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WO1995001355A1 - Composes a base de 9-deazahypoxanthines utilises comme inhibiteurs de pnp - Google Patents

Composes a base de 9-deazahypoxanthines utilises comme inhibiteurs de pnp Download PDF

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Publication number
WO1995001355A1
WO1995001355A1 PCT/IB1994/000165 IB9400165W WO9501355A1 WO 1995001355 A1 WO1995001355 A1 WO 1995001355A1 IB 9400165 W IB9400165 W IB 9400165W WO 9501355 A1 WO9501355 A1 WO 9501355A1
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WO
WIPO (PCT)
Prior art keywords
compound
pyrrolo
thienyl
cycloalkyl
furanyl
Prior art date
Application number
PCT/IB1994/000165
Other languages
English (en)
Inventor
John A. Montgomery
Shri Niwas
Original Assignee
Biocryst Pharmaceuticals, Inc.
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 Biocryst Pharmaceuticals, Inc. filed Critical Biocryst Pharmaceuticals, Inc.
Priority to AU68555/94A priority Critical patent/AU6855594A/en
Publication of WO1995001355A1 publication Critical patent/WO1995001355A1/fr

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Classifications

    • 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

  • Purine nucleoside phosphorylase catalyzes the phosphorolysis of purine nucleosides in a reversible reaction. Individuals who are deficient in PNP exhibit impaired T-cell development, resulting in lowered cell-mediated immunity, but normal B-cell development, which results in normal humoral immunity. Accordingly, specific inhibitors of PNP that selectively inhibit T-cell development without damaging humoral immunity could be potentially effective against disorders in which activated T-cells are pathogenic.
  • Preferred compounds in accordance with the present invention include 8-unsubstituted-9-deazahypoxanthines.
  • Exemplary compounds include 9-benzyl-9-deazahypoxanthine, 9-(3- chlorobenzyl)-9-deazahypoxanthine, 9-(pyridin-3-yl)methyl-9- deazahypoxanthine, 9-cyclopentylmethyl-9-deazahypoxanthine, 9-(2-thienylmethyl)-9-deazahypoxanthine, 9-(3-thienylmethyl)-9- deazahypoxanthine, 9-(3-benzyl-oxybenzyl)-9-deazahypoxanthine, 9-(2-furanylmethyl)-9-deazahypoxanthine, and 9-(3-furanylmethyl)- 9-deazahypoxanthine.
  • R is phenyl substituted with trifluoromethyl
  • the phenyl group carries no more substitutions or is substituted with C J -C 3 alkyl.
  • the present invention as represented above includes tautomeric forms, such as represented by the following formula:
  • Suitable C 5 _ 9 cycloalkyl groups include monocyclic, bicyclic, and bridged structures such as cyclopentyl, cycloheptyl, cyclooctyl, cyclononyl, and adamantyl, multi-ring cycloparafins such as 1- and 2-adamantyl, 1-norbornanyl, 2-exo- norbornanyl, 2-endo-norbornanyl, 1- and 2-bicyclo[2.2.2]octanyl, 1-, 2-, 3-, 6-, and 8-bicyclo[3.2.1]octanyl, and 1-, 2-, and 3- 5 bicyclo[3.3.1]nonanyl and cycloolefins such as 1- and 2- norbornenyl.
  • the invention further relates to pharmaceutical compositions suitable for enteral, such as oral or rectal, topical, transdermal and parenteral, administration to mammals including man, which are useful to inhibit purine nucleoside phosphorylase activity and for the treatment of disorders responsive thereto, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • a further aspect of the invention relates to a method of inhibiting the phosphorolysis and metabolic breakdown of antiviral or antitumor purine nucleosides in mammals which comprises administering in conjunction therewith to a mammal in need thereof, either separately or in combination therewith, an effective purine nucleoside phosphorylase inhibiting amount of a compound of the invention or of a said compound in combination with one or more pharmaceutically acceptable carriers.
  • such relates to a method of inhibiting the phosphorolysis and metabolic breakdown of purine nucleosides known in the art, e.g., of 2 -deoxyguanosine, 2',3'- dideoxyinosine, 2 ' ,3 '-dideoxyguanosine or 2 ' ,3'-dideoxyadenosine.
  • the invention thus relates to a method of potentiating the antiviral or antitumor effect of 2' or 3'- monodeoxypurine nucleosides or of 2 ',3 '-dideoxypurine nucleosides in mammals which comprises administering in conjunction therewith to a mammal in need thereof, either separately or in combination with a said nucleoside, an effective purine nucleoside phosphorylase inhibiting amount of a compound of the invention preferably in combination with one or more pharmaceutically acceptable carriers.
  • such relates to a method of enhancing or potentiating the effect of 2' ,3'-dideoxypurine nucleosides known in the art, e.g., of 2',3'-dideoxyinosine, 2 ' ,3 '-dideoxyguanosine or 2'-3'-dideoxyadenosine for the treatment of retrovirus infections, e.g., HIV-retrovirus infections (acquired immunodeficiency syndrome, AIDS).
  • retrovirus infections e.g., HIV-retrovirus infections (acquired immunodeficiency syndrome, AIDS).
  • retrovirus infections e.g., HIV-retrovirus infections (acquired immunodeficiency syndrome, AIDS).
  • retrovirus infections e.g., HIV-retrovirus infections (acquired immunodeficiency syndrome, AIDS).
  • retrovirus infections e.g., HIV-retrovirus infections (acquired immunodeficiency syndrome, AIDS).
  • the pharmaceutically acceptable effective dosage of active compound of the invention to be administered is dependent on the species of warm-blooded animal (mammal) , the body weight, age and individual condition, and on the form of administration.
  • the pharmaceutical composition may be oral, topical, parenteral, suppository or other form which delivers the compound into the bloodstream or target organ of a mammal to be treated.
  • An oral form has from about 1 to about 150 mg of the compound for an adult (50 to 70 kg) which is mixed together with pharmaceutically acceptable diluents such as lactose. In a typical capsule, 25 mg of the compound are mixed together with 192 mg lactose, 80 mg modified starch and 3 mg magnesium stearate. Injectable forms of the compound are also contemplated for administration.
  • the present invention is also useful with other therapeutic agents.
  • a daily dosage for a human weighing 50 to 70 kg of 1-50 mg/kg inhibits metabolic destruction of certain anticancer agents such as beta-2 -deoxy-6-thioguanosine and antiviral agents such as 2',3'-dideoxyinosine, an anti-AIDS drug.
  • anticancer agents such as beta-2 -deoxy-6-thioguanosine and antiviral agents such as 2',3'-dideoxyinosine, an anti-AIDS drug.
  • anticancer agents such as beta-2 -deoxy-6-thioguanosine and antiviral agents such as 2',3'-dideoxyinosine, an anti-AIDS drug.
  • the dimethylaminopyrrole derivative pictured above is made in this example.
  • the aminopyrrole is prepared following the procedure in Montgomery et al., J. Med. Chem. , 1993, 3 ⁇ , 55-69 (Compound 71).
  • the aminopyrrole (5 g, 16.5 mmol), is treated with N,N-dimethylformamide dimethyl acetal (50 ml) under argon and heated 24 hours at 60-70°C. After the reaction mixture is evaporated to dryness, it is redissolved in 50 ml CH 2 C1 2 , filtered and diluted with petroleum ether (P.E.) until cloudy. The mixture is scratched to induce crystallization and slowly diluted with an additional 400 ml P.E. The product is collected, washed with P.E. and dried.
  • EXAMPLE 4 7-(3-Pyridylmethyl)-3H,5H-pyrrolo[3,2-d]pyrimidine-4-one is prepared in this example.
  • a mixture of 2-methylthio-7-(3- pyridylmethyl)-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidine (prepared following the procedure in Montgomery et al., J. Med. Chem., 1993, .36, 55-69 (Compound lOw) ) (400 mg) , hydrazine hydrate (500 ⁇ l) and 20% Pd(OH) 2 on carbon (400 mg) in ethanol (75 ml) is refluxed for 24 hours.
  • More hydrazine hydrate (300 ⁇ l) and 20% Pd(OH) 2 on carbon (200 mg) are added for three consecutive days the mixture is refluxed for a total period of 5 days before it is filtered through Celite and the filtrate evaporated to dryness. The residue is stirred with methanol (10 ml) and the precipitate removed by filtration. The filtrate is concentrated and passed through a column of silica gel with EtOAc and MeOH (3:1 to 1:1) to give pure product.
  • EXAMPLE 8 Compounds in accordance with the present invention are tested and compared with the corresponding guanine derivatives.
  • a purine nucleoside phosphorylase (PNP) enzyme assay is performed in which the PNP activity (IC 50 ) for each of the compounds is found, which is determined radio chemically by measuring the formation of [ 1 C]-hypoxanthine from [ 14 C]-inosine (see Biomedicine. 1980, 33. 39) using calf spleen as the enzyme source.
  • the results at 1 mM phosphate are reported in the following table. Table 1

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

Abstract

L'invention se rapporte à des composés de formule (I) dans laquelle R1 est cycloalkyle en C5-9, phényle facultativement substitué par une ou deux moitiés choisies dans le groupe consistant en halogène, alkyle en C1-C3, alcoxy en C1-C3, benzyloxy, hydroxy et trifluorométhyle, 2- ou 3-thiényle, 2- ou 3-furanyle, 2-, 3-, ou 4-pyridyle, ou un de leurs sels ou hydrates; ces composés sont utiles comme inhibiteurs de la purine nucléoside phosphorylase (PNP).
PCT/IB1994/000165 1993-06-30 1994-06-20 Composes a base de 9-deazahypoxanthines utilises comme inhibiteurs de pnp WO1995001355A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU68555/94A AU6855594A (en) 1993-06-30 1994-06-20 9-deazahypoxanthines as pnp inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8463193A 1993-06-30 1993-06-30
US08/084,631 1993-06-30

Publications (1)

Publication Number Publication Date
WO1995001355A1 true WO1995001355A1 (fr) 1995-01-12

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PCT/IB1994/000165 WO1995001355A1 (fr) 1993-06-30 1994-06-20 Composes a base de 9-deazahypoxanthines utilises comme inhibiteurs de pnp

Country Status (4)

Country Link
AU (1) AU6855594A (fr)
EE (1) EE9400058A (fr)
LT (1) LT3337B (fr)
WO (1) WO1995001355A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831829A1 (fr) * 1995-06-07 1998-04-01 Pfizer Inc. Derives de pyrimidine heterocycliques a noyaux condenses
US6355244B1 (en) 1997-11-17 2002-03-12 University Of Kentucky Research Foundation Methods and compositions for the treatment of psoriasis
US6395733B1 (en) 1995-06-07 2002-05-28 Pfizer Inc Heterocyclic ring-fused pyrimidine derivatives
WO2005019219A1 (fr) * 2003-08-26 2005-03-03 Teijin Pharma Limited Dérivé de pyrrolopyrimidinone
US7557113B2 (en) 2003-08-26 2009-07-07 Teijin Pharma Limited Substituted pyrrolo[3,2-d]pyrimidine derivatives
US7763257B2 (en) 2004-12-09 2010-07-27 Christina Juneau Compositions comprising transforming growth factor (TGF)-β1 and TGF-β2 in admixture of proteins obtained from dairy products
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US10968307B2 (en) 2014-06-23 2021-04-06 Carbon, Inc. Methods of producing three-dimensional objects from materials having multiple mechanisms of hardening
WO2021083438A1 (fr) * 2019-10-30 2021-05-06 Ustav Organicke Chemie A Biochemie Av Cr, V. V. I. Inhibiteurs de la synthèse de la purine nucléoside phosphorylase et leur utilisation pour le traitement de la leucémie lymphoblastique aiguë à lymphocytes t et du lymphome

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0260491A1 (fr) * 1986-08-26 1988-03-23 Warner-Lambert Company 9-Déazaguanines
US4923872A (en) * 1986-08-26 1990-05-08 Warner-Lambert Co. Analogues of pyrrolo[3,2d]pyrimidin-4-ones

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0460116T3 (da) 1989-02-27 1998-03-30 Biocryst Pharm Inc 9-substitueret-8-usubstitueret-9-deazaguaniner

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0260491A1 (fr) * 1986-08-26 1988-03-23 Warner-Lambert Company 9-Déazaguanines
US4923872A (en) * 1986-08-26 1990-05-08 Warner-Lambert Co. Analogues of pyrrolo[3,2d]pyrimidin-4-ones

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831829A1 (fr) * 1995-06-07 1998-04-01 Pfizer Inc. Derives de pyrimidine heterocycliques a noyaux condenses
EP0831829A4 (fr) * 1995-06-07 1998-11-25 Pfizer Derives de pyrimidine heterocycliques a noyaux condenses
US6395733B1 (en) 1995-06-07 2002-05-28 Pfizer Inc Heterocyclic ring-fused pyrimidine derivatives
US6355244B1 (en) 1997-11-17 2002-03-12 University Of Kentucky Research Foundation Methods and compositions for the treatment of psoriasis
RU2358975C2 (ru) * 2003-08-26 2009-06-20 Тейдзин Фарма Лимитед Пирролопиримидиноновые производные
JPWO2005019219A1 (ja) * 2003-08-26 2006-10-19 帝人ファーマ株式会社 ピロロピリミジノン誘導体
WO2005019219A1 (fr) * 2003-08-26 2005-03-03 Teijin Pharma Limited Dérivé de pyrrolopyrimidinone
US7557113B2 (en) 2003-08-26 2009-07-07 Teijin Pharma Limited Substituted pyrrolo[3,2-d]pyrimidine derivatives
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US7763257B2 (en) 2004-12-09 2010-07-27 Christina Juneau Compositions comprising transforming growth factor (TGF)-β1 and TGF-β2 in admixture of proteins obtained from dairy products
US10968307B2 (en) 2014-06-23 2021-04-06 Carbon, Inc. Methods of producing three-dimensional objects from materials having multiple mechanisms of hardening
WO2021083438A1 (fr) * 2019-10-30 2021-05-06 Ustav Organicke Chemie A Biochemie Av Cr, V. V. I. Inhibiteurs de la synthèse de la purine nucléoside phosphorylase et leur utilisation pour le traitement de la leucémie lymphoblastique aiguë à lymphocytes t et du lymphome
CZ309199B6 (cs) * 2019-10-30 2022-05-11 Ústav organické chemie a biochemie AV ČR, v. v. i. Inhibitory purinnukleosidfosforylasy, jejich příprava a použití k léčení T-buněčné akutní lymfoblastické leukémie a lymfomů

Also Published As

Publication number Publication date
AU6855594A (en) 1995-01-24
EE9400058A (et) 1995-12-15
LT3337B (en) 1995-07-25
LTIP1982A (en) 1995-01-31

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