Note: Descriptions are shown in the official language in which they were submitted.
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NICOTINAMIDE DERIVATIVES USEFUL AS PDE4 INHIBITORS
This invention relates to nicotinamide derivatives of general formula
O
R~ \ N n \
H ( / N~ R4 (1 )
R2 N i ~'J~m Y
R3
in which R~, R2, R3, R4, X, Y, n and m have the meanings indicated below,
and to processes for the preparation of, intermediates used in the preparation
of, compositions containing and the uses of, such derivatives.
The 3',5'-cyclic nucleotide phosphodiesterases (PDEs) comprise a large
class of enzymes divided into at least eleven different families which are
structurally, biochemically and pharmacologically distinct from one another.
The enzymes within each family are commonly referred to as isoenzymes, or
isozymes. A total of more than fifteen gene products is included within this
class, and further diversity results from differential splicing and post-
translational processing of those gene products. The present invention is
primarily concerned with the four gene products of the fourth family of PDEs,
i.e., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively
referred to as being isoforms or subtypes of the PDE4 isozyme family.
The PDE4s are characterized by selective, high affinity hydrolytic
degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic
monophosphate (cAMP), and by sensitivity to inhibition by rolipram. A number
of selective inhibitors of the PDE4s have been discovered in recent years, and
beneficial pharmacological effects resulting from that inhibition have been
shown in a variety of disease models (see, e.g., Torphy et al., Environ.
Health
Perspect. ,1994, 102 Suppl. 10, p. 79-84 ; Duplantier et al., J. Med. Chem.,
1996, 39, p. 120-125 ; Schneider et al., Pharmacol. Biochem. Behav., 1995, 50,
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p. 211-217 ; Banner and Page, Br. J. Pharmacol., 1995, 114, p. 93-98 ;
Barnette et al., J. Pharmacol. Exp. Ther., 1995, 273, p. 674-679 ; Wright et
al.,
Can. J. Physiol. Pharmacol., 1997, 75, p. 1001-1008 ; Manabe et al., Eur. J.
Pharmacol., .1997, 332, p. 97-107 and Ukita et aL, J. Med. Chem., 1999, 42, p.
1088-1099). Accordingly, there continues to be considerable interest in the
art
with regard to the discovery of further selective inhibitors of PDE4s.
Successful results have already been obtained in the art with the
discovery and development of selective PDE4 inhibitors. In vivo, PDE4
inhibitors reduce the influx of eosinophils to the lungs of allergen-
challenged
animals while also reducing the bronchoconstriction and elevated bronchial
responsiveness occurring after allergen challenge. PDE4 inhibitors also
suppress the activity of immune cells (including CD4+ T-lymphocytes,
monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit
excitatory nonadrenergic noncholinergic neurotransmission (eNANC),
potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC),
reduce airway smooth muscle mitogenesis, and induce bronchodilation. PDE4
inhibitors also suppress the activity of a number of inflammatory cells
associated with the pathophysiology of COPD, including
monocytes/macrophages, CD4* T-lymphocytes, eosinophils and neutrophils.
PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and
potentially interfere with the ability of airway epithelial cells to generate
pro-
inflammatory mediators. Through the release of neutral proteases and acid
hydrolases from their granules, and the generation of reactive oxygen species,
neutrophils contribute to the tissue destruction associated with chronic
inflammation, and are further implicated in the pathology of conditions such
as
emphysema. Therefore, PDE4 inhibitors are particularly useful for the
treatment
of a great number of inflammatory, respiratory and allergic diseases,
disorders
or conditions, as well as for wounds and some of them are in clinical
development mainly for treatment of asthma, COPD, bronchitis and
emphysema.
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The effects ofi PDE4 inhibitors on various infilammatory cell responses
can be used as a basis fior profiling and selecting inhibifiors for further
study.
These effects include elevation of cAMP and inhibition of superoxide
production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFa)
release in eosinophils, neutrophils and monocytes.
As said above, the present invention relates to PDE4 inhibitors of the
nicotinamide derivatives family.
Nicotinamide derivatives having a PDE4 inhibitory activity have already
been synthetized. For example, the patent application N° WO 98/45268
discloses nicotinamide derivatives having activity as selective inhibitors of
PDE4D isozyme. These selective PDE4D inhibitors are represented by the
following formula
R6 A R2 R3 Ra.
R'
(D)p ~ ~R~
R$ N E(CHJ2m)rR5
(~)t
wherein in particular m and n may be equal to 1 and p may be equal to 0, A may
be oxygen, B may be NH, r may be equal to 0, E may be O, NH or S, R5 may
be a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group
containing 1 to 4 heteroatoms and R' may be an aryl optionally substituted by
various substituents.
Also, the patent application N° WO 01/57036 also discloses
nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of
various inflammatory allergic and respiratory diseases and conditions, of
formula
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R3 Rc R1
Y ~ N'~ n' Ra
Rd .Q Z
N~ W R2 L ~ J m
Rb
R4
R5
R6
wherein in particular : n is 1 or 2, m is 0 to 2, Y is =C(RE)- or -[N~(O)]-, W
is -
O-, -S(=O)t- or -N(R3)-, Q represents various rings among which phenyl, Z is -
OR~2, -C(=O)R~2 Or CN and R~2 is choosen from alkyl, alkenyl, cycloalkyl,
phenyl, benzyl and monocyclic heterocyclic moieties.
However, there is still a huge need for additional PDE4 inhibitors
showing improved therapeutic index with possibly less adverse effects such as
for example emesis.
Thus, the present invention concerns new nicotinamide derivatives of
general formula (1 )
O
R~ \ N n \
H ~ ~ H
N~ R4 (1 )
R2 N ~ ~'/.m Y
R3
in which
~:~ m is 0, 1, 2 or 3,
~:~ n is 0, 1, 2 or 3,
~:~ R~ and R2 are each a member independently selected from the group
consisting of hydrogen atom, halo, cyano, (C~-C4)alkyl and (C~-C4)alkoxy,
~:~ X is -O-, -S- or -NH-,
~:~ R3 is a member selected from the groups consisting of
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(a) phenyl, naphthyl, heteroaryl and (C3-Cs)cycloalkyl, each optionally
substituted with 1 to 3 substituents each selected from the group consisting
of
halo, cyano, (C~-C4)alkyl, (C~-C4)alkoxy, (C~-G4)thioalkyl, -C(=O)NH2,
C(=O)NH((G~-C4)alkyl), hydroxy, -O-C(=O)(C~-C4)alkyl, -C(=O)-O-(C~-C4)alkyl
and hydroxy(C~-C4)alkyl, or
(b) the bicyclic groups conforming to one of the following structures (1.1 )
to
(1.4)
/ / / /
O ~ O
O-l O
(1.1) (1.2) (1.3) (1.4)
where the symbol "*" indicates the point of attachment of each partial formula
(1.1 ) through (1.4) to the remaining portion of formula (1 ),
~:~ Y is a member selected from the group consisting of partial formulas (1.5)
through (1.11 )
O O
** O,~ ~O 0~~~ ~, **
N /S~ / N
* ** * H * ** * H
(1.5) (1.6) (1.7) (1.8)
~ O O
H O,~ ~O J,.' N *
**
N~ ~ /S~H **
* ~ S~~O
O
(1.9) (1.10) (1.11 )
where the symbol "*" indicates the point of attachment of each partial formula
(1.5) through (1.11 ) to the remaining portions -NH- of formula (1 ) and "**"
indicates the point of attachment of each partial formula (1.5) through (1.11
) to
the remaining portions -R4 of formula (1 ),
~:~ and R4 is a member selected from the groups consisting of
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(a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3
substituents each selected from the group consisting of carboxylic acid, C(=O)-
O-(C~-C4)alkyl, halo, cyano, -C(=O)NH2, (C~-C4)alkyl, (C~-C4)alkoxy, (C~-
C4)haloalkyl, hydroxy, and hydroxy(C~-C4)alkyl, or
(b) (C~-C4)alkyl optionally substituted with a hydroxy, carboxylic acid, C(=O)-
O-
(C~-C4)alkyl, phenyl, naphthyl or heteroaryl group wherein said phenyl,
naphthyl
and heteroaryl are each optionally substituted with 1 to 3 substituents each
selected from the group consisting of carboxylic acid, C(=O)O(C~-C4)alkyl,
halo,
cyano, -C(=O)NH2, (C~-C4)alkyl or (C~-C4)alkoxy, (C~-C4)haloalkyl, hydroxy,
and
hydroxy(C~-C4)alkyl,
or, if appropriate, their pharmaceutically acceptable salts andlor isomers,
tautomers, solvates, polymorphs, isotopic variations or metabolites thereof.
It has been found that these nicotinamide derivatives are inhibitors of
PDE4 isoenzymes, particularly useful for the treatment of inflammatory,
respiratory and allergic diseases and conditions and for the treatment of
wounds
by showing excellent therapeutic utility and therapeutic index.
In the here above general formula (1 ), halo denotes a halogen atom
selected from the group consisting of fluoro, chloro, bromo and iodo in
particular fluoro or chloro.
(C~-C4)alkyl radicals denote a straight-chain or branched group
containing 1, 2, 3 or 4 carbon atoms. This also applies if they carry
substituents
or occur as substituents of other radicals, for example in (C~-C4)alkoxy
radicals,
(C~-C4)thioalkyl radicals, (C~-C4)haloalkyl radicals, hydroxy(C~-C4)alkyl
radicals,
C(=O)O(C~-C4)alkyl radicals etc... . Examples of suitable (C~-C4)alkyl
radicals
are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and
tent butyl.
Examples of suitable (C~-C4)alkoxy radicals are methoxy, ethoxy, n-propyloxy,
iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and ten'-butyloxy.
Examples
of suitable (C~-C4)thioalkyl radicals are thiomethyl, thioethyl, thin-n-
propyl, thio-
iso-propyl, thio-n-butyl, thio-iso-butyl, thio-see-butyl and thio-tart butyl.
(C~-
C4)haloalkyl radicals are alkyl radicals substituted by halo. They can contain
1,
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2, 3, 4, 5, 6 or 7 halogen atoms, if not stated otherwise. Said halo is
preferably
a fluoro, a chloro, a bromo or a iodo, in particular fluoro or chloro. For
example
in a fluoro-substituted alkyl radical, a methyl group can be present as a
trifluoromethyl group. The same applies to hydroxy(C~-C4)alkyl radicals except
that they are alkyl radicals substituted by a hydroxy group (-OH). According
to a
preferred embodiment of said invention, such radicals contain one hydroxy
substituent. Examples of suitable hydroxy(C~-C4)alkyl radicals are
hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl.
(C3-C$)cycloalkyl radicals represent 3-membered to 3-membered
saturated monocyclic rings. Examples of suitable (C3-C$)cycloalkyl radicals
are
in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
and
cyclooctyl. These radicasl can be optionally substituted as indicated in the
definition of R3. Examples ,of substituted (C3-C$)cycloalkyl radicals are 2-
methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 5-methylcyclohexyl,
6-methylcyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-
hydroxycyclohexyl, 5-hydroxycyclohexyl, 6-hydroxycyclohexyl, 2-
fluorocyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 5-fluorocyclohexyl,
6-
fluorocyclohexyl 2-methyl-3-hydroxycyclohexyl, 2-methyl-4-hydroxycyclohexyl,
2-hydroxy-4-methylcyclohexyl, etc... .
In the hereabove general formula (1 ), heteroaryl is a radical of a
monocyclic or polycyclic aromatic system having 5 to 14 ring members, which
contains 1, 2, 3, 4 or 5 heteroatom(s) depending in number and quality of the
total number of ring members. Examples of heteroatoms are nitrogen (N),
oxygen (O) and sulphur (S). If several heteroatoms are contained, these can be
identical or different. Heteroaryl radicals can also be unsubstituted,
monosubstituted or polysubstituted, as indicated in the definition of R3 and
R4
hereabove for general formula (1 ) according to the present invention.
Preferably
the heteroaryl is a monocyclic or bicyclic aromatic radical which contains 1,
2, 3
or 4, in particular 1, 2 or 3, identical or different heteroatoms selected
from the
group consisting of N, O and S. Particularly preferably, the heteroaryl is a
monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in
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particular a 5-membered to 6-membered monocyclic aromatic radical which
contains (i) from 1 to 4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen
heteroatom(s) and 1 oxygen heteroatom or 1 sulphur heteroatom or (iii) 1 or 2
oxygen or sulphur heteroatom(s). Examples of suitable heteroaryl radicals are
the radicals derivated from pyrrole, furan, furazan, thiophene, imidazole,
pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triazine,
pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, indole, isoindole, indazole,
purine,
naphtyridine, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline,
cinnoline, and benzo-fused derivatives of these heteroaryls, such as for
example benzofuran, benzothiophene, benzoxazole, and benzothiazole.
Particularly preferred are the heteroaryl radicals selected from pyrrolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
thiazolyl,
isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl,
pyridinyl,
pyridazinyl, pyrimidinyl, and pyrazinyl. Nitrogen heteroaryl radicals can also
be
present as N-oxides or as quaternary salts.
In the general formula (1 ) according to the present invention, when a
radical is mono- or poly-substituted, said substituent(s) can be located at
any
desired position(s). Also, when a radical is polysubstituted, said
substituents
can be identical or different.
The nicotinamide derivatives of the formula (1 ) can be prepared using
conventional procedures such as by the following illustrative methods in which
R~, R2, R3, R4, X, Y, n and m are as previously defined for the nicotinamide
derivatives of the formula (1 ) unless otherwise stated.
The nicotinamide derivatives of the formula (1 ) may be prepared starting
from a compound of formula (2)
R.
H J n I \ NH (2)
R, m
R3
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wherein R~, R~, X, R3, n and m are as previously described for the
nicotinamide
derivatives of formula (1 ).
Where Y represents a group of partial formula (1.7), (1.8) or (1.10), the
compounds 1of formula (2) may be reacted with the corresponding R4-sulfonyl
chloride derivative (R4S02CI or R4NHS02CI or R4C(=O)NHSOZCI) in a suitable
solvent (e.g. dichloromethane) and in the presence of an organic base (e.g.
triethylamine) at a temperature ranging from 0°C to room temperature
(about
20°C).
Where Y represents a group of partial formula (1.5), (1.9) or (1.11 ), the
compounds of formula (2) may be reacted with the corresponding R4-carboxylic
acid derivative (R4COOH or R4SO~NH-CH2-COON or R4C(O)NH-CH2-COOH)
using an activating agent in the presence of a suitable solvent (e.g.
dimethylformamide) and organic base (e.g. N-methylmorpholine) at room
temperature. Activation of the acid may be achieved by using for example
a) 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride,
b) carbonyldiimidazole, or
c) oxalyl chloride and dimethylformamide (with dichloromethane as the
solvent).
Where Y represents a group of partial formula (1.6), the compounds of
formula (2) may be reacted with carbonyldiimidazole in a suitable solvent
(such
as dichloromethane) and the obtained intermediate is reacted with an amine
bearing the substituent R4.
It must be emphasized that where R3 and R4 in the nicotinamide
derivatives of formula (1 ) represent alkoxy substituted phenyl rings, these
structures can be converted to the hydroxy analogue using certain deprotection
conditions well-known to the one skilled in the art.
The compounds of general formula (2) may be prepared by removal of
the protecting group "Prot" from the compounds of general formula (3)
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R,
In I H
N
m ~ P rot
R3
wherein R~, R2, X, R3, n and m are as previously described for the
nicotinamide
derivatives of formula (1 ) and Prot is a suitable protecting group, which
includes
but is not limited to a ben~yl group, a carbamate (e.g. tart-
butyloxycarbonyl), an
amide (e.g. trifluoroacetamide) or an imide (e.g. phtalimide), using
deprotection
conditions well-known to the one skilled in the art.
The compounds of formula (3) may be prepared as shown in scheme 1
O O
R~ \ OR' , R3XH (7) R~ \ OR.
R2 N CI R2 ~N X
(6) (5.1 ) R
3
H2N n ~ \ O
H
N R~ \
(5) m ~Prot ~ ~ ~OH
R2 N X
(4,1 ) Rs
O
R~
i ~H n ~ \ N
R2 N X . / m ~ P rot
R3
Scheme 1
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wherein R~, R2, X, R3, n, m and Prot are as previously described and R'
represents a (C~-C4)alkyl radical.
In a typical procedure the nicotinate ester of the formula (6) may be
reacted with the appropriate alcohol, thiol or amine of formula R3XH (7) in
the
appropriate solvent (for example dimethylformamide or dioxan) containing a
base, such as cesium carbonate, at temperatures ranging from room
temperature to 100°C to give a compound of the formula (5.1 ). This can
be
saponified with an alkali-hydroxide to give an acid of the formula (4.1 )
which is
then converted to a compound of the formula (3) by reaction with a
monoprotected diamine of the formula (8)
H2N n I ~ (8)
N~
/ m Prot
using an activating agent such as those described in one of the activation
methods outlined before . (i.e. a) 1-hydroxybenzotriazole and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or b)
carbonyldiimidazole or c) oxalyl chloride and dimethylformamide, with
dichloromethane as the solvent).
According to another alternative, the compounds of formula (3) may be
prepared as shown in scheme 2
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O O
R~ ~ \ OR' ~ R~ \ OH
R2 N CI R NI _CI
z
(6)
(5.2)
(8) HzN n ~ H
/ N\
Prot
O
R3XH (7) R~ \ \
In ~ H
N
R2 N CI m \Prot
(4.2)
O
R~ \ N n \
R ~ N~~ H , I ~ N\
~-~m Prot
R3 (3)
Scheme 2
wherein R~, R2, X, R3, n, m, R' and Prot are as previously described.
In a typical procedure the nicotinate ester of the formula (6) may be
hydrolysed using an alkaline metal hydroxide to a nicotinic acid of the
formula
(5.~), which is reacted with a monoprotected diamine of the formula (8) using
one of the activation methods outlined before. The chloropyridine of the
formula
(4.2) obtained at the preceding step may be reacted with the appropriate
alcohol, thiol or amine of formula R3XH (7) in the appropriate solvent (for
example dimethylformamide or dioxan) containing a base, such as cesium
carbonate, at temperatures ranging from room temperature to 100°C.
The compounds of formula (6) and (7) are either commercial or they can
be prepared by conventional procedures well known to the one skilled in the
art.
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The monoprotected diamine of the formula (8) may be prepared by
reaction of a large excess of a diamine of formula (9)
9
H2N J, n ~ \ ( )
/ NH2
m
wherein m and n are as defined above, with a suitable derivatizing agent such
as di-tart-butyldicarboxylate (to give the tart butyloxycarbonyl derivative)
at
room temperature in a suitable solvent (such as dichloromethane).
The compounds of formula (9) are commercial or they can be easily
prepared by conventional procedures well known to the one skilled in the art.
All of the above reactions and the preparations of novel starting
mafierials using in the preceding methods are conventional and appropriate
reagents and reaction conditions for their performance or preparation as well
as
procedures for isolating the desired products will be well-known to those
skilled
in the art with reference to literature precedents and the examples and
preparations hereto.
For some of the steps of the here above described process of
preparation of the nicotinamide derivatives of formula (1 ), it can be
necessary
to protect the potential reactive functions that are not wished to react. In
such a
case, any compatible protecting radical can be used. In particular methods
such as those described by T.W. GREENE (Protective Groups in Organic
Synthesis, A. Wiley-Interscience Publication, 1981) or by McOMIE (Protective
Groups in Organic Chemistry, Plenum Press, 1973), can be used.
Also, the nicotinamide derivatives of formula (1 ) as well as intermediate
for the preparation thereof can be purified according to various well-known
methods, such as for example crystallization or chromatography.
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According to a general aspect of the present invention, the nicotinamide
derivatives of the formula (1 ) as previously described except the compounds
for
which
1 ) m is different from 0 simultaneously with Y representing the partial
formula (1.5) and R4 representing a non-substituted (C~-C4)alkyl,
2) m is equal to 0 simultaneously with Y representing the partial formula
(1.5) and R4 representing a phenyl, a naphtyl or a heteroaryl each
optionally substituted with 1 to 3 substituents independently selected
from the group consisting of carboxylic acid, halo, cyano, (C~-C4)alkyl,
(C~-C4)alkoxy, (C~-C~.)haloalkyl, hydroxy and hydroxy(C~-C4)alkyl or R4
representing a (C~-C4)alkyl optionally substituted with a hydroxy,
carboxylic acid, or a heteroaryl, which is optionally substituted with 1 to 3
substituents independently selected from the group consisting of
carboxylic acid, halo, cyano, (C~-C~.)alkyl, (C~-C4)alkoxy, hydroxy and
hydroxy(C~-C4)alkyl, and
3) m is equal to 0 simultaneously with Y representing the partial formula
(1.6) and R4 representing a phenyl or a naphtyl, each optionally
substituted with 1 to 3 substituents independently selected from the
group consisting of carboxylic acid, halo, cyano, (C~-C4)alkyl, (C~-
C4)alkoxy, (C~-C4)haloalkyl, hydroxy and hydroxy(C~-C4)alkyl,
are preferred.
Particularly preferred are nicotinamide derivatives of the formula (1 ) in
which
~:~ m and n are equal to 1,
~:~ R~ and R2 are each a member independently selected from the group
consisting of hydrogen atom, halo, cyano, (C~-C4)alkyl and (C~-C4)alkoxy,
~:~ ~C is -Q-
~:~ R3 is a member selected from the groups consisting of
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(a) phenyl, naphthyl, heteroaryl and (C3-C$)cycloalkyl, each optionally
substituted with 1 to 3 substituents each selected from the group consisting
of
halo, cyano, (C~-C4)alkyl, (C~-C4)alkoxy, (C~-C4)thioalkyl, -C(=O)NH2,
C(=O)NH((C.~-C4)alkyl), hydroxy, -O-C(=O)(C~-C4)alkyl, -C(=O)-O-(C~-C4)alkyl
and hydroxy(C~-C4)alkyl, or
(b) the bicyclic groups conforming to one of the following structures (1.1 )
to
(1.4)
/ / / /
O ~ O
O-~ O
(1.1) (1.2) (1.3) (1.4)
where the symbol "*" indicates the point of attachment of each partial formula
(1.1 ) through (1.4) to the remaining portion of formula (1 ),
~:~ Y is a group -C(=O)- of partial formula (1.5)
~:~ and R4 is a member selected from the groups consisting of
(a) phenyl, naphthyl and heteroaryl, each optionally substituted with 1 to 3
substituents each selected from the group consisting of carboxylic acid, C(=O)
O-(C~-C~.)alkyl, halo, cyano, -C(=O)NH2, (C~-C4)alkyl, (C~-C4)alkoxy, (C~
C4)haloalkyl, hydroxy, and hydroxy(C~-C4)alkyl, or
(b) (C~-C4)alkyl substituted with a hydroxy, carboxylic acid, C(=O)-O-(C~-
C4)alkyl, phenyl, naphthyl or heteroaryl group wherein said phenyl, naphthyl
and heteroaryl are each optionally substituted with 1 to 3 substituents each
selected from the group consisting of carboxylic acid, C(=O)O(C~-C4)alkyl,
halo,
cyano, -C(=O)NH2, (C~-C4)alkyl, (C~-C4)alkoxy, (C~-C4)haloalkyl, hydroxy, and
hydroxy(C~-C~.)alkyl,
or, if appropriate, their pharmaceutically acceptable salts and/or isomers,
tautomers, solvates, polymorphs, isotopic variations or metabolites thereof.
More particularly preferred are the nicotinamide derivatives of the
formula (1 ) in which
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~:~ m and n are equal to 1,
~:~ R~ and R2 are each a member independently selected from the group
consisting of hydrogen atom, halo and methyl,
,.
~:~ X is -O-
~:~ R3 is a phenyl optionally substituted with 1 to 3 substituents each
selected
from the group consisting of halo, cyano, (C~-C4)alkyl, (C~-C4)alkoxy, (C~-
C4)thioalkyl, -C(=O)NH2, -C(=O)NH((C~-C4)alkyl), hydroxy, -O-C(=O)(C~-
C4)alkyl, -C(=O)-O-(C~-C4)alkyl and hydroxy(C~-C4)alkyl,
~:~ Y is a group -C(=O)- of partial formula (1.5)
~:~ and R4 is a member selected from the groups consisting of
(a) phenyl optionally substituted with 1 to 3 substituents each selected from
the
group consisting of carboxylic acid, C(=O)-O-(C~-C4)alkyl, halo, cyano, -
C(=O)NH2, (C~-C4)alkyl, (C~-C4)alkoxy, (C~-C4)haloalkyl, hydroxy, and
hydroxy(C~-C4)alkyl, or
(b) (C~-C4)alkyl substituted with a hydroxy or a phenyl, wherein said phenyl
is
optionally substituted with 1 to 3 substituents each selected from the group
consisting of carboxylic acid, C(=O)O(C~-C4)alkyl, halo, cyano, -C(=O)NH2, (C~-
C4)alkyl or (C~-C4)alkoxy, (C~-C4)haloalkyl, hydroxy, and hydroxy(C~-C4)alkyl,
or, if appropriate, their pharmaceutically acceptable salts and/or isomers,
tautomers, solvates, polymorphs, isotopic variations or metabolites thereof.
Still more particularly preferred are the nicotinamide derivatives of the
formula (1 ) in which
~:~ m and n are equal to 1,
~:~ R~ is a hydrogen atom or a fluoro and R2 is a hydrogen atom,
~:~ X is -O-,
~:~ R3 is a phenyl optionally substituted with a substituent selected from the
group consisting of halo and -C(=O)-O-(C~-C4)alkyl,
~:~ Y is a group -C(=O)- of partial formula (1.5):
~:~ and R4 is a member selected from the groups consisting of
(a) phenyl optionally substituted with 1 to 3 substituents each selected from
the
group consisting of halo, (C~-C4)alkyl and hydroxy, or
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(b) (C~-C4)alkyl substituted with a hydroxy or a phenyl, wherein said phenyl
is
optionally substituted with 1 to 3 substituents each selected from the group
consisting of halo, (C~-C4)alkyl and hydroxy,
or, if appropriate, their pharmaceutically acceptable salts andlor isomers,
tautomers, solvates, polymorphs, isotopic variations or metabolites thereof.
Particularly preferred nicotinamide derivatives of the formula (1 ) are as
described in the Examples section hereafter, i.e.
2-(4-Fluoro-phenoxy)-N-{4-[(2-hydroxy-3-methyl-benzoyl amino)-methyl]-benzyl}
-nicotinamide,
3-(3-~4-[(3-Hydroxy-benzoylamino)-methyl]-benzyl carbamoyl}-pyridin-2-yloxy)-
benzoic acid ethyl ester,
2-(4-fluoro-phenoxy)-N-(4-[(6-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N-{4-[(5-fluoro-2-hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N-{4-[(3-hydroxy-4-methyl-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-IV ~4-[(3-hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N (4-[(2=hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N-(4-[(4-hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N-~4-[(2-hydroxy-4-methyl-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N-(4-[(3-hydroxy-2-methyl-benzoylamino)-methyl]-benzyl}-
nicotinamide,
2-(4-fluoro-phenoxy)-N {4-[(2-hydroxy-5-methyl-benzoylamino)-methyl]-benzyl}-
nicotinamide,
5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
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5-fluoro-2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-acetyl-amino)-methyl]-benzyl}-
nicotinamide,
5-fluoro-2-(4-fluoro-phenoxy)-N-~4-[(4-hydroxy-benzoylamino)-methyl]-benzyl}-
nicotinamide,
3-(3-~4-[(3-hydroxy-benzoylamino)-methyl] -benzylcarbamoyl)-pyridin-2-yloxy)-
benzoic acid ethyl ester,
3-(3-~4-[(2-hydroxy-phenacetyl-amino)-methyl]-benzylcarbamoyl}-pyridin-2-
yloxy)-benzoic acid ethyl ester,
3-(3-{4-[(3-hydroxy-phenacetyl-amino)-methyl]-benzylcarbamoyl}-pyridin-2-
yloxy)-benzoic acid ethyl ester,
3-(3-~4-[(4-hydroxy-phenacetyl-amino)-methyl]-benzylcarbamoyl}-pyridin-2-
yloxy)-benzoic acid ethyl ester.
The nicotinamide derivatives of formula (1 ) may also be optionally
transformed in pharmaceutically acceptable salts. In particular, these
pharmaceutically acceptable salts of the nicotinamide derivatives of the
formula
(1 ) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from mineral or organic non-toxic
acids which form non-toxic salts. Suitable examples of these acid addition
salts
are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate,
nitrate,
phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate,
citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate,
ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate
salts.
Suitable base salts are formed from bases, which form non-toxic salts,
such as alfcali metal salts, earth metal salts or addition salts with ammonia
and
physiologically tolerable organic amines. Suitable examples of these base
salts
are the sodium, potassium, aluminium, calcium, magnesium, zinc or ammonium
salts as well as addition salts with triethylamine, ethanolamine,
diethanolamine,
trimethylamine, methylamine, propylamine, diisopropylamine, N,N-
dimethylethanolamine, benzylamine, dicylohexylamine, N-benzyl-[i-
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phenethylamine, N,N'-dibenzylethylenediamine, diphenylenediamine, quinine,
choline, arginine, lysine, leucine, dibenzylamine, tris(2-hydroxyethyl)amine,
or
a,a,a-tris(hydroxymethyl)methylamine.
Compounds, which contain both acidic groups and basic groups can also
be present in the form of internal salts or betaines, which are also included
by
the present invention. For a review on suitable salts see Berge et al., J.
Pharm.
Sci., 1977, 66, p. 1-19.
Salts can generally bo obtained from the nicotinamide derivatives of the
formula (1 ) according to customary procedures known to the person skilled in
the art, for example by combining with an organic or inorganic acid or base
solvent or dispersant, or alternatively from other salts by anion exchange or
cation exchange. The salt may precipitate from solution and be collected by
filtration or may be recovered by evaporation of the solvent.
The nicotinamide derivatives of the formula (1 ) can also be present in
stereoisomeric forms. If the nicotinamide derivatives of the formula (1 )
contain
one or more centers of asymmetry, these can independently of one another
have the (S) configuration or the (R) configuration. The invention includes
all
possible stereoisomers of the nicotinamide derivatives of the formula (1 ),
for
example enantiomers and diastereomers, and mixtures of two or more stereo-
isomeric forms, for example mixtures of enantiomers and/or diastereomers, in
all ratios. The invention thus relates to enantiomers in enantiomerically pure
form, both as levorotatory and dextrorotatory antipodes, in the form of
racemates and in the form of mixtures of the two enantiomers in all ratios.
The
invention likewise relates to diastereomers in diastereomerically pure form
and
in the form of mixtures in all ratios. In the presence of cis/trans isomerism,
the
invention relates to both the cis form and the trans form and mixtures of
these
forms in all ratios. Individual stereoisomers can be prepared, if desired, by
use
of stereochemically homogeneous starting substances in the synthesis, by
stereoselective synthesis or by separation of a mixture according to customary
methods, for example by chromatography, crystallization or by chromatography
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on chiral phases. If appropriate, derivatization can be carried out before
separation of stereoisomers. A stereoisomer mixture can be separated at the
stage of the nicotinamide derivatives of the formula (1 ) or at the stage of a
starting substance or of an intermediate in the course of the synthesis.
The compounds of the formula (1 ) according to the invention can moreover
contain mobile hydrogen atoms, i.e. be present in various tautomeric forms.
The present invention also relates to all tautomers of the compounds of the
formula (1 ).
The present invention ,furthermore includes other types of derivatives of
nicotinamide derivatives of the formula (1 ), for example, solvates such as
hydrates and polymorphs, i.e. the various different crystalline structures of
the
nicotinamide derivatives according to the present invention.
The present invention also includes all suitable isotopic variations of the
nicotinamide derivatives of the formula (1 ) or a pharmaceutically acceptable
salt
thereof. An isotopic variation of the nicotinamide derivatives of the formula
(1 )
or a pharmaceutically acceptable salt thereof is defined as one in which at
least
one atom is replaced by an atom having the same atomic number but an
atomic mass different from the atomic mass usually found in nature. Examples
of isotopes that can be incorporated into the nicotinamide derivatives of the
formula (1 ) and pharmaceutically acceptable salts thereof include isotopes of
hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine such as 2H,
sH~ ~sC~ 14~~ 15N~ 170 1aO~ ~ 355 ~$F and 36CI, respectively. Certain isotopic
variations of the nicotinamide derivatives of the formula (1 ) and
pharmaceutically acceptable salts thereof, for example, those in which a
radioactive isotope such as 3H or ~4C is incorporated, are useful in drug
and/or
substrate tissue distribution studies. Tritiated, i.e. 3H, and carbon-14, i.e.
~4C,
isotopes are particularly preferred for their ease of preparation and
detectability.
Further, substitution with isotopes such as deuterium, i.e. 2H, may afford
certain
therapeutic advantages resulting from greater metabolic stability, for
example,
increased in vivo half-life or reduced dosage requirements and hence may be
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preferred in some circumstances. Isotopic variations of the nicotinamide
derivatives of the formula (1 ) and pharmaceutically acceptable salts thereof
of
this invention can generally be prepared by conventional procedures such as by
the illustrative methods or by the preparations described in the Examples and
Preparations sections hereafter using appropriate isotopic variations of
suitable
reagents.
If appropriate, the presenfi invention also concerns the active metabolites
of the nicotinamide derivatives of the formula (1 ), i.e. the derivatives
which are
formed during the cellular metabolism and that are active on organism. For
example, such metabolites can be glucuronide derivatives, N-oxide derivatives
or sulfonate derivatives of the compounds of the formula (1 ).
According to a further aspect, the present invention concerns mixtures of
nicotinamide derivatives of the formula (1 ), as well as mixtures with or of
their
pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms,
metabolites and/or isotope forms.
According to the present invention, all the here above mentioned forms
of the nicotinamide derivatives of formula (1 ) except the pharmaceutically
acceptable salts (i.e. said solvates, polymorphs, isomeric forms, tautomers,
metabolites and isotope forms), are defined as "derived forms" of the
nicotinamide derivatives of formula (1 ) in what follows (including the
claims).
The nicotinamide derivatives of formula (1 ), their pharmaceutically
acceptable salts and/or derived forms, are valuable pharmaceutical active
compounds, which are suitable for the therapy and prophylaxis of numerous
disorders in which the PDE4 enzymes are involved, in particular the
inflammatory disorders, allergic disorders, respiratory diseases and wounds.
The nicotinamide derivatives of formula (1 ) and their pharmaceutically
acceptable salts and derived forms as mentioned above can be administered
according to the invention to animals, preferably to mammals, and in
particular
to humans, as pharmaceuticals for therapy or prophylaxis. They can be
administered per se, in mixtures with one another or in the form of
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pharmaceutical preparations which permit enteral (gastric) or parenteral (non-
gastric) administration and which as active constituent contain an efficacious
dose of at least one nicotinamide derivative of the formula (1 ), its
pharmaceutically acceptable salts and/or derived forms, in addition to
customary pharmaceutically innocuous excipients and/or additives.
Thus, the present invention also relates to compositions containing a
nicotinamide derivative of formula (1 ) and/or their pharmaceutically
acceptable
salts and/or derived forms, together with customary pharmaceutically innocuous
excipients and/or additives. Such compositions are prepared according to well-
known methods compatible with the standard pharmaceutical practice. Said
compositions generally contain from 0.5 % to 60 % in weight of the active
compound and from 40 % to 99.5 % in weight of excipients and/or additives.
According to the present invention, said excipients and/or additives are
agents
well known to the artisan for providing favourable properties in the final
pharmaceutical composition. Typical excipients and/or additives include, but
are
by no mean limited to, acidifying and alkalizing agents, aerosol propellants,
anti-microbial agents (including anti-bacterial, anti-fungal and anti-
protozoa)
agents), antioxidants, buffering agents, chelating agents, dermatologically
active agents, dispersing agents, suspending agents, emollients, emulsifying
agents, penetration enhancers, preservatives, sequestering agents, solvents,
stabilizers, stiffening agents, sugars, surfactants and flavouring agents.
Furthermore, said compositions are prepared in a form compatible for the
intended route of administration, which is used for any given patient, as well
as
appropriate to the disease, disorder or condition for which any given patient
is
being treated. Suitable routes of administration that can be envisaged are
enteral and parenteral routes of administration, such as for example the
topical,
oral, intranasal, pulmonary, rectal, intra-veinous, intra-arterial, intra-
peritoneal,
intra-theca), intra-ventricular, intra-urethra), intra-sterna), intra-cranial,
intra-
muscular, subcutaneous or ocular routes.
When an administration by the oral route is intended, the nicotinamide
derivatives of formula (1 ), their pharmaceutically acceptable salts and/or
their
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derived forms, can be administered in the form of tablets, capsules, multi-
particulates, gels, films, ovules, elixirs, solutions or suspensions, which
may
contain flavouring or colouring agents, for immediate-, delayed-, modified-,
sustained-, . pulsed- or controlled-release applications. The nicotinamide
derivatives of formula (1 ), their pharmaceutically acceptable salts and/or
their
derived forms, may also be administered as fast-dispersing or fast-dissolving
dosage forms or in the form of a high energy dispersion or as coated
particles.
Suitable formulations of the nicotinamide derivatives of formula (1 ), their
pharmaceutically acceptable salts and/or their derived forms, may be in coated
or uncoated form, as desired.
Such solid pharmaceutical compositions, for example, tablets, may
contain excipients such as rnicrocrystalline cellulose, lactose, sodium
citrate,
calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably
corn, potato or tapioca starch), disintegrants such as sodium starch
glycollate,
croscarmellose sodium and certain complex silicates, and granulation binders
such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate
and talc may be included. ,
As a general example, a formulation of the tablet could typically contain
between about 0.01 mg and 500 mg of active compound whilst tablet fill
weights may range from 50 mg to 1000 mg. The tablets may be manufactured
by a standard process, for example by direct compression or by a wet or dry
granulation process. The tablet cores may be coated with appropriate
overcoats.
Solid compositions of a similar type may also be employed as fillers in
gelatin or HPMC capsules. Preferred excipients in this regard include lactose,
starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
For aqueous suspensions and/or elixirs, the nicotinamide derivatives of the
formula (1 ), their pharmaceutically acceptable salts and/or their derived
forms,
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may be combined with various sweetening or flavouring agents, colouring
matter or dyes, with emulsifying and/or suspending agents and with diluents
such as water, ethanol, propylene glycol and glycerin, and combinations
thereof.
The nicotinamide derivatives of the formula (1 ), their pharmaceutically
acceptable salts and/or their derived forms, can also be administered by
injection, for example, intravenously, intra-arterially, intraperitoneally,
intrathecally, intraventricularly, intraurethrally, intrasternally,
intracranially,
intramuscularly or subcutaneously, or they may be administered by infusion or
needleless injection techniques. For such administration they are best used in
the form of a sterile aqueous solution which may contain other substances, for
example, enough salts or glucose to make the solution isotonic with blood. The
aqueous solutions should be suitably buffered (preferably to a pH of from 3 to
9), if necessary. The preparation of such formulations under sterile
conditions is
readily accomplished by standard - pharmaceutical techniques well-known to
those skilled in the art.
For both oral administration and injection to human patients, the daily
dosage level of the nicotinamide derivatives of the formula (1 ), their
pharmaceutically acceptable salts and/or their derived forms, will usually be
from 0.001 mg/kg to 100 mg/kg (in single or divided doses).
The nicotinamide derivatives of the formula (1 ), their pharmaceutically
acceptable salts and/or their derived forms, can also be administered intra-
nasally or by inhalation and are conveniently delivered in the form of a dry
powder inhaler or an aerosol, spray presentation from a pressurised container,
pump, spray, atomiser or nebuliser, with or without the use of a suitable
propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-
tetrafluoroethane (HFA 134A [trade mark) or 1,1,1,2,3,3,3-heptafluoropropane
(HFA 227EA (trade mark]), carbon dioxide or other suitable gas. In the case of
a pressurised aerosol, the dosage unit may be determined by providing a valve
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to deliver a metered amount.'The pressurised container, pump, spray, atomiser
or nebuliser may contain a solution or suspension of the active compound, e.g.
using a mixture of ethanol and the propellant as the solvent, which may
additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and
cartridges
(made, for example, from gelatin) for use in an inhaler or insufflator may be
formulated to contain a powder mix of a nicotinamide derivative of the formula
(1 ) and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each
metered dose or "puff' contains from 1 pg to 4000 pg of a nicotinamide
derivative of the formula (1 ) for delivery to the patient. The overall daily
dose
with an aerosol will be in the range of from 1 ~,g to 20 mg, which may be
administered in a single dose or, more usually, in divided doses throughout
the
day.
The nicotinamide derivatives of the formula (1 ), their pharmaceutically
acceptable salts and/or their derived forms, can also be administered
topically,
or transdermally, in the form of creams, gels, suspensions, lotions,
ointments,
dusting powders, sprays, foams, mousses, drug-incorporated dressings,
solutions, sponges, fibres, microemulsions, films, skin patches, ointments
such
as petrolatum or white soft paraffin based ointments or via a skin patch or
other
device. Penetration enhancers may be used, and the compound may be used
in combination with cyclodextrins. In addition, the compound may be delivered
using iontophoresis, electropration, phonophoresis or sonophoresis. They could
be administered directly onto a wound site. They could be incorporated into a
coated suture. For example they can be incorporated into a lotion or cream
consisting of an aqueous or oily emulsion of mineral oils, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-
octyldodecanol, benzyl alcohol, water, polyethylene glycols and/or liquid
paraffin, or they can be incorporated into a suitable ointment consisting of
one
or more of the following : mineral oil, liquid petrolatum, white petrolatum,
propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying
wax and water, or as hydrogel with cellulose or polyacrylate derivatives or
other
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viscosity modifiers, or as a dry powder or liquid spray or aerosol with
butane/propane, HFA, CFC,~C02 or other suitable propellant, optionally also
including a lubricant such as sorbitan trioleate, or as a drug-incorporated
dressing either as a tulle dressing, with white soft paraffin or polyethylene
glycols impregnated gauze dressings or with hydrogel, hydrocolloid, alginate
or
film dressings.
For topical administration to human patients with acute/surgical wounds
or scars, the daily dosage level of the compounds, in suspension or other
formulation, could be from 0.01 to 50 mg/ml, preferably from 0.3 to 30 mg/ml.
The dosage will vary with the size of the wound, whether or not the wound is
open or closed or partially closed, and whether or not the skin is intact.
Alternatively, the nicotinamide derivatives of the formula (1 ), their
pharmaceutically acceptable, salts and/or their derived forms, can be rectally
administered, for example in the form of a suppository of a gel, although
other
forms can be considered.
They may also be administered by the ocular route, in particular for
ocular scarring. For ophthalmic use, the compounds can be formulated as
micronised suspensions in isotonic, pH adjusted, sterile saline, or,
preferably,
as solutions in isotonic, pH adjusted, sterile saline, optionally in
combination
with a preservative such as a benzylalkonium chloride. Alternatively, they may
be formulated in an ointment such as petrolatum.
The various pharmaceutical formulations as decribed here above are
also detailed in "Pharmacie galenique" from A. Lehir (Ed. Mason, 1992, 2~d
edition).
The physician in any event will determine the actual dosage which will be
most suitable for any individual patient and it will vary with the age,
weight,
health state and sex of the patient as well as the severity of the disease,
disorder or condition to treat, the optional combination with other
treatment(s),
the response of the particular patient and in general any factor peculiar to
the
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concerned disease, disorder or condition and to the patient. Thus, the daily
dose among men may usually contain from 50 mg to 5 g of active compound
for administration singly or two or more at a time, as appropriate. There can,
of
course, be . individual instances where higher or lower dosage ranges are
merited and such are within the scope of this invention.
According to the present invention, the nicotinamide derivatives of the
formula (1 ), their pharmaceutically acceptable salts and/or their derived
forms,
may also be used in combination with a cyclodextrin. Cyclodextrins are known
to form inclusion and non-inclusion complexes with drug molecules. Formation
of a drug-cyclodextrin complex may modify the solubility, dissolution rate,
bioavailability and/or stability property of a drug molecule. Drug-
cyclodextrin
complexes are generally useful for most dosage forms and administration
routes. As an alternative to direct complexation with the drug the
cyclodextrin
may be used as an auxiliary additive, e.g. as a carrier, diluent or
solubiliser. oc-,
Vii- and y-cyclodextrins are most commonly used and suitable examples are
described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
According to another embodiment of the present invention, the
nicotinamide derivatives of the formula (1 ), or pharmaceutically acceptable
salts, derived forms or compositions thereof, can also be used as a
combination with one or more additional therapeutic agents to be co-
administered to a patient to obtain some particularly desired therapeutic end
result. The second and more additional therapeutic agents may also be a
nicotinamide derivatives of fihe formula (1 ), or pharmaceutically acceptable
salts, derived forms or compositions thereof, or one or more PDE4 inhibitors
known in the art. More typically, the second and more therapeutic agents will
be
selected from a different class of therapeutic agents.
As used herein, the terms "co-administration", "co-administered" and "in
combination with", referring to the nicotinamide derivatives of formula (1 )
and
one or more other therapeutic agents, is intended to mean, and does refer to
and include the following
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~ simultaneous administration of such combination of nicotinamide
derivatives) and therapeutic agents) to a patient in need of treatment,
when such components are formulated together into a single dosage
form which releases said components at substantially the same time to
said patient,
~ substantially simultaneous administration of such combination of
nicotinamide derivatives) and therapeutic agents) to a patient in need
of treatment, when such components are formulated apart from each
other into separate dosage forms which are taken at substantially the
same time by said patient, whereupon said components are released at
substantially the same time to said patient,
~ sequential administration of such combination of nicotinamide
derivatives) and therapeutic agents) to a patient in need of treatment,
when such components are formulated apart from each other into
separate dosage forms which are taken at consecutive times by said
patient with a significant time interval between each administration,
whereupon said components are released at substantially different times
to said patient; and
~ sequential administration of such combination of nicotinamide
derivatives) and therapeutic agents) to a patient in need of treatment,
when such components are formulated together into a single dosage
form which releases said components in a controlled manner whereupon
they are concurrently, consecutively, and/or overlappingly administered
at the same and/or diffierent times by said patient.
Suifiable examples of other therapeutic agents which may be used in
combination with the nicotinamide derivatives of the formula (1 ), or
pharmaceutically acceptable salts, derived forms or compositions thereof,
include, but are by no mean limited to
(a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein
(FLAP) antagonists,
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(b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4,
and LTE4,
(c) Histaminic receptor antagonists including H1 and H3 antagonists,
(d) a~- and ~a2-adrenoceptor Aagonist vasoconstrictor sympathomimetic agents
for decongestant use,
(e) Muscarinic M3 receptor antagonists or anticholinergic agents,
(f) ~3~-adrenoceptor agonists,
(g) Theophylline,
(h) Sodium cromoglycate,
(i) COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors,
(j) Oral or inhaled Glucocorticosteroids,
(k) Monoclonal antibodies active against endogenous inflammatory entities,
(I) Anti-tumor necrosis factor (anti-TNF-a) agents,
(m)Adhesion molecule inhibitors including VLA-4 antagonists,
(n) Kinin-B~ - and B2-receptor antagonists,
(o) Immunosuppressive agents,
(p) Inhibitors of matrix metalloproteases (MMPs),
(q) Tachykinin NK~, NK2 and NK3 receptor antagonists,
(r) Elastase inhibitors,
(s) Adenosine A2a receptor agonists,
(t) Inhibitors of urokinase,
(u) Compounds that act on dopamine receptors, e.g. D2 agonists and
(v) Modulators of the NFK~3 pathway, e.g. IKK inhibitors,
According to the present invention, combination of the nicotinamide
derivatives of formula (1 ) with
- muscarinic M3 receptor agonists or anticholinergic agents including
in particular ipratropium salts, namely bromide, tiotropium salts,
namely bromide, oxitropium salts, namely bromide, perenzepine, and
telenzepine,
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- X32-adrenoceptor agonists including albutarol, salbutamol, formoterol
and salmeterol,
- glucocorticosteroids, in particular inhaled glucocorticosteroids with
reduced systemic 'side effects, including prednisone, prednisolone,
flunisolide, triamcinolone acetonide, beclomethasone dipropionate,
budesonide, fluticasone propionate, and mometasone furoate,
- or adenosine A2a receptor agonists,
are preferred.
It is to be appreciated that all references herein to treatment include
curative, palliative and prophylactic treatment. The description, which
follows,
concerns the therapeutic applications to which the nicotinamide derivatives of
formula (1 ) may be put.
The nicotinamide derivatives of formula (1 ) inhibit the PDE4 isozyme and
thereby have a wide range of therapeutic applications, as described further
below, because of the essential role, which the PDE4 family of isozymes plays
in the physiology of all mammals. The enzymatic role performed by the PDE4
isozymes is the intracellular hydrolysis of adenosine 3',5'-monophosphate
(CAMP) within pro-inflammatory leukocytes. cAMP, in turn, is responsible for
mediating the effects of numerous hormones in the body, and as a
consequence, PDE4 inhibition plays a significant role in a variety of
physiological processes. There is extensive literature in the art describing
the
effects of PDE inhibitors on various inflammatory cell responses, which in
addition to cAMP increase, include inhibition of superoxide production,
degranulation, chemotaxis and tumor necrosis factor (TNF) release in
eosinophils, neutrophils and monocytes.
Therefore, a further aspect of the present invention relates to the
nicotinamide derivatives of formula (1 ), or pharmaceutically acceptable
salts,
derived forms or compositions thereof, for use in the treatment of diseases,
disorders, and conditions in which the PDE4 isozymes are involved. More
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specifically, the present invention also concerns the nicotinamide derivatives
of
formula (1 ), or pharmaceutically acceptable salts, derived forms or
compositions thereof, for use in the treatment of diseases, disorders, and
conditions selected from the group consisting of
~ asthma of whatever type, etiology, or pathogenesis, in particular asthma
that is a member selected from the group consisting of atopic asthma,
non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated
asthma, bronchial asthma, essential asthma, true asthma, intrinsic
asthma caused by pathophysiologic disturbances, extrinsic asthma
caused by environmental factors, essential asthma of unknown or
inapparent cause, non-atopic asthma, bronchitic asthma,
emphysematous asthma, exercise-induced asthma, allergen induced
asthma, cold air induced asthma, occupational asthma, infective asthma
caused by bacterial, fungal, protozoal, or viral infection, non-allergic
asthma, incipient asthma and wheezy infant syndrome,
~ chronic or acute bronchoconstriction, chronic bronchitis, small airways
obstruction, and emphysema,
~ obstructive or inflammatory airways diseases of whatever type, etiology,
or pathogenesis, in particular an obstructive or inflammatory airways
disease that is a member selected from the group consisting of chronic
eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD),
COPD that includes chronic bronchitis, pulmonary emphysema or
dyspnea associated therewith, COPD that is characterized by
irreversible, progressive airways obstruction, adult respiratory distress
syndrome CARDS) and exacerbation of airways hyper-reactivity
consequent to other drug therapy,
~ pneumoconiosis of whatever type, etiology, or pathogenesis, in particular
pneumoconiosis that is a member selected from the group consisting of
aluminosis or bauxite workers' disease, anthracosis or miners' asthma,
asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis
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caused by inhaling the dust from ostrich feathers, siderosis caused by
the inhalation of iron particles, silicosis or grinders' disease, byssinosis
or
cotton-dust asthma and talc pneumoconiosis,
~ bronchitis of whatever type, etiology, or pathogenesis, in particular
bronchitis that is a member selected from the group consisting of acute
bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis,
catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious
asthmatic bronchitis, productive bronchitis, staphylococcus or
streptococcal bronchitis and vesicular bronchitis,
~ bronchiectasis of whatever type, etiology, or pathogenesis, in particular
bronchiectasis that is a member selected from the group consisting of
cylindric bronchiectasis, sacculated bronchiectasis, fusiform
bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry
bronchiectasis and foljicular bronchiectasis,
~ seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis of
whatever type, etiology, or pathogenesis, in particular sinusitis that is a
member selected from the group consisting of purulent or nonpurulent
sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary, or
sphenoid sinusitis,
~ rheumatoid arthritis of whatever type, etiology, or pathogenesis, in
particular rheumatoid arthritis that is a member selected from the group
consisting of acute arthritis, acute gouty arthritis, chronic inflammatory
arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis,
proliferative arthritis, psoriatic arthritis and vertebral arthritis,
~ gout, and fever and pain associated with inflammation,
~ an eosinophil-related disorder of whafiever type, etiology, or
pathogenesis, in particular an eosinophil-related disorder that is a
member selected from the group consisting of eosinophilia, pulmonary
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infiltration eosinophilia, Loffler's syndrome, chronic eosinophilic
pneumonia, tropical pulmonary eosinophilia, bronchopneumonic
aspergillosis, aspergilloma, granulomas containing eosinophils, allergic
granulomatous angiitis or Churg-Strauss syndrome, polyarteritis nodosa
(PAN) and systemic necrotizing vasculitis,
~ atopic dermatitis, allergic dermatitis, contact dermatitis, or allergic or
atopic eczema,
~ urticaria of whatever type, etiology, or pathogenesis, in particular
urticaria that is a member selected from the group consisting of immune-
mediated urticaria, complement-mediated urticaria, urticariogenic
material-induced urticaria, physical agent-induced urticaria, stress-
induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria,
angioedema, cholinergic urticaria, cold urticaria in the autosomal
dominant form or in the acquired form, contact urticaria, giant urticaria
and papular urticaria,
~ conjunctivitis of whatever type, etiology, or pathogenesis, in particular
conjunctivitis that is a member selected from the group consisting of
actinic conjunctivitis, 'acute catarrhal conjunctivitis, acute contagious
conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic
catarrhal conjunctivitis, purulent conjunctivitis and vernal conjunctivitis,
~ uveitis of whatever type, etiology, or pathogenesis, in particular uveitis
that is a member selected from the group consisting of inflammation of
all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis,
granulomatous uveitis, nongranulomatous uveitis, phacoantigenic
uveitis, posterior uveitis, choroiditis; and chorioretinitis,
~ psoriasis,
~ multiple sclerosis of whatever type, etiology, or pathogenesis, in
particular multiple sclerosis that is a member selected from the group
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consisting of primary progressive multiple sclerosis and relapsing
remitting mulfiiple sclerosis,
~ autoimmune/inflammatory diseases of whatever type, etiology, or
pathogenesis, in particular an autoimmune/inflammatory disease that is
a member selected from the group consisting of autoimmune
hematological disorders, hemolytic anemia, aplastic anemia, pure red
cell anemia, idiopathic thrombocytopenic purpura, systemic lupus
erythematosus, polychondritis, scleroderma, Wegner's granulomatosis,
dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-
Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel
diseases, ulcerative colitis, endocrin opthamopathy, Grave's disease,
sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary
biliary cirrhosis, juvenile diabetes or diabetes mellitus type I,
keratoconjunctivitis sicca, epidemic keratoconjunctivitis, diffuse
interstitial
pulmonary fibrosis or interstitial lung fibrosis, idiopathic pulmonary
fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic
syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome,
minimal change nephropathy, inflammatory/hyperproliferative skin
diseases, benign familial pemphigus, pemphigus erythematosus,
pemphigus foliaceus, and pemphigus vulgaris,
prevention of allogeneic graft rejection following organ transplantation,
~ inflammatory bowel disease (IBD) of whatever type, etiology, or
pathogenesis, in particular inflammatory bowel disease that is a member
selected from the group consisting of collagenous colitis, colitis
polyposa, transmural colitis, ulcerative colitis and Crohn's disease (CD),
septic shock of whatever type, etiology, or pathogenesis, in particular
septic shock that is a member selected from the group consisting of
renal failure, acute renal failure, cachexia, malarial cachexia,
hypophysial cachexia, uremic cachexia, cardiac cachexia, cachexia
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suprarenalis or Addison's disease, cancerous cachexia and cachexia as
a consequence of infection by the human immunodeficiency virus (HIV),
~ liver injury,
~ pulmonary hypertension of whatever type, etiology or pathogenesis
including primary pulmonary hypertension l essential hypertension,
pulmonary hypertension secondary to congestive heart failure,
pulmonary hypertension secondary to chronic obstructive pulmonary
disease, pulmonary venous hypertension, pulmonary arterial
hypertension and hypoxia-induced pulmonary hypertension,
~ bone loss diseases, primary osteoporosis and secondary osteoporosis,
~ central nervous system disorders of whatever type, etiology, or
pathogenesis, in particular a central nervous system disorder that is a
member selected from the group consisting of depression, Alzheimers
disease, Parkinson's disease, learning and memory impairment, tardive
dyskinesia, drug dependence, arteriosclerotic dementia and dementias
that accompany Huntington's chorea, Wilson's disease, paralysis
agitans, and thalamic atrophies,
~ infection, especially infection by viruses wherein such viruses increase
the production of TNF-a in their host, or wherein such viruses are
sensitive to upregulation of TNF-a in their host so that their replication or
other vital activities are adversely impacted, including a virus which is a
member selected from the group consisting of HIV-1, HIV-2, and HIV-3,
cytomegalovirus (CMV), influenza, adenoviruses and Herpes viruses
including Herpes zoster and Herpes simplex,
~ yeast and fungus infections wherein said yeast and fungi are sensitive to
upregulation by TNF-a or elicit TNF-a production in their host, e.g.,
fungal meningitis, particularly when administered in conjunction with
other drugs of choice for the treatment of systemic yeast and fungus
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infections, including but are not limited to, polymixins, e.g. Polymycin B,
imidazoles, e.g. clotrimazole, econazole, miconazole, and ketoconazole,
triazoles, e.g. fluconazole and itranazole as well as amphotericins, e.g.
Amphotericin B and liposomal Amphotericin B,
~ ischemia-reperfusion injury, ischemic heart disease, autoimmune
diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV
infections, lupus erythematosus, kidney and ureter disease, urogenital
and gastrointestinal disorders and prostate diseases,
~ reduction of scar formation in the human or animal body, such as scar
formation in the healing of acute wounds, and
~ psoriasis, other dermatological and cosmetic uses, including
antiphlogistic, skin-softening, skin elasticity and moisture-increasing
activities.
A still further aspect of the present invention also relates to the use of
the nicotinamide derivatives of formula (1 ), or pharmaceutically acceptable
salts, derived forms or compositions thereof, for the manufacture of a drug
having a PDE4 inhibitory activity. In particular, the present inventions
concerns
the use of the nicotinamide derivatives of formula (1 ), or pharmaceutically
acceptable salts, derived forms or compositions thereof, for the manufacture
of
a drug for the treatment of inflammatory, respiratory, allergic and scar-
forming
diseases, disorders, and conditions and more precisely for the treatment of
diseases, disorders, and conditions that are listed above.
As a consequence, the present invention provides a particularly
interesting method of treatment of a mammal, including a human being,
including treating said mammal with an effective amount of a nicotinamide
derivative of formula (1 ), or a pharmaceutically acceptable salt, derived
form or
composition thereof. More precisely, the present invention provides a
particularly interesting method of treatment of a mammal, including a human
being, to treat an inflammatory, respiratory, allergic and scar-forming
disease,
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disorder or condition, including treating said mammal with an effective amount
of a nicotinamide derivative of formula (1 ), its pharmaceutically acceptable
salts
and/or derived forms.
The following examples illustrate the preparation of the nicotinamide
derivatives of the formula (1 )
EXAMPLE 1 2-(4-Fluoro-phenoxy)-N-f4-f(2-hydroxy-3-methyl-benzoyl
amino)-methyll-benzyl~-nicotinamide
O
N w H
H I ~ N
N Q ~ ~Me
O OH
I
F
A solution of 2-Hydro~ey-3-methylbenzoic acid (118 mg, 0.773 mmol), 1-
hydroxybenzotriazole (157 mg, 1.16 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (193 mg, 1.01 mmol), N-(4-aminomethyl-
benzyl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide hydrochloride (300 mg,
0.773 mmol) (see Preparation 3) and N-methyl morpholine (0.17 ml,
1.55 mmol) in N,N-dimethylformamide (6 ml) was stirred under nitrogen at room
temperature for 18 hours. The mixture was then partitioned between ethyl
acetate (10 ml) and water (10 ml). The organic phase was separated, washed
with a saturated aqueous solution of sodium chloride (10 ml) and dried over
anhydrous magnesium sulphate. The solvent was then removed in vacu~ and
the residue was triturated with diethylether (3-fold 10 ml) giving 2-(4-fluoro-
phenoxy)-N-~4-[(2-hydroxy-3-methyl-benzoylamino)-methyl]-benzyl}-
nicotinamide (80 mg) as an off-white foam.
~H NMR (300MHz, DMSO-d6) : 8 = 13.11 (1 H, s), 8.32-8.42 (1 H, m), 8.15-8.21
(1 H, m), 8.08-8.14 (1 H, d), 7.66-7.75 (1 H, m), 7.10-7.60 (1 OH, m), 6.73-
6.81
(1 H, t), 4.37-4.56 (4H, m), 2.16 (3H, s) ppm.
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LRMS (thermospray) : m/z [M+H]+ 486, [M+NH4]+ 503
EXAMPLES 2-15
The compounds of the following tabulated examples (Table 1 ) of the general
formula
O
H
N O ~ N
,, O
F
were prepared by a similar method to that of Example 1 using the appropriate
amine and carboxylic acid as the starting material.
TABLE 1
Example N° Starting
Amine R~ R4
Pre . N°
F
2 3 H \
I
OH
' F
3 3 H
OH
Me
4 3 H
OH
5 3 H
OH
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/
6 3 H
OH
OH
7 3 H
Me
3 3 H
OH
9 3 H
OH
Me
Me
3 H
OH
11 ~'2 6 F \
OH
12~ 6 F ~OH
OH
13'2 6 F
The organic phase was washed sequentially with water and a saturated
aqueous solution of sodium hydrogen carbonate in the work-up procedure.
2 The compound was purified by flash column chromatography on silica gel
eluting with a solvent gradient of pentane : ethyl acetate (95 : 5 changing to
5 70 : 30, by volume).
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Example 2
~ H NMR (300 MHz, DMSO-d6) : b = 11.28 (1 H, s), 8.86-8.92 (1 H, m), 8.73-8.85
(1 H, m), 8.10-8.22 (2H, m), 7.16-7.36 (1 OH, m), 6.63-6.76 (2H, m), 4.47-4.56
(2H, d), 4.40-4.46 (2H, d) ppm.
LRMS (thermospray) : m/z [M+H]+ 490, [M+NH4]+ 507
Example 3
~H NMR (300MHz, DMSO-d~): 8 = 12.20 (1 H, s), 9.23-9.11 (1 H, m), 8.83-8.92
(1 H, m), 8.17-8.21 (1 H, m), 8.10-8.15 (2H, m), 7.67-7.75 (1 H, m), 7.18-7.33
(10H, m), 6.86-6.96 (2H, m), 4.42-4.51 (4H, m) ppm.
LRMS (thermospray) : m/z [M+H]+ 490, [M+NH4]+ 507
Example 4
~H NMR (300MHz, DMSO-d6): ~ = 9.46 (1 H, s), 8.83-8.92 (1 H, t), 8.75-8.82 (1
H,
t), 8.16-8.20 (1 H, d), 8.09-8.14 (1 H, d), 7.15-7.32 (11 H, m), 7.06-7.14 (1
H, d),
4.43-4.51 (2H, d), 4.34-4.42 (2H, d), 2.13 (3H, s) ppm.
LRMS (thermospray) : m/z [M+H]+ 486, [M+NH4]+ 503
Example 5
~H NMR (300MHz, CDCI3): 8 = 8.54-8.61 (1 H, d), 8.23-8.32 (1 H, m), 8.17-8.23
(1 H, m), 7.61-7.80 (1 H, m), 7.35-7.40 (2H, m), 7.02-7.30 (9H, m), 6.90-7.00
(1 H, m), 6.70-6.78 (1 H, m), 4.60-4.70 (2H, d), 4.48-4.59 (2H, d) ppm.
LRMS (thermospray) : m/z [M+H]+ 472, [M+NH4]+ 489.
Example 6
~H NMR (300MHz, CDCI3) : 8 = 12.02-12.50 (1 H, brs), 8.53-8.70 (1 H, brs),
8.10-8.26 (2H, brs), 6.92-7.50 (12H, m), 6.63-6.88 (2H, m), 4.56-4.77 (4H,
2xm)
ppm.
LRMS (thermospray) : m/z [M+H]+ 472, [M+NH4]+ 489.
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Example 7
~H NMR (300MHz, DMSO-d6) : 8 = 9.93 (1 H, s), 8.84-8.91 (1 H, t), 8.68-8.76
(1 H, t), 8.17-8.21 (1 H, m), 8.10-8.15 (1 H, d), 7.69-7.76 (2H, d), 7.18-7.33
(9H,
m), 6.74-6.81 (2H, d), 4.44-4.52 (2H, d), 4.37-4.43 (2H, d) ppm.
LRMS (thermospray) : m/z [M+H]+ 472, [M+NH4]+ 489.
Example 8
~H NMR (300MHz, DMSO-d6): 8 = 12.45-12.60 (1 H, brs), 9.17-9.25 (1 H, t),
8.84-8.92 (1 H, t), 8.16-8.20 (1 H, d), 8.09-8.14 (1 H, d), 7.72-7.78 (1 H,
d), 7.16-
7.34 (9H, m), 6.67-6.73 (2H, m), 4.40-4.58 (4H, 2xd), 2.25 (3H, s) ppm.
LRMS (thermospray) : m/z [M+H]+ 486, [M+NH4]+ 503
Example 9
~H NMR (300MHz, DMSO-ds): ~ = 9.43 (1 H, s), 8.87-8.96 (1 H, t), 8.60-8.67 (1
H,
t), 8.16-8.21 (1 H, d), 8.10-8.15 (1 H, d), 7.28-7.34 (1 H, d), 7.20-7.28 (8H,
m),
6.96-7.03 (1 H, t), 6.80-6.86 (1 H, d), 6.73-6.77 (1 H, d), 4.47-4.54 (2H, d),
4.34-
4.40 (2H, d), 2.07 (3H, s) ppm.
LRMS (thermospray) : m/z [M+H]+ 486, [M+NH4]+ 503
Example 10
~H NMR (300MHz, DMSO-d6): 8 = 12.23 (1 H, s), 9.18-9.26 (1 H, t), 8.82-8.92
(1 H, t), 8.15-8.20 (1 H, d), 8.10-8.15 (1 H, d), 7.69 (1 H, s), 7.12-7.34
(10H, m),
6.77-6.81 (1 H, d), 4.42-4.54 (4H, 2xd), 2.20 (3H, s) ppm.
LRMS (thermospray) : m/z [M'+H]+ 486, [M+NH4]+ 503
Example 11
~H NMR (400MHz, DMSO-d6): s = 9.24-9.31 (1 H, m), 8.92-9.00 (1 H, m), 8.18-
8.20 (1 H, d), 8.02-8.07 (1 H, dd), 7.83-7.87 (1 H, d), 7.35-7.40 (1 H, t),
7.18-7.35
(8H, m), 6.83-6.92 (2H, t), 4.42-4.56 (4H, m) ppm.
LRMS (electrospray) : m/z [M+Na]+ 512, [M-H]+ 488.
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Example 12
~H NMR (400MHz, DMSO-d6):8 = 8.93-9.00 (1 H, m), 8.13-8.22 (2H, m), 8.02-
8.08 (1 H, m), 7.14-7.27 (8H, m), 5.38-5.43 (1 H, t), 4.43-4.51 (2H, d), 4.21-
4.27
(2H, d), 3.79-3.84 (2H, d) ppm.
LRMS (electrospray) : m/z [M-H]+ 426.
Example 13
~H NMR (400MHz, DMSO-d6): b = 9.89 (1 H, s), 8.90-8.98 (1 H, t), 8.64-8.73 (1
H,
t), 8.19-8.21 (1 H, d), 8.02-8.06 (1 H, dd), 7.70-7.77 (2H, d), 7.24-7.30 (2H,
d),
7.17-7.23 (6H, d), 6.73-6.79 (2H, d), 4.42-4.48 (2H, d), 4.36-4.40 (2H, d)
ppm.
LRMS (electrospray) : m/z [M+Na]+ 512, [M-H]+ 488.
EXAMPLE 14 3-~3-f4-((3-Hydroxy-benzoylamino)-methyll-benzyl
carbamoyl'>'-pyridin-2-yloxyl-benzoic acid ethyl ester
O
I
N w H
H I ~ N
N O v ~OH
O
i
I O~Me
O
3-Hydroxy-benzoic acid (27 mg, 0.19 mmol), 1-hydroxybenzotriazole (31 mg,
0.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(45 mg, 0.23 mmol) were added to a solution of 3-[3-(4-aminomethyl-
benzylcarbamoyl)-pyridin-2-yloxy]-benzoic acid ethyl ester hydrochloride
(100 mg, 0.19 mmol) (see Preparation 9) and N-methyl morpholine (0.11 ml,
0.97 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred
at room temperature under a nitrogen atmosphere for 18 hours, concentrated in
vaeuo and the residue partitioned between dichloromethane (20 ml) and water
(20 ml). The organic phase was separated, washed with a saturated aqueous
solution of sodium chloride (20 ml), dried over anhydrous magnesium sulphate
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and concentrated under reduced pressure. The residue was then purified by
flash column chromatography on silica gel eluting with a solvent gradient of
dichloromethane : methanol (99 : 1 changing to 98 : 1, by volume) giving 3-(3-
~4-[(3-hydroxy-benzoylamino)-methyl]-benzylcarbamoyl}-pyridin-2-yloxy)-
benzoic acid ethyl ester (45 mg) as an off-white foam.
~H NMR (400MHz, CDCI3): & = 8.54-8.60 (1 H, d), 8.21-8.38 (2H, t + brs), 8.17-
8.20 (1 H, d), 7.86-7.92 (1 H, d) , 7.78 (1 H, s), 7.41-7.48 (1 H, t), 7.28-
7.37 (2H,
m), 7.08-7.26 (6H, m), 6.86-6.95 (2H, m), 4.61-4.67 (2H, d), 4.45-4.53 (2H,
d),
4.30-4.37 (2H, quart), 1.31-1.38 (3H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 526, (M+Na]+ 548, [M-H]+ 524.
EXAMPLES 15-18
The compounds of the following tabulated examples (Table 2) of the general
formula
O
N
H I / N R~
N O
O
O~Me
O
were prepared by a similar method to that of Example 14 using the appropriate
carboxylic acid starting material.
TABLE 2
Starting AmineR
Example N 4
Pre . N
OH
15 9 I
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16 ' 9
OH
17 9 ~
OH
OH
18 9
Example 15
~ H NMR (400MHz, CDCI3): 8 = 8.90-9.10 (1 H, brs), 8.49-8.53 (1 H, d), 8.28-
8.34 (1 H, m), 8.13-8.16 (1 H, d), 7.87-7.92 (1 H, d), 7.77 (1 H, s), 7.53-
7.59 (2H,
d), 7.40-7.47 (1 H, t), 7.28-7.33 (1 H, m), 7.14-7.26 (5H, m, partially masked
by
solvent), 7.08-7.13 (1 H, t), 6.75-6.81 (1 H, t), 6.66-6.73 (2H, d), 4.58-4.66
(2H,
d), 4.46-4.52 (2H, d), 4.28-4.34 (2H, quartet), 1.31-1.38 (3H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 526, [M+Na]+ 548, [M-H]+ 524.
Example 16
~H NMR (400MHz, CDCI3): ~ = 9.61 (1 H, s), 8.54-8.60 (1 H, d), 8.14-8.21 (2H,
m), 7.91-7.96 (1 H, d), 7.72-7.74 (1 H, m), 7.43-7.49 (1 H, t), 7.29-7.33 (1
H, d),
7.19-7.24 (2H, m), 7.08-7.18 (4H, m), 6.90-7.00 (2H, m), 6.73-6.80 (2H, m),
4.58-4.63 (2H, d), 4.29-4.39 (4H, m), 3.56 (2H, s), 1.35-1.41 (3H, t) ppm.
LRMS (electrospray) : mlz [M+H]+ 540, [M+Na]+ 562, [M-H]+ 538.
Example 17
'H NMR (400MHz, CDCI3): s 8.52-8.59 (1 H, d), 8.19-8.25 (1 H, m), 8.16-8.19
(1 H, d), 7.90-7.94 (1 H, d), 7.78 (1 H, s), 7.44-7.49 (1 H, t), 7.28-7.32 (1
H, d),
7.18-7.23 (2H, d), 7.04-7.18. (4H, m), 6.64-6.73 (3H, m), 6.28-6.35 (1 H, m),
4.58-4.66 (2H, d), 4.26-4.38 (4H, m), 3.42 (2H, s), 1.33-1.38 (3H, t) ppm.
LRMS (electrospray) : m/z [M-H]+ 538.
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Example 18
~H NMR (400MHz, CDCI3): 8 8.55-8.61 (1 H, d), 8.18-8.23 (1 H, m), 8.15-8.18
(1 H, d), 7.90-7.94 (1 H, d), 7.78 (1 H, s), 7.43-7.49 (1 H, t), 7.26-7.30 (1
H, d),
7.18-7.25 (2H, m), 7.04-7.17 (3H, m), 6.95-7.01 (2H, d), 6.64-6.75 (3H, m),
6.17-6.24 (1 H, m), 4.58-4.68 (2H, d), 4.30-4.40 (4H, m), 3.46 (2H, s), 1.32-
1.40
(3H, t) ppm.
LRMS (electrospray) : m/z [M+H]+ 540, [M+Na]+ 562, [M-H]+ 538.
The following Preparations describe the preparation of certain intermediates
used in the preceding Examples.
PREPARATION 1 ~ (4-Aminomethyl-benzyl)-carbamic acid tart-butyl ester
H2N ~ I ~ N O Me
Me
O Me
A solution of di-tart-butyl-dicarboxylate (4.62 g, 21.2 mmol) dissolved in
dichloromethane (50 ml) was added to a solution of 4-aminomethyl-
benzylamine (14.4 g, 106 mmol) in dichloromethane (50 ml) at 0°C under
an
atmosphere of nitrogen. The reaction mixture was allowed to warm to room
temperature and stirred for 18 hours. The reaction mixture was then washed
sequentially with water (100 ml) and a 10 % aqueous solution of citric acid
(200 ml) and the organic phase disgarded. The pH of the aqueous phase was
then adjusted to pH higher than 8 by addition of 0.88 ammonia and extracted
with dichloromethane (3-fold 200 ml). The combined organic extracts were then
dried over anhydrous magnesium sulphate and the solvent removed in vacuo
giving (4-aminomethyl-benzyl.)-carbamic acid tart butyl ester (4.29 g) as a
white
solid.
~H NMR (400MHz, CDCI3): 8 = 7.22-7.26 (4H, d), 4.80-4.90 (1 H, brs), 4.23-4.30
(2H, m), 3.82 (2H, s), 1.43 (2H, s), 1.38 (2H, s) ppm.
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LRMS (electrospray) : m/z [M-H]+ 237.
PREPARATION 2 : f4-(~~2-(4. -Fluoro-phenoxy)-pyridine-3-carbonyll-amino'~-
methyl)-benzyll-carbamic acid tert-butyl ester
O
N
~ H ( , N O Me
N O ~ ~Me
O Me
W
F
2-(4-Fluoro-phenoxy)-nicotinic acid (see reference Patent application
WO 98/45268) (6.20 g, 26 mmol), 1-hydroxybenzotriazole (5.39 g, 40 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.62 g,
34 mmol) were disolved in N,N-dimethylformamide (50 ml) at room temperature
and (4-aminomethyl-benzyl)-carbamic acid tent-butyl ester (6.28 g, 26 mmol)
(see Preparation 1 ) added followed by addition of N-methyl morpholine (4.4
ml,
40 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at
room temperature for 18 hours, and then partitioned between ethyl acetate
(100 ml) and water (100 ml) and the organic layer separated. The organic
phase was then washed with a saturated aqueous solution of sodium chloride
(100 ml), dried over anhydrous magnesium sulphate and the solvent removed
in vaeuo. The residue was triturated with diethylether (15 ml) giving [4-(~[2-
(4-
fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-
butyl ester (9.52 g) as an off-white solid.
~H NMR (300MHz, CDCI3) : 8 = 8.56-8.76 (1H, m), 8.06-8.14 (2H, m), 6.96-7.40
(9H, m, partialy masked by solvent), 4.58-4.95 (3H, m), 4.20-4.40 (2H, brs),
1.56 (9H, s) ppm.
LRMS (thermospray) : m/z [M+NH4]+ 469.
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PREPARATION 3 N-(4-Aminomethyl-benzyl)- 2-(4-fluoro-phenoxy)-
nicotinamide hydrochloride
O
N
H I ~ +NH3CI
N O
F
[4-({[2-(4-Fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-
carbamic acid tart butyl ester (9.51 g, 21 mmol) (see Preparation 2) was
dissolved in dichloromethane (60 ml) and hydrogen chloride gas bubbled into
the solution at 0°C until the solution became saturated (30 minutes).
The
reaction mixture was then stirred under an atmosphere of nitrogen at room
temperature for a further 1 hour before removal of the solvent in vacuo. The
resultant white precipitate was triturated with diethylether (3-fold 10 ml)
giving
N-(4-aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide
hydrochloride (7.92 g) as a white solid.
'H NMR (300MHz, DMSO-d6) : ~ = 8.96-9.07 (1H, m), 8.40-8.60 (2H, m), 8.17-
8.22 (1 H, d), 8.11-8.16 (1 H, m), 7.36-7.44 (4H, m), 7.18-7.33 (5H, m), 4.43-
4.58
(2H, m, partially masfced by solvent), 3.86-3.99 (2H, m) ppm.
LRMS (thermospray) : m/z [M+H]+ 352.
PREPARATION 4 (4-fi'2-Chloro-5-fluoro-pyridine-3-carbonyl)-aminol-
methyl)-benzyl)-carbamic acid tent-butyl ester
O
F ~ N
H I i N O Me
N CI ~ ~Me
O Me
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2-Chloro-5-fluoro-nicotinic acid (see Preparation 10) (2.0 g, 11.4 mmol), 1-
hydroxybenzotriazole (1.85 g, 13.7 mmol) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (2.62 g, 13.7 mmol) were stirred in N,N-
dimethylformamide (50 ml) at room temperature and (4-aminomethyl-benzyl)-
carbamic acid tart-butyl ester (2.69 g, 11.4 mmol) (see Preparation 1 ) added
followed by addition of N-methyl morpholine (2.5 ml, 22.8 mmol). The reaction
mixture was then stirred under an atmosphere of nitrogen at room temperature
for 18 hours, partitioned between dichloromethane (100 ml) and water (100 ml),
and the organic layer separated. The organic layer was then washed with a
saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous
magnesium sulphate and the solvent removed in vaeuo to give (4-([2-chloro-5-
fluoro-pyridine-3-carbonyl)-amino]-methyl)-benzyl)-carbamic acid tent-butyl
ester
(4.08 g) as a white solid.
~H NMR (400MHz, DMSO-d6) : 8 = 9.10-9.17 (1 H, t), 8.52-8.54 (1 H, d), 7.99
8.04 (1 H, dd), 7.26-7.35 (3H, m), 7.18-7.22 (2H, d), 4.39-4.44 (2H, d), 4.06-
4.11
(2H, d), 1.38 (9H, s) ppm.
LRMS (electrospray) : mlz [M+Na]+ 416, [M-H]+ 392.
PREPARATION 5 : f4-( f5-Fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyll
-amino'~-methyl)-benzyll-carbamic acid terf-butyl ester
O
F
~ H I / N ~ Me
N O ~ ~Me
O Me
~I
F
(4-{[2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-methyl)-benzyl)-carbamic
acid tart-butyl ester (100 mg, 0.29 mmol) (see Preparation 4), 4-fluorophenol
(28 mg, 0.29 mmol) and caesium carbonate (800 mg, 2.5 mmol) were stirred in
N,N-dimethylformamide (10 ml) at 60°C under an atmosphere of nitrogen
for 18
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hours. The reaction mixture was then partitioned between ethyl acetate (20 ml)
and water (20 ml), and the organic layer separated. The organic layer was then
washed with a saturated aqueous solution of sodium chloride (3-fold 10 ml),
the
solvent removed in vacuo and the residue purified by flash column
chromatography on silica gel 'eluting with a solvent gradient of 5:95 changing
to
30:70, by volume, ethyl acetate : pentane to give [4-({[5-fluoro-2-(4-fluoro-
phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tart-butyl
ester (57 mg) as a white foam.
'H NMR (400MHz, DMSO-d6) : ~ = 8.97-9.02 (1 H, t), 8.19-8.21 (1 H, d), 8.03-
8.08 (1 H, dd), 7.30-7.36 (1 H, m), 7.19-7.30 (6H, m), 7.11-7.16 (2H, d), 4.44-
4.50 (2H, d), 4.03-4.08 (2H, d), 1.36 (9H, s) ppm.
LRMS (electrospray) : m/z [M+Na]+ 492, [M-H]+ 468.
PREPARATION 6 : N-(4-Aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-phenoxy)
-nicotinamide hydrochloride
O
F
N ~ _
NH3 CI
N O
i
F
[4-({[5-Fluoro-2-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-
benzyl]-
carbamic acid tent butyl ester (1.62 g, 3.44 mmol) (see Preparation 5) was
dissolved in a 2.25 M solution of hydrochloric acid in methanol (100 ml) and
the
mixture stirred at room temperature under an atmosphere of nitrogen for 4
hours before removing the solvent in vacuo. The residue was dissolved in water
(50 ml), the pH adjusted to pH higher than 8 by addition of sodium hydrogen
carbonate and extracted with dichloromethane (3-fold 50 ml). The combined
organic extracts were dried over anhydrous magnesium sulphate and
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concentrated in vacuo to give N-(4-aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-
phenoxy)-nicotinamide hydrochloride (1.25 mg) as a gum.
PREPARATION 7 (4-f ~(2-Chloro-pyridine-3-carbonyl)-amino)-methyl'~-
benzyl)-carbamic acid tent-butyl ester
O
H I ~ N O Me
N CI ~ ~Me
O Me
2-Chloro-nicotinic acid (2.86 g, 18.2 mmol), 1-hydroxybenzotriazole (3.0 g,
21.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(4.18 g, 21.8 mmol) were dissolved in N,N-dimethylformamide (50 ml) at room
temperature and (4-aminomethyl-benzyl)-carbamic acid tart-butyl ester (4.29 g,
18.2 mmol) (see Preparation 1 ) added followed by addition of N-methyl
morpholine (4 ml, 36.3 mmol). The reaction mixture was stirred under an
atmosphere of nitrogen at room temperature for 18 hours, then partitioned
between ethyl acetate (100, ml) and water (100 ml) and the organic layer
separated. The organic layer was then washed with a saturated aqueous
solution of sodium chloride (100 ml), dried over anhydrous magnesium sulphate
and the solvent removed in vacuo. The residue was then triturated with
diethylether (2-fold 10 ml) to give (4-{[(2-chloro-pyridine-3-carbonyl)-amino]-
methyl)-benzyl)-carbamic acid tart butyl ester (6.71 g) as a white solid.
~H NMR (400MHz, DMSO-d6) : 8 = 9.01-9.08 (1 H, t), 8.43-8.47 (1 H, m), 7.89-
7.93 (1 H, d), 7.45-7.50 (1 H, m), 7.30-7.37 (1 H, m), 7.26-7.31 (2H, d), 7.17-
7.21
(2H, d), 4.39-4.43 (2H, d), 4.03-4.10 (2H, d), 1.37 (9H, s) ppm.
LRMS (electrospray) : m/z [M-H]+ 374.
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PREPARATION 8 : 3-f3-f4-tart-Butoxycarbonylamino-methyl)-benzylcarba-
moyll-nyridin-2-yloxy'~-benzoic acid ethyl ester
O
H ~ / N O Me
N O ~ ~Me
O Me
O~Me
O
(4-([(2-Chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-
butyl ester (12.0 g, 32.2 mmol) (see Preparation 7), 3-hydroxy-benzoic acid
ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol)
were stirred in dioxan (180 ml) at 70°C under an atmosphere of nitrogen
for 18
hours. Starting material remained, so a further aliquot of 3-hydroxy-benzoic
acid
ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol)
were added along with dioxan (420 ml) and N,N-dimethylformamide (40 ml) and
the reaction stirred at 70°C for a further 22 hours. The solvent was
then
removed under reduced pressure, the residue partitioned between ethyl acetate
(200 ml) and water (200 ml), and the organic layer separated. The organic
layer
was then washed with a saturated aqueous solution of sodium chloride (3-fold
100 ml), the solvent removed in vaeuo and the residue purified by flash column
chromatography on silica gel eluting with a solvent gradient of 0:100 changing
to 50:50, by volume, ethyl acetate : hexane to give 3-{3-[4-tert-
butoxycarbonylamino-methyl)-benzylcarbamoyl]-pyridin-2-yloxy)-benzoic acid
ethyl ester (7.42 mg) as an off-white foam.
~H NMR (400MHz, DMSO-d6) : 8 = 8.92-8.98 (1 H, t), 8.18-8.21 (1 H, d), 8.14-
8.18 (1 H, d), 7.81-7.85 (1 H, d), 7.77 (1 H, s), 7.54-7.60 (1 H, t), 7.46-
7.50 (1 H,
m), 7.27-7.31 (2H, d), 7.22-7.26 (1 H, m), 7.14-7.18 (3H, d), 4.47-4.51 (2H,
d),
4.29-4.35 (2H, quart), 4.04-4.08 (2H, d), 1.37 (9H, s), 1.28-1.35 (3H, t) ppm.
LRMS (electrospray) : m/z [M+Na]+ 528, [M-H]+ 504.
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PREPARATION 9 fN-(4-Aminomethyl-benzyl)-2-(4-fluoro-uhenoxy)l-
nicotinamide hydrochloride
O
N
NH3 CI -
N O
O~Me
O
3-~3-[4-tert-Butoxycarbonylamino-methyl)-benzylcarbamoyl]-pyridin-2-yloxyj~
benzoic acid ethyl ester (7.42 g, 14.7 mmol) (see Preparation 8) was dissolved
in dichloromethane (100 ml) and hydrogen chloride gas bubbled through the
solution at 0°C until the solution became saturated (30 minutes). The
solvent
was removed in vacuo giving [N-(4-aminomethyl-benzyl)-2-(4-fluoro-phenoxy)]-
nicotinamide hydrochloride (7.16 mg) as a white solid.
~H NMR (400MHz, DMSO-d6) : s = 9.48-9.54 (1 H, m), 8.83-9.03 (3H, brs), 8.62-
8.66 (1 H, m), 8.57-8.63 (1 H, d), 8.35-8.42 (1 H, d), 8.22 (1 H, s), 8.01-
8.08 (1 H,
t), 7.93-7.98 (1 H, d), 7.81-7.91 (4H, m), 7.68-7.74 (1 H, d), 4.94-5.01 (2H,
d),
4.76-4.81 (2H, quart), 4.36-4.42 (2H, m), 1.75-1.80 (3H, t) ppm.
LRMS (electrospray) : miz [M+H]+ 406.
PREPARATION 10 : 2-Chloro-5-fluoro nicotinic acid
O
OH
N- _CI
Ethyl-2-chloro-5-fluoro-nicotinoate (50.4 g, 0.247 mol) (see reference J. Med.
Chem., 1993, 36(18), 2676-88) was dissolved in tetrahydrofuran (350 ml) and a
2 M aqueous solution of lithium hydroxide (247 ml, 0.495 mol) added. The
reaction mixture was stirred at room temperature for 3 days. The pH of the
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solution was reduced to pH equal to 1 by addition of 6N hydrochloric acid and
then extracted with dichloromethane. The combined extracts were dried over
anhydrous magnesium sulphate and the solvent removed in vacuo to give a
solid which was triturated with diethyl ether and then dried in vacuo to give
2-
chloro-5-fluoro nicotinic acid (40.56 g) as a white solid.
~ H NMR (400MHz, DMSO-d6) : ~ = 8.20 (1 H, s), 8.62 (1 H, s) ppm.
LRMS (electrospray) : m/z [M+H]+ 174.
In vitro activity of the nicotinamide derivatives
The PDE4 inhibitory activity of the nicotinamide derivatives of the
formula (1 ) is determined by the ability of compounds to inhibit the
hydrolysis of
cAMP to AMP by PDE4 (see also reference 1 ). Tritium labelled CAMP is
incubated with PDE4. Following incubation, the radiolabelled AMP produced is
able to bind ytrium silicate SPA beads. These SPA beads subsequently
produce light that can be quantified by scintillation counting. The addition
of a
PDE4 inhibitor prevents the formation of AMP from CAMP and counts are
diminished. The ICSO of a PDE4 inhibitor can be defined as the concentration
of
a compound that leads to a 50% reduction in counts compared to the PDE4
only (no inhibitor) control wells.
The anti-inflammatory properties of the nicotinamide derivatives of the
formula (1) are demonstrated by their ability to inhibit TNFa release from
human peripheral blood mononuclear cells (see also reference 2). Venous
blood is collected from healthy volunteers and the mononuclear cells purified
by
centrifugation through Histopaque (Ficoll) cushions. TNFa production from
these cells is stimulated by addition of lipopolysaccharide. After 18 hours
incubation in the presence of LPS, the cell supernatant is removed and the
concentration of TNFa in the supernatant determined by ELISA. Addition of
PDE4 inhibitors reduces the amount of TNFa produced. An IC5n is determined
which is equal to the concentration of compound that gives 50% inhibition of
TNFa production as compared to the LPS stimulated control wells.
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All the examples were tested in the assay described above and found to have
an IC5o (TNFa screen) of less than 500 nM. And for most of the tested
compounds, they were found to have an ICSO (TNFa screen) of even less than
200 nM.
References
1. Thompson JW, Teraski WL, Epstein PM, Strada SJ., "Assay of
nucleotidephosphodiesterase and resolution of multiple molecular forms of the
isoenzyme", Advances in cyclic nucleotides research, edited by Brooker G,
Greengard P, Robinson GA. Raven Press, New York 1979, 10, p. 69-92.
2. Yoshimura T, Kurita C, Nagao T, Usami E, Nakao T, Watanabe S,
Kobayashi J, Yamazaki F, Tanaka H, Nagai H., "Effects of cAMP-
phosphodiesterase isozyme inhibitor on cytokine production by
lipopolysaccharide-stimulated human peripheral blood mononuclear cells", Gen.
Pharmacol., 1997, 29(4), p. 63
