inorganic and organic acids, and thus include hydrohalides such as hydrochloride and hydrobromide, sulfates, phosphates, nitrates, ammoniasulfonic acids Salt, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, sub Methyl-di- ⁇ -hydroxynaphthoate, 2, 5-dihydroxybenzoate, isethionate, di-p-toluoyl tartrate, mesylate, ethanesulfonate, Benzene sulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
  • hydrohalides such as hydrochloride and hydrobromide
  • sulfates phosphates, nitrates, ammoniasul
  • the compound of the present invention may be a solvate, such as a hydrate.
  • the compound of the present invention has effective pharmacological activity, and therefore can be incorporated into a pharmaceutical composition.
  • the present invention also includes a drug containing at least one compound of the present invention, a pharmaceutically acceptable carrier or excipient, and / or other drugs. combination.
  • Other drugs refer to other drugs used to treat or prevent myopia, such as atropine and pirenzepine equal anticholinergic drugs, Youyi Atropine.
  • the compound or composition of the present invention can be administered by a suitable method. In practice, it can usually be administered parenterally, topically, rectally, orally, by inhalation or by implantation. Such as treatment of degenerative retinal damage in addition to local administration also requires systemic administration.
  • the composition can be solid such as tablets, pills, powders, granules, capsules, dragees, etc., semi-solid such as ointments, gels, etc., liquid formulations such as injections, solutions, suspensions Liquid formulations, syrups, eye drops, etc., and gas dosage forms such as inhalants, etc., are preferably unit dose forms of precise doses suitable for single administration.
  • eye drops In consideration of the effects on other circulatory systems and their effects, it is preferably used in the form of topical administration of the eye, and particularly preferred are eye drops, ophthalmic ointments, gels, and ophthalmic compositions, which are suitable for inserting into the scale
  • eye drops ophthalmic ointments, gels, and ophthalmic compositions, which are suitable for inserting into the scale
  • Dosage form for the ocular area of a blind tube (pocket-like area formed with the conjunctiva) such as a drug-impregnated solid carrier inserted into the eye
  • the preparations in the above-mentioned administration form can be added to the compound with necessary additives such as commonly used carriers, excipients, binders, and stabilizers, and the preparations can be prepared according to conventional methods.
  • the compound of the present invention is mixed with a carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, isotonicity agent, dissolution aid, etc.) that are allowed on the preparation.
  • ophthalmic compositions are in a form suitable for oral administration, parenteral, topical, rectal, inhalation or implantation.
  • additives such as sucrose, lactose, cellulose, D-mannitol, maltitol, dextran, starch, agar, arginine ester, chitin, chitosan, pectin, yellow Tannin, acacia, gelatin, collagen, casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, glycerin, Polyethylene glycol, sodium bicarbonate, magnesium stearate, talc, etc.
  • the tablets can be made into tablets that are usually coated, such as sugar-coated tablets, enteric-coated tablets, film-coated tablets or bilayer tablets, multilayer tablets, if necessary.
  • animal and vegetable oils oil, corn oil, castor oil, etc.
  • mineral oils mineral oils
  • waxes Silicones, carnauba wax, beeswax, etc.
  • Polyethylene mineral oil gel partially or fully synthesized glycerin fatty acid esters (lauric acid, myristic acid, palmitic acid, etc.).
  • an ointment base (petrolatum, lanolin, plastic base), a preservative (benzyl ammonium chloride, parabens, chlorobutanol, etc.) may be appropriately selected. And so on.
  • additives such as sodium chloride, glucose, sorbitol, glycerol, olive oil, propylene glycol, ethanol, and the like are used.
  • Liquid preparations include injections, eye drops, and the like.
  • sterile aqueous solutions such as physiological saline
  • isotonic solutions such as sesame oil, soybean oil
  • oily solutions such as sesame oil, soybean oil
  • appropriate suspending agents such as sodium carboxymethyl cellulose, non-ionic surfactants, and dissolution aids (such as benzyl benzyl benzate, benzyl alcohol), etc. can be used together when necessary.
  • an aqueous liquid or solution especially a sterile aqueous solution for injection
  • various additives such as a buffer, a stabilizer, a wetting agent, an emulsifier, a suspending agent, a surfactant, an isotonicity agent, a preservative, and a tackifier may be appropriately added.
  • a phosphate buffer for example, a borate buffer, a citrate buffer, a tartaric acid buffer, an acetate buffer, an amino acid, and the like can be used.
  • sodium ethylenediamine tetraacetate, citric acid, and the like can be used as the stabilizer.
  • wetting agents such as glycerin.
  • An emulsifier is, for example, polyvinylpyrrolidone.
  • suspending agent examples include hydroxypropyl methyl cellulose and methyl cellulose.
  • surfactant examples include Tween 80 and polyoxyethylene hydrogenated castor oil.
  • sugars such as sorbitol, glucose, and mannitol
  • polyhydric alcohols such as glycerin and propylene glycol
  • salts such as sodium chloride
  • quaternary ammonium salts such as benzyl ammonium chloride and benzylmethoxyammonium chloride
  • parabens such as methyl parahydroxybenzoate and ethyl parahydroxybenzoate
  • benzyl alcohol phenylethanol
  • sorbitol Acids and their salts thimerosal, chlorobutanol, etc.
  • pH adjusting agents such as sodium hydroxide, hydrochloric acid or sulfuric acid.
  • hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof can be used.
  • a suspension If a suspension is used, its particle size should be less than 10 ⁇ m to minimize eye irritation.
  • the pH is usually adjusted to about 3 to 9. 5, preferably to about 6 to 8. 5, most preferably the pH value close to tears, that is, pH 7.4 or so.
  • various polymers can be used as a carrier for formulating an ophthalmic drug. The following literature describes this type of polymer: (Saettone, MF, et al., J. Pharm. Pharmocol (1984) 36: 229, and Park, K. et al., In Recent Advances in Drug Delivery Systems.
  • Drug release is typically through a process of dissolution or biological digestion, infiltration of the polymer, or a combination thereof.
  • the composition is formulated so that the release rate of the drug does not significantly interfere with tear tension.
  • the system includes a hydrophilic soft contact spectacle lens impregnated or impregnated with a desired drug, and a biodegradable or soluble structure that does not need to be removed after being placed in the eye.
  • the dissolvable ocular inserts may be composed of any degradable substance that can be tolerated by the eye and is compatible with the drug being administered.
  • Such materials include, but are not limited to, poly (vinyl alcohol), polymers and copolymers of polyacrylamide, ethyl acrylate and vinyl pyrrolidone, and cross-linked polypeptides or polysaccharides, such as chitin.
  • a capsule-type delivery system can also be used in the present invention. These systems use polymer membranes to control the release of the drug.
  • the composition is particularly useful for the delivery of hydrophilic drugs. Hydrophobic drugs can be administered via a silicone rubber construct.
  • the amount of the compound of the present invention in the prevention or treatment of myopia is 0.01 to 100% by weight of the preparation, suitably 0.1 to 10% by weight.
  • the dosage and the number of administrations vary according to the symptoms, the number of administrations, the age, the weight, and the mode of administration.
  • the compound of the present invention 0.1 -10w / v%, preferably 0. 5-1.
  • ⁇ / ⁇ % Of the preparation several times per day, preferably 1-6 times, each time, preferably 1-3 drops.
  • the formulation containing 0.1-10 w / w%, preferably 0.5-l.
  • OwA ⁇ of the compound can be applied, several times a day, preferably 1-6 times.
  • the range of administration can be L- 20mg / kg, preferably 8-15mg / kg, most preferably about 10mg / kg, several times a day, preferably 1-6 times.
  • the effective dose for controlling myopia is usually in the range of 0.1- 20mg / kg / day range.
  • the system can be implanted after surgery to prevent myopia. To treat myopia, new implants are placed every 3-10 days until day 60. New implants are preferably implanted every 5-7 days until the 30th day.
  • the amount of anticholinergic drugs in the prevention or treatment of myopia is 0.03-0.25% by weight of the preparation, and the concentration is too low to achieve the corresponding effect; but if the concentration is too high, it will cause vegetative effects. Nerve side effects.
  • the invention also includes a method of preventing or treating myopia, which method comprises administering to a patient a therapeutically effective amount of a compound or composition of the invention.
  • the compounds of the present invention can be prepared by known methods or modified versions thereof, that is, currently used methods or methods described in the literature.
  • X when X is S, they can be synthesized in the organic synthesis (Kidhara, Y., etc.) (Oxidative heterocyclization using diethyl azodicarboxylate Synthesis 1020-1030, 1990,); when X is 0, it can be prepared according to the method of JP11153851, which is incorporated herein by reference in its entirety.
  • the above reaction can be carried out in the presence or absence of a solvent, preferably in the presence of an inert solvent, and the solvent used is not limited as long as it is affectionate to the reaction without other side effects.
  • inert solvents include: Alcohols (methanol, ethanol, n-propanol, isopropanol, ethylene glycol, 2-methoxyethanol, etc.), acids (di- B ' Alkanes, tetrahydrofuran, diethyl ether, etc.), esters (ethyl acetate, ethyl acetate, n-butyl acetate, etc.), hydrocarbon generation (dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.) , Hydrocarbons (n-hexane, benzyl, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (ace
  • the acid addition salts of the compounds of the present invention can be prepared by reacting the free base with a suitable acid using known methods.
  • the acid addition salt of a compound of the present invention can be prepared by dissolving the free base in water or an aqueous alcohol solution or other suitable solvent containing a suitable acid and evaporating the solution to separate the salt, or by dissolving the free base and the acid in It is prepared by reaction in an organic solvent, in which case the salt can be isolated directly or the salt can be obtained by concentrating the solution.
  • the base addition salt of the compound of the present invention can be prepared by reacting a free acid with a suitable base by a known method.
  • the base addition salt of a compound of the present invention can be prepared by dissolving the free acid in water or an aqueous alcohol solution or other suitable solvent containing a suitable base and evaporating the solution to separate the salt, or by dissolving the free acid and base in It is prepared by reaction in an organic solvent, in which case the salt can be isolated directly or the salt can be obtained by concentrating the solution.
  • the compound of the present invention can be conveniently made or formed into a solvate, such as a hydrate.
  • a solvate such as a hydrate.
  • the hydrate of the compound of the present invention can be conveniently prepared by recrystallization in a water / organic solvent mixture using an organic solvent such as dioxane, tetrahydrofuran or methanol.
  • the starting materials and intermediates can be obtained commercially or prepared by known methods (Kihara, Y. et al., Synthesi s 1020-1030, 1990).
  • Kihara Yamahara, Y. et al., Synthesi s 1020-1030, 1990.
  • the present invention will be described in detail through examples, preparation examples and test examples, but the present invention is not limited by the examples, preparation examples and test examples.
  • Example 1 The compound of Example 1 was dissolved in distilled water for injection, and the pH was adjusted to 7 with sodium hydroxide. An eye drop was prepared according to the following formulation.
  • Example 1 lactose, corn starch, and crystalline cellulose were mixed, kneaded with a polyvinylpyrrolidone K30 paste, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, it was passed through a 24 mesh sieve, mixed with talc and magnesium stearate, and a punch with a diameter of 7 mm was used to make 120 mg tablets.
  • Example 1 lactose and corn starch were mixed, kneaded with polyvinylpyrrolidone K30 paste, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, it was passed through a 24-mesh sieve, mixed with talc and magnesium stearate, and filled into a hard gelatin shell (No. 4) to obtain 120 mg of gel tincture.
  • Retinal pigment epithelial cells (RPE cells, purchased from American Tissue and Cell Collection) and interleukin-1 ⁇ (100ng inl, Sigma Chemical) or carrier or interleukin-1 ⁇ (100ng / ml, S igma Chemical) and the compound of the present invention (100ng / ml)
  • RPE cells Retinal pigment epithelial cells
  • interleukin-1 ⁇ 100ng inl, Sigma Chemical
  • carrier or interleukin-1 ⁇ 100ng / ml, S igma Chemical
  • the compound of the present invention 100ng / ml
  • the membrane was blocked by co-incubation at room temperature with a 5% blocking solution (purchased from Amersham) prepared in Tris-buffered saline (TBS-T) containing 0.1% Tween-20. 60 minute. After the blocking solution was washed away in TBS-T, it was incubated with the anti-iNOS polyclonal antiserum (from cytokine-induced murine phagocytes, Cayman Chemical) to incubate the measured concentrated state at room temperature for 60 years. Minutes to probe the iNOS protein on the membrane.
  • a 5% blocking solution purchased from Amersham
  • TBS-T Tris-buffered saline
  • this membrane was bound with a peroxide-labeled goat anti-rabbit secondary antibody (purchased from Bio-Rad) to The measured concentrated state was incubated at room temperature for a total of 60 minutes. Then, the ECL Western Blot Detection Kit (purchased from Amersham) was used, and the film was exposed to X-ray film by chemiluminescence, and the protein bands on the film were observed.
  • a peroxide-labeled goat anti-rabbit secondary antibody purchased from Bio-Rad
  • the compound of the present invention, particularly the compound of Example 2 showed a significant blocking effect on IL- 1 ⁇ -induced iNOS, and the production of iNOS protein was inhibited by the compound of Example 2 (see Figure 1).
  • RPE cells purchased from American Tissue and Cell Collection
  • interleukin-1 ⁇ 100ng / ml, Sigma Chemical
  • carrier or interleukin 1 100ng / ml, Sigma Chemical
  • the compound of the present invention 100ng / ml.
  • the culture medium was removed, and the nitrate / nitrite colorimetric detection kit (purchased from Cayman Chemical) was used to measure the content of nitrogen oxide in the culture medium according to the procedures of its instructions.
  • the compound of the present invention has a significant blocking effect on iNOS induction.
  • This blocking effect can continuously eliminate the production of a large amount of N0 for a long time, and for myopia caused by excessive production of N0 , Especially high myopia has a good effect.
  • age-related speckle variability (AMD) and cataracts are effective for retinopathy caused by myopia.
  • the compound of the present invention has an induced blocking effect on iNOS.
  • This blocking effect can continuously eliminate a large amount of NO produced for a long time, and has a good effect on myopia caused by excessive NO production. Therefore, the compound of the present invention or The composition can be effectively used as a preventive or therapeutic agent for various myopia or myopia-related diseases, such as curvature myopia, malignant myopia, progressive myopia, proactive myopia, simple myopia, median myopia, and from the degree of myopia Divided high myopia, low myopia, true myopia, false myopia and so on. In addition, it also includes retinopathy from myopia to severe cases, age-related speckle degeneration (AMD), and cataracts. Among them, the effect on high myopia is particularly remarkable.
  • AMD age-related speckle degeneration

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Abstract

L'invention concerne la formule (I) dans laquelle R1 désigne un hydrogène sélectionné dans le groupe alkyle C1-C6 ; X désigne un atome d'O ou de S ; A désigne entre 5 et 10 mono- ou poly-hétérocycles à chaîne contenant entre 1 et 4 atomes identiques ou différents sélectionnés dans le groupe constitué par N, O et S ; et B désigne un noyau aromatique. L'invention concerne également un dérivé de semi-carbazide, son procédé de préparation, une composition pharmaceutique contenant ledit dérivé, les applications dudit dérivé lors de la préparation de la composition pharmaceutique indiquée pour le traitement ou la prévention de la myopie, les méthodes thérapeutiques et prophylactiques et les comprimés à vendre contenant ce dérivé. Les composés de cette invention sont efficaces dans le traitement et la prévention de la myopie.
PCT/CN2000/000284 2000-09-20 2000-09-20 Inhibiteur de la no synthetase inductible (inos) utilise pour le traitement ou la prevention de la myopie WO2002024250A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN00815738A CN1399547A (zh) 2000-09-20 2000-09-20 iNOS抑制剂用于治疗或预防近视眼
AU2000275033A AU2000275033A1 (en) 2000-09-20 2000-09-20 Use of inos inhibitors for treating or preventing myopia
PCT/CN2000/000284 WO2002024250A1 (fr) 2000-09-20 2000-09-20 Inhibiteur de la no synthetase inductible (inos) utilise pour le traitement ou la prevention de la myopie

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2000/000284 WO2002024250A1 (fr) 2000-09-20 2000-09-20 Inhibiteur de la no synthetase inductible (inos) utilise pour le traitement ou la prevention de la myopie

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WO2002024250A1 true WO2002024250A1 (fr) 2002-03-28

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AU (1) AU2000275033A1 (fr)
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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KIHARA YOSHITO ET AL., SYNTHESIS, no. 11, 1990, pages 1020 - 1023 *

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