U.S. patent application number 12/114297 was filed with the patent office on 2008-10-09 for piperdine derivatives as ccr5 inhibitors.
This patent application is currently assigned to Novartis AG. Invention is credited to Rainer ALBERT, Christian Bruns, Nigel Graham Cooke, Francois Nuninger, Markus Streiff, Gebhard Thoma, Hans-Gunter Zerwes.
Application Number | 20080249111 12/114297 |
Document ID | / |
Family ID | 9945424 |
Filed Date | 2008-10-09 |
United States Patent
Application |
20080249111 |
Kind Code |
A1 |
ALBERT; Rainer ; et
al. |
October 9, 2008 |
Piperdine Derivatives as CCR5 Inhibitors
Abstract
Disclosed are compounds of formula I: ##STR00001## wherein
R.sub.1, R.sub.2, R.sub.3 and X are as defined herein, in free or
salt form, which are useful as CCR5 inhibitors, e.g. in the
prevention or treatment of disorders mediated by interactions
between chemokine receptors and their ligands.
Inventors: |
ALBERT; Rainer; (Basel,
CH) ; Cooke; Nigel Graham; (Oberwil, CH) ;
Thoma; Gebhard; (Lorrach, DE) ; Bruns; Christian;
(Freiburg, DE) ; Nuninger; Francois; (Wittenheim,
FR) ; Streiff; Markus; (Birsfelden, CH) ;
Zerwes; Hans-Gunter; (Lorrach, DE) |
Correspondence
Address: |
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
400 TECHNOLOGY SQUARE
CAMBRIDGE
MA
02139
US
|
Assignee: |
Novartis AG
|
Family ID: |
9945424 |
Appl. No.: |
12/114297 |
Filed: |
May 2, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10529776 |
May 5, 2005 |
7399771 |
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PCT/EP2003/011035 |
Oct 6, 2003 |
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12114297 |
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Current U.S.
Class: |
514/256 ;
514/314; 514/316; 544/333; 546/165; 546/187; 546/191 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 31/00 20180101; A61P 35/00 20180101; A61P 21/04 20180101; A61P
7/06 20180101; A61P 35/04 20180101; A61P 25/00 20180101; A61P 13/12
20180101; C07D 409/14 20130101; A61P 1/04 20180101; A61P 29/00
20180101; A61P 11/06 20180101; A61P 27/00 20180101; A61P 37/08
20180101; C07D 405/14 20130101; A61P 11/02 20180101; A61P 35/02
20180101; A61P 17/06 20180101; A61P 31/12 20180101; C07D 401/14
20130101; A61P 19/00 20180101; A61P 37/02 20180101; A61P 9/10
20180101; A61P 37/06 20180101; A61P 5/14 20180101; A61P 11/00
20180101; A61P 37/00 20180101; A61P 31/18 20180101; A61P 17/14
20180101; C07D 417/14 20130101; A61P 3/10 20180101; C07D 211/58
20130101 |
Class at
Publication: |
514/256 ;
546/187; 544/333; 546/165; 546/191; 514/314; 514/316 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; C07D 401/14 20060101 C07D401/14; C07D 401/04 20060101
C07D401/04; C07D 417/14 20060101 C07D417/14; A61P 29/00 20060101
A61P029/00; A61P 37/00 20060101 A61P037/00; A61K 31/506 20060101
A61K031/506; A61K 31/4709 20060101 A61K031/4709 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 7, 2002 |
GB |
0223223.9 |
Claims
1-8. (canceled)
9. A compound of formula I ##STR00072## wherein a) R.sub.2 is a
residue of formula ##STR00073## wherein i) R.sub.1 is phenyl, X is
a direct bond and R.sub.3 is pyridyl or ii) R.sub.1 is pyridyl, X
is a direct bond and R.sub.3 is phenyl or b) R.sub.2 is a residue
of formula ##STR00074## wherein Y is --C.dbd. or --N.dbd. and
R.sub.1 is pyridyl, X is a direct bond and R.sub.3 is phenyl, or c)
R.sub.2 is a residue of formula ##STR00075## X is a direct bond and
one of R.sub.1 and R.sub.3 is phenyl and the other is pyridyl, or
d) R.sub.2 is a residue of formula ##STR00076## R.sub.1 is pyridyl,
X is a direct bond and R.sub.3 is phenyl, or e) R.sub.2 is
indol-4-yl, R.sub.1 is pyridyl, X is a direct bond and R.sub.3 is
phenyl, in free form or in salt form.
10. A compound of formula I as defined in claim 1 or a
pharmaceutically acceptable salt thereof for use as a
pharmaceutical.
11. A pharmaceutical composition comprising a compound of formula I
as defined in claim 1 or a pharmaceutically acceptable salt thereof
in association with a pharmaceutically acceptable diluent or
carrier therefor.
12. A method of preventing or treating a disorder or disease
comprising administering to a subject in need thereof the compound
of formula I as defined in claim 1 or a pharmaceutically acceptable
salt thereof, wherein said disorder or disease is selected from the
group consisting transplantation, acute or chronic rejection of
organ, tissue or cell allow or xenografts or delayed graft
function, autoimmune diseases, rheumatoid arthritis, systemic lupus
erythematosus, Hashimoto's thyroidis, multiple sclerosis,
myasthenia gravis, diabetes type I or II and the disorders
associated therewith, vasculitis, pernicious anemia, Sjoegren
syndrome, uveitis, psoriasis, alopecia areata and others, allergic
diseases, allergic asthma, atopic dermatitis, allergic
rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory
diseases optionally with underlying aberrant reactions,
inflammatory bowel disease, Crohn's disease or ulcerative colitis,
intrinsic asthma, inflammatory lung injury, inflammatory liver
injury, inflammatory glomerular injury, atherosclerosis,
osteoarthritis, irritant contact manifestations of
immunologically-mediated disorders, inflammatory eye disease,
keratoconjunctvits, myocarditis or hepatitis, ischemia/reperfusion
injury, myocardial infarction, stroke, gut ischemia, renal failure
or hemorrhage shock, traumatic shock, cancer, solid tumors or
lymphatic cancer, T cell lymphomas or T cell leukemias,
metastasizing or angiogenesis, infectious diseases, toxic shock,
septic shock, adult respiratory distress syndrome, and viral
infections.
13. A pharmaceutical combination comprising a) a first agent which
is a compound of formula I as defined in claim 1, in free form or
in pharmaceutically acceptable salt form, and b) at least one
co-agent.
Description
[0001] The present invention relates to piperidine derivatives,
process for their production, their uses and pharmaceutical
compositions containing them.
[0002] More particularly, the present invention provides a compound
of formula I
##STR00002##
wherein 1) R.sub.2 is a residue of formula
##STR00003## [0003] and [0004] a) R.sub.1 is thienyl, furyl,
thiazolyl or 2-methyl-thiazolyl, [0005] X is --CH.sub.2--, and
[0006] R.sub.3 is benzo[1,3]dioxol-yl or phenyl optionally
monosubstituted by halogen, [0007] or [0008] b) R.sub.1 is phenyl
substituted by --SO.sub.2CH.sub.3 or CN [0009] X is --CH.sub.2--,
and [0010] R.sub.3 is phenyl [0011] or [0012] c) R.sub.1 is phenyl
[0013] X is a direct bond, and [0014] R.sub.3 is pyridyl, [0015] or
2) R.sub.2 is a residue of formula
[0015] ##STR00004## [0016] and [0017] a) R.sub.1 is pyridyl, phenyl
optionally substituted by carboxy or C.sub.1-4alkoxycarbonyl,
[0018] 2-methylthiazolyl, indolyl or benzimidazol-2-yl, [0019]
X.sub.1 is --CH.sub.2-- or CH.sub.2--CH.sub.2--, and [0020] R.sub.3
is phenyl optionally substituted by Hal, [0021] or [0022] b)
R.sub.1 is phenyl [0023] X is a direct bond [0024] R.sub.3 is
pyridyl, [0025] or [0026] c) R.sub.1 is 2-methyl-thiazolyl, [0027]
X is --CH.sub.2--, and [0028] R.sub.3 is 1-methyl-indolyl [0029] or
3) R.sub.2 is a residue of formula
[0029] ##STR00005## [0030] and [0031] a) R.sub.1 is
2-methyl-thiazolyl [0032] X is --CH.sub.2--, and [0033] R.sub.3 is
phenyl substituted by halogen [0034] or [0035] b) R.sub.1 is
pyridyl [0036] X is a direct bond, and [0037] R.sub.3 is phenyl
[0038] or 4) R.sub.2 is a residue of formula
[0038] ##STR00006## [0039] wherein [0040] Hal is F or Cl, [0041] Z
is --C.dbd. or --N.dbd. [0042] and [0043] a) R.sub.1 is phenyl, X
is a direct bond and R.sub.3 is pyridyl [0044] or [0045] b) R.sub.1
is pyridyl, X is a direct bond and R.sub.3 is phenyl [0046] or 5)
R.sub.2 is a residue of formula
[0046] ##STR00007## [0047] wherein Y is --C.dbd. or --N.dbd. [0048]
and [0049] R.sub.1 is pyridyl, X is a direct bond and R.sub.3 is
phenyl, [0050] or 6) R.sub.2 is a residue of formula
[0050] ##STR00008## [0051] X is a direct bond and one of R.sub.1
and R.sub.3 is phenyl and the other is pyridyl, [0052] or 7)
R.sub.2 is a residue of formula
[0052] ##STR00009## [0053] wherein each of R.sub.a and R.sub.b,
independently, is H, CH.sub.3 or C.sub.2H.sub.5, R.sub.1 and
R.sub.3 are phenyl, and X is a direct bond [0054] or 8) R.sub.2 is
a residue of formula
[0054] ##STR00010## [0055] R.sub.1 is pyridyl, X is a direct bond
and R.sub.3 is phenyl, [0056] or 9) R.sub.2 is indol-4-yl, R.sub.1
is pyridyl, X is a direct bond and R.sub.3 is phenyl, in free form
or in salt form.
[0057] Halogen is F, Cl, Br or I. Phenyl monosubstituted by halogen
is preferably para substituted.
[0058] When phenyl is substituted by carboxy or
C.sub.1-4alkoxycarbonyl, it is preferably in position meta. Indolyl
is preferably 3-indolyl.
[0059] The compounds of formula I may exist in free form or in salt
form, e.g. addition salts with e.g. organic or inorganic acids, for
example, hydrochloric acid, acetic acid when e.g. R.sub.1, R.sub.2,
and/or R.sub.3 comprises an optionally substituted amino group or a
heterocyclic residue which can form addition salts. The compounds
of formula I have one or more asymmetric centers in the molecule,
and the present invention is to be understood as embracing the
various optical isomers, as well as racemates, diastereoisomers and
mixtures thereof.
[0060] The present invention also includes a process for the
preparation of a compound of formula I which process comprises
a) amidating a compound of formula II
##STR00011## [0061] wherein R.sub.1, R.sub.3 and X are as indicated
above [0062] with a compound of formula III
[0062] R.sub.2--CO-A III [0063] wherein R.sub.2 is as defined
above, A is a leaving group, e.g. Cl or Br; or b) reacting a
compound of formula IV
[0063] ##STR00012## [0064] wherein R.sub.2 and R.sub.3 are as
defined above, with a compound of formula V
[0064] R.sub.1-X-Hal V [0065] wherein R.sub.1 and X are as defined
above; and, where required, converting the resulting compound of
formula I obtained in free form into the desired salt form, or vice
versa.
[0066] The reaction steps a) or b) may be performed in accordance
with methods known in the art or as disclosed in the Examples
below.
[0067] Compounds of formula II, used as starting material may be
prepared as follows:
##STR00013##
wherein X, R.sub.1 and R.sub.3 are as defined above and Hal is Cl,
Br or I. In above formulae, Boc is a protecting group which means
tert.-butyloxycarbonyl. This protecting group may be replaced in
above reaction scheme by any amino protecting group, e.g. as
disclosed in "Protective Groups in Organic Synthesis" by T. W.
Greene, J. Wiley & Sons NY, 2.sup.nd ed., Chapter 7, 1991 and
references therein, e.g. benzyloxycarbonyl or 9-fluorenylmethoxy
carbonyl.
[0068] Alternatively, compounds of formula II may be prepared as
follows:
##STR00014##
wherein R.sub.1, R.sub.3, X and Hal are as herein defined and Bn is
benzyl.
[0069] Compounds of formula IV, used as starting material, may be
prepared as follows:
##STR00015##
wherein R.sub.1, R.sub.3, X and Bn are as defined above.
[0070] Above reactions may be carried out in accordance with
methods known in the art or as disclosed hereafter.
[0071] Insofar as the production of the starting materials is not
particularly described, the compounds are known or may be prepared
analogously to methods known in the art or as described
hereafter.
[0072] The following Examples are illustrative of the invention,
without limitation.
EXAMPLE 1
(2,
Dimethyl-pyridin-3-yl)-[4'-methyl-4-(phenyl-pyridin-3-yl-amino)-[1,4']-
bipiperidinyl-1'-yl]-methanone
##STR00016##
[0074] It is prepared from
(4'-methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-3-yl-amine and
2,4-dimethyl-nicotinic acid using a procedure as described for
Example 1 of International patent application PCT/EP0203871 MS/ESI
484 [M+H].sup.+.
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-3-yl-amine used
as starting material can be prepared from tent-Butyl
4-phenylaminopiperidine-1-carboxylate and 3-bromopyridine using
procedures as described in Example 1a-1d of PCT/EP02/03871. MS/ESI
351 [M+H]+
[0075] By following the procedure as disclosed in example 1, the
compounds of formula X.sub.1
##STR00017##
wherein R.sub.2 has the significances as indicated in Table 1, may
be prepared.
TABLE-US-00001 TABLE 1 Example R.sub.2 MS/ESI (M + H).sup.+ 2
##STR00018## 561 3 ##STR00019## 505 4 ##STR00020## 523/525 5
##STR00021## 506 6 ##STR00022## 506 7 ##STR00023## 501 8
##STR00024## 491 9 ##STR00025## 470 10 ##STR00026## 525 11
##STR00027## 473
EXAMPLE 12
(2,
Dimethyl-1-oxy-pyridin-3-yl)-[4'-methyl-4-(phenyl-pyridin-2-yl-amino)--
[1,4']bipiperidinyl-1'-yl]-methanone
##STR00028##
[0077] Is prepared from
(4'-methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-2-yl-amine and
2,4-dimethyl-1-oxy-nicotinic acid using a procedure as described
for Example 1 above. MS/ESI 500 [M+H].sup.+.
[0078]
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-2-yl-amine used
as starting material can be prepared from tert-butyl
4-(phenyl-pyridin-2-ylamino)piperidine-1-carboxylate using a
procedure as described Example 1b-1d of PCT/EP02/03871. MS/ESI 351
[M+H].sup.+.
[0079] tert-Butyl
4-(phenyl-pyridin-2-ylamino)piperidine-1-carboxylate may be
prepared as follows: A mixture of tert-Butyl
4-phenylamino-piperidine-1-carboxylate (0.8 g; 3 mmol),
2-bromopyridine (0.3 ml; 3 mmol),
tris(dibenzylideneacetone)-di-palladium (0) (0.27 g, 0.3 mmol),
9,9-dimethyl-bi(diphenylphosphine)xanthene (0.26 g, 0.45 mmol) and
potassium tert-butoxide (3 ml, 1 mol solution in THF) in toluene
(30 ml) is heated to 110.degree. C. for 11 h. The cooled mixture is
filtered and the filtrate is diluted with ethyl acetate. The
filtrate is washed with sodium hydrogen carbonate and brine and
dried with sodium sulfate. The solvent is removed and the residue
is recrystallized from acetonitrile to afford the title compound as
a brown solid. MS/ESI 354 [M+H].sup.+
EXAMPLE 13
(2,6-Dimethyl-phenyl)-[4'-methyl-4-(phenyl-pyridin-4-yl-amino)-[1,4']bipip-
eridinyl-1'-yl]-methanone
##STR00029##
[0081] It is prepared from
(4'-methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-4-yl-amine and
2,6-dimethyl-benzoic acid using a procedure as described in above
Example 1. MS/ESI 483 [M+H].sup.+.
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-4-yl-amine used
as starting material can be prepared from tert-butyl
4-phenylaminopiperidine-1-carboxylate and 4-bromopyridine
hydrochloride using procedures as described in Example 1a-1d of
PCT/EP02/03871. MS/ESI 351 [M+H].sup.+
[0082] By following the procedure as disclosed in example 13, the
compounds of formula X.sub.2
##STR00030##
wherein R.sub.2 has the significances as indicated in Table 2, may
be prepared.
TABLE-US-00002 TABLE 2 Example R.sub.2 MS/ESI (M + H).sup.+ 14
##STR00031## 491 15 ##STR00032## 506 16 ##STR00033## 523/525 17
##STR00034## 494 18 ##STR00035## 500 19 ##STR00036## 505
EXAMPLE 20
(4-Dimethylamino-naphthalen-1-yl)-(4-diphenylamino-4'-methyl[1,4']bipiperi-
dinyl-1'-yl)-methanone
##STR00037##
[0084] It is prepared from
(4'-methyl-[1,4']bipiperidinyl-4-yl)-diphenyl-amine and
4-Dimethylamino-naphthalene-1-carboxylic acid using a procedure as
described in above Example 1. MS/ESI 547 [M+H].sup.+.
4'-Methyl-[1,4']bipiperidinyl-4-yl)-diphenyl-amine used as starting
material may be prepared using a procedure as described in Example
1a-1d of PCT/EP02/03871. MS/ESI 350 [M+H].sup.+
EXAMPLE 21
[0085] By following the procedure as disclosed in example 20, the
compound of formula
##STR00038##
may be prepared. MS/ESI (M+H).sup.+ 519
EXAMPLE 22
4({[1'-(2,6-Dimethyl-benzoyl)-4'-methyl-[1,4']bipiperidinyl-4-yl]-phenyl-a-
mino}-methyl)-benzoic acid methyl ester
##STR00039##
[0087] It is prepared from
(2,6-dimethyl-phenyl)-(4'-methyl-4-phenylamino-[1,4']bipiperidinyl-1'-yl)-
-methanone and 4-bromomethyl-benzoic acid methyl ester using a
procedure as described for Example 52 of PCT/EP02/03871. MS/ESI 554
[M+H].sup.+.
(2,6-Dimethyl-phenyl)-(4'-methyl-4-phenylamino-[1,4']bipiperidinyl-1'-yl)-
-methanone used as starting material may be prepared using a
procedure similar to that described in Example 51a-e of
PCT/EP02/03871. MS/ESI 406 [M+H].sup.+
[0088] By following the procedure as disclosed in example 22, the
compounds of formula X.sub.3
##STR00040##
wherein -X-R.sub.1, has the significances as indicated in Table 3,
may be prepared.
TABLE-US-00003 TABLE 3 Example X--R.sub.1 MS/ESI (M + H).sup.+ 23
##STR00041## 554 24 ##STR00042## 497 25 ##STR00043## 536 26
##STR00044## 510 27 ##STR00045## 549
EXAMPLE 28
4-({[1'-(2,6-Dimethyl-benzoyl)-4'-methyl-[1,4']bipiperidinyl-4-yl]-phenyl--
amino}-methyl)-benzoic acid
##STR00046##
[0090] A mixture of
4-({[1'-(2,6-Dimethyl-benzoyl)-4'-methyl-[1,4']bipiperidinyl-4-yl]-phenyl-
-amino}-methyl)-benzoic acid methyl ester (180 mg, 0.325 mmol),
methanol (10 ml), water (3 ml) and LiOH (200 mg, 8.33 mmol) was
heated under reflux for 2 h. The pH was adjusted to 1 with 2 N HCl
and then to pH 7 with NaHCO.sub.3. The mixture was extracted with
ethyl acetate and dried with Na.sub.2SO.sub.4. The solvent was
evaporated and the residue crystallized from methanol/water to give
4-({[1'-(2,6-Dimethyl-benzoyl)-4'-methyl-[1,4']bipiperidinyl-4-yl]-phenyl-
-amino}-methyl)-benzoic acid. MS/ESI 540 [M+H].sup.+
EXAMPLE 29
[0091] By following the procedure as disclosed in Example 28, the
compound of formula
##STR00047##
may be prepared. MS/ESI (M+H).sup.+ 540
EXAMPLE 30
{4-[(4-Chloro-phenyl)-(2-methyl-thiazol-4-ylmethyl)-amino]-4'-methyl-[1,4'-
]bipiperidinyl-1'-yl}-(2,4-dimethyl-pyridin-3-yl)-methanone
##STR00048##
[0093] It is prepared from
(4-chloro-phenyl)-(4'-methyl-[1,4']bipiperidinyl-4-yl)-(2-methyl-thiazol--
4-ylmethyl)-amine and 2,4-dimethyl-nicotinic acid using a procedure
as described in Example 1 of PCT/EP02/03871. MS/ESI 552
[M+H].sup.+.
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-phenyl-pyridin-3-yl-amine used
as starting material can be prepared from 4-chloro-phenylamine,
4-oxo-piperidine-1-carboxylic acid tert-butyl ester and
4-chloromethyl-2-methyl-thiazole using procedures as described in
Example 51e, 52, 1b, 1c and 1d of PCT/EP02/03871. MS/ESI 419
[M+H].sup.+
[0094] By following the procedure as disclosed in Example 30, and
by using the corresponding 4-halogeno-phenylamines, the
corresponding 4-chloromethyl-thiazoles and the corresponding
carboxylic acids the compounds of formula X.sub.4
##STR00049##
wherein X-R.sub.1, R.sub.2 and Hal have the significances as
indicated in Table 4, may be prepared
TABLE-US-00004 TABLE 4 Example X--R.sub.1 R.sub.2 Hal MS/ESI (M +
H).sup.+ 31 ##STR00050## ##STR00051## F 536 32 ##STR00052##
##STR00053## Cl 551 33 ##STR00054## ##STR00055## F 535 34
##STR00056## ##STR00057## Cl 568 35 ##STR00058## ##STR00059## F
552
EXAMPLE 36
(2,4-Dimethyl-1-oxy-pyridin-3-yl)-[4'-methyl-4-(phenyl-thiophen-3-ylmethyl-
-amino)-[1,4']bipiperidinyl-1'-yl]-methanone
##STR00060##
[0096] It is prepared from
(4'-methyl-[1,4']bipiperidinyl-4-yl)-phenyl-thiophen-3-ylmethyl-amine
and 2,4-dimethyl-1-oxy-nicotinic acid using a procedure as
described in Example 1 of PCT/EP02/03871. MS/ESI 519
[M+H].sup.+.
[0097]
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-phenyl-thiophen-3-ylmethyl-ami-
ne used as starting material may be prepared as follows:
[0098] a)
4-(Benzyl-phenyl-amino)-4'-methyl-[1,4']bipiperidinyl-1'-carboxy-
lic acid tert-butyl ester may be obtained from
benzyl-phenyl-piperidin-4-yl-amine and
4-oxo-piperidine-1-carboxylic acid tert-butyl ester using a
procedure as in Example 1c of PCT/EP02/03871. MS/ESI 464
[M+H].sup.+.
[0099] b) 4'-Methyl-4-phenylamino-[1,4']bipiperidinyl-1'-carboxylic
acid tert-butyl ester is prepared by heating a mixture of
4-(benzyl-phenyl-amino)-4'-methyl-[1,4']bipiperidinyl-1'-carboxylic
acid tert-butyl ester (4.50 g, 9.70 mmol), ammonium formate (2.60
g, 41.3 mmol), Pd(OH).sub.2 (20% on charcoal; 1.0 g) and methanol
(100 ml) for 3 h under reflux. The catalyst is filtered off and
washed with ethyl acetate. The solution is washed with brine, with
Na2SO4 and the solvent evaporated. MS/ESI 374 [M+H].sup.+
[0100] c)
4'-Methyl-4-(phenyl-thiophen-3-ylmethyl-amino)-[1,4']bipiperidin-
yl-1'-carboxylic acid tert-butyl ester may be prepared from
4'-Methyl-4-phenylamino-[1,4']bipiperidinyl-1'-carboxylic acid
tert-butyl ester and 3-chloromethyl-thiophene using a procedure
similar to that described in Example 52 of PCT/EP02/03871. MS/ESI
470 [M+H].sup.+
[0101] d)
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-phenyl-thiophen-3-ylmethyl--
amine may be prepared from
4'-methyl-4-(phenyl-thiophen-3-ylmethyl-amino)-[1,4']bipiperidinyl-1'-car-
boxylic acid tert-butyl ester using a procedure similar to that
described in Example 1b of PCT/EP02/03871. MS/ESI 406
[M+H].sup.+
[0102] By following the procedure as disclosed in Example 36, the
compounds of formula X.sub.5
##STR00061##
wherein X-R.sub.1 has the significances as indicated in Table 5,
may be prepared.
TABLE-US-00005 TABLE 5 Example X--R.sub.1 MS/ESI (M + H).sup.+ 37
##STR00062## 591 38 ##STR00063## 538 39 ##STR00064## 538 40
##STR00065## 503 41 ##STR00066## 520 42 ##STR00067## 538
EXAMPLE 43
(2,6-Dimethyl-phenyl)-(4'-methyl-4-[(1-methyl-1H-indol-7-yl)-(2-methyl-thi-
azol-4-ylmethyl)-amino]-[1,4']bipiperidinyl-1'-yl)-methanone
##STR00068##
[0104] It is prepared from
(2,6-dimethyl-phenyl)-[4-(1-methyl-4-(1-methyl-1H-indol-7-ylamino)-[1,4']-
bipiperidinyl-1'-yl]-methanones and
4-chloromethyl-2-methyl-thiazole using a procedure as described for
Example 52 of PCT/EP02/03871. MS/ESI 570 [M+H].sup.+.
(2,6-Dimethyl-phenyl)-[4'-methyl-4-(1-methyl-1H-indol-7-ylamino)-[1,4']bi-
piperidinyl-1'-yl]-methanone used as starting material may be
prepared from
1'-(2,6-dimethyl-benzoyl)-4'-methyl-[1,4']bipiperidinyl-4-one and
1-methyl-1H-indol-7-ylamine using a procedure as described in
Example 51e of PCT/EP02/03871. MS/ESI 459 [M+H].sup.+.
1'-(2,6-Dimethyl-benzoyl)-4'-methyl-[1,4']bipiperidinyl-4-one may
be prepared using a procedure as described in Example 51a-d of
PCT/EP02/03871. MS/ESI 329 [M+H].sup.+.
EXAMPLE 44
[4-(Benzo[1,3]dioxol-5-yl-benzyl-amino)-4'-methyl-[1,4']bipiperidinyl-1'-y-
l]-(2,4-dimethyl-1-oxy-pyridin-3-yl)-methanone
##STR00069##
[0106] It is prepared from
benzo[1,3]dioxol-5-yl-benzyl-(4'-methyl-[1,4']bipiperidinyl-4-yl)-amine
and 2,4-dimethyl-1-oxy-nicotinic acid using a procedure as
described in Example 1 of PGT/EP02/03871. MS/ESI 557 [M+H].sup.+.
Benzo[1,3]dioxol-5-yl-benzyl-(4'-methyl-[1,4']bipiperidinyl-4-yl)-amine
used as starting material can be prepared from
benzo[1,3]dioxol-5-ylamine, 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester and benzyl chloride using procedures as described
in Examples 51e, 52, 1b, 1c and 1d of PCT/EP02/03871. MS/ESI 408
[M+H].sup.+
EXAMPLE 45
{4-[Benzo[1,3]dioxol-5-yl-(2-methyl-thiazol-4-ylmethyl)-amino]-4'-methyl-[-
1,4']bipiperidinyl-1'-yl}-(2,4-dimethyl-1-oxy-pyridin-3-yl)-methanone
##STR00070##
[0108] It is prepared from
benzo[1,3]dioxol-5-yl-(4'-methyl-[1,4']bipiperidinyl-4-yl)-(2-methyl-thia-
zol-4-ylmethyl)-amine and 2,4-dimethyl-1-oxy-nicotinic acid using a
procedure as described for Example 1 of PCT/EP02/03871. MS/ESI 557
[M+H].sup.+.
Benzo[1,3]dioxol-5-yl-(4'-methyl-[1,4']bipiperidinyl-4-yl)-(2-methyl-thia-
zol-4-ylmethyl)-amine used as starting material can be prepared
from benzo[1,3]dioxol-5-ylamine, 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester and 4-chloromethyl-2-methyl-thiazole using
procedures as described in Examples 51e, 52, 1b, 1c and 1d of
PCT/EP02/03871, MS/ESI 429 [M+H)+
EXAMPLE 46
(4,6-Dimethyl-2-phenyl-pyrimidin-5-yl)-{4'-methyl-4-(2-methyl-thiazol-4-yl-
methyl)-phenyl-amino]-[1,4']bipiperidinyl-1'-yl}-methanone
##STR00071##
[0110] It is prepared from
(4'-methyl-[1,4']bipiperidinyl-4-yl)-(2-methyl-thiazol-4-ylmethyl)-phenyl-
-amine and 4,6-dimethyl-2-phenyl-pyrimidine-5-carboxylic acid using
a procedure as described for Example 1 of PCT/EP02/03871. MS/ESI
595 [M+H].sup.+.
(4'-Methyl-[1,4']bipiperidinyl-4-yl)-(2-methyl-thiazol-4-ylmethyl)-phenyl-
-amine used as a starting material may be prepared using procedures
described in example 83 of PCT/EP02/03871. MS/ESI 385
[M+H].sup.+
[0111] The compounds of formula I in free form or in
pharmaceutically acceptable salt form exhibit valuable
pharmacological properties, e.g. as CCR5 antagonists, e.g. as
indicated in in vitro tests and therefore indicated for
therapy.
a) CCR5 Membrane Binding Assay
[0112] Human CCR5 is used to generate stable transfectants in CHO
K1 cells. Membranes prepared from these CCR5 transfectants are used
in a radioligand binding assay using 125-I MIP-1.alpha. as a ligand
and the compounds of formula I are tested for inhibitory activity.
The data are reported as IC.sub.50, i.e. the concentration of
compound required to achieve 50% inhibition of [1-125]MIP-1.alpha.
binding. In this assay, compounds of formula I have an
IC.sub.50.ltoreq.1 .mu.M. Compounds of Examples 32 and 39 have an
IC.sub.50 of 0.5 nM, respectively.
b) CCR5 Functional Assay--Ca.sup.2+ Mobilization
[0113] Human CCR5 is used to generate stable transfectants in CHO
K1 cells. These CCR5 transfectants are used for assessing Ca.sup.2+
mobilization in response to stimulation by the CCR5 ligands
MIP-1.alpha., MIP-1.beta., HCC-1 (9-74) or RANTES. For the assay
the cells are loaded with a Ca.sup.2+-sensitive fluorochrome (Fluo3
or Fluo4). Ligand concentrations between 0.01-100 nM are used to
induce Ca.sup.2+ mobilization which is monitored in a fluorometer
with appropriate settings.
[0114] To assess the activity of the compounds to be tested, a
baseline fluorescence reading is taken after which the compounds at
the desired concentration are added to the cells and fluorescence
is further recorded for a certain time to assess whether compounds
show agonistic effects. Next the agonist is added to the mixture
and fluorescence monitored. The inhibition of Ca.sup.2+ flux in the
presence of the compounds to be tested is calculated tram the
inhibition of maximal fluorescence induced by the agonist.
IC.sub.50 values are calculated from dose-response curves obtained
with the compounds. In this assay, compounds of formula I have an
IC.sub.50.ltoreq.1 .mu.M. For example, compounds of Examples 12 and
36 have IC.sub.50 values of 29 nM and 8 nM, respectively.
c) CCR5 Functional Assay--Chemotaxis
[0115] CCR5 transfectants are generated in Jurkat T cells or the
mouse pre B cell line L1.2. Migration of CCR5 transfectants is
tested in transwell tissue chamber inserts system with the CCR5
agonist MIP-1.alpha. at concentrations of 1-100 nM. Cells migrated
in response to the agonist compared to a buffer control are
quantified in a flow cytometer. The compounds to be tested are
added to the cells and the agonist compartments. IC.sub.50 values
are calculated from concentration-response curves obtained with the
compounds in the presence of MIP-1.alpha.. In this assay, compounds
of formula I have an IC.sub.50.ltoreq.1 .mu.M.
[0116] d) Experiments performed in murine animal models show that
vessel wall remodeling after experimental injury (e.g. induced by
allotransplantation) is significantly inhibited in the absence of
functional CCR5.
[0117] The compounds of formula I are, therefore, useful in the
prevention and/or treatment of diseases or disorders mediated by
interactions between chemokine receptors, e.g. CCR5, and their
ligands, e.g. in transplantation, such as acute or chronic
rejection of organ, tissue or cell allo- or xenografts or delayed
graft function, autoimmune diseases, e.g. rheumatoid arthritis,
systemic lupus erythematosus, Hashimoto's thyroidis, multiple
sclerosis, myasthenia gravis, diabetes type I or II and the
disorders associated therewith, vasculitis, pernicious anemia,
Sjoegren syndrome, uveitis, psoriasis, alopecia greata and others,
allergic diseases, e.g. allergic asthma, atopic dermatitis,
allergic rhinitis/conjunctivitis, allergic contact dermatitis,
inflammatory diseases optionally with underlying aberrant
reactions, e.g. inflammatory bowel disease, Crohn's disease or
ulcerative colitis, intrinsic asthma, inflammatory lung injury,
inflammatory liver injury, inflammatory glomerular injury,
atherosclerosis, osteoarthritis, irritant contact dermatitis and
further eczematous dermatitises, seborrhoeic dermatitis, cutaneous
manifestations of immunologically-mediated disorders, inflammatory
eye disease, keratoconjunctivitis, myocarditis or hepatitis,
ischemia/reperfusion injury, e.g. myocardial infarction, stroke,
gut ischemia, renal failure or hemorrhage shock, traumatic shock
and others, cancer, e.g. solid tumors or lymphatic cancer such as T
cell lymphomas or T cell leukemias, metastasizing or angiogenesis,
infectious diseases, e.g. toxic shock (e.g. superantigen induced),
septic shock, adult respiratory distress syndrome or viral
infections, e.g. AIDS. By transplantation is meant allo- or xeno
grafts of e.g. cells, tissues or solid organs, for example
pancreatic islets, stem cells, bone marrow, corneal tissue,
neuronal tissue, heart, lung, combined heart-lung, kidney, liver,
bowel, pabcreas, trachea or oesophagus. Chronic rejection is also
named graft vessel diseases.
[0118] For the above uses the required dosage will of course vary
depending on the mode of administration, the particular condition
to be treated and the effect desired. In general, satisfactory
results are indicated to be obtained systemically at daily dosages
of from about 0.01 to 10 mg/kg per body weight. An indicated daily
dosage in the larger mammal, e.g. humans, is in the range from
about 0.5 mg to about 1000 mg, conveniently administered, for
example, in divided doses up to four times a day or in retard form.
Suitable unit dosage forms for oral administration comprise from
ca. 1 to 500 mg active ingredient.
[0119] The compounds of formula I may be administered by any
conventional route, in particular enterally, e.g. orally, e.g. in
the form of tablets or capsules, or parenterally, e.g. in the form
of injectable solutions or suspensions, topically, e.g. in the form
of lotions, gels, ointments or creams, or in a nasal or a
suppository form. Pharmaceutical compositions comprising a compound
of formula I in free form or in pharmaceutically acceptable salt
form in association with at least one pharmaceutical acceptable
carrier or diluent may be manufactured in conventional manner by
mixing with a pharmaceutically acceptable carrier or diluent.
[0120] The compounds of formula I may be administered in free form
or in pharmaceutically acceptable salt form e.g. as indicated
above. Such salts may be prepared in conventional manner and
exhibit the same order of activity as the free compounds.
[0121] In accordance with the foregoing the present invention
further provides: [0122] 1.1 A method for preventing or treating
disorders or diseases mediated by interactions between chemokine
receptors and their ligands, e.g. such as indicated above, in a
subject in need of such treatment, which method comprises
administering to said subject an effective amount of a compound of
formula I or a pharmaceutically acceptable salt thereof; [0123] 1.2
A method for preventing or treating acute or chronic transplant
rejection or inflammatory or autoimmune diseases, e.g. as indicated
above, in a subject in need of such treatment, which method
comprises administering to said subject an effective amount of a
compound of formula I or a pharmaceutically acceptable salt
thereof; [0124] 2. A compound of formula I or a pharmaceutically
acceptable salt thereof for use as a pharmaceutical, e.g. in any of
the methods as indicated under 1.1 or 1.2 above. [0125] 3. A
pharmaceutical composition, e.g. for use in any of the methods as
in 1.1 or 1.2 above comprising a compound of formula I or a
pharmaceutically acceptable salt thereof in association with a
pharmaceutically acceptable diluent or carrier therefor. [0126] 4.
A compound of formula I or a pharmaceutically acceptable salt
thereof for use in the preparation of a pharmaceutical composition
for use in any of the method as in 1.1 or 1.2 above. [0127] 5. Use
of a compound of formula I or a pharmaceutically acceptable salt
thereof for preventing or treating a disorder or disease mediated
by interactions between chemokine receptors and their ligands, e.g.
such as indicated above. [0128] 6. Use of a compound of formula I
or a pharmaceutically acceptable salt thereof for preventing or
treating acute or chronic transplant rejection or inflammatory or
autoimmune diseases, e.g. as indicated above. [0129] 7. Use of a
compound of formula I or a pharmaceutically acceptable salt thereof
for the preparation of a medicament for preventing or treating a
disorder or disease mediated by interactions between chemokine
receptors and their ligands, e.g. such as indicated above. [0130]
8. Use of a compound of formula I or a pharmaceutically acceptable
salt thereof for the preparation of a medicament for preventing or
treating acute or chronic transplant rejection or inflammatory or
autoimmune diseases, e.g. as indicated above.
[0131] The compounds of formula I may be administered as the sole
active ingredient or in conjunction with, e.g. as an adjuvant to,
other drugs e.g. in immunosuppressive or immunomodulating regimens
or other anti-inflammatory agents, e.g. for the treatment or
prevention of alto- or xenograft acute or chronic rejection or
inflammatory or autoimmune disorders, a chemotherapeutic agent or
an anti-infective agent, e.g. an anti-viral agent such as e.g. an
anti-retroviral agent or an antibiotic. For example, the compounds
of formula I may be used in combination with a calcineurin
inhibitor, e.g. cyclosporin A, ISA 247 or FK 506; a macrocyclic
lactone having immunosuppressive properties, e.g. an mTOR
inhibitor, e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779
or ABT578; an ascomycin having immunosuppressive properties, e.g.
ABT-281, ASM981, etc.; corticosteroids; cathepsin S inhibitors;
cyclophosphamide; azathioprine; methotrexate; leflunomide;
mizoribine; mycophenolic acid; mycophenolate mofetil;
15-deoxyspergualine or an immunosuppressive homologue, analogue or
derivative thereof; a sphingosine-1-phosphate receptor agonist,
e.g. FTY720 or Y-36018; monoclonal antibodies to leukocyte
receptors, e.g., MHC, CD2, CD3, CD4, CD7, CDB, GD11a/CD18,
CO.sub.25, CO.sub.27, CD28, CD40, CD45, CD58, CD80, CD86, CD137,
ICOS, C150 (SLAM), OX40, 4-1 BB or to their ligands, e.g. CD154, or
antagonists thereof; other immunomodulatory compounds, e.g. a
recombinant binding molecule having at least a portion of the
extracellular domain of CTLA4 or a mutant thereof, e.g. an at least
extracellular portion of CTLA4 or a mutant thereof joined to a
non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC
68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule
inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists,
VGAM-4 antagonists or VLA-4 antagonists, e.g. natalizumab
(ANTEGREN.RTM.); or antichemokine antibodies or antichemokine
receptor antibodies or low molecular weight chemokine receptor
antagonists, e.g. anti MCP-1 antibodies.
[0132] Where the compounds of formula I are administered in
conjunction with other immunosuppressive/immunomodulatory,
anti-inflammatory or chemotherapeutic therapy, dosages of the
co-administered immunosuppressant, immunomodulatory,
anti-inflammatory or chemotherapeutic compound will of course vary
depending on the type of co-drug employed, e.g. whether it is a
steroid or a calcineurin inhibitor, on the specific drug employed,
on the condition being treated and so forth. In accordance with the
foregoing the present invention provides in a yet further aspect:
[0133] 5. A method as defined above comprising co-administration,
e.g. concomitantly or in sequence, of a therapeutically effective
non-toxic amount of a compound of formula I and at least a second
drug substance, e.g. an immunosuppressant, immunomodulatory,
anti-inflammatory, anti-infective or chemotherapeutic drug, e.g. as
indicated above. [0134] 6. A pharmaceutical combination, e.g. a
kit, comprising a) a first agent which is a CCR5 antagonist, e.g. a
compound of formula I as disclosed herein, in free form or in
pharmaceutically acceptable salt form, and b) at least one
co-agent, e.g. an immunosuppressant, immunomodulatory,
anti-inflammatory, anti-infective or chemotherapeutic drug. The kit
may comprise instructions for its administration.
[0135] The terms "co-administration" or "combined administration"
or the like as utilized herein are meant to encompass
administration of the selected therapeutic agents to a single
patient, and are intended to include treatment regimens in which
the agents are not necessarily administered by the same route of
administration or at the same time.
[0136] The term "pharmaceutical combination" as used herein means a
product that results from the mixing or combining of more than one
active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound of
formula I and a co-agent, are both administered to a patient
simultaneously in the form of a single entity or dosage. The term
"non-fixed combination" means that the active ingredients, e.g. a
compound of formula I and a co-agent, are both administered to a
patient as separate entities either simultaneously, concurrently or
sequentially with no specific time limits, wherein such
administration provides therapeutically effective levels of the 2
compounds in the body of the patient. The latter also applies to
cocktail therapy, e.g. the administration of 3 or more active
ingredients.
* * * * *