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WO2001077082A1 - Derives de naphtalene - Google Patents

Derives de naphtalene Download PDF

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Publication number
WO2001077082A1
WO2001077082A1 PCT/JP2000/002278 JP0002278W WO0177082A1 WO 2001077082 A1 WO2001077082 A1 WO 2001077082A1 JP 0002278 W JP0002278 W JP 0002278W WO 0177082 A1 WO0177082 A1 WO 0177082A1
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WIPO (PCT)
Prior art keywords
methyl
naphthyl
group
hydroxy
compound
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PCT/JP2000/002278
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English (en)
Japanese (ja)
Inventor
Hiroshi Ashizawa
Hiroyuki Uchiyama
Atsushi Midorikawa
Hiroyuki Kawamura
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Torii Pharmaceutical Co Ltd
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Torii Pharmaceutical Co Ltd
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Priority claimed from PCT/JP1999/002938 external-priority patent/WO2000031045A1/fr
Application filed by Torii Pharmaceutical Co Ltd filed Critical Torii Pharmaceutical Co Ltd
Priority to AU36737/00A priority Critical patent/AU3673700A/en
Publication of WO2001077082A1 publication Critical patent/WO2001077082A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a naphthalene derivative having a fibrinolysis-promoting action and useful as a thrombolytic agent and an antithrombotic agent.
  • the blood coagulation system acts as a defense mechanism to prevent bleeding, and forms a hemostatic thrombus at the damaged site.
  • the fibrinolytic system that dissolves thrombus formed in blood vessels and keeps blood flow.
  • t-PA tissue plasminogen activator
  • plasminolysis As a plasminogen activator (PA) other than t-PA, perokinase-type plasminogen activator (u-PA) is known to be present in blood vessels. Dissolution of this thrombus must occur at the appropriate time. If the thrombus dissolves too early, it causes bleeding, and if it is too late, the thrombus increases, resulting in narrowing or occlusion of blood vessels.
  • PA plasminogen activator
  • u-PA perokinase-type plasminogen activator
  • the homeostasis of the living body is maintained by this delicate balance between the coagulation system and the fibrinolysis system.
  • this delicate balance is lost and the coagulation system leans, it becomes easily thrombotic and produces thrombi.
  • the blood clot narrows or blocks the blood vessel, The underlying tissue causes severe ischemic damage, such as myocardial infarction, stroke, angina, pulmonary embolism, and disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • thrombolytic therapy Fabrinolytic therapy
  • the thrombolytic agents used in this fibrinolytic therapy include in vivo substances such as perokinase (UK) and t-PA, bacterial cell producing substances such as streptokinase (SK) and staphylokinase (SAK), and their genes. Recombinants and the like are known.
  • thrombolytic drugs are all protein preparations, they have a short half-life in blood, are rapidly metabolized in the liver, and have thrombus in the body due to the presence of inhibitors in the body.
  • large dose administration is required. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate.
  • a transient large-volume administration of a thrombolytic agent significantly enhances the thrombolytic activity systemically, resulting in thromboembolic sites. Is expected to be opened, but serious side effects of bleeding are observed.
  • the embolization site is temporarily opened by administration of these thrombolytic agents, reocclusion tends to occur easily, which is a major problem.
  • the method of administration used for treatment is intravenous systemic administration or intracoronary administration, and since it is directly administered into blood vessels, there is a problem that long-term administration requires a large burden on patients. . Therefore, development of orally administrable thrombolytic agents based on a new mechanism of action is desired.
  • this compound is different from that of the compound of the present invention in the 2-position substituent on the naphthalene ring and the 5-position substituent on the pyrimidin ring.
  • Dot Patent No. 1974484339 discloses that the following compound is used as a liquid crystal composition.
  • this compound is different from that of the compound of the present invention in the 1-position substituent of the naphthalene ring.
  • JP-A-9-1202749 discloses that the following compound is used as a liquid crystal composition.
  • this compound differs from that of the present invention in the 5-position substituent on the pyrimidine ring.
  • JP-A-9-140595 discloses that the following compound is used as a liquid crystal composition.
  • JP-A-9-171578 discloses that the following compound is used as a liquid crystal composition.
  • this compound is different from that of the compound of the present invention in the 5-position substituent on the pyrimidine ring as in the above (6).
  • Japanese Patent Application Laid-Open No. 9-110837 Japanese Patent No. 7511133, U.S. Pat.
  • This compound is different from that of the compound of the present invention in the 2-position alkoxy group of the naphthalene ring and the 5-position substituent of the pyridine ring.
  • JP-A-7-150142 discloses the following compound as a liquid crystal composition:
  • this compound is different from that of the compound of the present invention in the 2-position alkoxy group of the naphthalene ring.
  • this compound is different from that of the compound of the present invention in the 2-position alkoxy group on the naphthalene ring and the 5-position substituent on the pyrimidine ring.
  • JP-A-6-122648 discloses that the following compound is used as a liquid crystal composition.
  • this compound is different from that of the compound of the present invention in the 2-position alkoxy group of the naphthalene ring and the 5-position alkoxy group of the pyrimidine ring.
  • JP-A-6-228057 discloses the following compounds
  • JP-A-6-25102 discloses that the following compound is used as a liquid crystal composition.
  • the compound differs from the compound of the present invention in the 2-position alkoxy group of the naphthalene ring and the 5-position alkoxy group of the pyrimidine ring.
  • JP-A-6-25060 discloses the following compounds
  • JP-A-60-146877 discloses a general formula
  • the compound is different from that of the compound of the present invention in the 5-position substituent on the pyrimidine ring.
  • WO 951 9358 (Patent No. 739341) Is the following compound as a herbicide
  • An object of the present invention is to provide an antithrombotic agent and a thrombolytic agent which have a fibrinolysis promoting action and can be orally administered.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the following naphthalene derivatives have an excellent fibrinolysis-promoting action and are extremely useful as antithrombotic agents and thrombolytic agents. That is, the present invention provides a compound represented by the following [1] to [27], a salt compound thereof, a solvate thereof, a pharmaceutical composition containing them as an active ingredient, an antithrombotic agent, a thrombolytic agent and It relates to a fibrinolysis accelerator.
  • a naphthalene compound represented by the following general formula (1) substituted with a pyrimidyl group or a 1-methyl-hydantoyl group, a salt thereof, or a solvate thereof.
  • R 1 a is
  • R 1 b represents a C 9 alkyl group
  • R 1 c and Rld are the same or different
  • Ring A is a pyrimidyl group or a 1-methyluhydantoin group represented by the following general formulas a to c:
  • iii a mono- or dihydroxy-substituted Ci- 6 alkyl group, or a C- 6 alkyl group substituted with a 6-alkoxy group (the alkoxy group is substituted with a Ci-6 alkoxy group-substituted Ci-6 alkoxy group; may be), iv) Futaruimi de group, morpholino groups, C E _ 9 alkyl group substituted with a heterocyclic group selected from pyridyl group, and a piperidino group,
  • R z 3 and R z 4 are the same or different
  • R 10 represents an oxygen atom or one NH—
  • R 1 1 is, C ⁇ substituted with CJ- 6 alkoxycarbonyl group - means an alkyl group.
  • C — means a 6 alkyl group
  • d. means an amidino group
  • R 9 represents a C i-e alkyl group which may be amino-substituted.
  • R1 is a hydroxyl group or a hydroxyl group or Ci—eAk—R1a
  • R2 is a hydrogen atom
  • R5 is a methyl group
  • R6 is a hydroxyl group or a hydroxyl group or 1—O—C—e
  • R 1 is a hydroxyl group or —O—C— 6 Ak—R 1a
  • R2 is a hydrogen atom
  • R 7 is a hydroxyl group, an amino group or one O—C— 6 Ak—R z 1 9.
  • CJ _ 6 Ak, R 1 a and R z 1 is Ru der agree with that in the item [1].
  • R 1 is a hydroxyl group or - O-C ⁇ - 6 AK- first [1 2] naphthalene compound according to claim is R 1 a, a salt thereof, or a solvate.
  • the ring A1 is a pyrimidine ring A1-1 represented by the following general formula (10),
  • R 1 is a hydroxyl group or a O-C ⁇ - 6 AK- a R 1 a
  • R 2 is a hydrogen atom
  • R 5 is a methyl group
  • R6 is hydroxyl or - O-C ⁇ - 6 AK- first
  • naphthalene compound according to claim which is Rz 1, a salt thereof, or a solvate.
  • the compound is 2- (6-hydroxy-1-naphthyl) -1-6-methylpyrimidine-14-ol, methyl 2- (6-hydroxy-11-naphthyl) -16-methyl-4_pyrimidinyl
  • the naphthalene compound according to item [16] which is xyacetate or 2- (6-hydroxy-1-naphthyl) -6-methyl-4-pyrimidinyloxyacetic acid, a salt thereof, or a solvate thereof.
  • R 2 and Ry are both hydrogen atoms, R 1 is a hydroxyl group or 1 O—di— 6 Ak—R 1a, and R z is a hydroxyl group or —O—C— 6 A k _ R [18]
  • R 1 Gar O- Ji ⁇ - 6 AK- R 1 a (C ⁇ - means of 6 A k and R 1 a are as defined above) and, R2 is a hydrogen atom, a [21] The naphthalene compound according to the above, a salt thereof or a solvate thereof.
  • the compound is 1-methyl-1-methoxycarbonylmethyl-5- (6-methoxycarbonylmethoxy-2-naphthylmethylene) hydantoin or 1-methyl-13-methoxycarbonylmethyl-5_ (6-methyl
  • the naphthalene compound according to item [22] which is toxinylcarbonyl-2- (2-naphthylmethylene) hydantoin_2- ⁇ T mid, a salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising, as an active ingredient, the naphthalene compound according to any one of [1] to [23], a salt thereof, or a solvate thereof.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the “rCi-e alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, and hexyl group. Preferably, it is a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
  • “Ci- 9 alkyl group” means a linear or branched alkyl group having 1 to 9 carbon atoms.
  • C 2 6 alkenyl group means a straight-chain or branched alkenyl group having a carbon number of 2 to 6 having one double bond, specifically, Piniren group, Ariru group, 2- Mechirubi Examples include a diene group and a butyr group. Preferably, it is a straight-chain or branched alkenyl group having 2 to 4 carbon atoms.
  • alkoxy group "means a straight or branched an alkoxy group having 1 to 6 carbon atoms, specifically, main butoxy group, an ethoxy group, a propoxy group, iso epoxy group, butoxy group, isobutoxy Groups, sec-butoxy group, tert-butoxy group, pentoxy group, and hexoxy group.
  • Preferred is an alkoxy group having 1 to 4 carbon atoms which may be linear or branched.
  • C ⁇ 6 alkoxycarbonyl group means a alkoxycarbonyl two Le group having a straight-chain or branched C ⁇ _ 6 alkoxy groups above-described carbon number 1 to 6, specifically, main Toxoxycarbonyl group, ethoxycarbonyl group, propoxycarbo And a tert-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentoxycarpoxy group, a hexoxycarpoxyl group, and the like.
  • it is an alkoxycarbonyl group having a straight-chain or branched alkoxy group having 1 to 4 carbon atoms.
  • Ak — 6 alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms, specifically, methylene, ethylene, propylene, isopropyl Examples include a propylene group, a butylene group, an isobutylene group, a sec-butylene group, a tert-butylene group, a pentylene group, and a hexylene group. Preferably, it is a linear or branched alkylene group having 1 to 4 carbon atoms.
  • amino group substituted C i - 6 alkyl group a mono- or current events 1 - 6 alkylamino substituted Ji ⁇ - 6 alkyl group
  • 1 to 3 preferably one amino group, mono C j- 6 alkyl substituted with 6 alkylamino group - amino group or a di C ⁇
  • C-6 alkyl group and the substitution position of these amino groups with respect to the alkyl group may be arbitrary. Examples include an aminomethyl group, a 2-aminoethyl group, a 3-aminopropyl group, a methylaminomethyl group, a dimethylaminomethyl group and the like.
  • C i _ 6 alkyl group substituted by a carboxy group preferably intended to mean a single force Rubokishi C i-e alkyl group substituted with a group, substituted carboxyl groups to the alkyl group
  • the position is arbitrary.
  • a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group and the like can be mentioned.
  • Ci- 6 alkyl group refers to a C1-ealkyl group having 1 to 6 carbon atoms, which is substituted with one or two hydroxy groups. For example, a 2-hydroxyhydroxyl group And 2,3-dihydroxypropyl group.
  • C is C i _ 6 alkyl group was substituted with 6 alkoxy group
  • C E such as the - C ⁇ of 6 carbon atoms substituted with an alkoxy group 1 to 6 - a 6 alkyl group, for example, A methoxymethyl group and a 2-methoxyl group.
  • C ⁇ - 6 alkoxycarbonyl group substituted C ⁇ - 6 alkyl group and, C-mentioned upper Symbol of C i-6 alkoxy carbon atoms substituted with a carbonyl group 1 to 6 - be a 6 alkyl group For example, a methoxycarbonylmethyl group.
  • the "Futaruimi de group, morpholino group, a pyridyl group or CI_ 9 alkyl group substituted with a piperidino group” is a linear or branched C i-9 alkyl group substituted by these heterocyclic rings, more specifically Examples thereof include a methyl group, an ethyl group, a propyl group, an octyl group, a nonanyl group, an isopropyl group, an isobutyl group, a t-butyl group and the like.
  • the "one N (R z 3) C ⁇ _ 6 alkyl group substituted with (R z 4)", as defined above - N (R z 3) carbon atoms substituted with (R z 4) It is a straight-chain or branched Ci-e alkyl group of 1 to 6, and examples thereof include an aminomethyl group and a dimethylaminoethyl group.
  • the “Ci- 6 alkyl group substituted by one CO_N (Rz 3) (Rz 4)” also has 1 to 6 carbon atoms substituted by one CO—N (Rz 3) (Rz 4). Is a linear or branched C i-6 alkyl group.
  • C ⁇ -6 alkoxycarbonyl-substituted C ⁇ - 6 alkylcarbonyl group is the above-mentioned C - C is substituted with 6 alkoxycarbonyl group - a 6 alkylcarbonyl group, e.g., 2- (2- Methoxycarbonyl) ethoxycarbonyl group and the like.
  • the “C- 6 alkoxycarbonyloxy group” is an alkoxycarbonyloxy group having a C- 6 alkoxy group such as a methoxycarbonyloxy group.
  • C 2 - 6 Arukeniruokishi group is meant Arukeniruokishi group having a straight-chain or branched alkenyl group having 2 to 6 carbon atoms having one double bond, specifically, Ariruokishi And the like.
  • amino protecting group is a substituent for protecting an amino group, and is a commonly used protecting group.
  • a t-butoxycarbonyl group called Boc
  • And benzyloxycarbonyl group is a substituent for protecting an amino group.
  • R 1 examples include a hydroxyl group, a carboxy group, one O-C! _ 6 Ak-R 1 a, and -CO-N (R 1 c) (R 1 d), which are particularly preferable. More specifically, a hydroxyl group is 1 O— 6 Ak—R la, and a particularly preferred example of R la is a carboxy group, —COORlb.
  • R2 is a hydrogen atom.
  • Preferred as ring A is ring A1, and particularly preferred is ring A1-1.
  • Preferred substituents Rx, Ry and Rz of the pyrimidyl group are listed below.
  • Rx is an alkyl group, particularly a methyl group
  • Ry is preferably a hydrogen atom, a carboxy group, an amidino group, or the like.
  • R z is a hydroxyl group, an amino group, or 1 O—. ⁇ - 6 Ak- R zl, but and the like, in particular rather preferably has a hydroxyl group, one O-C - a 6 Ak- R z 1.
  • R zl examples include a carboxy group, one COORz 2 and one N (R z 3) (R z 4).
  • R1, R2, Rx, Ry, and Rz in the present invention are not necessarily limited to the substituents exemplified above, and various other preferable substituents are present. What can be done will be clear from the description of various examples and test examples in the specification of the present application. This will be easily understood by those skilled in the art.
  • the compound represented by the formula (1) of the present invention more specifically, the compounds represented by the formulas (2), (3), (7), (8), (9), (11), (12) and (13) ) Can be converted to a pharmacologically acceptable salt, if necessary, or the resulting salt can be converted to a free base or a free acid. Further, those compounds may be solvates. Salts include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, and amino acid addition salts.
  • acid addition salts include inorganic acid salts such as hydrochloride, phosphate, sulfate, etc., and organic acid salts such as acetate, citrate, methanesulfonate, etc., and metal salts such as sodium salt And alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and the like, aluminum salts and the like, ammonium salts such as ammonium salts, and morpholine as organic amine salt addition salts.
  • Addition salts such as piperidine; and amino acid addition salts include addition salts such as glycine and lysine. I can do it. Examples of the solvates include hydrates.
  • tautomers of the pyrimidine derivative and any tautomers are the compounds of the present invention.
  • the position of ring A in formula (1) is not particularly limited, and may be any of positions 5 to 8, but is preferably position 6.
  • R 15 represents a lower alkoxycarbonyl group, a lower acyl group or a cyano group
  • Ri 6 represents a hydrogen atom, a lower alkoxyalkenyl group or a lower alkyl group which may have a substituent.
  • R17 represents a lower alkyl group
  • R18 and R20 may be the same or different, and represent a hydrogen atom, a lower alkyl group, an amino group or a hydroxyl group
  • R19 is a hydrogen atom A lower alkyl group, a lower alkoxycarbonyl group or a cyano group which may have a substituent
  • R 1 and R 2 are as described above.
  • a general synthesis method of a pyrimidine derivative a pyrimidine synthesis method of P inner [GW Kenner, Sir A. To dd, "Py rimidine and Its Derivatives, in RC
  • j3-diketone derivative and The pyrimidine derivative can be produced by conducting the substituted amidine derivative in the presence or absence of a suitable base in a solvent or without solvent at room temperature to 150 ° C.
  • a suitable base in a solvent or without solvent at room temperature to 150 ° C.
  • the [3-diketone] to be used there can be used] 3-ketoaldehyde,] 3-dialdehyde, ⁇ -ketoester, —dicarboxylic acid or an equivalent thereof.
  • the compound represented by the formula (16) can be produced by reacting with a substituted) 3-diketone equivalent represented by the formula (14) in the presence of a base.
  • a substituted) 3-diketone equivalent represented by the formula (14) for example, when 6-amidino-12-naphthol is used as the compound represented by the formula (15) and ethyl acetoacetate is used as the compound represented by the formula (14), the compound represented by the formula (16) is 6-Hydroxy-12-naphthyl) 1-methylpyrimidin-4-ol is obtained.
  • the obtained 2- (6-hydroxy-1-naphthyl) -1-6-methylpyrimidin-4-ol is interchangeable with 2- (6-hydroxy-12-naphthyl) -1 3H-6-methylpyrimidin-4-one.
  • the pyrimidine derivative described in the present invention shows both tautomers unless otherwise specified.
  • the base referred to herein is an inorganic base such as sodium, alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, sodium hydroxide or the like, or an organic base such as triethylamine or pyridine.
  • the base described in the present invention is the same as described above unless otherwise specified.
  • a pyrimidine derivative represented by the formula (16) can be synthesized.
  • the functional groups represented by Rl, R2, Rl8, Rl9 and R20 are It can be converted to other functional groups by known methods.
  • a hydroxyl group is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride in an appropriate solvent or without a solvent in the presence or absence of a base such as triethylamine or pyridine.
  • a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride in an appropriate solvent or without a solvent in the presence or absence of a base such as triethylamine or pyridine.
  • a base such as triethylamine or pyridine.
  • it can be converted to a substituted or unsubstituted lower alkoxy group by reacting with a substituted or unsubstituted
  • the compound can be converted to a hydroxysulfonyloxy group by reacting with an io-N, N-dimethylformamide complex in an appropriate solvent.
  • the cyano group is determined by the Pinner method [R. Roger, D. Nei 1 son, Chem. Rev. 61, 179 (1961)]. ] Can be converted to an amidino group.
  • the alkoxycarbonyl group can be converted into a carboxyl group by reacting with an appropriate base, for example, a base such as sodium hydroxide or hydroxylated lime in an appropriate solvent.
  • the carboxyl group can be formed in an appropriate solvent in the presence or absence of additives such as 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole hydrate (HOBt), p-ditrophenol, and triethylamine.
  • DMAP 4-dimethylaminopyridine
  • HOBt 1-hydroxybenzotriazole hydrate
  • p-ditrophenol p-ditrophenol
  • triethylamine triethylamine
  • 1- (3-dimethylaminopropyl) _ 3 _ethylcarposimid 'hydrochloride (WS C ⁇ HC 1), N, N, -dicyclohexylcarbodiimide (DCC), benzotriazole
  • condensing agents such as 1-yloxy-tris- (dimethylamino) phosphonium hexafenoleo-phosphate (BOP reagent), 2-iodine-1-methyl-pyridinium, diphenylphosphoryl azide and amino derivatives
  • BOP reagent 1-yloxy-tris- (dimethylamino) phosphonium hexafenoleo-phosphate
  • 2-iodine-1-methyl-pyridinium diphenylphosphoryl azide and amino derivatives
  • the substituted or unsubstituted amino group can be converted to the corresponding amide compound by reacting with a condensing agent and a carboxylic acid derivative in a suitable
  • the above conversion can also be performed on a compound represented by the formula (15), which is a precursor of the pyrimidine derivative (formula (16)).
  • a compound represented by the formula (15) which is a precursor of the pyrimidine derivative (formula (16)).
  • Each functional group may be protected with an appropriate protecting group in advance. Methods for introducing and removing protecting groups commonly used in synthetic organic chemistry are described in, for example, T.W.
  • R4 represents a hydroxyl group or one OCH2COO—R14 (R14 represents a hydrogen atom or a lower alkyl group))
  • the compounds represented by the formulas (19) and (22) are both naphthoic acid derivatives
  • the compounds represented by the formulas (19) and (22) can also be produced by using the Pinner method.
  • the compound represented by the formula (19) or (22) can be converted into various pyrimidine derivatives by the method shown in scheme A.
  • R 22 represents a halogen or a trifluoromethanesulfonyloxy group
  • R 23 and R 24 are the same or different and each represents hydrogen, cyano, Represents a substituted or unsubstituted lower alkyl group or lower alkoxycarbonyl group
  • the compound represented by the formula (25) can be produced by carrying out a Heck reaction using the method described in Chickester, 1995.
  • 6-cyano-12-naphthyl trifluoromethanesulfonate is used as the compound represented by the formula (23) and methyl acrylate is used as the compound represented by the formula (24)
  • methyl 3 is used as the compound represented by the formula (25).
  • 6-Cyanol 2-naphthyl) Atarilate is obtained.
  • the compound represented by the formula (25) will have an alkenylcarboxylic acid having 4 or 5 carbon atoms, respectively.
  • a 6-cyanonaphthalene derivative into which an alkyl ester has been introduced can be produced.
  • the obtained compound represented by the formula (24) can be converted into various pyrimidine derivatives after converting a cyano group into an amidino group by the methods shown in schemes A and B.
  • the above method is an example, and other known methods can be used.
  • R 25 is a substituted or unsubstituted lower alkyl.
  • R22 is as defined above
  • R23 and R24 are as defined above in formula (27), wherein R23 and R24 are as defined above.
  • a compound represented by the formula (27) can be produced by using the same synthesis method as the compound represented by the formula (25). For example, using the 6-promo-2-naphthol derivative as the compound represented by the formula (26) and acrylonitrile as the compound represented by the formula (24), the Heck reaction is used to obtain the compound represented by the formula (27).
  • the thus obtained compound (27) in which R 23 or R 24 is a cyano group can be converted into various pyrimidine derivatives after converting the cyano group into an amidino group by the above-mentioned P inner method.
  • R23 or R24 is a substituent other than a cyano group
  • the substituent is converted to a cyano group by a known method and then amidinated, or a carboxy group or a carboxy group.
  • the desired pyrimidine derivative can be easily obtained by converting it to a rubamoyl group and then amidinating it according to the scheme B method.
  • R 25 when R 25 is a hydrogen atom, the ability to protect the hydroxyl group with the protecting group described in Scheme A, in an appropriate solvent in the presence of an organic base such as triethylamine or pyridin, or in the presence of lithium carbonate or carbonate
  • an organic base such as triethylamine or pyridin
  • lithium carbonate or carbonate After reacting with a substituted lower alkyl halide in the presence of an inorganic base such as sodium to give an etherified compound, a Heck reaction can also be used.
  • an organic base such as triethylamine or pyridin
  • lithium carbonate or carbonate After reacting with a substituted lower alkyl halide in the presence of an inorganic base such as sodium to give an etherified compound, a Heck reaction can also be used.
  • the above method is an example, and other equivalent known methods can also be used.
  • R 26 represents a lower alkyl group having a substituent
  • Ri i is as described above
  • Rl 0 is As described above
  • a suitable solvent for example, a solvent such as DMF, methanol, ethanol, dimethylsulfoxide, and ethyl acetate, or a mixed solvent
  • a suitable base is dissolved. Heating in the presence gives the compound of formula (30).
  • 1-methylhydantoin is used as the compound represented by the formula (29)
  • 5- (6-hydroxy-2-naphthylmethylene) -11-methylhydantoin is obtained as the compound represented by the formula (30). .
  • Equation (31) a substituted alkyl halide in an organic solvent such as DMF or acetone in the presence of a suitable base, thereby introducing a compound having an alkyl group having a substituent at the corresponding R11 and R26.
  • Equation (31) can be produced.
  • 1-methyl-13-methoxycarbonylmethyl 5- (6-methoxycarbonylmethyl-12-naphthylmethylene) hydantoin (Formula (31)) Is obtained.
  • the above method is an example, and other known methods can be used.
  • compositions containing a naphthalene derivative represented by the general formula (1) and a salt thereof or a solvate thereof as an active ingredient, which are produced as described above, are usually administered to a mammal (including a human patient) in the form of tablets, It can be administered as an oral preparation such as capsules, powders, fine granules and syrups, a rectal preparation, or an injection. Further, the compound of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. Although they may be administered alone, they are generally administered in the form of a pharmaceutical composition. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives.
  • Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or the like, or may be presented as a dry syrup prepared with water or other suitable solvent before use. good. Said solutions may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository.
  • Suppositories are based on suitable substances such as cocoa butter, lauric fat, macrogol, grease mouth gelatin, witetbsol, sodium stearate or a mixture thereof, and may contain emulsifiers, suspending agents if necessary. Preservatives can be added. Injectables are soluble or dissolution aids such as distilled water for injection, physiological saline, 5% vudose sugar solution, propylene dalicol, etc., which can constitute aqueous or ready-to-use dosage forms, pH adjusters, etc. Formulation components such as tonicity agents and stabilizers are used. Specific examples of the excipient and the like used in the above composition are shown below.
  • Excipients calcium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate aluminate, aluminum hydroxide, magnesium hydroxide, magnesium silicate, calcium carbonate, magnesium carbonate, light silicic anhydride, silicate anhydride, Avicel, various types Starch, dextrin, carboxymethyl starch (CMS), lactose, etc.
  • Ethylcellulose EC
  • carboxymethylcellulose Na CMC-Na
  • low-substituted hydroxypropylcellulose L-HPC
  • HPMC hydroxypropyl propylmethylcellulose
  • MC methylcellulose
  • Droxypropyl cellulose HPC
  • various starches dextrin, sodium alginate, gelatin, polyvinyl alcohol (PVA), polyvinylpyrrolidone (P VP) etc.
  • Disintegrators synthetic aluminum silicate, magnesium metasilicate, CMC—Ca, CMC, Avicel, L—HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS), etc.
  • Anti-solidification agent Light caustic anhydride, synthetic aluminum silicate, etc.
  • Lubricants synthetic aluminum silicate, carboxylic anhydride, talc, Avicel, etc.
  • Flavoring agents mannitol, citrate, sodium citrate, sugar, etc.
  • Emulsifiers gelatin, cunic acid, sodium citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, phospholipids, etc.
  • Stabilizers sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene dalycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, phosphorus' Lipids and the like.
  • Absorption promoters polyoxyethylene hydrogenated castor oil, PEG, propylene dalicol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, medium chain fatty acid triglycerides, etc.
  • Dissolution aids ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene propylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, etc.
  • Suspending agent CMC—Na, HPMC, MC, HPC, sodium alginate, gelatin, propylene glycol, lauryl sulfate Na, etc.
  • Coating agents EC, magnesium silicate, tanolek, titanium oxide, calcium carbonate, triacetin, carboxymethylethylcellulose (CMEC), senorelose phthalate acetate (CAP), HPMC, hydroxypropyl methylcellulose phthalate ( HPMCP), MC, HPC, sodium alginate, polyvier acetate Rugetylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid or methacrylic acid derivatives, polyglycolic acid Na, and the like.
  • CMEC carboxymethylethylcellulose
  • CAP senorelose phthalate acetate
  • HPMC hydroxypropyl methylcellulose phthalate
  • HPC hydroxypropyl methylcellulose phthalate
  • sodium alginate polyvier acetate Rugetylaminoacetate
  • polyacrylic acid Na copolymers of various acrylic acid or methacrylic acid derivatives, polyglycolic acid Na, and the like.
  • Colorant titanium oxide, tar dye, caramel, etc.
  • the dosage of the compound of the present invention when administered to humans varies depending on the age, symptoms, etc. of the patient.In general, in the case of an adult, oral administration or rectal administration is performed in an amount of about 1 mg to 100 mg Omg per day. 0 to 50 Omg / person day. These values are merely examples, and the dose may be adjusted appropriately according to various conditions such as the patient's symptoms.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the residue was partitioned with a 5% aqueous solution of ethyl acetate.
  • the ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was dissolved in a 0.01 N aqueous hydrochloric acid solution and freeze-dried to obtain Compound 5.
  • Methyl 2- (6-hydroxy-1-naphthyl) 16-methyl-14-pyrimidi-2-oxyacetate (Compound 12) (2.8 g) was dissolved in methanol (20 ml), and 1N water was added. An aqueous sodium oxide solution (42 ml) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, neutralized with hydrochloric acid, and the precipitated solid was collected by filtration. I got 14.
  • 6-amidino-l-hydroxyl-l-naphthyl acetoamide hydrochloride (1.6 g) and ethyl acetoacetate (920 mg) synthesized according to the method of T. Na kayama et al. was added to a solution of sodium metal (430 mg) in anhydrous methanol (40 ml), and the mixture was stirred at room temperature for 4 hours. After adding purified water to the reaction solution, the mixture was neutralized with a dilute hydrochloric acid aqueous solution, and the precipitated solid was collected by filtration to obtain Compound 21.
  • reaction solution was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-form-methanol) to obtain Compound 22. .
  • Echinole 2-(1-canolebamoinolemethinole _ 2-hydroxy-1-naphthinole) 1-6-methyl-14-pyrimidinyloxy acetate (Compound 23) (25 Omg) in methanol ( The resulting solution was dissolved in 5 ml), a 1N aqueous solution of sodium hydroxide (1.9 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was acidified with a 5% aqueous solution of citric acid, and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound 24.
  • Example 27 The 1N hydrochloric acid washing solution obtained in Example 27 was allowed to stand under ice cooling, and the precipitated solid was collected by filtration to obtain Compound 28.
  • reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid.
  • the ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by a silica gel column (chloroform) to obtain t-butyl N-t_butoxycarbonyl-N- ⁇ 2- [2- (6-hydroxy-12-naphthyl) -16-methyl-14-pyrimidinyloxy] ethyl ⁇ aminoacetate (1. Og) was obtained.
  • Methyl 2- (6-methoxycarbonylmethoxy-2-naphthyl) 16-methyl 41-pyrimidinyl oxyacetate (Compound 13) (512 mg) was dissolved in methanol (10 ml), and 1 A normal aqueous sodium hydroxide solution (6.5 ml) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, neutralized with hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 33.
  • Ethyl 4_ [2- (6-hydroxy-2-naphthyl) -16-methyl-4-pyrimidininoleoxy] butylate (Compound 34) (80 mg) dissolved in methanol (5 ml) and 1N under ice-cooling An aqueous solution of sodium hydroxide (11 ml) was added dropwise. After stirring at room temperature for 24 hours, the mixture was neutralized with a 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration and washed with purified water to obtain Compound 36 as a yellow solid.
  • 6-Methyl-2- (2-naphthyl) pyrimidin-4-ol (Compound 42) (236 mg) was dissolved in DMF (5 ml), anhydrous potassium carbonate (415 mg) and methyl bromide acetate (184 mg) were added, and the mixture was added at room temperature. For 5 hours. The reaction solution was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified with a silica gel column (hexane-ethyl acetate) to obtain Compound 43.
  • Methyl 6-methyl-2- (2-naphthyl) -14-pyrimidinyloxyacetate (compound 43) (24 mg) was dissolved in methanol (5 ml), and 1N water was added. An aqueous sodium oxide solution (2.3 ml) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was partitioned with ethyl acetate-5% aqueous citric acid solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain Compound 44.
  • 6-Methyl-1- (2-naphthyl) pyrimidin-1-ol (compound 42) (236 mg) was dissolved in DMF (5 ml), and anhydrous potassium carbonate (415 mg) and N- (t-butoxycarbonyl) were dissolved.
  • 2-Chloramine chloride (270 mg) was added, and the mixture was stirred at 80 ° C for 7 hours.
  • the reaction solution was distributed between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a silica gel column (hexane monoethyl acetate).
  • 1N hydrochloric acid / monoacetic acid solution (2 ml), and the mixture was stirred at room temperature for 2 hours, and then solidified by adding ether to obtain Compound 45.
  • 6-Cyan-2-naphthol (10 g) was dissolved in pyridine (50 ml), trifluoromethanesulfonic anhydride (11.6 ml) was added at 0 ° C, and the mixture was stirred at room temperature overnight. .
  • the reaction solution was partitioned with ether-purified water, the ether layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (hexane-ethyl acetate) to give 6-cyano-2-naphthyl.
  • Trifluoromethanesulfonate was obtained as a white solid.
  • 6-cyano 2-naphthyl trifluoromethanesulfonate (3 g) was dissolved in DMF (30 ml), and methyl acrylate (1.3 ml), dichlorobis (triphenylinolephosphine) palladium (14 Omg), And triethylamine (6.2 ml) were added, and the mixture was stirred at 90 ° C for 6 hours.
  • the reaction mixture was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried to give methyl (2E) -3- (6-cyano-1-naphthyl). I got the propenate.
  • the reaction solution was partitioned between ethyl acetate and a 5% aqueous solution of citric acid, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and purified water, and then concentrated under reduced pressure.
  • the precipitated white solid was collected by filtration, dissolved in DMF (3 ml), added with 4N hydrochloric acid-dioxane solution (12 ml), and stirred at room temperature for 6 hours.
  • Ether was added to the reaction solution, and the resulting yellow oily substance was washed with ether and acetone, and the precipitated yellow solid was collected by filtration to obtain Compound 49.
  • Methyl 2- (6-hydroxy-2-naphthyl) -1-6-methyl-14-pyrimidi
  • DMF dioxoacetate
  • N— (t-butoxycarbonyl) -3—propylpropylamine 250 mg
  • the reaction solution was partitioned between ethyl acetate and a 5% aqueous solution of citric acid, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and purified water.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by a silica gel column (hexane monoethyl acetate).
  • the obtained white solid was dissolved in methanol (5 ml), 4N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred for 2 hours.
  • the precipitated white solid was collected by filtration, washed with purified water, then dissolved in 4N hydrochloric acid-dioxane solution (2 ml), and stirred at room temperature for 3 hours.
  • Ether was added to the reaction solution, and the precipitated solid was collected by filtration and washed with ether to obtain Compound 50.
  • the reaction solution was partitioned with ethyl acetate-5% aqueous solution of formic acid, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and purified water, and then concentrated under reduced pressure.
  • the residue was dissolved in ethanol (5 ml), 4N aqueous sodium hydroxide solution (14 ml) was added, and the mixture was stirred for 3 hours.
  • Ethanol and purified water were added to the reaction solution, and the precipitated solid was collected by filtration.
  • the obtained solid was dissolved in 4N hydrochloric acid-dioxane solution (12 ml) and stirred at room temperature for 3 hours. Ether and acetone were added to the reaction solution, and the precipitated yellow solid was washed with acetone to obtain Compound 51.
  • the residue was dissolved in anhydrous methanol (30 ml), ethyl acetate (351 mg) was added, and the mixture was refluxed for 4 hours.
  • the reaction solution was concentrated under reduced pressure, the residue was neutralized by adding a 10% aqueous solution of citric acid, and the precipitated white solid was collected by filtration.
  • the obtained solid was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (5.4 ml) was added, and the mixture was stirred at room temperature for 1.5 hours.
  • the reaction solution was neutralized with a 10% aqueous solution of citric acid, and the precipitated solid was collected by filtration to give 2-hydroxy-1-6- (4-hydroxy-16-methyl-1-pyrimidinyl) -1-naphthylacetic acid.
  • Hexyl) -1- (6-hydroxy-12-naphthyl) -6-methylpyrimidin-1-ol (11 Omg) was obtained as a white solid.
  • the obtained 5- (6-aminohexyl) 1-2- (6-hydroxy-12-naphthyl) -6-methylpyrimidin-4-ol (ll Omg) and potassium carbonate anhydride (33 mg) were added to DMF (2m l), t-butyl bromide acetate (0.04 ml) was added at room temperature, and the mixture was stirred overnight.
  • the reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and purified water.
  • Triethylene glycol monomethyl ether (0.8 ml) was dissolved in pyridine (2 ml), methanesulfonic acid chloride (0.39 ml) was added at 0 ° C, and the mixture was stirred for 2 hours.
  • the reaction solution was distributed with ethyl acetate-dilute hydrochloric acid aqueous solution, and the ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution and purified water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- [2- ( 2-Methoxyxetoxy) ethoxy] ethyl methanesulfonate was prepared.
  • reaction solution was distributed with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified on a silica gel column (chloroform-ethanol) to give Compound 59. Obtained.
  • Chloromethyl bivalate (0.07 ml) was added to a DMF (lm l) solution of cesium 2- (6-hydroxy-12-naphthyl) -16-methyl-14-pyrimidinyloxyacetate (200 mg). In addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (hexane-ethyl acetate). 64 was obtained as a colorless oil.
  • Example 65 Preparation of N, N-dimethylaminocarbonylmethyl 2_ (6-hydroxy-l-naphthyl) -l- 6-methyl-4-pyrimigeroxyacetate (Compound 65) Cesium 2- (6-hydroxyl To a solution of 2-naphthyl) 6-methyl-14-pyrimidinyloxyacetate (200 mg) in DMF (lm l) was added N, N-dimethylacetamide bromide (0.09 ml). Stirred at room temperature for 2 hours. Purified water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with chloroform and hexane to obtain Compound 65.
  • (+) — 2,2-Dimethyl-1,3-dioxolan-14-methyl methanesulfonate was obtained.
  • the obtained (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methylmethanesulfonate (210 mg) was converted to cesium 2- (6-hydroxy-2-naphthyl) -16-methinole 4
  • the mixture was added to a solution of 1-pyrimidinyl oxyacetate (400 mg) in DMF (2 ml) and stirred for 2 hours.
  • methyl 6- (2-pyrimidyl) _2-naphthyloxyacetate 24 mg was suspended in ethanol (5 ml), and 2N aqueous sodium hydroxide solution (0.2 ml) was added. Stirred for minutes. The reaction solution was neutralized with dilute hydrochloric acid and then concentrated under reduced pressure. Compound 68 was obtained by adding purified water to the residue and collecting the precipitated solid by filtration.
  • Example 70 the yellow oily substance (2- ⁇ 2- [6- (2-acetoxethoxytoxy) -12-naphthyl] -12-naphthyl] —6-methyl-14-pyrimi obtained lastly with compound 70 Dinyloxyethyl acetate (10 Omg) was dissolved in methanol (1 ml), 4N aqueous sodium hydroxide solution (1. Oml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with a 4N hydrochloric acid-dioxane solution, purified water was added and the mixture was stirred, and the precipitated solid was collected by filtration to obtain Compound 71.
  • Toluene (6000 ml) was added to dimethyl 2,6-naphthalenedicarboxylate (201 g), and dissolved by heating.
  • a solution of potassium hydroxide (46 g) in methanol (920 ml) was added.
  • the mixture was stirred at ° C for 1 hour.
  • the reaction solution was returned to room temperature, and the precipitated solid was collected by filtration and washed with toluene and purified water.
  • the obtained solid was dissolved by heating in purified water (4000 ml), concentrated hydrochloric acid was added, and the precipitated solid was collected by filtration and washed with acetone to obtain 6-methoxycarbonyl-12-naphthoic acid.
  • 6-methoxycarbonyl-2-naphthoic acid 136 g was dissolved in toluene (82 Oml), and thionyl chloride (84.5 g) and DMF (0.1 ml) were added. Heated to reflux. After cooling the reaction solution, a 28% aqueous ammonia solution (110 ml) was added, and the mixture was stirred at room temperature for 1 hour. Purified water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with toluene to obtain methyl 6-forcerubamoyl-12-naphthalate as a white solid.
  • reaction mixture is concentrated under reduced pressure, the residue is washed with ether and acetone, dissolved in methanol (1900 ml) under ice-cooling, ammonia gas is passed under ice-cooling until saturation, and the stopper is sealed. And stirred at room temperature for 6 days.
  • purified water 300 ml
  • concentrated hydrochloric acid 280 ml
  • the chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (form-form-methanol).
  • the obtained product was dissolved in acetone (100 ml), concentrated hydrochloric acid (0.5 ml) was added, and the precipitated pale yellow solid was collected by filtration to obtain Compound 74.
  • reaction solution is filtered, the filtrate is concentrated under reduced pressure, the residue is partitioned with ethyl acetate-purified water, the ethyl acetate layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then concentrated on a silica gel column (black The residue was purified by tert-butyl 5-ethoxycarbonyl-1- (6-hydroxy-12-naphthyl) -141-pyrimigeroxyacetic acid as a white solid.
  • the obtained product was suspended in purified water (30 ml), sodium hydroxide (500 mg) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was filtered, the filtrate was neutralized with acetic acid. The precipitated solid was collected by filtration, dissolved in acetone (30 ml), concentrated hydrochloric acid (1 ml) was added, and the precipitated yellow solid was collected by filtration to obtain Compound 76.
  • Example 81 Preparation of ethyl 4- (2-aminoethoxy) -2- (6-hydroxy-1-2-naphthyl) —5-pyrimidinecarboxylate dihydrochloride (Compound 81) ethyl 4- (2_t-butoxycarbonylaminoethoxy) To a solution of 2- (6-hydroxy-12-naphthyl) -5-pyrimidine carboxylate (compound 77) (28 Omg), a 4N hydrochloric acid-dioxane solution (5 ml) was added, and the mixture was stirred at room temperature for 3 hours. The precipitated yellow solid was collected by filtration to obtain Compound 81.

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Abstract

La présente invention concerne des dérivés de naphtalène représentés par la formule (1) qui possèdent un puissant effet accélérant la fibrinolyse et qui sont utiles en tant que médicaments antithrombotiques ou thrombolytiques pouvant être administrés par voie orale. Dans la formule (1), R1 représente hydrogène, halogéno, hydroxyle, carboxyle, -OSO3H, -O-C1-6 Ak-R1a, alcényle C2-6 substitué par alcoxycarbonyle C1-6 ou CO-N (R1c) (R1d) ; R2 représente hydrogène, halogéno ou C1-6 Ak-CO- N(R1c) (R1d) ; et A représente un groupe comportant un anneau pyrimidine ou 1-méthylhydantoïne tel que celui représenté par la formule (a), (b) ou (c).
PCT/JP2000/002278 1999-06-02 2000-04-07 Derives de naphtalene Ceased WO2001077082A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0096657A2 (fr) * 1982-06-08 1983-12-21 Ciba-Geigy Ag 2-Phényl-2-naphtyl- et 2-hétérocyclylpyrimidines comme antidote pour protéger les cultures de plantes avant les dégâts phytotoxiques causés par les herbicides
EP0151294A1 (fr) * 1984-01-11 1985-08-14 Chisso Corporation (Pyrimidinyl)-2 substitué en position 5)-6 naphtalène 2-substitué et compositions de cristaux liquides les contenant
EP0190356A1 (fr) * 1984-07-25 1986-08-13 TORII & CO., LTD. Nouveaux composes d'amidine
JPS61286361A (ja) * 1985-06-14 1986-12-16 Torii Yakuhin Kk アミジン誘導体
US4786640A (en) * 1987-06-12 1988-11-22 American Home Products Corporation 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acid aldose reductase inhibitors
JPH0219363A (ja) * 1988-07-06 1990-01-23 Fujisawa Pharmaceut Co Ltd イミダゾリジン誘導体
EP0811377A1 (fr) * 1995-01-05 1997-12-10 Torii Pharmaceutical Co., Ltd. Agent thrombolytique
WO2000031045A1 (fr) * 1998-11-20 2000-06-02 Torii Pharmaceutical Co., Ltd. Derives de naphtalene

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0096657A2 (fr) * 1982-06-08 1983-12-21 Ciba-Geigy Ag 2-Phényl-2-naphtyl- et 2-hétérocyclylpyrimidines comme antidote pour protéger les cultures de plantes avant les dégâts phytotoxiques causés par les herbicides
EP0151294A1 (fr) * 1984-01-11 1985-08-14 Chisso Corporation (Pyrimidinyl)-2 substitué en position 5)-6 naphtalène 2-substitué et compositions de cristaux liquides les contenant
EP0190356A1 (fr) * 1984-07-25 1986-08-13 TORII & CO., LTD. Nouveaux composes d'amidine
JPS61286361A (ja) * 1985-06-14 1986-12-16 Torii Yakuhin Kk アミジン誘導体
US4786640A (en) * 1987-06-12 1988-11-22 American Home Products Corporation 2,6-disubstituted-5-cyano-4-pyrimidinyloxyacetic acid aldose reductase inhibitors
JPH0219363A (ja) * 1988-07-06 1990-01-23 Fujisawa Pharmaceut Co Ltd イミダゾリジン誘導体
EP0811377A1 (fr) * 1995-01-05 1997-12-10 Torii Pharmaceutical Co., Ltd. Agent thrombolytique
WO2000031045A1 (fr) * 1998-11-20 2000-06-02 Torii Pharmaceutical Co., Ltd. Derives de naphtalene

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Title
Chemical Abstracts Service (C A S); 1 January 1967 (1967-01-01), RISALITI A, FATUTTA S, FORCHIASSIN M: "VINYLAMINES. VII. MORE SUBSTITUTED ALKYLATED ENAMINES FROM CYCLOHEXANONE ENAMINES AND PHENYL VINYL SULFONE", XP002929071 *
Chemical Abstracts Service (C A S); 1 January 1969 (1969-01-01), PLAS DER VAN H C, ZUURDEEG B: "RING TRANSFORMATIONS IN REACTIONS OF HETROCYCLIC HALO COMPOUNDS WITH NUCLEOPHILES. XIV. CONVERSION OF 2-SUBSTITUTED 4-CHLOROPYRIMIDINES BY POTASSIUM AMID EIN LIQUID AMMONIA INTO 2-SUBSTITUTED-4-METHYL-S-TRIAZINES", XP002929072 *
ELLINGBOE J. ET AL.: "(Pyrimidinyloxy)acetic Acids and Pyrimidineacetic Acids as a Novel Class of Aldose Reductase Inhibitors", J. MED. CHEM.,, vol. 33, no. 10, 1990, pages 2892 - 2899, XP002929070 *
NUGENT R.A. ET AL.: "Pyrimidine Thioethers: A Novel Class HIV-1 Reverse Transcriptase Inhibitors with Activity Against BHAP-resistant HIV", J. MED. CHEM.,, vol. 41, no. 20, 1998, pages 3793 - 3803, XP002929069 *

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