Title: Guanidine derivatives quinazoline and quinoline for use in the treatment of autoimmune diseases
Abstract: The invention concerns quinazoline and quinoline derivatives of Formula (I) wherein Q1 includes a quinazoline or quinoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q3—X1— wherein X1 includes a direct bond and O and Q3 includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R2, R3 and R5 is hydrogen or (1-6C)alkyl, provides that one of the parts of groups R2 and R4 together, R3 and R4 together and R5 and R4 together forms a bond; R6 is an optionally substituted group selected from (2-6C) alkenyl, (2-6C) alkynyl, (3-7C)cycloalkyl and (3-7C) cycloalkenyl, or R6 is a substituted (1-6C) alkyl group; and Q2 includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the prevention or treatment of T cell mediated diseases or medical conditions in a warm-blooded animal.
Patent Number: 7,001,904 Issued on 02/21/2006 to Poyser
| Inventors:
|
Poyser; Jeffrey Philip (Macclesfield, GB)
|
| Assignee:
|
AstraZeneca AB (SE)
|
| Appl. No.:
|
311587 |
| Filed:
|
June 19, 2001 |
| PCT Filed:
|
June 19, 2001
|
| PCT NO:
|
PCT/GB01/02698
|
| 371 Date:
|
December 18, 2002
|
| 102(e) Date:
|
December 18, 2002
|
| PCT PUB.NO.:
|
WO02/00644 |
| PCT PUB. Date:
|
January 3, 2002 |
Foreign Application Priority Data
| Jun 24, 2000[GB] | 0015376 |
| Dec 19, 2000[GB] | 0030989 |
| Current U.S. Class: |
514/234.5; 514/266.2; 514/266.22; 514/266.24; 514/266.4; 544/119; 544/293 |
| Current Intern'l Class: |
C07D 403/12 (20060101); C07D 413/12 (20060101); A61K 31/50.5 (20060101) |
| Field of Search: |
544/119,293,234.5,266.2,266.22,266.24,266.4
|
References Cited [Referenced By]
U.S. Patent Documents
| 5773459 | Jun., 1998 | Tang et al.
| |
| 6806274 | Oct., 2004 | Crawley et al.
| |
| Foreign Patent Documents |
| 95/15758 | Jun., 1995 | WO.
| |
| 97/03069 | Jan., 1997 | WO.
| |
| 98/38984 | Sep., 1998 | WO.
| |
| 98/50047 | Nov., 1998 | WO.
| |
| 98/50370 | Nov., 1998 | WO.
| |
| 98/52558 | Nov., 1998 | WO.
| |
| 99/09024 | Feb., 1999 | WO.
| |
| 01/04102 | Jan., 2001 | WO.
| |
Other References
Casanova et al., PubMed Abstract (Rev Neurol 28(9):909-15), May 1999.
Gibson et al., "Epidermal growth factor receptor tyrosine kinase: structure-activity
relationships and antitumour activity of novel quinazolines", Bioorganic & Medicinal
Chemistry Letters, vol. 7, No. 21, Nov. 4, 1997, pp. 2723-2728, XP004136520, ISSN: 0960-894X.
Hong et al.; "Synthesis and Billogical Activities of Some N4-Substituted
4-Aminopyrazolo 3,4-d-pyrimidines"; Journal of Medicinal Chemistry, 1976,
vol. 19, No. 4, pp. 555-558.
Myers et al.; "The Preparation and SAR of 4-(Anilino), 4-(Phenoxy), and 4-Thiophenoxy)-Quinazolines:
Inhibitors of p56 ick and EGF-R Tyrosine Kinase Activity"; Bioorganic
& Medicinal Chemistry Letters, 1997, vol. 7, No. 4, pp. 417-420.
van Muijlwijk-Koezen et al.; "Isoquinoline and Quinazoline Urea Analogues as
Antagonists for the Human Adenosine A3 Receptor"; J. Med. Chem., 2000,
vol. 43, pp. 2227-2238.
|
Primary Examiner: Rao; Deepak
Attorney, Agent or Firm: Morgan Lewis & Bockius LLP
Claims
The invention claimed is:
1. A quinazoline derivative of the Formula I
##STR15##
wherein Q
1 is a quinazoline ring of the formula Ia
##STR16##
wherein:
m is 0, 1, 2, 3 or 4;
each R
1 group, which may be the same or different, is selected from
halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl,
carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,
or from a group of the formula:
Q
3—X
1—
wherein X
1 is a direct bond or is selected from O, S, SO, SO
2,
N(R
7), CO, CH(OR
7), CON(R
7), N(R
7)CO,
SO
2N(R
7), N(R
7)SO
2, OC(R
7)
2,
SC(R
7)
2 and N(R
7)C(R
7)
2,
wherein R
7 is hydrogen or (1-6C)alkyl, and Q
3 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C) cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or
(R
1)
m is (1-3C)alkylenedioxy,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R
1
substituent are optionally separated by the insertion into the chain of a
group selected from O, S, SO, SO
2, N(R
8), CO, CH(OR
8),
CON(R
8), N(R
8)CO, SO
2N(R
8), N(R
8)SO
2,
CH═CH and C≡C wherein R
8 is hydrogen or (1-6C)alkyl,
and wherein any CH
2═CH— or HC≡C— group within
a R
1 substituent optionally bears at the terminal CH
2═
or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group
of the formula:
Q
4—X
2—
wherein X
2 is a direct bond or is selected from CO and N(R
9)CO,
wherein R
9 is hydrogen or (1-6C)alkyl, and Q
4 is aryl, aryl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH
2 or CH
3, group within a R
1 substituent
optionally bears on each said CH
2 or CH
3 group one or more
halogeno substituents or a substituent selected from hydroxy, cyano, amino, carboxy,
carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from
a group of the formula:
—X
3—Q
5
wherein X
3 is a direct bond or is selected from O, S, SO, SO
2,
N(R
10), CO, CH(OR
10), CON(R
10), N(R
10)CO,
SO
2N(R
10), N(R
10)SO
2, C(R
10)
2O,
C(R
10)
2S and N(R
10)C(R
10)
2,
wherein R
10 is hydrogen or (1-6C)alkyl, and Q
5 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on
R
1 optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,
carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from
a group of the formula:
—X
4—R
11
wherein X
4 is a direct bond or is selected from O and N(R
12),
wherein R
12 is hydrogen or (1-6C)alkyl, and R
11 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoylalkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl
or N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, or from a group of the formula:
—X
5—Q
6
wherein X
5 is a direct bond or is selected from O and N(R
13),
wherein R
13 is hydrogen or (1-6C)alkyl, and Q
6 is aryl, aryl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and
any Q
6 group optionally bears 1 or 2 substituents, which may be the
same or different, selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy,
and wherein any heterocyclyl group within a substituent or R
1 optionally
bears 1 or 2 oxo or thioxo substituents;
R
2 is hydrogen or (1-6C)alkyl and R
3 is hydrogen or (1-6C)alkyl,
or R
2 and R
3 together form a CH
2, (CH
2)
2
or (CH
2)
3 group,
R
5 is hydrogen or (1-6C)alkyl, R
5 and R
6 together
with the N atom to which they are attached from a 4- to 7-membered heterocyclic
ring optionally containing a further heteroatom selected from O, N and S,
provided that one of the pairs of groups R
2 and R
4 together,
R
3 and R
4 together and R
5 and R
4 together
forms a bond;
Q
2 is aryl, aryl-(1-3C)alkyl, aryl-(3-7C)cycloalkyl, heteroaryl, heteroaryl-(1-3C)alkyl
or heteroaryl-(3-7C)cycloalkyl wherein each aryl group is phenyl or naphthyl and
each heteroaryl group is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic
heteroaryl ring containing 1 or 2 nitrogen heteroatoms and optionally containing
a further heteroatom selected from nitrogen, oxygen and sulphur, and
Q
2 is optionally substituted with 1, 2, 3 or 4 substituents, which
may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro,
hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,
(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,
or from a group of the formula:
—X
6—R
14
wherein X
6 is a direct bond or is selected from O and N(R
15),
wherein R
15 is hydrogen or (1-6C)alkyl, and R
14 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group
of the formula:
—X
7—Q
7
wherein X
7 is a direct bond or is selected from O, S, SO, SO
2,
N(R
16), CO, CH(OR
16), CON(R
16), N(R
16)CO,
SO
2N(R
16), N(R
16)SO
2, C(R
16)
2O,
C(R
16)
2S and C(R
16)
2N(R
16),
wherein each R
16 is hydrogen or (1-6C)alkyl, and Q
7is aryl,
aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
or Q
2 is optionally substituted with a (1-3C)alkylenedioxy group,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on
Q
2 optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,
carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from
a group of the formula:
—X
8—R
17
wherein X
8 is a direct bond or is selected from O and N(R
18),
wherein R
18 is hydrogen or (1-6C)alkyl, and R
17 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on Q
2 optionally
bears 1 or 2 oxo or thioxo substituents; and
R
6 is an optionally substituted group selected from (2-6C)alkenyl,
(2-6C)alkynyl, (3-7C)cycloalkyl and (3-7C)cycloalkenyl, or R
6 is a substituted
(1-6C)alkyl group,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R
6
group are optionally separated by the insertion into the chain of a group
selected from O, S, SO, SO
2, N(R
19), CO, CH(OR
19),
CON(R
19), N(R
19)CO, SO
2N(R
19), N(R
19)SO
2,
CH═CH and C≡C wherein R
19 is hydrogen or (1-6C)alkyl,
and wherein any CH
2═CH— or HC≡C group within a
R
6 group optionally bears at the terminal CH
2═ or
HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl
and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q
8—X
9—
wherein X
9 is a direct bond or is selected from CO and N(R
20),
CO, wherein R
20 is hydrogen or (1-6C)alkyl, and Q
8 is aryl,
aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH
2 or CH
3 group within a R
6 group
optionally bears on each said CH
2 or CH
3 group one or more
of the following substituents, provided that the R
6 group when it is
(1-6C)alkyl must bear at least one such substituent, one or more halogeno substituents
or a substituent selected from hydroxy, cyano, amidino, amino, carboxy, carbamoyl,
(1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino,
di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl,
(2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino,
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, (1-6C)alkoxycarbonylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonylamino,
N-[hydroxy-(2-6C)alkyl]carbamoyl, N-[(1-6C)alkoxy-(2-6C)alkyl]carbamoyl, N-[amino-(2-6C)alkyl]carbamoyl,
N-[(1-6C)alkylamino-(2-6C)alkyl]carbamoyl, N-{di-[(1-6C)alkyl]amino-(2-6C)alkyl}carbamoyl,
N,N-di-[hydroxy-(2-6C)alkyl]carbamoyl, N,N-di-[(1-6C)alkoxy-(2-6)alkyl]carbamoyl,
N,N-[amino-(2-6C)alkyl]carbamoyl, N,N-di-[(1-6C)alkylamino-(2-6C)alkyl]carbamoyl
and N,N-di-{di-[(1-6C)alkyl]amino-(2-6C)alkyl}carbamoyl,
or from a group of the formula:
—X
10—Q
9
wherein X
10 is a direct bond or is selected from O, S, SO, SO
2,
N(R
21), CO, CH(OR
21), CON(R
21), N(R
21)CO,
SO
2N(R
21), N(R
21)SO
2, C(R
21)
2O,
C(R
21)
2S and N(R
21)C(R
21)
2,
wherein R
21 is hydrogen or (1-6C)alkyl, and Q
9 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a R
6 group,
or any heterocyclic group formed when R
5 and R
6 together
with the N atom to which they are attached form a ring, optionally bears 1, 2 or
3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl,
cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,
(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,
or from a group of the formula:
—X
11—R
22
wherein X
11 is a direct bond or is selected from O and N(R
23),
wherein R
23 is hydrogen or (1-6C)alkyl, and R
22 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl
or N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl,
or from a group of the formula:
—X
12—Q
10
wherein X
12 is a direct bond or is selected from O and N(R
24),
wherein R
24 is hydrogen or (1-6C)alkyl, and Q
10 is aryl,
aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and any Q
10 group optionally bears 1 or 2 substituents, which may be
the same or different, selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy,
and wherein any heterocyclyl group within a R
6 group, or the heterocyclic
group formed when R
5 and R
6 together with the N atom to which
they are attached form a ring, optionally bears 1 or 2 oxo or thioxo substituents;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
2. A quinazoline derivative of the Formula I according to claim 1 wherein:
m is 1 and the R
1 group is located at the 6- or 7-position and is
selected from methoxy, benzyloxy, cyclopropylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,
3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy,
pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy,
3-pyrid-2-propoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy,
3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy,
N-methylpyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 2-(N-methylpyrrolidin-2-yl)ethoxy,
3-pyrrolidin-2-ylpropoxy, 3-(N-methylpyrrolidin-2-yl)propoxy, 2-(2-oxoimidazolidin-1-yl)ethoxy,
2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,
piperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy,
N-methylpiperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy,
piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy,
3-(4-aminomethylpiperidin-1-yl)propoxy, 3-(4-tert-butoxycarbonylaminopiperidin-1yl)propoxy,
3-(4-carbamoylpiperidin-1-yl)propoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy,
2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-morpholinobut-2-en-1-yloxy,
4-morpholinobut-2-yn-1-yloxy, 2-(2-morpholinoethoxy)ethoxy, 2-methylsulphonylethoxy,
3-methylsulphonylpropoxy, 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy, 3 -[N-(2-methoxyethyl)-N-methylamino]propoxy,
2-(2-methoxyethoxy)ethoxy, 3-methylamino-1-propynyl, 3-dimethylamino-1-propynyl,
3-diethylamino-1-propynyl, 6-methylamino-1-hexynyl, 6-dimethylamino-1-hexynyl,
3-(pyrrolidin-1-yl)-1-propynyl, 3-(piperidino)-1-propynyl, 3-(morpholino)-1-propynyl,
3-(4-methylpiperazin-1-yl)-1-propynyl, 6-(pyrrolidin-1yl)-1-hexynyl, 6-(piperidino)-1-hexynyl,
6-(morpholino)-1-hexynyl, 6-(4-methylpiperazin-1-yl)-1-hexynyl, piperazin-1-yl,
4-methylpiperazin-1-yl, 3-imidazol-1-ylpropylamino, 3-pyrrolidin-1-ylpropylamino,
3-morpholinopropylamino, 3-piperidinopropylamino and 3-piperazin-1-ylpropylamino,
or m is 2 and the R
1 groups are located at the 6- and 7-positions,
one R
1 group is located at the 6- or 7-position and is selected from
the groups defined immediately hereinbefore and the other R
1 group is
a methoxy group;
each of R
2, R
3 and R
5 is hydrogen except that
one of the pairs of the groups R
2 and R
4 together, R
3
and R
4 together and R
5 and R
4 together forms
a bond;
Q
2 is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3
substituents, which may be the same or different, selected from fluoro, chloro,
bromo, trifluoromethyl, nitro, methyl, ethyl and methoxy provided that at least
one substituent is located at an ortho position; and
R
6 is an optionally substituted group selected from allyl, 2-propynyl,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, or R
6 is a substituted
methyl, ethyl, propyl or butyl group,
and wherein adjacent atoms in any (2-6C)alkylene chain within a R
6 group
are optionally separated by the insertion into the chain of a group selected from
O, NH, CH═CH and C≡C,
and wherein any CH
2 or CH
3 group within a R
6 group
optionally bears on each said CH
2 or CH
3 group one or more
of the following substituents, provided that the R
6 group when it is
a methyl, ethyl, propyl or butyl group must bear at least one such substituent,
one, two, or three fluoro substituents or a substituent selected from hydroxy,
cyano, amidino, amino, carboxy, methoxy, methylthio, methylsulphinyl, methylsulphonyl,
methylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl,
acetamido, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-imidazolyl,
2-imidazolyl, 4-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuran-2-yl,
pyrrolidin-1-yl, 1,4-dioxan-2-yl, morpholino, piperidino, piperazin-1-yl, homopiperidin-1-yl
and homopiperazin-1-yl,
and wherein any phenol, imidazolyl, pyridyl or heterocyclyl group within a R
6
group optionally bears 1 or 2 substituents, which may be the same or different,
selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl,
ethyl and methoxy,
and wherein any heterocyclyl group within a R
6 group optionally bears
1 or 2 oxo substituents,
or a pharmaceutically-acceptable acid-addition salt thereof.
3. A quinazoline derivative of the Formula I according to claim 1 wherein:—
m is 1 and the R
1 group is located at the 6- or 7-position and is
selected from 2-(2-methoxyethoxy)ethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy,
tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-2-ylmethoxy,
N-methylpyrrolidin-3-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,
3-morpholinylmethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy,
3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy,
piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy,
N-(2-methoxyethyl)piperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy,
benzyloxy, cyclopropylmethoxy, 3-methylsulphonylpropoxy and 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy;
or m is 2 and one R
1 group is located at the 7-position and is selected
from the groups defined immediately hereinbefore and the other R
1 group
is a 6-methoxy group;
or m is 2 and one R
1 group is located at the 6-position and is selected
from the groups defined immediately hereinbefore and the other R
1 group
is a 7-methoxy group;
each of R
2, R
3 and R
5 is hydrogen except that
one of the pairs of groups R
2 and R
4 together, R
3 and
R
4 together and R
5 and R
4 together forms a bond;
Q
2 is phenyl which bears 1, 2 or 3 substituents, which may be the
same or different, selected from fluoro, chloro, bromo, trifluoromethyl, nitro,
methyl, ethyl and methoxy provided that at least one substituent is located at
an ortho position; and
R
6 is allyl, 2-propynyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,
cyclopentyl or 4-hydroxycyclohexyl, or R
6 is a substituted methyl, ethyl,
propyl or butyl group,
and wherein adjacent carbon atoms in any propyl or butyl group are optionally
separated by the insertion into the chain of an O group,
and wherein any CH
2 or CH
3 group within a R
6 group
when it is a methyl, ethyl, propyl or butyl group bears one, two or three fluoro
substituents or a substituent selected from hydroxy, cyano, amidino, amino, carboxy,
methoxy, ethoxy, methylthio, methylsulphinyl, methylsulphonyl, methylamino, ethylamino,
isopropylamino, dimethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert-butoxycarbonyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl,
N-tert-butylcarbamoyl, acetamido, phenyl, cyclopropyl, 2-furyl, 2-thienyl, 4-imidazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,
2-oxopyrrolidin-1-yl, 1,4-dioxan-2-yl, morpholino, piperidino, piperidin-2-yl and piperazin-1-yl,
and wherein any phenyl, heteroaryl or heterocyclyl group within a R
6 group
optionally bears 1 or 2 substituents, which may be the same or different, selected
from fluoro, chloro, trifluoromethyl, hydroxy, methyl ethyl and methoxy;
or a pharmaceutically-acceptable acid-addition salt thereof.
4. A quinazoline derivative of the Formula I according to claim 1 wherein:—
m is 2 and one R
1 group is a 6-methoxy group and the other R
1
group is located at the 7-position and is selected from 2-(2-methoxyethoxy)ethoxy,
2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, N-methylpiperidin-4-ylmethoxy, N-(2-methoxyethyl)piperidin-4-ylmethoxy,
2-(4-methylpiperazin-1-yl)ethoxy and 3-(4-methylpiperazin-1-yl)propoxy;
each of R
2, R
3 and R
5 is hydrogen except that
one of the pairs of groups R
2 and R
4 together, R
3 and
R
4 together and R
5 and R
4 together forms a bond;
Q
2 is phenyl which bears 1, 2 or 3 substituents, which may be the
same or different, selected from fluoro, chloro, bromo and methyl provided that
at least one substituent is located at an ortho position; and
R
6 is allyl, 2-propynyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,
4-hydroxycyclohexyl, 2,2,2-trifluoromethyl, 2,3-dihydroxypropyl, 2-aminoethyl,
3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl,
2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-methylthioethyl,
3-methylthiopropyl, 2-methylsulphonylethyl, 3-methylsulphonylpropyl, 2-(2-hydroxyethoxy)ethyl,
2-cyanoethyl, 5-cyanopentyl, 2-amidinoethyl, carboxymethyl, 2-carboxyethyl, methoxycarbonylmethyl,
2-methoxycarbonylethyl, tert-butoxycarbonylmethyl, 2-(tert-butoxycarbonyl)ethyl,
N-methylcarbamoylmethyl, N-isopropylcarbamoylmethyl, N-tert-butylcarbamoylmethyl,
benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 2,6-difluorobenzyl, phenethyl, 2-furylmethyl,
2-thienylmethyl, 2-imidazol-4-ylethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,
2-pyrid-2-ylethyl, tetrahydrofuran-2-ylmethyl, 1,4-dioxan-2-ylmethyl, 2-pyrrolidin-1-ylethyl,
2-(2-oxopyrrolidin-1-yl)ethyl, 2-(N-methylpyrrolidin-2-yl)ethyl, 3-pyrrolidin-1-ylpropyl,
3-(2-oxopyrrolidin-1-yl)propyl, 2-morpholinoethyl, 3-morpholinopropyl , 2-piperdinoethyl,
3-piperidinopropyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,
N-methylpiperidin-3-ylmethyl or N-methylpiperidin-4-ylmethyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
5. A quinazoline derivative of the Formula I according to claim 1 selected from:—
N-(2-chloro-6-methylphenyl)-N′-(2-hydroxyethyl)-N"-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]guanidine,
N-allyl-N′-(2-chloro-6-methylphenyl)-N"-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]guanidine,
N-allyl-N′-(2,6-dimethylphenyl)-N"-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]guanidine, and
N-(2-chloro-6-methylphenyl)-N′-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]-N"-(2-propynyl)guanidine;
or a pharmaceutically-acceptable acid-addition salt thereof.
6. A process for the preparation of a quinazoline derivative of the Formula I,
or a pharmaceutically-acceptable salt thereof, according to claim 1 which comprises:—
(a) the reaction of a thiourea of the Formula VI
##STR17##
wherein Q
1, R
2, Q
2 and R
3 have any
of the meanings defined in claim 1 except that any functional group is protected
if necessary, with an amine of the Formula VII
##STR18##
wherein R
5 and R
6 have any of the meanings defined in claim
1 except that any functional group is protected if necessary, whereafter any protecting
group that is present is removed by conventional means;
(b) for the production of those compounds of the Formula I wherein Q
1,
R
6 or Q
2 contains a carboxy group, the cleavage of the corresponding
compound of Formula I wherein Q
1, R
6 and Q
2 contains
a protected carboxy group;
(c) for those compounds of the Formula I wherein R
6 or a substituent
on Q
1 or Q
2 contains an alkylcarbamoyl groups or a substituted
alkylcarbamoyl group, the reaction of the corresponding compound of Formula I wherein
R
6 or a substituent on Q
1 or Q
2 is a carboxy group,
or a reactive derivative thereof, with an amine or substituted amine as appropriate;
(d) for those compounds of the Formula I wherein a substituent on Q
1 or
Q
2 contains an amino-(1-6C)alkyl group or R
6 an amino-(1-6C)alkyl
group, the cleavage of the corresponding compound of Formula I wherein a substituent
on Q
1 or Q
2 is a protected amino-(1-6C)alkyl group or R
6
is a protected amino-(1-6C)alkyl group as appropriate;
(e) for those compounds of the Formula I wherein a substituent on Q
1 or
Q
2 contains an amino group, the reduction of a corresponding compound
of Formula I wherein a substituent on Q
1 or Q
2 contains a
nitro group; or
(f) for the production of those compounds of the Formula I wherein Q
1 contains
a R
1 group in a quinazoline-like ring of the formula Ia that is linked
via an oxygen atom, the alkylation of the corresponding compound of Formula I wherein
the R
1 group in Q
1 is a hydroxy group;
and optionally forming a pharmaceutically-acceptable salt thereof.
7. A pharmaceutical composition which comprises a quinazoline derivative of the
Formula I, or a pharmaceutically-acceptable salt thereof, according to claim 1
in association with a pharmaceutically-acceptable diluent or carrier.
8. A method for the treatment of rheumatoid arthritis in a warm-blooded animal
in need thereof, which comprises administering to said animal an effective amount
of a quniazoline derivative of the Formula I, according to claim 1 or a pharmaceutically-acceptable
salt thereof.
9. A method for the treatment of transplant rejection in a warm-blooded animal
in need thereof, which comprises administering to said animal an effective amount
of a quinazoline derivative of the Formula I, according to claim 1 or a pharmaceutically-acceptable
salt thereof.
Description
This application is a 371 of PCT/GB01/02698 filed Jun. 19, 2001.
This invention concerns certain novel quinazoline derivatives which possess
pharmacological properties of use in the treatment of autoimmune diseases or medical
conditions, for example T cell mediated disease such as transplant rejection or
rheumatoid arthritis. The invention also concerns processes for the manufacture
of the quinazoline derivatives of the invention, pharmaceutical compositions containing
them and their use in therapeutic methods, for example by virtue of inhibition
of T cell mediated disease.
A critical requirement of the immune system is the ability to differentiate between
"self" and "non-self" (i.e. foreign) antigens. This discrimination is required
to enable the immune system to mount a response to foreign proteins such as those
on the surface of pathogens whilst maintaining tolerance to endogenous proteins
and thereby preventing damage to normal tissues. An autoimmune disease results
when self-tolerance breaks down and the immune system reacts against tissues such
as the joints in rheumatoid arthritis or nerve fibres in multiple sclerosis. Stimulation
of the human immune response is dependent on the recognition of protein antigens
by T cells. However T cells do not become activated by and respond to antigen alone
but are only triggered into action when the antigen is complexed with major histocompatibility
complex (MHC) molecules on the surface of an antigen-presenting cell such as a
B cell, macrophage or dendritic cell. Thus T cell activation requires the docking
into the T cell receptor of the peptide/MHC complex expressed on an antigen-presenting
cell. This interaction, which confers the antigen specificity to the T cell response,
is essential for full activation of T lymphocytes. Subsequent to this docking,
some of the earliest signal transduction events leading to full T cell activation
are mediated through the action of multiple tyrosine-specific protein kinases (E.
Hsi et al.,
J. Biol. Chem., 1989, 264, 10836) including p56
lck and
ZAP-70. The tyrosine kinase p56
lck is a lymphocyte specific member of
the src family of non-receptor protein tyrosine kinases (J. D. Marth et al.,
Cell,
1985, 43, 393). The enzyme is associated with the inner surface of the plasma
membrane where it binds to the T cell receptor associated glycoproteins CD4 (in
helper T cells) and CD8 (in cytotoxic or killer T cells) (C. E. Rudd et al.,
Proc.
Natl. Acad. Sci. USA, 1988, 85, 5190 and M. A. Campbell et al.,
EMBO J,
1990, 9, 2125).
It is believed that p56
lck tyrosine kinase plays an essential role
in T cell activation as, for example, the loss of p56
lck expression
in a human Jurkat T cell line prevents the normal T cell response to stimulation
of the T cell receptor (D. B. Straus et al.,
Cell, 1992, 70 , 585) and a
deficiency in p56
lck expression causes severe immune deficiency in humans
(F. D. Goldman et al.,
J. Clin. Invest, 1988, 102, 421).
Certain autoimmune conditions or diseases such as inflammatory diseases (for
example rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis and
lung fibrosis), multiple sclerosis, psoriasis, hypersensitivity reactions of the
skin, atherosclerosis, restenosis, allergic asthma and insulin-dependent diabetes
are believed to be associated with inappropriate T cell activation (see, for example,
J. H. Hanke et al.,
Inflamm. Res., 1995, 44, 357). In addition the acute
rejection of transplanted organs can also be interpreted as a consequence of inappropriate
T cell activation. Therefore, compounds which modulate T cell activation by way
of inhibition of one or more of the multiple tyrosine-specific protein kinases
which are involved in the early signal transduction steps which lead to full T
cell activation, for example by way of inhibition of P56
lck tyrosine
kinase, are expected to provide therapeutic agents for such pathological conditions.
Without wishing to imply that the compounds disclosed in the present invention
possess pharmacological activity only by virtue of an effect on a single biological
process, it is believed that the compounds modulate T cell activation by way of
inhibition of one or more of the multiple tyrosine-specific protein kinases which
are involved in the early signal transduction steps which lead to full T cell activation,
for example by way of inhibition of p56
lck tyrosine kinase.
In particular, the quinazoline derivatives of the invention are expected to be
useful as immunoregulation or immunosuppressive agents for the prevention or treatment
of organ rejection following transplant surgery.
Agents of this kind would offer therapy for transplant rejection and autoimmune
diseases whilst avoiding toxicities associated with the commonly used, less selective
immunosuppressants. The leading agent for the prevention or treatment of transplant
rejection is cyclosporin A which, although effective, is often associated with
side-effects such as renal damage and hypertension which results in kidney failure
in a substantial number of patients. It is contemporary practice to treat rheumatoid
arthritis initially with symptom relief agents such as NSAIDs, which do not have
any beneficial effect on disease progression and are often associated with unwanted
side-effects. A rationally based, disease modifying agent, without such deleterious
side-effects, would therefore offer significant benefits in the prevention or treatment
of transplant rejection or autoimmune conditions such as rheumatoid arthritis.
As stated above, the present invention is based, in particular, on the discovery
that the quinazoline derivatives of the invention modulate T cell activation by
way of inhibition of one or more of the multiple tyrosine-specific protein kinases
which are involved in the early signal transduction steps which lead to full T
cell activation. Accordingly compounds of the present invention possess higher
inhibitory potency against particular non-receptor tyrosine kinases such as p56
lck
tyrosine than against other non-receptor tyrosine kinases or against receptor
tyrosine kinases (RTKs) such as epidermal growth factor (EGF) RTK. In general,
the quinazoline derivatives of the invention possess sufficient potency in inhibiting
non-receptor tyrosine kinases such as p56
lck tyrosine kinase that they
may be used in an amount sufficient to inhibit, for example, p56
lck tyrosine
kinase whilst demonstrating reduced potency, preferably whilst demonstrating no
significant activity, against RTKs such as EGF RTK. Thus the quinazoline derivatives
of the invention can be used in the clinical management of those particular diseases
which are sensitive to inhibition of such non-receptor tyrosine kinases, for example
autoimmune diseases or medical conditions, for example T cell mediated disease
such as transplant rejection or rheumatoid arthritis.
It is disclosed by K. H. Gibson et al.,
Bioorganic & Medicinal Chemistry Letters,
1997, 7, 2723-2728 that certain 4-anilinoquinazoline derivatives possess useful
EGF RTK inhibitory properties. It is also disclosed that 1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea
is inactive as an EGF RTK inhibitor.
It is disclosed in International Patent Application WO 98/50370 that certain
5-substituted
quinazoline derivatives may be useful as inhibitors of serine/threonine protein
kinases. Whilst most of the examples are 4-amino-5-phenoxyquinazolines, there is
the disclosure of three 4-ureido-5-phenoxyquinazolines, namely of:—
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea and 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea.
It is disclosed by C. I. Hong et al.,
J. Med. Chem., 1976, 19, 555-558
that certain 4-aminopyrazolo[3,4-d]pyrimidine derivatives possess growth inhibitory
activity against cultured L1210 leukemia cells. The disclosed compounds include:—
1-phenyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea, 1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea, 1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and 1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea.
It is disclosed in International Patent Application WO 97/03069 that certain
quinoline
and quinazoline derivatives may be useful as protein tyrosine kinase inhibitors.
All of the disclosed examples are 4-heteroarylaminoquinazoline derivatives and
none of them are 1-heteroaryl-3-(quinazolin-4-yl)urea derivatives.
It is disclosed in International Patent Application WO 98/43960 that certain
3-cyanoquinoline
derivatives may be useful as protein tyrosine kinase inhibitors. Almost all of
the 398 disclosed examples were 3-cyano-4-anilinoquinoline or 3-cyano-4-benzylaminoquinoline
derivatives. There is no disclosure of any (3-cyanoquinolin-4-yl)urea derivatives.
It is disclosed in International Patent Application WO 99/09024 that certain
1-phenyl-3-(quinolin-4-yl)urea
derivatives may be useful as antagonists of the human HFGAN72 receptor, a G-protein
coupled neuropeptide receptor, and hence may be of potential use in the treatment
of obesity. There is no disclosure as examples of any 1-phenyl-3-(quinazolin-4-yl)urea
or 1 -phenyl-3-(3-cyanoquinolin-4-yl)urea compounds.
According to one aspect of the invention there is provided a quinazoline
derivative of the Formula I
##STR1##
wherein Q
1 is a quinazoline-like ring such as a group of the formula
Ia, Ib, Ic or Id
##STR2##
wherein:
Y
1 together with the carbon atoms to which it is attached forms
a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms
selected from O, N and S;
Y
2 together with the carbon atoms to which it is attached forms
a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms
selected from O, N and S;
m is 0, 1, 2, 3 or 4;
each R
1 group, which may be the same or different, is selected from
halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl,
carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1,6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,
or from a group of the formula:
Q
3—X
1—
wherein X
1 is a direct bond or is selected from O, S, SO, SO
2,
N(R
7), CO, CH(OR
7), CON(R
7), N(R
7)CO,
SO
2N(R
7), N(R
7)SO
2, OC(R
7)
2,
SC(R
7)
2 and N(R
7)C(R
7)
2,
wherein R
7 is hydrogen or (1-6C)alkyl, and Q
3 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or
(R
1)
m is (1-3C)alkenedioxy,
- and wherein adjacent carbon atoms in any (2-6C)alkylene chain within
a R1 substituent are optionally separated by the insertion into the
chain of a group selected from O, S, SO, SO2, N(R8), CO,
CH(OR8), CON(R8), N(R8)CO, SO2N(R8),
N(R8)SO2, CH═CH and C≡C wherein R8 is
hydrogen or 1-6C)alkyl,
and wherein any CH
2═CH— or HC≡C— group within
a R
1 substituent optionally bears at ther terminal CH
2═
or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino (1-6C)alkyl or from a group
of the formula:
Q
4—X
2—
wherein X
2 is a direct bond or is selected from CO and N(R
9)CO,
wherein R
9 is hydrogen or (1-6C)alkyl, and Q
4 is aryl, aryl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH
2 or CH
3 group within a R
1 substituent
optionally bears on each said CH
2 or CH
3 group one or more
halogeno substituents or a substituent selected from hydroxy, cyano, amino, carboxy,
carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino and N-(1-6-C)alkyl-(1-6C)alkanesulphonylamino, or from
a group of the formula:
—X
3—Q
5
wherein X
3 is a direct bond or is selected from O, S, SO, SO
2,
N(R
10), CO, CH(OR
10), CON(R
10), N(R
10)CO,
SO
2N(R
10), N(R
10)SO
2, C(R
10)
2O,
C(R
10)
2S and N(R
10)C(R
10)
2,
wherein R
10 is hydrogen or (1-6C)alkyl, and Q
5 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on
R
1 optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,
carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from
a group of the formula:
—X
4—R
11
wherein X
4 is a direct bond or is selected from O and N(R
12),
wherein R
12 is hydrogen or (1-6C)alkyl, and R
11 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl,
(1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl
or N,N-di-[(1-6C)akyl]carbamoyl-(1-6C)alkyl, or from a group of the formula:
—X
5—Q
6
wherein X
5 is a direct bond or is selected from O and N(R
13),
wherein R
13 is hydrogen or (1-6C)alkyl, and Q
6 is aryl, aryl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and
any Q
6 group optionally bears 1 or 2 substituents, which may be the
same or different, selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy,
and wherein any heterocyclyl group within a substituent on R
1 optionally
bears 1 or 2 oxo or thioxo substituents;
R
2 is hydrogen or (1-6C)alkyl and R
3 is hydrogen or
(1-6C)alkyl, or R
2 and R
3 together form a CH
2,
(CH
2)
2 or (CH
2)
3 group,
R
5 is hydrogen or (1-6C)alkyl, or R
5 and R
6 together
with the N atom to which they are attached form a 4- to 7-membered heterocyclic
ring optionally containing a further heteroatom selected from O, N and S,
provided that one of the pairs of groups R
2 and R
4 together,
R
3 and R
4 together and R
5 and R
4 together
forms a bond;
Q
2 is aryl, aryl-(1-3C)alkyl, aryl-(3-7C)cycloalkyl, heteroaryl,
heteroaryl-(1-3C)alkyl or heteroaryl-(3-7C)cycloalkyl wherein each aryl group is
phenyl or naphthyl and each heteroaryl group is a 5- or 6-membered monocyclic or
a 9- or 10-membered bicyclic heteroaryl ring containing 1 or 2 nitrogen heteroatoms
and optionally containing a further heteroatom selected from nitrogen, oxygen and
sulphur, and
Q
2 is optionally substituted with 1, 2, 3, or 4 substituents,
which may be the same or different, selected from halogeno, trifluoromethyl, cyano,
nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl,
(1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl,
(1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy,
(2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino,
(3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,
or from a group of the formula:
—X
6—R
14
wherein X
6 is a direct bond or is selected from O and N(R
15),
wherein R
15 is hydrogen or (1-6C)alkyl, and R
14 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group
of the formula:
—X
7—Q
7
wherein X
7 is a direct bond or is selected from O, S, SO, SO
2,
N(R
16), CO, CH(OR
16), CON(R
16), N(R
16)CO,
SO
2N(R
16), N(R
16)SO
2, C(R
16)
2O,
C(R
16)
2S and C(R
16)
2N(R
16),
wherein each R
16 is hydrogen or (1-6C)alkyl, and Q
7 is aryl,
aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
or Q
2 is optionally substituted with a (1-3C)alkylenedioxy group,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on
Q
2 optionally bears 1, 2 or 3 substituents, which may be the same or
different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino,
carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy,
(2 -6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl,
(1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino,
N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl,
(1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from
a group of the formula:
—X
8—R
17
wherein X
8 is a direct bond or is selected from O and N(R
18),
wherein R
18 is hydrogen or (1-6C)alkyl, and R
17 is halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on Q
2 optionally
bears 1 or 2 oxo or thioxo substituents; and
R
6 is an optionally substituted group selected from (2-6C)alkenyl,
(2-6C)alkynyl, (3-7C)cycloalkyl and (3-7C)cycloalkenyl, or R
6 is a substituted
(1-6C)alkyl group,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R
6
group are optionally separated by the insertion into the chain of a group
selected from O, S, SO, SO
2, N(R
19), CO, CH(OR
19),
CON(R
19), N(R
19)CO, SO
2N(R
19), N(R
19)SO
2
, CH═CH and C≡C wherein R
19 is hydrogen or (1-6C)alkyl,
and wherein any CH
2═CH or HC≡C— group within a
R
6 group optionally bears at the terminal CH
2═ or
HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl
and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q
8—X
9—
wherein X
9 is a direct bond or is selected from CO and N(R
20)CO,
wherein R
20 is hydrogen or (1-6C)alkyl, and Q
8 is aryl, aryl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH
2 or CH
3 group within a R
6 group
optionally bears on each said CH
2 or CH
3 group one or more
of the following substituents, provided that the R
6 group when it is
(1-6C)alkyl must bear at least one such substituent,
one or more halogeno substituents or a substituent selected from hydroxy, cyano,
amidino, amino, carboxy, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio,
(1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino,
(1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl,
(2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino, N-(1-6C)alkyl-(1-6C)alkanesulphonylamino,
(1-6C)alkoxycarbonylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonylamino, N-[hydroxy-(2-6C)alkyl]carbamoyl,
N-[(1-6C)alkoxy-(2-6C)alkyl]carbamoyl, N-[amino-(2-6C)alkyl]carbamoyl, N-[(1-6C)alkylamino-(2-6C)alkyl]carbamoyl,
N-{di -[(1-6C)alkyl]amino-(2-6C)alkyl}carbamoyl, N,N-di-[hydroxy-(2-6C)alkyl]carbamoyl,
N,N-di-[(1-6C)alkoxy-(2-6C)alkyl]carbamoyl, N,N-di-[amino-(2-6C)alkyl]carbamoyl,
N,N-di-[(1-6C)alkylamino-(2-6C)alkyl]carbamoyl and N,N-di-{di-[(1-6C)alkyl]amino-(2-6C)alkyl}carbamoyl,
or from a group of the formula:
—X
10—Q
9
wherein X
10 is a direct bond or is selected from O, S, SO, SO
2,
N(R
21), CO, CH(OR
21), CON(R
21), N(R
21)CO,
SO
2N(R
21), N(R
21)SO
2, C(R
21)
2O,
C(R
21)
2S and N(R
21)C(R
21)
2,
wherein R
21 is hydrogen or (1-6C)alkyl, and Q
9 is aryl, aryl-(1-6C)alkyl,
(3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl,
heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(
