Quinazoline derivatives as medicaments

• US 6,476,031 B1
• Filed: 08/27/1999
• Issued: 11/05/2002
• Est. Priority Date: 08/28/1998
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Liu, David Y., Lewicki, John A., Chakravarty, Sarvajit, Dugar, Sundeep, Schreiner, George F., Perumattam, John J.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Liu, Hong
• Application Number:
  US09/383,825
• Time in Patent Office: 1,166 Days
• Field of Search: 514/259, 514/249, 514/258, 514/252.17, 544/293, 544/279, 544/258
• US Class Current: 514/249
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The invention is directed to methods to inhibit TGF-β and/or p38-α kinase using compounds of the formula

or the pharmaceutically acceptable salts thereof

wherein R³ is a noninterfering substituent;

each Z is CR² or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;

each R² is independently a noninterfering substituent;

L is a linker;

n is 0 or 1; and

Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

Claims

1. A method to inhibit p38-α

activity and/or TGF-β

activity, which method comprises contacting said p38-α and

/or TGF-β

with a compound of the formula;

or the pharmaceutically acceptable salts thereof

wherein R³ comprises

a substituted or unsubstituted aromatic moiety, wherein said aromatic moiety is a monocyclic or fused bicyclic moiety containing 5-12 ring member atoms, wherein optionally one or more of said member atoms can independently be O, S and N;

each Z is CR² or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;

each R² is either

(i) independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyl, wherein each of alkyl, alkenyl, alkynyl and acyl may optionally contain 1-2 O, S or N, aryl and arylalkyl, each of said aryl and arylalkyl optionally containing 1 or more O, S or N and wherein in each of the foregoing other than H may be unsubstituted or substituted with 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR —

SO₃R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C), and wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂ , —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR, —

SO₃R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C), or

(ii) independently selected from the group consisting of halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, NRSOR, NRSO₂R, —

OCONR₂, RCO, —

COOR, —

SO₂R, NRSOR, NRSO₂R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C);

wherein L is S(CR²₂)_m, —

NR¹SO₂(CR²₂)₁, SO₂(CR²₂)_m, SO₂NR¹(CR²₂)₁, NR¹(CR²₂)_m, NR¹CO(CR²₂)₁, O(CR²₂)_m, or OCO(CR²₂)₁, or

 

wherein Z is N or CH and wherein m is 0-4 and 1 is 0-3;

R¹ is H, aryl or arylalkyl where the aryl moiety may be substituted by 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl aryl, alkylaryl, aroyl N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR, —

SO₃R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C); and

wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR, —

SO₂R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C),

n is 1; and

Ar′

is a monocyclic or polycyclic aromatic moiety optionally substituted with 1-3 substituents, wherein two of said substituents may form a 5-7 member cyclic aliphatic ring and wherein Ar′ and

any said substituents thereon forming a cyclic aliphatic ring, may optionally contain one or more ring atoms selected from O, S and N.

2. The method of claim 1 wherein any substituents on the aromatic moiety of R³ are independently selected from the group consisting of halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR, —

SO₃R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently selected from H, alkyl (1-4C) and alkyl (1-6C).

3. The method of claim 1 wherein said substituents on substituted Ar′

are independently selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR, —

SO₃R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C),

and wherein any aryl or aroyl groups on said substituents maybe further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —

SOR, —

SO₂R, —

OCOR, —

NRCOR, —

NRCONR₂, —

NRCOOR, —

NRSOR, —

NRSO₂R, —

OCONR₂, RCO, —

COOR —

SO₃R, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C).

4. The method of claim 3 wherein Ar′

is phenyl, 2-, 3-, or 4-pyridyl, 2- or 4-pyrimidyl, indolyl, isoquinolyl, quinlyl, benzimdazolyl, bezotriazolyl, benzothiazolyl, benzofuranyl, pyridyl, thienyl, furyl pyrrolyl, thiazolyl, oxazolyl, or imdazolyl, all of which may optionally be substituted.

5. The method of claim 1 wherein said optional substituents on R² are independently selected from the group consisting of R⁴, halo, OR⁴, NR⁴₂, SR⁴, —

OOCR⁴, —

NROCR⁴, —

COOR⁴, R⁴CO, —

CONR⁴₂, —

SO₂NR⁴₂, CN, CF₃, and NO₂, wherein each R⁴ is independently optional substituted alkyl (1-6C), or optionally substituted arylalkyl (7-12C) and wherein two R⁴ or two substituents on said alkyl or arylalkyl taken together may form a fused aliphatic ring of 5-7 members.

6. The method of claim 1 wherein the compound of formula (1) is selected from group consisting of

(a) the compounds listed in Table 2 below, wherein Z⁵-Z⁸ are CH;

Z³ is N;

R¹ in compound No. 11 is 2-propyl;

R¹ in compound No 12 is 4-methoxyphenyl, and R¹ in compound No. 41 is 4-methoxybenzyl; and

wherein L, Ar′ and

R³ are as shown in Table 2;

7. The method of claim 1 wherein the compound of formula (1) is selected from the group consisting of:

8. The method of claim 1 wherein

L is -R¹N(CH₂)_n—

wherein R¹ is H or is alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, —

SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C) and n is 0, 1 or 2; and

(a) Ar′

is phenyl, substituted with at least one group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NOCR, RCO, —

COOR, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C), or pyridyl, indolyl, or pyrimidyl each optionally substituted with at least one group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C); and

R³ is phenyl optionally substituted with 1-3 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, —

SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C);

or

(b) Ar′

is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted allyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROC, RCO, —

COOR, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C); and

R³ is phenyl substituted with 1-3 substituents which substituents arc selected from the group consisting of alkyl (1-6C), halo, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, —

SO₂NR₂, CN, and CF₃, wherein each R is independently H or lower alkyl (1-4C);

or

(c) Ar′

is phenyl substituted with a group selected from the group consisting of optionally substituted NR₂, SR, —

NROCR, RCO, —

CONR₂, SO₂NR₂, CN, and CF₃, wherein each R is independently H or lower alkyl (1-4C);

or pyridyl substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C);

or indolyl or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower allyl (1-4C); and

R₃ is phenyl optionally substituted with 1-3 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, —

SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C);

or

(d) Ar′

is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR₂, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C); and

R³ is phenyl substituted with 1-3 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, SR, —

OOCR, —

NROCR, RCO, —

COOR, —

CONR₂, —

SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C).

9. The method of claim 1 wherein the compound of formula 1 is selected from the group consisting of

2-phenyl-4-(4-pyridylamino)-quinazoline;

2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline;

2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline;

2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline;

2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline;

2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline;

2-(3-methoxyaniyl)-4-(4-pyridylamino)-quinazoline;

2-(2,6-dichlorophenyl)-4-(4-pyridylamino)-quinazoline;

2-(2,6-dibrophonyl)-4 -(4-pyridylamino)-quinazoline;

2-(2,6-difluomrophenyl)-4-(4-pyridylamino)-quinazoline;

2-(2-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;

2-(4-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;

2-(2-fluorophenyl)-4-(4-pyridylamino)-6-nitroquinazoline;

2-(2-fluorophenyl)-4-(4-pyridylamino)-6-aminoquinazoline;

2-(2-fluorophenyl)-4-(4-pyxdylamino)-7-aminoquinazoline;

2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(3-methoxybenzylamino)-quinazoline;

2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4methoxybenzyrlamino)-quinazoiine;

2-(2-fluorophenyl)-4-(4-pyridylamino)-6(2-isobutylamino)-quinazoline; and

2-(2-fluorophenyl)-4-(4-pyridylamino)-6(4methymercaptobenzylamino)-quinazoline.