Pyrimidine-5-carboxamide derivatives

• US 6,432,963 B1
• Filed: 06/15/2000
• Issued: 08/13/2002
• Est. Priority Date: 12/15/1997
• Status: Expired due to Term

• Current Assignee: Astellas Pharma Incorporated
• Original Assignee: Yamanouchi Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Nakai, Eiichi, Naito, Ryo, Takeuchi, Makoto, Hisamichi, Hiroyuki, Kawazoe, Souichirou, Ichikawa, Atsushi, Toyoshima, Akira, Tanabe, Kazuhito, Orita, Akiko
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): McKenzie, Thomas C
• Application Number:
  US09/581,595
• Time in Patent Office: 789 Days
• Field of Search: 514/256, 514/269, 514/272, 514/273, 514/275, 544/310, 544/311, 544/316, 544/317, 544/320, 544/321, 544/323, 544/324, 544/328, 544/329, 544/331, 544/332, 544/333, 544/335
• US Class Current: 514/256
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/38 One sulfur atom
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 239/56 One oxygen atom and one sulfur atom
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Pyrimidine-5-carboxamide derivatives represented by a general formula (I) or salts thereof

[wherein each symbol has the following meaning;

X: O, S, NR¹, CO, NR¹CO, CONR¹, C═N—OR¹ or a bond,

Y: a lower alkylene group which may be substituted by OR¹ or —NHR¹, or a bond,

Z: O, NR² or a bond,

A: H, or a lower alkyl which may have a substituent, a —CO-lower alkyl which may have a substituent, an aryl which may have a substituent, a heteroaryl which may have a substituent, a cycloalkyl which may have a substituent or a nitrogen-containing saturated heterocyclic group which may have a substituent,

B: an aryl which may have a substituent or a heteroaryl group which may have a substituent,

R¹, R²: H, a lower alkyl or a —CO-lower alkyl group].

Claims

1. A pyrimidine-5-carboxamide derivative represented by a formula (I) or a salt thereof

wherein each symbol has the following meaning;

X;

O;

S;

NR¹;

CO;

NR¹CO;

CONR¹;

C═

N—

OR¹ or a bond,

Y;

a lower alkylene group which may be substituted by OR¹ or —

NHR¹;

or a bond,

Z;

O or NR²,

A;

H;

or a lower alkyl which may have from 1 to 4 substituent(s) selected from Group a or Group c;

a —

CO-lower alkyl which may have from 1 to 4 substituent(s) selected from Group a or Group c;

an aryl which may have from 1 to 4 substituent(s) selected from Group a or Group b;

a five- to eight-membered monocyclic heteroaryl group which (i) has from 1 to 4 hetero atoms selected from O, S, and N and (ii) may have from 1 to 4 substituent(s) selected from Group a or Group b;

a cycloalkyl which may have from 1 to 4 substituent(s) selected from Group a;

or a five- to eight-membered saturated heterocyclic group which (i) has at least one N as a ring atom, (ii) may have one O or S as a ring atom, and (iii) may have from 1 to 4 substituent(s) selected from Group a,

B;

an aryl which may have from 1 to 4 substituent(s) selected from Group a or Group b or a five- to eight-membered monocyclic heteroaryl group which (i) has from 1 to 4 hetero atoms selected from O, S, and N and (ii) may have from 1 to 4 substituent(s) selected from Group a or Group b, and

R¹, R²;

H;

a lower alkyl or —

CO-lower alkyl group,

Group a;

—

NH₂;

—

NH₂ in a prodrug form;

-lower alkylene-NH₂;

-lower alkylene-NH₂ in a prodrug form;

—

NH-lower alkyl;

—

N(lower alkyl)₂;

—

NH-lower alkylene-aryl;

—

NH-aryl;

—

NH-cycloalkyl;

—

NH-a five- to eight-membered monocyclic heteroaryl group which has from 1 to 4 hetero atoms selected from O, S, and N;

—

NHCO-lower alkyl;

—

NHSO₂-lower alkyl;

—

NHC(NH)NH₂;

—

NHCONH₂;

—

OH;

—

O-lower alkyl;

—

CO₂H;

—

CONHOH;

—

CO₂-lower alkyl;

—

CONH-lower alkyl;

or —

CON(lower alkyl)₂,

Group b;

-lower alkyl;

-halogen atom selected from the group consisting of F, Cl, Br, and I;

-lower alkyl having One or more hydrogen atoms substituted by a halogen atom selected from the group consisting of F, Cl, Br, and I;

—

O-lower alkylene-aryl;

—

O-aryl;

—

O-lower alkylene-aryl-O-lower alkyl;

—

S-lower alkylene-aryl;

—

S-lower alkylene-aryl-O-lower alkyl;

—

NO₂;

or —

CN, and

Group c;

-halogen atom selected from the group consisting of F, Cl, Br, and I;

—

O-lower alkylene-aryl, —

O-aryl;

—

O-lower alkylene-aryl-O-lower alkyl;

—

S-lower alkylene-aryl;

—

S-lower alkylene-aryl-O-lower alkyl;

—

NO₂;

—

CN;

-aryl which may be substituted by a group selected from Group a;

-cycloalkyl;

-a five- to eight-membered monocyclic heteroaryl group which has from 1 to 4 hetero atoms selected from 0, S, and N;

-a five- to eight-membered saturated heterocyclic group having from 1 to 4 hetero atoms selected from O, S, and N;

-vinyl;

-(1-propenyl);

or -ethynyl,

 

with the proviso that A is a group other than an ethyl group when X is NH, Y and Z are respectively a bond and B is 2-methylphenyl, and

wherein —

NH₂ in the prodrug form means a group selected from the group consisting of (Z)-3-{2-(acetoxy)phenyl}-2-propenoylanino-, (acetoxy)rnethoxycarbonylamino-, 4-azidobenzyloxycarbonylamino-, (5-methyl-2-oxo-1,3-dioxol-4-en-4-yl)methoxycarbonylamino-, and {(2-hydroxyphenyl)(phenyl)methylidene}amino-.

2. The compound or a salt thereof according to claim 1, wherein X is NR¹, R¹ is H or a lower alkyl, Y is a bond, Z is NH and B is an aryl which may have 1 to 3 substituents selected from —

NH₂, -lower alkylene-NH₂, -lower alkyl, -halogen atom, —

CF₃ and —

O-lower alkyl group.

3. The compound or a salt thereof according to claim 2, wherein A is a lower alkyl group substituted by a group selected from —

NH₂ and —

NH₂ in a prodrug form.

4. The compound or a salt thereof according to claim 2, wherein A is a cycloalkyl group substituted by a group selected from —

NH₂, —

NH₂ in a prodrug form and -lower alkylene-NH₂.

6. A pharmaceutical composition which comprises the compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

5. A compound selected from 2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(3-trifluoromethylanilino)pyrimidine-5-carboxamide, 2-(4-aminobutylamino)-4-(3-trifluoromethylanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(3-bromoanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(3-nitroanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(3,5-dimethylanilino)pyrimidine-5-carboxamide, 2-(2-aminoethylamino)-4-(2-naphthylamino)pyrimidine-5-carboxamide, 2-(cis-2-aminocyclohexylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide, 2-(cis-2-aminocyclohexylamino)-4-(3-bromoanilino)pyrimidine-5-carboxamide, 2-(cis-2-aminocyclohexylamino)-4-(3,5-dichloroanilino)pyrimidine-5-carboxamide and 2- (cis-2-aminocyclohexylamino) -4-(3,4,5-trimethoxyanilino)pyrimidine-5-carboxamide, or a salt thereof.