WO1998057645A1 - Medicament contre l'oedeme hepatique - Google Patents

Medicament contre l'oedeme hepatique Download PDF

Info

Publication number
WO1998057645A1
WO1998057645A1 PCT/JP1998/002634 JP9802634W WO9857645A1 WO 1998057645 A1 WO1998057645 A1 WO 1998057645A1 JP 9802634 W JP9802634 W JP 9802634W WO 9857645 A1 WO9857645 A1 WO 9857645A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
hepatic edema
acceptable salt
hydroxy
Prior art date
Application number
PCT/JP1998/002634
Other languages
English (en)
Japanese (ja)
Inventor
Junichi Shimada
Fumio Suzuki
Ken Nagashima
Hiroko Okano
Akira Karasawa
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU76755/98A priority Critical patent/AU7675598A/en
Publication of WO1998057645A1 publication Critical patent/WO1998057645A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • 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
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

  • the present invention relates to a therapeutic agent for hepatic edema.
  • a xanthine derivative related to a compound represented by the formula (I) described below has a selective antagonism at adenosine A1 receptor, and has a diuretic effect, a renal protective effect, a tracheodilatory effect, and an improvement in brain function. It is known to exhibit an action, an anti-dementia action or an anti-ulcer action [Japanese Patent Application Laid-open No. Hei 3-173888 (EP Publication No. 0 686 675)], Japanese Patent Laid-Open No. Hei 3-1 No. 7 388 9 (EP publication 0 415 556), Japanese Unexamined Patent Publication No.
  • Japanese Patent Publication No. 0 2222 Japanese Patent Application Laid-Open No. 5-58913 (EP Publication No. 497258), Japanese Patent Application Laid-Open No. 5-59056 (EP Publication No. No. 79), Japanese Patent Laid-Open No. 6-1
  • the present invention provides a compound of the formula (I)
  • R 1 and R 2 are the same or different and are hydrogen, aryl, propargyl, R 3 — (CH 2 ) m — (wherein, R 3 represents a substituted or unsubstituted alicyclic alkyl, and m is Represents 0, 1 or 2) or hydroxy-substituted, oxo-substituted or unsubstituted lower alkyl, Y represents a bond or alkylene, and Q represents Wherein R 4 and R 5 are the same or different and represent hydrogen or hydroxy, or together represent oxo, and n represents 0 or 1. (Wherein, R 6 and R 7 are the same or different and each represents a substituted or unsubstituted alicyclic alkyl)] or a pharmaceutically acceptable salt thereof as an active ingredient Hepatic edema therapeutic agent.
  • the present invention also relates to a method for treating hepatic edema, which comprises administering an effective amount of a xanthine derivative represented by the formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention also relates to the use of a xanthine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof for the production of a pharmacological composition useful for a therapeutic agent for hepatic edema.
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl , Isopentyl, hexyl and the like.
  • Alkylene includes linear or branched C 1-4 alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, methylmethylene, propylene, ethylethylene and the like.
  • the number of hydroxy or O Kiso substitution at R ⁇ and R 2 are 1-2, the substitution position may be arbitrary.
  • Alicyclic alkyls include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • substituent of the alicyclic alkyl include the same or different substituents having 1 to 3 substituents, for example, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, amino, carboxy, etc., and lower alkyl and lower alkoxy.
  • Halogen includes fluorine, chlorine, bromine and iodine atoms.
  • R 1 and R 2 Or propyl substituted at the 2- or 3-position with hydroxy, oxo, or unsubstituted.
  • the bonding position with Y and the position of hydroxy or oxo substitution may be arbitrary.
  • the preferred Q, 9-position or 6-position hydroxy-substituted, Okiso substituted or unsubstituted 3 - tricyclo [3.3 ⁇ 0 3 '7] nonyl or 3-position hydroxy-substituted or unsubstituted 1, - tricyclo [3.3. 1.1 3 ' 7 ] Decyl etc. can be mentioned.
  • Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, acetate, maleate, fumarate, tartrate, quer Organic salts such as carboxylate and methanesulfonate are exemplified.
  • examples of pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkali salts such as magnesium salt and calcium salt.
  • pharmacologically acceptable ammonium salts include, for example, salts of ammonium, tetramethylammonium, etc .
  • pharmacologically acceptable organic Amine addition salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include lysine, glycine, phenylalanine and the like. With salting, and the like.
  • Compound (I) can be produced by the method disclosed in the above publication or according to the method.
  • the target compound in the production method can be isolated and purified by a purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like.
  • compound (I) when it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, or if it can be obtained in the form of a free base, dissolve in an appropriate solvent Alternatively, they may be suspended and an acid or a base may be added to form a salt.
  • Compound (I) and its pharmacologically acceptable salt may be water or various solvents. Although they may be present in the form of adducts with a medium, these adducts can also be used as the therapeutic agent of the present invention.
  • Compound 1 8— (3-noradamantyl) —1,3-dipropylxanthine (Japanese Unexamined Patent Application Publication No. 3-1783889)
  • Test Example 1 Effect on hepatic edema
  • Compound 1 (0.01, 0.1 and lmg / kg) or furosemide (30 mg / kg) was suspended in 5% arabia gum (5 ml / kg), and the suspension was orally administered once a day for 5 days.
  • the control group and the normal group were orally administered 5% gum arabic (5 ml / kg) once a day for 5 days.
  • the table shows urine volume, urinary Na and K excretion, and ascites volume when Compound 1 (0.01, 0.1 and lmg / kg) or furosemide (30 mg / kg) was administered. Each measured value was shown by the mean soil standard error, and a significant difference test of the average value between the control group and the normal group or the test compound administration group was performed using Student's West. Regarding the obtained results, when the risk ratio was less than 5%, it was judged that there was a significant difference, and was marked * in the above table. If the hazard rate is less than 1%, ** is displayed in the above table. From the above test results, it was clarified that Test Compound 1 showed a diuretic effect on hepatic edema disease, was effective in reducing ascites, and its effect was superior to that of furosemide.
  • Test example 2 Acute toxicity test
  • test compound was orally or intraperitoneally administered to three dd male mice (body weight: 20 ⁇ lg) per group.
  • body weight 20 ⁇ lg
  • the death status on the 7th day after administration was observed, and the minimum lethal dose (MLD) value was determined.
  • the MLD of compound 1 was> 1000 mg / kg by oral administration.
  • compound (I) or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent for hepatic edema.
  • Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms.
  • the pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient.
  • These pharmaceutical compositions are desirably in a unit dosage form suitable for administration, for example, rectally, orally or parenterally (including subcutaneously, intravenously and intramuscularly).
  • any useful pharmaceutically acceptable carrier can be used.
  • Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil and soybean oil. It can be produced using oils, preservatives such as P-hydroxybenzoic acid esters, and flavors such as stove beef flavor and peppermint.
  • Powders, pills, Capsules and tablets include lactose, glucose, sucrose, mannitol and other excipients, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, It can be produced using a binder such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. When manufacturing tablets and capsules, a solid pharmaceutical carrier is used.
  • the injection can be prepared using a carrier comprising distilled water, a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. At this time, it is prepared as a solution, suspension or dispersion using an appropriate auxiliary according to a conventional method.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection in the above-mentioned pharmaceutical form. Although it depends on the age, body weight, symptoms, etc., 1 to 900 mg / 60 kg / day, preferably 1 to 200 mg / 60 kg / day is appropriate.
  • a tablet having the following composition was prepared by a conventional method.
  • a capsule having the following composition was prepared by a conventional method.
  • An injection having the following composition was prepared by a conventional method.
  • Compound 1 1 g was dissolved in 100 g of purified soybean oil, and 12 g of purified egg yolk lecithin and 25 g of glycerin for injection were added. This mixture was kneaded and emulsified in a conventional manner to 1000 ml with distilled water for injection. The resulting dispersion is aseptically filtered using a 0.2 / m disposable membrane filter, and then aseptically filled into glass vials in 2 ml increments for injection (containing 2 mg of active ingredient per vial) I got Formulation compound 1 2 mg
  • a formulation for rectal administration having the following composition was prepared by a conventional method.
  • Witebsol TM H15 manufactured by Dynamite Nobel
  • 290.9 g of Witebsol TM E75 manufactured by Dynamite Nobel
  • 2.5 g of Compound 1, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein.
  • the mixed and dispersed product was filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
  • the present invention t hepatic edema therapeutic agent is provided

Abstract

L'invention concerne un médicament contre l'oedème hépatique contenant un dérivé de xanthine de formule générale (I) ou un sel pharmaceutiquement acceptable de ce dernier en tant que principe actif.
PCT/JP1998/002634 1997-06-16 1998-06-16 Medicament contre l'oedeme hepatique WO1998057645A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76755/98A AU7675598A (en) 1997-06-16 1998-06-16 Hepatic edema remedy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP15863697 1997-06-16
JP9/158636 1997-06-16

Publications (1)

Publication Number Publication Date
WO1998057645A1 true WO1998057645A1 (fr) 1998-12-23

Family

ID=15676052

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/002634 WO1998057645A1 (fr) 1997-06-16 1998-06-16 Medicament contre l'oedeme hepatique

Country Status (2)

Country Link
AU (1) AU7675598A (fr)
WO (1) WO1998057645A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034610A1 (fr) * 1999-11-12 2001-05-17 Biogen, Inc. Polycycloalkylpurines comme antagonistes du recepteur d'adenosine
US6605600B1 (en) 1999-11-12 2003-08-12 Biogen, Incorporated Adenosine receptor antagonists and methods of making and using the same
WO2007069675A1 (fr) * 2005-12-14 2007-06-21 Kyowa Hakko Kogyo Co., Ltd. Préparation orale facilement absorbée contenant un dérivé de la xanthine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07228534A (ja) * 1993-04-07 1995-08-29 Kyowa Hakko Kogyo Co Ltd キサンチン誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07228534A (ja) * 1993-04-07 1995-08-29 Kyowa Hakko Kogyo Co Ltd キサンチン誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUSAKA H, NAGASHIMA K, KARASAWA A: "EFFECTS OF KW-3902, AN ADENOSINE A1-RECEPTOR ANTAGONIST, ON ASCITESVOLUME IN PUROMYCIN AMINONUCLEOSIDE (PAN)-INDUCED NEPHROTIC RATS", JAPANESE JOURNAL OF PHARMACOLOGY., THE JAPANESE PHARMACOLOGICAL SOCIETY, KYOTO, JP, vol. 68, no. 02, 1 January 1995 (1995-01-01), KYOTO, JP, pages 213 - 216, XP002917825, ISSN: 0021-5198, DOI: 10.1254/jjp.68.213 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034610A1 (fr) * 1999-11-12 2001-05-17 Biogen, Inc. Polycycloalkylpurines comme antagonistes du recepteur d'adenosine
JP2003513982A (ja) * 1999-11-12 2003-04-15 バイオジェン インコーポレイテッド アデノシンレセプターアンタゴニストとしてのポリシクロアルキルプリン
US6605600B1 (en) 1999-11-12 2003-08-12 Biogen, Incorporated Adenosine receptor antagonists and methods of making and using the same
US6649600B1 (en) 1999-11-12 2003-11-18 Biogen, Inc. Adenosine receptor antagonists and methods of making and using the same
AU784556B2 (en) * 1999-11-12 2006-05-04 Biogen Idec Ma Inc. Polycycloalkylpurines as adenosine receptor antagonists
EP2070930A1 (fr) * 1999-11-12 2009-06-17 Biogen Idec MA, Inc. Polycycloalkylpurines comme antagonistes du récepteur de l'adénosine
US7579354B2 (en) 1999-11-12 2009-08-25 Kiesman William F Adenosine receptor antagonists and methods of making and using the same
BG65720B1 (bg) * 1999-11-12 2009-08-31 Biogen, Inc. Полициклоалкилпурини, антагонисти на аденозин рецептор
EP2305684A1 (fr) * 1999-11-12 2011-04-06 Biogen Idec MA Inc. Polycycloalkylpurines comme antagonistes du recepteur de l'adenosine
WO2007069675A1 (fr) * 2005-12-14 2007-06-21 Kyowa Hakko Kogyo Co., Ltd. Préparation orale facilement absorbée contenant un dérivé de la xanthine

Also Published As

Publication number Publication date
AU7675598A (en) 1999-01-04

Similar Documents

Publication Publication Date Title
JP2988711B2 (ja) 縮合プリン誘導体
US20080207649A1 (en) Method of treating brain ischemia
US4820709A (en) 6-thioxanthine derivatives
DE3921188A1 (de) Carboxamidverbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische zusammensetzungen
EP0503471A1 (fr) Hétrazépines acylaminosubstituées
EP0501379A2 (fr) Dérivés de Xanthine
WO1998057645A1 (fr) Medicament contre l'oedeme hepatique
US3925393A (en) Novel salts of vincanol
DE3239721T1 (de) Ascorbinsäure-Derivate
WO1998057644A1 (fr) Agent de prevention et remede contre la nephropathie induite par les medicaments
EP1234576B1 (fr) Remedes contre les troubles de l'alimentation
JPH0623102B2 (ja) 脂質低下剤
US3911128A (en) Substituted purines as hypolipidemics
JPH04270222A (ja) 脳機能改善剤
US3432490A (en) 2-(beta-hexamethylene imino ethyl) cyclohexanone - 2 - carboxylic acid benzyl ester and salts thereof
KR950007909B1 (ko) 치매 치료제
CA2299909C (fr) Agent therapeutique pour troubles neurodegeneratifs
BE723211A (fr)
JPH0753561A (ja) テトラヒドロチエノピリジン誘導体、その製造方法及び抗血球凝集剤
WO2005000313A1 (fr) Agent antiepileptique
JPH05105631A (ja) 抗痴呆薬
JPS61210032A (ja) 抗腫瘍剤
NL8006341A (nl) Voor roentgenstralen amorfe, fysiologisch toelaatbare zuuradditiezouten van ergotalkaloiden en dihydroer- gotalkaloiden, werkwijze voor de bereiding en toepas- sing daarvan in de therapie.
JPH0374644B2 (fr)
JPH0217554B2 (fr)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BG BR CA CN CZ HU IL JP KR MX NO NZ PL RO SG SI SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA