WO2002016364A1 - Derives de pyrazolopyrimidinone polyethoxylee, leur procede de preparation et compositions pharmaceutiques contenant ces derives pour traiter l'impuissance - Google Patents

Derives de pyrazolopyrimidinone polyethoxylee, leur procede de preparation et compositions pharmaceutiques contenant ces derives pour traiter l'impuissance Download PDF

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Publication number
WO2002016364A1
WO2002016364A1 PCT/KR2000/000951 KR0000951W WO0216364A1 WO 2002016364 A1 WO2002016364 A1 WO 2002016364A1 KR 0000951 W KR0000951 W KR 0000951W WO 0216364 A1 WO0216364 A1 WO 0216364A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
following formula
formula
pyrazolo
Prior art date
Application number
PCT/KR2000/000951
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English (en)
Inventor
Bong-Youl Chung
In-Sang Lee
Bong-Jun Park
Young-Keun Kim
Sung-Ji Kim
Seung-Hyun Yoon
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Lg Life Sciences 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.)
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Publication date
Application filed by Lg Life Sciences Ltd. filed Critical Lg Life Sciences Ltd.
Priority to AU2000267375A priority Critical patent/AU2000267375A1/en
Priority to PCT/KR2000/000951 priority patent/WO2002016364A1/fr
Publication of WO2002016364A1 publication Critical patent/WO2002016364A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the sildenafil citrate is reported to exhibit a maximum plasma concentration no earlier than 60 minutes from oral administration and also to show a decrease of absorption rate in an amount of about 29% average when it is administered together with fatty acid. Therefore, it may cause some problems when used for the aged who require a very small amount of dose and for the special patients who are suffered from kidney or liver failure, etc. It may also cause a side effect of the decrease of blood pressure, and must not be used in a combined treatment with nitrate preparations.
  • the present inventors extensively studied to improve the most serious defect of the aforementioned pyrazolo pyrimidinone derivatives, i.e., low solubility in water.
  • the pyrazolo pyrimidinone derivatives according to the present invention have a high water solubility and minimized side effects, and then completed the present invention.
  • the present invention relates to new polyethoxylated pyrazolo pyrimidinone derivatives having a variety of physical and chemical characteristics, wherein the neutral polyether, that is, polyethylene glycol, is combined by a covalent bond.
  • the neutral polyether that is, polyethylene glycol
  • the present compounds do not have a basic but a neutral molecular structure, they have a superior water solubility to the existing inhibitors against cyclic guanosine 3',5'-monophosphate phosphodiesterase(cGMP PDEs), for example, sildenafil citrate.
  • the present invention provides compounds of the following formula (1):
  • Ri represents hydrogen; C ⁇ ⁇ C 6 alkyl; C ⁇ C 6 alkyl substituted by C 3 ⁇ C 6 cycloalkyl; C 3 ⁇ C 5 cycloalkyl; Ci ⁇ C 3 perfluoroalkyl; C 3 ⁇ C 6 alkenyl; C 3 ⁇ C 6 alkynyl; or Ci ⁇ C 3 alkoxy C 2 ⁇ C 6 alkyl; wherein the substituents are present in straight-chain or branched type; and n represents an integer of 2 —400, or pharmaceutically acceptable salts thereof.
  • the compound of formula (1) may be prepared from a compound of the following formula (2):
  • the compound of formula (2) used in the above reaction may be prepared by hydrolyzing a compound of the following formula (3a):
  • Ri and n are defined as previously described, and
  • Ri and n are defined as previously described, and R 2 represents hydrogen, C ⁇ -C 4 alkyl, or sulfonyl group such as p-toluenesulfonyl, Ci-
  • a suitable inert solvent for example, a solvent mixture of methanol-water in the presence of a suitable strong base, for example, potassium hydroxide or sodium hydroxide to remove the protecting group of R 2 ', removing the solvent, and then reacting with a known compound of the following formula (4):
  • the compound of formula (3) may be prepared by a process characterized in that
  • the compound of formula (6) used in the above reaction may be prepared by introducing a reactive leaving group of X (where, X represents halogen, preferably bromine or iodine, or sulfonate) into a compound of the following formula (6a):
  • the compound according to the present invention When used for clinical purpose, it is administered in an amount ranging from 0.001 to 50mg, preferably from 0.01 to 50mg, most preferably from 0.1 to 20mg per kg of body weight a day.
  • the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex, hygienic condition and diet of the subject patient, time and method of administration, mixing ratio of the agent, severity of the disease to be treated, etc.
  • Injections for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent.
  • Solvents which can be used for preparing injections include the conventional solvents or suspending media such as water, sterilized fixing oil, etc.
  • l-Methyl-3-n-propylpyrazole-5-carboxylic acid(12.1g, 0.072mol) as obtained above was introduced into a mixture of fuming sulfuric acid(13m ⁇ ) and fuming nitric acid(llm ⁇ ) while maintaining a temperature of 60 ° C or less.
  • the mixture was heated at 60 ° C for 12 hours, cooled, and then added dropwise to an ice.
  • the precipitate was filtered to give nitropyrazole(11.5g, 75%, m.p.124-127 ° C) as a white solid.
  • Triethyleneglycol mono methyl ether(32.84g, 0.2mol), toluene(200" ⁇ ), p-toluene sulfonyl chloride(43.85g, 0.23mol), and triethylamine(60.7g, O. ⁇ mol) were mixed together and stirred at room temperature.
  • the reaction solution was reacted for further 4 hours.
  • a large quantity of water was added to separate the layer and then dried over MgSO 4 .
  • the solvent was removed under reduced pressure to give the title compound(60.4g, 95%) as a liquid.
  • the title compound(65g, 92%) as a liquid was obtained according to the same procedure as Preparation 2 except that polyethyleneglycol methyl ether( Average molecular weight: 550)(55g, 0. lmol) was used instead of triethyleneglycol mono methyl ether.
  • the resulting tissue section was introduced into an organ chamber in which lOcc of Kreb's solution(sodium chloride 118.3, potassium chloride 4.7, magnesium sulfate 0.6, potassium hydrogen phosphate 1.2, calcium hypochloride 2.5, sodium hydrogen carbonate 25.0 and glucose 11.1 ; each unit is mM/! ) was contained. After both ends of the section were tied together with a suture, one end was bound to a L-shaped metallic ring to be fixed in the organ chamber and the other end was bound to a fixed ring of a tension converter. Mixed gas of 95% oxygen(O 2 ) and 5% carbon dioxide(CO2) was passed through, and pH 7.4 and a temperature of 37 ° C were maintained. The section of corpus cavernosum was culcured for 2 hours during which the medium was replaced with a fresh one at every 20 — 30minutes.
  • the section was washed and cultivated again and then, phenylephrine(10 "8 — 10 " 3 M) was added as an accumulated concentration to measure the maximum tension at the time of contraction of the section.
  • concentration which induces EC50 was calculated.
  • the compounds of formula (1) show a significantly high relaxation rate (p ⁇ 0.01) compared with sildenafil citrate at concentrations of 10 "5 — 10 "4 M.
  • OJm-0 of distilled water was added to 10 "5 mol of the compound of formula (1) to observe whether or not the compound is dissolved in water.
  • 40/ ⁇ of the aqueous solution was diluted with lm-g of acetonitrile, and the remaining aqueous solution was filtered through a filter having a pore size of 0.1 m.
  • 40/t ⁇ of the filtrate was diluted with l ⁇ ti! of acetonitrile. Those two kinds of samples were analyzed by liquid chromatography to determine whether or not the compound is dissolved.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de pyrazolopyrimidinone polyéthoxylée ou leurs sels acceptables sur le plan pharmaceutique, un procédé servant à les préparer et des compositions pharmaceutiques les contenant afin de traiter l'impuissance. Elle concerne, de plus, des intermédiaires obtenus pendant le déroulement du procédé décrit ci-dessus et le procédé de préparation de ces intermédiaires.
PCT/KR2000/000951 2000-08-23 2000-08-23 Derives de pyrazolopyrimidinone polyethoxylee, leur procede de preparation et compositions pharmaceutiques contenant ces derives pour traiter l'impuissance WO2002016364A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2000267375A AU2000267375A1 (en) 2000-08-23 2000-08-23 Polyethoxylated pyrazolo pyrimidinone derivatives, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence
PCT/KR2000/000951 WO2002016364A1 (fr) 2000-08-23 2000-08-23 Derives de pyrazolopyrimidinone polyethoxylee, leur procede de preparation et compositions pharmaceutiques contenant ces derives pour traiter l'impuissance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2000/000951 WO2002016364A1 (fr) 2000-08-23 2000-08-23 Derives de pyrazolopyrimidinone polyethoxylee, leur procede de preparation et compositions pharmaceutiques contenant ces derives pour traiter l'impuissance

Publications (1)

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WO2002016364A1 true WO2002016364A1 (fr) 2002-02-28

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WO (1) WO2002016364A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100361834B1 (ko) * 2000-08-23 2002-11-22 주식회사 엘지생명과학 폴리에톡실레이티드 피라졸로피리미디논 유도체, 그의제조방법 및 그를 포함하는 발기부전증 치료용 약제학적조성물
WO2004108726A1 (fr) 2003-06-06 2004-12-16 Tianjin Tasly Group Co., Ltd. Derives phenyl-5,7-dialalkyl-3,7-dihydropyrrol[2,3-d]pyrimidine-4-one substitues en position 2, leur preparation et leur utilisation en pharmacie
CN103044331A (zh) * 2013-01-14 2013-04-17 常州市亚邦医药研究所有限公司 制备西地那非中间体4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺的新方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017772A1 (fr) * 1979-03-28 1980-10-29 Bayer Ag Procédé d'amélioration de la solubilité d'agents biologiquement actifs dans l'eau et dans les alcools aliphatiques inférieurs ainsi que composés à solubilité améliorée
EP0463756A1 (fr) * 1990-06-20 1992-01-02 Pfizer Limited Pyrazolopyrimidones comme agents antiangineux
US5089261A (en) * 1989-01-23 1992-02-18 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
US5622685A (en) * 1990-05-30 1997-04-22 Deutches Krebsforchunszentrum Stiftung Des Offentlichen Rechts Polyether-substituted porphyrin anti-tumor agents
WO1998049166A1 (fr) * 1997-04-25 1998-11-05 Pfizer Limited PYRAZOLOPYRIMIDINONES INHIBANT LA PHOSPHODIESTERASE D'ACIDE GUANOSINE-3'5'-MONOPHOSPHATE CYCLIQUE (cGMP PDE5) S'UTILISANT POUR TRAITER DES DYSFONCTIONS SEXUELLES

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017772A1 (fr) * 1979-03-28 1980-10-29 Bayer Ag Procédé d'amélioration de la solubilité d'agents biologiquement actifs dans l'eau et dans les alcools aliphatiques inférieurs ainsi que composés à solubilité améliorée
US5089261A (en) * 1989-01-23 1992-02-18 Cetus Corporation Preparation of a polymer/interleukin-2 conjugate
US5622685A (en) * 1990-05-30 1997-04-22 Deutches Krebsforchunszentrum Stiftung Des Offentlichen Rechts Polyether-substituted porphyrin anti-tumor agents
EP0463756A1 (fr) * 1990-06-20 1992-01-02 Pfizer Limited Pyrazolopyrimidones comme agents antiangineux
WO1994028902A1 (fr) * 1993-06-09 1994-12-22 Pfizer Limited Pyrazolopyrimidinones utilisees pour traiter l'impuissance
WO1998049166A1 (fr) * 1997-04-25 1998-11-05 Pfizer Limited PYRAZOLOPYRIMIDINONES INHIBANT LA PHOSPHODIESTERASE D'ACIDE GUANOSINE-3'5'-MONOPHOSPHATE CYCLIQUE (cGMP PDE5) S'UTILISANT POUR TRAITER DES DYSFONCTIONS SEXUELLES

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100361834B1 (ko) * 2000-08-23 2002-11-22 주식회사 엘지생명과학 폴리에톡실레이티드 피라졸로피리미디논 유도체, 그의제조방법 및 그를 포함하는 발기부전증 치료용 약제학적조성물
WO2004108726A1 (fr) 2003-06-06 2004-12-16 Tianjin Tasly Group Co., Ltd. Derives phenyl-5,7-dialalkyl-3,7-dihydropyrrol[2,3-d]pyrimidine-4-one substitues en position 2, leur preparation et leur utilisation en pharmacie
US7741483B2 (en) 2003-06-06 2010-06-22 Yangtze River Pharmaceutical (Group) Co., Ltd. Process for making substituted pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of phosphodiesterase 5
CN103044331A (zh) * 2013-01-14 2013-04-17 常州市亚邦医药研究所有限公司 制备西地那非中间体4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺的新方法
CN103044331B (zh) * 2013-01-14 2017-09-15 常州市亚邦医药研究所有限公司 制备西地那非中间体4‑氨基‑1‑甲基‑3‑正丙基吡唑‑5‑甲酰胺的新方法

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