U.S. patent application number 11/910497 was filed with the patent office on 2008-10-02 for substituted oxazole derivatives and their use as tyrosine kinase inhibitors.
This patent application is currently assigned to AB SCIENCE. Invention is credited to Abdellah Benjahad, Martine Croisy, David Grierson, Alain Moussy.
Application Number | 20080242704 11/910497 |
Document ID | / |
Family ID | 36932894 |
Filed Date | 2008-10-02 |
United States Patent
Application |
20080242704 |
Kind Code |
A1 |
Grierson; David ; et
al. |
October 2, 2008 |
Substituted Oxazole Derivatives and their Use as Tyrosine Kinase
Inhibitors
Abstract
The present invention relates to novel compounds selected from
substituted oxazole derivatives of formula (I) that selectively
modulate, regulate, and/or inhibit signal transduction mediated by
certain native and/or mutant tyrosine kinases implicated in a
variety of human and animal diseases such as cell proliferative,
metabolic, allergic, and degenerative disorders. More particularly,
these compounds are potent and selective c-kit, bcr-abl and Fit-3
inhibitors. ##STR00001##
Inventors: |
Grierson; David;
(Versailles, FR) ; Benjahad; Abdellah; (Champigny
S/Marne, FR) ; Moussy; Alain; (Paris, FR) ;
Croisy; Martine; (Cernay La Ville, FR) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
AB SCIENCE
|
Family ID: |
36932894 |
Appl. No.: |
11/910497 |
Filed: |
April 4, 2006 |
PCT Filed: |
April 4, 2006 |
PCT NO: |
PCT/IB2006/001249 |
371 Date: |
January 24, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60667771 |
Apr 4, 2005 |
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|
Current U.S.
Class: |
514/340 ;
514/375; 514/377; 546/271.4; 548/222; 548/234 |
Current CPC
Class: |
A61P 37/08 20180101;
A61P 1/00 20180101; A61P 11/02 20180101; C07D 263/46 20130101; A61P
9/00 20180101; A61P 29/00 20180101; A61P 37/00 20180101; A61P 13/12
20180101; A61P 17/04 20180101; A61P 25/00 20180101; A61P 43/00
20180101; C07D 263/48 20130101; A61P 35/02 20180101; A61P 17/00
20180101; C07D 413/04 20130101; C07D 413/12 20130101; A61P 1/04
20180101; A61P 19/02 20180101; A61P 37/06 20180101; A61P 35/00
20180101; A61P 27/14 20180101; C07D 417/12 20130101; C07D 413/14
20130101; A61P 17/06 20180101; C07D 263/58 20130101; A61P 11/06
20180101 |
Class at
Publication: |
514/340 ;
546/271.4; 548/222; 514/375; 548/234; 514/377 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 413/04 20060101 C07D413/04; C07D 413/12 20060101
C07D413/12; A61K 31/423 20060101 A61K031/423; A61K 31/422 20060101
A61K031/422; A61P 29/00 20060101 A61P029/00; A61P 37/00 20060101
A61P037/00; A61P 35/00 20060101 A61P035/00; C07D 413/14 20060101
C07D413/14 |
Claims
1. A compound of formula I: ##STR00053## Wherein substituents A, B,
B', Q and R1-R5 in Formula I are defined as follows: A and B' is
one of the following: i) (R6)N(CH2).sub.n where n is 0 or 1, ii)
O(CH2).sub.n where n is 0 or 1, iii) S(CH2).sub.n where n is 0 or
1, iv) (CH2).sub.n where n is 0, 1 or 2, and v) C(O)(CH2).sub.n
where n is 0 or 1; or when A and B' each are a nitrogen, they may
be taken together to form a bivalent radical of formula:
--(CH2).sub.s--X1-(CH2).sub.t-- (a) wherein s and t each
independently is 1 or 2, and X1 is O, S, NR10, N[C(.dbd.O)R10] or
(CH2).sub.n wherein n is 0 or 1, and wherein each hydrogen in said
formula (a) may be substituted with halo or C.sub.1-4alkyl; B is
one of the following: i) (R6)N, ii) Oxygen, iii) S(O).sub.n where n
is 0, 1 or 2, iv) CH(R6)(R7), v) C=.delta., where .delta. is
oxygen, sulfur, NH or N--CN, vi) C(R6).dbd.C(R7), and vii)
N.dbd.C(R6), wherein R6 and R7 each independently are hydrogen,
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl, C.sub.1-6alkoxy,
C.sub.1-4hydroxyalkyl; R1 is selected from: i) hydrogen, halogen
(selected from F, Cl, Br or I), ii) an alkyl.sup.1 group defined as
a linear, branched or cycloalkyl group containing from 1 to 10
carbon atoms and optionally substituted with one or more
hetereoatoms such as halogen (selected from F, Cl, Br or I),
oxygen, and nitrogen (the latter optionally in the form of a
pendant basic nitrogen functionality); as well as trifluoromethyl,
carboxyl, cyano, nitro, formyl; as well as CO--R, COO--R, CONH--R,
SO2-R, and SO2NH--R wherein R is a linear or branched alkyl group
containing 1 to 10 carbon atoms and optionally substituted with at
least one heteroatom, notably a halogen (selected from F, Cl, Br or
I), oxygen, and nitrogen, the latter optionally in the form of a
pendant basic nitrogen functionality; as well as a cycloalkyl or
aryl.sup.1 or heteroaryl.sup.1 group optionally substituted by a
pendant basic nitrogen functionality, iii) an aryl.sup.1 group
defined as phenyl or a substituted variant thereof bearing any
combination, at any one ring position, of one or more substituents
such as halogen (selected from I, F, Cl or Br); an alkyl.sup.1
group; a cycloalkyl, aryl or heteroaryl group optionally
substituted by a pendant basic nitrogen functionality;
trifluoromethyl, O-alkyl.sup.1, carboxyl, cyano, nitro, formyl,
hydroxy, NH-alkyl.sup.1, N(alkyl.sup.1)(alkyl.sup.1), and amino,
the latter nitrogen substituents optionally in the form of a basic
nitrogen functionality; NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R
or NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogen, alkyl.sup.1, aryl or heteroaryl,
iv) a heteroaryl.sup.1 group defined as a pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl,
pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
indolyl, benzimidazole, benzoxazole, benzothiazole, quinolinyl
group, which may additionally bear any combination, at any one ring
position, of one or more substituents such as halogen (selected
from F, Cl, Br or I); an alkyl.sup.1 group; a cycloalkyl, aryl or
heteroaryl group optionally substituted by a pendant basic nitrogen
functionality, trifluoromethyl, O-alkyl.sup.1, carboxyl, cyano,
nitro, formyl, hydroxy, NH-alkyl.sup.1,
N(alkyl.sup.1)(alkyl.sup.1), and amino, the latter nitrogen
substituents optionally in the form of a basic nitrogen
functionality; NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R or
NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogern, alkyl.sup.1, v) an
O-aryl.sup.1, or NH-aryl.sup.1, or O-heteroaryl.sup.1 or
NH-heteroaryl.sup.1 group, vi) trifluoromethyl, O-alkyl.sup.1,
carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl.sup.1,
N(alkyl.sup.1)(alkyl.sup.1), and amino, the latter nitrogen
substituents optionally in the form of a basic nitrogen
functionality, and vii) NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R
or NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogen, alkyl.sup.1, aryl or heteroaryl
R2, R3, R4 and R5 each independently are selected from hydrogen,
halogen (selected from F, Cl, Br or I), a linear or branched alkyl
group containing from 1 to 10 carbon atoms and optionally
substituted with one or more hetereoatoms such as halogen (selected
from F, Cl, Br or I), oxygen, and nitrogen, the latter optionally
in the form of a pendant basic nitrogen functionality; as well as
trifluoromethyl, C.sub.1-6alkyloxy, amino, C.sub.1-6alkylamino,
di(C.sub.1-6alkyl)amino, carboxyl, cyano, nitro, formyl, hydroxy,
and CO--R, COO--R, CONH--R, SO2-R, and SO2NH--R wherein R is a
linear or branched alkyl group containing from 1 to 10 carbon atoms
and optionally substituted with at least one heteroatom, notably a
halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the
latter optionally in the form of a pendant basic nitrogen
functionality; Q is selected from: i) Alkyl.sup.1, ii) Aryl.sup.1,
and iii) Heteroaryl.sup.1.
2. The compound according to claim 1 of formula II: ##STR00054##
Wherein Y is oxygen, sulfur, NH or N--CN, Z is oxygen, sulfur,
N(R6) or (CH2).sub.n where n is 0, 1 or 2, L is selected from
Alkyl.sup.1, Aryl.sup.1 or Heteroaryl.sup.1 and R1, R2, R3, R4, R5
and R6 as defined in claim 1.
3. The compound according to claim 1 of formula III: ##STR00055##
Wherein n is an integer of 0, 1 or 2; M is oxygen, sulfure or
(CH2).sub.n where n is 0, 1 or 2; P is selected from N(R8)(R9),
Alkyl.sup.1, Aryl.sup.1 or Heteroaryl.sup.1; wherein R8 and R9 each
independently is hydrogen, Alkyl.sup.1, Aryl or Heteroaryl.sup.1;
R8 and R9 may be taken together to form a bivalent radical of
formula: --(CH2).sub.v--X2-(CH2).sub.w-- (b) wherein v and w each
independently is 1 or 2 and X2 being CH2, O, S, NR10 or
N[C(.dbd.O)R10] and wherein each hydrogen in said formula (b) maybe
substituted with halo or C.sub.1-4alkyl; R10 is hydrogen,
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl, C.sub.1-6alkoxy,
C.sub.1-4hydroxyalkyl; R1, R2, R3, R4 and R5 have the meaning
described above.
4. The compound according to claim 1 of formula IV: ##STR00056##
Wherein G is oxygen, sulfur, N(R11) or (CH2).sub.n where n is 1 or
2; H is oxygen, N(R11) or (CH2).sub.n where n is 1 or 2; J is
selected from N(R12)(R13), Alkyl.sup.1, Aryl.sup.1 or
Heteroaryl.sup.1; wherein R12 and R13 each independently is
hydrogen, Alkyl.sup.1, Aryl.sup.1 or Heteroaryl.sup.1; R12 and R13
maybe taken together to form a bivalent radical of formula:
--(CH2).sub.v--X2-(CH2).sub.w-- (c) wherein v and w each
independently is 1 or 2 and X2 being CH2, O, S, NR14 or
N[C(.dbd.O)R14] and wherein each hydrogen in said formula (c) maybe
substituted with halo or C.sub.1-4alkyl; R11 and R14 each
independently is hydrogen, C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl,
C.sub.1-6alkoxy, C.sub.1-4hydroxyalkyl; R1, R2, R3, R4 and R5 have
the meaning described above.
5. The compound as claimed in claim 1 selected from:
N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-C-phenyl-methane
sulfonamide,
4-{2-[5-(Benzooxazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzon-
itrile,
4-{2-[5-(Benzooxazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-
-benzonitrile,
4-{2-[5-(Benzothiazol-2-ylammo)-2-methyl-phenylamino]-oxazol-5-yl}-benzon-
itrile,
N1-Benzooxazol-2-yl-4-methyl-N3-(5-pyridin-3-yl-oxazol-2-yl)-benze-
ne-1,3-diamine,
N-(5-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-be-
nzene-1,3-diamine,
N1-(6-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine,
N1-(5-Ethanesulfonyl-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-
-2-yl)-benzene-1,3-diamine,
4-Methyl-N1-(5-methyl-benzooxazol-2-yl)-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine,
N1-Fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-benz-
ene-1,3-diamine,
N1-(6-Fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine,
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamin-
o}-oxazol-5-yl)-benzonitrile,
4-(2-{5-[3-(3-cyano-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino-
}-oxazol-5-yl)-benzonitrile,
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamin-
o}-oxazol-5-yl)-benzamide,
1-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-pheny-
l]-imidazolidin-2-one,
1-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-(3-trifmorometh-
yl-phenyl)-imidazolidin-2-one,
1-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-pheny-
l]-tetrahydro-pyrimidin-2-one,
1-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-phenyl-propan-1-
-one,
4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile,
4-(2-{5-[3-(4-Fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl-
)-benzonitrile.
4-{2-[2-Methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitr-
ile.
4-(2-{5-[3-(3-Fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol--
5-yl)-benzonitrile
4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzamide.
1-(4-Fluoro-phenyl)-2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-pheny-
lamino]-ethanone,
1-(4-Fluoro-phenyl)-2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamin-
o)-phenyl]-amino}-ethanone,
4-({Methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-a-
cetyl)-benzonitrile
2-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylammo)-phenylamino]-1-phenyl-etha-
none,
4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenylamino}-
-oxazol-5-yl)-benzonitrile,
4-(2-{5-[2-(4-Cyano-phenyl)-2-oxo-ethylamino]-2-chloro-phenylamino}-oxazo-
l-5-yl)-benzonitrile,
N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzyl]-benzamide,
and
2-{Methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-1--
phenyl-ethanone.
6. The compound according to claim 1, wherein R1 is pyridyl or
benzonitril which may additionally bear any combination, at any one
ring position, of one or more substituents such as hydrogen;
halogen (selected from F, Cl, Br or I); an alkyl group; an
aryl.sup.1 group; trifluoromethyl, O-alkyl.sup.1, carboxyl, cyano,
nitro, formyl, hydroxy, NH-alkyl.sup.1,
N(alkyl.sup.1)(alkyl.sup.1), and amino, the latter nitrogen
substituents optionally in the form of a basic nitrogen
functionality; and NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R or
NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogen, alkyl.sup.1 aryl.sup.1
group.
7. A pharmaceutical composition comprising a compound according to
claim 1.
8. A pharmaceutical composition according to claim 7 comprising a
pharmaceutically acceptable carrier suitable for oral or topical
administration.
9. A pharmaceutical composition according to claim 7 formulated as
tablets, pills, dragees, capsules, liquids, gels, syrups, slurries,
and suspensions.
10. A cosmetic composition for topical administration comprising a
compound according to claim 1.
11-16. (canceled)
17. A pharmaceutical composition comprising a compound according to
claim 5, and a pharmaceutically acceptable carrier.
18. A method of treating a neoplastic disease comprising
administering to a subject in need thereof an effective amount of
the compound according to claim 1.
19. The method of claim 18, wherein the neoplastic disease is
mastocytosis, canine mastocytoma, solid tumor, human
gastrointestinal stromal tumor ("GIST"), small cell lung cancer,
non-small cell lung cancer, acute myelocytic leukemia, acute
lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous
leukemia, colorectal carcinomas, gastric carcinomas,
gastrointestinal stromal tumor, testicular cancer, glioblastomas,
or astrocytomas.
20. A method of treating an allergic disease comprising
administering to a subject in need thereof an effective amount of
the compound according to claim 1.
21. The method of claim 20, wherein the allergic disease is asthma,
allergic rhinitis, allergic sinusitis, anaphylactic syndrome,
urticaria, angioedema, atopic dermatitis, allergic contact
dermatitis, erythema nodosum, erythema multiforme, cutaneous
necrotizing venulitis, insect bite skin inflammation, or blood
sucking parasitic infestation.
22. A method of treating an inflammatory disease comprising
administering to a subject in need thereof an effective amount of
the compound according to claim 1.
23. The method of claim 22, wherein the inflammatory disease is
rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis, or other arthritic conditions.
24. A method of treating an autoimmune disease comprising
administering to a subject in need thereof an effective amount of
the compound according to claim 1.
25. The method of claim 24, wherein the autoimmune disease is
multiple sclerosis, psoriasis, intestine inflammatory disease,
ulcerative colitis, Crohn's disease, rheumatoid arthritis and
polyarthritis, local and systemic scleroderma, systemic lupus
erythematosus, discoid lupus erythematosus, cutaneous lupus,
dermatomyositis, polymyositis, Sjogren's syndrome, nodular
panarteritis, autoimmune enteropathy, or proliferative
glomerulonephritis.
26. A method of treating a graft-versues-host disease or
graft-rejection in an organ transplantation, comprising
administering to a subject in need thereof an effective amount of
the compound according to claim 1.
27. The method of claim 26, wherein the organ is a kidney,
pancreas, liver, heart, lung, or bone marrow.
28. A method of treating a neoplastic disease, an allergic disease,
an inflammatory disease, an autoimmune disease, a
graft-versues-host disease, or graft-rejection in an organ
transplantation, comprising administering to a subject in need
thereof an effective amount of the compound according to claim 5.
Description
[0001] The present invention is concerned with substituted oxazole
derivatives that selectively modulate, regulate, and/or inhibit
signal transduction mediated by certain native and/or mutant
tyrosine kinases implicated in a variety of human and animal
diseases such as cell proliferative, metabolic, allergic, and
degenerative disorders. More particularly, these compounds are
potent and selective c-kit, bcr-abl and Flt-3 inhibitors.
[0002] Tyrosine kinases are receptor type or non-receptor type
proteins, which transfer the terminal phosphate of ATP to tyrosine
residues of proteins thereby activating or inactivating signal
transduction pathways. These proteins are known to be involved in
many cellular mechanisms, which in case of disruption, lead to
disorders such as abnormal cell proliferation and migration as well
as inflammation.
[0003] As of today, there are about 58 known receptor tyrosine
kinases. Included are the well-known VEGF receptors (Kim et al.,
Nature 362, pp. 841-844, 1993), PDGF receptors, c-kit, Flt-3 and
the FLK family. These receptors can transmit signals to other
tyrosine kinases including Src, Raf, Frk, Btk, Csk, Abl, Fes/Fps,
Fak, Jak, Ack, etc.
[0004] Among tyrosine kinase receptors, c-kit is of special
interest. Indeed, c-kit is a key receptor activating mast cells,
which have proved to be directly or indirectly implicated in
numerous pathologies for which the Applicant filed WO 03/004007, WO
03/004006, WO 03/003006, WO 03/003004, WO 03/002114, WO 03/002109,
WO 03/002108, WO 03/002107, WO 03/002106, WO 03/002105, WO
03/039550, WO 03/035050, WO 03/035049, U.S. 60/359,652, U.S.
60/359,651 and U.S. 60/449,861.
[0005] It was found that mast cells present in tissues of patients
are implicated in or contribute to the genesis of diseases such as
autoimmune diseases (rheumatoid arthritis, inflammatory bowel
diseases (IBD)) allergic diseases, bone loss, cancers such as solid
tumors, leukaemia and GIST, tumor angiogenesis, inflammatory
diseases, interstitial cystitis, mastocytosis, graft-versus-host
diseases, infection diseases, metabolic disorders, fibrosis,
diabetes and CNS diseases. In these diseases, it has been shown
that mast cells participate in the destruction of tissues by
releasing a cocktail of different proteases and mediators such as
histamine, neutral proteases, lipid-derived mediators
(Prostaglandins, thromboxanes and leucotrienes), and various
cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-.alpha.,
GM-CSF, MIP-1a, MIP-1b, MIP-2 and IFN-.gamma.).
[0006] The c-kit receptor also can be constitutively activated by
mutations leading to abnormal cell proliferation and development of
diseases such as mastocytosis (D816V mutation) and various cancers
such as GIST (c-kit.DELTA.27, a juxtamembrane deletion).
[0007] Sixty to 70% of patients presenting with AML have blasts
which express c-kit, the receptor for stem cell factor (SCF)
(Broudy, 1997). SCF promotes growth of hematopoietic progenitors,
and act as a survival factor for AML blasts. In some cases (1 to
2%) of AML, a mutation in a conserved residue of the kinase domain
(Kit816) resulting in constitutive activation of c-kit has been
described (Beghini et al., 2000; Longley et al., 2001). This gain
of function mutation (Asp to Val/Tyr substitution) has been
identified in mast cell leukemic cell lines and in samples derived
from patients with mastocytosis (Longley et al., 1996). Preliminary
results show that this mutation is expressed in most cases of
systemic mastocytosis ([.about.60%], P Dubreuil, AFIRMM, study in
progress on about 300 patients).
[0008] For this reason, it has been proposed to target c-kit to
deplete the mast cells responsible for these disorders.
[0009] The main objective underlying the present invention is
therefore to find potent and selective compounds capable of
inhibiting wild type and/or mutated c-kit.
[0010] Many different compounds have been described as tyrosine
kinase inhibitors, for example, bis monocyclic, bicyclic or
heterocyclic aryl compounds (WO 92/20642), vinylene-azaindole
derivatives (WO 94/14808), 1-cyclopropyl-4-pyridyl-quinolones (U.S.
Pat. No. 5,330,992), styryl compounds (U.S. Pat. No. 5,217,999),
styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606),
selenoindoles and selenides (WO 94/03427), tricyclic polyhydroxylic
compounds (WO 92/21660), benzylphosphonic acid compounds (WO
91/15495), pyrimidine derivatives (U.S. Pat. No. 5,521,184 and WO
99/03854), indolinone derivatives and pyrrole-substituted
indolinones (U.S. Pat. No. 5,792,783, EP 934 931, U.S. Pat. No.
5,834,504, U.S. Pat. No. 5,883,116, U.S. Pat. No. 5,883,113, U.S.
Pat. No. 5,886,020, WO 96/40116 and WO 00/38519), as well as bis
monocyclic, bicyclic aryl and heteroaryl compounds (EP 584 222,
U.S. Pat. No. 5,656,643 and WO 92/20642), quinazoline derivatives
(EP 602 851, EP 520 722, U.S. Pat. No. 3,772,295 and U.S. Pat. No.
4,343,940) and aryl and heteroaryl quinazoline (U.S. Pat. No.
5,721,237, U.S. Pat. No. 5,714,493, U.S. Pat. No. 5,710,158 and WO
95/15758).
[0011] However, none of these compounds have been described as
potent and selective inhibitors of c-kit or of the c-kit
pathway.
[0012] In connection with the present invention, we have discovered
that compounds displaying specific substitutions in oxazole
derivatives are potent and selective inhibitors of c-kit, bcr-abl,
Flt-3 or c-kit pathway. These compounds are good candidates for
treating diseases such as autoimmunes diseases, inflammatory
diseases, cancers and mastocytosis.
DESCRIPTION
[0013] Therefore, the present invention relates to compounds
belonging to the substituted oxazole derivatives. These compounds
are capable of selectively inhibiting signal transduction involving
the tyrosine phosphokinase c-kit, bcr-abl, Flt-3 and mutant forms
thereof.
[0014] In a first embodiment, the invention is aimed at compounds
of formula I, which may represent either free base forms of the
substances or pharmaceutically acceptable salts thereof:
##STR00002##
wherein substituents A, B, B', Q and R1-R5 in Formula I are defined
as follows: A and B' is one of the following: i) (R6)N(CH2).sub.n
where n is 0 or 1 ii) O(CH2).sub.n where n is 0 or 1 iii)
S(CH2).sub.n where n is 0 or 1 iv) (CH2).sub.r where n is 0, 1 or 2
v) C(O)(CH2).sub.n where n is 0 or 1 or when A and B' each are a
nitrogen, they may be taken together to form a bivalent radical of
formula:
--(CH2).sub.s--X1-(CH2).sub.t-- (a)
where s and t each independently is 1 or 2 and X1 being O, S, NR10,
N[C(.dbd.O)R10] or (CH2).sub.n where n is 0 or 1, and wherein each
hydrogen in said formula (a) may be substituted with halo or
C.sub.1-4alkyl. B is one of the following:
i) (R6)N
ii) Oxygen
[0015] iii) S(O).sub.n where n is 0, 1 or 2
iv) CH(R6)(R7)
[0016] v) C=.delta., where .delta. is oxygen, sulfur, NH or
N--CN
vi) C(R6).dbd.C(R7)
[0017] vii) N.dbd.C(R6) R6 and R7 each independently are hydrogen,
C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4hydroxyalkyl, C.sub.1-4alkylamino. R1 is selected from: i)
hydrogen, halogen (selected from F, Cl, Br or I), or ii) an
alkyl.sup.1 group defined as a linear, branched or cycloalkyl group
containing from 1 to 10 carbon atoms and optionally substituted
with one or more hetereoatoms such as halogen (selected from F, Cl,
Br or I), oxygen, and nitrogen (the latter optionally in the form
of a pendant basic nitrogen functionality); as well as
trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO--R,
COO--R, CON--H--R, SO2-R, and SO2NH--R wherein R is a linear or
branched alkyl group containing 1 to 10 carbon atoms and optionally
substituted with at least one heteroatom, notably a halogen
(selected from F, Cl, Br or I), oxygen, and nitrogen, the latter
optionally in the form of a pendant basic nitrogen functionality;
as well as a cycloalkyl or aryl.sup.1 or heteroaryl.sup.1 group
optionally substituted by a pendant basic nitrogen functionality,
or iii) an aryl.sup.1 group defined as phenyl or a substituted
variant thereof bearing any combination, at any one ring position,
of one or more substituents such as [0018] halogen (selected from
I, F, Cl or Br); [0019] an alkyl.sup.1 group; [0020] a cycloalkyl,
aryl or heteroaryl group optionally substituted by a pendant basic
nitrogen functionality; [0021] trifluoromethyl, O-alkyl.sup.1,
carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl.sup.1,
N(alkyl.sup.1)(alkyl.sup.1), and amino, the latter nitrogen
substituents optionally in the form of a basic nitrogen
functionality; [0022] NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R
or NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogen, alkyl.sup.1, aryl or heteroaryl,
or iv) a heteroaryl.sup.1 group defined as a pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl,
pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,
indolyl, benzimidazole, benzoxazole, benzothiazole, quinolinyl
group, which may additionally bear any combination, at any one ring
position, of one or more substituents such as [0023] halogen
(selected from F, Cl, Br or I); [0024] an alkyl.sup.1 group; [0025]
a cycloalkyl, aryl or heteroaryl group optionally substituted by a
pendant basic nitrogen functionality, [0026] trifluoromethyl,
O-alkyl.sup.1, carboxyl, cyano, nitro, formyl, hydroxy,
NH-alkyl.sup.1, N(alkyl.sup.1)(alkyl.sup.1), and amino, the latter
nitrogen substituents optionally in the form of a basic nitrogen
functionality; [0027] NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R
or NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogern, alkyl.sup.1, or v) an
O-aryl.sup.1, or NH-aryl.sup.1, or O-heteroaryl.sup.1 or
NH-heteroaryl.sup.1 group vi) trifluoromethyl, O-alkyl.sup.1,
carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl.sup.1,
N(alkyl.sup.1)(alkyl.sup.1), and amino, the latter nitrogen
substituents optionally in the form of a basic nitrogen
functionality, or vi) NHCO--R or NHCOO--R or NHCONH--R or NHSO2-R
or NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or SO2NH--R
wherein R corresponds to hydrogen, alkyl.sup.1, aryl.sup.1 or
heteroaryl.sup.1.
[0028] R2, R3, R4 and R5 each independently are selected from
hydrogen, halogen (selected from F, Cl, Br or I), a linear or
branched alkyl group containing from 1 to 10 carbon atoms and
optionally substituted with one or more hetereoatoms such as
halogen (selected from F, Cl, Br or I), oxygen, and nitrogen, the
latter optionally in the form of a pendant basic nitrogen
functionality; as well as trifluoromethyl, C.sub.1-6alkyloxy,
amino, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, carboxyl,
cyano, nitro, formyl, hydroxy, and CO--R, COO--R, CONH--R, SO2-R,
and SO2NH--R wherein R corresponds to hydrogen, alkyl.sup.1, aryl
or heteroaryl.
and wherein Q is selected from:
i) Alkyl.sup.1
ii) Aryl.sup.1
[0029] iii) Heteroaryl.sup.1 as defined above.
[0030] In one particular embodiment, group Q is a substituted
alkyl, aryl or heteroaryl group bearing a pendant basic nitrogen
functionality represented for example by the structures a to m
shown below, wherein the wavy line and the arrow line correspond to
the point of attachment to core structure of formula I.
##STR00003## ##STR00004##
[0031] Also, for g to m, the arrow may include a point of
attachment to the core structure via a phenyl group.
[0032] Furthermore, among the preferred compounds of formula I, II,
III and IV, the invention concerns the compounds in which R1 is
pyridyl or benzonitrile which may additionally bear any
combination, at any one ring position, of one or more substituents
such as [0033] hydrogen; [0034] halogen (selected from F, Cl, Br or
I); [0035] an alkyl.sup.1 group; [0036] an aryl.sup.1 group; [0037]
trifluoromethyl, O-alkyl.sup.1, carboxyl, cyano, nitro, formyl,
hydroxy, NH-alkyl.sup.1, N(alkyl.sup.1)(alkyl.sup.1), and amino,
the latter nitrogen substituents optionally in the form of a basic
nitrogen functionality; [0038] NHCO--R or NHCOO--R or NHCONH--R or
NHSO2-R or NHSO2NH--R or CO--R or COO--R or CONH--R or SO2-R or
SO2NH--R wherein R corresponds to hydrogern, alkyl.sup.1 or
aryl.sup.1 group.
[0039] Unless stated otherwise, for the purpose of the present
invention, the term "alkyl group" is intended to mean any linear or
branched, substituted or unsubstituted, C1-C10 alkyl group, such as
C1-C4 or C1-C6, in particular a methyl, ethyl group, propyl group,
preferably methyl. The term "alkenyl" as used in the present
invention refers to C1-C6, in particular C1-C4, straight or
branched chain substituted or unsubstituted alkenyl radicals
containing from 1 to 30 carbon atoms including, but not limited to,
ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like. The
term "alkoxy group" is intended to mean any alkoxy group having 1
to 6 linear or branched, substituted or unsubstituted, carbon
atoms, in particular the group OCH3. The term "aryl group" is
intended to mean one or more aromatic rings having 5 to 6 carbon
atoms, which may be joined or fused, and substituted or
unsubstituted. In particular, the aryl groups may be phenyl or
pyridyl and the substituents may be halogen atoms, cyano, amino,
alkoxy groups as defined above, alkyl groups as defined above or a
nitro group.
[0040] An example of preferred compounds of the above formula is
depicted below:
001:
N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-C-phenyl-meth-
ane sulfonamide
##STR00005##
[0041] 002:
4-{2-[5-(Benzooxazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzon-
itrile
##STR00006##
[0042] 003:
4-{2-[5-(Benzothiazol-2-ylamino)-2-methyl-phenylamino]-oxazol-5-yl}-benzo-
nitrile
##STR00007##
[0043] 004:
N1-Benzooxazol-2-yl-4-methyl-N3-(5-pyridin-3-yl-oxazol-2-yl)-benzene-1,3--
diamine
##STR00008##
[0044] 005:
N1-(5-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine
##STR00009##
[0045] 006:
N1-(6-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine
##STR00010##
[0046] 007:
N1-(5-Ethanesulfonyl-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-
-2-yl)-benzene-1,3-diamine
##STR00011##
[0047] 008:
4-Methyl-N1-(5-methyl-benzooxazol-2-yl)-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine
##STR00012##
[0049] .sup.1H NMR (DMSO-d.sup.6, 300 MHz) .delta.=2.25 (s, 3H);
2.50 (s, 3H); 6.91 (d, J=8.1, 1H); 7.14 (s, 1H); 7.20 (d, J=8.4,
1H); 7.33 (d, J=8.1, 1H); 7.47-7.53 (m, 3H); 7.79 (s, 1H); 8.13 (d,
J=2.1, 1H); 8.53 (s, 1H); 8.55 (s, 1H); 9.60 (s, 1H); 10.53 (s,
1H).
009:
N1-(5-Fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-y-
l)-benzene-1,3-diamine
##STR00013##
[0050] 010:
N1-(6-Fluoro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine
##STR00014##
[0052] Among the particular compounds of formula I, the invention
is directed to compounds of the following formula II:
##STR00015##
[0053] Wherein Y is oxygen, sulfur, NH or N--CN, Z is oxygen,
sulfur, N(R6) or (CH2).sub.n where n is 0, 1 or 2.
[0054] L is selected from Alkyl.sup.1, Aryl.sup.1 or
Heteroaryl.sup.1 as defined above.
[0055] R1, R2, R3, R4, R5 and R6 have the meaning described
above.
[0056] An example of preferred compounds of the above formula is
depicted below:
011:
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenyl-
amino}-oxazol-5-yl)-benzonitrile
##STR00016##
[0057] 012:
4-(2-{5-[3-(3-cyano-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamino-
}-oxazol-5-yl)-benzonitrile
##STR00017##
[0058] 013:
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamin-
o}-oxazol-5-yl)-benzamide
##STR00018##
[0059] 014:
1-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-pheny-
l]-imidazolidin-2-one
##STR00019##
[0060] 015:
1-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-(3-trifluoromet-
hyl-phenyl)-imidazolidin-2-one
##STR00020##
[0061] 016:
1-(4-Fluoro-phenyl)-3-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-pheny-
l]-tetrahydro-pyrimidin-2-one
##STR00021##
[0063] Among the particular compounds of formula I, the invention
is directed to compounds of the following formula III:
##STR00022##
With n being an integer of 0, 1 or 2. M is oxygen, sulfur or
(CH2).sub.n where n is 0, 1 or 2. P is selected from N(R8)(R9),
Alkyl.sup.1, Aryl.sup.1 or Heteroaryl.sup.1. R8 and R9 each
independently is hydrogen, Alkyl.sup.1, Aryl.sup.1 or
Heteroaryl.sup.1. R8 and R9 may be taken together to form a
bivalent radical of formula
--(CH2).sub.v--X2-(CH2).sub.w-- (b)
where v and w each independently is 1 or 2 and X2 being CH2, O, S,
NR10 or N[C(.dbd.O)R10] and wherein each hydrogen in said formula
(b) may be substituted with halo or C.sub.1-4alkyl. R10 is
hydrogen, C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-7cycloalkyl, C.sub.1-4haloalkyl, C.sub.1-6alkoxy,
C.sub.1-4hydroxyalkyl.
[0064] R1, R2, R3, R4 and R5 have the meaning described above.
EXAMPLES
017:
1-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-3-phenyl-prop-
an-1-one
##STR00023##
[0065] 018:
4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile
##STR00024##
[0066] 019:
4-(2-{5-[3-(4-Fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl-
)-benzonitrile
##STR00025##
[0067] 020:
4-{2-[2-Methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitr-
ile
##STR00026##
[0068] 021:
4-(2-{5-[3-(3-Fluoro-phenyl)-propionyl]-2-methyl-phenylamino}-oxazol-5-yl-
)-benzonitrile
##STR00027##
[0069] 022:
4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzamide
##STR00028##
[0071] Among the particular compounds of formula I, the invention
is directed to compounds of the following formula IV:
##STR00029##
G is oxygen, sulfur, N(R11) or (CH2).sub.n where n is 1 or 2. H is
oxygen, N(R11) or (CH2).sub.n where n is 1 or 2. J is selected from
N(R12)(R13), Alkyl.sup.1, Aryl.sup.1 or Heteroaryl.sup.1. R12 and
R13 each independently is hydrogen, Alkyl.sup.1, Aryl.sup.1 or
Heteroaryl.sup.1. R12 and R13 may be taken together to form a
bivalent radical of formula:
--(CH2).sub.v--X2-(CH2).sub.w-- (c)
where v and w each independently is 1 or 2 and X2 being CH2, O, S,
NR14 or
[0072] N[C(.dbd.O)R14] and wherein each hydrogen in said formula
(c) may be substituted with halo or C.sub.1-4alkyl.
[0073] R 11 and R14 each independently is hydrogen, C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-7cycloalkyl,
C.sub.1-4haloalkyl, C.sub.1-6alkoxy, C.sub.1-4hydroxyalkyl.
[0074] R1, R2, R3, R4 and R5 have the meaning described above.
Examples
023:
1-(4-Fluoro-phenyl)-2-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-p-
henylamino]-ethanone
##STR00030##
[0075] 024:
1-(4-Fluoro-phenyl)-2-{methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamin-
o)-phenyl]-amino}-ethanone
##STR00031##
[0076] 025:
4-({Methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino}-a-
cetyl)-benzonitrile
##STR00032##
[0077] 026:
2-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenylamino]-1-phenyl-eth-
anone
##STR00033##
[0078] 027:
4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenylamino}-oxaz-
ol-5-yl)-benzonitrile
##STR00034##
[0079] 028:
4-(2-{5-[2-(4-Cyano-phenyl)-2-oxo-ethylamino]-2-chloro-phenylamino}-oxazo-
l-5-yl)-benzonitrile
##STR00035##
[0081] 029:
N-[4-Methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-benzyl]-benzamide
##STR00036##
[0082] .sup.1H NMR (DMSO-d.sup.6, 300 MHz) .delta.=2.25 (s, 3H);
4.45 (d, J=5.7, 2H); 6.99 (d, J=7.2, 1H); 7.17 (d, J=7.2, 1H);
7.45-7.52 (m, 5H); 7.72 (s, 2H); 7.88 (d, J=7.2, 2H); 8.49 (d,
J=5.1, 2H); 9.05 (t, J=5.7, 1H); 9.54 (s, 1H).
030:
2-{Methyl-[4-methyl-3-(5-pyridin-4-yl-oxazol-2-ylamino)-phenyl]-amino-
}-1-phenyl-ethanone
##STR00037##
[0084] .sup.1H NMR (DMSO-d.sup.6, 300 MHz) .delta.=2.14 (s, 3H);
3.00 (s, 3H); 4.96 (s, 2H); 6.37 (d, J=9.2, 1H); 6.95 (d, J=8.4,
1H); 7.13 (s, 1H); 7.42 (d, J=5.4, 2H); 7.52-7.65 (m, 4H); 7.99.
(d, J=7.2, 2H); 8.51 (d, J=5.7, 2H); 9.37 (s, 1H).
[0085] The compounds of the present invention may be prepared using
the general protocole as follows:
Compounds of formula 4 can be prepared by the condensation of an
azide of general formula 1 with an isocyanate of the type 2 or an
isothiocyanate of the type 3.
##STR00038##
[0086] Group E in formula 2 and 3 corresponds to nitro, cyano,
CH2OH, CO2CH3, CONH2, COCH3 or to A-B-B'-Q group. A-B-B'-Q group is
as described in formula I.
[0087] The reaction of 1 either with 2 or 3 in a solvent such as
methylene chloride or dioxane in the presence of
triphenylphosphine, leads to an oxazole-type product of formula
4.
##STR00039##
[0088] R1, R2, R3, R4 and R5 have the meaning described above.
[0089] The following example is intended to illustrate the present
invention.
Example of Compound Synthesis
[0090] General: All chemicals used were commercial reagent grade
products. Solvents were of anhydrous commercial grade and were used
without further purification. Dioxane is freshly distilled under a
stream of argon before use. The progress of the reactions was
monitored by thin layer chromatography using precoated silica gel
60F 254, Merck TLC plates, which were visualized under UV light.
Multiplicities in .sup.1H NMR spectra are indicated as singlet (s),
broad singlet (br s), doublet (d), triplet (t), quadruplet (q), and
multiplet (m) and the NMR spectrum were realized on a 300 MHz
Bruker spectrometer.
Preparation of 4-Azidoacetyl-benzonitrile
##STR00040##
[0092] To a solution of the commercially available
4-bromoacetyl-benzonitrile (5 g, 22.32 mmol) in 150 mL of methanol
was added sodium azide (1.74 g, 26.78 mmol) and the contents
stirred at room temperature for 2 h. After removal of the solvent,
the residue was treated with water (50 mL) and extracted with
dichloromethane (3.times.50 mL). The combined organic layers were
dried over MgSO.sub.4 and concentrated to give a yellow solid (3.90
g, 94%). This compound was used for the next step without any
further purification.
Preparation of
4-[2-(2-Methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile
##STR00041##
[0094] To a solution of 4-Azidoacetyl-benzonitrile (1.5 g, 8.06
mmol) in dioxane 25 mL was added 2-methyl-5-nitrophenyl isocyanate
(1.43 mg, 8.06 mmol) (commercially available), and
triphenylphosphine (2.11 g, 8.06 mmol). The reaction mixture was
placed in an oil bath preheated to 100.degree. C. and stirred for
30 min. After evaporation of the solvent under reduced pressure,
the solid residue was recrystallized from ethanol to give the title
compound as yellow micro crystals (1.16 g, 45%).
[0095] m.p.>260.degree. C.
Preparation of
4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile
##STR00042##
[0097] To a solution of
4-[2-(2-Methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile (500
mg, 1.56 mmol) in ethanol (15 mL) was added tin(II) chloride
dihydrate (677 mg, 3 mmol). The reaction mixture was heated under
reflux for 4 h. The mixture was then concentrated, saturated
aqueous NaHCO.sub.3 was added and the resultant suspension was
extracted with ethyl acetate (3.times.15 mL). The combined organic
layers were washed with brine (30 mL), dried over anhydrous
MgSO.sub.4 and concentrated. The residue was alumina column
chromatographed (dichloromethane/ethanol:99/1).
4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was
obtained as pale yellow powder (172 mg, 38%).
[0098] m.p.=236.degree. C.
[0099] .sup.1H NMR (DMSO-d.sup.6) .delta.=2.14 (s, 3H); 4.91 (br s,
2H); 6.25 (dd, J=7.8-1.9, 1H); 6.82 (d, J=8.0, 1H); 7.01 (d, J=2.4,
1H); 7.68 (m, 3H); 7.84 (d, J=8.5, 2H); 9.22 (s, 1H).
Preparation of
4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenyl
amino}-oxazol-5-yl)-benzonitrile
##STR00043##
[0101] To a solution of
4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (60
mg, 0.207 mmol) in dimethylacetamide (3 mL) was added
4-fluorophenacyl bromide (45 mg, 0.207 mmol), NaHCO.sub.3 (18 mg,
0.207 mmol). The mixture was stirred at room temperature for 2 h.
After removal of the solvent, the residue was treated with
saturated aqueous NaHCO.sub.3 (10 mL) and extracted with ethyl
acetate (3.times.10 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO.sub.4 and concentrated.
4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenyl
amino}-oxazol-5-yl)-benzonitrile was obtained after silica gel
column chromatography (dichloromethane/ethanol:98/2) (38 mg, 43%)
as beige solid.
[0102] m.p.=199.degree. C.
[0103] .sup.1H NMR (DMSO-d) .delta.=2.12 (s, 3H); 4.62 (d, J=4.8,
2H); 5.81 (t, J=4.8, 1H); 6.37 (d, J=6.0, 1H); 6.91 (d, J=8.1, 1H);
7.08 (s, 1H); 7.37 (m, 2H); 7.67 (m, 3H); 7.83 (d, J=8.4, 2H); 8.14
(m, 2H); 9.30 (s, 1H).
Preparation of
4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile
##STR00044##
[0105] In a similar manner as described for the preparation of
4-[2-(2-Methyl-5-nitro-phenylamino)-oxazol-5-yl]-benzonitrile, from
4-Azidoacetyl-benzonitrile (2.70 g, 14.5 mmol) and
1-(3-Isothiocyanato-4-methyl-phenyl)-ethanone (2.22 g, 11.6 mmol)
was obtained the title compound (1.43, 31%), as a yellow solid.
[0106] .sup.1H NMR (DMSO-d.sup.6) .delta.=2.41 (s, 3H); 2.59 (s,
3H); 7.41 (d, J=7.8, 1H); 7.67 (dd, J=7.8-1.6, 1H); 7.75 (s, 1H);
7.79 (d, J=8.4, 2H); 7.72 (d, J=8.4, 2H); 8.51 (d, J=1.6, 1H); 9.73
(s, 1H).
Preparation of
4-{2-[2-Methyl-5-(3-phenyl-propionyl)-phenylamino]-oxazol-5-yl}-benzonitr-
ile
##STR00045##
[0108] To a stirred solution of
4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (100
mg, 0.315 mmol) and benzaldehyd (0.035 mL, 0.35 mmol) in ethanol,
was added dropwise at 0.degree. C., 1 mL of aqueous NaOH 30%. After
the mixture was stirred at room temperature for 16 h and poured
into ice water (ca. 10 mL). The precipitate was filtered, washed
diethyl ether and dried under vacuum.
[0109] The yellow solid obtained was dissolved in ethanol (2 mL)
and THF (2 mL), treated with palladium on carbon (10%, 20 mg) and
hydrogenated. The catalyst was removed by filtration throught a pad
of celite. The filtrate was evaporated under reduce pressure to
give the title compound (77 mg, 60%) as yellow powder.
[0110] .sup.1H NMR (DMSO-d.sup.6) .delta.=2.41 (s, 3H); 2.98 (t,
J=7.7, 2H); 3.36 (t, J=7.7, 2H); 7.23 (m, 1H); 7.32 (m, 4H); 7.40
(d, J=7.8, 1H); 7.69 (dd, J=7.8-1.6, 1H); 7.72 (s, 1H); 7.89 (d,
J=8.4, 2H) 7.94 (d, J=8.4, 2H); 8.52 (d, J=1.6, 1H); 9.73 (s,
1H).
Preparation of 4-Bromoacetylpyridine, HBr Salt
##STR00046##
[0112] Bromine (24 g, 150 mmol) in 4 mL of 45% HBr was added drop
wise under vigorous stirring to a solution at 70.degree. C. of
4-acetyl-pyridine (18 g, 148 mmol) in acetic acid containing 45% of
HBr (165 mL). The vigorously stirred mixture was kept at 70.degree.
C. for 3 h. The mixture was cooled and the precipitate collected by
filtration and washed with petroleum ether(40-65.degree.
C.)/methanol (1/1, 100 mL) to give 35.8 g of a white crystals of
(85%).
Preparation of
2-Methyl-5-nitro-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine
##STR00047##
[0114] To a solution of 4-bromoacetylpyridine hydrobromide (5 g,
17.8 mmol) in 80 mL of water was added sodium azide (1.16 g, 17.8
mmol) and the contents stirred at room temperature for 30 min. The
reaction mixture was cooled to 0.degree. C., treated slowly with
saturated aqueous NaHCO.sub.3 until pH=6-7, extracted with
dichloromethane (3.times.30 mL) and the combined organic phases
were dried over MgSO.sub.4, concentrated at room temperature under
reduced pressure to a final volume of 25 mL, and diluted with
dioxane (30 mL). The resulting solution was concentrated to remove
the remaining (lower boiling) dichloromethane. To the final volume
(25 mL) was added at 0.degree. C., 2-methyl-5-nitrophenyl
isocyanate (1.58 g, 8.9 mmol) (commercially available) and portion
wise triphenylphosphine (2.62 g, 8.9 mmol). The reaction mixture
was then stirred for 1 h at room temperature and heated for an
additional 2 h at 100.degree. C. After evaporation of the solvent
under reduced pressure the residue was crystallized in
dichloromethane/ethanol (10 mL/5 mL), to give the title compound as
yellow crystals (0.9 g, 34%).
[0115] mp>220.degree. C.
Preparation of
(2-Methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine
##STR00048##
[0117] A solution of
(2-methyl-5-nitro-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (1 g,
3.39 mmol) in ethanol (50 mL) was treated with 10% Pd/C (120 mg)
and hydrazine hydrate (3.50 mL, 112.5 mmol) was added drop wise
over 10 min. The reaction mixture was stirred at room temperature
for 30 min and then refluxed for 2 h. The hot solution was filtered
through a short pad of Celite, and the catalyst was washed with hot
ethanol. The filtrates were concentrated under reduced vacuum to
give the crude pruduct. This was silica gel column chromatographed
(dichloromethane/ethanol:97/3). 720 mg (80%) of
(2-methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine was
obtained as pale yellow powder.
[0118] mp 158.degree. C.
[0119] .sup.1H NMR (DMSO-d) .delta.=2.14 (s, 3H); 4.96 (bs, 2H);
6.30 (dd, J=8.1-2.1, 1H); 6.87 (d, J=8.1, 1H); 7.04 (d, J=2.1, 1H);
7.50 (d, J=6.0, 2H); 8.58 (d, J=6.0, 2H); 7.76 (s, 1H); 9.28 (s,
1H).
Preparation of
(5-Isothiocyanato-2-methyl-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine
##STR00049##
[0121] To a solution of
(2-Methyl-5-amino-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine (500
mg, 1.88 mmol) in dichloromethane (70 mL) was added
1,1'-Thiocarbonyldi-2(1H)-pyridine (525 mg, 2.26 mmol). The mixture
was stirred at room temperature overnight. After evaporation of the
solvent under reduced pressure, the residue was silica gel column
chromatographed (ethyl acetate/heptane:50/50) to give 528 mg (91%)
of the title compound as a beige solid.
[0122] .sup.1H NMR (DMSO-d) .delta.=2.36 (s, 3H); 7.10 (dd,
J=8.1-2.1, 1H); 7.32 (d, J=8.1, 1H); 7.56 (d, J=6.0, 2H); 7.86 (s,
1H); 8.08 (d, J=2.1, 1H); 8.62 (d, J=6.0, 2H); 9.80 (s, 1H).
Preparation of
N1-(5-Chloro-benzooxazol-2-yl)-4-methyl-N3-(5-pyridin-4-yl-oxazol-2-yl)-b-
enzene-1,3-diamine
##STR00050##
[0124] To a solution of
(5-Isothiocyanato-2-methyl-phenyl)-(5-pyridin-4-yl-oxazol-2-yl)-amine
(120 mg, 0.39 mmol) in DMF (8 mL), was added
2-Amino-4-chloro-phenol (61 mg, 0.43 mmol). The mixture was stirred
at room temperature overnight and yellow Mercury (II) oxide (72 mg,
0.39 mmol) was added. The mixture was stirred at room temperature 1
h the precipitate was filtered through a short pad of Celite. The
filtrate was concentrated under reduced vacuum to give the crude
product. This was silica gel column chromatographed
(dichloromethane/ethanol:95/5) to give 112 mg (69%) of the title
compound as a yellow solid.
[0125] .sup.1H NMR (DMSO-d.sup.6) .delta.=2.26 (s, 3H); 7.14 (dd,
J=8.7-2.1, 1H); 7.22 (d, J=8.7, 1H); 7.40 (d, J=2.1, 1H); 7.47-7.53
(m, 4H); 7.79 (s, 1H); 8.12 (d, J=2.1, 1H); 8.53 (s, 1H); 8.55 (s,
1H); 9.61 (s, 1H); 10.77 (s, 1H).
Preparation of
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamin-
o}-oxazol-5-yl)-benzonitrile
##STR00051##
[0127] To a solution of
4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (558
mg, 2 mmol) and chloroacetaldehyde (50 wt. % in water, 628 mg, 4
mmol) in acetonitril (60 mL), was added at RT NaBH.sub.3CN (253 mg,
4 mmol) and dropwise acetic acid (0.4 mL). The mixture was stirred
at room temperature 1 h. Ethyl acetate (50 mL) and saturated
aqueous NaHCO.sub.3 (50 mL) were added. The organic layer was
washed with brine (20 mL), dried over MgSO.sub.4 and concentrated
to give a yellow solid. This was dissolved in toluene (40 mL) and
treated withyl-Fluoro-3-isocyanato-benzene (274 mg, 2 mmol) at
reflux for 2 h. After evaporation of solvent under reduced vacuum,
the crude product was dissolved in isopropanol (60 mL) and treated
with potassium tert-butoxide (1.8 g, 16 mmol) at RT for 5 h. Water
(20 mL) was added, the organic layer was separated dried over
MgSO.sub.4 and concentrated. The crude product was silica gel
column chromatographed (dichloromethane/ethanol 95/5) to give 408
mg (45%) of the title compound as a beige solid.
[0128] .sup.1H NMR (DMSO-d.sup.6) .delta.=2.26 (s, 3H); 3.98 (s,
4H); 6.90 (t, J=9.0, 1H); 7.20 (bs, 2H); 7.33-7.42 (m, 2H);
7.65-7.85 (m, 6H); 8.19 (s, 1H); 9.82 (s, 1H).
Preparation of
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenylamin-
o}-oxazol-5-yl)-benzonitrile
##STR00052##
[0130] Compound
4-(2-{5-[3-(3-Fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-2-methyl-phenyl
amino}-oxazol-5-yl)-benzonitrile (30 mg, 0.066 mmol), was treated
in EtOH (2 mL) with 3N NaOH (1 mL). The resulting mixture was
stirred at reflux for 3 h. After cooling to RT, 1N HCl was added
until pH=6-7 and the precipitate filtered to give the title
compound as a yellow solid (9 mg, 29%).
[0131] ES/MS: m/z=471 [M-H].sup.-.
[0132] In a second embodiment, the invention relates to a
pharmaceutical composition comprising a compound as depicted
above.
[0133] Such medicament can take the form of a pharmaceutical
composition adapted for oral administration, which can be
formulated using pharmaceutically acceptable carriers well known in
the art in suitable dosages. Such carriers enable the
pharmaceutical compositions to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions,
and the like, for ingestion by the patient. In addition to the
active ingredients, these pharmaceutical compositions may contain
suitable pharmaceutically-acceptable carriers comprising excipients
and auxiliaries which facilitate processing of the active compounds
into preparations which can be used pharmaceutically. Further
details on techniques for formulation and administration may be
found in the latest edition of Remington's Pharmaceutical Sciences
(Maack Publishing Co., Easton, Pa.).
[0134] The composition of the invention can also take the form of a
pharmaceutical or cosmetic composition for topical
administration.
[0135] Such compositions may be presented in the form of a gel,
paste, ointment, cream, lotion, liquid suspension aqueous,
aqueous-alcoholic or, oily solutions, or dispersions of the lotion
or serum type, or anhydrous or lipophilic gels, or emulsions of
liquid or semi-solid consistency of the milk type, obtained by
dispersing a fatty phase in an aqueous phase or vice versa, or of
suspensions or emulsions of soft, semi-solid consistency of the
cream or gel type, or alternatively of microemulsions, of
microcapsules, of microparticles or of vesicular dispersions to the
ionic and/or nonionic type. These compositions are prepared
according to standard methods.
[0136] The composition according to the invention comprises any
ingredient commonly used in dermatology and cosmetic. It may
comprise at least one ingredient selected from hydrophilic or
lipophilic gelling agents, hydrophilic or lipophilic active agents,
preservatives, emollients, viscosity enhancing polymers,
humectants, surfactants, preservatives, antioxidants, solvents, and
fillers, antioxidants, solvents, perfumes, fillers, screening
agents, bactericides, odor absorbers and coloring matter.
[0137] As oils which can be used in the invention, mineral oils
(liquid paraffin), vegetable oils (liquid fraction of shea butter,
sunflower oil), animal oils, synthetic oils, silicone oils
(cyclomethicone) and fluorinated oils may be mentioned. Fatty
alcohols, fatty acids (stearic acid) and waxes paraffin, carnauba,
beeswax) may also be used as fatty substances.
[0138] As emulsifiers which can be used in the invention, glycerol
stearate, polysorbate 60 and the PEG-6/PEG-32/glycol stearate
mixture are contemplated.
[0139] As hydrophilic gelling agents, carboxyvinyl polymers
(carbomer), acrylic copolymers such as acrylate/alkylacrylate
copolymers, polyacrylamides, polysaccharides such as
hydroxypropylcellulose, clays and natural gums may be mentioned,
and as lipophilic gelling agents, modified clays such as bentones,
metal salts of fatty acids such as aluminum stearates and
hydrophobic silica, or alternatively ethylcellulose and
polyethylene may be mentioned.
[0140] As hydrophilic active agents, proteins or protein
hydrolysates, amino acids, polyols, urea, allantoin, sugars and
sugar derivatives, vitamins, starch and plant extracts, in
particular those of Aloe vera may be used.
[0141] As lipophilic active, agents, retinol (vitamin A) and its
derivatives, tocopherol (vitamin E) and its derivatives, essential
fatty acids, ceramides and essential oils may be used. These agents
add extra moisturizing or skin softening features when
utilized.
[0142] In addition, a surfactant can be included in the composition
so as to provide deeper penetration of the compound capable of
depleting mast cells, such as a tyrosine kinase inhibitor,
preferably a c-kit and/or a bcr-abl inhibitor.
[0143] Among the contemplated ingredients, the invention embraces
penetration enhancing agents selected for example from the group
consisting of mineral oil, water, ethanol, triacetin, glycerin and
propylene glycol; cohesion agents selected for example from the
group consisting of polyisobutylene, polyvinyl acetate and
polyvinyl alcohol, and thickening agents.
[0144] Chemical methods of enhancing topical absorption of drugs
are well known in the art. For example, compounds with penetration
enhancing properties include sodium lauryl sulfate (Dugard, P. H.
and Sheuplein, R. J., "Effects of Ionic Surfactants on the
Permeability of Human Epidermis: An Electrometric Study," J. Ivest.
Dermatol., V. 60, pp. 263-69, 1973), lauryl amine oxide (Johnson
et. al., U.S. Pat. No. 4,411,893), azone (Rajadhyaksha, U.S. Pat.
Nos. 4,405,616 and 3,989,816) and decylmethyl sulfoxide (Sekura, D.
L. and Scala, J., "The Percutaneous Absorption of Alkylmethyl
Sulfides," Pharmacology of the Skin, Advances In Biolocy of Skin,
(Appleton-Century Craft) V. 12, pp. 257-69, 1972). It has been
observed that increasing the polarity of the head group in
amphotelic molecules increases their penetration-enhancing
properties but at the expense of increasing their skin irritating
properties (Cooper, E. R. and Berner, B., "Interaction of
Surfactants with Epidermal Tissues: Physiochemical Aspects,"
Surfactant Science Series, V. 16, Reiger, M. M. ed. (Marcel Dekker,
Inc.) pp. 195-210, 1987).
[0145] A second class of chemical enhancers are generally referred
to as co-solvents. These materials are absorbed topically
relatively easily, and, by a variety of mechanisms, achieve
permeation enhancement for some drugs. Ethanol (Gale et. al., U.S.
Pat. No. 4,615,699 and Campbell et. al., U.S. Pat. Nos. 4,460,372
and 4,379,454), dimethyl sulfoxide (U.S. Pat. Nos. 3,740,420 and
3,743,727, and U.S. Pat. No. 4,575,515), and glycerine derivatives
(U.S. Pat. No. 4,322,433) are a few examples of compounds which
have shown an ability to enhance the absorption of various
compounds.
[0146] The pharmaceutical compositions of the invention can also be
intended for administration with aerosolized formulation to target
areas of a patient's respiratory tract.
[0147] Devices and methodologies for delivering aerosolized bursts
of a formulation of a drug is disclosed in U.S. Pat. No. 5,906,202.
Formulations are preferably solutions, e.g. aqueous solutions,
ethanoic solutions, aqueous/ethanoic solutions, saline solutions,
colloidal suspensions and microcrystalline suspensions. For example
aerosolized particles comprise the active ingredient mentioned
above and a carrier, (e.g., a pharmaceutically active respiratory
drug and carrier) which are formed upon forcing the formulation
through a nozzle which nozzle is preferably in the form of a
flexible porous membrane. The particles have a size which is
sufficiently small such that when the particles are formed they
remain suspended in the air for a sufficient amount of time such
that the patient can inhale the particles into the patient's
lungs.
The invention encompasses the systems described in U.S. Pat. No.
5,556,611: [0148] liquid gas systems (a liquefied gas is used as
propellent gas (e.g. low-boiling FCHC or propane, butane) in a
pressure container, [0149] suspension aerosol (the active substance
particles are suspended in solid form in the liquid propellent
phase), [0150] pressurized gas system (a compressed gas such as
nitrogen, carbon dioxide, dinitrogen monoxide, air is used.
[0151] Thus, according to the invention the pharmaceutical
preparation is made in that the active substance is dissolved or
dispersed in a suitable nontoxic medium and said solution or
dispersion atomized to an aerosol, i.e. distributed extremely
finely in a carrier gas. This is technically possible for example
in the form of aerosol propellent gas packs, pump aerosols or other
devices known per se for liquid misting and solid atomizing which
in particular permit an exact individual dosage.
[0152] Therefore, the invention is also directed to aerosol devices
comprising the compound as defined above and such a formulation,
preferably with metered dose valves.
[0153] The pharmaceutical compositions of the invention can also be
intended for intranasal administration.
[0154] In this regard, pharmaceutically acceptable carriers for
administering the compound to the nasal mucosal surfaces will be
readily appreciated by the ordinary artisan. These carriers are
described in the Remington's Pharmaceutical Sciences" 16th edition,
1980, Ed. By Arthur Osol, the disclosure of which is incorporated
herein by reference.
[0155] The selection of appropriate carriers depends upon the
particular type of administration that is contemplated. For
administration via the upper respiratory tract, the composition can
be formulated into a solution, e.g., water or isotonic saline,
buffered or unbuffered, or as a suspension, for intranasal
administration as drops or as a spray. Preferably, such solutions
or suspensions are isotonic relative to nasal secretions and of
about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4
or, from pH 6.0 to pH 7.0. Buffers should be physiologically
compatible and include, simply by way of example, phosphate
buffers. For example, a representative nasal decongestant is
described as being buffered to a pH of about 6.2 (Remington's, Id.
at page 1445). Of course, the ordinary artisan can readily
determine a suitable saline content and pH for an innocuous aqueous
carrier for nasal and/or upper respiratory administration.
[0156] Common intranasal carriers include nasal gels, creams,
pastes or ointments with a viscosity of, e.g., from about 10 to
about 3000 cps, or from about 2500 to 6500 cps, or greater, may
also be used to provide a more sustained contact with the nasal
mucosal surfaces. Such carrier viscous formulations may be based
upon, simply by way of example, alkylcelluloses and/or other
biocompatible carriers of high viscosity well known to the art (see
e.g., Remington's, cited supra. A preferred alkylcellulose is,
e.g., methylcellulose in a concentration ranging from about 5 to
about 1000 or more mg per 100 ml of carrier. A more preferred
concentration of methyl cellulose is, simply by way of example,
from about 25 to about mg per 100 ml of carrier.
[0157] Other ingredients, such as art known preservatives,
colorants, lubricating or viscous mineral or vegetable oils,
perfumes, natural or synthetic plant extracts such as aromatic
oils, and humectants and viscosity enhancers such as, e.g.,
glycerol, can also be included to provide additional viscosity,
moisture retention and a pleasant texture and odor for the
formulation. For nasal administration of solutions or suspensions
according to the invention, various devices are available in the
art for the generation of drops, droplets and sprays.
[0158] A premeasured unit dosage dispenser including a dropper or
spray device containing a solution or suspension for delivery as
drops or as a spray is prepared containing one or more doses of the
drug to be administered and is another object of the invention. The
invention also includes a kit containing one or more unit
dehydrated doses of the compound, together with any required salts
and/or buffer agents, preservatives, colorants and the like, ready
for preparation of a solution or suspension by the addition of a
suitable amount of water.
[0159] Another aspect of the invention is directed to the use of
said compound to manufacture a medicament. In other words, the
invention embraces a method for treating a disease related to
unregulated c-kit transduction comprising administering an
effective amount of a compound as defined above to a mammal in need
of such treatment.
[0160] More particularly, the invention is aimed at a method for
treating a disease selected from autoimmune diseases, allergic
diseases, bone loss, cancers such as leukemia and GIST, tumor
angiogenesis, inflammatory diseases, inflammatory bowel diseases
(IBD), interstitial cystitis, mastocytosis, infections diseases,
metabolic disorders, fibrosis, diabetes and CNS disorders
comprising administering an effective amount a compound depicted
above to a mammal in need of such treatment.
[0161] The above described compounds are useful for manufacturing a
medicament for the treatment of diseases related to unregulated
c-kit transduction, including, but not limited to: [0162]
neoplastic diseases such as mastocytosis, canine mastocytoma, solid
tumours, human gastrointestinal stromal tumor ("GIST"), small cell
lung cancer, non-small cell lung cancer, acute myelocytic leukemia,
acute lymphocytic leukemia, myelodysplastic syndrome, chronic
myelogenous leukemia, colorectal carcinomas, gastric carcinomas,
gastrointestinal stromal tumors, testicular cancers, glioblastomas,
solid tumors and astrocytomas. [0163] tumor angiogenesis. [0164]
metabolic diseases such as diabetes mellitus and its chronic
complications; [0165] obesity; diabete type II; hyperlipidemias and
dyslipidemias; atherosclerosis; hypertension; and cardiovascular
disease. [0166] allergic diseases such as asthma, allergic
rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria,
angioedema, atopic dermatitis, allergic contact dermatitis,
erythema nodosum, erythema multiforme, cutaneous necrotizing
venulitis and insect bite skin inflammation and blood sucking
parasitic infestation. [0167] interstitial cystitis. [0168] bone
loss (osteoporosis). [0169] inflammatory diseases such as
rheumatoid arhritis, conjunctivitis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis and other arthritic conditions.
[0170] autoimmune diseases such as multiple sclerosis, psoriasis,
intestine inflammatory disease, ulcerative colitis, Crohn's
disease, rheumatoid arthritis and polyarthritis, local and systemic
scleroderma, systemic lupus erythematosus, discoid lupus
erythematosus, cutaneous lupus, dermatomyositis, polymyositis,
Sjogren's syndrome, nodular panarteritis, autoimmune enteropathy,
as well as proliferative glomerulonephritis. [0171]
graft-versus-host disease or graft rejection in any organ
transplantation including kidney, pancreas, liver, heart, lung, and
bone marrow. [0172] Other autoimmune diseases embraced by the
invention active chronic hepatitis and chronic fatigue syndrome.
[0173] subepidermal blistering disorders such as pemphigus. [0174]
Vasculitis. [0175] HIV infection. [0176] melanocyte dysfunction
associated diseases such as hypermelanosis resulting from
melanocyte dysfunction and including lentigines, solar and senile
lentigo, Dubreuilh melanosis, moles as well as malignant melanomas.
In this regard, the invention embraces the use of the compounds
defined above to manufacture a medicament or a cosmetic composition
for whitening human skin. [0177] CNS disorders such as psychiatric
disorders, migraine, pain, memory loss and nerve cells degeneracy.
More particularly, the method according to the invention is useful
for the treatment of the following disorders: Depression including
dysthymic disorder, cyclothymic disorder, bipolar depression,
severe or "melancholic" depression, atypical depression, refractory
depression, seasonal depression, anorexia, bulimia, premenstrual
syndrome, post-menopause syndrome, other syndromes such as mental
slowing and loss of concentration, pessimistic worry, agitation,
self-deprecation, decreased libido, pain including, acute pain,
postoperative pain, chronic pain, nociceptive pain, cancer pain,
neuropathic pain, psychogenic pain syndromes, anxiety disorders
including anxiety associated with hyperventilation and cardiac
arrhythmias, phobic disorders, obsessive-compulsive disorder,
posttraumatic stress disorder, acute stress disorder, generalized
anxiety disorder, psychiatric emergencies such as panic attacks,
including psychosis, delusional disorders, conversion disorders,
phobias, mania, delirium, dissociative episodes including
dissociative amnesia, dissociative fugue and dissociative identity
disorder; depersonalization, catatonia, seizures, severe
psychiatric emergencies including suicidal behaviour, self-neglect,
violent or aggressive behaviour, trauma, borderline personality,
and acute psychosis, schizophrenia including paranoid
schizophrenia, disorganized schizophrenia, catatonic schizophrenia,
and undifferentiated schizophrenia, [0178] neurodegenerative
diseases including Alzheimer's disease, Parkinson's disease,
Huntington's disease, the prion diseases, Motor Neurone Disease
(MND), and Amyotrophic Lateral Sclerosis (ALS). [0179] substance
use disorders as referred herein include but are not limited to
drug addiction, drug abuse, drug habituation, drug dependence,
withdrawal syndrome and overdose. [0180] Cerebral ischemia [0181]
Fibrosis [0182] Duchenne muscular dystrophy
[0183] Regarding mastocytosis, the invention contemplates the use
of the compounds as defined above for treating the different
categories which can be classified as follows: The category I is
composed by two sub-categories (IA and IB). Category IA is made by
diseases in which mast cell infiltration is strictly localized to
the skin. This category represents the most frequent form of the
disease and includes: i) urticaria pigmentosa, the most common form
of cutaneous mastocytosis, particularly encountered in children,
ii) diffuse cutaneous mastocytosis, iii) solitary mastocytoma and
iv) some rare subtypes like bullous, erythrodermic and
teleangiectatic mastocytosis. These forms are characterized by
their excellent prognosis with spontaneous remissions in children
and a very indolent course in adults. Long term survival of this
form of disease is generally comparable to that of the normal
population and the translation into another form of mastocytosis is
rare. Category IB is represented by indolent systemic disease (SM)
with or without cutaneous involvement. These forms are much more
usual in adults than in children. The course of the disease is
often indolent, but sometimes signs of aggressive or malignant
mastocytosis can occur, leading to progressive impaired organ
function.
[0184] The category II includes mastocytosis with an associated
hematological disorder, such as a myeloproliferative or
myelodysplastic syndrome, or acute leukemia. These malignant
mastocytosis does not usually involve the skin. The progression of
the disease depends generally on the type of associated
hematological disorder that conditions the prognosis.
[0185] The category III is represented by aggressive systemic
mastocytosis in which massive infiltration of multiple organs by
abnormal mast cells is common. In patients who pursue this kind of
aggressive clinical course, peripheral blood features suggestive of
a myeloproliferative disorder are more prominent. The progression
of the disease can be very rapid, similar to acute leukemia, or
some patients can show a longer survival time.
[0186] Finally, the category IV of mastocytosis includes the mast
cell leukemia, characterized by the presence of circulating mast
cells and mast cell progenitors representing more than 10% of the
white blood cells. This entity represents probably the rarest type
of leukemia in humans, and has a very poor prognosis, similar to
the rapidly progressing variant of malignant mastocytosis. Mast
cell leukemia can occur either de novo or as the terminal phase of
urticaria pigmentosa or systemic mastocytosis.
[0187] The invention also contemplates the method as depicted for
the treatment of recurrent bacterial infections, resurging
infections after asymptomatic periods such as bacterial cystitis.
More particularly, the invention can be practiced for treating FimH
expressing bacteria infections such as Gram-negative enterobacteria
including E. coli, Klebsiella pneumoniae, Serratia marcescens,
Citrobactor freudii and Salmonella typhimurium. In this method for
treating bacterial infection, separate, sequential or concomitant
administration of at least one antibiotic selected bacitracin, the
cephalosporins, the penicillins, the aminoglycosides, the
tetracyclines, the streptomycins and the macrolide antibiotics such
as erythromycin; the fluoroquinolones, actinomycin, the
sulfonamides and trimethoprim, is of interest.
[0188] In one preferred embodiment, the invention is directed to a
method for treating neoplastic diseases such as mastocytosis,
canine mastocytoma, solid tumours, human gastrointestinal stromal
tumor ("GIST"), small cell lung cancer, non-small cell lung cancer,
acute myelocytic leukemia, acute lymphocytic leukemia,
myelodysplastic syndrome, chronic myelogenous leukemia, colorectal
carcinomas, gastric carcinomas, gastrointestinal stromal tumors,
testicular cancers, glioblastomas, and astrocytomas comprising
administering a compound as defined herein to a human or mammal,
especially dogs and cats, in need of such treatment.
[0189] In one other preferred embodiment, the invention is directed
to a method for treating allergic diseases such as asthma, allergic
rhinitis, allergic sinusitis, anaphylactic syndrome, urticaria,
angioedema, atopic dermatitis, allergic contact dermatitis,
erythema nodosum, erythema multiforme, cutaneous necrotizing
venulitis and insect bite skin inflammation and blood sucking
parasitic infestation comprising administering a compound as
defined herein to a human or mammal, especially dogs and cats, in
need of such treatment.
[0190] In still another preferred embodiment, the invention is
directed to a method for treating inflammatory diseases such as
rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis,
osteoarthritis, gouty arthritis and other arthritic conditions
comprising administering a compound as defined herein to a human in
need of such treatment.
[0191] In still another preferred embodiment, the invention is
directed to a method for treating autoimmune diseases such as
multiple sclerosis, psoriasis, intestine inflammatory disease,
ulcerative colitis, Crohn's disease, rheumatoid arthritis and
polyarthritis, local and systemic scleroderma, systemic lupus
erythematosus, discoid lupus erythematosus, cutaneous lupus,
dermatomyositis, polymyositis, Sjogren's syndrome, nodular
panarteritis, autoimmune enteropathy, as well as proliferative
glomerulonephritis comprising administering a compound as defined
herein to a human in need of such treatment.
[0192] In still another preferred embodiment, the invention is
directed to a method for treating graft-versus-host disease or
graft rejection in any organ transplantation including kidney,
pancreas, liver, heart, lung, and bone marrow comprising
administering a compound as defined herein to a human in need of
such treatment.
Example
In Vitro TK Inhibition Assays
[0193] Procedures
[0194] C-Kit WT and Mutated C-Kit (JM and Kinase Domain 816)
Assay
Proliferation Assays
[0195] Cells were washed two times in PBS before plating at
5.times.10.sub.4 cells per well of 96-well plates in triplicate and
stimulated either with hematopoietic growth factors (HGF) or
without. After 2 days of culture, 37 Bq (1.78 Tbq/mmol) of
[.sup.3H] thymidine (Amersham Life Science, UK) was added for 6
hours. Cells were harvested and filtered through glass fiber
filters and [.sup.3H] thymidine incorporation was measured in a
scintillation counter.
[0196] For proliferation assay, all drugs were prepared as 20 mM
stock solutions in DMSO and conserved at -80.degree. C. Fresh
dilutions in PBS were made before each experiment. DMSO dissolved
drugs were added at the beginning of the culture. Control cultures
were done with corresponding DMSO dilutions. Results are
represented in percentage by taking the proliferation without
inhibitor as 100%.
Cells
[0197] Ba/F3 murine kit and human kit, Ba/F3 mkit.DELTA.27
(juxtamembrane deletion), and hkitD816V are derived from the murine
IL-3 dependent Ba/F3 proB lymphoid cells. The FMA3 and P815 cell
lines are mastocytoma cells expressing endogenous mutated forms of
Kit, i.e., frame deletion in the murine juxtamembrane coding region
of the receptor-codons 573 to 579. The human leukaemic MC line
HMC-1 expresses a double point mutation (i.e. mutations JM-V560G
and the kinase domain mutation kitD816V), whereas the HMC1 subclone
.alpha.155 expresses only the mutation JM-V560G.
Immunoprecipitation Assays and Western Blotting Analysis
[0198] For each assay, 5.106 Ba/F3 cells and Ba/F3-derived cells
with various c-kit mutations were lysed and immunoprecipitated as
described (Beslu et al., 1996), excepted that cells were stimulated
with 250 ng/ml of rmKL. Cell lysates were immunoprecipitated with
rabbit immunsera directed against the KIT cytoplasmic domain either
with an anti murine KIT (Rottapel et al., 1991) or an anti human
KIT (Santa Cruz). Western blot was hybridized either with the 4G10
anti-phosphotyrosine antibody (UBI) or with the appropriate rabbit
immunsera anti KIT or with different antibodies (described in
antibodies paragraph). The membrane was then incubated either with
HRP-conjugated goat anti mouse IgG antibody or with HRP-conjugated
goat anti rabbit IgG antibody (Immunotech), Proteins of interest
were then visualized by incubation with ECL reagent (Amersham).
[0199] Experimental Results
[0200] The experimental results for various compounds according to
the invention using above-described protocols are set forth at
Table 1:
TABLE-US-00001 TABLE 1 in vitro inhibitions of various compounds
against c-Kit WT, c-Kit JM.DELTA.27 and c-Kit D816V. Target IC50
(.mu.M) Compounds c-Kit WT IC50 < 1 .mu.M 001; 002; 004; 011;
017; 021; 028; 030 c-Kit JM.DELTA.27 IC50 < 1 .mu.M 001; 017;
027; 028; 029; 030 c-Kit IC50 .ltoreq. 1 .mu.M 001; 002; 011; 017;
021; 030 D816V
* * * * *