US 7,115,592 B2Granted

Phosphonate substituted pyrimidine compounds and methods for therapy

AssigneesInstitute of Organic Chemistry, Biochemistry of the Academy of Sciences of the Czech Republic

InventorsJan M. R. Balzarini, Erik D. A. De Clercq, Antonin Holy, Dana Hockova

Life of this patent

Estimating the term…

Abstract

Novel compounds are provided having formula (I) where R1, R2, R3, R4, Z, X and * are defined herein. Also provided are antiviral methods for use and processes for synthesis of the compounds of formula (I).

Claims34

Dependent claims

A compound of the formula (I):

wherein
* designates a chiral carbon atom;
R1 is H, amino, or methylsulfanyl;
R2 is H, methyl, halo, —N(R5)2, hydroxy, or protected hydroxy;
R3 is independently methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R4 is selected from:
(i) C1 to C10 alkyl,
(ii) C2 to C10 alkenyl, or,
(iii) C2 to C10 alkynyl,
(iv) C3–C8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C7–C14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH2OH,
(x) —CH2OR5
(xi) —CH2C(O)R5,
(xii) —CH2R6,
(xiii) —CH2OC(O)R5
(xiv) —CH2OC(O)CH(R7)(NHR8),
(xv) —CH2NR9R10,
(xvi) —CH2CN,
(xvii) —CO2R5
(xviii) —CH2CH2OH,
(xix) —CH2CH2OR5
(xx) —CH2CH2OC(O)R5
(xxi) —CH2CH2OC(O)CH(R7)(NHR8),
(xxii) —CH2SH,
(xxiii) —C(O)H,
(xxiv) —CH2CO2R9,
(xxv) —CH2SO3H,
(xxvi) —CH2CH2SO3H,
(xxvii) —CH2CH2PO3H2,
(xxviii) —CH2CH2OCH2PO3H2,
(xxix) —CH2OPO3H2,
(xxx) —OCH2PO3H2,
(xxxi) —OH,
(xxxii) —OR10
(xxxiii) —NH2,
(xxxiv) —NR11R12,
(xxxv) —SH,
(xxxvi) —SR5,
(xxxvii) —SCN,
(xxxviii) —N3,
(xxxix) —CN,
(xl) —CONR11R12
(xli) —CH2CONR11R12
(xlii) —NHOH,
(xliii) —NHOR5,
(xliv) —NO,
(xlv) —NO2,
(xlvi) —NHNR11R12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C1–C10 2-(alkoxycarbonyl)ethenyl,
(1) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl;
and
(lvi) —CH2N3;
X independently is oxygen, sulfur, or a bond;
Z independently is hydroxy, an ester or amide;
R5 is independently H, C1–C10 alkyl or a protecting group;
R6 is F, Cl, Br or I;
R7 is the side chain of any of the unprotected or N-protected α-amino acids;
R8 is H or —C(O)CH(R7)(NH2);
R9 and R10 are independently selected from H, C1–C10 alkyl, carboxyalkyl, aminoalkyl, and C2–C10 alkenyl, or both together form a cycle with or without participation of heteroatom;
and
R11 and R12 are independently selected from H, C1 to C10 alkyl, C3–C8 cycloalkyl, heteroaryl and C7–C12 arylalkyl, or both together form a cycle with or without participation of heteroatom;
and
salts and solvates thereof.

71 more elements

A compound of the formula (Iaa):

wherein
R1 is H, amino, or methylsulfanyl;
R2 is H, methyl, halo, —N(R5)2, hydroxy, or protected hydroxy;
R3 is independently H, methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R4 is selected from:
(i) C1 to C10 alkyl,
(ii) C2 to C10 alkenyl, or,
(iii) C2 to C10 alkynyl,
(iv) C3–C8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C7–C14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH2OH,
(x) —CH2OR5
(xi) —CH2C(O)R5,
(xii) —CH2R6,
(xiii) —CH2OC(O)R5
(xiv) —CH2OC(O)CH(R7)(NHR8),
(xv) —CH2NR9R10,
(xvi) —CH2CN,
(xvii) —CO2R5
(xviii) —CH2CH2OH,
(xix) —CH2CH2OR5
(xx) —CH2CH2OC(O)R5
(xxi) —CH2CH2OC(O)CH(R7)(NHR8),
(xxii) —CH2SH,
(xxiii) —C(O)H,
(xxiv) —CH2CO2R9,
(xxv) —CH2SO3H,
(xxvi) —CH2CH2SO3H,
(xxvii) —CH2CH2PO3H2,
(xxviii) —CH2CH2OCH2PO3H2,
(xxix) —CH2OPO3H2,
(xxx) —OCH2PO3H2,
(xxxi) —OH,
(xxxii) —OR10
(xxxiii) —NH2,
(xxxiv) —NR11R12,
(xxxv) —SH,
(xxxvi) —SR5,
(xxxvii) —SCN,
(xxxviii) —N3,
(xxxix) —CN,
(xl) —CONR11R12
(xli) —CH2CONR11R12
(xlii) —NHOH,
(xliii) —NHOR5,
(xliv) —NO,
(xlv) —NO2,
(xlvi) —NHNR11R12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C1–C10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl;
and
(lvi) —CH2N3;
X independently is oxygen, sulfur, or a bond;
Z independently is hydroxy, an ester or amide;
R5 is independently H, C1–C10 alkyl or a protecting group;
R6 is F, Cl, Br or I;
R7 is the side chain of any of the unprotected or N-protected α-amino acids;
R8 is H or —C(O)CH(R7)(NH2);
R9 and R10 are independently selected from H, C1–C10 alkyl, carboxyalkyl, aminoalkyl, and C2–C10 alkenyl, or both together form a cycle with or without participation of heteroatom;
and
R11, and R12 are independently selected from H, C1 to C10 alkyl, C3–C8 cycloalkyl, heteroaryl and C7–C12 arylalkyl, or both together form a cycle with or without participation of heteroatom:
and
salts and solvates thereof.

70 more elements

A method of preparation of compounds of formula (I)

comprising reacting a compound of formula (II):
with a compound of the formula (III):
where Y is a leaving group;
in dipolar aprotic solvent in the presence of a base;
wherein * designates a chiral carbon atom;
R1 is H, amino, or methylsulfanyl;
R2 is H, methyl, halo, —N(R5)2, hydroxy, protected hydroxy or a group of the formula (Ia)
R3 is independently methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R4 is selected from:
(i) C1 to C10 alkyl,
(ii) C2 to C10 alkenyl, or,
(iii) C2 to C10 alkynyl,
(iv) C3–C8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C7–C14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH2OH,
(x) —CH2OR5
(xi) —CH2C(O)R5,
(xii) —CH2R6,
(xiii) —CH2OC(O)R5
(xiv) —CH2OC(O)CH(R7)(NHR8),
(xv) —CH2NR9R10,
(xvi) —CH2CN,
(xvii) —CO2R5
(xviii) —CH2CH2OH,
(xix) —CH2CH2OR5
(xx) —CH2CH2OC(O)R5
(xxi) —CH2CH2OC(O)CH(R7)(NHR8),
(xxii) —CH2SH,
(xxiii) —C(O)H,
(xxiv) —CH2CO2R9,
(xxv) —CH2SO3H,
(xxvi) —CH2CH2SO3H,
(xxvii) —CH2CH2PO3H2,
(xxviii) —CH2CH2OCH2PO3H2,
(xxix) —CH2OPO3H2,
(xxx) —OCH2PO3H2,
(xxxi) —OH,
(xxxii) —OR10
(xxxiii) —NH2,
(xxxiv) —NR11R12,
(xxxv) —SH,
(xxxvi) —SR5,
(xxxvii) —SCN,
(xxxviii) —N3,
(xxxix) —CN,
(xl) —CONR11R12
(xli) —CH2CONR11R12
(xlii) —NHOH,
(xliii) —NHOR5,
(xliv) —NO,
(xlv) —NO2,
(xlvi) —NHNR11R12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C1–C10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl;
and
(lvi) —CH2N3;
X is O or S;
Z independently is hydroxy, an ester or amide;
R5 is independently H, C1–C10 alkyl or a protecting group;
R6 is F, Cl, Br or I;
R7 is the side chain of any of the unprotected or N-protected α-amino acids;
R8 is H or —C(O)CH(R7)(NH2);
R9 and R10 are independently selected from H, C1–C10 alkyl, carboxyalkyl, aminoalkyl, and C2–C10 alkenyl, or both together form a cycle with or without participation of heteroatom;
and
R11 and R12 are independently selected from H, C1 to C10 alkyl, C3–C8 cycloalkyl, heteroaryl and C7–C12 arylalkyl, or both together form a cycle with or without participation of heteroatom.

72 more elements

A method of preparation of compounds of formula (Iaa)

comprising reacting a compound of formula (II):
with a compound of the formula (III):
Y—CH2CH(R3)—O—CH2P(O)(Z)2 (III)
where Y is a leaving group;
in dipolar aprotic solvent in the presence of a base;
wherein
R1 is H, amino, or methylsulfanyl;
R2 is H, methyl, halo, —N(R5)2, hydroxy, protected hydroxy or a group of the formula (Ia)
R3 is independently H, methyl, hydroxymethyl, halomethyl, or protected hydroxymethyl;
R4 is selected from:
(i) C1 to C10 alkyl,
(ii) C2 to C10 alkenyl, or,
(iii) C2 to C10 alkynyl,
(iv) C3–C8 cycloalkyl,
(v) aryl,
(vi) heteroaryl,
(vii) C7–C14 arylalkyl,
(viii) heteroarylalkyl,
(ix) —CH2OH,
(x) —CH2OR5
(xi) —CH2C(O)R5,
(xii) —CH2R6,
(xiii) —CH2OC(O)R5
(xiv) —CH2OC(O)CH(R7)(NHR8),
(xv) —CH2NR9R10,
(xvi) —CH2CN,
(xvii) —CO2R5
(xviii) —CH2CH2OH,
(xix) —CH2CH2OR5
(xx) —CH2CH2OC(O)R5
(xxi) —CH2CH2OC(O)CH(R7)(NHR8),
(xxii) —CH2SH,
(xxiii) —C(O)H,
(xxiv) —CH2CO2R9,
(xxv) —CH2SO3H,
(xxvi) —CH2CH2SO3H,
(xxvii) —CH2CH2PO3H2,
(xxviii) —CH2CH2OCH2PO3H2,
(xxix) —CH2OPO3H2,
(xxx) —OCH2PO3H2,
(xxxi) —OH,
(xxxii) —OR10
(xxxiii) —NH2,
(xxxiv) —NR11R12,
(xxxv) —SH,
(xxxvi) —SR5,
(xxxvii) —SCN,
(xxxviii) —N3,
(xxxix) —CN,
(xl) —CONR11R12
(xli) —CH2CONR11R12
(xlii) —NHOH,
(xliii) —NHOR5,
(xliv) —NO,
(xlv) —NO2,
(xlvi) —NHNR11R12
(xlvii) 2-halovinyl,
(xlviii) 3,3,3-trifluoropropenyl,
(xlix) C1–C10 2-(alkoxycarbonyl)ethenyl,
(l) 2-carboxyethenyl,
(li) 2-cyanoethenyl,
(lii) difluoromethyl,
(liii) trifluoromethyl,
(liv) 2,2,2-trifluoroethyl,
(lv) 2-haloethyl;
and
(lvi) —CH2N3;
X is O or S;
Z independently is hydroxy, an ester or amide;
R5 is independently H, C1–C10 alkyl or a protecting group;
R6 is F, Cl, Br or I;
R7 is the side chain of any of the unprotected or N-protected α-amino acids;
R8 is H or —C(O)CH(R7)(NH2);
R9 and R10 are independently selected from H, C1–C10 alkyl, carboxyalkyl, aminoalkyl, and C2–C10 alkenyl, or both together form a cycle with or without participation of heteroatom;
and
R11 and R12 are independently selected from H, C1 to C10 alkyl, C3–C8 cycloalkyl, heteroaryl and C7–C12 arylalkyl, or both together form a cycle with or without participation of heteroatom.

73 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/869,005Filed 16 Jun 2004 · us provisional application
Priority: 16 Jun 2003
Published: US 2005/0075318 A17 Apr 2005
Granted: 3 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07F 9/6512
Six-membered rings: having the nitrogen atoms in positions 1 and 3
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/18
For RNA viruses: for HIV

Family

Application60/478,893Us provisional application · filed 16 Jun 2003
US 2005/0075318 A1Pre-grant publication · published 7 Apr 2005
US 7,115,592 B2This patent

From the US filing history. Foreign family members aren’t listed.

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