WO1999030715A1 - Agents prophylactiques contre les troubles du sommeil et remedes aux troubles du sommeil - Google Patents

Agents prophylactiques contre les troubles du sommeil et remedes aux troubles du sommeil Download PDF

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Publication number
WO1999030715A1
WO1999030715A1 PCT/JP1998/005639 JP9805639W WO9930715A1 WO 1999030715 A1 WO1999030715 A1 WO 1999030715A1 JP 9805639 W JP9805639 W JP 9805639W WO 9930715 A1 WO9930715 A1 WO 9930715A1
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WIPO (PCT)
Prior art keywords
group
formula
substituted
represented
lower alkyl
Prior art date
Application number
PCT/JP1998/005639
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English (en)
Japanese (ja)
Inventor
Junichi Shimada
Shunji Ichikawa
Fumio Suzuki
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU15070/99A priority Critical patent/AU1507099A/en
Publication of WO1999030715A1 publication Critical patent/WO1999030715A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to a medicament useful for prevention and / or treatment of sleep disorders.
  • Sleep disorders include sleep disorders such as intrinsic sleep disorders, extrinsic sleep disorders, and circadian rhythm sleep disorders; parasomnias such as arousal disorders, sleep-wake transition disorders; and mental disorders and neurological disorders. These disorders are roughly classified into a number of diseases that amount to about 90 types. (International diagnostic classification of sleep disorders: I CSD (International and iassif ication or sleep Disorders) 1 990). For sleep disorders having various symptoms and etiologies, various drugs such as barbile acids, benzodiazepines, and psychotropic drugs are used in accordance with the symptoms and etiologies. Drugs such as caffeine and pentoxifylline have been used as xanthin derivatives.
  • I CSD International and iassif ication or sleep Disorders
  • xanthine derivatives having an adenosine A 2 receptor antagonistic action, an anti-parkinsonian action, an antidepressant action, an anti-asthmatic action, a bone resorption inhibitory action, or a central stimulating action are known [Japanese Patent Publication No. 47-26516] J. Med. Chem. 34, 143, 1991; J. Med. Chem. 36, J. Med. Chem. Pp. 1333, 19993; WO92 / 06976; JP-A-6-211856; JP-A-6-239862; WO9523165; JP-A-6-16. No. 559; and WO94Z01114]
  • the above publications do not suggest or teach that these xanthine derivatives are useful for preventing or treating sleep disorders. Disclosure of the invention
  • An object of the present invention is to provide a medicament useful for preventing and / or treating sleep disorders.
  • the present inventors have conducted intensive research to solve the above-mentioned problems, and found that the xanthine derivative disclosed in the above publication has a physiological effect such as an effect of shortening sleep time and an effect of wakefulness. It has been found that it is useful as an active ingredient of a medicament for preventing and / or treating disorders.
  • the present invention has been completed based on the above findings.
  • R 1 , R 2 , and R 3 each independently represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group;
  • R 4 represents a cycloalkyl group, 1 (CH 2 ) n ⁇ R s (wherein, R 5 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, and n represents an integer of 0 to 4), or the following formula A:
  • Y ′ and Y 2 each independently represent a hydrogen atom, a halogen atom, or a lower alkyl group, Z represents a substituted or unsubstituted aryl group, and the following formula B:
  • R 6 is a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, Represents a halogen atom, a nitro group, or a substituted or unsubstituted amino group, and m represents an integer of 1 to 3), or a substituted or unsubstituted heterocyclic group.
  • X ′ and X 2 each independently represent O or S) selected from the group consisting of xanthine derivatives, pharmaceutically acceptable salts thereof, and hydrates and solvates thereof.
  • the present invention provides a preventive and / or therapeutic agent for sleep disorders containing a substance as an active ingredient.
  • R 4 is a group represented by the formula A (where Y 1 and are both hydrogen atoms), and X ′ and ⁇ 2 are both ⁇ .
  • the above-mentioned prophylactic and / or therapeutic agent comprising as an active ingredient a substance selected from the group consisting of the xanthine derivative represented and a pharmaceutically acceptable salt thereof, and a hydrate and a solvate thereof; ⁇ ) — 8 -— (3,4-Dimethoxystyryl) — 1,3-Getyl-7-methylxanthine and pharmaceutically acceptable salts thereof, and substances selected from the group consisting of hydrates and solvates thereof.
  • the above prophylactic and / or therapeutic agent comprising as an active ingredient is provided.
  • the xanthine derivative represented by the above formula (I) and a pharmaceutically acceptable salt thereof, and a hydrate and a solvate thereof for the production of the above prophylactic and / or therapeutic agent is a method for preventing and / or treating sleep disorders, which comprises a step of administering an effective amount of the substance to a mammal including a human.
  • the term “lower” for a certain substituent means that the substituent has 1 to 6 carbon atoms (2 to 6 for a substituent containing an unsaturated bond) unless otherwise specified. , Preferably 1 to 4 (2 to 4 for a substituent containing an unsaturated bond).
  • lower alkyl group or the term “lower alkyl” in a substituent containing one or more lower alkyl groups as a constituent (lower alkylamino group ⁇ lower alkanol group, etc.)
  • the term “or its synonyms” does not have 1 carbon atom.
  • lower alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, neopentyl Group, n-hexyl group and the like can be used.
  • R 1 R y and R 3 each independently represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group.
  • the lower alkenyl group may be straight-chain or branched, for example, vinyl group, aryl group, methacryl group, crotyl group, 3- butenyl group, 2-pentenyl group, 4-pentenyl group, 2-xenyl group, 5 —Hexenyl group and the like can be used.
  • the number of double bonds contained in the alkenyl group is not particularly limited, but is one or two, and preferably one.
  • the lower alkynyl group may be straight-chain or branched, and includes, for example, ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentulyl, 4-pentynole, 2-hexynyl Group, 5-xynyl group, 4-methyl-2-pentynyl group and the like.
  • the number of triple bonds contained in the alkynyl group is not particularly limited, but is preferably one.
  • R 4 represents a cycloalkyl group, — (CH 2 ) n —R 5 (n represents an integer of 04), or a group represented by the above formula A.
  • a 3- to 8-membered cycloalkyl group can be used, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentizole group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. are preferable.
  • One or more lower alkyl groups may be substituted on the ring of the above-mentioned alkyl group.
  • R represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group.
  • aryl group for example, a phenyl group or a naphthyl group can be suitably used.
  • heterocyclic group for example, a 5- to 10-membered monocyclic heterocyclic group or a fused heterocyclic group can be used, and these heterocyclic groups are a nitrogen atom, a sulfur atom, an oxygen atom. Two or more identical or different heteroatoms selected from May be included.
  • heterocyclic group examples include a furyl group, a chenyl group, a pyrrolyl group, a pyraryl group, a thiopyranyl group, a pyridyl group, a thiazolyl group, an imidazolyl group, a pyrimidyl group, a triazinyl group, an indolyl group, a quinolyl group, A benzyl group, a benzothiazolyl group, or the like can be used.
  • a substituent when substituted or unsubstituted, it means that the substituent may have one or more, preferably one to three functional groups. When two or more such functional groups are present, they may be the same or different. Examples of such a functional group include a lower alkyl group, a hydroxy group, a lower alkoxy group (a methoxy group, an ethoxy group, etc.), a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom).
  • the types of the functional groups are not limited to these, and the functional groups specifically described above may further have one or more functional groups.
  • the functional group to be substituted with lower alkoxy includes, for example, a hydroxy group, a lower alkoxy group, a halogen atom, an amino group, an azide group, a carboxy group, And a lower alkoxycarbonyl group.
  • Y ′ and Yz each independently represent a hydrogen atom, a halogen atom, or a lower alkyl group.
  • Upsilon 'wavy line for ⁇ and Zeta are, Upsilon' is a mixture of and Upsilon 2 Do is either cis or trans configuration about the double bond (or ⁇ or Zeta), or both of the isomers Is shown.
  • the halogen atom any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom may be used.
  • Upsilon 1 and Upsilon 2 are in the trans configuration, is preferably both hydrogen atoms.
  • ⁇ represents a substituted or unsubstituted aryl group, a group represented by the above formula ⁇ , or a substituted or unsubstituted heterocyclic group.
  • aryl group or the heterocyclic group those exemplified above can be used.
  • R 6 represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, or a substituted or unsubstituted amino group
  • m represents 1 Shows an integer of ⁇ 3.
  • the lower alkoxy group a methoxy group, an ethoxy group, or the like can be used, and as the halogen atom, any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom may be used.
  • substituted amino group examples include a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group (such as an acetylamino group), and an aralkylamino group (such as a benzylamino group).
  • R 6 is a group other than a hydrogen atom
  • the substitution position of R 6 on the phenyl group is not particularly limited.
  • X 1 and X 2 each independently represent O or S, and both are preferably oxygen atoms.
  • a pharmacologically acceptable salt of the compound represented by the formula (I) can be used as the active ingredient of the medicament of the present invention.
  • Such salts include, for example, acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
  • the acid addition salt include, for example, inorganic acid salts such as hydrochloride, sulfate, and phosphate, or organic acids such as acetate, maleate, fumarate, tartrate, citrate, and methanesulfonate. Salts can be used.
  • Alkali metal salts such as thorium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like can be used.
  • the ammonium salt include salts such as ammonium and tetramethylammonium
  • examples of the organic amine addition salt include addition salts such as morpholine and piperidine.
  • examples of the amino acid addition salt include addition salts such as lysine, glycine, and phenylalanine.
  • the compound represented by the formula (I) or a pharmacologically acceptable salt thereof may be present in the form of a hydrate or an adduct (solvate) with various solvents.
  • any hydrate or any physiologically acceptable solvate may be used.
  • the organic solvent forming the solvate is not particularly limited as long as it is physiologically acceptable.
  • ethanol, acetone and the like can be used.
  • the compound of formula (I) may have one or more asymmetric carbons, but may be in the form of an optical or diastereoisomer in pure form, or any mixture of these isomers, Racemates and the like may be used as the active ingredient of the medicament of the present invention.
  • geometric isomers based on one or more double bonds may exist, but pure forms of geometric isomers or any mixture of geometric isomers may be used as the active ingredient of the medicament of the present invention. May be used.
  • a salt-form substance can be produced, for example, from a compound of the formula (I) in a free form according to a method well known to those skilled in the art.
  • (E) -8- (3,4 page) (Methoxystyryl) 1,1,3-getyl-7-methylxanthine (the compound described in Example 2 of JP-A-6-218856) can be mentioned, but the active ingredient of the medicament of the present invention can be mentioned. Is not limited to the above compounds.
  • the medicament of the present invention is useful for preventing and / or treating sleep disorders.
  • sleep disorders Various classifications of sleep disorders have been reported, and various symptoms and etiologies have been identified. For example, according to the International Classification of Sleep Disorders (ICSD, Diagnostic and Coding Manual, American Sleep Disorders Association, 1990), sleep disorders include (A) sleep disorders (intrinsic sleep disorders, extrinsic sleep disorders).
  • the medicament of the present invention is applicable to any of these sleep disorders, and may be classified into other categories (for example, ASDC of the American Federation of Sleep Disorders Centers; -IV; applicable to any sleep disorder identified according to the International Classification of Diseases, such as ICD-10
  • the pharmaceuticals of the present invention are preferably applied to, for example, narcolepsy, recurrent hypersomnia (recurrent hypersomnia, recurrent hypersomnia; hypersomnia), external
  • rhythmic sleep (circadian rhythm sleep disorders)
  • the application target of the medicament of the present invention is not limited to these. Since the medicament of the present invention has a wakefulness effect, it is also useful as a preventive and / or therapeutic agent for senile dementia.
  • a compound selected from the group consisting of the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a hydrate and a solvate thereof is used as the medicament of the present invention.
  • Two or more substances selected from these groups may be used in appropriate combination.
  • the substance itself selected from these groups may be administered as the medicament of the present invention, but usually, a pharmaceutical composition comprising a substance selected from these groups and a pharmaceutically acceptable additive for a pharmaceutical preparation It is desirable to administer in the form.
  • Such a pharmaceutical composition may appropriately contain one or more active ingredients of other medicines, for example, one or more active ingredients of other medicines used for prevention and / or treatment of sleep disorders. It is possible.
  • a pharmaceutical composition which is a preferred embodiment of the medicament of the present invention, comprises mixing a substance which is an active ingredient selected from the above group with one or more pharmaceutically acceptable excipients for pharmaceutical preparations.
  • Such pharmaceutical compositions are in unit dosage form.
  • the route of administration of the medicament of the present invention is not particularly limited, but it is desirable to appropriately select the most effective route for prevention and prevention or treatment.
  • Pharmaceutical compositions suitable for oral administration include, for example, capsules, powders, tablets, granules, fine granules, syrups, solutions, suspensions and the like.
  • compositions suitable for parenteral administration examples include: inhalants, sprays, rectal administration, injections, drops, ointments, creams, transdermal absorbers, transmucosal absorbers, eye drops, nasal drops, ear drops, tapes And patches.
  • inhalants sprays, rectal administration, injections, drops, ointments, creams, transdermal absorbers, transmucosal absorbers, eye drops, nasal drops, ear drops, tapes And patches.
  • the form of the medicament of the present invention is not limited to the preparations exemplified above.
  • liquid preparations such as emulsions and syrups include: water; saccharides such as sucrose, sorbite, fructose; glycols such as polyethylene glycol and propylene glycol; sesame oil and olive oil And oils such as soybean oil; preservatives such as p-hydroxybenzoic acid esters; and additives for pharmaceutical preparations such as flavors such as strobe leaf flavor and peppermint.
  • Solid preparations such as capsules, tablets, powders, and granules include excipients such as lactose, glucose, sucrose and mannitol; disintegrants such as starch and sodium alginate; magnesium dispersants such as magnesium stearate and talc.
  • Lubricant polyvinyl alcohol, hydroxypropylcell It can be produced using a binder such as loin and gelatin; a surfactant such as a fatty acid ester; and a plasticizer such as glycerin.
  • liquid preparations in the form of injections, drops, eye drops and the like can be preferably prepared as sterile isotonic liquid preparations.
  • an injection can be prepared using an aqueous medium consisting of a salt solution, a glucose solution, or a mixture of saline and a glucose solution.
  • Rectal preparations can be prepared usually in the form of suppositories, using carriers such as fatty acid, hydrogenated fat or hydrogenated carboxylic acid.
  • a non-irritating carrier which disperses the above-mentioned substance as an active ingredient as fine particles to facilitate absorption can be used.
  • Such carriers include, for example, lactose, glycerin and the like, and the form of the preparation can be selected from aerosol, dry powder and the like.
  • the diluents, fragrances, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for oral preparations are also used.
  • One or more pharmaceutical additives selected from the following can be used as appropriate.
  • the pharmaceutical additives used in the production of the medicament of the present invention are not limited to those described above, and any additives may be used as long as they can be used by those skilled in the art.
  • the dose and the number of times of administration of the medicament of the present invention are not particularly limited. ⁇ 900mg / 60kg, preferably; ⁇ 200mg / 60kg is appropriate.
  • the above dosages may be administered once or several times a day.
  • the above dosage and frequency of administration are appropriately determined in consideration of the administration route, the patient's age and body weight, the type of disease to be treated and / or prevented, the purpose of treatment and / or prevention, the symptoms and the severity, etc. It is desirable to increase or decrease.
  • a tablet having the following composition was prepared by a conventional method.
  • Compound 1 40 g
  • lactose (286.8 g) and potato starch 60 g
  • a 10% aqueous solution of hydroxypropyl cellulose 120 g
  • the mixture was kneaded by a conventional method, granulated, dried, and then sized to obtain granules for tableting.
  • Magnesium stearate 1.2 g was added to the granules and mixed, and the mixture was tableted using a tableting machine (RT-15 type, manufactured by Kikusui) with a punch having a diameter of 8 mm. Per active ingredient).
  • a capsule having the following composition was prepared by a conventional method.
  • Compound 1 (200 g), Avicel (995 g) and magnesium stearate (5 g) were mixed by a conventional method.
  • This mixture was filled into a hard capsule No. 4 (capacity: 120 mg / capsule) using a capsule filling machine (Zanasi LZ-64 type), and a capsule (containing 20 mg of active ingredient per capsule) was prepared. Obtained.
  • An injection having the following composition was prepared by a conventional method.
  • Compound 1 (1 g) was dissolved in purified soybean oil (100 g), and purified egg yolk lecithin (12 g) and glycerin for injection (25 g) were added.
  • This mixture was kneaded and emulsified to 1,000 ml with distilled water for injection by a conventional method.
  • the resulting dispersion is aseptically filtered using a disposable membrane filter of 0.2 / xm, and aseptically filled into glass vials in 2 ml increments for injection (containing 2 mg of active ingredient per vial). )
  • a formulation for rectal administration having the following composition was prepared by a conventional method.
  • Witebzol “* HI5 (Dynamite Tonobel, 678.8 g) and Witebzol TM E75 (Dynamite Tonobel, 290.9 g) were melted at 40 to 50 ° C. 1 (2.5 g), monobasic phosphate phosphate (13.6 g) and dibasic sodium phosphate (14.2 g) were uniformly mixed and dispersed, and then the mixed dispersion was placed in a plastic seat. After filling into the preparation form, the mixture was gradually cooled to give a rectal suppository (containing 2.5 mg of active ingredient per preparation).
  • Example 5 Test example (Effect of the drug of the present invention on sodium pentobarbital-induced sleep time)
  • mice Male ddY mice (Japan SLC) weighing 21-23 g were used for the experiments. After adding Tween 80 (manufactured by Wako Pure Chemical Industries, Ltd.) (concentration: 0.5%), the test compound was used by suspending in distilled water for injection (Otsuka Pharmaceutical Co., Ltd.). Caffeine (manufactured by Sigma) was dissolved in distilled water for injection. The dose of the solution was 0.1 ml per 10 g of mouse body weight.
  • mice were used as 8 to 10 mice per group.
  • the disappearance time of the righting reflex was measured as sleep time.
  • Table 1 shows the test results. As is clear from these results, Compound 1 significantly reduced the sleep time. Caffeine used as a control also showed a tendency to shorten the hypnotic time, but the extent was clearly weaker than the test compound.
  • Test compounds were orally or intraperitoneally administered to three dd male mice (body weight: 20 ⁇ 1 g) in three groups. The death status on day 7 after administration was observed, and the minimum lethal dose (MLD) value was determined. As a result, the MLD of Compound 1 was 1,000 mg / kg or more by oral administration. Industrial applicability
  • the medicament of the present invention is useful for prevention and Z or treatment of sleep disorders such as narcolepsy, repetitive hypersomnia, sudden hypersomnia, and circadian rhythm sleep disorders.

Abstract

L'invention concerne des médicaments renfermant des dérivés de xanthine en tant que principe actif, ces médicaments étant représentés par la formule (I) (par exemple, (E)-8-(3,4-diméthoxystyryl)-1,3-diéthyl-7-méthylxanthine) ou des sels pharmaceutiquement acceptables de ceux-ci. Ces médicaments sont utiles pour prévenir ou traiter les troubles du sommeil tels que la narcolepsie, l'hypersomnie récurrente, ou les dysfonctionnements du rythme circadien. Dans la formule (I), R?1, R2, et R3¿ représentant chacun hydrogène, alkyle inférieur, etc.; R4 représentant cycloalkyle, -(CH¿2?)n-R?5 (R5¿ représentant aryle éventuellement substitué, etc.; et n désignant un nombre entier variant entre 0 et 4), etc.; et X1 et X2 représente chacun O ou S.
PCT/JP1998/005639 1997-12-15 1998-12-14 Agents prophylactiques contre les troubles du sommeil et remedes aux troubles du sommeil WO1999030715A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15070/99A AU1507099A (en) 1997-12-15 1998-12-14 Preventives/remedies for sleep disturbance

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP34482697 1997-12-15
JP9/344826 1997-12-15

Publications (1)

Publication Number Publication Date
WO1999030715A1 true WO1999030715A1 (fr) 1999-06-24

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PCT/JP1998/005639 WO1999030715A1 (fr) 1997-12-15 1998-12-14 Agents prophylactiques contre les troubles du sommeil et remedes aux troubles du sommeil

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AU (1) AU1507099A (fr)
WO (1) WO1999030715A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005213235A (ja) * 2004-02-02 2005-08-11 Kyowa Hakko Kogyo Co Ltd キサンチン誘導体水和物
JP2007503443A (ja) * 2003-08-25 2007-02-22 アデノシン、セラピューティックス、リミテッド、ライアビリティ、カンパニー 置換８−ヘテロアリールキサンチン

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211856A (ja) * 1992-09-28 1994-08-02 Kyowa Hakko Kogyo Co Ltd パーキンソン氏病治療剤
JPH09507249A (ja) * 1994-06-08 1997-07-22 ファイザー・インコーポレーテッド コルチコトロピン放出因子（ｃｒｆ）アンタゴニスト

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211856A (ja) * 1992-09-28 1994-08-02 Kyowa Hakko Kogyo Co Ltd パーキンソン氏病治療剤
JPH09507249A (ja) * 1994-06-08 1997-07-22 ファイザー・インコーポレーテッド コルチコトロピン放出因子（ｃｒｆ）アンタゴニスト

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OKUDEIRA N.: "THEOPHYLLINE DELAYS HUMAN SLEEP PHASE.", LIFE SCIENCES., PERGAMON PRESS, OXFORD, GB, vol. 34., no. 10., 1 January 1984 (1984-01-01), GB, pages 933 - 938., XP002920228, ISSN: 0024-3205, DOI: 10.1016/0024-3205(84)90297-2 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007503443A (ja) * 2003-08-25 2007-02-22 アデノシン、セラピューティックス、リミテッド、ライアビリティ、カンパニー 置換８−ヘテロアリールキサンチン
JP4769721B2 (ja) * 2003-08-25 2011-09-07 トロヴィス ファーマシューティカルズ リミテッド ライアビリティ カンパニー 置換８−ヘテロアリールキサンチン
JP2005213235A (ja) * 2004-02-02 2005-08-11 Kyowa Hakko Kogyo Co Ltd キサンチン誘導体水和物
JP4731121B2 (ja) * 2004-02-02 2011-07-20 協和発酵キリン株式会社 キサンチン誘導体水和物

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