Nova Patents
IL147195A

2-c-pyrazolyl adenosine derivatives having a2a receptor agonist activity, pharmaceutical compositions containing them and their use in coronary diagnosis

Abstract

This record has no abstract on file.

IL147195A, drawing sheet 1
Sheet 1 of 42

Term

No projected expiry on record.

  1. Priority
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  3. Published
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45 claims: 8 independent, 37 dependent

  1. 1
    A composition of matter having the formula:wherein R 1 is —CH 2 OH, and —C(=O)NR 5 R 6 : R 2 is selected from the group consisting of hydrogen. Cj.!5 alkyd, C2-15 alkenyl, C2.!5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alky־L alkenyl, alkynyl. aryl, heterocyclyl, and heteroaiyl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, NO?, heterocyclyl. aryl, heteroaryl, CF'3, CN, OR , sr 20 , n(r 2c ')2, s(0)r 22 , so?r-, so2n(r 20 )2, so2nr 20 cor־, SO2NR 20 CO2R“, SO2K 20 CON(R 20 )?, NR 20 C02R-,K^. 20 CON(R 20 ) 2־ NR 20 C(MR 20 )NHR 20 , ;COR 20 , CO2R 20 , CON(R 20 )2, conr 2c so?r~ nr 20 so2r־, so2nr 20 co2r 22 , oconr. 20 so?r 22 , OC(0)R 2c , C(O)OCH2OC(O)R 20 l and 0C0N(R 2c ')2 and wherein each optional heteroaiyl, aryl, and heterocyclyl substituent is optionally substituted with halo, NO 2 , alkyl. CF 3 , amino, mono- or dialkjdamino. alkyl or aryl or heteroary] amide. NCOR~, NR 20 SO? R 22 , COR 20 , CO7R 20 , CON(R~°)2: NR 20 CON(R 20 )2, OC(O)R 20 , OC(0)N(R 20 )2, SR 20 , S(O)R~. SO? R 22 . SO2N(R 20 )?, CN, or OR 20 ;R. R 4 are each individually selected from the group consisting of hydrogen, C!.! 5 alkyl. C2.'15 alkenyl, C2.]5 alkynyl, heterocyclyl, aryl, and heteroaryl, halo, NO?, CF3, CN, OR 20 , SR 20 , N(R 20 )?, S(O)R 22 , SO2R 22 , SO?NfR 20 )2. SO 2 NR 20 COR 22 ;S02NR 2c C02R 22 , S02 NR 20 CON(R 20 )2, NR 20 C02R 22 ,NR 20 CON(R 20 )2:NR 20 C(NR 20 )NW 20 ;cor 20 , co2r 20 , CON(R 20 )2, CONR 20 S02R 22 , NR 20 SO?R 22 , S02NR 20 C02R 22 , OCONR 20 S02R 22 , OC(O)R 20 , C(O)OCH2OCvO)R 20 : and OCON(R 20 ) 2 wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroary] substituents are optionally substituted with from 1 to 3 substituents individually selected from tire group consisting of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF;. CN, OR 20 , SR 20 , N(R 20 )2, S(O)R 22 , SO2R 22 , SO2N(R 20 )2, SO 2 NR 20 COR 22 , SO2NR 20 CO2R 22 , SO 2 NR 20 CON(R 20 )2, NR 20 C02R 22 , NR 20 CON(R 20 ) 2 , NR 2o C(NR 2o )NHR 2 °, COR 20 , CO 2 R 20 , CON(R 20 )2, conr 20 so2r 22 , nr 20 so2r 22 , so2nr 20 co 2 r 22 , OCONR 20 SO2R 22 , OC(O)R 20 , C(O)OCH2OC(O)R 20 , and OCON(R 20 )2 and wherein each optional heteroaryl, aryl, and heterocyciyl substituent is optionally substituted with halo, NO2, alkyl, CF3, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NCOR 22 , NR 20 SO2R 22 , COR 20 , CO2R 20 , CON(R 20 )2, NR 20 CON(R 20 )2j OC(O)R 20 , OC(O)N(R 20 )2, SR 20 , S(O)R 22 , SO2R 22 , SO2N(R 20 )2, CN, and OR 20 ;R 5 and R 6 are each individually selected from H, C1.! 5 alkyl with from 1 to 2 substituents independently selected from the group consisting of halo, NO 2 , heterocyciyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 )2, S(O)R 22 , SO2R 22 , SO2N(R 20 )2, SO 2 NR 20 COR 22 , S0 2 NR 20 C02R 22 , SO2NR 20 CON(R 20 )2, NR 20 CO2R 22 , NR 20 CON(R 20 )2, NR 20 C(NR 20 )NHR 20 , COR 20 , CO2R 20 , CON(R 20 )2, conr 20 so2r 22 , NR 20 SO2R 22 , SO2NR 20 CO2R 22 , OCONR 20 SO2R 22 , OC(O)R 20 , C(O)OCH2OC(O)R 20 , and OCON(R )2, and wherein each optional heteroaryl, aryl, and heterocyciyl substituent is optionally substituted with halo, NO2, alkyl, CF3, amino, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, NCOR 22 , NR 20 SO2R 22 , COR 20 , CO2R 20 , CON(R 20 )2, NR 20 CON(R 20 )2, OC(O)R 20 , OC(0)N(R 20 )2, SR 20 , S(O)R 22 , SO2R 22 , SO2N(R 20 )2, CN, and OR 20 ;R is selected from the group consisting of H, C!.!5 alkyl, C 2 .!5 alkenyl, C 2 .! 5 alkynyl, heterocyciyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyciyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-C1-6 alkyl, CF 3 , aryl, and heteroaryl;and R 22 is a member selected from the group consisting of Cm5 alkyl,C2.!5 alkenyl, C2.!5 alkynyl, heterocyciyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyciyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-C!.6 alkyl, CF3, and heteroaryl wherein, when R 1 is CH2OH, and R 3 is H and R 4 is H, and the pyrazole ring is attached through C 4 , R 2 is not H.
  2. 4
    5. The composition of claim ! wherein R 2 is independently selected from the group consisting of hydrogen;Cj_! 5 alkyl and aryl, wherein the alkyl and aryl substituents are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, OR 20 , aryl, C?3. CN, and wherein each optional aryl substituent is optionally substituted with halo, alkyl, CF;or CN;, ' R. and R are each individually selected from the group consisting of hydrogen, C!. צג alkyl, aryl, halo, CF3, and CN, wherein the alkyl, and aryl substituents are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, aryl, CF3, CN, and wherein each optional aryl substituent is optionally substituted with halo, alkyl, CF 3 or CN;R and R are each individually selected from H, and C].!5 alkyl;and R 0 is selected from H and C!-6 alkyl.
  3. 5
    6. The composition of claims 1 or 2 or 3 or 4 or 5 wherein the point of attachment of the pyrazole zing is C-4. OH
  4. 6
    7. The composition of claims 1 or 2 or 3 or 4 or 5 wherein the point of attachment of the pwazole ringisC-3. k!e 2 OH. OH
  5. 7
    8. The composition of claims 1 or 2 or 3 or 4 or 5 wherein the point of attachment of the pyrazole ring is C-5.
  6. 8
    9. The composition of claims 6 or 7 or 8 wherein R 2 is CH?OH.
  7. 24
    26. The composition of claim ך wherein R 1 is —CONHEt:R־ is independently selected from the group consisting of hydrogen, and C!_6 alkyl that is optionally substituted with aryl that is optionally substituted with alkyl: and R־ and R 4 are each hydrogen.
  8. 25
    27. The composition of claim S wherein R ! is —CONHEt; and R is selected from hydrogen, and methyl:R 3 and R׳.are each individually selected from the group consisting of hydrogen, and C!-6 alkyl, wherein the alkyd, is optionally substituted with aryl that is optionally substituted with alkyl;and R 4 is selected from hydrogen and methyl.
  9. 29
    31. The use of claim 29 wherein the mammal is a human.
  10. 32
    34. A compound selected from the group consisting of:(4S,2R,3R,5R)-2-{6-amino-2-[l-decylpyrazol-4-yl]purin־9־yl}5־-(hydroxymethyl)oxolane-3,4-diol, (4S,2R3 ־ R,5R)-26}־-amino-2-[l-(cyclohexylmethyl)pyrazol-4-yl]purin-9-yl}-5- (hydroxymethyl) 54 147195/4 oxolane-3 >4-diol, ׳ (4S,2R,3R,5R)-2-{6־amino-2-[l-(2-phenylethyl)pyrazol-4-yl]purin-9-yl}-5-(hydroxymetbyl) oxolane-3,4-diol, (4S,2R,3R,5R)-2-{6-amino-2-[ 1 3)־-cyclohexylpropyl)pyrazol־4־yl]purin-9-yl} - 5-(hydroxymethyl) oxolane-3,4-diol, and (4 S,2R,3R,5R)-2- {6-amino-2-[ 1 -(2-cyclohexylethyI)pyrazol-4-yl]purin-9-yl} -5 -(hydroxymethyl) oxolane-3,4-diol. 5. Use of a therapeutically effective amount of a compound of claim 34 in the preparation of a medicament adapted to stimulate coronary vasodilatation in a mammal, wherein said coronary vasodilatation is sufficient to stress the heart and induce ε coronary-steal situation for the purposes of imaging the heart.
Independent claims10