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Novel 4-amino-5,6-substituted thiopheno 2,3-d]pyrimidines

A compound, alkyl technology, applied in the field of 4-amino-5, can solve problems such as cell death

Inactive Publication Date: 2004-08-18
BAYER CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Bang et al. ((1994) Proc. Natl. Acad. Sci. USA 91:5330-5334) reported that the growth of prostate cancer cell lines DU 145 and LNCaP was inhibited by administration of cAMP derivatives and phosphodiesterase inhibitors, And a durable phenotypic transition from epithelial to neuronal morphology was observed; Matousovic et al. ((1995) J. Clin. Invest. 96:401-410) suggested that inhibitors of cyclic nucleotide phosphodiesterase isozymes Has the potential to regulate the proliferation of mesangial cells; Joulain et al. ((1995) J.Mediat.Cell Signal 11:63-79) reported that cyclic nucleotide phosphodiesterase is an important target involved in the control of lymphocyte proliferation; Deonarain et al. ((1994) Brit. J. Cancer 70:786-94) proposed a tumor-targeted approach to cancer treatment involving the intracellular delivery of phosphodiesterases to specific cellular compartments, resulting in cell death

Method used

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  • Novel 4-amino-5,6-substituted thiopheno 2,3-d]pyrimidines
  • Novel 4-amino-5,6-substituted thiopheno 2,3-d]pyrimidines
  • Novel 4-amino-5,6-substituted thiopheno 2,3-d]pyrimidines

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Embodiment approach

[0499] Preferred embodiments include:

[0500] Preferred compounds include compounds of formula VI and pharmaceutically acceptable salts thereof:

[0501]

[0502] in

[0503] R 1 and R 2 independently selected from

[0504] hydrogen,

[0505] Alkyl having 1-8 carbon atoms,

[0506] Alkenyl having 2-8 carbon atoms,

[0507] Alkynyl having 2-8 carbon atoms,

[0508] Cycloalkyl with 3-7 carbon atoms,

[0509] Heterocycloalkyl having 2-6 carbon atoms and 1-2 heteroatoms selected from NH, S and O,

[0510] An aryl group having 6-12 carbon atoms, which may be substituted by the following groups: an alkyl group having 1-6 carbon atoms, an alkenyl group having 2-6 carbon atoms, an alkenyl group having 2-6 Alkynyl with carbon atoms, alkoxy with 1 to 6 carbon atoms, halogen, haloalkyl with 1 to 6 carbon atoms and a number of halogen atoms up to the level of perhalogenation, with 1 to 6 carbon atoms and haloalkoxy of the number of halogen atoms up to the level of perhalogen...

Embodiment 1

[0915] Preparation of ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate

[0916]

[0917]To a solution of cyclopentanone (20 g, 0.23 g) and ethyl cyanoacetate (26.9 g, 0.25 mol) in 80 mL of ethanol was added sulfur powder (8.0 g, 0.25 mol) under argon atmosphere and stirring. To this mixture was added dropwise 17.4 g of diethylamine (0.238 mol) via an addition funnel over 25 minutes, and stirred at room temperature for 3 hours. The solvent was removed and the residue was partitioned between 60 mL water and 60 mL ethyl acetate. The organic layer was extracted with 3 x 60 ml ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and dried over magnesium sulfate. The solids were removed by filtration and the solvent was removed in vacuo to give the crude product which was used without further purification.

Embodiment 2

[0919] Preparation of ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate

[0920]

[0921] To a mixture of 250 g tetrahydropyran-4-one (0.25 mol), 28.2 g ethyl cyanoacetate (0.25 mol, 26.6 mL) and 18.26 g diethylamine (25.8 mL) in 100 mL ethanol was added 8.4 g sulfur (0.262 mol). Ensuring a slightly exothermic reaction, the mixture formed a dark red solution. After stirring overnight at room temperature under an atmosphere of argon, an orange precipitate formed. The mixture was poured into 200 g of ice and the resulting solid was filtered off by filtration. The solid was washed with 2 x 200 mL of water, then with 100 mL of diethyl ether. A light orange solid was obtained weighing 44.6 g (78.6%), TLC (90:1, EtOAc:Hexane): R f , 0.16.

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Abstract

The invention relates to 4-amino-5,6-substituted thiopheno [2,3-d] pyrimidines, pharmaceutical compositions containing the same and their use to treat or prevent diseases and conditions mediated by the phosphodiesterase enzyme 7B(PDE7B). Diseases and conditions mediated by PDE7B include osteoporosis, osteopenia and asthma.

Description

field of invention [0001] The present invention relates to 4-amino-5,6-substituted thieno[2,3-d]pyrimidine compounds, pharmaceutical compositions containing said compounds, and said compounds in the treatment or prevention of phosphodiesterase 7 B (PDE7 B )-mediated diseases and conditions. by PDE7 B Mediated diseases and conditions include osteoporosis, osteopenia, and asthma. The present invention also relates to methods of preparing 4-amino-5,6-substituted thieno[2,3-d]pyrimidine compounds, and methods of preparing compositions containing said compounds. Background of the invention [0002] Cyclic nucleotide phosphodiesterase (PDE) exhibits specificity for purine cyclic nucleotide substrates and catalyzes the hydrolysis of cyclic AMP (cAMP) and cyclic GMP (cGMP) (Thompson, W.J. (1991) Pharma.Ther.51 :13-33). Cyclic nucleotide phosphodiesterases regulate steady-state levels of cAMP and cGMP and regulate the magnitude and duration of cyclic nucleotide signaling. These...

Claims

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Application Information

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IPC IPC(8): A61K31/4365A61K31/519A61K31/5377A61K31/541A61P1/04A61P1/18A61P3/10A61P9/00A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P19/02A61P19/10A61P25/00A61P25/08A61P25/24A61P29/00A61P35/00A61P37/02A61P37/06A61P37/08A61P43/00C07D495/04C07D495/14C07D521/00
CPCC07D495/14C07D495/04C07D231/12A61K31/519C07D249/08A61K31/4365A61K31/5377C07D233/56A61K31/541A61P1/04A61P1/18A61P11/00A61P11/02A61P11/04A61P11/06A61P17/00A61P17/06A61P19/02A61P19/10A61P25/00A61P25/08A61P25/24A61P29/00A61P35/00A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00A61P9/00A61P9/08A61P9/10A61P3/10
Inventor A·施托勒D·E·比雷尔陈元伟范冬平B·哈特M·K·莫纳汉W·J·斯科特
Owner BAYER CORP
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