World Intellectual Property Organization (19) (10) International

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
5 January 2006 (05.01.2006)
PCT
(51) International Patent Classification :
C07D 211/58,
401/06, 409/06, 413/06, 417/06, A61K 31/4523, A61P
11/00, 17/00, 19/00, 29/00, 37/00
(21) International Application Number:
PCT/SE2005/000952
(22) International Filing Date:
20 June 2005 (20.06.2005)
(25) Filing Language:
English
(26) Publication Language:
English
(30) Priority Data:
0401657-2
24 June 2004 (24.06.2004)
SE
(71) Applicant (for all designated States except US): ASTRAZENECA AB [SE/SE]; S-151 85 Sδdertalje (SE).
(72) Inventor; and
(75) Inventor/Applicant (for US only): TUCKER, Howard
[GB/GB]; 32 Millers Meadow, Rainow, Macclesfield,
Cheshire SKlO 5UE (GB).
(74) Agent: ASTRAZENECA; Global Intellectual Property,
S-151 85 Sδdertalje (SE).
(10) International Publication Number
WO 2006/001751 Al
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
VN, YU, ZA, ZM, ZW
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
GQ, GW, ML, MR, NE, SN, TD, TG).
Published:
— with international search report
For two-letter codes and other abbreviations, refer to the "G uid
ance Notes on Codes and Abbreviations" appearing at the beg in
ning of each regular issue of the PCT Gazette.
(54) Title: CHEMICAL COMPOUNDS I
(57) Abstract: Compounds of formula (I)
compositions comprising them, processes
for preparing them and their use in medical
therapy (for example modulating CCR5
receptor activity in a warm blooded animal).
(I)
Applicant:
AstraZeneca AB
S- 151 85 Sodertalje
Sweden
T itle:
Novel
CCR5.
piperidine
derivates
a s modulators
Reference:
101470 FOREIGN FILING
Inventor:
Howard Tucker
o f chemokine
receptor
1
CHEMICAL COMPOUNDS L
The present invention relates to heterocyclic derivatives having pharmaceutical
activity, to processes for preparing such derivatives, to pharmaceutical compositions
comprising such derivatives and to the use of such derivatives as active therapeutic agents.
Pharmaceutically active piperidine derivatives are disclosed in WO03/042205.
Pharmaceuticals need to be bioavailable and the compounds of the present invention show
better levels of bioavailability, and greater selectivity (for example reduced muscarinic
activity) than the compounds of WO03/042205.
Chemokines are chemotactic cytokines that are released by a wide variety of cells to
attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation
and also play a role in the maturation of cells of the immune system. Chemokines play an
important role in immune and inflammatory responses in various diseases and disorders,
including asthma and allergic diseases, as well as autoimmune pathologies such as
rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing
superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The
chemokine superfamily can be divided into two main groups exhibiting characteristic
structural motifs, the Cys-X-Cys (C-X-C, or α) and Cys-Cys (C-C, or β) families. These are
distinguished on the basis of a single amino acid insertion between the NH-proximal pair of
cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of
neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes
but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-I, MCP-2 and
MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and
the macrophage inflammatory proteins l α and l β (MIP- l α and MIP- l β).
Studies have demonstrated that the actions of the chemokines are mediated by
subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl,
CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO,
CXCRl , CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug
development since agents which modulate these receptors would be useful in the treatment of
disorders and diseases such as those mentioned above.
2
The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages,
dendritic cells, microglia and other cell types. These detect and respond to several
chemokines, principally "regulated on activation normal T-cell expressed and secreted"
(RANTES), macrophage inflammatory proteins (MIP) MIP- l α and MIP- l β and monocyte
chemoattractant protein-2 (MCP-2).
This results in the recruitment of cells of the immune system to sites of disease. In
many diseases it is the cells expressing CCR5 which contribute, directly or indirectly, to
tissue damage. Consequently, inhibiting the recruitment of these cells is beneficial in a wide
range of diseases.
CCR5 is also a co-receptor for HIV-I and other viruses, allowing these viruses to
enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation
with a CCR5 agonist protects cells from viral infection.
The present invention provides a compound of formula (I):
wherein
R 1 is S(O)2R6, S(O)2NR 10 R 1 1 , C(O)R 7 or C(O)NHR 7;
R2 is 3,5-difluorophenyl, 3-trifluoromethylphenyl or 3-fluoro-5-chlorophenyl;
R3 is hydrogen or Ci- alkyl;
R4 is hydrogen, methyl, ethyl, allyl or cyclopropyl;
R 5 is phenyl(C .2)alkyl or phenyl(Ci -2 alkyl)NH; wherein the phenyl rings are optionally
substituted by halo, cyano, nitro, hydroxy, C i- alkyl, Ci-4 alkoxy, S(O)k(Ci -4 alkyl),
S(O) 2NR 8R9, NHS(O) 2(C 1-4 alkyl), NH2, NH(C
-4
alkyl), N(C 1-4 alkyl)2, NHC(O)NH 2,
C(O)NH 2, C(O)NH(C 1-4 alkyl), C(O)N(Ci -4 alkyl) 2, NHC(O)(C
M
alkyl), CO2H, CO2(C 1-4
alkyl), C(O)(Ci -4 alkyl), CF3, CHF2, CH2F, CH2CF 3 or OCF 3;
k is O, 1 or 2 ;
R 6 is Ci-6 alkyl [optionally substituted by C 1-4 alkoxy, phenyl {which itself optionally
substituted by halo, C M alkyl, C M alkoxy, cyano, nitro, CF3, OCF3, (C 1-4 alkyl)C(O)NH,
S(O) 2NH2, C 1-4 alkylthio, S(O)(C
-4
alkyl) or S(O) 2(C
-4
alkyl)} or heteroaryl {which itself
optionally substituted by halo, C i-4 alkyl, C i-4 alkoxy, cyano, nitro, CF 3, (Ci -4 alkyl)C(O)NH,
3
S(O) 2NH 2, C 1-4 alkylthio, S(O)(C 1-4 alkyl) or S(O) 2(C 1-4 alkyl)}], C3-7 cycloalkyl,
tetrahydropyranyl, phenyl {optionally substituted by halo, C i-4 alkyl, Ci -4 alkoxy, cyano,
nitro, CF 3, OCF 3, (C 1-4 alkyl)C(O)NH, S(O) 2NH 2, Ci-4 alkylthio, S(O)(Ci -4 alkyl) or S(O) 2(C
4
-
alkyl)} or heteroaryl {optionally substituted by halo, Ci-4 alkyl, C ]-4 alkoxy, cyano, nitro,
CF 3, (C
-4
alkyl)C(O)NH, S(O) 2NH 2, Ci 4 alkylthio, S(O)(C 1-4 alkyl) or S(O) 2(Ci -4 alkyl)};
R7 is hydrogen, Ci 6 alkyl [optionally substituted by halo (such as fluoro), Ci-4 alkoxy, phenyl
{which itself optionally substituted by halo, Ci alkyl, C
-4
(Ci -4 alkyl)C(O)NH, S(O) 2NH2, Ci-4 alkylthio, S(O)(C
alkyl) or S(O) 2(C
-4
alkoxy, cyano, nitro, CF3, OCF 3,
-4
alkyl)} or
heteroaryl {which itself optionally substituted by halo, Ci -4 alkyl, Ci-4 alkoxy, cyano, nitro,
CF 3, (C
-4
alkyl)C(O)NH, S(O) 2NH 2, C
alkylthio, S(O)(C
4
-4
alkyl) or S(O) 2(C
4
alkyl)}],
C3-7 cycloalkyl, tetrahydropyranyl, phenyl {optionally substituted by halo, Ci-4 alkyl, C
alkoxy, cyano, nitro, CF3, OCF 3, (C
-4
alkyl)C(O)NH, S(O)2NH2, C
-4
alkylthio, S(O)(C
alkyl) or S(O)2 (Ci -4 alkyl)} or heteroaryl {optionally substituted by halo, C 1-4 alkyl, C
alkoxy, cyano, nitro, CF 3, (C -4 alkyl)C(O)NH, S(O) 2NH2, C
S(O) 2(C
-4
-4
-4
-4
-4
alkylthio, S(O)(C ]-4 alkyl) or
alkyl)};
R8 and R9 are, independently, hydrogen or C
-4
alkyl, or together with a nitrogen or oxygen
atom, may join to form a 5- or 6-membered ring which is optionally substituted with Ci-4
alkyl, C(O)H or C(O)(C
-4
alkyl);
R 10 and R 1 1 are, independently, hydrogen or Ci-4 alkyl, or may join to form a 5- or 6membered ring which is optionally substituted with C i-4 alkyl or phenyl (wherein the phenyl
ring is optionally substituted by halo, cyano, nitro, hydroxy, C
alkyl, S(O) 2NH 2, S(O)2NH(C
NH(C
-4
alkyl), N(C
-4
alkyl), CO2H, CO2(C
-4
alkyl), S(O) 2N(C
4
-4
alkyl, C
alkyl) 2, NHS(O) 2(C
alkyl) 2, NHC(O)NH 2, C(O)NH 2, C(O)NH(C
-4
alkyl), C(O)(C
-4
-4
-4
-4
alkoxy, S(0) mC
-4
alkyl), NH 2,
alkyl), NHC(O)(C
-4
alkyl), CF 3, CHF 2, CH 2F, CH 2CF 3 or OCF 3) ;
or a pharmaceutically acceptable salt thereof.
Certain compounds of the present invention can exist in different isomeric forms (such
as enantiomers, diastereomers, geometric isomers or tautomers). The present invention
covers all such isomers and mixtures thereof in all proportions.
Suitable salts include acid addition salts such as a hydrochloride, hydrobromide,
phosphate, acetate, fumarate, maleate, succinate, tartrate, citrate, oxalate, methanesulphonate
or p-toluenesulphonate.
The compounds of the invention may exist as solvates (such as hydrates) and the
present invention covers all such solvates.
4
Alkyl groups and moieties are straight or branched chain and are, for example, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl. Methyl is sometimes abbreviated
to Me hereinbelow.
Fluoroalkyl includes, for example, one to six, such as one to three, fluorine atoms, and
comprises, for example, a CF3 group. Fluoroalkyl is, for example, CHF2, CH 2F, CF 3 or
CH 2CF 3.
Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl.
Phenyl(C .2 alkyl)alkyl is, for example, benzyl, l-(phenyl)eth-l-yl or l-(phenyl)eth-2yi-
Phenyl(Ci-2 alkyl)NH is, for example, benzylamino.
Heteroaryl is an aromatic 5 or 6 membered ring, optionally fused to one or more other
rings, comprising at least one heteroatom selected from the group comprising nitrogen,
oxygen and sulphur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof. Heteroaryl is,
for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, thiazolyl, isothiazolyl,
pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, [l,2,4]-triazolyl, pyridinyl, pyrimidinyl, indolyl,
benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or
benzthiophenyl), indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 1,2,3benzothiadiazolyl, an imidazopyridinyl (such as imidazo[l,2a]pyridinyl), thieno[3,2b]pyridin-6-yl, 1,2,3-benzoxadiazolyl (also known as benzo[l,2,3]thiadiazolyl), 2,1,3benzothiadiazolyl, benzofurazan (also known as 2,1,3-benzoxadiazolyl), quinoxalinyl, a
pyrazolopyridine (for example lH-pyrazolo[3,4-b]pyridinyl), quinolinyl, isoquinolinyl, a
naphthyridinyl (for example [l,6]naphthyridinyl or [l,8]naphthyridinyl), a benzothiazinyl or
dibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof, or an S-oxide or Sdioxide thereof. Heteroaryl can also be pyrazinyl. Heteroaryl is, for example, pyridinyl,
pyrimidinyl, indolyl or benzimidazolyl.
When R and R together with a nitrogen or oxygen atom, join to form a 5- or 6membered ring, said ring is, for example, a piperazinyl or morpholinyl ring.
When R 10 and R 1 1 join to form a 5- or 6-membered ring the ring formed is, for
example, a piperinyl ring.
In one particular aspect the present invention provides a compound of the invention
wherein R 6 is Ci 6 alkyl (for example Ci 4 alkyl, such as methyl) or C
cyclohexyl).
7
cycloalkyl (such as
5
In a further aspect the present invention provides a compound of the invention
wherein R 1 is S(O) 2R6, wherein R6 is as defined above (for example R6 is C 1-4 alkyl). For
example R 1 is S(O) 2CH3.
In another aspect the present invention provides a compound of the invention wherein
R 2 is 3,5-difluorophenyl.
In yet another aspect the present invention provides a compound of the invention
wherein R3 is hydrogen.
In a further aspect the present invention provides a compound of the invention
wherein R4 is ethyl or cyclopropyl. In a still further aspect the present invention provides a
compound of formula (I) wherein R4 is ethyl.
In a still further aspect the present invention provides a compound of the invention
wherein R5 is phenyl(Ci -2)alkyl (for example benzyl) or phenyl(Ci -2 alkyl)NH (for example
benzylamino); wherein the phenyl rings are substituted (for example in the para-position) by
S(O) 2(C 1-4 alkyl) (for example S(O)2CH3).
In another aspect the present invention provides a compound of the invention wherein
R 5 is benzyl wherein the phenyl ring is substituted in the para-position by S(O) 2 (C M alkyl)
(for example S(O) 2CH 3) .
In yet another aspect the present invention provides a pharmaceutically acceptable salt
of a compound of the invention, for example a hydrochloride, hydrobromide, phosphate,
acetate, fumarate, maleate, succinate, tartrate, citrate, oxalate, methanesulphonate oτp -
toluenesulphonate salt of. a compound of the invention (such as a fumarate or succinate salt).
The carbon labelled Λ in the representation of formula (I) shown below:
is always chiral and has, for example, the R absolute configuration. Thus, in another aspect
the present invention provides a compound of the invention having the R absolute
configuration at the carbon Λ identified above. In yet another aspect the present invention
provides a pharmaceutically acceptable salt of a compound of the invention having the R
absolute configuration at the carbon Λ identified above.
In yet another aspect the present invention provides a compound of formula (Ia):
wherein R 1, R2 and R4 are as defined above, and X is CH 2 or NHCH 2. In a further aspect the
present invention provides a pharmaceutically acceptable salt of a compound of formula (Ia)
wherein R 1, R2 and R4 are as defined above, and X is CH 2 or NHCH 2.
In a further aspect the present invention provides a compound of formula (I) having
the R absolute configuration at the carbon Λ identified above, wherein:
R 1 is S(O) 2R6 [wherein R 6 is as defined above (for example R 6 is C i-4 alkyl, such as methyl)];
R2 is 3,5-difluorophenyl;
R3 is hydrogen;
R4 is ethyl or cyclopropyl [for example R4 is ethyl];
R5 is phenyl(Ci -2)alkyl or phenyl(Ci. 2 alkyl)NH wherein the phenyl rings are substituted (for
example in the para-position) by S(O) 2(C 1-4 alkyl) (for example S(O) 2CH 3) [for example R5 is
benzyl wherein the phenyl ring is substituted in the para-position by S(O) 2(C 1-4 alkyl) (for
example S(O) 2CH 3)];
or a pharmaceutically acceptable salt of a compound of formula (I) [for example a
hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, succinate, tartrate,
citrate, oxalate, methanesulphonate orp-toluenesulphonate salt (such as a fumarate or
succinate salt)].
In a still further aspect the present invention provides a compound of formula (Ia)
having the R absolute configuration at the carbon Λ identified above, wherein:
R 1 is S(O) R6 [wherein R 6 is as defined above (for example R6 is C i- alkyl, such as methyl)];
R2 is 3,5-difluorophenyl;
R4 is ethyl or cyclopropyl [for example R4 is ethyl];
X is CH 2 or NHCH 2 [for example X is CH2];
or a pharmaceutically acceptable salt of a compound of formula (Ia) [for example a
hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, succinate, tartrate,
citrate, oxalate, methanesulphonate or/7-toluenesulphonate salt (such as a fumarate or
succinate salt)].
In another aspect the present invention provides the compound:
N-(I- {(3i?)-3-(3,5-difluorophenyl)-3-[ 1-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4yl)-iV-ethyl-2-[4-(methylsulfonyl)phenyl]-acetamide;
the succinate salt of -(l-{(3/?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-
yl]propyl}piperidm-4-yl)-N -ethyl-2-[4-(memylsulfonyl)phenyl]acetamide;
the fumarate salt of -(I- {(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-
yl]propyl}piperidin-4-yl)- N -ethyl-2-[4-(methylsulfonyl)phenyl]acetamide; or,
N -(l-{(3/?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4yl)-N -ethyl-2-[3-(methylsulfonyl)phenyl]acetamide.
The compounds listed in Table I illustrate the invention.
TABLE I
Table I comprises compounds of formula (Ia).
In a further aspect the invention provides each individual compound listed in Table I.
The compounds of the invention can be prepared by using or modifying the
preparative methodologies, Methods, Schemes or Examples of WO03/042205.
8
Thus, a compound of the invention can be prepared by reacting a compound of
formula (II):
wherein R2, R3, R4 and R5 are as defined above, with, depending on the compound of the
invention it is desired to make:
a . an acid of formula R 1CO2H in the presence of a suitable coupling agent (for example
PyBrOP [bromo-tris-pyrrolidino-phosphonium hexafluorophosphate] or HATU [O-(7azabenzotriazol-l-y^-TV^V /V'
'-tetramethyluronium hexafluorophosphate]) in the
presence of a suitable base (such as a tri(Ci -6 alkyl)amine, for example
diisopropylethylamine) in a suitable solvent (for example
-methylpyrrolidinone or a
chlorinated solvent, such as dichloromethane) at room temperature (for example 103 O0C);
or,
b. an acid chloride of formula R 1C(O)Cl or sulphonyl chloride of formula R 1S(O)2Cl, in
the presence of a suitable base (such as a tri(C 1-6 alkyl)amine, for example
triethylamine or diisopropylethylamine) in a suitable solvent (for example a
chlorinated solvent, such as dichloromethane) at room temperature (for example 103 O0C).
Alternatively, a compound of the invention can be prepared by coupling a compound
of formula (III):
wherein R 1, R2, R3 and R4 are as defined above, with:
a) an acid of formula R 5CO2H in the presence of a suitable coupling agent (for example
PyBrOP or HATU) in the presence of a suitable base (such as a tri(Ci. 6 alkyl)amine,
for example diisopropylethylamine) in a suitable solvent (for example TVmethylpyrrolidinone or a chlorinated solvent, such as dichloromethane) at room
temperature (for example 10-30 0C); or,
b) an acid chloride of formula R C(O)Cl, in the presence of a suitable base (such as a
tri(Ci-6 alkyl)amine, for example triethylamine or diisopropylethylamine) in a suitable
solvent (for example a chlorinated solvent, such as dichloromethane) at room
temperature (for example 10-30 0C).
A compound of the invention can be prepared by reductive amination of a compound
of formula (IV):
with a compound of formula (V):
in the presence OfNaBH(OAc) 3 (wherein Ac is C(O)CH 3) and acetic acid, in a suitable
solvent (such as a Ci-6 aliphatic alcohol, for example ethanol) at room temperature (for
example 10-300C).
A compound of formula (V) can be prepared by removal of the protecting group (PG)
from a compound of formula (VI). For example where PG is benzyloxylcarbonyl or benzyl
removal may be effected by hydrogenation (for example hydrogen in the presence of
palladium on carbon catalyst); where PG is ert-butyloxycarbonyl removal may be effected by
treatment with acid (such as hydrochloric acid or trifluoroacetic acid).
A compound of the invention can also be prepared by the alkylation of a compound of
formula (V) with a compound of formula (VII):
10
wherein R 1, R2 and R3 are as defined above, and LG is a leaving group (such as halide,
mesylate, tosylate or triflate); in the presence of a suitable base (such as potassium carbonate
or a tertiary amine (for example Hϋnig's base or triethylamine)) in a suitable solvent (such as
acetonitrile or THF) at room temperature (for example 10-30 0C). Compounds of formula
(VII) can be prepared by methods described, or by routine adaptation of methods described,
in the patent or scientific literature.
In the processes described suitable protecting groups and details of processes for adding
and removing such groups may be found in "Protective Groups in Organic Synthesis", 3rd
Edition ( 1999) by Greene and Wuts.
The starting materials for these processes are either commercially available or can be
prepared by literature methods, adapting literature methods or by following or the disclosure
ofWO03/042205.
In a still further aspect the invention provides processes for preparing the compounds
of formula (I) or (Ia). Many of the intermediates in the processes are novel and these are
provided as further features of the invention.
A compound of the invention, or a pharmaceutically acceptable salt thereof, can be
used in the treatment of:
1.
respiratory tract: obstructive diseases of the airways including: asthma, including
bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and
NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all
severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary
disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema;
bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,
idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic
infection, including tuberculosis and aspergillosis and other fungal infections; complications
of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and
11
pulmonary hypertension; antitussive activity including treatment of chronic cough associated
with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and
chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and
seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral
infection including the common cold, and infection due to respiratory syncytial virus,
influenza, coronavirus (including SARS) and adenovirus;
2.
bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis,
both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar
spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative
spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis
and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies
and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome;
acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate
deposition disease, and calcium apatite related tendon, bursal and synovial inflammation;
Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited
scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and
undifferentiated connective tissue disease; inflammatory myopathies including
dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including
idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes,
and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis,
Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis,
and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and
paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and
Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and
myopathies;
3.
pain and connective tissue remodelling of musculoskeletal disorders due to injury [for
example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis,
gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or
temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis,
Paget's disease or osteonecrosis), polychondritis, scleroderma, mixed connective tissue
disorder, spondyloarthropathies or periodontal disease (such as periodontitis);
4.
skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses,
and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic
12
dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma
gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,
epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous
eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian
syndrome, erythema multiforme; cellulitis, both infective and non-infective;
panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions;
drug-induced disorders including fixed drug eruptions;
5.
eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis;
iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory
disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis;
infections including viral , fungal, and bacterial;
6.
gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux;
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative
colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related
allergies which may have effects remote from the gut (for example migraine, rhinitis or
eczema);
7.
abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis
of the liver; cholecystitis; pancreatitis, both acute and chronic;
8.
genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic
syndrome; cystitis including acute and chronic (interstitial) cystitis and thinner's ulcer; acute
and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis;
Peyronie's disease; erectile dysfunction (both male and female);
9.
allograft rejection: acute and chronic following, for example, transplantation of
kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or
chronic graft versus host disease;
10.
CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD;
amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis
and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute,
intermittent or persistent, whether of central or peripheral origin) including visceral pain,
headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain
arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post¬
herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous
system complications of malignant, infectious or autoimmune processes;
13
11.
other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves'
disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura,
eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12.
other disorders with an inflammatory or immunological component; including
acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic
syndromes;
13.
cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation;
pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including
myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis
including infective (for example syphilitic); vasculitides; disorders of the proximal and
peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and
complications of varicose veins;
14.
oncology: treatment of common cancers including prostate, breast, lung, ovarian,
pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the
bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's
and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease
and tumour recurrences, and paraneoplastic syndromes; or,
15.
gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis,
mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis,
irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related
allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
in a warm blooded animal, such as man.
The compounds of the invention have activity as pharmaceuticals, in particular as
modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine
receptor (for example CCR5) activity, and may be used in the treatment of autoimmune,
inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated
diseases (including rejection of transplanted organs or tissues and Acquired
Immunodeficiency Syndrome (AIDS)).
The compounds of the present invention are also of value in inhibiting the entry of
viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of
value in the prevention of infection by viruses (such as HIV), the treatment of infection by
viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency
syndrome (AIDS).
14
According to a further feature of the invention there is provided a compound of the
formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, for use in a method of
treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
According to a further feature of the present invention there is provided a method for
modulating chemokine receptor activity (for example CCR5 receptor activity) in a warm
blooded animal, such as man, in need of such treatment, which comprises administering to
said animal an effective amount of a compound of the present invention, or a
pharmaceutically acceptable salt thereof.
The present invention also provides the use of a compound of the formula (I) or (Ia),
or a pharmaceutically acceptable salt thereof, as a medicament, for example a medicament for
the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (for
example rheumatoid arthritis). [Respiratory disease is, for example, COPD, asthma {such as
bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate
asthma (for example late asthma or airways hyper-responsiveness)} or rhinitis {acute,
allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,
rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including
croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis
including rhinitis nervosa (hay fever) or vasomotor rhinitis} ; and is particularly asthma or
rhinitis].
In another aspect the present invention provides the use of a compound of the formula
(I) or (Ia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for use in therapy (for example modulating chemokine receptor activity (for example CCR5
receptor activity (such as rheumatoid arthritis)) in a warm blooded animal, such as man).
The invention also provides a compound of the formula (I) or (Ia), or a
pharmaceutically acceptable salt thereof, for use as a medicament, for example a medicament
for the treatment of rheumatoid arthritis.
In another aspect the present invention provides the use of a compound of the formula
(I) or (Ia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament
for use in therapy (for example modulating chemokine receptor activity (for example CCR5
receptor activity (for example rheumatoid arthritis)) in a warm blooded animal, such as man).
The invention further provides the use of a compound of formula (I) or (Ia), or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the
treatment of:
15
1.
respiratory tract: obstructive diseases of the airways including: asthma, including
bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and
NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all
severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary
disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema;
bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,
idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic
infection, including tuberculosis and aspergillosis and other fungal infections; complications
of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and
pulmonary hypertension; antitussive activity including treatment of chronic cough associated
with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and
chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and
seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral
infection including the common cold, and infection due to respiratory syncytial virus,
influenza, coronavirus (including SARS) and adenovirus;
2.
bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis,
both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar
spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative
spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis
and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies
and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome;
acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate
deposition disease, and calcium apatite related tendon, bursal and synovial inflammation;
Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited
scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and
undifferentiated connective tissue disease; inflammatory myopathies including
dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including
idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes,
and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis,
Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis,
and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and
paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and
16
Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and
myopathies;
3.
pain and connective tissue remodelling of musculoskeletal disorders due to injury [for
example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis,
gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or
temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis,
Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue
disorder, spondyloarthropathies or periodontal disease (such as periodontitis);
4.
skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses,
and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic
dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma
gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid,
epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous
eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian
syndrome, erythema multiforme; cellulitis, both infective and non- infective;
panniculitis ;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions;
drug-induced disorders including fixed drug eruptions;
5.
eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis;
iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory
disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis;
infections including viral , fungal, and bacterial;
6.
gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux;
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative
colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related
allergies which may have effects remote from the gut (for example migraine, rhinitis or
eczema);
7.
abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis
of the liver; cholecystitis; pancreatitis, both acute and chronic;
8.
genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic
syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute
and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis;
Peyronie's disease; erectile dysfunction (both male and female);
17
9.
allograft rejection: acute and chronic following, for example, transplantation of
kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or
chronic graft versus host disease;
10.
CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD;
amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis
and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute,
intermittent or persistent, whether of central or peripheral origin) including visceral pain,
headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain
arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, postherpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous
system complications of malignant, infectious or autoimmune processes;
11.
other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves'
disease, Addison's disease, diabetes mellirus, idiopathic thrombocytopaenic purpura,
eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;
12.
other disorders with an inflammatory or immunological component; including
acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic
syndromes;
13.
cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation;
pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including
myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis
including infective (for example syphilitic); vasculitides; disorders of the proximal and
peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and
complications of varicose veins;
14.
oncology: treatment of common cancers including prostate, breast, lung, ovarian,
pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the
bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's
and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease
and tumour recurrences, and paraneoplastic syndromes; or,
15.
gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis,
mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis,
irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related
allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
in a warm blooded animal, such as man.
18
In another aspect the invention further provides the use of a compound of formula (I)
or (Ia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for
use in the treatment of:
(1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive
pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial,
allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for
example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic
bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa,
hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa;
membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or
scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor
rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or
idiopathic interstitial pneumonia;
(2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative
spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's
disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
(3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous
dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus,
Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous
eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis,
mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related
allergies which have effects remote from the gut (for example migraine, rhinitis or
eczema);
(5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney,
heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease;
and/or
(6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis,
Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus
erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia
gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,
leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic
thrombocytopenia pupura or disorders of the menstrual cycle;
19
in a warm blooded animal, such as man.
The present invention further provides a method of treating a chemokine mediated
disease state (for example a CCR5 mediated disease state) in a warm blooded animal, such as
man, which comprises administering to a mammal in need of such treatment an effective
amount of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof.
In order to use a compound of the invention, or a pharmaceutically acceptable salt
thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular
modulating chemokine receptor (for example CCR5 receptor) activity, said ingredient is
normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical
composition.
Therefore in another aspect the present invention provides a pharmaceutical
composition which comprises a compound of the formula (I) or (Ia), or a pharmaceutically
acceptable salt thereof (active ingredient), and a pharmaceutically acceptable adjuvant,
diluent or carrier. In a further aspect the present invention provides a process for the
preparation of said composition which comprises mixing active ingredient with a
pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of
administration, the pharmaceutical composition will comprise from 0.05 to 99 %w (per cent
by weight), such as from 0.05 to 80 %w, for example from 0.10 to 70 %w (such as from 0.10
to 50 %w) of active ingredient, all percentages by weight being based on total composition.
The pharmaceutical compositions of this invention may be administered in standard
manner for the disease condition that it is desired to treat, for example by topical (such as to
the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these
purposes the compounds of this invention may be formulated by means known in the art into
the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups,
powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible
powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily
solutions or suspensions.
A suitable pharmaceutical composition of this invention is one suitable for oral
administration in unit dosage form, for example a tablet or capsule which contains between
0.1 mg and Ig of active ingredient.
In another aspect a pharmaceutical composition of the invention is one suitable for
intravenous, subcutaneous or intramuscular injection.
20
Each patient may receive, for example, an intravenous, subcutaneous or intramuscular
dose of O.Olmgkg 1 to lOOmgkg 1 of the compound, for example in the range of O.lmgkg 1 to
20mgkg 1 of this invention, the composition being administered 1 to 4 times per day. The
intravenous, subcutaneous and intramuscular dose may be given by means of a bolus
injection. Alternatively the intravenous dose may be given by continuous infusion over a
period of time. Alternatively each patient will receive a daily oral dose which is
approximately equivalent to the daily parenteral dose, the composition being administered 1
to 4 times per day.
The following illustrate representative pharmaceutical dosage forms containing the
compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof (hereafter
Compound X), for therapeutic or prophylactic use in humans:
(a)
21
(b)
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol,
polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl βcyclodextrin may be used to aid formulation.
22
The above formulations may be obtained by conventional procedures well known in
the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for
example to provide a coating of cellulose acetate phthalate.
The invention further relates to a combination therapy wherein a compound of the
invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or
formulation comprising a compound of the invention, is administered concurrently or
sequentially or as a combined preparation with another therapeutic agent or agents, for the
treatment of one or more of the conditions listed.
In particular, for the treatment of the inflammatory diseases such as (but not restricted
to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary
disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention
may be combined with agents listed below.
Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including non-selective
cyclo-oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such
as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,
ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac,
azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective
COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib,
parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs);
glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or
intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine;
auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular
therapies such as hyaluronic acid derivatives; and nutritional supplements such as
glucosamine.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or
antagonist of cytokine function, (including agents which act on cytokine signalling pathways
such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons;
insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 17, and
interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- α)
inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and
CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as
etanercept) and low-molecular-weight agents such as pentoxyfylline.
23
In addition the invention relates to a combination of a compound of the invention, or a
pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting BLymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig,
HuMax 11-15).
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine
receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4,
CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl,
CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CRl for the C-X 3 -C
family.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix
metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well
as aggrecanase; for example collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3
(MMP- 13), stromelysin- 1 (MMP-3), stromelysin-2 (MMP- 10), and stromelysin-3 (MMP- 11)
and MMP-9 and MMP- 12, including agents such as doxycycline.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis
inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP)
antagonist such as; zileuton; ABT-761 ; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a
N-(5-substituted)-thiophene-2-alkylsulfonamide;
2,6-di-tert-butylphenolhydrazones;
a
methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-2 10661; a pyridinylsubstituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound
such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY
x 1005.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for
leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the
phenothiazin-3-ls such as L-65 1,392; amidino compounds such as CGS-25019c;
benzoxalamines such as ontazolast; benzenecarboximidamides
such as BIIL 284/260; and
compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
24
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE)
inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective
PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or
an inhibitor of PDE5.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor
antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine,
astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or
mizolastine; applied orally, topically or parenterally.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as
omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine
type 4 receptor.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2 adrenoceptor
agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine,
phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride,
oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride,
tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agents
including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine,
glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine
or telenzepine.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor agonist
(including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol,
salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer
thereof.
25
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium
cromoglycate or nedocromil sodium.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as
flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone
propionate, ciclesonide or mometasone furoate.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a
nuclear hormone receptor such as PPARs.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin
(Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE
(for example omalizumab).
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and another systemic or topicallyapplied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid,
dithranol or calcipotriol.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates
and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and
immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent
such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone,
metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir,
famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin,
zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and
saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine,
stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such
as nevirapine or efavirenz.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a
26
calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme
(ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin
or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an
anticoagulant such as a platelet aggregation inhibitor.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an
antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa,
ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor
such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a
nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an
anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor,
propentofylline or metrifonate.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of
acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an
opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or
other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.
The present invention further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or
topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative
thereof.
A compound of the present invention, or a pharmaceutically acceptable salt thereof,
can also be used in combination with an anti-osteoporosis agent including a hormonal agent
such as raloxifene, or a biphosphonate such as alendronate.
The present invention still further relates to the combination of a compound of the
invention, or a pharmaceutically acceptable salt thereof, together with a : (i) tryptase inhibitor;
(ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE)
inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4
antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such
as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine
kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or
IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii)
glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl. - or B.sub2. -receptor
27
antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for
example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or
benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor
(TGF β); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for
example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony
stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subl. or NK.sub3.
receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase
inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE);
(xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-
homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor
of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent
modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of
transcription factor activation such as NFkB, API, or STATS.
A compound of the invention, or a pharmaceutically acceptable salt thereof, can also
be used in combination with an existing therapeutic agent for the treatment of cancer, for
example suitable agents include:
(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical
oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide,
nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite
(for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur,
raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an
antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin,
doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or
mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine,
vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a
topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide,
amsacrine, topotecan or a camptothecin);
(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene,
droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant),
an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a
LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a
progestogen (for example megestrol acetate), an aromatase inhibitor (for example as
28
anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5α-reductase such as
finasteride;
(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor
like marimastat or an inhibitor of urokinase plasminogen activator receptor function);
(iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example
the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl
transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an
inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase
inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3moφ holinopropoxy)quinazolin-4-amine (gefϊ tinib, AZDl 839), N-(3-ethynylphenyl)-6,7-
bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the
platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;
(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial
growth factor (for example the anti-vascular endothelial cell growth factor antibody
bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO
98/13354), or a compound that works by another mechanism (for example linomide, an
inhibitor of integrin αv β3 function or an angiostatin);
(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO
99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(vii) an agent used in antisense therapy, for example one directed to one of the targets listed
above, such as ISIS 2503, an anti-ras antisense;
(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant
genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme
pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a
bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy
or radiotherapy such as multi-drug resistance gene therapy;
(ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo
approaches to increase the immunogenicity of patient tumour cells, such as transfection with
cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating
factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such
as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell
lines and approaches using anti-idiotypic antibodies; or
29
(x) a compound useful in the treatment of AIDS and/or HIV infection for example: an agent
which prevents or inhibits the viral protein gpl20 from engaging host cell CD4 {such as
soluble CD4 (recombinant); an anti-CD4 antibody (or modified / recombinant antibody) for
example PRO542; an anti-group 120 antibody (or modified / recombinant antibody); or
another agent which interferes with the binding of groupl20 to CD4 for example BMS806};
an agent which prevents binding to a chemokine receptor, other than CCR5, used by the HIV
virus {such as a CXCR4 agonist or antagonist or an anti-CXCR4 antibody}; a compound
which interferes in the fusion between the HIV viral envelope and a cell membrane {such as
an anti-group 4 1 antibody; enfuvirtide (T-20) or T-1249}; an inhibitor of DC-SIGN (also
known as CD209) {such as an anti-DC-SIGN antibody or a»inhibitor of DC-SIGN binding} ;
a nucleoside/nucleotide analogue reverse transciptase inhibitor {for example zidovudine
(AZT), nevirapine, didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC),
abacavir, adefovir or tenofovir (for example as free base or as disoproxil fumarate)}; a nonnucleoside reverse transciptase inhibitor {for example nevirapine, delavirdine or efavirenz}; a
protease inhibitor {for example ritonavir, indinavir, saquinavir (for example as free base or as
mesylate salt), nelf ϊ navir (for example as free base or as mesylate salt), amprenavir, lopinavir
or atazanavir (for example as free base or as sulphate salt)}; a ribonucleotide reductase
inhinbitor {for example hydroxyurea}; or an antiretroviral {for example emtricitabine}.
The invention will now be illustrated by the following non-limiting Examples in
which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations were carried out at room or
ambient temperature, that is, at a temperature in the range of 18-25°C;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent
was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30
mm Hg) with a bath temperature of up to 6 O0 C;
(iii) chromatography unless otherwise stated means flash chromatography on silica gel; thin
layer chromatography (TLC) was carried out on silica gel plates; where a "Bond Elut"
column is referred to, this means a column containing 1Og or 2Og of silica of 40 micron
particle size, the silica being contained in a 60ml disposable syringe and supported by a
porous disc, obtained from Varian, Harbor City, California, USA under the name "Mega
Bond Elut SI". Where an "Isolute™ SCX column" is referred to, this means a column
containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent
Technology Ltd., 1st House, Duffryn lndustial Estate, Ystrad Mynach, Hengoed, Mid
30
Glamorgan, UK. Where "Argonaut™ PS- ra-amine scavenger resin" is referred to, this
means a fra-(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies
Inc., 887 Industrial Road, Suite G, San Carlos, California, USA.
(iv) in general, the course of reactions was followed by TLC and reaction times are given for
illustration only;
(v) yields, when given, are for illustration only and are not necessarily those which can be
obtained by diligent process development; preparations were repeated if more material was
required;
(vi) when given, 1H NMR data is quoted and is in the form of delta values for major
diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an
internal standard, determined at 300 MHz using perdeuterio DMSO (CD SOCD 3) as the
solvent unless otherwise stated; coupling constants (J) are given in Hz;
(vii) chemical symbols have their usual meanings; SI units and symbols are used;
(viii) solvent ratios are given in percentage by volume;
(ix) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical
ionisation (APCl) mode using a direct exposure probe; where indicated ionisation was
effected by electrospray (ES); where values for m/z are given, generally only ions which
indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the
positive mass ion - (M+H) +;
(x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233
XL sampler and Waters ZMD4000 mass spectrometer. The LC comprised water symmetry
4.6x50 column C l 8 with 5 micron particle size. The eluents were: A, water with 0.05%
formic acid and B, acetonitrile with 0.05% formic acid. The eluent gradient went from 95%
A to 95% B in 6 minutes. Where indicated ionisation was effected by electrospray (ES);
where values for m/z are given, generally only ions which indicate the parent mass are
reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H) +
and
(xi) the following abbreviations are used:
DMF
V,
-dimethylformamide;
m.pt.
melting point
TMEDA
Λ
THF
tetrahydrofuran.
',
'-tetramethylethylenediamine;
31
EXAMPLE 1
This Example illustrates the preparation of 7V-(l-{(3 )-3-(3,5-difluorophenyl)-3-[l(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-7V-ethyl-2-[4-(methylsulfonyl)phenyl]acetamide (Compound 1 of Table I)
Sodium triacetoxyborohydride (2.5g) was added to a solution of (3i?)-3-(3,5difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanal
(1.98g) and N -ethyl-2-[4-
(methylsulfonyl)phenyl]- N -piperidin-4-ylacetamide (1.94g) in dichloromethane (100 ml) and
the mixture was stirred for 2 hours, then washed with 2M NaOH (2x100 ml) and dried. The
organics were poured on to a 50g SCX2 cartridge and eluted with methanol (6x50 ml) and IM
methanolic ammonia (7x50 ml). The combined methanolic ammonia washings were
evaporated to dryness to give the title compound as a white foam, yield 2.6g. NMR (CDCl 3) :
1.2-2.1 (m, 19H), 2.3-2.7 (m, 3H), 2.75 (s, 3H), 2.8-2.9 (m, 2H), 3.0 (s, 3H), 3.3 (q, 2H), 3.7-
3.9 (m, 4H), 6.65 (m, 3H), 7.4 (m, 2H), 7.9 (d, 2H).
EXAMPLE 2
This Example illustrates the preparation of the succinate salt of -(I- {(3i?)-3-(3,5difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-
N -ethyl-2-[4-
(methylsulfonyl)phenyl]acetamide.
A hot solution of succinic acid (59 mgs) in ethanol (3 ml) was added to a hot solution
Of N -(I- {(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-
yl)- N -ethyl-2-[4-(methylsulfonyl)phenyl]acetamide (640 mgs) in ethanol (16 ml) and the
mixture was allowed to cool. After 24 hours the mixture was triturated using a spatula and
allowed to stand for an additional 24 hours. The solid was filtered and dried, m.pt.
175-175.5 0C. This solid was recyrstallized from ethanol (14 ml) to give the title compound,
m.pt. 177-177.5°C.
32
EXAMPLE 3
This Example illustrates the preparation of the fumarate salt of JV-(I -{(3/?)-3-(3,5difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-iV-ethyl-2-[4(methylsulfonyl)phenyl]acetamide.
A hot solution of fumaric acid (55 mgs) in methanol (3 ml) was added to a hot
solution of N-(I- {(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4yl]propyl}piperidin-4-yl)-JV-ethyl-2-[4-(methylsulfonyl)phenyl]acetamide
(300 mgs) in
methanol ( 4 ml) and the mixture allowed to cool. The mixture was then cooled in an ice bath
and finally allowed to stand in a refrigerator for 14 hours. The solid was filtered and dried at
60 0C under vacuum for 2 hours m.pt. 164-166.5°C.
EXAMPLE 4
This Example illustrates the preparation of -(l-{(3i?)-3-(3,5-difluorophenyl)-3-[l(methylsulfonyl)piperidin-4-yl]propyl}piperidin-4-yl)-JV-ethyl-2-[3(methylsulfonyl)phenyl]acetamide.
3-(Methylsulfonyl)phenylacetic acid (96 mg) was disolved in dichloromethane (5 ml)
and carbonyldiimidazole (73 mg) added. The reaction mixture was stirred at room
temperature for 3hours. JV-(I- {(3i?)-3-(3,5-Difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4yl]propyl}piperidin-4-yl)-iV-ethylamine (200 mg) in dichloromethane (5 ml) was added and
the reaction mixture was allowed to stand at room temperature for 72 hours. PS isocyanate
resin (1. mm/g) (0.5 g) was added and the reaction mixture stirred at room temperature for
2hours, then filtered and evaporated. The residue was purified by column chromatography
eluting with ethyl acetate-20%methanol/ethyl acetate to yield the title compound as a foam
(105 mg).
33
NMR CDCl 3 : 1.0-2.1 (m, 21H), 2.3-2.6 (m, 3H), 2.65 (s, 3H), 2.9 (s, 3H), 3.3 (m, 2H),
3.65 (d, IH), 3.7 (m, 2H), 3.75 (d, IH), 6.6 (m, 3H), 7.5 (m, 2H), 7.75 (m, 2H).
Method A
Preparation of (3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanal
Step 1 Preparation of (2E)-3-[l-(methylsulfonyl)piperidin-4-yl]acryloyl
chloride.
Oxalyl chloride (5.1 g) was added to a solution of (2 )-3-[l(methylsulfonyl)piperidin-4-yl]acrylic acid (9.4g) in dichloromethane containing 2-3 drops of
DMF and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was
evaporated to dryness and the residue obtained was used directly in the next step.
Step 2 Preparation of (4i?,5 S)-l,5-dimethyl-3-{(2
)-3-[l-(methylsulfonyl)piperidin-4-yl]prop-
2-enoyl}-4-phenylimidazolidin-2-one.
Lithium bis(trimethylsilyl)amide (8 ml of a IM solution in THF) was added dropwise
to a suspension of (4R,5S)-l,5-dimethyl-4-phenyl-2-imidazolidinone
(1.52g) in THF (20 ml)
under argon at -10 0 C. The reaction mixture was stirred at -1O 0 C for 10 minutes, allowed to
warm to O0 C and maintained at this temperature for 10 minutes then cooled again to -10 0C.
The solution of the acid chloride (2g dissolved in 10 ml of dichloromethane) prepared in Step
34
1 was added dropwise and the reaction mixture was allowed to warm to room temperature and
washed with water (100 ml). The aqueous extract was extracted with ethyl acetate (3x50 ml)
and the ethyl acetate extracts were dried and the residue passed through a 9Og Biotage column
eluting with a solvent gradient (50% ethyl acetate/isohexane - 70% ethyl acetate/isohexane).
Yield 1.89g. LC-MS MH+ 406, NMR (CDCl3) : 0.8 (d, 3H), 1.5-1.6 (m, 3H), 1.9 (m, 2H), 2.3
(m, IH), 2.7 (m, 2H), 2.75 (s, 3H), 2.8 (s, 3H), 3.75 (m, 2H), 3.9 (m, IH), 5.3 (d, IH), 6.85 (dd, IH), 7.1 (d, IH), 7.2-7.35 (m, 3H), 7.45 (d, IH).
Step 3 Preparation of (4S,5R)- 1- {(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-
4-yl]propanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one.
Step A
TMEDA ( 1 1.6g) was added to a suspension of copper iodide (19.4g) in THF (240 ml)
under argon and the mixture was stirred for 45 minutes then cooled to -70°C. A solution of
3,5-difluorophenyl magnesium bromide in THF (20 1.1 ml of a 0.5M solution in THF) was
added over 10 minutes and the mixture was stirred at —70°C for 30 minutes.
Step B
Di-n-butylboron triflate (100.7 ml of IM solution in dichloromethane) was added to a
suspension of (4i?,55)-l,5-dimethyl-3-{(2 )-3-[l-(methylsulfonyl)piperidin-4-yl]prop-2enoyl}-4-phenylimidazolidin-2-one (20.4Ig) [Step 2] in THF maintained at -40°C and
stirring was continued for 10 minutes and the mixture was cooled to -70°C and added via a
cannula to the cuprate suspension prepared in step A . The reaction mixture was stirred at 70°C for 1 hour and allowed to warm to room temperature, then saturated ammonium
chloride solution (200 ml) was added. The THF was evaporated and ethyl acetate (200 ml)
was added. Air was blown through this mixture for 1 hour. The ethyl acetate layer was
collected and the aqueous portion was extracted with ethyl acetate (2x100 ml). The combined
ethyl acetate extracts were washed with saturated ammonium chloride solution (2x100 ml),
dried and evaporated to dryness. The residue was purified by chromatography on silica
eluting with a solvent gradient of ethyl acetate-isohexane (1:1) to neat ethyl acetate to give
35
the title compound as a white solid, yield 25g, NMR (CDCl 3) 0.78 (d, 3H), 1.2-1.6 (m, 6H),
1.9 (m, IH), 2.4-2.65 (m, 2H), 2.75 (s, 3H), 2.85 (s, 3H), 3-3.2 (m, 2H), 3.7-3.9 (m, 4H), 5.2
(d, IH), 6.6(m, 3H), 6.85 (m, 2H), 7.2 (m, 3H).
Step 4 Preparation of (3i?)-3-(3,5-difiuorophenyl)-3-[l-(methylsulfonyl)piperidin-4-
yl]propan-l-ol
Lithium borohydride (48 ml of 2M solution in THF) was added to a solution of
(45,5i?)-l-{(3i?)-3-(3,5-difluorophenyl)-3-[l-(methylsulfonyl)piperidin-4-yl]propanoyl}-3,4dimethyl-5-phenylimidazolidin-2-one (25g) in THF (200 ml) and the mixture was heated at
70°C for 3 hours then allowed to cool to room temperature and stirring was continued for 16
hours. Ethanol was added carefully (20 ml) and the reaction mixture was acidified to pH 4 by
addition of 2M HCl. The THF was evaporated and the residue dissolved in dichloromethane
(100 ml) and this was washed with water (100 ml) and dried. The solvent was removed and
the product was purified by chromatography on a Biotage 65 column eluted with a 1:1
mixture of ethyl acetate/isohexane. Yield 13g, NMR (CDCl 3) : 1.2-1.8 (m, 5H), 1.95-2.2 (m,
2H), 2.5-2.7 (m, 3H), 2.75 (s, 3H), 3.3-3.6 (m, 2H), 3.7 -3.9 (m, 2H), 6.65 (m, 3H).
Step 5 Preparation of title compound.
Dess-Martin periodinane (5.09g) was added to a solution of (R) 3-(Nmethanesulphonylpiperidin-4-yl)-3-(3,5-difluorophenyl)propanol
(4.Og) in dichloromethane
(100 ml) and the mixture was stirred for 1.5 hours. The reaction mixture was washed with 2M
NaOH (2x100 ml) and dried. The solution of the title compound in dichloromethane was used
in subsequent reactions.
Method B
-ethyl-2-[4-(methylsulfonyl)phenyl]-7V-piperidin-4-ylacetamide
36
Step 1: Preparation of l-phenylmethyl-4-ethylamino
To a solution of l-phenylmethyl-4-piperidone
ρiperidine dihydrochloride
(25.Og, 132mmol) in THF (25OmL) was
added ethylamine hydrochloride (12.Og, 147 mol) and methanol (5OmL) and the resulting
mixture stirred at room temperature for lOmin. Sodium triacetoxyborohydride (4Og,
189mmol) was added portionwise and the resulting mixture stirred at room temperature for
Ih. 2M Sodium hydroxide solution (25OmL) was added and the resulting mixture extracted
with diethyl ether. The organic extracts were dried (K 2CO3) and evaporated to give 1phenylmethyl-4-ethylaminopiperidine
as an oil. This was dissolved in ethanol (50OmL) and
concentrated hydrochloric acid (2OmL) was added. The resulting crystals were collected,
washed with diethyl ether and dried yield (38 g); NMR: (CDCl 3) : 1.10 (t, 3H), 1.40 (m, 2H),
1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, IH), 7.2 - 7.4
(m, 5H); MS: 219 (MH+).
Step 2 : Preparation of N-(I -benzylpiperidin-4-yl)-
-ethyl-2-[4-
(methylsulfonyl)phenyl]acetamide.
To a solution of l-phenylmethyl-4-ethylaminopiperidine
dihydrochloride (32.Og,
1lOmmol) in DCM (50OmL) was added N ,N-άiisopropvlethylamine (6OmL) with stirring to
ensure complete dissolution. 4-Methanesulfonylphenylacetic
acid (25.0g, 117mmol), 4-
dimethylaminopyridine (2.Og) and dicyclohexylcarbodiimide (25.Og, 121mmol) were added
and the resulting mixture was stirred at room temperature for 2Oh. The precipitate was
37
removed by filtration and the resulting solution was washed successively with 2N aqueous
HCl, water and IN aqueous NaOH, dried (MgSO ) and evaporated. The residue was purified
by silica gel chromatography (eluent: 10% MeOH/ethyl acetate) to afford the sub-titled
compound (35 g, 76%); NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H),
2.80 (br m , 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70
and 4.10 (m, IH), 7.2 - 7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415 (MH+).
Step 3 : Preparation of the title compound
To a solution of -(l-benzylpiperidin-4-yl)-
-ethyl-2-[4-(methylsulfonyl)phenyl]-
acetamide (34g, 82mmol) in ethanol (60OmL) was added ammonium formate (4Og). The
mixture was purged with argon and 30% Pd on carbon (4.2g) was added. The resulting
mixture was stirred at reflux for 4h, then allowed to cool and filtered through diatomaceous
earth. The filtrate was evaporated to give a thick oil which solidified on standing to yield the
title compound (24.9g, 94%); NMR: 1.02 and 1.15 (t, 3H), 1.4 -1.6 (br m, 4H), 2.45 (m, 2H),
2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.32 (q, 2H), 3.72 and 4.18 (m, IH), 3.80 and 3.87 (s,
2H), 7.50 (m, 2H), 7.85 (m, 2H); MS: 325 (MH+).
EXAMPLE 5
The ability of compounds to inhibit the binding of RANTES was assessed by an in
vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells
which expressed the recombinant human CCR5 receptor. These membranes were incubated
with 0.InM iodinated RANTES, scintillation proximity beads and various concentrations of
the compounds of the invention in 96-well plates. The amount of iodinated RANTES bound
to the receptor was determined by scintillation counting. Competition curves were obtained
for compounds and the concentration of compound which displaced 50% of bound iodinated
RANTES was calculated (IC50). Compounds of formula (I) having an IC5 0 of less than 50 µM
form a further aspect of the invention.
EXAMPLE 6
The ability of compounds to inhibit the binding of MIP-I α was assessed by an in vitro
radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells
which expressed the recombinant human CCR5 receptor. These membranes were incubated
with 0.InM iodinated MlP- l α , scintillation proximity beads and various concentrations of
δ
the compounds of the invention in 96-well plates. The amount of iodinated MIP- l α bound to
the receptor was determined by scintillation counting. Competition curves were obtained for
compounds and the concentration of compound which displaced 50% of bound iodinated
MIP- l α was calculated (IC 0 ) . Compounds of formula (I) having an IC50 of less than 50 µM
form yet another aspect of the invention.
Results from this test for certain compounds of the invention are presented in Table II.
In Table II the results are presented as Pic50 values. A Pic50 value is the negative log (to
base 10) of the IC50 result, so an IC50 of l µM (that is 1 x 10 6 M) gives a Pic50 of 6. If a
compound was tested more than once then the data below is an average of the probative tests
results.
Table II
39
CLAIMS
A compound of formula (I):
wherein
R 1 is S(O) 2R6, S(O) 2NR 10 R 1 1 , C(O)R 7 or C(O)NHR 7;
R2 is 3,5-difluorophenyl, 3-trifluoromethylphenyl or 3-fluoro-5-chlorophenyl;
R3 is hydrogen or Ci - alkyl;
R4 is hydrogen, methyl, ethyl, allyl or cyclopropyl;
R5 is phenyl(C 1-2 )alkyl or phenyl(Ci -2 alkyl)NH; wherein the phenyl rings are
optionally substituted by halo, cyano, nitro, hydroxy, Ci -4 alkyl, C 1-4 alkoxy, S(O)I (C 1.
4
alkyl), S(O) 2NR 8R9, NHS(O) 2(Ci -4 alkyl), NH 2, NH(C 1-4 alkyl), N(Ci -4 alkyl)2,
NHC(O)NH 2, C(O)NH 2, C(O)NH(Ci -4 alkyl), C(O)N(C 1-4 alkyl) 2, NHC(O)(Ci -4
alkyl), CO2H, CO2(C 1-4 alkyl), C(O)(Ci -4 alkyl), CF3, CHF2, CH2F, CH 2CF3 or OCF3;
k is O, l or 2;
R 6 is Ci -6 alkyl [optionally substituted by Ci-4 alkoxy, phenyl {which itself optionally
substituted by halo, C
-4
alkyl, Ci-4 alkoxy, cyano, nitro, CF 3, OCF 3, (C
alkyl)C(O)NH, S(O) 2NH2, C
-4
alkylthio, S(O)(Ci -4 alkyl) or S(O) 2(C
heteroaryl {which itself optionally substituted by halo, C
nitro, CF 3, (C
-4
alkyl)C(O)NH, S(O) 2NH 2, C
-4
-
-4
4
alkyl)} or
alkyl, Ci -4 alkoxy, cyano,
alkylthio, S(O)(C
-4
alkyl) or
S(O)2(Ci -4 alkyl)}], C3-7 cycloalkyl, tetrahydropyranyl, phenyl {optionally substituted
by halo, C M alkyl, C
S(O)2NH 2, C
-4
-4
alkoxy, cyano, nitro, CF 3, OCF3, (C
alkylthio, S(O)(C
-4
alkyl) or S(O)2(C
-4
-4
alkyl)C(O)NH,
alkyl)} or heteroaryl
{optionally substituted by halo, Ci -4 alkyl, Ci -4 alkoxy, cyano, nitro, CF3, (C
alkyl)C(O)NH, S(O)2NH2, C
R7 is hydrogen, C
-6
-4
alkylthio, S(O)(C
-4
alkyl) or S(O)2(C
alkyl)} ;
alkyl [optionally substituted by halo (such as fluoro), C
phenyl {which itself optionally substituted by halo, C i-4 alkyl, C
nitro, CF 3, OCF3, (C
-4
-4
alkyl)C(O)NH, S(O) 2NH 2, C
-4
-4
-4
-4
alkoxy,
alkoxy, cyano,
alkylthio, S(O)(C
-4
alkyl) or
S(O) (Ci -4 alkyl)} or heteroaryl {which itself optionally substituted by halo, C
-4
alkyl,
40
C 1-4 alkoxy, cyano, nitro, CF3, (C
4
-4
alkyl)C(O)NH, S(O) 2NH2, C 1-4 alkylthio, S(O)(Ci
alkyl) or S(O) 2(Ci -4 alkyl)}], C3-7 cycloalkyl, tetrahydropyranyl, phenyl {optionally
substituted by halo, C i-4 alkyl, C ]-4 alkoxy, cyano, nitro, CF 3, OCF 3, (Ci -4
alkyl)C(O)NH, S(O) 2NH2, C
-4
alkylthio, S(O)(Ci -4 alkyl) or S(O)2(C
-4
alkyl)} or
heteroaryl {optionally substituted by halo, Ci-4 alkyl, Ci-4 alkoxy, cyano, nitro, CF 3,
(Ci -4 alkyl)C(O)NH, S(O) 2NH 2, C
-4
alkylthio, S(O)(Ci -4 alkyl) or S(O)2(C 1-4 alkyl)};
R and R are, independently, hydrogen or Ci-4 alkyl, or together with a nitrogen or
oxygen atom, may join to form a 5- or 6-membered ring which is optionally
substituted with C )-4 alkyl, C(O)H or C(O)(Ci 4 alkyl);
R 10 and R 1 1 are, independently, hydrogen or Ci-4 alkyl, or may join to form a 5- or 6membered ring which is optionally substituted with Ci -4 alkyl or phenyl (wherein the
phenyl ring is optionally substituted by halo, cyano, nitro, hydroxy, C i-4 alkyl, Ci-4
alkoxy, S(O)mC M alkyl, S(O) 2NH2, S(O) 2NH(Ci -4 alkyl), S(O) 2N(C
NHS(O) 2(C
C(O)NH(C
-4
-4
alkyl), NH2, NH(C 1-4 alkyl), N(C
alkyl), NHC(O)(C
-4
-4
-4
alkyl)2,
alkyl)2, NHC(O)NH 2, C(O)NH2,
alkyl), CO2H, CO 2(C 1-4 alkyl), C(O)(C
4
alkyl),
CF3, CHF 2, CH 2F, CH2CF 3 or OCF3);
or a pharmaceutically acceptable salt thereof.
2.
A compound as claimed in claim 1 wherein R 1 is S(O) 2R6.
3.
A compound as claimed in claim 1 or 2 wherein R6 is Ci-6 alkyl or C3-7 cycloalkyl.
4.
A compound as claimed in claim 1, 2 or 3 wherein R2 is 3,5-difluorophenyl.
5.
A compound as claimed in claim 1, 2, 3 or 4 wherein R 3 is hydrogen.
6.
A compound as claimed in any one of the preceding claims wherein R4 is ethyl or
cyclopropyl.
7.
A compound as claimed in any one of the preceding claims wherein R 5 is phenyl(C.
2)alkyl
4
or phenyl(C. 2 alkyl)NH; wherein the phenyl rings are substituted by S(O)2(C
alkyl).
-
41
8.
A compound as claimed in any one of the preceding claims which is a
pharmaceutically acceptable salt of a compound of formula (I).
9.
A compound as claimed in any one of the preceding claims having the R absolute
configuration at the carbon
Λ
identified above, wherein:
R 1 is S(O) 2R6 [wherein R 6 is C 1 4 alkyl];
R 2 is 3, 5-di fluorophenyl;
R 3 is hydrogen;
R4 is ethyl or cyclopropyl;
R 5 is phenyl(C .2)alkyl or phenyl(Ci -2 alkyl)NH wherein the phenyl rings are
substituted by S(O)2(C
-4
alkyl);
or a pharmaceutically acceptable salt thereof.
10.
A compound as claimed in any one of the preceding claims which is a fumarate or
succinate salt of a compound of formula (I).
11.
A process for preparing of a compound as claimed in claim 1, the process comprising:
a.
reacting a compound of formula (II):
wherein R2, R3, R4 and R5 are as defined above, with, depending on the compound
of formula (I) the invention it is desired to make:
i)
an acid of formula R 1CO2H in the presence of a suitable coupling agent in
the presence of a suitable base in a suitable solvent at room temperature; or,
ii)
an acid chloride of formula R 1C(O)Cl or sulphonyl chloride of formula
R 1S(O) 2Cl, in the presence of a suitable base in a suitable solvent at room
temperature;
b.
coupling a compound of formula (III):
wherein R 1, R2, R3 and R4 are as defined above, with:
i)
an acid of formula R 5CO2H in the presence of a suitable coupling agent in
the presence of a suitable base in a suitable solvent at room temperature; or,
ii) an acid chloride of formula R5C(O)Cl, in the presence of a suitable base in a
suitable solvent at room temperature
c.
reductive amination of a compound of formula (IV):
with a compound of formula (V):
in the presence OfNaBH(OAc) 3 (wherein Ac is C(O)CH ) and acetic acid, in a
suitable solvent at room temperature; or,
d.
alkylation of a compound of formula (V) with a compound of formula (VII):
wherein R 1, R2 and R3 are as defined above, and LG is a leaving group; in the
presence of a suitable base in a suitable solvent at room temperature.
43
12.
A pharmaceutical composition which comprises a compound as claimed in claim 1, or
a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
adjuvant, diluent or carrier.
13.
A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, for
use as a medicament.
14.
A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in therapy.
15.
A method of treating a CCR5 mediated disease state comprising administering to a
patient in need of such treatment an effective amount of a compound as claimed in
claim 1, or a pharmaceutically acceptable salt thereof.
International application No.
INTERNATIONAL SEARCH REPORT
PCT/SE 2005/000952
A. CLASSIFICATION OF SUBJECT MATTER
IPC7: C07D 211/58, C07D 401/06, C07D 409/06, C07D 413/06, C07D 417/06,
A61K 31/4523, A61P 11/00, A61P 17/00,19/00,29/00,
37/00
According to International Patent Classification (IPC) or to both national classification and IPC
B.
FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC7: C07D, A61K, A61P
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
SE, DK, FI, NO classes
a s above
Electronic data base consulted during the international search (name of data base and, where practicable, se arch terms used)
STN-CAPLUS, EPO-INTERNAL, PAJ, WPI
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages
WO 2004054974 A2 (SMITHKLINE BEECHAM CORPORATION),
1 July 2004 (01.07.2004), claims 1-61
1-15
WO 2004056773 A l (ASTRAZENECA AB), 8 July 2004
(08.07.2004), compound I
1-15
WO 0114333 A l (ASTRAZENECA UK LIMITED),
1 March 2001 (01.03.2001), formula I
1-15
WO 9925686 A l (TEIJIN LIMITED), 27 May
(27.05.1999),
claims 1-54
Further documents are listed in the continuation of Box C.
*
Spe σ al categories of α ted documents:
"A"
document defining the genera] state of the art which is not considered
t o be of particular relevance
earlier application or patent but published on or after the international
filing date
document which may throw doubts on pπ oπ t y daim(s) or which is
α ted to establish the publication date of another citation or other
special reason (as specified)
document referring t o an oral disclosure, use, exhibition or other
means
document published pπ or to the international filing date but later than
the pπ oπ ty date claimed
"E"
"L"
O
"P"
Relevant to claim No.
Date of the actual completion of the international search
1999
See patent family annex.
T "
later document published after the international filing date or pno π t y
date and not in conflict with the application but cited to understand
the pnnciple αr theory underlying the invention
"X"
document of particular relevance: the claimed invention cannot b e
considered novel or cannot be considered to involve an inventive
step when the document i s taken alone
"Y"
document of particular relevance: the claimed invention cannot b e
considered to involve an inventive step when the document i s
combined with one or more other such documents, such combination
being obvious to a person skilled in the art
"&"
document member of the same patent family
Date of mailing of the international search report
11
19 Sept 2005
Name and mailing address of the ISA/
Swedish Patent Office
Box 5055, S-102 42 STOCKHOLM
Facsimile No. + 46 8 666 02 86
Form PCT/ISA/210 (second sheet) (April 2005)
1-15
-09- 2005
Authorized officer
FERNANDO FARIETA/Els
Telephone No. + 46 8 782 25 00
INTERNATIONAL
SEARCH REPORT
International application No.
PCT/SE2005/000952
Box No. II
Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)
This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
] Claims Nos.: 1 5
because they relate to subject matter not required to be searched by this Authority, namely:
Claim 15 relates to a method o f treatment of the human or
animal body by surgery or by therapy, as well a s diagnostic
methods
/Rule 39.1(iv).
Nevertheless,
a search has been
executed for this claim. The search has been based on the
alleged effects of the compounds.
2-
Claims Nos.:
because they relate to parts of the international application that do not comply with the prescribed requirements to such an
extent that no meaningful international search can be carried out, specifically:
3.
Claims Nos.:
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box No. Ill
Observations where unity of invention is lacking (Continuation of item 3 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
1.
2.
3.
I ] A S all required additional search fees were timely paid by the applicant, this international search report covers all searchable
claims.
As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of
any additional fee.
I ] A S only some of the required additional search fees were timely paid by the applicant, this international search report covers
only those claims for which fees were paid, specifically claims Nos.:
No required additional search fees were timely paid by the applicant. Consequently, this international search report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest
The additional search fees were accompanied by the applicant's protest and, where applicable,
the payment of a protest fee.
I I The additional search fees were accompanied by the applicant's protest but the applicable
protest fee was not paid within the time limit specified in the invitation.
I J N o protest accompanied the payment of additional search fees.
[~~J
Form PCT/ISA/210 (continuation of first sheet (2)) (April 2005)
International application No.
INTERNATIONAL SEARCH REPORT
PCT/SE 2005/000952
C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
1-15
EP 1013276 A l (PFIZER INC.), 28 June 2000
(28.06.2000), the claims
WO 03042177 A l (ASTRAZENECA AB), 22 May
(22.05.2003), formula I
2003
1-15
WO 03042205 A l (ASTRAZENECA AB), 22 May
(22.05.2003), formula I
2003
1-15
WO 0187839 A l (ASTRAZENECA AB), ZZ November 2001
(22.11.2001), compound 34,35
1-15
WO 9937619 A l (LEUKOSITE INC.), 29 July 1999
(29.07.1999), formula I
1-15
Form PCT/ISA/210 (continuation of second sheet) (April 2005)
INTERNATIONAL SEARCH REPORT
International application No.
PCT/SE 2005/000952
WO
2004054974
A2
01/07/2004
AU
2003300902 A
00/00/0000
WO
2004056773 Al
08/07/2004
AU
2003288856
0203821
2003216022
1487869
0300499
2003259004
0314688
2497280
1546130
0301425
A
D
A
A
D
A
A
A
A
D
00/00/0000
00/00/0000
00/00/0000
22/12/2004
00/00/0000
00/00/0000
02/08/2005
08/04/2004
29/06/2005
00/00/0000
6461600
1212299
2003507456
9902987
6903085
A
A
T
D
B
19/03/2001
12/06/2002
25/02/2003
00/00/0000
07/06/2005
744685 B
1374199 A
28/02/2002
07/06/1999
31/01/2001
31/07/2001
27/05/1999
SE
AU
EP
SE
AU
BR
CA
EP
SE
WO
0114333
Al
01/03/2001
AU
EP
JP
SE
US
WO
9925686
Al
27/05/1999
AU
AU
BG
104441 A
BR
CA
9814645 A
2309328 A
CN
CN
1279668 A, T
1496981 A
EE
EP
EP
EP
HR
HU
ID
IL
JP
NO
NZ
PL
A
A
A
A
A
A
24475 A
135488
2001523661
20002486
503782
342207
D
T
A
A
A
RU
2216540 C
SK
US
5532000 A
200001399 T
6451842 B
UA
67757 C
TR
Form PCT/ISA/210 (patent family annex) (April 2 005)
200000294
1030840
1535909
1553085
20000214
0004200
10/01/2001
19/05/2004
15/08/2001
30/08/2000
01/06/2005
13/07/2005
31/12/2001
28/03/2001
00/00/0000
00/00/0000
27/11/2001
18/07/2000
28/03/2002
21/05/2001
20/11/2003
12/02/2001
00/00/0000
17/09/2002
15/11/2000
INTERNATIONAL SEARCH REPORT
Information on patent family members
EP
1013276
Al
28/06/2000
International application No.
31/08/2005
AP
AP
AU
AU
AU
AU
BG
BG
BR
BR
BR
CA
CA
CA
CN
CN
CN
CZ
CZ
EA
EE
EE
EP
EP
GB
HK
HR
HR
HU
HU
ID
ID
IL
IL
JP
JP
JP
JP
JP
NO
NO
NZ
NZ
PL
PL
SK
SK
TR
TR
TR
TW
US
WO
WO
ZA
Form PCIVIS A/2 10 (patent family annex) (April 20O 5 )
PCT/SE 2005/000952
200102186
200102187
763644
769449
1290400
1675100
105709
105721
9905977
9916585
9917007
2292984
2350073
2350573
1150192
1331591
1331691
20012297
20012298
4988
200100344
200100345
1140085
1140920
9828420
1039942
20010468
20010478
0104795
0104910
28965
29031
143510
143512
3602795
2000212159
2002533393
2002533461
2004099618
20013149
20013183
D
D
B
B
A
A
A
A
A
A
A
A
A
A
C
A,T
AT
A
A
B
A
A
A
A
D
A
A
A
A
A
A
A
D
D
B
A
T
T
A
A
A
511794 A
511796
349091
349495
8752001
8762001
200101793
200101867
200200938
577888
6586430
0038680
0039125
200104211
A
A
A
A
A
T
T
T
B
B
A
A
A
00/00/0000
00/00/0000
31/07/2003
29/01/2004
31/07/2000
31/07/2000
28/02/2002
28/02/2002
14/01/2003
16/10/2001
30/10/2001
23/06/2000
06/07/2000
06/07/2000
19/05/2004
16/01/2002
16/01/2002
11/09/2002
11/09/2002
28/10/2004
15/10/2002
16/12/2002
10/10/2001
10/10/2001
00/00/0000
03/12/2004
28/02/2003
30/06/2002
29/04/2002
28/10/2002
00/00/0000
00/00/0000
00/00/0000
00/00/0000
15/12/2004
02/08/2000
08/10/2002
08/10/2002
02/04/2004
23/08/2001
08/08/2001
31/10/2003
28/11/2003
01/07/2002
29/07/2002
04/02/2003
04/02/2003
00/00/0000
00/00/0000
00/00/0000
00/00/0000
01/07/2003
06/07/2000
06/07/2000
14/01/2002
INTERNATIONAL SEARCH REPORT
Information on patent family members
EP
WO
1013276
03042177
Al
Al
28/06/2000
22/05/2003
International application No.
31/08/2005
ZA
GB
200104254 A
BR
0214141 A
2464861 A
1589261 A
Al
22/05/2003
A
A
A
A
A
D
T
D
A
19/10/2004
22/05/2003
23/02/2005
25/08/2004
28/02/2005
00/00/0000
21/04/2005
00/00/0000
30/12/2004
5898101 A
0110767 A
2407258 A
EP
1448524 A
HU
0402567 A
IL
JP
161594 D
0214140
2464347
1585763
1448548
EP
0402261
HU
IL
161699
2005510522
JP
0103818
SE
US 20040267016
BR
CA
CN
WO
0187839
Al
22/11/2001
20023777
200200647
EE
EP
1289957
0011838
GB
0302153
HU
152418
IL
JP
2003533510
PA02011304
MX
NO
20025430
365118
PL
SK
16152002
20040006081
US
ZA
200208894
A
A
A
D
A
D
T
A
A
A
A
A
A
26/11/2001
11/02/2003
22/11/2001
10/09/2003
14/05/2003
16/08/2004
12/03/2003
00/00/0000
28/10/2003
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11/11/2003
25/04/2003
18/12/2002
27/12/2004
02/05/2003
08/01/2004
02/02/2004
2335699
2318088
1047675
2002501052
6433165
A
A
A
T
B
09/08/1999
29/07/1999
02/11/2000
15/01/2002
13/08/2002
AU
BR
CA
CN
CZ
WO
9937619
Al
29/07/1999
AU
CA
EP
JP
US
Form PCT/ISA/210 (patent family annex) (April 2005)
01/11/2002
00/00/0000
2005513017 T
SE
0103819 D
US 20050014788 A
CN
03042205
9922702 D
19/10/2004
22/05/2003
02/03/2005
25/08/2004
29/03/2005
00/00/0000
12/05/2005
00/00/0000
20/01/2005
CA
WO
PCT/SE 2005/000952
1441781 A, T
`