NZ611695B2 - Pyrazole compounds as crth2 antagonists - Google Patents
Pyrazole compounds as crth2 antagonists Download PDFInfo
- Publication number
- NZ611695B2 NZ611695B2 NZ611695A NZ61169512A NZ611695B2 NZ 611695 B2 NZ611695 B2 NZ 611695B2 NZ 611695 A NZ611695 A NZ 611695A NZ 61169512 A NZ61169512 A NZ 61169512A NZ 611695 B2 NZ611695 B2 NZ 611695B2
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- NZ
- New Zealand
- Prior art keywords
- alkyl
- formula
- alkoxy
- cycloalkyl
- compounds
- Prior art date
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The disclosure relates to pyrazole compounds of formula (1a) or (1b) and pharmaceutically acceptable salts thereof, wherein the variables Ra, Rb, Rc, Rd, Y1, Y2, Y3, Y4, Y5, Z, R1, R2, R3 and n have one of the meanings as indicated in the specification, to their use as medicaments, to pharmaceutical formulation containing said compounds and to pharmaceutical formulations said compounds in combination with one or more active substances. These compounds have chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonistic activity and are suitable for treating inflammatory, infectious and immunoregulatory disorders, respiratory or gastrointestinal diseases, inflammatory diseases of the joints and allergic diseases of the nasopharynx, eyes, and skin. formulation containing said compounds and to pharmaceutical formulations said compounds in combination with one or more active substances. These compounds have chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonistic activity and are suitable for treating inflammatory, infectious and immunoregulatory disorders, respiratory or gastrointestinal diseases, inflammatory diseases of the joints and allergic diseases of the nasopharynx, eyes, and skin.
Description
PYRAZOLE COMPOUNDS AS CRTH2 ANTAGONISTS
The present invention relates to pyrazole compounds of formula (la) or (lb) and
pharmaceutically acceptable salts thereof having CRTH2 nistic activity,
O 1 C
R R
HO d 3
R (R )n
/ o
a ,1
R Rb ’N NJKfZ
Y\Z/7 5 2
R H I1 Y\
\.Y4
2_ 3
(la) Y—Y
Rd (R3)n
H ”z
0b) Ix, .v5
Y\Y4
1O wherein Ra, Rb, RC, Rd, Y1, Y2, Y3, Y4, Y5, Z, R1, R2, n and R3 have one of the meanings as
ted in the specification and claims, to their use as medicaments, to pharmaceutical
formulations containing said compounds and to pharmaceutical formulations said
compounds in combination with one or more active substances.
BACKGROUND OF THE ION
Prostaglandin D2 (PGD2) is an eicosanoid generated by the metabolism of arachidonic acids
upon stimulation of inflammatory cells with allergens, matory stimuli or by tissue
damage. PGD2 is primarily released by mast cells with Th2 cells, dendritic cells, and
macrophages being secondary sources. PGD2 is the major arachidonic acid metabolite
produced by mast cells upon allergen challenge (Lewis et al., J. lmmunol. 1982, 129:1627-
1631) and has been ed in high concentrations in the always of asthmatic ts
(Murray et al, N. Engl. J. Med., 1986, 315:800-804; Liu etal., Am. Rev. Respir. Dis., 1990,
142 126-132; Zehr et al., Chest, 1989, 95:1059-63; Wenzel et al., J. Allergy. Clin. lmmunol.,
1991, 87540-548). PGD2 production is also sed in patients with systemic mastocytosis
(Roberts N. Engl. J. Med. 1980, 303, 404; Butterfield et al., lntArch Allergy Immunol,
2008,147:338-343) allergic is (Naclerio et al., Am. Rev. . Dis., 1983, 128:597-602;
Brown et al., Arch Otolaryngol Head Neck Surg, 1987, 113:179-183; Lebel et al., J. y
Clin. l, 1988, 82:869-877), urticaria (Heavy et al., J. Allergy. Clin. Immunol, 1986,
78:458-461), chronic inusitis (Yoshimura et al., Allergol. Int, 2008, 57:429-436),
chronic obstructive pulmonary disease (Csanky et al., ophoresis, 2009, 30:1228-1234)
and during anaphylaxis (Ono et al., Clin. Exp. Allergy, 2009, 39:72-80).
1O lnstillation of PGD2 into always can provoke features of asthmatic response including
bronchoconstriction (Hardy et al., 1984, N Engl J. Med 311:209-213; Sampson et al 1997,
Thorax 52: 513-518) and eosinophil accumulation (Emery et al., 1989, J. Applied l 67:
959-962). The potential of PGD2 to trigger inflammatory responses has been confirmed by
the overexpression of human PGD2 synthase in mice resulting in elevated eosinophil lung
inflammation and Th2 cytokine production in response to allergen (Fujitani et al, 2002 J.
l. 168:443-449).
PGD2 is an agonist of two 7-transmembrane type G protein-coupled receptors, the PGD2
receptor DP1 (Boie et al., J Biol Chem, 1995, 270:18910-6) and the recently identified
CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor
(also referred to as DP2 receptor) (Nagata et al., J. Immunol, 1999, 162:1278-86).
CRTH2 is expressed on Th2 cells, eosinophils, basophils and mast cells (Nagata et al.,
FEBS Lett, 1999, 459: 195-199; Nagata et al., J Immunol, 1999, 162: 1278-1286; Cosmi et
al., EurJ Immunol, 2000, 30:2972-2979; Boehme et al., Int Immunol, 2009, 21: 621-32).
Using selective CRTH2 agonists like 13,14 dihydroketo-PGD2 (DK-PGD2) and 15R-
methyl-PGD2, it has been shown that CRTH2 activation tes cellular ses that lead
to the recruitment and activation of inflammatory cells (Spik et al., J. Immunol,
2005;174:3703-8; Shiraishi, J. Pharmacol. Exp. Ther., 2005, 312:954-60; Monneret et al., J.
3O Pharmacol. Exp. Ther., 2003, 304:349-355). Using CRTH2 selective antagonists it has been
shown that inflammatory responses and pathophysiological changes in animal models of
diseases like asthma, allergic rhinitis, atopic dermatitis and COPD can be shed (Uller
et al., Respir Res. 2007, 8:16; Lukacs et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2008,
295:L767-79; s, Bioorg. Med. Chem. Lett. 2009,19:4647-51; Nomiya, J Immunol,
2008, 180:5680-5688; Boehme et al., Int. Immunol, 2009, 21:1-17; Boehme et al., lnt
Immunol, 2009, 21:81-93; Takeshita et al., Int Immunol, 2004, 16:947-59; ns et al., J.
Pharmacol. Exp. Ther. 2009). Moreover, genetic deletion of CRTH2 in mice diminished
matory responses in animal models of allergy (Shiraishi et al., J. lmmunol.
2008;180:541-549; Oiwa, Clin Exp Allergy, 2008, 38:1357-66; Satoh et al., J. Immunol,
2006,177:2621-9). In contrast, the selective DP1 t BW245C does not promote
inflammatory responses, like migration or activation of Th2 lymphocytes, basophils or
eosinophils (Yoshimura-Uchiyama et al., Clin. Exp. y, 2004, 34:1283-90; Xue et al.,
Immunol, 2005, 31-6; Gervais et al., J. Allergy Clin. Immunol, 2001, 108:982-8).
Therefore, agents that antagonize the effects of PGD2 at the CRTH2 receptor should be
1O useful for the treatment of respiratory or gastrointestinal complaints, as well as inflammatory
diseases of the joints and allergic diseases of the nasopharynx, eyes and skin.
teaches pyrimidine derivatives of formula (a) and salts thereof,
NI / N
RSIQ 1
wherein R6 is carboxy, carboxamide, nitrile or tetrazolyl, said derivatives having CRTH2
antagonistic activity and can be used for the prophylaxis and ent of diseases
associated with CRTH2 activity.
claims alkylthio substituted pyrimidine nds of formula (b),
Rgfio;\ ( )kR 4:1:WN
said compounds having CRTH2 antagonistic activity.
claims 2—S-benzyl pyrimidine compounds of formula (c),
I R
2 A (R5)m (0)
R N 8(0)k
said compounds having CRTH2 antagonistic activity.
EP 0 480 659 claims compounds of general a (d),
/ ii
wherein Z2 inter alia may be carboxyl-C1-C1O-alkyl-C= and Y may be substituted , said
1O compounds being useful for the treatment of hyperuricemia.
claims compounds of general a (e),
R21) R8
N/ \
t >’ 1 R
R2a f
said nds being useful for the treatment of conditions such as pain, or an
inflammatory, immunological, bone, neurodegenerative or renal disorder.
WO 01/38325 claims compounds of general formula (f),
Ital
REijCEHzlfiWY (align mil 3' w-(mni—ni
wherein A is an aromatic ring and B is a nitrogen-containing 5-membered hetero ring
which may r be substituted, said nds having hypoglycemic and
hypolipidemic activity.
It is an objective of the present invention to provide further nds having CRTH2
antagonistic ty.
Preferably the compounds of the present invention have enhanced al stability,
enhanced pharmacokinetic properties (PK) and/or enhanced activity in a whole cell assay.
SUMMARY OF THE INVENTION
A first aspect of the invention provides for a pyrazole compound of formula (Ia) or (Ib) or
a pharmaceutically acceptable salt thereof,
O R1 Rc
HO Rd (R3)
N O
Ra Rb N Z
R2 H Y5
Y1 Y4
(Ia) Y2 Y3
O R1 Rc
HO Rd (R3)
N O
Ra Rb N Y1
R2 H Z
(Ib) Y2
Y3 Y4
wherein
Ra and Rb are independently ed from hydrogen, hydroxy, halogen, C1-C6-alkyl,
C1-C6 haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and C3-C8-cycloalkyl, or Ra and
Rb together with the carbon atom they are bound to form may form a carbonyl group, or
Ra and Rb together with the carbon atom they are bound to form a 3- to ered ring,
wherein said ring may contain 1 or 2 heteroatoms selected from O, N and S as ring
member and wherein the ring members of said ring may optionally be independently
substituted by hydroxy, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy,
C1-C6-haloalkoxy and C3-C8-cycloalkyl;
(9925931_1):KZA
Rc and Rd are independently selected from hydrogen, hydroxy, halogen, C1-C6-alkyl,
C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and C3-C8-cycloalkyl, or Ra and
Rb together with the carbon atom they are bound to form may form a carbonyl group, or
Ra and Rb together with the carbon atom they are bound to form a 3- to 8-membered ring,
wherein said ring may n 1 or 2 heteroatoms selected from O, N and S as ring
member and wherein the ring members of said ring may optionally be independently
substituted by hydroxy, halogen, alkyl, C1-C6-haloalkyl, C1-C6-alkoxy,
C1-C6-haloalkoxy and C3-C8-cycloalkyl;
Y1, Y2, Y3, Y4 and Y5 are independently selected from N and CRy, wherein each Ry is
ndently selected from H, hydroxy, halogen, cyano, nitro, SF5, C(O)NRfRg,
C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3- C8-cycloalkyl,
C1-C6-haloalkyl, alkoxy, alkoxy-C1-C6-alkoxy, C1-C6-haloalkoxy,
C3-C8-cycloalkoxy, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkylsulfonyl, phenyl,
phenoxy, 5- or 6-membered heterocyclyl and 5- or 6-membered heterocyclyloxy, wherein
Rf and Rg are independently from each other selected from H, C1-C6-alkyl,
haloalkyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl and 5- or 6-membered
heterocyclyl or Rf and Rg together with the nitrogen atom to which they are bound form a
cyclic amine, which may comprise a further heteroatom selected from O, N and S as a
ring member;
Z is selected from O, S and NRz, wherein Rz is H, C1-C6-alkyl or benzyl;
R1 and R2 independently from each other are ed from H, halogen, alkyl,
C2-C6-alkenyl, C2-C6-alkynyl, alkoxy, C1-C6-alkylthio, -NRfRg, cycloalkyl,
C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8-cycloalkyl-C2-C6-alkenyl, C3-C8-cycloalkenyl,
C3-C8-cycloalkenyl-C1-C6-alkyl, C3-C8-cycloalkenyl-C2-C6-alkenyl, phenyl,
phenyl-C1-C6-alkyl, phenyl-C2-C6-alkenyl, naphthyl, naphthyl-C1-C6-alkyl,
naphthyl-C2-C6-alkenyl, heterocyclyl, cyclyl-C1-C6-alkyl, and
heterocyclyl-C2-C6-alkenyl, wherein
the C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl moieties in the aforementioned radicals
R1 and R2 are unsubstituted or carry at least one substituent selected from hydroxy,
halogen, cyano, nitro, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino,
di C1-C6-alkylamino and C1-C6-alkylsulfonyl and/or
(9925931_1):KZA
wherein two radicals bound to the same carbon atom of said C1-C6-alkyl, C2-C6-alkenyl
and C2-C6-alkynyl moieties in the aforementioned ls R1 and R2 together with said
carbon atom may form a carbonyl group, and wherein
the C3-C8-cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclyl moieties in the
aforementioned radicals R1 and R2 are unsubstituted or carry at least one substituent
selected from hydroxy, halogen, cyano, nitro, C1-C6-alkyl, C3-C8-cycloalkyl,
C1-C6-haloalkyl, alkoxy, haloalkoxy, C1-C6-alkylamino,
di-C1-C6-alkylamino, C1-C6-alkylsulfonyl, phenyl and 5- or 6- membered hetaryl and/or
wherein two ls bound to the same carbon atom of said C3-C8-cycloalkyl,
cycloalkenyl and heterocyclyl moieties of the radicals R1 and R2 together with said
carbon atom may form a carbonyl group, and wherein
Rf and Rg are independently from each other selected from H, C1-C6-alkyl,
C1-C6-haloalkyl, C3-C8-cycloalkyl, cycloalkenyl and heterocyclyl or
Rf and Rg together with the nitrogen atom to which they are bound form a cyclic amine,
which may comprise a further heteroatom selected from O, N and S as a ring ;
n is an integer selected from 0, 1, 2 or 3; and
R3 if present are selected independently from each other from halogen,
C1-C6-alkoxy and C1-C6-haloalkoxy.
A second aspect of the invention provides for use of a pyrazole compound of formula (Ia)
or (Ib) ing to the first aspect of the invention, or a pharmaceutically acceptable salt
thereof, for ing a medicament for the treatment of diseases related to
CRTH2 activity.
A third aspect of the invention provides for use of a pyrazole compound of
formula (Ia) or (Ib) according to the first aspect of the invention, or a pharmaceutically
acceptable salt thereof, for preparing a medicament for the prevention and/or ent of
inflammatory, infectious and immunoregulatory disorders, respiratory or gastrointestinal
diseases or complaints, inflammatory diseases of the joints and allergic es of the
nasopharynx, eyes, and skin.
(9925931_1):KZA
A fourth aspect of the invention provides for a pharmaceutical formulation, containing
one or more of the pyrazole compounds of a (Ia) and/or (Ib) according to the first
aspect of the invention, or a pharmaceutically acceptable salt thereof.
A fifth aspect of the invention provides for a pharmaceutical formulation, containing one
or more pyrazole compounds of formula (Ia) and/or (Ib) according to the first aspect of
the ion, or a pharmaceutically acceptable salt thereof, in combination with one or
more active substances selected from among betamimetics, anticholinergics,
corticosteroids, PDE4 tors, LTD4 antagonists, EGFR inhibitors, CCR3 antagonists,
CCR5 antagonists, CCR9 antagonists, 5-LO inhibitors, ine-receptor antagonists,
SYK inhibitors and sulfonamides.
DETAILED DESCRIPTION OF THE INVENTION
The present invention s to pyrazole compounds of formula (Ia) or (Ib) and
pharmaceutically acceptable salts thereof,
O R1 Rc
HO Rd (R3)
N O
Ra Rb N Z
R2 H Y5
Y1 Y4
(Ia) Y2 Y3
O R1 Rc
HO Rd (R3)
N O
Ra Rb N Y1
R2 H Z
(Ib) Y2
Y4
wherein
Ra and Rb are independently selected hydrogen, hydroxy, halogen, C1-C6-alkyl, C1-C6
haloalkyl, alkoxy, C1-C6-haloalkoxy and C3-C8-cycloalkyl, or Ra and Rb together
with the carbon atom they are bound to form may form a carbonyl group, or Ra and Rb
together with the carbon atom they are bound to form a 3- to 8-membered ring, n
said ring may contain 1 or 2 heteroatoms selected from O, N and S as ring member and
wherein the ring members of said ring may optionally be independently
(9925931_1):KZA
tuted by hydroxy, halogen, C1-Cs-alkyl, C1-C6-haloalkyl, C1-Cs-alkoxy, C1-C6-
haloalkoxy and C3-Cg-cycloalkyl;
RC and Rd are independently selected hydrogen, hydroxy, halogen, C1-Cs-alkyl, C1-C6-
haloalkyl, C1-C6-alkoxy, haloalkoxy and Cs-Cg-cycloalkyl, or RC and Rd together
with the carbon atom they are bound to form may form a carbonyl group, or RC and Rd
together with the carbon atom they are bound to form a 3- to 8—membered ring,
wherein said ring may contain 1 or 2 heteroatoms selected from O, N and S as ring
member and wherein the ring s of said ring may optionally be independently
1O substituted by y, halogen, C1-Cs-alkyl, haloalkyl, C1-Cs-alkoxy, C1-C6-
haloalkoxy and C3-Cg-cycloalkyl;
Y1, Y2, Y3, Y4 and Y5 are independently selected from N and CRY, wherein each Ry is
independently selected from H, hydroxy, halogen, cyano, nitro, SF5, C(O)NRfR9, C1-
Cs-alkyl, hydroxy-C1-Cs-alkyl, C1-Cs-alkoxy-C1-Cs-alkyl, Cs- Cg-cycloalkyl, C1-C6-
kyl, C1-C6-alkoxy, C1-Cs-alkoxy-C1-C6-alkoxy, C1-Cs-haloalkoxy, C3-C8-
cycloalkoxy, alkylamino, di-C1-Cs-alkylamino, C1-Cs-alkylsulfonyl, phenyl,
phenoxy, 5- or 6-membered heterocyclyl and 5- or 6-membered heterocyclyloxy,
wherein Rf and R9 are independently from each other selected from H, C1-Cs-alkyl,
C1-C6-haloalkyl, C3-Cg-cycloalkyl, C3-Cg-cycloalkenyl and 5- or 6-membered
heterocyclyl or Rf and R9 together with the nitrogen atom to which they are bound
form a cyclic amine, which may se a further heteroatom selected from O, N
and S as a ring member;
is selected from O, S and NRZ, wherein RZ is H, C1-Cs-alkyl or benzyl;
R1 and R2 are independently from each other selected from H, halogen, C1-Cs-alkyl, Cz-Cs-
alkenyl, Cz-Cs-alkynyl, C1-C6-alkoxy, C1-Cs-alkylthio, -NRfR9, C3-Cg-cycloalkyl, C3-C8-
lkyl-C1-C6-alkyl, cycloalkyl-Cz-Cs-alkenyl, C3-Cg-cycloalkenyl, C3-C8-
3O cycloalkenyl-C1-C6-alkyl, C3-Cg-cycloalkenyl-Cz-Cs-alkenyl, , phenyl-C1-Cs-alkyl,
phenyl-Cz-Cs-alkenyl, naphthyl, naphthyl-C1-Cs-alkyl, naphthyl-Cz-Cs-alkenyl,
heterocyclyl, heterocyclyl-C1-Cs-alkyl, and heterocyclyl-Cz-Cs-alkenyl, wherein
the C1-Cs-alkyl, Cz-Cs-alkenyl and C2-C6-alkynyl moieties in the aforementioned
radicals R1 and R2 are unsubstituted or carry at least one substituent selected from
hydroxy, halogen, cyano, nitro, C1-C6-alkoxy, C1-Cs-haloalkoxy, alkylamino, di
C1-C6-alkylamino and C1-C6-alkylsulfonyl and/or
wherein two radicals bound to the same carbon atom of said C1-Cs-alkyl, Cz-Cs-
alkenyl and C2-C6-alkynyl moieties in the aforementioned radicals R1 and R2 together
with said carbon atom may form a carbonyl group, and wherein
the Cs-Cg-cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclyl moieties in the
aforementioned ls R1 and R2 are unsubstituted or carry at least one substituent
1O selected from hydroxy, halogen, cyano, nitro, C1-Cs-alkyl, C3-Cg-cycloalkyl, C1-C6-
haloalkyl, C1-C6-alkoxy, C1-Cs-haloalkoxy, C1-Cs-alkylamino, di-C1-Cs-alkylamino, C1-
Cs-alkylsulfonyl, phenyl and 5- or 6- membered hetaryl and/or
wherein two ls bound to the same carbon atom of said C3-Cg-cycloalkyl, C3-C8-
cycloalkenyl and heterocyclyl moieties of the radicals R1 and R2 together with said
carbon atom may form a carbonyl group, and wherein
Rf and R9 are independently from each other selected from H, C1-Cs-alkyl, C1-C6-
haloalkyl, Cs-Cg-cycloalkyl, cycloalkenyl and heterocyclyl or
Rf and R9 er with the nitrogen atom to which they are bound form a cyclic
amine, which may comprise a further atom selected from O, N and S as a ring
member;
is an r selected from 0, 1, 2 or 3; and
if present are selected independently from each other from halogen, C1-Cs-alkyl, C1-
Cs-haloalkyl, C1-Cs-alkoxy, C1-C6-haloalkoxy and C3-Cg-cycloalkyl.
singly it has been found that the compounds of formula (la) or (lb) according to the
present ion have significant CRTH2 antagonistic activity. Further it has been found that
said compounds generally have enhanced chemical stability, enhanced pharmacokinetic
properties (PK) and/or enhanced activity in a whole cell assay.
Thus the pyrazole compounds of formula (la) or (lb) according to the present invention are
suitable for the prevention and/or treatment of diseases related to CRTH2—activity.
Accordingly the present invention further relates to the use of le compounds of formula
(la) or (lb) according to the present invention as ments.
Furthermore the t invention relates to the use of compounds of formula (la) or (lb) for
preparing a medicament for the treatment of diseases related to CRTH2—activity. More
specifically the present invention s to the use of pyrazole compounds of formula (la) or
1O (lb) for preparing a medicament for the prevention and/or treatment of inflammatory,
infectious and immunoregulatory disorders, respiratory or gastrointestinal diseases or
ints, inflammatory diseases of the joints and allergic diseases of the nasopharynx,
eyes, and skin.
The present invention further relates to compounds of formula (la) or (lb) according to the
invention for treating and/or preveting diseases related to CRTH2—activity More specifically
the present invention relates to compounds of formula (la) or (lb) for use as a ment
for treating diseases related to CRTH2—activity. More specifically the present invention
relates to pyrazole compounds of formula (la) or (lb) for use as a medicament for the
prevention and/or treatment of inflammatory, infectious and regulatory disorders,
atory or gastrointestinal diseases or complaints, inflammatory diseases of the joints and
allergic diseases of the nasopharynx, eyes, and skin.
Furthermore the present invention relates to ceutical formulations, containing one or
more of the pyrazole compounds of formula (la) or (lb) according to the present invention as
sole active substance or in ation with one or more active substances selected from
among betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists,
EGFR inhibitors, CCR3 antagonists, CCR5 antagonists, CCR9 antagonists, 5-LO inhibitors,
histamine-receptor antagonists, SYK inhibitors and sulphonamides.
The ty in a whole cell eosinophil shape change assay of the compounds of the invention
can be ined, for e, according to the following nces: (i) Mathiesen JM,
Ulven T, Martini L, Gerlach LO, Heinemann A, Kostenis E. Identification of indol derivatives
exclusively interfering with a G protein-independent signalling pathway of the prostaglandin
D2 receptor CRTH2. Mol Pharmacol. 2005 Aug;68(2):393-402; (ii) Schuligoi R, Schmidt R,
WO 01043
Geisslinger G, Kollroser M, Peskar BA, Heinemann A. PGD2 metabolism in plasma: kinetics
and relationship with bioactivity on DP1 and CRTH2 receptors. m col. 2007
Jun 30;74(1):107-17; (iii) Royer JF, Schratl P, Carrillo JJ, Jupp R, Barker J, Weyman-Jones
C, Beri R, Sargent C, Schmidt JA, Lang-Loidolt D, Heinemann A. A novel antagonist of
prostaglandin D2 blocks the locomotion of eosinophils and basophils. Eur J Clin Invest. 2008
Sep;38(9):663-71.
The chemical stability of the compounds of the invention can be determined, for example,
under the following conditions: (i) 3 days tion at 60°C in 0.1 N HCI (hydrolytic stability
1O under acidc conditions); (ii) 3 days incubation at 60°C in pH 4.0 buffer solution (hydrolytic
stability under weakly acidic ions); (iii) 3 days incubation at 60°C in pH 7.4 buffer
solution (hydrolytic stability at physiological pH); (iv) 3 days incubation at 20°C in 0.3 %
hydrogen peroxide (stability against oxidants); (v) 24 h tion under UV-radiation
(lambda = 300 - 800 nm, P = 250 W/m2) in water (stability against light). The kinetics of
degradation can, for example, be ined by HPLC analysis.
The pharmacokinetic properties (PK) of the compounds of the invention can be determined in
pre-clinical animal species, for example, mouse, rat, dog, guinea pig, mini pig, cynomolgus
monkey, rhesus monkey. The pharmacokinetic properties of a compound can be bed,
for example, by the following parameters: Mean residence time, half-life, volume-of-
distribution, AUC (area under the , clearance, bioavailability after oral administration.
USED TERMS AND DEFINITIONS
Terms not ically defined herein should be given the meanings that would be given to
them by one of skill in the art in light of the disclosure and the context. As used in the
specification, however, unless specified to the contrary, the following terms have the
meaning indicated and the following conventions are d to.
3O In the groups, ls or moieties defined below, the number of carbon atoms is often
specified preceding the group. As an example "C1-C6-alkyl" means an alkyl group or radical
having 1 to 6 carbon atoms.
In general, for groups comprising two or more subgroups, the last named group is the radical
attachment point.
Unless ise specified, conventional definitions of terms control and conventional stable
atom valences are presumed and achieved in all formulas and groups.
In l all tautomeric forms and isomeric forms and mixtures, whether individual
geometric isomers or l isomers or racemic or non-racemic es of isomers of a
al structure or nd, are comprised, unless the specific stereochemistry or
isomeric form is specifically indicated in the nd name or structure.
1O The term "substituted" as used herein, means that any one or more hydrogens on the
designated atom, moiety or radical is replaced with a ion from the ted group of
radicals, provided that the designated atom's normal valence is not exceeded, and that the
substitution results in a stable compound.
The nds disclosed herein can exist as pharmaceutically acceptable salts. The
present invention includes compounds in the form of salts, including acid addition salts.
Suitable salts include those formed with both organic and inorganic acids. Such acid addition
salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically
acceptable salts may be of utility in the preparation and cation of the compound in
question. Basic on salts may also be formed and be pharmaceutically acceptable. For a
more complete discussion of the preparation and selection of salts, refer to Pharmaceutical
Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCH, Zurich, Switzerland,
2002).
The term "pharmaceutically acceptable salt," as used , represents salts or zwitterionic
forms of the compounds disclosed herein which are water or oil-soluble or dispersible and
pharmaceutically acceptable as defined herein. The salts can be prepared during the final
ion and purification of the compounds or separately by reacting the appropriate
compound in the form of the free base with a suitable acid. Representative acid addition salts
3O include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate
(besylate), bisulfate, butyrate, camphorate, camphor sulfonate, citrate, digluconate, formate,
fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate,
hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2—hydroxyethansulfonate
ionate), lactate, maleate, malonate, DL-mandelate, mesitylene sulfonate, methane
sulfonate, naphthylene sulfonate, nate, 2—naphthalenesulfonate, oxalate, pamoate,
WO 01043
pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate,
pyroglutamate, succinate, sulfonate, tartrate, rate, trichloroacetate, trifluoroacetate,
phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate.
Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl,
propyl, and butyl chlorides, bromides, and s; dimethyl, diethyl, dibutyl, and diamyl
sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and
phenethyl bromides. Examples of acids which can be ed to form therapeutically
acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic
acid, sulfuric acid and oric acid, and organic acids such as oxalic acid, maleic acid,
1O ic acid and citric acid. Salts can also be formed by coordination of the compounds with
an alkali metal or alkaline earth ion. Hence, the present invention comprises sodium,
potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
Basic addition salts can be ed during the final isolation and cation of the
compounds by reacting a carboxy group with a suitable base such as the hydroxide,
carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary,
secondary, or tertiary amine. The cations of pharmaceutically acceptable salts e
lithium, sodium, potassium, m, magnesium, and aluminum, as well as nontoxic
quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine,
tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, namine,
and N,N'-dibenzylethylenediamine. Other entative organic amines useful for the
formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine,
piperidine and piperazine.
While it may be possible for the compounds of the present invention to be administered as
the raw chemical, it is also le to t them as a pharmaceutical formulation.
Accordingly, provided herein are pharmaceutical formulations which comprise one or more of
3O certain compounds disclosed herein, or one or more pharmaceutically acceptable salts,
esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically
acceptable carrier and optionally one or more other therapeutic ingredients. The carrier(s)
must be "acceptable" in the sense of being compatible with the other ingredients of the
ation and not deleterious to the recipient thereof. Proper formulation is dependent
upon the route of administration . Any of the well-known techniques, carriers and
excipients may be used as suitable and as understood in the art; e.g. in Remington's
Pharmaceutical Sciences. The pharmaceutical itions disclosed herein may be
manufactured in any manner known in the art, e.g., by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or
compression processes.
The term en" as used herein denotes a n substituent selected from fluoro,
chloro, bromo or iodo.
1O The term "C1-Cs-alkyl" as used herein (including the alkyl moieties of C1-C6-alkoxy,
C1-Cs-alkylamino, di-C1-Cs-alkylamino, C1-Cs-alkylthio and the like) denotes branched and
unbranched alkyl moieties with 1 to 6 carbon atoms attached to the remaining compound at
any position of the alkyl chain. The term -alkyl" accordingly denotes a branched or
unbranched alkyl moiety with 1 to 4 carbon atoms. -alkyl" is generally preferred.
Examples of "C1-Cs-alkyl" include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-
butyl, tert-butyl, yl, iso-pentyl, ntyl or hexyl. Unless stated othenNise, the
definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups
in question. Thus, for e, propyl includes n-propyl and iso-propyl, butyl es iso-
butyl, sec-butyl and tert-butyl etc.
The term "C1-Cs-haloalkyl" as used herein (including the alkyl moieties of C1-Cs-haloalkoxy,
C1-Cs-haloalkylamino, di-C1-Cs-haloalkylamino, C1-Cs-haloalkylthio and the like) denotes
branched and unbranched alkyl moieties with 1 to 6 carbon atoms wherein one or more
hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or
bromine, preferably fluorine and ne, particularly preferably fluorine. The term
-haloalkyl" accordingly denotes branched and ched alkyl moieties with 1 to 4
carbon atoms, n one or more hydrogen atoms are replaced analogously to what was
stated above. C1_C4-haloalkyl is generally preferred. Preferred examples include: CHZF, CHFZ
and CFs.
The term "CZ-Cs-alkenyl" as used herein (including the alkenyl moieties of other radicals)
denotes branched and unbranched alkenyl groups with 2 to 6 carbon atoms attached to the
remaining compound at any position of the alkenyl chain and having at least one double
bond. The term "C2-C4-alkenyl" accordingly s branched and unbranched alkenyl
moieties with 2 to 4 carbon atoms. Preferred are alkenyl moieties with 2 to 4 carbon atoms.
Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless otherwise
stated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric
forms of the moieties in question. Thus, for example, propenyl includes 1-propenyl and 2-
propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methylpropenyl, 1-methylpropenyl
etc.
The term "CZ-Cs-alkynyl" as used herein (including the alkynyl moieties of other radicals)
denotes ed and unbranched alkynyl groups with 2 to 6 carbon atoms attached to the
remaining compound at any position of the alkynyl chain and having at least one triple bond.
1O The term "CZ-C4-alkynyl" accordingly denotes ed and unbranched alkynyl moieties
with 2 to 4 carbon atoms. Alkynyl moieties with 2 to 4 carbon atoms are preferred. Examples
include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl. Unless stated othenrvise, the
definitions propynyl, butynyl, pentynyl and hexynyl include all the possible ic forms of
the respective moieties. Thus, for e, propynyl includes ynyl and 2-propynyl,
butynyl includes 1-, 2- and 3-butynyl, 1-methylpropynyl, 1-methylpropynyl etc.
The term "Cs-Cg-cycloalkyl" as used herein (including the cycloalkyl es of other
radicals) denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Preferred are cyclic alkyl groups with 3 to 6 carbon atoms, such as cyclopropyl, entyl
and cyclohexyl.
The term "Cs-Cg-cycloalkenyl" as used herein (including the cycloalkenyl moieties of other
radicals) denotes yclic radicals having 3 to 8 carbon atoms and containing at least
one, preferably one or two, non-conjugated double bonds. Examples are cyclopentenyl,
cyclopantadienyl, cyclohexenyl and exadienyl.
The term "heterocyclyl" as used herein (including the heterocyclyl es of other radicals)
denotes 5- to ered heterocyclic radicals and 5- to‘lO-membered, ic heterocyclic
radicals, containing one, two or three atoms, selected from O, N and S as ring
3O members. The heterocyclyl may be linked to the molecule by a carbon atom or, if present, by
a nitrogen atom. The term "heterocyclyl" as used herein encompasses saturated or partially
unsaturated heterocyclyl as well as hetaryl.
The term "saturated or partially unsaturated heterocyclyl" as used herein (including the
cyclyl moieties of other radicals) denotes 5- to 7-membered monocyclic heterocyclic
radicals as defined above containing a number of double bonds such that no aromatic
system is formed as well as 5- to 10-membered bicyclic heterocyclic radicals as defined
above containing a number of double bonds such that no aromatic system is formed in at
least one of the cycles.
Examples of monocyclic saturated or partially unsaturated heterocyclyl include pyrrolidine,
tetrahydrofurane, tetrahydrothiophene, thiazolidine, dioxolane, piperidine, tetrahydropyrane,
tetrahydrothiopyrane, piperazine, morpholine, thiomorpholine, oxazepane, and the like.
1O Examples of bicyclic saturated or partially unsaturated heterocyclyl include
dihydropyrrolizine, pyrrolizine, tetrahydroquinoline, tetrahydroisoquinoline,
tetrahydroimidazopyridine, tetrahydropyrazolopyridine, benzopyrane, benzodiazepine, and
the like.
The term "hetaryl" as used herein (including the cyclyl moieties of other radicals)
denotes 5- to ered monocyclic heterocyclic radicals as defined above containing a
number of double bonds such that an ic system is formed as well as 5- to 10-
membered bicyclic heterocyclic radicals as defined above containing a number of double
bonds such that an aromatic system is formed in both cycles.
Examples of monocyclic aromatic heterocyclyl include furan, thiazole, pyrrole, thiophene,
pyrazole, imidazole, thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, oxazole, oxadiazole,
pyridine, pyridazine, pyrimidine, pyrazine, and the like.
es of ic aromatic heterocyclyl include pyrrolizine, indol, indolizine, isoindol,
l, purine, quinoline, isoquinoline, benzimidazol, uran, benzothiazol,
sothiazol, pyridopyrimidine, pteridine, dopyrimidine, imidazopyridine,
lopyridine, and the like.
3O The term "fused carbocyclic or heterocyclic " as used herein denotes C3-Cg-cycloalkyl,
Cs-Cg-cycloalkenyl, benzene and heterocyclyl moieties as defined above, wherein said
moieties share at least one bond with the cyclic moiety they are bound to. As an example
benzene fused to benzene is naphthalene. Preferred are fused cyclic moieties sharing one
bond with the cyclic moiety they are fused to. r preferred the fused moiety is benzene.
The term "3- to 8—membered ring formed by two radicals er with the carbon atom they
are bound, wherein said ring may n 1 or 2 heteroatoms selected from O, N and S as
ring member" as used herein denotes C3-Cg-cycloalkyl, Cs-Cg-cycloalkenyl and heterocyclyl
moieties as defined above.
The term "cyclic amine formed by two radicals together with the en atom to which they
are bound, wherein said ring may comprise a further heteroatom selected from O, N and S
as a ring member" as used herein denotes cyclic amines having 3 to 8, ably 5 or 6, ring
s. Examples of such formed amines are pyrrolidine, piperidine, piperazine,
1O morpholine, pyrrol, imidazole, and the like.
The terms "heterocyclyl-C1-Cs-alky|", "C3-Cg-cycloalkyl-C1-Cs-alky|", "phenyl-C1-C6-alkyl" and
"naphthyl-Ci-Cs-alkyl" as used herein denote alkyl moieties as defined above having 1 to 6
carbon atoms, wherein any one of the hydrogen atoms is ed by a cyclic moiety as
defined above. In these terms the alkyl moiety preferably has 1 to 4 carbon atoms (Ci-C4-
alkyl). More preferably the alkyl moiety is methyl or ethyl, and most preferred methyl.
Preferred examples of -Ci-Cs-alkyl are benzyl or phenethyl.
The terms "heterocyclyl-Cz-Cs-alkenyl", "C3-Cg-cycloalkyl-Cz-Cs-alkenyl", "phenyl-Cz-Cs-
alkenyl" and "naphthyl-Cz-Cs-alkenyl" as used herein denote alkenyl moieties as defined
above having 2 to 6 carbon atoms, wherein any one of the hydrogen atoms is replaced by a
cyclic moiety as defined above. In these terms the alkenyl moiety preferably has 2 to 4
carbon atoms (CZ-C4-alkenyl). More preferably the alkenyl moiety is ethenyl. A preferred
example of phenyl-Cz-Cs-alkenyl is henyl.
The specific and preferred definitions given for the individual ls and moieties Ra, Rb, RC,
Rd, Y1, Y2, Y3, Y4, Y5, Z, R1, R2, n and R3 herein below are valuable on their own as well as in
combination. As will be understood preferred are compounds of formula (la) or (lb) wherein
one ore more of the individual radicals and moieties Ra, Rb, RC, Rd, Y1, Y2, Y3, Y4, Y5, Z, R1,
R2, n and R3 have one of the meanings indicated as preferred herein-below and wherein the
remaining radicals and moities are as specified hereinbefore. Most preferred are compounds
of a (la) or (lb) wherein all of the individual ls and moieties Ra, Rb, RC, Rd, Y1, Y2,
Y3, Y4, Y5, Z, R1, R2, n and R3 have one of the meanings indicated as preferred herein-below.
One particular embodiment of the invention relates to pyrazole compounds of formula (la),
wherein the individual moieties have one of the meanings given in the specification.
Preferred are compounds of formula (la), wherein the individual moieties have one of the
preferred gs given in the specification.
r ular embodiment of the ion s to pyrazole compounds of formula
(lb), wherein the individual moieties have one of the meanings given in the specification.
Preferred are compounds of formula (lb), wherein the individual es have one of the
preferred meanings given in the specification.
Preferred are pyrazole compounds of formula (la) or (lb), n R8 and Rb are
independently selected hydrogen, C1-Cs-alkyl, C1-Cs haloalkyl and C3-Cg-cycloalkyl.
Particularly preferred are pyrazole compounds of formula (la) or (lb), wherein R8 and Rb are
both en.
Likewise preferred are pyrazole compounds of formula (la) or (lb), wherein RC and Rd are
ndently selected hydrogen, C1-Cs-alkyl, C1-Cs-haloalkyl and C3-Cg-cycloalkyl.
Particularly preferred are pyrazole compounds of formula (la) or (lb), wherein RC and Rd are
both hydrogen.
Likewise preferred are pyrazole compounds of formula (la) or (lb), wherein Y1 is CRy1 or N,
wherein Ry1 has one of the meanings given for RV.
More preferred are pyrazole compounds of a (la) or (lb), wherein Y1 is CR“, in
particular wherein Ry1 is selected from H, C1-Cs-alkyl, C1-Cs-alkoxy-C1-C6-alkyl and C1-C6-
haloalkyl.
3O Likewise preferred are pyrazole compounds of formula (la) or (lb), wherein Y2 is CRYZ, Y3 is
CR”, Y4 is CRy4 and/or Y5 is CRy5, wherein Rfi, RVs, RW and RW independently from each
other have one of the meanings as defined for RV.
More preferred are pyrazole compounds of formula (la) or (lb), wherein Y2 is CRYZ, Y3 is
CR”, Y4 is CRy4 and Y5 is CRY5, n Rfi, R”, RW and RW independently from each other
have one of the meanings as d for RV, in particular wherein Rfi, R”, RW and RW are
independently selected from H, halogen, alkoxy, C1-C6-alkoxy-C1-Cs-alkoxy and C1-C6-
haloalkoxy.
One particular ment of the ion relates to pyrazole nds of formula (la) or
(lb), wherein Z is O and the remaining moieties have one of the meanings given in the
specification, preferably one of the preferred gs given in the specification.
Another particular embodiment of the invetion relates to pyrazole compounds of formula (la)
1O or (lb), wherein Z is S and the remaining moieties have one of the meanings given in the
specification, preferably one of the preferred meanings given in the specification.
Another particular embodiment of the ion relates to pyrazole nds of formula (la)
or (lb), wherein Z is NRZ, n RZ is H, C1-C6-alkyl or benzyl, and the remaining moieties
have one of the meanings given in the ication, preferably one of the preferred
meanings given in the specification.
Likewise preferred are pyrazole compounds of formula (la) or (lb), wherein R1 and R2
independently from each other are selected from H, C1-Cs-alkyl, C3-Cg-cycloalkyl, phenyl and
naphthyl.
More preferred are pyrazole compounds of formula (la) or (lb), wherein R1 and R2
independently from each other are selected from H, C1-C4-alkyl, C3-Cs-cycloalkyl and phenyl.
Particularly preferred are pyrazole compounds of formula (la) or (lb), wherein R1 and R2 are
selected from C1-C4-alkyl.
Likewise preferred are pyrazole compounds of formula (la) or (lb), wherein n is 0, 1, 2 or 3, in
particular n n is 0 or 1.
Likewise preferred are pyrazole compounds of formula (la) or (lb), wherein R3 if present are
independently selected from halogen, C1-Cs-alkoxy and haloalkoxy.
More preferred are pyrazole compounds of formula (la) or (lb), wherein R3 if present are
independently selected from halogen, in particular from F, Cl and Br.
2012/050830
One preferred particular embodiment of the invention relates to pyrazole compounds
selected from compounds of formula (la’),
HO I
('3')
wherein Z, R1, R2, R3, R“, Rfi, RVs, RW and RW have one of the meanings given above and n
isOor1.
More preferred are pyrazole compounds (la’) wherein at least one of the moieties Z, R1, R2,
R3, R“, RYZ, R”, RW and RW have one of the preferred meanings given above.
Another preferred particular embodiment of the invention relates to pyrazole compounds
selected from compounds of formula (lb’),
R 3
(R ),
/ O Rw
HO P
O R2 N Z
(Ib') Ry
wherein Z, R1, R2, R3, R“, Rfi, RVs, RW and RW have one of the meanings given above.
More preferred are pyrazole compounds (la’) n at leastone of the moieties Z, R1, R2,
R3, R“, RYZ, R”, RW and RW have one of the red meanings given above.
A further embodiment of the t invention relates to compounds of formula (la) or (lb),
wherein the compounds of formula (la) or (lb) are present in the form of the individual optical
isomers, es of the individual enantiomers or racemates, preferably in the form of the
enantiomerically pure compounds.
A further embodiment of the present invention relates to compounds of formula (la) or (lb),
wherein the compounds of formula (la) or (lb) are present in the form of the acid addition
salts thereof with pharmacologically acceptable acids as well as optionally in the form of the
es and/or hydrates.
PREPARATION
The compounds ing to the invention may be ed using methods of synthesis
which are known to a person skilled in the art and described in the literature of organic
1O sis. Preferably the compounds are obtained analogously to the methods of preparation
explained more fully hereinafter, in particular as described in the experimental section.
Compounds of formula (la) according to the present inventioncan be prepared according to
scheme 1.
Scheme 1
O 1
R R°
PG 0_ d
R (R3)n
/ + LG
Ra b pH
R “’N
R2 N02
Starting material I Starting material ll
(R3). 3
R )n
N02 tion) NH2
PG-O PG-O
Intermediate l Intermediate ll
Y\1\Z/7 5 Z/§\¥ 3
\\Y4 2Y
2_ 5 O \ 1
Y—Y Y
(R3) "
Starting Material lll NH
(Coupling) (Deprotectron)
—> R0 —> (la)
R1 N. . lll Intermediate
O \ /N
b 2
PG-O RaR R
According to scheme 1 the compounds of the present invention can be prepared employing
as starting al | (1 H-pyrazolyl)acetic acid derivatives, which are substituted with
tuents Ra, Rb, R1, R2 and with a ylic acid protecting group PG. These
compounds can, in some cases, be obtained from commercial sources or can be ed
according to literature procedures, for example . Suitable protecting groups
can be ed from T. W. , Protective Groups in Organic Synthesis, Wiley, 3rd
edition, 1999. Preferred protecting groups PG are , ethyl, tert—butyl.
Intermediate I can be obtained by alkylation of starting material | with a suitable 4-nitrobenzyl
1O compounds as starting material ll, wherein LG is a suitable leaving group such as halogen, in
particular Br, or mesylate, in the presence of a base. Suitable bases are inorganic bases
such as carbonates, especially potassium carbonate. The reaction is preferably d out in
an organic solvent such as dimethylformamide, dimethylsulfoxid, itrile,
tetrahydrofuran, romethane or a e of ts. The reaction usually takes place
within 1 to 48 hours. Preferred reaction temperatures are between 0°C and the boiling point
of the reaction mixture. When R1 is different from R2, the alkylation reaction may yield a
mixture of regioisomers. The individual isomers may be separated by methods which are
known to a person skilled in the art, for example, chromatography over silica gel employing a
suitable solvent or solvent mixtures, or preparative reversed phase chromatography,
ing a suitable gradient of solvents, or trituration or crystallization from suitable
solvents or solvent mixtures.
Amine intermediate II can be prepared from intermediate l by reduction of the nitro group, for
instance by enolysis in the presence of a catalyst, such as palladium on carbon or
Raney Nickel. The reaction is preferably carried out in an inert organic solvent, such as
methanol, ethanol, acetic acid, ethyl acetate or a mixture of solvents. The reaction usually
takes place within 1 to 48 hours. Preferred reaction temperatures are between 0°C and 50°C.
WO 01043
Preferred reaction pressures are between atmospheric pressure and 100 bar. The reduction
of the nitro group in intermediate II can also be carried out according to alternative methods
described in J. March, Advanced Organic Chemistry, Wiley, 4th n, 1992, p. 1216-1217.
Amide intermediate lll can be prepared from amine intermediate II by ng with a
carboxylic acid (Starting Material III) in the presence of a coupling reagent, such as 2-(1H-
benzotriazoleyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), and a base, such as
diisopropylethylamine. The reaction is preferably carried out in an inert organic solvent, such
as dimethylformamide, tetrahydrofuran, dichloromethane or a mixture of solvents. The
reaction usually takes place within 1 to 48 hours. Preferred reaction atures are
1O between 0°C and 30°C. The coupling of a carboxylic acid to the amino group of intermediate
lll can also be carried out according to alternative methods described in J. March, Advanced
Organic Chemistry, Wiley, 4th n, 1992, p. 419-421. Alternatively, instead of the
carboxylic acid (starting material Ill) and a coupling t, the corresponding acyl chloride
or ide may be employed.
Compounds of formula (la) can be obtained from intermediate III by removal of the protecting
group PG. In the case the hydroxycarbonyl group is protected by CH3 or C2H5, this
conversion can be carried out under aqueous conditions in the presence of an inorganic
base, such as NaOH or LiOH. The on is preferably carried out in water or a mixture of
water with CH30H, C2H5OH, tetrahydrofuran or dioxane. The reaction y takes place
within 1 to 48 hours. Preferred reaction temperatures are n 0°C and the boiling point
of the reaction mixture. In the case that PG is tert-butyl, the ection can be carried out
under acidic conditions, for instance with trifluoroacetic acid, hydrochloric acid or
montmorillonit. When using trifluoroacetic acid, the reaction can be carried out in neat
trifluoroacetic acid or in an inert solvent, such as dichloromethane. The reaction usually takes
place within 1 to 48 hours. Preferred reaction temperatures are n 0°C and 30°C. The
cleavage of the protecting group PG may also be carried out according to alternative
methods described in J. March, Advanced Organic Chemistry, Wiley, 4th n, 1992, p.
378-383 or in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, 3rd n, 1999.
Compounds of formula (lb) can be obtained ing the procedure depicted in scheme I
using starting material of formula lll’, wherein
Starting material lll'
Y1, Y2, Y3, Y4, Y5 and Z have one of the meanings indicated above, instead of starting
material lll.
INDICATIONS
The compounds of formula (la) or (lb) according to the present invention are especially
useful for manufacturing a medicament for the prevention and/or treatment of es
1O wherein the activity of a CRTH2—receptor is involved.
One embodiment of the t invention relates to the manufacturing of a medicament for
the prevention and/or treatment of a wide variety of inflammatory, infectious, and
immunoregulatory disorders, respiratory or gastrointestinal diseases or complaints,
matory diseases of the joints and allergic diseases of the nasopharynx, eyes, and skin.
Such disorders diseases and complaints include asthma and allergic diseases, eosinophilic
diseases, chronic ctive pulmonary disease, infection by pathogenic microbes (which,
by definition, includes viruses), as well as autoimmune pathologies, such as the rheumatoid
arthritis and atherosclerosis.
Preferred is the manufacturing of a medicament for the prevention and/or treatment of
inflammatory or allergic diseases and conditions, including allergic or non-allergic rhinitis or
sinusitis, chronic sinusitis or rhinitis, nasal polyposis, c rhinosinusitis, acute
inusitis, , pediatric asthma, allergic bronchitis, itis, Farmer’s disease,
hyperreactive ainrvays, allergic conjunctivitis, bronchitis or pneumonitis caused by infection,
e.g. by bacteria or viruses or helminthes or fungi or protozoons or other pathogens,
bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema,
bronchitis or pneumonitis or interstitial nitis caused by different origins, e.g.
aspiration, tion of toxic gases, vapors, itis or pneumonitis or interstitial
pneumonitis caused by heart failure, , radiation, chemotherapy, itis or
pneumonitis or interstitial pneumonitis associated with collagenosis, e.g. lupus
erythematodes, systemic derma, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF),
titial lung diseases or interstitial pneumonitis of different origin, including asbestosis,
silicosis, m. Boeck or sarcoidosis, granulomatosis, cystic fibrosis or mucoviscidosis, or 0L1-
ypsin deficiency, eosinophilic cellulites (e.g., Well's syndrome), eosinophilic pneumonias
(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e. g.,
Shulman's syndrome), delayed-type hypersensitivity, non-allergic asthma; exercise induced
oconstriction; chronic obstructive pulmonary disease (COPD), acute bronchitis,
c bronchitis, cough, pulmonary emphysema; systemic anaphylaxis or ensitivity
responses, drug allergies (e.g., to penicillin, cephalosporin), eosinophilia-myalgia syndrome
due to the ingestion of contaminated tryptophane, insect sting allergies; autoimmune
1O diseases, such as rheumatoid tis, psoriatic arthritis, multiple sclerosis, systemic lupus
erythematosus, myasthenia gravis, immune ocytopenia (adult ITP, neonatal
thrombocytopenia, pediatric ITP), immune hemolytic anemia (auto-immune and drug
induced), Evans me (platelet and red cell immune enias), Rh disease of the
n, Goodpasture’s syndrome (anti-GBM disease), Celiac, autoimmune cardio-
myopathyjuvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's
disease; graft rejection (e.g., in transplantation), including allograft rejection or graftversus-
host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis;
spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and
inflammatory dermatoses such as an dermatitis, eczema, atopic itis, allergic contact
dermatitis, urticaria; vasculitis (e. g., necrotizing, cutaneous, and hypersensitivity itis);
erythema nodosum; eosinophilic myositis, philic fasciitis, cancers with leukocyte
infiltration of the skin or organs.
METHOD OF TREATMENT
Accordingly, the compounds of formula (la) or (lb) according to the present invention are
useful in the prevention and/or treatment of a wide variety of inflammatory, infectious, and
immunoregulatory ers and diseases. Such disorders and es include but are not
limited to asthma and allergic diseases, chronic obstructive pulmonary e, infection by
3O pathogenic microbes , by definition, includes viruses), autoimmune pathologies such
as the rheumatoid arthritis and atherosclerosis.
As an example, an instant nd of formula (la) or (lb) which inhibits one or more
functions of a mammalian CRTH2 receptor (e. g., a human CRTH2 receptor) may be
administered to inhibit (i.e., reduce or prevent) inflammation and bronchoconstriction. As a
2012/050830
result, one or more inflammatory ses, such as leukocyte emigration, adhesion,
chemotaxis, exocytosis (e. g., of enzymes, growth factors, histamine, cytotoxic proteins),
inflammatory mediator release, survival or proliferation of CRTH2 expressing cells is
inhibited. For example, activation or recruitment of Th2 cells, mast cells, basophils and
philic to inflammatory sites (e. g., in asthma or allergic is) can be inhibited
according to the present method.
In particular, the compounds of the ing examples have activity in blocking the activation
and migration of cells expressing the CRTH2 receptor using the appropriate CRTH2 agonists
1O in the entioned assays.
Diseases or ions of humans which can be d with inhibitors of CRTH2 or
function, include, but are not limited to inflammatory or ic diseases and conditions,
including allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, nasal
polyposis, c rhinosinusitis, acute rhinosinusitis, asthma, pediatric asthma, allergic
bronchitis, itis, Farmer’s disease, hyperreactive airways, allergic conjunctivitis,
bronchitis or pneumonitis caused by infection, e.g. by bacteria or viruses or helminthes or
fungi or protozoons or other pathogens, bronchiectasis, adult respiratory distress syndrome,
bronchial and pulmonary edema, bronchitis or pneumonitis or interstitial pneumonitis caused
by different origins, e.g. aspiration, inhalation of toxic gases, vapors, bronchitis or
pneumonitis or interstitial pneumonitis caused by heart failure, X—rays, radiation,
chemotherapy, bronchitis or pneumonitis or interstitial pneumonitis associated with
collagenosis, e.g. lupus erythematodes, ic scleroderma, lung fibrosis, idiopathic
pulmonary lung fibrosis (IPF), interstitial lung diseases or interstitial nitis of different
origin, including asbestosis, silicosis, m. Boeck or sarcoidosis, granulomatosis, cystic fibrosis
or mucoviscidosis, or a1-antitrypsin deficiency, eosinophilic cellulites (e.g. Well's syndrome),
eosinophilic pneumonias (e.g. Loeffler's syndrome, chronic eosinophilic pneumonia),
eosinophilic fasciitis (e.g. Shulman's syndrome), delayed-type ensitivity, non-allergic
asthma, exercise induced bronchoconstriction; chronic obstructive pulmonary disease
3O (COPD), acute itis, chronic bronchitis, cough, pulmonary emphysema; ic
anaphylaxis or hypersensitivity responses, drug allergies (e. g., to penicillin, cephalosporin),
eosinophilia-myalgia syndrome due to the ingestion of contaminated tryptophane, insect
sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple
sclerosis, systemic lupus erythematosus, myasthenia gravis, immune ocytopenia
(adult ITP, neonatal ocytopenia, pediatric ITP), immune hemolytic anemia (auto-
immune and drug induced), Evans syndrome (platelet and red cell immune cytopaenias), Rh
disease of the newborn, Goodpasture’s syndrome (anti-GBM disease), Celiac, autoimmune
cardio-myopathyjuvenile onset diabetes; glomerulonephritis, autoimmune ditis,
Behcet's disease; graft rejection (e.g. in transplantation), including allograft rejection or
graftversus-host disease; inflammatory bowel diseases, such as Crohn's disease and
ulcerative s; spondyloarthropathies; scleroderma; psoriasis ding T-cell mediated
psoriasis) and inflammatory dermatoses such as an dermatitis, eczema, atopic dermatitis,
allergic contact dermatitis, urticaria; vasculitis (e.g. necrotizing, ous, and
hypersensitivity vasculitis); erythema nodosum; eosinophilic myositis, eosinophilic fasciitis;
1O cancers with leukocyte infiltration of the skin or .
COMBINATIONS
The compounds of a (la) or (lb) according to the present ion may be used on
their own or in combination with other compounds of formula (la) or (lb). The compounds of
formula (la) or (lb) may optionally also be combined with other pharmacologically active
substances.
Such pharmacologically active substances useable in the pharmaceutical composition
containing compounds of formula (la) or (lb) of the t invention may be selected from
but are not limited to the s consisting of f52—adrenoceptor—agonists (short and long-
acting beta mimetics), anti-cholinergics (short and long-acting), anti-inflammatory steroids
(oral and l corticosteroids), dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4
inhibitors, PDE7 inhibitors, LTD4 antagonists, EGFR inhibitors, PAF antagonists, Lipoxin A4
derivatives, FPRL1 tors, LTB4-receptor (BLT1, BLT2) antagonists, histamine-receptor
antagonists, Pl3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example
LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, tors of MAP s as for example p38,
ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors of the NF-KB signaling y as for
example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 tors, leukotriene biosynthesis
3O inhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4
hydrolase inhibitors or FLAP inhibitors, non-steroidal anti-inflammatory agents (NSAle),
DP1-receptor modulators, thromboxane receptor antagonists, CCR1 antagonists, CCR2
antagonists, CCR3 antagonists, CCR4 antagonists, CCR5 antagonists, CCR6 antagonists,
CCR7 nists, CCR8 antagonists, CCR9 antagonists, CCR10 antagonists, CXCR1
antagonists, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists, CXCR5
antagonists, CXCR6 antagonists, CX3CR1 antagonists, neurokinin (NK1, NK2) antagonists,
sphingosine 1-phosphate receptor tors, sphingosine 1-phosphate-lyase inhibitors,
Adenosine or modulators as for example A2a-agonists, modulators of purinergic
receptors as for example P2X? inhibitors, Histone Deacetylase (HDAC) activators,
Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gamma modulators, Rho-kinase
inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-like receptor (TLR)
modulators, HMG-CoA reductase tors, VLA-4 antagonists, lCAM-1 inhibitors, SHIP
agonists, GABAa receptor antagonist, nhibitors, Melanocortin receptor (MC‘IR,
MCZR, MC3R, MC4R, MCSR) modulators, CGRP antagonists, Endothelin antagonists,
1O mucoregulators, immunotherapeutic agents, compounds against swelling of the always,
compounds against cough, CBZ agonists, retinoids, immunosuppressants, mast cell
stabilizers, methylxanthine, opioid receptor agonists, laxatives, anti-foaming agents,
antispasmodic agents, 5-HT4 ts but also combinations of two or three active
substances.
Preferred are combinations of two or three active nces, i.e.: CRTH2 antagonists
according to the present invention with betamimetics, anticholinergics, corticosteroids, PDE4
tors, LTD4 nists, EGFR inhibitors, CCR3 antagonists, CCR5 antagonists, CCR9
antagonists, 5-LO inhibitors, histamine receptor antagonists, SYK inhibitors and
amides, or i.e.:
. CRTH2 antagonists with betamimetics and corticosteroids, PDE4 inhibitors, CCR3
antagonists or LTD4 nists,
. CRTH2 antagonists with olinergics and betamimetics, corticosteroids, PDE4
inhibitors, CCR3 nists or LTD4 antagonists,
. CRTH2 antagonists with corticosteroids and PDE4 inhibitors, CCR3 antagonists or
LTD4 antagonists
. CRTH2 antagonists with PDE4 inhibitors and CCR3 antagonists or LTD4 antagonists
In the pharmaceutical compositions according to the present invention the CRTH2
3O antagonists of formula (la) or (lb) may be contained in a form selected from ers,
optical isomers, enantiomers, racemates, diastereomers, cologically acceptable acid
addition salts, es or hydrates, as far as such forms exist, depending on the individual
compound. Pharmaceutical compositions comprising one or more, preferably one, compound
1 in form of a substantially pure enantiomer are preferred.
2012/050830
In the pharmaceutical compositions according to the present invention more than one
CRTH2 nist of formula (la) or (lb) and more than one further pharmacologically active
compound can be t.
PHARMACEUTICAL FORMS
Suitable preparations for stering the compounds of a (la) or (lb) include for
example tablets, capsules, suppositories, solutions and powders etc. The t of the
pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%,
1O preferably 0.1 to 50 wt.-% of the composition as a whole.
Suitable s may be obtained, for example, by mixing the active substance(s) with known
excipients, for example inert diluents such as m carbonate, calcium phosphate or
lactose, disintegrants such as corn starch or alginic acid, binders such as starch or ne,
lubricants such as magnesium te or talc and/or agents for delaying release, such as
carboxymethyl ose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may
also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the
tablets with substances normally used for tablet coatings, for example collidone or shellac,
gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent
incompatibilities the core may also consist of a number of layers. Similarly the tablet coating
may consist of a number or layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the
invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or
sugar and a flavor er, e.g. a flavoring such as vanillin or orange extract. They may
also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose,
3O wetting agents such as, for example, condensation ts of fatty alcohols with ethylene
oxide, or preservatives such as p-hydroxybenzoates.
Solutions are prepared in the usual way, e.g. with the addition of isotonic agents,
vatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of
ethylenediaminetetraacetic acid, optionally using emulsifiers and/or dispersants, while if
water is used as diluent, for example, organic solvents may ally be used as solubilisers
or dissolving aids, and the solutions may be transferred into ion vials or ampoules or
infusion bottles.
Capsules containing one or more active substances or combinations of active substances
may for example be prepared by mixing the active substances with inert rs such as
e or sorbitol and packing them into ne capsules.
Suitable itories may be made for example by mixing with carriers provided for this
1O purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
Excipients which may be used include but are not limited to water, pharmaceutically
acceptable organic solvents such as paraffins (e.g. petroleum ons), vegetable oils (e.g.
groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers
such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral
powders (e.g. highly dispersed c acid and silicates), sugars (e.g. cane sugar, lactose and
glucose), emulsifiers (e.g. lignin, spent te liquors, methylcellulose, starch and
polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium
lauryl sulphate).
For oral use the tablets may obviously contain, in addition to the carriers specified, additives
such as sodium citrate, calcium carbonate and dicalcium phosphate together with various
additional substances such as starch, preferably potato starch, gelatine and the like.
Lubricants such as ium te, sodium laurylsulphate and talc may also be used to
produce the tablets. In the case of aqueous suspensions the active substances may be
combined with various flavor enhancers or ngs in on to the abovementioned
excipients.
The compounds of formula (la) or (lb) may also be administered as preparations or
3O pharmaceutical formulations suitable for inhalation. lnhalable preparations include inhalable
powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions.
Within the scope of the present invention, the term propellant-free inhalable solutions also
include trates or sterile inhalable solutions ready for use. The formulations which may
be used within the scope of the present invention are described in more detail in the next part
of the specification.
The inhalable powders which may be used according to the invention may n (la) or (lb)
either on its own or in admixture with le physiologically acceptable excipients.
If the active nces (la) or (lb) are present in admixture with physiologically acceptable
excipients, the following physiologically acceptable excipients may be used to prepare these
inhalable powders according to the invention: monosaccharides (e.g. e or arabinose),
disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g.
dextrans), polyalcohols (e.g. ol, mannitol, xylitol), salts (e.g. sodium chloride, calcium
1O carbonate) or mixtures of these excipients. Preferably, mono- or disaccharides are used,
while the use of lactose or glucose is preferred, particularly, but not ively, in the form of
their hydrates. For the purposes of the invention, lactose is the particularly preferred
excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the present invention the excipients
have a maximum average particle size of up to 250 um, preferably n 10 and 150 um,
most preferably between 15 and 80 pm. It may sometimes seem appropriate to add finer
excipient ons with an e particle size of 1 to 9 pm to the excipient mentioned
above. These finer excipients are also selected from the group of possible excipients listed
before. Finally, in order to prepare the inhalable powders according to the invention,
micronised active substance 1, preferably with an average particle size of 0.5 to 10 um, more
preferably from 1 to 5 um, is added to the excipient mixture. Processes for producing the
ble powders according to the invention by grinding and micronising and finally mixing
the ingredients together are known from the prior art.
The inhalable powders according to the ion may be stered using inhalers known
from the prior art.
The tion aerosols containing propellant gas according to the invention may contain the
3O compounds of formula (la) or (lb) dissolved in the propellant gas or in dispersed form. The
compounds of formula (la) or (lb) may be contained in separate formulations or in a common
formulation, in which the compounds of formula (la) or (lb) are either both dissolved, both
sed or in each case only one component is dissolved and the other is dispersed. The
propellant gases which may be used to prepare the inhalation aerosols are known from the
prior art. Suitable propellant gases are selected from among hydrocarbons such as
n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of
methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned
propellant gases may be used on their own or mixed together. Particularly preferred
propellant gases are halogenated alkane tives selected from TG‘l34a and TG227 and
mixtures f.
The propellant-driven inhalation aerosols may also contain other ingredients such as
co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH ers. All these
ingredients are known in the art.
The propellant-driven inhalation aerosols according to the invention mentioned above may
be stered using inhalers known in the art (MDls = metered dose inhalers).
Moreover, the active substances of formula (la) or (lb) according to the invention may be
administered in the form of propellant-free ble solutions and suspensions. The solvent
used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be
water on its own or a mixture of water and ethanol. The relative proportion of ethanol
compared with water is not limited but the maximum is preferably up to 70 percent by
volume, more particularly up to 60 percent by volume and most preferably up to 30 percent
by . The remainder of the volume is made up of water. The ons or suspensions
containing compounds of formula (la) or (lb) are adjusted to a pH of 2 to 7, preferably 2 to 5,
using le acids. The pH may be adjusted using acids ed from nic or organic
acids. Examples of particularly suitable inorganic acids include hydrochloric acid,
hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly
suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,
succinic acid, fumaric acid, acetic acid, formic acid and/or nic acid etc. Preferred
inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which
have already formed an acid on salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the
above acids may be used, particularly in the case of acids which have other properties in
addition to their acidifying ies, e.g. as flavorings, antioxidants or complexing agents,
such as citric acid or ascorbic acid, for example. According to the invention, it is particularly
preferred to use hydrochloric acid to adjust the pH.
If desired, the addition of editic acid (EDTA) or one of the known salts thereof, sodium
edetate, as stabilizer or complexing agent may be omitted in these formulations. Other
embodiments may contain this compound or these compounds. In a preferred ment
the content based on sodium edetate is less than 100 mg/100 ml, preferably less than
00ml, more ably less than 20 mg/100 ml. Generally, inhalable ons in which
the t of sodium edetate is from 0 to 10 mg/100 ml are preferred.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions.
Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g.
1O alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol,
polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and
polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote
any pharmacologically acceptable substance which is not an active substance but which can
be ated with the active nce or substances in the physiologically suitable t
in order to improve the qualitative properties of the active substance formulation. Preferably,
these substances have no pharmacological effect or, in connection with the desired therapy,
no appreciable or at least no undesirable pharmacological effect. The excipients and
additives include, for example, tants such as soya lecithin, oleic acid, sorbitan esters,
such as polysorbates, nylpyrrolidone, other stabilizers, complexing agents, antioxidants
and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical
formulation, ings, vitamins and/or other additives known in the art. The additives also
include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for example, provided
that it has not already been used to adjust the pH, n A, vitamin E, tocopherols and
similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with pathogens.
Suitable preservatives are those which are known in the art, particularly cetyl pyridinium
chloride, konium chloride or benzoic acid or benzoates such as sodium benzoate in
the concentration known from the prior art. The preservatives mentioned above are
preferably present in concentrations of up to 50 mg/100 ml, more preferably between 5 and
mg/100 ml.
The dosage of the compounds according to the invention is naturally highly dependent on the
method of administration and the complaint which is being treated. When administered by
inhalation the nds of formula (la) or (lb) are characterized by a high potency even at
doses in the ug range. The compounds of formula (la) or (lb) may also be used effectively
above the ug range. The dosage may then be in the gram range, for example.
In another aspect the present invention relates to the above-mentioned pharmaceutical
formulations as such which are characterized in that they n a compound of formula (la)
or (lb), particularly the above-mentioned pharmaceutical formulations which can be
administered by inhalation.
The following examples of formulations illustrate the present invention without restricting its
scope:
Examples of ceutical formulations:
A) Tablets per tablet
active substance (la) or (lb) 100 mg
lactose 140 mg
maize starch 240 mg
polyvinylpyrrolidone 15 mg
magnesium stearate 5 mg
2 500 mg
The finely ground active substance, lactose and some of the maize starch are mixed
together. The mixture is screened, then moistened with a solution of nylpyrrolidone in
water, d, wet granulated and dried. The granules, the remaining maize starch and the
magnesium stearate are screened and mixed together. The e is pressed into tablets of
suitable shape and size.
B) Tablets per tablet
active substance (la) or (lb) 80 mg
lactose 55 mg
maize starch 190 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
sodium carboxymethyl starch 23 mg
magnesium stearate 2 mg
2 400 mg
The finely ground active substance, some of the corn , lactose, microcrystalline
cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked
1O with the remaining corn starch and water to form a granulate which is dried and ed.
The sodium carboxymethyl starch and the ium stearate are added and mixed in and
the mixture is compressed to form tablets of a suitable size.
C) e solution
active substance (la) or (lb) 50 mg
sodium chloride 50 mg
water for in]. 5 ml
The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and
sodium chloride is added to make the solution ic. The resulting solution is filtered to
remove pyrogens and the filtrate is transferred under aseptic conditions into ampoules which
are then sterilized and heat-sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active
substance.
D) Metering aerosol
active substance (la) or (lb) 0.005
sorbitan trioleate 0.1
monofluorotrichloromethane and
TG134a : T6227 2:1 ad 100
The suspension is transferred into a conventional aerosol ner with metering valve.
Preferably 50 ul sion are released on each actuation. The active substance may also
be released in higher doses if desired (e.g. 0.02 wt.-%).
2012/050830
E) Solutions (in mg/100ml)
active substance (la) or (lb) 333.3 mg
benzalkonium chloride 10.0 mg
EDTA 50.0 mg
HCI (1N) ad pH 2.4
This solution can be prepared in the usual way.
1O F) lnhalable powder
active substance (la) or (lb) 12 ug
lactose monohydrate ad 25 mg
The inhalable powder is ed in the usual way by mixing the individual ingredients.
The following examples serve to further illustrate the present invention without cting its
scope.
EXAMPLES
|. HPLC METHODS
Method A:
HPLC-MS: t 1100
Mobile phase:
A: water with 0.032% NH4OH
B: methanol
time in min %A %B flowrate in ml/min
0.00 95 5 1.50
3O 2.00 0 100 1.50
2.50 0 100 1.50
2.60 95 5 1.50
2.90 95 5 1.50
Column: XBridge C18, 3,5um, 4,6 x 50mm (column temperature: constant at 40°C).
Detection by diode array detector at 210-500 nm wavelength.
Method B:
HPLC-MS: Waters ZQ MS, Alliance 2690/2695 HPLC, 2996 diode array detector
Mobile Phase:
A: water with 0.1% TFA
B: methanol
timeinmin %A %B flow rate in ml/min
0.00 95 5 4.0
0.20 95 5 4.0
1.60 0 100 4.0
2.10 0 100 4.0
: Waters XBridge C18, 4.6 x 20 mm, 3.5 um (column temperature: constant at 40°C).
Detection by diode array detector at 210-400 nm ngth.
Method C:
HPLC: Waters Acquity with DA and MS or
Mobile Phase:
A: water with 0.1% TFA
B: methanol
time in min %A %B flowrate in ml/min
0.00 99 1 1.5
0.05 99 1 1.5
1.05 0 100 1.5
1.20 0 100 1.5
Column: Waters XBridge BEH C18, 2.1 x 30 mm, 1.7 um (column temperature: constant at
60°C). Detection by diode array detector at 210-400 nm wavelength.
Method D:
HPLC: Waters Acquity with DA and MS detector
Mobile Phase:
A: water with 0.13% TFA
B: methanol with 0.05% TFA
time in min %A %B flow rate in ml/min
0.00 99 1 1.3
0.05 99 1 1.3
1.05 0 100 1.3
1.20 0 100 1.3
Column: Waters XBridge BEH C18, 2.1 x 30 mm, 1.7 pm (column temperature: constant at
60°C). Detection by diode array detector at 210-400 nm wavelength.
Method E:
HPLC: Waters y with DA and MS detector
Mobile Phase:
A: water with 0.1% TFA
B: methanol
time in min %A %B flowrate in ml/min
0.00 95 5 1.4
0.05 95 5 1.4
1.00 0 100 1.4
1.10 0 100 1.4
Column: Waters XBridge C18, 2.1 x 30 mm, 2.5 pm (column temperature: constant at 60°C).
Detection by diode array detector at 210-400 nm wavelength.
Method F:
HPLC: Agilent 1200 with DA and MS detector
Mobile Phase:
A: water with 0.1 % TFA
B: methanol
time in min %A %B flowrate in ml/min
0.00 95 5 2.0
0.20 95 5 2.0
1.50 0 100 2.0
1.55 0 100 2.6
1.75 0 100 2.6
Column: Waters XBridge C18, 3 x 30 mm, 2.5 pm n temperature: nt at 60°C).
Detection by diode array detector at 210-400 nm wavelength.
Method G:
HPLC-MS: Waters Alliance with DA and MS detector
Mobile Phase:
A: water with 0.1% NH3
B: methanol with 0.1% NH3
time in min %A %B flowrate in ml/min
0.00 95 5 4.0
0.20 95 5 4.0
1.50 0 100 4.0
1.75 0 100 4.0
Column: Waters XBridge C18, 4.6 x 30 mm, 3.5 pm n temperature: constant at 60°C).
Detection by diode array detector at 210-400 nm wavelength.
Method H:
HPLC-MS: Waters Alliance with DA and MS detector
Mobile Phase:
A: water with 0.1% TFA
B: methanol
time in min %A %B flowrate in ml/min
0.00 95 5 4.8
1.60 0 100 4.8
1.85 0 100 4.8
1.90 95 5 4.8
Column: Waters SunFire C18, 4.6 x 30 mm, 3.5 pm (column temperature: nt at 60°C).
Detection by diode array detector at 210-400 nm wavelength.
Method J:
HPLC: Waters Acquity with DA and MS detector
Mobile Phase:
A: water with 0.13 % TFA
B: ol with 0.05 % TFA
time in min %A %B flowrate in ml/min
0.00 99 1 1.2
0.15 99 1 1.2
1.10 0 100 1.2
1.25 0 100 1.2
Column: Waters Sunfire C18, 2.1 x 30 mm, 2.5 pm (column ature: constant at 60°C).
Detection by diode array detector at 210-400 nm wavelength.
Method K:
HPLC-MS: Waters Alliance with DA and MS detector
Mobile Phase:
A: water with 0.1% TFA
B: methanol with 0.1% TFA
timeinmin %A %B flow rate in ml/min
0.00 95 5 4.0
0.20 95 5 4.0
1.50 0 100 4.0
1.75 0 100 4.0
1.85 95 5 4.0
Column: Waters XBridge C18, 4.6 x 30 mm, 3.5 um (column temperature: constant at 60°C).
Detection by diode array or at 210-400 nm wavelength.
Method L:
HPLC-MS: Waters Alliance with DA and MS detector
Mobile Phase:
A: water with 0.1% TFA
B: methanol
time in min %A %B flow rate in ml/min
0.00 95 5 4.8
1.60 0 100 4.8
1.85 0 100 4.8
1.90 95 5 4.8
Column: Waters XBridge C18, 4.6 x 30 mm, 3.5 um (column temperature: nt at 60°C).
Detection by diode array detector at 210-400 nm ngth.
Method M:
HPLC-MS: Waters 2695 HPLC, ZQ MS, 2996 diode array detector, 2695 autosampler
Mobile Phase:
A: water with 0.1% NH3
B: methanol with 0.1% NH3
time in min %A %B flow rate in ml/min
0.00 95 5 4.0
0.20 95 5 4.0
1.50 0 100 4.0
1.75 0 100 4.0
Column: Waters XBridge C18, 4.6 x 30 mm, 3.5 pm n temperature: constant at 60°C).
ion by diode array detector at 210-400 nm wavelength.
Method N:
HPLC: Waters Acquity with DA and MS detector
Mobile Phase:
A: water with 0.13% TFA
B: methanol with 0.08% TFA
time in min %A %B flowrate in ml/min
0.00 99 1 1.3
0.05 99 1 1.3
0.35 0 100 1.3
0.50 0 100 1.3
Column: Waters XBridge BEH C18, 2.1 x 30 mm, 1.7 pm (column temperature: constant at
60°C). Detection by diode array detector at 210-400 nm wavelength.
Method 0:
HPLC: t 1200 with DA and MS or
Mobile Phase:
A: water with 0.1 % TFA
B: methanol
time in min %A %B flowrate in ml/min
0.00 95 5 1.9
0.20 95 5 1.9
1.55 0 100 1.9
1.60 0 100 2.4
1.80 0 100 2.4
Column: Waters XBridge C18, 3 x 30 mm, 2.5 pm (column temperature: constant at 60°C).
Detection by diode array detector at 210-400 nm wavelength.
||. SYNTHESIS OF STARTING COMPOUNDS
A) Synthesis of Amines
1.) [1-(4-Aminobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid methyl ester
a) To a solution of (3,5-dimethyl-1H-pyrazolyl)-acetic acid methyl ester (3.90 g, 23 mmol)
and 4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in acetonitrile is added K2C03 (2.76 g, 19.9
mmol) and the mixture is stirred for one hour at room temperature. The reaction e is
poured into water and extracted twice with ethyl acetate. The organic phase is dried over
1O MgSO4 and evaporated under d re. To yield 7.50 g of [3,5-Dimethyl(4-nitro-
)-1H-pyrazolyl]—acetic acid methyl ester (ESI mass spectrum: [M+H]+ = 304).
b) To a on of [3,5-dimethyl(4-nitro-benzyl)-1H-pyrazolyl]—acetic acid methyl ester
(3.90 g, 10.3 mmol) in methanol (10 mL) is added 10 % palladium on charcoal (500 mg) and
the mixture is hydrogenated. The catalyst is filtered off and the te is concentrated under
reduced pressure. The mixture is purified via preparative reversed phase HPLC (gradient of
methanol in water + 0.1 % NHs) to yield 1.18 g of the title compound (ESI mass spectrum:
[M+H]+ = 274; Retention time HPLC: 2.13 min (method A))
2.) [1-(4-Aminochloro-benzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid ethyl ester
a) To a solution of (3,5-dimethyl-1H-pyrazolyl)-acetic acid ethyl ester (1.40 g, 7.7 mmol)
and 2-chloronitrobenzyl bromide (4.60 g, 20.7 mmol) in 20 mL acetonitrile is added K2C03
(1.59 g, 11.5 mmol) and the mixture is stirred for 48 hours at room temperature. The solvent
is removed by evaporation and the residue is dissolved in dichloromethane/water. After
extraction with dichloromethane the organic layer is dried over NaZSO4 and evaporated under
reduced pressure to yield 2.79 g of [3,5-dimethyl(2-chloronitro-benzyl)-1H-pyrazolyl]-
acetic acid ethyl ester (ESI mass spectrum: [M+H]+ = 352; Retention time: 1.95 min (method
A).
b) To a on [3,5-dimethyl(2-chloronitro-benzyl)-1H-pyrazolyl]acetic acid ethyl
ester (2.39 g, 6.8 mmol) in methanol (40 mL) is added Raney nickel (250 mg) and the
mixture is hydrogenated. The catalyst is filtered off and the filtrate is concentrated under
reduced pressure to yield 1.18 g of the title compound (ESI mass spectrum: [M+H]+ = 322;
Retention time HPLC: 1.76 min (method A)).
3.) [1-(4-Amino-benzyl)—3,5-diethyl-1H-pyrazolyl]-acetic acid ethyl ester
a) To a solution of (3,5-diethyl-1H-pyrazolyl)-acetic acid ethyl ester (10.95 g, 52.1 mmol)
and 4-nitrobenzyl bromide (14.625 g, 68 mmol) in acetonitrile (110 mL) is added K2C03
(10.80 g, 78.1 mmol) and the mixture is stirred for 48 hours at room temperature. The
1O reaction e is poured into water and extracted twice with ethyl acetate. The c
phase is dried over MgSO4 and ated under reduced pressure. The residue is ed
by MPLC with ethyl acetate/cyclohexane to yield 12.50 g [3,5-diethyl(4-nitro-benzyl)-1H-
pyrazolyl]acetic acid ethyl ester (ESI mass spectrum: [M+H]+ = 346; Retention time HPLC:
1.42 min (method B)).
b) To a solution of [3,5-diethyl(4-nitro-benzyl)—1H-pyrazolyl]acetic acid ethyl ester (6.66
g, 19.3 mmol) in methanol (500 mL) is added Raney nickel (500 mg) and the mixture is
hydrogenated at 50 psi and room temperature. The catalyst is filtered off and the te is
concentrated under reduced pressure to yield 4.38 g of the title nd (ESI mass
spectrum: [M+H]+ = 316; Retention time HPLC: 1.09 min (method B)).
4.) [1-(4-Aminofluorobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid methyl ester
a) To a solution of (3,5-dimethyl-1H-pyrazolyl)—acetic acid methyl ester (10 g, 48.9 mmol)
and 2-fluoronitrobenzyl bromide (11.5 g, 49.1 mmol) in acetonitrile (150 mL) is added
K2C03 (10.1 g, 73.3 mmol) and the mixture is stirred for 48 hours at 60°C. The solvent is
removed by evaporation and the residue is dissolved in dichloromethane/water. After
extraction with romethane the organic layer is dried over NaZSO4 and evaporated under
3O reduced pressure. The residue is purified by MPLC (cyclohexane/diethyl ether 7:3) to yield
13 g of [3,5-dimethyl(2-fluoronitro-benzyl)—1H-pyrazolyl]acetic acid methyl ester (ESI
mass spectrum: [M+H]+ = 322; Retention time (HPLC): 0.85 min (method C)).
b) To a solution of [3,5-dimethyl(2-fluoronitro-benzyl)-1H-pyrazolyl]acetic acid methyl
ester (13 g, 40.4 mmol) in ol (250 mL) is added Raney nickel (6 g) and the mixture is
hydrogenated at 50 psi and 50°C. The st is filtered off and the filtrate is concentrated
under d pressure. The mixture is purified by crystallization in diisopropyl ether to yield
12.8 g of the title compound (ESI mass spectrum: [M+H]+ = 292; Retention time HPLC: 0.61
min (method C)).
.) Aminochloro-benzyl)-3,5-dimethyl-1H-pyrazolyl]—acetic acid tert-butyl ester
a) To a solution of (3,5-dimethyl-1H-pyrazolyl)—acetic acid utyl ester (2.6 g, 12.4
1O mmol, preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-
heptanedione) and ronitrobenzyl bromide (3.11 g, 12.4 mmol) in acetonitrile (30 mL)
is added K2C03 (2.575 g, 18.6 mmol) and the mixture is stirred for 48 hours at room
temperature and after that 2 hours at 60°C. The solid is filtered off and the solvent is
removed by evaporation. The residue is dissolved in dichloromethane/water. After extraction
with dichloromethane the organic layer is dried over MgSO4 and evaporated under reduced
pressure to yield 4.4 g of [3,5-dimethyl(2-chloronitrobenzyl)-1H-pyrazolyl]acetic acid
tert-butyl ester (ESI mass spectrum: [M+H]+ = 380).
b) To a solution of [3,5-dimethyl(2-chloronitrobenzyl)-1H-pyrazolyl]acetic acid tert-
butyl ester (4.40 g, 11.6 mmol) in methanol (80 mL) is added Raney nickel (440 mg) and the
mixture is hydrogenated at 50 psi and room temperature for 12 hours. The st is filtered
off and the filtrate is concentrated under reduced pressure to yield 2.4 g of the title compound
(ESI mass spectrum: [M+H]+ = 350; Retention time HPLC: 0.76 min d D)).
6.) [1-(4-Aminobenzyl)—3,5-dimethyl-1H-pyrazolyl]acetic acid tert-butyl ester
The title compound (ESI mass spectrum: [M+H]+ = 316; Retention time HPLC: 0.65 min
(method E)) is synthesized in analogy to procedure ||.A.5 by using 4-nitrobenzylbromide
3O instead of ronitrobenzylbromide.
7.) [1-(4-Aminofluorobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid tert-butyl ester
a) To a solution of (3,5-dimethyl-1H-pyrazolyl)acetic acid tert-butyl ester (10 g, 47.6 mmol,
preparation according to WO2007/141267 by using 2,4-pentanedione instead of 3,5-
heptanedione) and 2-fluoronitrobenzyl bromide (11.2 g, 47.9 mmol) in itrile (150
mL) is added K2C03 (6.615 g, 47.9 mmol) and the mixture is stirred for 24 hours at room
temperature. The solid is filtered off and the solvent is removed by evaporation. The residue
is dissolved in dichloromethane/water. After extraction with dichloromethane the c
layer is dried over MgSO4 and evaporated under reduced pressure. The residue is purified by
MPLC (cyclohexane/ethyl acetate 7:3, silicagel 60) to yield 13.6 g of [3,5-dimethyl(2-
fluoronitrobenzyl)-1H-pyrazolyl]acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+
= 364 TLC: Rf = 0.23 (cyclohexan/ethyl acetate 7:3, solicagel 60 F254)).
1O b) To a solution of [3,5-dimethyl(2-fluoronitrobenzyl)—1H-pyrazolyl]acetic acid tertbutyl
ester (13.6 g, 37.4 mmol) in methanol (250 mL) is added Raney nickel (6 g) and the
mixture is hydrogenated at 50 psi and 50°C for 12 hours. The catalyst is filtered off and the
filtrate is trated under reduced pressure to yield 11.6 g of the tiltle compound (ESI
mass spectrum: [M+H]+ = 334; TLC: Rf = 0.53 (dichloromethane/methanol 95:5, gel 60
F254)).
B) Synthesis of carboxylic acids
1.) 1-Ethylfluoro-1H-indolecarboxylic acid
a) To a solution of roindolethyl ester (200 mg, 0.965 mmol) in dimethylsulfoxide (6
mL) is added potassium tert-butylate (108 mg, 0.965 mmol) and the mixture is stirred at 50°C
for 30 minutes. After cooling to room ature thane (0.081 mL, 1.06 mmol) is
added and the mixture is stirred at room temperature for 2.5 hours. With cooling water is
added and the mixture is extracted with ethyl acetate. The organic layer is washed with water
and saturated aqueous NaCl solution, dried over MgSO4 and the solvent is evaporated in
vacuo to yield 200 mg of lfluoro-1H-indolecarboxylic acid ethyl ether (ESI mass
3O spectrum: [M+H]+ = 236).
b) To a solution of lfluoro-1H-indolecarboxylic acid ethyl ether (200 mg, 0.85
mmol) in dioxan (2 mL) is added an aqueous solution of NaOH (1 M, 1.7 mL) and the mixture
is stirred at 60°C for 1 hour. After evaporation of the solvent the residue was suspended in a
few water and neutralized with acetic acid (2 M). The precipitate is filtered, washed with
water and dried to yield 140 mg of the title compound (ESI mass spectrum: [M+H]+ = 208;
Retention time HPLC: 1.21 min (method F)).
The following indole carboxylic acids are ed likewise in anlaogy to this method:
1-Benzyl-1H-indolecarboxylic acid (ESI mass spectrum: [M+H]+ = 252 Retention time
HPLC: 0.84 min (method E));
1O 1-Butyl-1H-indolecarboxylic acid (ESI mass spectrum: [M+H]+ = 218);
-Fluoropropyl-1H-indolecarboxylic acid (ESI mass spectrum: [M+H]+ = 222);
1-Butylfluoro-1H-indolecarboxylic acid (ESI mass um: [M+H]+ = 236);
1-Propyl-1H-indolecarboxylic acid (ESI mass spectrum: [M+H]+ = 204);
1-Ethylfluoro-1H-indolecarboxylic acid (ESI mass spectrum: [M+H]+ = 208; Retention
time HPLC: 0.80 min (method E);
1-Ethylfluoro-1H-indolecarboxylic acid (ESI mass spectrum: [M+H]' =206; Retention
time HPLC: 0.71 min (method E));
6-Fluoropropyl-1H-indolecarboxylic acid (ESI mass spectrum: [M-H]' = 220; Retention
time HPLC: 0.77 min (method E)).
2.) 3-Ethylfluorobenzofurancarboxylic acid
a) To a solution of 5-fluorohydroxy-propiophenone (0.9 g, 5.2 mmol) and tert-butyl
3O bromoacetate (0.9 mL, 6.1 mmol) in acetonitrile (15 mL) is added K2C03 (1.08 g, 7.8 mmol)
and the mixture is refluxed for 3 hours. After cooling to room temperature the mixture is
poured into water and extracted with ethyl acetate. The c layer is washed twice with
water, dried over MgSO4 and the t is evaporated in vacuo to yield 1.47 g of (4-fluoro
nylphenoxy)acetic acid tert-butyl ester (ESI mass spectrum: [M+H]+ = 283; Retention
time HPLC: 0.88 min (method D)).
b) To a solution of (4-fluoropropionylphenoxy)acetic acid tert-butyl ester (1.47 g, 5.2 mmol)
in dry ethanol (20 mL) is added on of sodium methanolat in methanol (5.4 M, 20 mL)
and the mixture is stirred at 80°C for 12 hours. After cooling to room temperature and
evaporation of the solvent the residue was dissolved in water and acidified with hydrochloric
acid (1 M). The precipitate is filtered, washed with water and dried to yield 440 mg of the title
compound (ESI mass spectrum: [M-H]' = 207; ion time HPLC: 0.87 min (method 6)).
The following benzofuran carboxylic acids are prepared likewise in analogy to this method:
7-Chloromethylbenzofurancarboxylic acid (ESI mass spectrum: [M-H]' = 209; Retention
time HPLC: 1.28 min (method H));
-Fluoropropylbenzofurancarboxylic acid (ESI mass spectrum: [M-H]' = 221; Retention
time HPLC: 1.01 min (method 6));
3-Ethylfluorobenzofurancarboxylic acid (ESI mass um: [M-H]' = 207; Retention
time HPLC: 0.77 min (method E));
3-Ethyl-5,7-difluorobenzofurancarboxylic acid (ESI mass spectrum: [M-H]' = 225;
Retention time HPLC: 1.32 min (method L));
6-Chlorobenzofurancarboxylic acid (ESI mass spectrum: [M-H]' = 195; ion time
HPLC: 1.72 min (method H)).
lll) SYNTHESIS OF NDS (la) and (lb)
Compound 1: (1-(2-fluoro[(1H-indolecarbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol
3O tic acid (Coupling method C1):
a) To a solution of indolecarboxylic acid (80 mg, 0.50 mmol) in N,N-dimethylformamide
(1.5 mL) are added TBTU (139 mg, 0.43 mmol) and N,N-diisopropyl amine (0.126 mL, 0.74
mmol). Subsequently [1-(4-aminofluorobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid
methyl ester (120 mg, 0.41 mmol) is added. The mixture is stirred at room temperature for 12
hours. After that an aqueous solution of K2C03 (2 M, 0.5 mL) is added. The obtained mixture
is flushed through A1203 with dichloromethane/methanol (9:1, 10 mL). The solvent is d
in vacuo to yield 82.3 mg of (1-(2-fluoro[(1H-indolecarbonyl)amino]benzyl)-3,5-dimethyl-
1H-pyrazolyl)acetic acid methyl ester (ESI mass spectrum: [M+H]+ = 435; Retention time
HPLC: 0.41 min (method N).
b) (1-(2-Fluoro[(1H-indolecarbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazolyl)acetic
acid methyl ester (82 mg, 0.19 mmol) is dissolved in ol (0.5 mL). An aqueous solution
of NaOH (4M, 0.3 mL) is added and the mixture is stirred at room temperature for 2 hours.
1O The resulting mixture is diluted with methanol/water, the solid is filtered off and after
ation the residue is purified by HPLC (Gilson, XRS Pursuit, methanol/HZO+0.1 %
conc. NH3). The fractions containing the title nd are concentrated and lyophilized to
yield 15 mg of the title compound (ESI mass spectrum: [M+H]+ = 421; Retention time HPLC:
1.04 min (method 6)).
1H-NMR 400 MHz (DMSO-d6): 5 [ppm] = 2.03 (s, 3H), 2.14 (s, 3H), 2.52 (s, 3H), 3.21 (s, 2H),
.16 (s, 2H), 6.99 (t, 1H), 7.08 (t, 1H), 7.23 (t, 1H), 7.39 (s, 1H), 7.48 (m, 2H), 7.66 (d, 1H),
7.79 (d, 1H), 10.45 (s, 1H), 11.79 (br., 1H).
Compounds 2 and 3 of table 1 below have likewise been prepared in analogy to ng
method C1 using le starting amines and carboxylic acids.
Compound 4: [(5-Fluoromethylbenzofurancarbonyl)amino]benzyl}-3,5-dimethyl-
1H-pyrazolyl)acetic acid (Coupling method C2):
a) To a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid methyl ester
(400 mg, 1.46 mmol) in 5 mL dichloromethane are added diisopropylethylamine (1.5 mL, 8.8
mmol) and 5-fluoromethylbenzofurancarboxylic acid (369 mg, 1.9 mmol). After
stirring at room temperature for 10 minutes a 50 % solution of 1-propylphosphonic acid cyclic
3O ide in ethyl acetate (1.725 mL, 2.93 mmol) is added with cooling and the mixture is
stirred at room temperature for 12 hours. The solvent is evaporated in vacuo and the residue
is purified by MPLC (dichloromethane/methanol 98:2) to yield 410 mg of (1-{4-[(5-fluoro
methylbenzofurancarbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazolyl)acetic acid methyl
ester (ESI mass spectrum: [M+H]+ = 450; TLC: Rf = 0.56 (dichloromethane/methanol 95:5,
silicagel 60 F254)).
b) To a solution of (1-{4-[(5-f|uoromethylbenzofurancarbonyl)amino]benzyl}-3,5-
dimethyl-1H-pyrazolyl)acetic acid methyl ester (410 mg, 0.91 mmol) in dioxan/water (10
mL/10 mL) is added 1 M NaOH (2.3 mL) and the mixture is d at room temperature for
24 hours. The e is diluted with water and ied with hloric acid (1 M, 3.25
mL). The precipitate is filtered, washed with water and dried to yield 338 mg of the title
compound (ESI mass um: [M+H]+ = 436; Retention time HPLC: 0.85 min d D).
1H-NMR 400 MHz (DMSO-d6): 6 [ppm] = 2.05 (s, 3H), 2.10 (s, 3H), 2.52 (s, 3H), 3.24 (s, 2H),
1O 5.16 (s, 2H), 7.10 (d, 2H), 7.37 (t, 1H), 7.66 (m, 2H), 7.75 (d, 2H), 10.40 (s, 1H), 12.05 (br.,
1H).
Compounds 5 to 26 and 57 to 59 of tables 1 and 2 below have likewise been prepared in
analogy to coupling method C2 using suitable starting amines and carboxylic acids.
Compound 27: (1-{2-Fluoro[(5-fluoromethylbenzofurancarbonyl)amino]benzyl}-3,5-
dimethyl-1H-pyrazolyl)-acetic acid (Coupling method C3):
a) To a solution of 5-fluoromethylbenzofurancarboxylic acid (194 mg, 1 mmol) in 5
mL dimethylformamide is added diisopropylethylamine (0.516 mL, 3 mmol) and HATU (399
mg, 1.05 mmol) is added. After ng at room temperature for 25 minutes
dimethylformamide (1 mL) and then intermediate [1-(4-aminofluorobenzyl)-3,5-dimethyl-
1H-pyrazolyl]acetic acid methyl ester (291 mg, 1 mmol) is added. Subsequently
diisopropylethylamine (0.344 mL, 2 mmol) and dimethylformamide (2 mL) is added, and the
mixture is stirred at room temperature for 48 hours. Then ethyl actetate and water are added
and the precipitate is filtered off. The organic layer is extracted twice with acetic acid (1 N),
once with an aqueous solution of NaHCO3 (5 % by weight) and twice with water, dried over
MgSO4. The solvent is removed by evaporation in vacuo. The residue is prurified by MPLC
(dichloromethane/methanol 96:4) to yield 120 mg of (1-(2-fluoro[(5-fluoro
3O methylbenzofurancarbonyl)-amino]-benzyl)-3,5-dimethyl-1H-pyrazolyl)-acetic acid
methyl ester (ESI mass spectrum: [M+H]+ = 468; TLC: Rf = 0.72 (dichloromethane/methanol
9:1, silicagel 60 F254)).
b) To a solution of (1-(2-f|uoro[(5-fluoromethylbenzofurancarbonyl)-amino]-benzyl)-
3,5-dimethyl-1H-pyrazolyl)-acetic acid methyl ester (119 mg, 0.26 mmol) in dioxan/water
(7 mL/7 mL) is added an aqueous solution of NaOH (1 M, 2.3 mL) and the mixture is stirred
at room temperature for 12 hours and at 60°C for 2 hours. The mixture is diluted with water,
acidified with hydrochloric acid (1 M, 1 mL) and extracted with ethyl acetate. The organic
layer is dried over MgSO4, the solvent evaporated in vacuo, the residue is llized with
diisopropylether and the precipitate is isolated by filtration to yield 69 mg of the title
compound (ESI mass spectrum: [M+H]+ = 454; Retention time HPLC: 0.90 min (method D)).
1H-NMR 400 MHz (DMSO-d6): 6 [ppm] = 2.03 (s, 3H), 2.14 (s, 3H), 2.57 (s, 3H), 3.28 (s, 2H),
.18 (s, 2H), 6.96 (t, 1H), 7.37 (t, 1H), 7.54 (d, 1H), 7.66 (m, 2H), 7.79 (d, 1H), 10.60 (s, 1H),
1O 1207 (br., 1H).
Compounds 28 to 31 of table 1 below have likewise been prepared in analogy to coupling
method C3 using suitable starting amines and carboxylic acids.
Compounds 32: (1-(4-[(1-Ethylfluoro-1H-indolecarbonyl)amino]fluorobenzyl)-3,5-
dimethyl-1H-pyrazolyl)acetic acid (Coupling method C4):
a) To a solution of 1-ethylfluoro-1H-indolecarboxylic acid (140 mg, 0.68 mmol) in 6 mL
dichloromethane is added oxalyl chloride (0.094 mL, 0.68 mmol) and a drop
dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by
evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a
solution of [1-(4-aminofluorobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid methyl ester
(177 mg, 0.61 mmol) and ropylethylamine (0.23 mL, 1.35 mmol) in dichloromethane (5
mL). After addition of thylaminopyridine (8.255 mg, 0.069 mmol) the solution is d
at room temperature for 12 hours. The solution is extracted twice with hydrchloric acid (1 M),
twice with water, twice with an aqueous solution of NaOH (1 M) and twice with water. The
organic layer is dried over MgSO4, ed and the t is ated in vacuo. The
residue is purified by MPLC (dichloromethane/methanol 95:5) to yield 160 mg of (1-(4-[(1-
ethylfluoro-1H-indolecarbonyl)amino]fluorobenzyl)-3,5-dimethyl-1H-pyrazol
3O yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+ = 481; Retention time HPLC: 0.93
min (method D)).
b) To a solution of (1-(4-[(1-ethylfluoro-1H-indolecarbonyl)amino]fluorobenzyl)-3,5-
yl-1H-pyrazolyl)acetic acid methyl ester (160 mg, 0.33 mmol) in dioxan (2mL) is
added an aqueous solutio of NaOH (1 M, 0.66 mL) and the mixture is stirred at 60°C for 1
hour. The solvent is ated in vacuo, and the e is suspended in water and treated
with acetic acid (2 M). The precipitate is dryfreezed, dissolved in ol and few
dimethylformamide, and the product is precipitated with a few water, filtered and dried to
yield 137 mg of the title compound (ESI mass spectrum: [M+H]+ = 467; Retention time HPLC:
0.89 min (method D)).
1H-NMR 400 MHz (DMSO-d6): 6 [ppm] = 1.30 (t, 6H), 2.04 (s, 3H), 2.13 (s, 3H), 3.25 (s,
2H), 4.55 (q, 4H), 5.16 (s, 2H), 6.97 (t, 1H), 7.17 (t, 1H), 7.29 (s, 1H), 7.47 (m, 1H), 7.62 (dd,
1H), 7.74 (d, 1H), 10.52 (s, 1H).
nd 33: (1-(4-[(7-Chloromethylbenzofurancarbonyl)amino]benzyl)-3,5-dimethyl-
1H-pyrazolyl)acetic acid (Coupling method C4):
a) To a solution of 7-chloromethylbenzofurancarboxylic acid (185 mg, 0.88 mmol) in 6
mL dichloromethane is added oxalyl chloride (0.123 mL, 1.14 mmol) and a drop of
dimethylformamide. After stirring at room temperature for 1 hour the solvent is d by
evaporation in vacuo. The residue is dissolved in dichloromethane (5 mL) and dropped to a
solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid tert-butyl ester (428
mg, 1 mmol) in form of the toluenesulphonate salt and diisopropylethylamine (0.39 mL, 2.27
mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (11 mg, 0.09
mmol) the solution is stirred at room temperature for 12 hours. The solution is extracted twice
with hydrochloric acid (1 M), twice with water, twice with an aqueous solution of NaOH (1 M)
and twice with water. The organic layer is dried over MgSO4, filtered and the solvent is
evaporated in vacuo to yield 426 mg of (1-(4-[(7-chloromethyl-benzofuran
carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4—yl)acetic acid tert-butyl ester (ESI mass
spectrum: [M+H]+ = 508; Retention time HPLC: 1.60 min (method H)).
b) To a solution of (1-(4-[(7-chloromethyl-benzofurancarbonyl)amino]benzyl)-3,5-
dimethyl-1H-pyrazolyl)acetic acid tert-butyl ester (426 mg, 0.84 mmol) in romethane
3O (10mL) is added trifluoroacetic acid (400 mL, 5.2 mmol) and the mixture is stirred at room
temperature for 3 days. The solvent is evaporated in vacuo, and the residue is suspended in
water and treated with diethylether and the precipitating t is filtered off to yield 174 mg
of the title compound (ESI mass spectrum: [M+H]+ = 452; Retention time HPLC: 1.39 min
(method J)).
1H-NMR 400 MHz (DMSO-d6): 5 [ppm] = 2.07 (s, 3H), 2.14 (s, 3H), 2.57 (s, 3H), 3.29 (s,
2H), 5.17 (s, 2H), 7.12 (d, 2H), 7.38 (t, 1H), 7.62 (d, 1H), 7.74 (d, 2H), 7.76 (d, 1H), 10.33 (s,
1H).
nd 48: (1-(4-[(3-Ethylfluorobenzofurancarbonyl)amino]benzyl)-3,5-dimethyl-1H-
pyrazolyl)-acetic acid (Coupling method C4)
a) To a solution of 3-ethylfluorobenzofurancarboxylic acid (450 mg, 2.16 mmol) in 10
mL dichloromethane is added oxalyl de (0.335 mL, 3.1 mmol) and a drop
1O dimethylformamide. After stirring at room temperature for 1 hour the solvent is removed by
evaporation in vacuo. The residue is dissolved in dichloromethane (10 mL) and dropped to a
on of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazolyl]acetic acid tert-butyl ester (1.054
g, 2.16 mmol) in the form of the 4-toluenesulphonate salt and ropylethylamine (1.3 mL,
7.57 mmol) in dichloromethane (5 mL). After addition of 4-dimethylaminopyridine (26.4 mg,
0.216 mmol) the solution is stirred at room temperature for 12 hours. The solvent is
evaporated in vacuo, dissolved in 100 mL ethyl acetate, and the solution is extracted twice
with water, once with hydrochloric acid (0.5 M), once with water, once with an s
solution of NaHCOs (5% by weight) and once with water. The organic layer is dried over
MgSO4, filtered and the solvent is evaporated in vacuo. The residue is purified by MPLC
(dichloromethane/methanol 98:2) to yield 150 mg of 1-(4-[(3-ethylfluorobenzofuran
carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4—yl)-acetic acid tert-butyl ester (ESI mass
spectrum: [M+H]+ = 506; Retention time HPLC: 1.02 min (method D)).
b) To a solution of (3-ethylfluorobenzofurancarbonyl)amino]benzyl)-3,5-dimethyl-
1H-pyrazolyl)-acetic acid tert-butyl ester (150 mg, 0.30 mmol) in acetonitrile (25mL) is
added montmorillonite KSF (300 mg) and the mixture is refluxed for 6 hours. The mixture is
diluted to 400 mL with acetonitrile, refluxed for 5 s and filtered. The t is
evaporated in vacuo and the residue is washed with dimethylformamide (300 mL). After
filtration the solvent is removed by evaporation and the residue is treated with acetone (200
3O mL). After trituration the precipitate is filtered off and washed with acetone to yield 112 mg of
the title compound (ESI mass spectrum: [M+H]+ = 450; Retention time HPLC: 0.85 min
(method E)).
1H-NMR 400 MHz (DMSO-d6): 5 [ppm] = 1.21 (t, 6H), 2.04 (s, 3H), 2.11 (s, 3H), 3.09 (q, 4H),
3.27 (s, 2H), 5.16 (s, 2H), 7.09 (d, 2H), 7.33 (t, 1H), 7.67 (m, 2H), 7.76 (d, 2H), 10.39 (s, 1H).
Compounds 34 to 47 and 49 to 56 of table 1 below have likewise been prepared in analogy
to coupling method C4 using suitable starting amines and ylic acids.
IV) BIOLOGICAL ASSAYS
The compounds of formula (la) and (lb) according to the invention were tested using the
following biological test methods to determine their ability to displace PGDZ from the CRTH2
receptor and for their ability to antagonise the functional effects of PGDZ at the CRTH2
1O receptor in a whole system.
PREPARATION OF HUMAN CRTH2 RECEPTOR NES AND RADIOLIGAND
BINDING ASSAY
The binding of CRTH2 antagonists is determined using membranes prepared from Chinese
hamster ovary cells (CHO-K1 cells) ected with the human CRTH2 receptor (CHO-K1-
hCRTH2 cells, Perkin Elmer, Cat No ESC). To produce cell membranes the CHO-K1-
hCRTH2 cells are cultured in suspension in CHO SFMII medium supplemented with
400 ug/ml G418. The cells are harvested by centrifugation at 300 g for 10 min at room
temperature. The cell pellet is resuspended in Phosphate Buffer Saline (PBS) including a
protease inhibitor mix (Complete, Roche) and adjusted to a concentration of 10E7 cells/ml.
The CHO-K1-hCRTH2 cells are disrupted by nitrogen osition to obtain the membrane
preparation. Cell debris is removed by fugation (500 g at 4°C, 30 min) and the
supernatant is transferred into fresh tubes followed by a second centrifugation at 40000 g for
1 h at 4 °C to sediment the nes. The membranes are suspended in SPA tion
buffer (50mM Tris HCI, 10 mM MgClz, 150 mM NaCl, 1 mM EDTA, pH 7.4) without bovine
serum albumin, homogenized by passing through a single use needle (Terumo, 23Gx1”),
and stored in aliquots at -80 °C.
3O The CRTH2 receptor binding assay is performed in a scintillation ity assay (SPA)
format with the radioligand [3H]-PGD2 n Elmer, NET616000MC). CHO-K1-hCRTH2 cell
membranes are again homogenized by passing through a single use needle (Terumo,
23Gx1”) and diluted in SPA incubation buffer in suitable trations (0.5 —10 ug
protein/well). The SPA assay is set up in 96 well microtiter plates n Elmer, CatNo.
6005040) in SPA incubation buffer with a final volume of 200 pl per well and final
concentration of 50 mM Tris-HCl, 10 mM MgClz, 150 mM NaCl, 1 mM EDTA pH 7.4, 0.1%
bovine serum albumin). The SPA assay mixture contains 60 pl of the membrane suspension,
80 pl of Wheat Germ Agglutinin coated PVT beads (GE Healthcare, RPNQ-0001, 0.3
mg/well) 40 pl of [3H]-PGD2 diluted in SPA buffer to a final concentration of 1 nM (50 000
dpm) and 20 pl of the test compound (dissolved in ylsulfoxid). The SPA assay mixture
is incubated for 3 h at room temperature. Bound radioactivity is determined with a scintillation
counter (Micro Beta Trilux, Wallac).
The binding of [3H]-PGD2 to CHO-K1-hCRTH2 cell membranes is determined in the absence
(total g, Bo) and presence (non-specific binding, NSB) of unlabelled PGD2 (1 uM,
1O Cayman Chemical, Cat No 12010) or a reference CRTH2 antagonist (10 uM CAY10471,
Cayman Chemical, Cat No 10006735).
Determination of the ty of a test compound is calculated by subtraction of the non-
ic binding (NSB) from the total binding (B0) or the binding in the presence of the test
compound (B) at a given compound concentration. The NSB value is set to 100% inhibition.
The Bo-NSB value is set to 0% inhibition.
% inhibition values were obtained at a d compound concentration, e.g. at 1 uM,
% inhibition of the test compound was calculated by the formula 100-((B-NSB)*100/(Bo-
NSB)). % inhibition values above 100% are founded by assay variance.
The dissociation constant Ki was calculated by iterative fitting of mental data obtained
at several compound concentrations over a dose range from 0.1 to 30 000 nM using the law
of mass action based m "easy sys" (Schittkowski, Num Math 68, 129-142 ).
CRTH2 CAMP FUNCTIONAL ASSAY PROTOCOL
The assay is conducted in CHO-K1-hCRTH2 cells. ellular cAMP is generated by
stimulating the cells with 10 uM Forskolin, an adenylate cyclase activator. PGD2 is added to
activate the CRTH2 receptor which results in the ation of the forskolin-induced cAMP
generation. Test compounds are tested for their ability to inhibit the PGD2-mediated
attenuation of the Forskolin-induced cAMP generation in CHO-K1-hCRTH2 cells.
CHO-K1-hCRTH2 cells are cultured in roller bottles in CHO SFMII medium supplemented
with 400ug/ml G418. The cells are harvested by centrifugation at 300 g for 10 min at room
temperature. The cell pellet is washed and ded in PBS. The cells are ed to a
final concentration of 4x10E6 cells/ ml.
Test compounds are diluted in dimethylsulfoxid and tested at several compound
concentrations over a dose range from 0.1 to 3 000 nM.
The cAMP levels are determined by an AlphaScreen cAMP assay (Perkin Elmer CatNo.
6760625M) in 384 well optiplates (PerkinElmer, CatNo. 6007290) with a total assay volume
of 50 pl. 10 ul of cells 0 cells per well) are incubated for 30 min at 37 °C with 10 ul of a
stimulation mix containing a final concentration of 10uM lin, 30 nM PGD2, 0.5 mM
IBMX, 5 mM HEPES, 1xHBSS , 0.1% BSA, adjusted to pH 7.4, and the test compound
1O at various concentrations. Thereafter, 30 ul of a lysis and ion mix is added containing
SA donor beads, biotinylated cAMP, anti-cAMP acceptor beads, 0.3% -20, 5 mM
HEPES, 0.1% BSA, adjusted to pH 7.4. After 2 h incubation time the AlphaScreen signal is
read on an AlphaQuest—HTS instrument. The IC50 values are calculated by using the Prism
software.
OTHER CRTH2 FUNCTIONAL ASSAY PROTOCOLS
The ability of the tested compounds to antagonise the functional effects of PGD2 at the
CRTH2 or may also be demonstrated by methodology known in the art, such as by a
whole cell binding assay, a GTPgS assay, a BRET assay, an inositol phosphate
accumulation assay, an CRTH2 cell surface expression assay, a Ca2+ influx assay, an ERK
phosphorylation assay, an cell migration assay, an eosinophil shape change assay, a Th2
cell degranulation assay, or a basophil activation assay as described by Mathiesen et al., Mol
Pharmacol. 2005, 68:393-402; Mimura et al., J. Pharmacol. Exp. Ther., 2005, 314:244-51;
Sandham et al., Bioorg. Med. Chem. Lett., 2007,17:4347-50; Sandham Bioorg. Med. Chem.
Lett., 2009,19:4794-8; Crosignani et al., J Med Chem, 2008, 51:2227-43; Royer et al., Eur J
Clin , 2008, 38:663-71; Boehme et al., lnt lmmunol, 2009, 21:621-32; Sugimoto et al.,
Pharmacol. Exp. Ther., 2003, 305:347-52; Monneret et al., J Pharmacol Exp Ther, 2005,
312:627-34; Xue etal., J. lmmunol., 2005,175:6531-6.
Cell lines for expressing the CRTH2 or include those naturally expressing the CRTH2
receptor, such as AML14.3D10 and NCl-H292 cells (Sawyer et al., Br. J. Pharmacol., 2002,
137:1163-72; Chiba et al., Int. Arch. Allergy. lmmunol., 2007,143 Suppl 1:23-7), those
induced to express the CRTH2 receptor by the addition of chemicals, such as HL-60 or
AML14.3D10 cells treated with, for example, butyric acid (Sawyer et al., Br. J. Pharmacol.,
2002, 137:1163-72) or a cell line engineered to express a recombinant CRTH2 receptor,
such as L1.2, CHO, HEK-293, K562 or CEM cells (Liu et al., Bioorg. Med. Chem. Lett.,
2009,19:6840-4; Sugimoto et al., Pharmacol Exp Ther, 2003, 305:347-52; Hata et al., Mol.
Pharmacol., 2005, 67:640-7; Nagata et al., FEBS Lett, 1999, 459:195-9).
Finally, blood or tissue cells, for example human peripheral blood phils, isolated using
methods as described by Hansel et al., J. lmmunol. Methods., 1991, 145,105-110, or human
Th2 cells isolated and treated as described by Xue et al., J. lmmunol., 2005,175:6531-6, or
human ils isolated and terized as described by Monneret et al., J. Pharmacol.
1O Exp. Ther., 2005, 312:627-34 can be utilized in such assays.
In particular, the nds of the present ion have activity in binding to the CRTH2
receptor in the aforementioned assays and inhibit the activation of CRTH2 by CRTH2
ligands. As used herein, "activity" is intended to mean a compound demonstrating an
inhibition of 50% at 1 uM or higher in inhibition, or a K, value < 1 uM, when measured in the
aforementioned assays. Such a result is indicative of the sic activity of the compounds
as inhibitor of CRTH2 receptor activity. Antagonistic activities of ed compounds are
shown in tables 1 and 2 below.
Table 1: Compounds of formula la”
('8")
Cmpd Z Ry ; Ry ; Ry ; MS Retention Ki
M;method G
' '
method B
C6H5 methodD
n-n -IiimethodD
Cmpd Z Ry ; Ry ; Ry ; MS Retention Ki
Ry“; Ry5 [M+H]+ Time [nM]
-I-- -methodD
H H method D
-I-- --methodD
-I--methodB
H; H
H; H
I-- -H H hod D
-I--methodK
-In-WHH method B
-fl-n F --Iii method D
-I- ”‘0th _--I-CH3 F; H method E
WO 01043
-HW-Cmpd Z Ry ; Ry ; Ry ; MS Retention Ki
F; H method E
H; H method C
H; H method C
H; H method D
H; CI method J
H; H; F method L
F; H; F method L
CI; H method M
H; CI method J
H; F method E
C' H method M
; H method E
; H method E
CH3 ; method E
H; H method D
' method D
' method D
; method D
H; H method D
H; H method E
H; H method F
H; F method F
H; H method F
H; H method D
CH3 H; H method 0
-flW-HCmpd MS ion [Ki]
-I-H‘CHHZ' CH3 method D
HHCHHH H H H
CH3 H;H-H method-E
H‘CHHH H ---
CH3 ;HH methodE
Table 2: Compounds of formula lb”
R R3”
”0 fifi
o R2 N /
H z
(|b") Ry5
[M+H] Time [n M]
method B
H; H; H; H; H 420
Claims (23)
1. A pyrazole nd of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, O R1 Rc HO Rd (R3) N O Ra Rb N Z R2 H Y5 Y1 Y4 (Ia) Y2 Y3 O R1 Rc HO Rd (R3) N O Ra Rb N Y1 R2 H Z (Ib) Y2 5 Y4 wherein Ra and Rb are ndently selected from en, hydroxy, halogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and C3-C8-cycloalkyl, or Ra and Rb together with the carbon atom they are 10 bound to form may form a carbonyl group, or Ra and Rb together with the carbon atom they are bound to form a 3- to 8-membered ring, wherein said ring may contain 1 or 2 heteroatoms selected from O, N and S as ring member and wherein the ring members of said ring may optionally be independently substituted by hydroxy, halogen, 15 C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and C3-C8-cycloalkyl; (9925931_1):KZA Rc and Rd are independently selected from hydrogen, hydroxy, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and C3-C8-cycloalkyl, or Ra and Rb together with the carbon atom they are bound to form may form a yl group, or Ra and Rb together with 5 the carbon atom they are bound to form a 3- to 8-membered ring, wherein said ring may contain 1 or 2 heteroatoms selected from O, N and S as ring member and wherein the ring s of said ring may optionally be independently substituted by y, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and 10 C3-C8-cycloalkyl; Y1, Y2, Y3, Y4 and Y5 are independently selected from N and CRy, wherein each Ry is independently selected from H, hydroxy, halogen, cyano, nitro, SF5, C(O)NRfRg, C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1- C6-alkyl, C3- C8-cycloalkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6- 15 alkoxy-C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkoxy, C1-C6- alkylamino, di-C1-C6-alkylamino, C1-C6-alkylsulfonyl, phenyl, phenoxy, 5- or 6-membered cyclyl and 5- or 6-membered heterocyclyloxy, wherein Rf and Rg are independently from each other ed from H, C1-C6-alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8- 20 cycloalkenyl and 5- or 6-membered cyclyl or Rf and Rg together with the nitrogen atom to which they are bound form a cyclic amine, which may comprise a further heteroatom selected from O, N and S as a ring member; Z is selected from O, S and NRz, wherein Rz is H, C1-C6-alkyl or benzyl; 25 R1 and R2 independently from each other are selected from H, halogen, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkylthio, - NRfRg, C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8- cycloalkyl-C2-C6-alkenyl, C3-C8-cycloalkenyl, cycloalkenyl-C1- C6-alkyl, C3-C8-cycloalkenyl-C2-C6-alkenyl, phenyl, phenyl-C1-C6- 30 alkyl, phenyl-C2-C6-alkenyl, naphthyl, naphthyl-C1-C6-alkyl, naphthyl- C2-C6-alkenyl, heterocyclyl, cyclyl-C1-C6-alkyl, and heterocyclyl- C2-C6-alkenyl, wherein (9925931_1):KZA the C1-C6-alkyl, alkenyl and C2-C6-alkynyl moieties in the aforementioned radicals R1 and R2 are unsubstituted or carry at least one substituent selected from hydroxy, halogen, cyano, nitro, alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, di C1-C6-alkylamino and C1-C6- 5 alkylsulfonyl and/or n two radicals bound to the same carbon atom of said C1-C6- alkyl, alkenyl and C2-C6-alkynyl moieties in the aforementioned radicals R1 and R2 together with said carbon atom may form a carbonyl group, and n 10 the C3-C8-cycloalkyl, cycloalkenyl, phenyl, naphthyl and heterocyclyl moieties in the aforementioned radicals R1 and R2 are unsubstituted or carry at least one substituent selected from y, halogen, cyano, nitro, C1-C6-alkyl, C3-C8-cycloalkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1- C6-haloalkoxy, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6- 15 alkylsulfonyl, phenyl and 5- or 6- membered hetaryl and/or wherein two radicals bound to the same carbon atom of said C3-C8- lkyl, C3-C8-cycloalkenyl and heterocyclyl moieties of the radicals R1 and R2 together with said carbon atom may form a carbonyl group, and wherein 20 Rf and Rg are ndently from each other selected from H, C1-C6- alkyl, C1-C6-haloalkyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl and heterocyclyl or Rf and Rg together with the nitrogen atom to which they are bound form a cyclic amine, which may comprise a further heteroatom selected from 25 O, N and S as a ring member; n is an integer selected from 0, 1, 2 or 3; and R3 if present are selected independently from each other from halogen, C1- C6-alkoxy and C1-C6-haloalkoxy.
2. A pyrazole compound of formula (Ia) or (Ib) according to claim 1, wherein Ra 30 and Rb are both hydrogen. (9925931_1):KZA
3. A pyrazole compound of formula (Ia) or (Ib) according to claim 1 to 2, wherein Rc and Rd are both hydrogen.
4. A pyrazole compound of a (Ia) or (Ib) ing to any one of claims 1 to 3, wherein Y1 is CRy1 or N, wherein Ry1 has one of the meanings as defined for 5 Ry in claim 1.
5. A pyrazole nd of formula (Ia) or (Ib) according to claim 4, wherein Y1 is CRy1.
6. A pyrazole nd of formula (Ia) or (Ib) according to claim 5, wherein Ry1 is selected from H, C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl and haloalkyl. 10
7. A pyrazole compound of formula (Ia) or (Ib) according to any one of claims 1 to 6, wherein Y2 is CRy2, Y3 is CRy3, Y4 is CRy4 and Y5 is CRy5, wherein Ry2, Ry3, Ry4 and Ry5 independently from each other have one of the meanings as defined for Ry in claim 1.
8. A pyrazole compound of formula (Ia) or (Ib) according to claim 7, wherein Ry2, 15 Ry3, Ry4 and Ry5 are independently selected from H, halogen, C1-C6-alkoxy, C1- C6-alkoxy-C1-C6-alkoxy and C1-C6-haloalkoxy.
9. A pyrazole compound of formula (Ia) or (Ib) according to any one of claims 1 to 8, wherein Z is O.
10. A pyrazole compound of formula (Ia) or (Ib) according to any one of 20 claims 1 to 8, wherein Z is S.
11. A le compound of formula (Ia) or (Ib) according to any one of claims 1 to 8, wherein Z is NRz.
12. A pyrazole compound of formula (Ia) or (Ib) according to any one of claims1 to 11, wherein R1 and R2 independently from each other are ed from H, C1- 25 C6-alkyl, C3-C8-cycloalkyl, phenyl and naphthyl.
13. A pyrazole compound of formula (Ia) or (Ib) according to claim 12, wherein R1 and R2 independently from each other are selected from H, C1-C4-alkyl, C3-C6- cycloalkyl and phenyl. (9925931_1):KZA
14. A pyrazole compound of formula (Ia) or (Ib) according to claim 13, wherein R1 and R2 are selected from alkyl.
15. A pyrazole compound of formula (Ia) or (Ib) according to any one of claims 1 to 14, n n is 0 or 1. 5
16. A pyrazole nd of formula (Ia) or (Ib) according to any one of claims 1 to 15, wherein R3 if present are independently selected from halogen.
17. A pyrazole compound of formula (Ia) according to any one of claims 1 to 16, wherein the pyrazole compound is ed from a compound of formula (Ia’), (R3) N O N Z Ry5 O N R2 H Ry2 Ry3 (Ia') 10 wherein Z, R1, R2, R3, Ry1, Ry2, Ry3, Ry4 and Ry5 have one of the meanings given in any one of the preceding claims and n is 0 or 1.
18. A pyrazole compound of formula (Ib) according to any one of claims 1 to 16, wherein the pyrazole compound is selected from a compound of general formula (Ib’), (R3) N O Ry1 O N R2 H Z (Ib') Ry5 15 Ry4 wherein Z, R1, R2, R3, Ry1, Ry2, Ry3, Ry4 and Ry5 have one of the meanings given in any one of the preceding claims and n is 0 or 1. (9925931_1):KZA
19. Use of a le compound of formula (Ia) or (Ib) according to any one of claims 1 to 18, or a pharmaceutically able salt thereof, for preparing a medicament for the treatment of diseases related to CRTH2 activity.
20. Use of a pyrazole nd of formula (Ia) or (Ib) according to any one of 5 claims 1 to 18, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the prevention and/or treatment of inflammatory, infectious and immunoregulatory ers, atory or gastrointestinal diseases or complaints, inflammatory diseases of the joints and allergic diseases of the nasopharynx, eyes, and skin. 10
21. A pharmaceutical formulation, containing one or more of the pyrazole compounds of a (Ia) and/or (Ib) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical formulation, containing one or more pyrazole compounds of formula (Ia) and/or (Ib) according to any of claims 1 to 18, or a pharmaceutically 15 acceptable salt thereof, in combination with one or more active substances selected from among betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CCR3 antagonists, CCR5 nists, CCR9 antagonists, 5-LO inhibitors, histamine-receptor nists, SYK inhibitors and sulfonamides. 20
23. A pyrazole compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof O R1 Rc HO Rd (R3) N O Ra Rb N Z R2 H Y5 Y1 Y4 (Ia) Y2 Y3 O R1 Rc HO Rd (R3) N O Ra Rb N Y1 R2 H Z (Ib) Y2 Y3 Y4 (9925931_1):KZA as defined in claim 1 and substantially as hereinbefore described with nce to any one of the Examples. Boehringer Ingelheim International GmbH By the Attorneys for the Applicant 5 SPRUSON & FERGUSON Per: (9925931_1):KZA
Applications Claiming Priority (3)
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EP11151876.7 | 2011-01-24 | ||
EP11151876 | 2011-01-24 | ||
PCT/EP2012/050830 WO2012101043A1 (en) | 2011-01-24 | 2012-01-20 | Pyrazole compounds as crth2 antagonists |
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