U.S. patent application number 11/911575 was filed with the patent office on 2008-07-24 for pyrimidylaminobenzamide derivatives for sytemic mastocytosis.
Invention is credited to Leila Alland, Doriano Fabbro, Paul W. Manley, Jurgen Mestan.
Application Number | 20080176879 11/911575 |
Document ID | / |
Family ID | 36867557 |
Filed Date | 2008-07-24 |
United States Patent
Application |
20080176879 |
Kind Code |
A1 |
Alland; Leila ; et
al. |
July 24, 2008 |
Pyrimidylaminobenzamide Derivatives For Sytemic Mastocytosis
Abstract
The present invention relates to the use of
pyrimidylaminobenzamide derivatives for the preparation of a drug
for the treatment of systemic mastocytosis.
Inventors: |
Alland; Leila; (Chatham,
NJ) ; Fabbro; Doriano; (Arlesheim, CH) ;
Mestan; Jurgen; (Denzlingen, DE) ; Manley; Paul
W.; (Arlesheim, CH) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
36867557 |
Appl. No.: |
11/911575 |
Filed: |
May 1, 2006 |
PCT Filed: |
May 1, 2006 |
PCT NO: |
PCT/US06/16541 |
371 Date: |
October 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60676740 |
May 2, 2005 |
|
|
|
Current U.S.
Class: |
514/275 |
Current CPC
Class: |
A61P 11/02 20180101;
A61P 25/00 20180101; A61P 35/00 20180101; A61P 35/02 20180101; A61K
31/506 20130101; A61P 11/00 20180101; A61P 37/08 20180101; A61P
17/00 20180101; A61P 17/04 20180101; A61P 35/04 20180101; A61P 7/00
20180101; A61P 37/00 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/275 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61P 35/04 20060101 A61P035/04 |
Claims
1. A method for the treatment or prevention of systemic
mastocytosis comprising administration of a pyrimidylaminobenzamide
derivative of formula (I): ##STR00003## wherein R.sub.1 represents
hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower
alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or
phenyl-lower alkyl; R.sub.2 represents hydrogen, lower alkyl,
optionally substituted by one or more identical or different
radicals R.sub.3, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl
group, or a mono- or bicyclic heteroaryl group comprising zero,
one, two or three ring nitrogen atoms and zero or one oxygen atom
and zero or one sulfur atom, which groups in each case are
unsubstituted or mono- or polysubstituted; and R.sub.3 represents
hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl,
carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or
disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a
mono- or bicyclic heteroaryl group comprising zero, one, two or
three ring nitrogen atoms and zero or one oxygen atom and zero or
one sulfur atom, which groups in each case are unsubstituted or
mono- or polysubstituted; or wherein R.sub.1 and R.sub.2 together
represent alkylene with four, five or six carbon atoms optionally
mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl,
phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino,
oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or
five carbon atoms; oxaalkylene with one oxygen and three or four
carbon atoms; or azaalkylene with one nitrogen and three or four
carbon atoms wherein nitrogen is unsubstituted or substituted by
lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl,
carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or
N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower
alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,
pyrimidinyl, or pyrazinyl; R.sub.4 represents hydrogen, lower
alkyl, or halogen; and a N-oxide or a pharmaceutically acceptable
salt of such a compound.
2. A method according to claim 1 where the systemic mastocytosis
has resistance to imatinib.
3. A method according to claim 1 where the compound of formula (I)
is
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imida-
zol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula (II):
##STR00004## and N-oxides or pharmacutially acceptable salts
thereof.
4. A method according to claim 1 wherein the systemic mastocytosis
is associated with FIP1L1-PDGFR.alpha..
5. (canceled)
6. (canceled)
7. A method according to claim 1 for the treatment of systemic
matocytosis associated with FIP1L1-PDGFR.alpha.-gene fusion.
8. A method for treating mammals suffering from systemic
mastocytosis comprising administering to a mammal in need of such
treatment a FIP1L1-PDGFR.alpha.-induced inhibiting amount of a
compound of formula (II): ##STR00005## or an N-oxide or
pharmaceutically acceptable salts thereof.
9. A pharmaceutical preparation for the treatment of
FIP1L1-PDGFR.alpha.-induced systemic mastocytosis comprising a
compound of formula (II): ##STR00006## or an N-oxide or
pharmaceutically acceptable salts thereof.
10. A method for treating mammals, including man, suffering from
systemic mastocytosis comprising administering to a mammal in need
of such treatment a compound of formula (II):
Description
SUMMARY OF THE INVENTION
[0001] The present invention relates to the use of
pyrimidylaminobenzamide derivatives for the preparation of a drug
for the treatment of systemic mastocyctosis. The present invention
also relates to a method of treating systemic mastocyctosis.
BACKGROUND OF THE INVENTION
[0002] Systemic mastocytosis (SM) can be classified into indolent
SM (little or no evidence of impaired organ function), aggressive
SM (presence of impaired organ function), SM associated hematologic
non-mast cell disease (SM-AHNMD) and mast cell leukemia. Clinical
presentation in adult SM is heterogenous and includes skin disease
(usually urticaria pigmentosa), mast cell mediator-release symptoms
(headache, flushing, lightheadedness, syncope, anaphylaxis, etc),
and direct or indirect organ damage (bone pain from lytic bone
lesions, osteoporosis or bone fractures, hepatosplenomegaly,
cytopenia from bone marrow involvement). In addition, around 20% of
patients with SM may display significant and sometimes isolated
blood eosinophilia (Tefferi and Pardanani 2004).
[0003] In general, mast cell leukemia is a terminal disease with
survival measured in months and no effective therapy to date. The
natural history of indolent SM is far better with median survival
measured in decades and infrequent progression to aggressive SM and
SM-AHNMD. Outcome in SM-AHNMD is determined by the associated AHNMD
and is significantly worse than SM without AHNMD. In both indolent
and aggressive SM without AHNMD, increased bone marrow mast cell
and eosinophil content, elevated serum alkaline phosphatase,
anemia, and hepatosplenomegaly have been associated with poor
prognosis (Tefferi and Pardanani 2004). Complete histologic and
clinical remission has been achieved in patients with SM associated
with the FIP1L1-PDGFR.alpha. gene fusion when treated with
Gleevec.RTM. (Pardanani 2003a, Pardanani 2003b).
[0004] It has now been found that pyrimidylaminobenzamide
derivatives are effective against SM, especially SM associated with
the FIP1L1-PDGFR.alpha. gene fusion.
[0005] The problem to be solved by the present invention is to
pyrimidylaminobenzamide derivatives which are useful in the
treatment of especially systemic mastocytosis, especially SM
associated with the FIP1L1-PDGFR.alpha. gene fusion.
SUMMARY OF THE INVENTION
[0006] The present invention relates to the use of
pyrimidylaminobenzamide compounds of formula (I) (hereinafter:
"PYRIMIDYLAMINOBENZAMIDE DERIVATIVES"):
##STR00001##
[0007] wherein
[0008] R.sub.1 represents hydrogen, lower alkyl, lower alkoxy-lower
alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower
alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl,
[0009] R.sub.2 represents hydrogen, lower alkyl, optionally
substituted by one or more identical or different radicals R.sub.3,
cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono-
or bicyclic heteroaryl group comprising zero, one, two or three
ring nitrogen atoms and zero or one oxygen atom and zero or one
sulfur atom, which groups in each case are unsubstituted or mono-
or polysubstituted;
[0010] and R.sub.3 represents hydroxy, lower alkoxy, acyloxy,
carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or
N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino,
cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic
heteroaryl group comprising zero, one, two or three ring nitrogen
atoms and zero or one oxygen atom and zero or one sulfur atom,
which groups in each case are unsubstituted or mono- or
polysubstituted;
[0011] or wherein R.sub.1 and R.sub.2 together represent alkylene
with four, five or six carbon atoms optionally mono- or
disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl,
hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo,
pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five
carbon atoms; oxaalkylene with one oxygen and three or four carbon
atoms; or azaalkylene with one nitrogen and three or four carbon
atoms wherein nitrogen is unsubstituted or substituted by lower
alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl,
carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or
N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower
alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,
pyrimidinyl, or pyrazinyl;
[0012] R.sub.4 represents hydrogen, lower alkyl, or halogen;
[0013] and a N-oxide or a pharmaceutically acceptable salt of such
a compound for the preparation of a pharmaceutical composition for
the treatment of systemic mastocytosis and SM associated with the
FIP1L1-PDGFR.alpha. gene fusion. The present invention further
relates to use of compounds of formula I to treat or prevent
systemic mastocytosis.
[0014] The general terms used hereinbefore and hereinafter
preferably have within the context of this disclosure the following
meanings, unless otherwise indicated:
[0015] The prefix "lower" denotes a radical having up to and
including a maximum of 7, especially up to and including a maximum
of 4 carbon atoms, the radicals in question being either linear or
branched with single or multiple branching.
[0016] Where the plural form is used for compounds, salts, and the
like, this is taken to mean also a single compound, salt, or the
like.
[0017] Any asymmetric carbon atoms may be present in the (R)-, (S)-
or (R,S)-configuration, preferably in the (R)- or
(S)-configuration. The compounds may thus be present as mixtures of
isomers or as pure isomers, preferably as enantiomer-pure
diastereomers.
[0018] The invention relates also to possible tautomers of the
compounds of formula I.
[0019] Lower alkyl is preferably alkyl with from and including 1 up
to and including 7, preferably from and including 1 to and
including 4, and is linear or branched; preferably, lower alkyl is
butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl,
such as n-propyl or isopropyl, ethyl or methyl. Preferably lower
alkyl is methyl, propyl or tert-butyl.
[0020] Lower acyl is preferably formyl or lower alkylcarbonyl, in
particular acetyl.
[0021] An aryl group is an aromatic radical which is bound to the
molecule via a bond located at an aromatic ring carbon atom of the
radical. In a preferred embodiment, aryl is an aromatic radical
having 6 to 14 carbon atoms, especially phenyl, naphthyl,
tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is
unsubstituted or substituted by one or more, preferably up to
three, especially one or two substituents, especially selected from
amino, mono- or disubstituted amino, halogen, lower alkyl,
substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl,
hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy,
esterified carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or
N,N-disubstituted carbamoyl, amidino, guanidino, ureido, mercapto,
sulfo, lower alkylthio, phenylthio, phenyl-lower alkylthio, lower
alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl, phenyl-lower
alkylsulfinyl, lower alkylphenylsulfinyl, lower alkylsulfonyl,
phenylsulfonyl, phenyl-lower alkylsulfonyl, lower
alkylphenylsulfonyl, halogen-lower alkylmercapto, halogen-lower
alkylsulfonyl, such as especially trifluoromethanesulfonyl,
dihydroxybora (--B(OH).sub.2), heterocyclyl, a mono- or bicyclic
heteroaryl group and lower alkylene dioxy bound at adjacent C-atoms
of the ring, such as methylene dioxy. Aryl is more preferably
phenyl, naphthyl or tetrahydronaphthyl, which in each case is
either unsubstituted or independently substituted by one or two
substituents selected from the group comprising halogen, especially
fluorine, chlorine, or bromine; hydroxy; hydroxy etherified by
lower alkyl, e.g. by methyl, by halogen-lower alkyl, e.g.
trifluoromethyl, or by phenyl; lower alkylene dioxy bound to two
adjacent C-atoms, e.g. methylenedioxy, lower alkyl, e.g. methyl or
propyl; halogen-lower alkyl, e.g. trifluoromethyl; hydroxy-lower
alkyl, e.g. hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower
alkyl; e.g. methoxymethyl or 2-methoxyethyl; lower
alkoxycarbonyl-lower alkyl, e.g. methoxy-carbonylmethyl; lower
alkynyl, such as 1-propynyl; esterified carboxy, especially lower
alkoxycarbonyl, e.g. methoxycarbonyl, n-propoxy carbonyl or
iso-propoxy carbonyl; N-mono-substituted darbamoyl, in particular
carbamoyl monosubstituted by lower alkyl, e.g. methyl, n-propyl or
iso-propyl; amino; lower alkylamino, e.g. methylamino; di-lower
alkylamino, e.g. dimethylamino or diethylamino; lower
alkylene-amino, e.g. pyrrolidino or piperidino; lower
oxaalkylene-amino, e.g. morpholino, lower azaalkylene-amino, e.g.
piperazino, acylamino, e.g. acetylamino or benzoylamino; lower
alkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or
phenylsulfonyl.
[0022] A cycloalkyl group is preferably cyclopropyl, cyclopentyl,
cyclohexyl or cycloheptyl, and may be unsubstituted or substituted
by one or more, especially one or two, substitutents selected from
the group defined above as substitutents for aryl, most preferably
by lower alkyl, such as methyl, lower alkoxy, such as methoxy or
ethoxy, or hydroxy, and further by oxo or fused to a benzo ring,
such as in benzcyclopentyl or benzcyclohexyl.
[0023] Substituted alkyl is alkyl as last defined, especially lower
alkyl, preferably methyl; where one or more, especially up to
three, substituents may be present, primarily from the group
selected from halogen, especially fluorine, amino, N-lower
alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino,
hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower
alkoxycarbonyl. Trifluoromethyl is especially preferred.
[0024] Mono- or disubstituted amino is especially amino substituted
by one or two radicals selected independently of one another from
lower alkyl, such as methyl; hydroxy-lower alkyl, such as
2-hydroxyethyl; lower alkoxy lower alkyl, such as methoxy ethyl;
phenyl-lower alkyl, such as benzyl or 2-phenylethyl; lower
alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the
phenyl radical is especially substituted by one or more, preferably
one or two, substituents selected from nitro, amino, halogen,
N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano,
carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and
phenyl-lower alkoxycarbonyl, wherein the phenyl radical is
unsubstituted or especially substituted by one or more, preferably
one or two, substituents selected from nitro, amino, halogen,
N-lower alkylamino, N,N-di-lower alkylamino, hydroxy, cyano,
carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and
is preferably N-lower alkylamino, such as N-methylamino,
hydroxy-lower alkylamino, such as 2-hydroxyethylamino or
2-hydroxypropyl, lower alkoxy lower alkyl, such as methoxy ethyl,
phenyl-lower alkylamino, such as benzylamino, N,N-di-lower
alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N,N-di-lower
alkylphenylamino, lower alkanoylamino, such as acetylamino, or a
substituent selected from the group comprising benzoylamino and
phenyl-lower alkoxycarbonylamino, wherein the phenyl radical in
each case is unsubstituted or especially substituted by nitro or
amino, or also by halogen, amino, N-lower alkylamino, N,N-di-lower
alkylamino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower
alkanoyl, carbamoyl or aminocarbonylamino. Disubstituted amino is
also lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or
piperidino; lower oxaalkylene-amino, e.g. morpholino, or lower
azaalkylene-amino, e.g. piperazino or N-substituted piperazino,
such as N-methylpiperazino or N-methoxycarbonylpiperazino.
[0025] Halogen is especially fluorine, chlorine, bromine, or
iodine, especially fluorine, chlorine, or bromine.
[0026] Etherified hydroxy is especially C.sub.8-C.sub.20alkyloxy,
such as n-decyloxy, lower alkoxy (preferred), such as methoxy,
ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such
as benzyloxy, phenyloxy, halogen-lower alkoxy, such as
trifluoromethoxy, 2,2,2-trifluoroethoxy or
1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by
mono- or bicyclic heteroaryl comprising one or two nitrogen atoms,
preferably lower alkoxy which is substituted by imidazolyl, such as
1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as
1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl,
pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl,
especially 3-isoquinolinyl, quinolinyl, indolyl or thiazolyl.
[0027] Esterified hydroxy is especially lower alkanoyloxy,
benzoyloxy, lower alkoxycarbonyloxy, such as
tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as
benzyloxycarbonyloxy.
[0028] Esterified carboxy is especially lower alkoxycarbonyl, such
as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or
ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or
phenyloxycarbonyl.
[0029] Alkanoyl is primarily alkylcarbonyl, especially lower
alkanoyl, e.g. acetyl.
[0030] N-Mono- or N,N-disubstituted carbamoyl is especially
substituted by one or two substituents independently selected from
lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower
alkylene, oxa-lower alkylene or aza-lower alkylene optionally
substituted at the terminal nitrogen atom.
[0031] A mono- or bicyclic heteroaryl group comprising zero, one,
two or three ring nitrogen atoms and zero or one oxygen atom and
zero or one sulfur atom, which groups in each case are
unsubstituted or mono- or polysubstituted, refers to a heterocyclic
moiety that is unsaturated in the ring binding the heteroaryl
radical to the rest of the molecule in formula I and is preferably
a ring, where in the binding ring, but optionally also in any
annealed ring, at least one carbon atom is replaced by a heteroatom
selected from the group consisting of nitrogen, oxygen and sulfur;
where the binding ring preferably has 5 to 12, more preferably 5 or
6 ring atoms; and which may be unsubstituted or substituted by one
or more, especially one or two, substitutents selected from the
group defined above as substitutents for aryl, most preferably by
lower alkyl, such as methyl, lower alkoxy, such as methoxy or
ethoxy, or hydroxy. Preferably the mono- or bicyclic heteroaryl
group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl,
benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl,
quinnolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl,
isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
triazolyl, tetrazolyl, furazanyl, benzo[d]pyrazolyl, thienyl and
furanyl. More preferably the mono- or bicyclic heteroaryl group is
selected from the group consisting of pyrrolyl, imidazolyl, such as
1H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl,
indazolyl, especially 5-indazolyl, pyridyl, especially 2-, 3- or
4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl,
isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially
4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl,
benzo[d]pyrazolyl, thienyl, and furanyl. In one preferred
embodiment of the invention the pyridyl radical is substituted by
hydroxy in ortho position to the nitrogen atom and hence exists at
least partially in the form of the corresponding tautomer which is
pyridin-(1H)2-one. In another preferred embodiment, the pyrimidinyl
radical is substituted by hydroxy both in position 2 and 4 and
hence exists in several tautomeric forms, e.g. as
pyrimidine-(1H,3H)2,4-dione.
[0032] Heterocyclyl is especially a five, six or seven-membered
heterocyclic system with one or two heteroatoms selected from the
group comprising nitrogen, oxygen, and sulfur, which may be
unsaturated or wholly or partly saturated, and is unsubstituted or
substituted especially by lower alkyl, such as methyl, phenyl-lower
alkyl, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl;
heterocyclyl is especially 2- or 3-pyrrolidinyl,
2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-lower
alkyl-4-piperidinyl, N-lower alkyl-piperazinyl, morpholinyl, e.g.
2- or 3-morpholinyl, 2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or
2-methyl-1,3-dioxolan-2-yl.
[0033] Salts are especially the pharmaceutically acceptable salts
of compounds of formula I.
[0034] Such salts are formed, for example, as acid addition salts,
preferably with organic or inorganic acids, from compounds of
formula I with a basic nitrogen atom, especially the
pharmaceutically acceptable salts. Suitable inorganic acids are,
for example, halogen acids, such as hydrochloric acid, sulfuric
acid, or phosphoric acid. Suitable organic acids are, for example,
carboxylic, phosphonic, sulfonic or sulfamic acids, for example
acetic acid, propionic acid, octanoic acid, decanoic acid,
dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic
acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic
acid, tartaric acid, citric acid, amino acids, such as glutamic
acid or aspartic acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic
acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic
acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or
ethane-sulfonic acid, 2-hydroxyethanesulfonic acid,
ethane-1,2-disulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3-
or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric
acid, dodecylsulfuric acid, N-pyclohexylsulfamic acid, N-methyl-,
N-ethyl- or N-propyl-sulfamic acid, or other organic protonic
acids, such as ascorbic acid.
[0035] In the presence of negatively charged radicals, such as
carboxy or sulfo, salts may also be formed with bases, e.g. metal
or ammonium salts, such as alkali metal or alkaline earth metal
salts, for example sodium, potassium, magnesium or calcium salts,
or ammonium salts with ammonia or suitable organic amines, such as
tertiary monoamines, for example triethylamine or
tri(2-hydroxyethyl)amine, or heterocyclic bases, for example
N-ethyl-piperidine or N,N'-dimethylpiperazine.
[0036] When a basic group and an acid group are present in the same
molecule, a compound of formula I may also form internal salts.
[0037] For isolation or purification purposes it is also possible
to use pharmaceutically unacceptable salts, for example picrates or
perchlorates. For therapeutic use, only pharmaceutically acceptable
salts or free compounds are employed (where applicable in the form
of pharmaceutical preparations), and these are therefore
preferred.
[0038] In view of the close relationship between the novel
compounds in free form and those in the form of their salts,
including those salts that can be used as intermediates, for
example in the purification or identification of the novel
compounds, any reference to the free compounds hereinbefore and
hereinafter is to be understood as referring also to the
corresponding salts, as appropriate and expedient.
[0039] Compounds within the scope of formula I and the process for
their manufacture are disclosed in WO 04/005281 published on Jan.
15, 2004 which is hereby incorporated into the present application
by reference. A preferred compound is
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imida-
zol-1-yl)-3-(trifluoromethyl)phenyl]benzamide and pharmacutially
acceptable salts thereof of formula (II):
##STR00002##
[0040] In each case where citations of patent applications or
scientific publications are given in particular for the
PYRIMIDYLAMINOBENZAMIDE DERIVATIVE compounds, the subject-matter of
the final products, the pharmaceutical preparations and the claims
are hereby incorporated into the present application by reference
to these publications.
[0041] The structure of the active agents identified by code nos.,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g.
Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by
reference.
[0042] It has now surprisingly been found that
PYRIMIDYLAMINOBENZAMIDE DERIVATIVES possesses therapeutic
properties, which render it particularly useful as an inhibitor of
PDGFR.alpha. (platelet derived growth factor .alpha., also
abbreviated as PDGRA) and especially for the treatment and
prophylaxis of FIP1L1-PDGFR.alpha.-induced diseases such as
systemic mastocytosis.
[0043] FIP1L1-PDGFR.alpha., as used hereinbefore and hereinafter,
is the designation of the fusion product of the genes FIP1L1 (FIP1
like 1) with PDGFR.alpha..
[0044] The present invention thus concerns the use of
PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the preparation of a drug
for the treatment of FIP1L1-PDGFR.alpha.-induced systemic
mastocytosis, or other diseases associated with FIPL1-PDGFR.alpha.
or similar mutations that activate PDGFR.alpha..
[0045] Systemic Mastocytosis (SM) includes indolent SM, aggressive
SM, and SM associated hematologic non-mast cell disease and mast
cell leukemia.
[0046] In another embodiment, the instant invention relates to the
use of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the preparation of a
pharmaceutical composition for use in treating allergic rhinitis,
allergic dermatitis, drug allergy or food allergy, angioedema,
urticaria, sudden infant death syndrome, bronchopulmonary
aspergillosis, multiple sclerosis, or mastocytosis, more
particularly for treating allergic rhinitis, allergic dermatitis,
drug allergy or food allergy, angioedema, urticaria, sudden infant
death syndrome, bronchopulmonary aspergillosis, multiple sclerosis,
or mastocytosis with resistance to imatinib.
[0047] The term "allergic rhinitis" as used herein means any
allergic reaction of the nasal mucosa. Such allegic reaction may
occur, e.g., perennially, e.g. vernal conjunctivitis, or
seasonally, e.g., hay fever.
[0048] The term "allergic dermatitis" as used herein means
especially atopic dermatitis, allergic contact dermatitis and
eczematous dermatitis, but comprises, e.g., also seborrhoeic
dermatitis, Lichen planus, urticaria and acne. Atopic dermatitis as
defined herein is a chronic inflammatory skin disorder seen in
individuals with a hereditary predisposition to a lowered cutaneous
threshold to pruritus. It is principally characterized by extreme
itching, leading to scratching and rubbing that in turns results in
the typical lesons of eczema. Allergic contact dermatitis as
defined herein is a form of dermatitis that is due to the allergic
sensitization to various substances that produce inflammatory
reactions in the skin of those who have acquired hypersensitivity
to the allergen as a result of previous exposure to it.
[0049] The term "drug allergy or food allergy" as used herein
pertains to an allergic reaction produced by a drug or ingested
antigens, such as, for example, strawberries, milk or eggs.
[0050] The term "bronchopulmonary aspergillosis" relates to an
infection of the lungs with Aspergillus.
[0051] The term "mastocytosis" as used herein, relates to systemic
mastocytosis, for example mastocytoma, and also to canine mast cell
neoplasms. Mastocytosis is a myeloproliferative disorder with
limited treatment options and generally a poor prognosis. The
pathogenesis of mastocytosis has been attributed to constitutive
activation of the receptor tyrosine kinase KIT. In a large majority
of mastocytosis patients, the deregulated tyrosine kinase activity
of KIT is due to a mutation within the codon 816 of the protein
(D816V) which also confers resistance to imatinib or imatinib
mesylate, the latter being marketed as Gleevec.RTM. in the United
States or Glivec.RTM. elsewhere, in vitro and in vivo.
[0052] Mast cells play an important role as the primary effector
cells in the allergic disorders mentioned herein. Antigen-specific
IgE-mediated degranulation of mast cells leads to the subsequent
release of chemical mediators and multiple cytokines and to
leukotriene synthesis. Furthermore, mast cells are involved in the
pathogenesis of multiple sclerosis.
[0053] Mast cell neoplasms occur in both humans and animals. In
dogs, mast cell neoplasms are called mastocytomas, and the disease
is common, representing 7%-21% of canine tumors. A distinction must
be drawn between human mastocytosis, which is usually transient or
indolent, and canine mast cell neoplasia, which behaves
unpredictably and is often aggressive and metastatic. For instance,
human solitary mastocytomas do not often metastasize; in contrast,
50% of canine mastocytomas behave in a malignant fashion, as
estimated by Hottendorf & Nielsen (1969) after review of 46
published reports of tumors in 938 dogs.
[0054] Cancer in the pet population is a spontaneous disease. Pet
owners, motivated by prolonging the quality of their animals' life,
frequently seek out the specialized care and treatment of
veterinary oncologists at private referral veterinary hospitals and
veterinary teaching hospitals across the country. Therapeutic
modalities of veterinary cancer patients are similar to humans,
including surgery, chemotherapy, radiation therapy, and biotherapy.
It has been estimated that there are 42 million dogs and
approximately 20 million cats in the United States. Using crude
estimates of cancer incidence, there are roughly 4 million new
cancer diagnoses made in dogs and a similar number in cats made
each year.
[0055] Cutaneous mast cell tumors in dogs are a common problem.
Most mast cell tumors are benign and are cured with simple
resection; however, if recurrent or metastatic to distant sites
therapeutic options are limited. Treatment options for recurrent
lesions can include external beam radiation therapy. For distant
metastases or disseminated disease the use of Lomustine.RTM. and
vinblastine containing chemotherapy protocols have demonstrated
some benefit. Sites for metastases for mast cell tumors include
skin, regional lymph nodes, spleen, liver, and bone marrow.
[0056] The KIT receptor's involvement in the pathogenesis of
mastocytosis is suggested by the observation that several mutations
resulting in constitutive activation of KIT have been detected in a
number of mast cell lines. For instance, a point mutation in human
c-KIT, causing substitution of Val for Asp816 in the
phosphotransferase domain and receptor autoactivation, occurs in a
long-term human mast cell leukemia line (HMC-1) and in the
corresponding codon in two rodent mast cell lines. Moreover, this
activating mutation has been identified in situ in some cases of
human mastocytosis. Two other activating mutations have been found
in the intracellular juxtamembrane region of KIT, ie. the Val560Gly
substitution in the human HMC-1 mast cell line, and a seven amino
acid deletion (Thr573-His579) in a rodent mast cell line called
FMA3.
[0057] The present invention more particularly concerns the use of
PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the preparation of a drug
for the treatment of systemic mastocytosis.
[0058] In another embodiment, the instant invention provides a
method for treating systemic mastocytosis comprising administering
to a mammal in need of such treatment a therapeutically effective
amount of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES, or pharmaceutically
acceptable salts or prodrugs thereof.
[0059] Preferably the instant invention provides a method for
treating mammals, especially humans, suffering from systemic
mastocytosis comprising administering to a mammal in need of such
treatment an FIP1L1-PDGFR.alpha. inhibiting amount of
4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imida-
zol-1-yl)-3-(trifluoromethyl)phenyl]benzamide (Compound (II)) or a
pharmaceutically acceptable salt thereof.
[0060] In the present description, the term "treatment" includes
both prophylactic or preventative treatment as well as curative or
disease suppressive treatment, including treatment of patients at
risk of contracting the disease or suspected to have contracted the
disease as well as ill patients. This term further includes the
treatment for the delay of progression of the disease.
[0061] The term "curative" as used herein means efficacy in
treating ongoing episodes involving systemic mastocytosis.
[0062] The term "prophylactic" means the prevention of the onset or
recurrence of diseases involving systemic mastocytosis.
[0063] The term "delay of progression" as used herein means
administration of the active compound to patients being in a
pre-stage or in an early phase of the disease to be treated, in
which patients for example a pre-form of the corresponding disease
is diagnosed or which patients are in a condition, e.g. during a
medical treatment or a condition resulting from an accident, under
which it is likely that a corresponding disease will develop.
[0064] This unforeseeable range of properties means that the use of
PYRIMIDYLAMINOBENZAMIDE DERIVATIVES are of particular interest for
the manufacture of a medicament for the treatment of d systemic
mastocytosis.
[0065] This effect can especially be clinically relevant for
patients with systemic mastocytosis.
[0066] To demonstrate that PYRIMIDYLAMINOBENZAMIDE DERIVATIVES are
particularly suitable for the treatment of systemic mastocytosis
with good therapeutic margin and other advantages, clinical trials
can be carried out in a manner known to the skilled person.
[0067] The precise dosage of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES to
be employed for inhibiting systemic mastocytosis depends upon
several factors including the host, the nature and the severity of
the condition being treated, the mode of administration. The
compound of formula I can be administered by any route including
orally, parenterally, e.g., intraperitoneally, intravenously,
intramuscularly, subcutaneously, intratumorally, or rectally, or
enterally. Preferably the compound of formula I is administered
orally, preferably at a daily dosage of 1-300 mg/kg body weight or,
for most larger primates, a daily dosage of 50-5000, preferably
500-3000 mg. A preferred oral daily dosage is 1-75 mg/kg body
weight or, for most larger primates, a daily dosage of 10-2000 mg,
administered as a single dose or divided into multiple doses, such
as twice daily dosing.
[0068] Usually, a small dose is administered initially and the
dosage is gradually increased until the optimal dosage for the host
under treatment is determined. The upper limit of dosage is that
imposed by side effects and can be determined by trial for the host
being treated.
[0069] Compounds of formula I may be combined with one or more
pharmaceutically acceptable carriers and, optionally, one or more
other conventional pharmaceutical adjuvants and administered
enterally, e.g. orally, in the form of tablets, capsules, caplets,
etc. or parenterally, e.g., intraperitoneally or intravenously, in
the form of sterile injectable solutions or suspensions. The
enteral and parenteral compositions may be prepared by conventional
means.
[0070] The PYRIMIDYLAMINOBENZAMIDE DERIVATIVES can be used alone or
combined with at least one other pharmaceutically active compound
for use in these pathologies. These active compounds can be
combined in the same pharmaceutical preparation or in the form of
combined preparations "kit of parts" in the sense that the
combination partners can be dosed independently or by use of
different fixed combinations with distinguished amounts of the
combination partners, i.e., simultaneously or at different time
points. The parts of the kit of parts can then, e.g., be
administered simultaneously or chronologically staggered, that is
at different time points and with equal or different time intervals
for any part of the kit of parts. Non-limiting examples of
compounds which can be cited for use in combination with
PYRIMIDYLAMINOBENZAMIDE DERIVATIVES are cytotoxic chemotherapy
drugs, such as cytosine arabinoside, daunorubicin, doxorubicin,
cyclophosphamide, VP-16, or imatinib etc. Further,
PYRIMIDYLAMINOBENZAMIDE DERIVATIVES could be combined with other
inhibitors of signal transduction or other oncogene-targeted drugs
with the expectation that significant synergy would result.
[0071] The invention further pertains the combination of a
PYRIMIDYLAMINOBENZAMIDE DERIVATIVE as described hereinbefore with
imatinib for the treatment of the diseases and conditions described
hereinbefore. The administration of such a combination may be
affected at the same time, for instance in the form of a fixed,
combined pharmaceutical composition or preparation, or sequentially
or timely staggered. The administration of a
PYRIMIDYLAMINOBENZAMIDE DERIVATIVE in a dosage form as described
hereinbefore and of imatinib in its marketed form of GLEEVEC.RTM.
in the US/GLIVEC.RTM. in Europe and with the dosages envisaged for
these dosage forms is currently preferred.
[0072] The treatment of systemic mastocytosis with the above
combination may be a so-called first line treatment, i.e. the
treatment of a freshly diagnosed disease without any preceeding
chemotherapy or the like, or it may also be a so-called second line
treatment, i.e. the treatment of the disease after a preceeding
treatment with imatrinib or a PYRIMIDYLAMINOBENZAMIDE DERIVATIVE,
depending on the severity or stage of the disease as well as the
over all condition of the patient etc.
[0073] The efficacy of PYRIMIDYLAMINOBENZAMIDE DERIVATIVES for the
treatment of systemic mastocytosis is illustrated by the results of
the following examples. These examples illustrate the invention
without in any way limiting its scope:
[0074] IL-3 Independence Cell Proliferation Assays:
[0075] The effects of compounds on viability and proliferation of
the cells is determined using the luminescent ATP Detection assay
kit ATPLite.TM. from Perkin Elmer Life Sciences (Cat. No: 6016947)
according to the instructions of the suppliers. This assay system
is based on the production of light (luminescence) caused by the
reaction of ATP with added luciferase and D-luciferin.
[0076] Ba/F3 FIP-PDGFR.alpha., Ba/F3 kit D-816-V, Ba/F3 kit
D-816-Y, Ba/F3 kit delVV, Ba/F3 kit R-634-W cell lines, grown in
suspension in RPMI 1640 (Invitromex, Cat.No.: L0501), 10% fetal
calf serum (Amimed, Cat.No.: 2-01F86-I), 2 mM L-glutamine (Gibco),
are seeded into black 96-well tissue culture plates (Packard) at a
density of 10000 cells per well in 50 .mu.L complete medium
immediately followed by addition of 50 .mu.L per well serial
two-fold dilutions of 2.times. concentrated compounds (duplicates).
Cells without compound are used as a control and medium without
cells is used to determine the assay background signal. After 70 h
incubation (37.degree. C., 5% CO.sub.2), the cells are lysed by
addition of 50 .mu.L per well mammalian cell lysis solution
(provided with the kit) and 5 min shaking in an orbital plate
shaker at 700 rpm. Subsequently, 50 .mu.L substrate solution
(luciferase and D-luciferin) is added and after 5 min shaking and
10 min dark-adaptation of the plates, light emission is measured
with a Packard TopCount.
[0077] The compound activity is determined as total growth
inhibition (TGI) of the cell cultures and is calculated as follows:
After subtraction of the background signal the signal obtained for
the control cells is taken as 100%. The effect of the compound is
expressed as percent reduction of the control signal. The TGI50
values are determined from the dose response curves by graphical
extrapolation.
[0078] GIST882, is a human gastrointestinal stromal tumor (GIST)
cell line expressing an activating KIT mutation (exon 13, K-642-E)
(Tuveson D A, Willis N A, Jacks T, Griffin J D, Singer S, Fletcher
C D, Fletcher J A, Demetri G D, ST1571 inactivation of the
gastrointestinal stromal tumor c-KIT oncoprotein: biological and
clinical implications, Oncogene, Aug. 16, 2001; 20(36):5054-8). The
GIST882 cells are cultivated in RPMI 1640 (Invitromex, Cat. No:
L0501), supplemented with 15% FCS, and 2 mM glutamine (Gibco). Cell
culture flasks and 96 well tissue culture plates are treated with
1.5% gelatine solution in nanopure water for 30-60 min at
37.degree. C. prior to seeding the cells to improve adherence and
cell growth. The gelatine (BIORAD, EIA purity reagent, #170-6537)
is sterilized before use by heating (autoclave).
[0079] GIST882 cells are seeded into black 96-well tissue culture
plates (Packard) at a density of 10000 cells per well in 50 .mu.L
complete medium and incubated for one day in order to allow for
attachment of the cells. Serial two-fold dilutions of 2.times.
concentrated compound is added (50 .mu.L per well) in duplicates
(final volume: 100 .mu.L per well). Cells without compound are used
as a control and medium without cells is used to determine the
assay background signal. After 70 h incubation (37.degree. C., 5%
CO.sub.2), the cells are lysed by addition of 50 .mu.L per well
mammalian cell lysis solution (provided with the kit) and 5 min
shaking in an orbital plate shaker at 700 rpm. Subsequently, 50
.mu.L substrate solution (luciferase and D-luciferin) is added and
after 5 min shaking and 10 min dark-adaptation of the plates, light
emission was measured with a Packard TopCount.
[0080] The compound activity is determined as total growth
inhibition (TGI) of the cell cultures and is calculated as follows:
After subtraction of the background signal the signal obtained for
the control cells is taken as 100%. The effect of the compound is
expressed as percent reduction of the control signal. The TGI50
values are determined from the dose response curves by graphical
extrapolation.
[0081] Compound (II) inhibits the proliferation of GIST882 cells
with a mean IC50 value of <200 nM.
[0082] Assay to Determine Effects on Kit Autophosphorylation in
Cells:
[0083] The phosphorylation status of the cellular targets in
lysates from cells--untreated or treated with compound--is
determined with capture ELISAs. Adherent cells are grown in 96-well
flat-bottom tissue culture plates close to confluency. Cells
growing in suspension are seeded at 100000-150000 cells per well.
After treatment with serial compound dilutions cells are washed
once with PBS following cell lysis with 100 to 150 .mu.L lysis
buffer (50 mM Tris/HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA,
1 mM EGTA, 1% NP-40, 2 mM sodium ortho-vanadate, 1 mM PMSF, 50
.mu.g/mL aprotinin and 80 .mu.g/mL leupeptin). Cell lysates are
used immediately or stored at -20.degree. C.50 .mu.L of the lysates
are transferred to black ELISA plates (NUNC-Maxisorp, Cat. No.:
Nr.437111) that are previously coated with a monoclonal anti-CD117
antibody obtained from Diaclone (#854.510.000) is used. For
coating, the antibody is diluted in PBS and incubated with the
plates overnight at 4.degree. C. (50 .mu.L/well). Phosphorylation
of the captured Kit is detected using a commercial anti-P-Tyr Ab,
labeled with alkaline phosphatase (AP), PY20 AP from Zymed, at a
final concentration range between 1:3000 and 1:10000 (0.1 to 0.33
.mu.g/ml). The second Ab is added after removal of the cell
lysates. Finally, 90 .mu.L per well of a chemiluminescent AP
substrate (CDPStar RTU with Emerald II from Applied Biosystems
(Cat. No.: T2388C) are added and incubated for 45 min at RT in the
dark. The plates are sealed with Packard TopSeal.TM.-A plate
sealers (Cat. No. 6005185) and luminescence is quantified by
measuring counts per second (CPS) with a Packard Top Count
Microplate Scintillation Counter (Top Count).
[0084] The difference between the ELISA-readout (CPS) obtained with
the lysates of the untreated cells and the readout for the
assay-background (all components, but without cell lysate) is
calculated and taken as 100% reflecting the constitutively
phosphorylated Kit protein present in these cells. The activity of
the compound on the Kit kinase activity is expressed as percent
reduction of the Kit phosphorylation. The values for the IC50 and
IC90 are determined from the dose response curves by graphical
extrapolation.
EXAMPLE I
[0085] A Phase II, open-label study was designed to evaluate the
safety and efficacy of Compound (II) administered orally 400 mg
twice daily. SM patients meeting specific disease criteria and with
a clinical indication for treatment were enrolled. The results are
based on preliminary data for the first 23 pts in this study.
Results: The median age was 49 (range 33-78) yrs and the median
time from diagnosis of SM was 27 (range 1 to 292) months. For those
with data available, 13/17 pts had a c-kit D816V mutation in bone
marrow cells. The median exposure to Compound (II) was 144 days.
Treatment is ongoing for 18 (78%) pts; 5 (22%) discontinued, 3
(13%) for adverse events and 2 (9%) withdrew consent. Three (13%)
responses were reported (2 incomplete remission and 1 minor
response), based on serum tryptase, bone marrow mast cell counts
and improvement of clinical symptoms. Baseline mutation data are
available for 2 of the 3 responding pts and revealed the c-kit
D816V mutation. These data suggest that Compound (II) has clinical
activity and an acceptable safety and tolerability profile in pts
with SM.
* * * * *