Pyrimidine derivatives and processes for the preparation thereof

• US 5,521,184 A
• Filed: 04/28/1994
• Issued: 05/28/1996
• Est. Priority Date: 04/03/1992
• Status: Expired due to Term

• Current Assignee: Novartis Corporation (Novartis Ag)
• Original Assignee: Ciba-Geigy Corporation (Novartis Ag)
• Inventors: Zimmermann, Jurg
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/234,889
• Time in Patent Office: 761 Days
• Field of Search: 514/252, 514/272, 544/295, 544/322, 544/331, 544/332
• US Class Current: 514/252.11
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

There are described N-phenyl-2-pyrimidine-amine derivatives of formula I ##STR1## wherein R₁ is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R², R³, R⁹, X, Y, n and R¹⁰ are defined in claim 1

These compounds can be used, for example, in the therapy of tumoral diseases.

Claims

1. An N-phenyl-2-pyrimidine-amine compound of formula I ##STR9## wherein R₁ is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,

R₂ and R₃ are each independently of the other hydrogen or lower alkyl, one or two of the radicals R₄, R₅, R₆, R₇ and R₈ are each nitro, fluoro-substituted lower alkoxy or a radical of formula II

View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)

2. A compound of formula I according to claim 1, wherein one or two of the radicals R₄, R₅, R₆, R₇ and R₈ are each nitro or a radical of formula II

wherein

R₉ is hydrogen or lower alkyl,

X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,

Y is oxygen or the group NH,

n is 0 or 1 and

R₁₀ is an aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or hetero-cyclicaliphatic radical,

and the remaining radicals R₄, R₅, R₆, R₇ and R₈ are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy,

and the remaining substituents are as defined in claim 1,

or a salt of such a compound having at least one salt-forming group.

3. A compound of formula I according to claim 1,

wherein

R₁ is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated by one or two lower alkyl radicals or acylated by lower alkanoyl or by benzoyl, 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,

R₂ and R₃ are each independently of the other hydrogen or lower alkyl, one or two of the radicals R₄, R₅, R₆, R₇ and R₈ are each nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein

R₉ is hydrogen or lower alkyl,

X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino,

Y is oxygen or the group NH,

n is 0 or 1 and

R₁₀ is an aliphatic hydrocarbon radical having 5-22 carbon atoms, a phenyl or naphthyl radical each of which is unsubstituted or substituted by cyano, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, (4-methyl-piperazinyl)-lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or by lower alkoxycarbonyl, or phenyl-lower alkyl wherein the phenyl radical is unsubstituted or substituted as indicated above, a cycloalkyl or cycloalkenyl radical having up to 30 carbon atoms, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl each having up to 30 carbon atoms in the cycloalkyl or cycloalkenyl moiety, a monocyclic radical having 5 or 6 ring members and 1-3 ring hetero atoms selected from nitrogen, oxygen and sulfur, to which radical one or two benzene radicals may be fused, or lower alkyl substituted by such a monocyclic radical,

and the remaining radicals R₄, R₅, R₆, R₇ and R₈ are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by amino, lower alkylamino, di-lower alkylamino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or lower alkoxycarbonyl,

or a salt of such a compound having at least one salt-forming group.

4. A compound of formula I according to claim 1,

wherein

R₁ is pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen,

R₂ and R₃ are each hydrogen,

R₄ is hydrogen or lower alkyl,

R₅ is hydrogen, lower alkyl or fluoro-substituted lower alkoxy,

R₆ is hydrogen,

R₇ is nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein

R₉ is hydrogen,

X is oxo,

n is 0 and

R₁₀ is an aliphatic hydrocarbon radical having 5-22 carbon atoms, a phenyl radical that is unsubstituted or substituted by cyano, lower alkyl, (4-methyl-piperazinyl)-lower alkyl, lower alkoxy, halogen or by carboxy;

a cycloalkyl radical having up to 30 carbon atoms or a monocyclic radical having 5 or 6 ring members and 1-3 sulfur ring atoms, and

R₈ is hydrogen,

or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

5. A compound of formula I according to claim 1,

wherein

R₁ is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom,

R₂ and R₃ are each hydrogen,

R₄ is hydrogen or lower alkyl,

R₅ is hydrogen, lower alkyl or trifluoromethyl,

R₆ is hydrogen,

R₇ is nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein

R₉ is hydrogen,

X is oxo,

n is the number 0 and

R₁₀ is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinylmethyl, or C₅ -C₇ alkyl, thienyl, 2-naphthyl or cyclohexyl, and

R₈ is hydrogen,

or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

6. A compound according to claim 1 of formula I, wherein R₄ and R₈ are each hydrogen and the remaining substituents are as defined in claim 1, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

7. A compound according to claim 3 of formula I, wherein R₄ and R₈ are each hydrogen and the remaining substituents are as defined in claim 3, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

8. A compound according to claim 4 of formula I, wherein R₄ and R₈ are each hydrogen and the remaining substituents are as defined in claim 4, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

9. A compound according to claim 5 of formula I, wherein R₄ and R₈ are each hydrogen and the remaining substituents are as defined in claim 5, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

10. A compound according to claim 1 of formula I, wherein at least one of the radicals R₄ and R₈ is lower alkyl, and the remaining substituents are as defined in claim 1, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

11. A compound according to claim 3 of formula I, wherein at least one of the radicals R₄ and R₈ is lower alkyl, and the remaining substituents are as defined in claim 3, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

12. A compound according to claim 4 of formula I, wherein at least one of the radicals R₄ and R₈ is lower alkyl, and the remaining substituents are as defined in claim 4, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

13. A compound according to claim 5 of formula I, wherein at least one of the radicals R₄ and R₈ is lower alkyl, and the remaining substituents are as defined in claim 5, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

14. A compound according to claim 1 of formula I,

wherein

R₁ is pyridyl bonded at a carbon atom,

R₂, R₃, R₄, R₅, R₆ and R₈ are each hydrogen and

R₇ is nitro or a radical of formula II wherein

R₉ is hydrogen,

X is oxo,

n is the number 0 and

R₁₀ is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by fluorine, chlorine, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or C₅ -C₇ alkyl, thienyl or cyclohexyl,

or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 1 of formula I, wherein R₁ is 4-pyridyl, N-oxido-4-pyridyl, or 3-indolyl, and R₇ is fluoro-substituted alkoxy containing up to 2 carbon atoms, or a salt of such a compound containing at least one salt-forming group.

16. A compound of formula I according to claim 1, wherein R₁ is 4-pyridyl, N-oxido-4-pyridyl, or 3-indolyl, and R₇ is trifluoromethoxy or 1,1,2,2-tetrafluoroethoxy, or a salt of such a compound containing at least one salt-forming group.

17. N-(5-Benzoylamido-2-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.

18. N-[3-(1,1,2,2-Tetrafluoroethoxy)phenyl]-4-(4-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.

19. A compound according to claim 1 of the formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group selected from N-(3-Nitro-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(4-Chlorobenzoylamido)-phenyl]-4-(3-pyridyl)-2--pyrimidine-amine,

N-(3-Benzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(2-Pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(3-pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(4-pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Pentafluoro-benzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(2-Carboxy-benzoylamido )-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-n-Hexanoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Nitro-phenyl)-4-(2-pyridyl)-2-pyrimidine-amine,

N-(3-Nitro-phenyl)-4-(4-pyridyl)-2-pyrimidine-amine,

N-[3-(2-Methoxy-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(4-Fluoro-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(4-Cyano-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(2-Thienylcarboxamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Cyclohexycarboxamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(4-Methyl-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[3-(4-Chloro-benzoylamido)-phenyl]-4-(4-pyridyl)-2-pyrimidine-amine,

N-{3-[4-(4-Methyl-piperazinomethyl)-benzoylamido]-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine,

N-[5-(4-Methyl-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[5-(2-Naphthoylamido )-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[5-(4-Chloro-benzoylamido )-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-[5-(2-Methoxy-benzoylamido )-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Trifluoromethoxy-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-[1,1,2,2-tetrafluoro-ethoxy]-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Nitro-5-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Nitro-5-trifluoromethyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine,

N-(3-Nitro-phenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine,

N-(3-Benzoylamido-5-methyl-phenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine and the pharmaceutically acceptable salts of such a compound having at least one salt-forming group.

20. A compound according to claim 1 of the formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group selected from N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(N-oxido-4-pyridyl)-2-pyrimidine-amine and N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(3-indolyl)-2-pyrimidine-amine and the pharmaceutically acceptable salts of such a compound having at least one salt-forming group.

21. A pharmaceutical composition for the treatment of tumours in warm-blooded animals including humans, comprising, in a dose effective against tumours, a compound of formula I according to claim 1, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutical carrier.

22. A method of treating warm-blooded animals including humans, which comprises administering to such a warm-blooded animal suffering from a tumoral disease a dose, effective against tumours, of a compound of formula I according to claim 1 or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.

23. The compound according to claim 1 of the formula I, said compound being N-{5-[4-(4-Methyl-piperazino-methyl)-benzoylamido]-2-methyl-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof.