U.S. patent application number 10/489661 was filed with the patent office on 2005-01-06 for pyrrolidinone derivatives.
Invention is credited to Dasse, Olivier, Evans, Janelle, Higgins, Paul, Kintigh, Jeremy, Knerr, Laurent, Kondru, Rama, Schwartz, Eric, Zhai, Hai-Xiao, Zou, Dong.
Application Number | 20050004180 10/489661 |
Document ID | / |
Family ID | 27017198 |
Filed Date | 2005-01-06 |
United States Patent
Application |
20050004180 |
Kind Code |
A1 |
Zou, Dong ; et al. |
January 6, 2005 |
Pyrrolidinone derivatives
Abstract
The present invention provides pharmaceutical compositions and
novel compounds useful in the treatment of conditions mediated by
CCR2, MCP-1 or the interaction thereof. The compounds of the
present invention are pyrrolidinones and pyrrolidine-thiones.
Inventors: |
Zou, Dong; (Concord, MA)
; Dasse, Olivier; (Marlborough, MA) ; Evans,
Janelle; (Newton, MA) ; Higgins, Paul;
(Danvers, MA) ; Kintigh, Jeremy; (Waltham, MA)
; Knerr, Laurent; (Braine-le-Chateau, BE) ;
Kondru, Rama; (South Weymouth, MA) ; Schwartz,
Eric; (Wakefield, MA) ; Zhai, Hai-Xiao;
(Bedford, MA) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Family ID: |
27017198 |
Appl. No.: |
10/489661 |
Filed: |
September 3, 2004 |
PCT Filed: |
September 26, 2002 |
PCT NO: |
PCT/EP02/10810 |
Current U.S.
Class: |
514/343 ;
514/422; 514/424 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 37/08 20180101; A61P 25/00 20180101; A61P 39/02 20180101; C07D
405/04 20130101; A61P 1/16 20180101; A61P 19/02 20180101; C07D
413/06 20130101; A61P 1/04 20180101; A61P 25/28 20180101; A61P 9/10
20180101; A61P 13/12 20180101; C07D 207/24 20130101; A61P 21/02
20180101; A61P 7/02 20180101; A61P 27/16 20180101; C07D 207/36
20130101; A61P 11/02 20180101; A61P 31/18 20180101; A61K 31/4015
20130101; A61P 9/14 20180101; C07D 409/06 20130101; A61P 11/00
20180101; A61K 31/4439 20130101; C07D 207/273 20130101; A61P 17/00
20180101; A61P 37/02 20180101; A61P 29/00 20180101; A61P 17/06
20180101; A61P 31/04 20180101; A61P 15/00 20180101; C07D 401/04
20130101; A61P 35/00 20180101; A61P 17/04 20180101; C07D 409/04
20130101; A61P 11/06 20180101 |
Class at
Publication: |
514/343 ;
514/422; 514/424 |
International
Class: |
A61K 031/4439; A61K
031/4025; A61K 031/4015 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 3, 2001 |
US |
09970140 |
Aug 1, 2002 |
US |
60400807 |
Claims
1 A pharmaceutical composition comprising a compound according to
formula I 3wherein, Y is oxygen or sulfur; G and G', together with
the bond linking them, are HC--CH or C.dbd.C; V is aryl,
heterocycle or cycloalkyl; Z is halogen, alkyl, alkenyl, alkynyl,
hydroxyl, amino, alkoxy, aryloxy, nitro or cyano; R.sup.1 is
hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, aryl or heterocycle; R.sup.2 is hydrogen or hydroxy;
R.sup.3 is --C(O)R.sup.3a, --C(O)OR.sup.3a,
--C(O)N(R.sup.3a)(R.sup.3b), --S(O).sub.2R.sup.3a, --S(O)R.sup.3a
or --SR.sup.3a wherein R.sup.3a and R.sup.3b have independently the
same meaning as R.sup.1; R.sup.4 is hydroxy, sulfanyl or amino; t
is 0, 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt or
metabolically cleavable derivative thereof, together with a
pharmaceutically acceptable diluent or carrier.
2 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and the meaning of V is selected from, a) aryl, especially phenyl,
benzyl, naphthyl, naphthylmethyl, indenyl, dihydro indenyl;
heterocycle especially pyridyl; b) phenyl, benzyl, naphthyl,
naphthylmethyl, indenyl, dihydro indenyl or pyridyl; c) phenyl,
benzyl or dihydroindenyl; d) phenyl or dihydroindenyl; e) phenyl or
benzyl; and f) phenyl.
3 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and the meaning of Z is selected from, a) halogen, alkyl, alkoxy,
OH, NO.sub.2 or NH.sub.2; b) halogen, alkyl, alkoxy, NO.sub.2 or
NH.sub.2; c) fluoro, chloro, bromo, iodo, C.sub.1-4-alkyl,
C.sub.1-4 alkoxy, trifluoromethyl, NO.sub.2 or NH.sub.2; d) fluoro,
chloro, bromo, iodo, C.sub.1-4-alkyl, methoxy, trifluoromethyl,
NO.sub.2 or NH.sub.2; e) fluoro, chloro, bromo, C.sub.1-4-alkyl,
C.sub.1-4-alkoxy, trifluoromethyl, NO.sub.2 or NH.sub.2; f) fluoro,
chloro, bromo, C.sub.1-4-alkyl, methoxy, trifluoromethyl, NO.sub.2
or NH.sub.2; g) fluoro, chloro, bromo, iodo, C.sub.1-4 alkyl; h)
fluoro, chloro, bromo, iodo, methyl or ethyl; i) fluoro, chloro,
bromo, C.sub.1-4 alkyl; and j) fluoro, chloro, bromo, methyl or
ethyl.
4 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and t is selected from, a) 0, 1, 2 or 3; and b) 0, 1 or 2.
5 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and the meaning of R.sup.1 is selected from, a) alkyl, cycloalkyl,
cycloalkenyl, optionally substituted phenyl or heterocycle; b)
C.sub.1-10 alkyl, C.sub.C.sub.3-10 cycloalkyl, C.sub.6-8
cycloalkenyl, optionally substituted phenyl or heterocycle; c)
C.sub.1-8 alkyl, C.sub.3-10cycloalkyl, C.sub.6-8 cycloalkenyl,
optionally substituted phenyl or heterocycle; d) C.sub.1-8 alkyl,
C.sub.3-10 cycloalkyl, C.sub.6-8 cycloalkenyl, furyl, thienyl or
phenyl, optionally substituted by one or more alkyl or halogen,; e)
methyl, ethyl, propyl, i-propyl, 3,3,3-trifluoropropyl, i-butyl,
t-butyl, pentyl, 1-ethylpropyl, neo-pentyl, 1,2-dimethylbutyl or
1-propylbutyl, cyclopropyl, cyclopentyl, cyclohexyl,
cyclohexylmethyl, cycloheptyl, cyclooctyl, adamantyl or
noradamantyl, 2-cyclohexenyl or bicyclo[2.2.1]hept-5-enyl, furyl,
thienyl or phenyl, optionally substituted by one or more alkyl or
halogen; and f) 1-ethylpropyl, cyclohexyl, phenyl, optionally
substituted by one or more methyl, fluoro, chloro, bromo or
cyano;
6 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and R.sup.2 is hydrogen.
7 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and R.sup.3 is --C(O)R.sup.3a wherein the meaning of R.sup.3a is
selected from, a) alkyl, optionally substituted aryl or
heterocycle; b) C.sub.1-5-alkyl, optionally substituted phenyl,
benzyl, phenethyl, or thienyl; and c) methyl.
8 A composition according to claim 1 wherein in the formula I Y is
oxygen, G and G', together with the bond linking them, are C.dbd.C,
and R.sup.4 is hydroxy.
9 A composition according to claim 1 wherein the compound of
formula I is selected from those numbered 10, 13, 17, 18, 24, 25,
51, 53, 54, 56, 63, 65, 69, 70, 72, 79, 118, 119, 120, 121, 125,
127, 129, 135, 137, 139, 140, 141, 142, 144, 148, 149, 150, 151,
153, 154, 155, 156, 157 and 169 in Table 1.
10 A composition according to claim 9 wherein the compound of
formula I is selected from those numbered 10, 17, 18, 24, 51, 53,
54, 69, 72, 118, 119, 120, 121, 125, 127, 129, 135, 137, 139, 140,
141, 142, 144, 148, 149, 150, 151, 153, 154, 155, 156, 157 and 169
in Table 1.
11 A composition according to claim 10 wherein the compound of
formula I is selected from those numbered 51, 125, 129, 140, 144,
148, 149, 155 and 156 in Table 1.
12 A composition according to claim 1 wherein the compound of
formula I is in the form of its (-)-enantiomer.
13 A composition according to claim 1 wherein the compound of
formula I is in the forn of its (R)-enantiomer.
14 A compound of formula I as illustrated in claim 1 wherein, Y is
sulphur; and the remaining substituents are as defined in claim
1.
15 A compound of formula I as illustrated in claim 1 wherein,
R.sup.1 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl or heterocycle and R.sup.2 is hydroxy
and the remaining substituents are as defined in claim 1.
16 A compound of formula I as illustrated in claim 1 wherein,
R.sup.1 is as defined above except for hydrogen, C.sub.1-7-alkyl,
phenyl, C.sub.3-5-cycloalkyl, or methylene (C.sub.3-5-cycloalkyl)
wherein each alkyl or phenyl group may be substituted with one or
two methyl, methoxy, ethyl or trifluoromethyl, or up to three
halogens and R.sup.2 is hydrogen and the remaining substituents are
as defined in claim 1.
17 A compound of formula I as illustrated in claim 1 wherein, one
of R.sup.1 and R.sup.2 is other than hydrogen and the remaining
substituents are as defined in claim 1.
18 A compound of formula I as illustrated in claim 1 wherein
R.sup.3 is as defined in claim 1 except for --C(O)R.sup.3a wherein
R.sup.3a is hydrogen, C.sub.1-7-alkyl, C.sub.2-3-alkenyl, phenyl,
C.sub.3-5-cycloalkyl, or methylene (C.sub.3-5-cycloalkyl) wherein
each alkyl, phenyl or alkenyl group may be substituted with one
nitro, methoxy or ethoxy, with one or two methyl, ethyl or
trifluoromethyl, or with up to three halogens and the remaining
substituents are as defined in claim 1.
19 A compound of formula I as defined in claim 1 wherein when Y is
oxygen; and G and G', together with the bond linking them, are
C.dbd.C; then R.sup.1 is other than hydrogen, C.sub.1-7-alkyl,
phenyl, C.sub.3-5-cycloalkyl, or methylene (C.sub.3-5-cycloalkyl)
wherein each alkyl or phenyl group may be substituted with one or
two methyl, methoxy, ethyl or trifluoromethyl, or up to three
halogens when R.sup.2 is hydrogen; or R.sup.3 is other than
--C(O)R.sup.3a wherein R.sup.3a is hydrogen, C.sub.1-7-alkyl,
C.sub.2-3-alkenyl, phenyl, C.sub.3-5-cycloalkyl, or methylene
(C.sub.3-5-cycloalkyl) wherein each alkyl, phenyl or alkenyl group
may be substituted with one nitro, methoxy or ethoxy, with one or
two methyl, ethyl or trifluoromethyl, or with up to three
halogens.
20 A compound of formula I as illustrated in claim 1 in fully or
partially resolved isomeric form.
21 A compound of formula I as illustrated in claim 1 which is
selected from the compounds of Table 1 except for those numbered 1,
2, 3, 4, 5, 9 and 122.
22 A method of treating or preventing conditions mediated by CCR2,
MCP-1 or the interaction thereof, the method comprising
administering to a patient an amount of a CCR2 antagonist
sufficient to prevent, reduce or eliminate the condition.
23 A method according to claim 22 wherein the CCR2 antagonist is a
compound of formula I 4wherein, Y is oxygen or sulfur; G and G',
together with the bond linking them, are HC--CH or C.dbd.C; V is
aryl, heterocycle or cycloalkyl; Z is halogen, alkyl, alkenyl,
alkynyl, hydroxyl, amino, alkoxy, aryloxy, nitro or cyano; R.sup.1
is hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,
alkynyl, aryl or heterocycle; R.sup.2 is hydrogen or hydroxy;
R.sup.3 is --C(O)R.sup.3a, --C (O)OR.sup.3a,
--C(O)N(R.sup.3a)(R.sup.3b), --S(O).sub.2R.sup.3a, --S(O)R.sup.3a
or --SR.sup.3a wherein R.sup.3a and R.sup.3b have independently the
same meaning as R.sup.1; R.sup.4 is hydroxy, sulfanyl or amino; t
is 0, 1, 2, 3, 4 or 5; or a pharmaceutically active derivative or
salt thereof.
24 A method of treating or preventing conditions mediated by CCR2,
MCP-1 or the interaction thereof, the method comprising
administering to a patient an amount of a compound of formula I as
defined in claim 1, or a pharmaceutically active derivative or salt
thereof, sufficient to prevent, reduce or eliminate the
condition.
25 A method according to claim 22 wherein the condition is selected
from asthma, seasonal and perennial allergic rhinitis, sinusitus,
conjunctivitis, food allergy, scombroid poisoning, psoriasis,
urticaria, pruritus, eczema, inflammatory bowel disease, chronic
obstructive pulmonary disease, thrombotic disease, otitis media,
neuroinflammatory diseases such as multiple sclerosis,
atherosclerosis, other inflammatory diseases such as rheumatoid
arthritis and nephritis, liver cirrhosis, cardiac disease,
pulmonary fibrosis, restenosis such as vascular restenosis,
Alzheimer's disease, sepsis, systemic sclerosis, ulcerative
colitis, atopic dermatitis, stroke, acute nerve injury,
sarcoidosis, hepatitis, endometriosis, HIV infection, AIDS,
autoimmune diseases and cancer;
26 A method according to claim 24 wherein the condition is selected
from asthma, seasonal and perennial allergic rhinitis, sinusitus,
conjunctivitis, food allergy, scombroid poisoning, psoriasis,
urticaria, pruritus, eczema, inflammatory bowel disease, chronic
obstructive pulmonary disease, thrombotic disease, otitis media,
neuroinflammatory diseases such as multiple sclerosis,
atherosclerosis, other inflammatory diseases such as rheumatoid
arthritis and nephritis, liver cirrhosis, cardiac disease,
pulmonary fibrosis, restenosis such as vascular restenosis,
Alzheimer's disease, sepsis, systemic sclerosis,ulcerative colitis,
atopic dermatitis, stroke, acute nerve injury, sarcoidosis,
hepatitis, endometriosis, HIV infection, AIDS, autoimmune diseases
and cancer.
27 A method according to claim 25 wherein the condition is selected
from asthma, atherosclerosis, multiple sclerosis and rheumatoid
arthritis.
28 A method according to claim 26 wherein the condition is selected
from asthma, atherosclerosis, multiple sclerosis and rheumatoid
arthritis.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to the field of pharmaceutical
compounds in particular pyrrolidinones and pyrrolidine-thiones and
analogs thereof.
[0003] The invention further concerns processes for preparing these
pharmaceutical compounds, compositions containing them and their
use for the treatment and prevention of disease.
[0004] 2. Summary of the Related Art
[0005] Chemokines (chemotactic cytokines) are a large class of
proteins that share structural homology and possess chemotactic
activity for a variety of cell types (Luster, A. (1998), N. Eng. J.
Med. 338:436; Kim, C. and Broxmeyer, H. (1999), J. Leuk. Biol. 65:
6.). They are divided into four groups based on the number and
positioning of the first two cysteines of their sequence. The two
major groups are the CC or beta chemokines (having two adjacent
cysteines) and the CXC or alpha chemokines (X representing a single
amino acid in between the cysteines). Examples of the former group
include MIP-1.alpha., MIP-1.beta., RANTES, MCP-1, (Kim, ibid;
Strader, C. et al (1995), FASEB J. 9: 745; Salcedo, R. et al
(2000), Blood 96: 34), Eotaxin, TARC, MDC, MIP-3.alpha.,
MIP-3.beta. and I-309. Examples of the latter group include IL-8,
NAP-1, MGSA-.alpha., .beta., and .gamma., ENA-78, IP-10, Mig,
I-TAC, SDF-1 and BLC. In addition to the CC and CXC chemokines, two
other types of chemokine are known, each consisting of a single
known chemokine. Fractalkine is a CX3C type, having three amino
acids between its first two cysteines, and lymphotactin is a C type
chemokine having only one cysteine in the N-terminal domain.
[0006] Numerous chemokine receptors have been identified and
extensively characterized with respect to the chemokines they bind
and the cells on which they are expressed. These receptors (CCRs,
CXCRs, CX3CRs and CRs, depending on which type of chemokine they
bind) exhibit a significant degree of sequence homology. Chemokine
receptors are members of the large receptor family known as
G-protein coupled receptors (GPCRs)(Strader, C. et al (1995), FASEB
J. 9: 745), which are characterized by having seven-transmembrane
helical domains and being functionally associated with
heterotrimeric GTP-binding proteins (G-proteins). The existence of
such a variety of chemokines (over 40) and chemokine receptors (at
least 19 have been identified), in addition to their differential
expression on specific cell types, provides for enormous diversity
and specificity of ligand-receptor interactions. Consequently, the
biological functions mediated by these proteins are diverse and
complex.
[0007] MCP-1 is a chemokine produced by a number of cell types,
including macrophages, mast cells, epithelial cells, endothelial
cells, and fibroblasts and astrocytes. It is a potent
chemoattractant for a number of different types of immune cells,
such as monocytes, macrophages, activated T cells, basophils, and
immature dendritic cells. MCP-1 has also been shown to induce
biological responses in endothelial cells and astrocytes (Salcedo,
R. et al (2000), Blood 96: 34; Dorf, M. et al (2000), J.
Neuroimmunol. 111: 109). MCP-1 binds to CCR2 and, to date, no other
high affinity receptor specific for MCP-1 has been confirmed. CCR2
is constitutively expressed in many immune cells and is also
up-regulated under inflammatory conditions. CCR2 is also expressed
in the human monocytic cell line THP-1 (Van Riper, G. et al (1993),
J. Exp. Med. 177: 851).
[0008] It is well established that MCP-1 is a central factor in the
immunoregulation of inflammatory responses. Numerous studies in
animals have demonstrated the direct effect of MCP-1 on the
infiltration of immune effector cells in vivo. For example,
transgenic mice expressing MCP-1 in specific tissues exhibit an
enhanced localized infiltration of monocytes in those tissues (Gu,
L. et al (1997), J. Leuk. Biol. 62: 577; Gunn, M. et al (1997), J.
Immunol. 158: 376). Injection of MCP-1 protein into animals has
also been shown to induce the infiltration of basophils and T cells
(Taub, D. et al (1995), J. Clin. Invest. 95: 1370; Conti, P. et al
(1997), Int. Immunol. 9: 1563; Kuntsfeld, R. et al (1998), J.
Invest. Dermatol. 111: 1040). Knockout mice lacking either MCP-1
(Lu, B. et al (1998), J. Exp. Med. 187: 601) or CCR2 (Kurihara, T.
et al (1997), J. Exp. Med. 186: 1757; Kuziel, W. et al (1997),
Proc. Nat. Acad. Sci. USA 94: 12053) exhibit a reduction in the
extravasation and tissue infiltration of monocytes and macrophages
in response to inflammatory stimuli. Neutralization of MCP-1 with
monoclonal antibodies has been shown to inhibit the infiltration of
monocytes (Ajuebor, M. et al (1998), J. Leuk. Biol. 63: 108) and T
cells (Rand, M. et al (1996), Am. J. Pathol. 148: 855) in
experimentally-induced models of inflammation in animals.
[0009] The immune response to pathogens initially involves
presentation of antigen to CD4.sup.+ T cells followed by clonal
expansion and differentiation of the T cells into Th1 and Th2
subpopulations (Paul, W. (1992), in Inflammation, J. Gallin, I.
Goldstein, and R. Snyderman (eds), pp 775-790. Raven Press; Abbas,
A. et al (1996), Nature 383: 787). The two T cell subsets produce
different types of cytokines that mediate the induction of
different types of immune responses. Th1 cells produce IFN.alpha.,
IL-2, IL-12, and TNF.beta. which function to generate antiviral
immunity in the form of cytotoxic T cells, natural killer cells,
and antibody subclasses that mediate antibody dependent cellular
cytotoxicity (ADCC). Th2 cells produce IL-4, IL-5, IL-10, and
IL-13, which generate allergic and anti-parasitic immune responses
by inducing the proliferation and activation of eosinophils and
mast cells and the synthesis of IgE antibodies. MCP-1, in addition
to its direct effect on the migration of monocytes and T cells, has
been shown to play a part in the regulation of T cell responses.
MCP-1 has been shown to bias differentiation of activated T cells
towards the Th2 phenotype, both in vitro and in vivo (Karpus, W. et
al (1997), J. Immunol. 158: 4129; Gu, L. et al (2000), Nature 404:
407).
[0010] The production and biological activity of MCP-1 makes it a
central player in the pathogenesis of inflammatory diseases by
acting at many levels. For example, in atopic asthma, exposure to
allergen induces immediate release of MCP-1 by activated mast cells
and MCP-1 production at later times by epithelium and endogenous
macrophages. MCP-1 subsequently induces the chemotaxis of T
lymphocytes, macrophages and basophils into the challenged tissues
and induces T cells to differentiate to the Th2 subtype. This
results in the generation of IL-4 and IL-5 and, subsequently, the
production of IgE and the proliferation and migration of
eosinophils. These coordinated biological responses, centrally
mediated by MCP-1, lead to the infiltration and activation of
immune effector cells, increased sensitization of mast cells in the
lung, and maintenance of the asthmatic condition.
[0011] It is evident that CCR2 is an appropriate target for
inhibiting the excessive inflammatory responses that contribute to
disease. The present invention is based on the discovery of
compounds that antagonize CCR2. By antagonizing this receptor, the
compounds block the biological effects of MCP-1 and thus inhibit
the inflammatory processes mediated by the chemokine.
[0012] Published International Patent Application No. WO 95/19362
describes generically certain dihydropyrrole derivatives as
intermediates. Said compounds are disclosed solely as racemates and
no reference is made to isomers or isomerism. Furthermore, the only
compounds of this type specifically disclosed in WO 95/19362 are
unsubstituted in the 5-position of the dihydropyrrole ring.
[0013] The synthesis of certain 1,5-dihydro-2H-pyrrol-2-ones is
known from: Zh. Org. Khim. (1986) 22: 1749-1756; Zh. Org. Khim
(1986) 22: 1790-1791; Khim. Geterotsikl. Soedin. (1987) 5: 625-628;
Zh. Org. Khim. (1988) 24: 875-881; Khim.-Farm. Zh. (1991) 25:
37-40; Zh. Org. Khim. (1992) 28: 779-785; Khim.Geterotsikl. Soedin.
(1992) 1: 32-36; Zh. Obshch. Khim. (1992) 62: 2633-2634;
Heterocycles (1993) 36: 2541-2547; Russian J. Gen Chem. (1994) 64:
1084-1086; Chem. Heterocycl. Compd. (1998) 34: 739; Russian J. Gen.
Chem. (1999) 69: 668-669. The synthesis of certain
3-amino-2-mercaptopyrroles is known from Phos. Sulf. Silic. Relat.
Elem. (1999) 148: 117-130.
[0014] Compound 1 in the table disclosed hereinafter was purchased
from Biospecs in Rijswijk, The Netherlands and compounds 2, 3, 4
and 122 in the table disclosed hereinafter were purchased from
Ambinter in Paris, France.
[0015] In none of these instances is reference made to
pharmaceutical compositions comprising the compounds or to their
use as pharmaceuticals.
SUMMARY OF THE INVENTION
[0016] The present invention provides pyrrolidinones and
pyrrolidine-thiones and analogs thereof which act inter alia as
CCR2 antagonists.
[0017] The compounds of the invention are indicated for use in
treating or preventing conditions in which there is likely to be a
component involving MCP-1, CCR2 or the interaction between these
two. These conditions include one or more of the following: asthma,
seasonal and perennial allergic rhinitis, sinusitus,
conjunctivitis, food allergy, scombroid poisoning, psoriasis,
urticaria, pruritus, eczema, inflammatory bowel disease, chronic
obstructive pulmonary disease, thrombotic disease, otitis media,
neuroinflammatory diseases such as multiple sclerosis,
atherosclerosis, other inflammatory diseases such as rheumatoid
arthritis and nephritis, liver cirrhosis, cardiac disease,
pulmonary fibrosis, restenosis such as vascular restenosis,
Alzheimer's disease, sepsis, systemic sclerosis, ulcerative
colitis,atopic dermatitis, stroke, acute nerve injury, sarcoidosis,
hepatitis, endometriosis, HIV infection, AIDS, autoimmune diseases
and cancer
[0018] Accordingly, the invention also provides pharmaceutical
compositions comprising the compounds of the invention and methods
of treating and/or preventing the diseases set forth above.
[0019] The compounds disclosed herein can also be used as research
tools to study biological pathways involving both MCP-1 and
CCR2.
[0020] All patent applications, patents, and other publications
recited herein are hereby incorporated by reference in their
entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0021] In one aspect, the present invention concerns pharmaceutical
compositions comprising a compound of formula I 1
[0022] wherein,
[0023] Y is oxygen or sulfur;
[0024] G and G', together with the bond linking them, are HC--CH or
C.dbd.C;
[0025] V is aryl, heterocycle or cycloalkyl;
[0026] Z is halogen, alkyl, alkenyl, alkynyl, hydroxyl, amino,
alkoxy, aryloxy, nitro or cyano;
[0027] R.sup.1 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl or heterocycle;
[0028] R.sup.2 is hydrogen or hydroxy;
[0029] R.sup.3 is --C(O)R.sup.3a, --C(O)OR.sup.3a,
--C(O)N(R.sup.3a)(R.sup- .3b), --S(O).sub.2R.sup.3a, --S(O)R.sup.3a
or --SR.sup.3a wherein R.sup.3a and R.sup.3b have independently the
same meaning as R.sup.1;
[0030] R.sup.4is hydroxy, sulfanyl or amino;
[0031] t is 0, 1, 2, 3, 4 or 5;
[0032] or a pharmaceutically acceptable salt or metabolically
cleavable derivative thereof.
[0033] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds of the invention and
are intended to apply uniformly throughout the specification and
claims unless expressly stated otherwise.
[0034] The term alkyl as used herein is defined as including a
univalent, saturated, straight or branched alkane moiety preferably
containing one to ten, especially one to six, carbon atoms and
specifically includes, but is not limited to, methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl,
neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl and
2,3- dimethylbutyl.
[0035] The term cycloalkyl as used herein is defined as including a
mono- or polycyclic alkane moiety preferably containing three to
ten carbon atoms and specifically includes, but is not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl,adamantyl and noradamantyl.
[0036] The term alkenyl as used herein is defined as including a
univalent straight or branched, hydrocarbon with at least one
double bond, preferably containing two to ten carbon atoms.
Examples include, but are not limited to, vinyl, allyl and
2-butenyl.
[0037] The term cycloalkenyl as used herein is defined as including
a mono- or polycyclic hydrocarbon with at least one double bond,
preferably containing three to ten carbon atoms. Examples include,
but are not limited to, 2-cyclohexenyl or
bicyclo[2.2.1]hept-5-enyl.
[0038] The term alkynyl as used herein is defined as including a
univalent straight or branched hydrocarbon with at least one triple
bond preferably containing two to ten carbon atoms, and
specifically includes , but is not limited to, acetenyl, propynyl,
and --C.ident.C--CH.sub.2 (alkyl) including
--C.ident.--C--CH.sub.2(CH.sub.3).
[0039] The term aryl as used herein is defined as including phenyl
(preferably), biphenyl, napthyl or heteroaryl (as defined
below).
[0040] The term heterocycle as used herein is defined as including
an aromatic moiety that includes at least one heteroatom in the
aromatic ring (heteroaryl) as well as a cycloalkyl or cycloalkenyl
moiety, as defined above, wherein one or more ring carbon atoms are
replaced with a heteroatom. Examples include furyl, pyrryl,
pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl,
benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,
pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl,
carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl,
1,2,4-thiadiazolyl, isooxazolyl, quinazolinyl, pyridazinyl,
cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl,
pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,
imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl as
well as pyrrolidinyl, piperidinyl and piperazinyl.
[0041] Alkoxy and aryloxy as used herein refer respectively to
alkyl or aryl attached to the rest of the molecule via an oxygen
atom.
[0042] Amino as used herein refers to --NH.sub.2 in which one or
both of the hydrogen atoms may optionally be replaced by alkyl or
aryl or one of each.
[0043] Alkyl, alkenyl and alkynyl groups are in the n-form unless
otherwise stated and can optionally be substituted with any
suitable group including but not limited to one or more, same or
different, moieties selected from the group consisting of halo,
hydroxyl, nitro, cyano, amino, alkoxy, heterocycle, aryl or
aryloxy.
[0044] Aryl, cycloalkyl, cycloalkenyl and heterocycle groups can
optionally be mono- or poly-(preferably di- or tri-) substituted
with any suitable group, including but not limited to one or more,
same or different, moieties selected from the group consisting of
halogen, alkyl, alkenyl, alkynyl, methylene (CH.sub.2.dbd.),
hydroxyl, amino, alkoxy, aryl, aryloxy, nitro or cyano, whereby
when two or more non-cyclic substituents are present these may
optionally be linked together to form a ring.
[0045] Aryl, cycloalkyl, cycloalkenyl and heterocycle groups may be
attached to the pyrrolidine ring either directly or via alkylene
(such as in the case of benzyl), alkenylene (such as in the case of
styryl) or alkynylene (such as in the case of phenylethynyl).
[0046] The term halogen refers to chloro, fluoro, bromo or
iodo.
[0047] The terms sulfanyl and mercapto each refer to --SH
analogously to hydroxy referring to --OH
[0048] The term heteroatom means O, S, or N.
[0049] Where V is substituted by more than one Z moiety these may
be the same or different and, when non-cyclic, may optionally be
linked together to form a ring.
[0050] Unsubstituted valencies are satisfied by hydrogen.
[0051] Open valencies on the radical moieties described herein can
occur on any one (or more for divalent radicals) of the atoms
within the moiety. For example, a monovalent C.sub.3 alkyl moiety
includes both propyl and isopropyl. As another example, a divalent
C.sub.4 alkylene moiety includes both tetramethylene
(--CH.sub.2(CH.sub.2).sub.2CH.sub.2--- ), 1,2-dimethylethylene
(--CH(CH.sub.3) (CH.sub.3)CH--), 1,1-dimethylethylene
(--C(CH.sub.3).sub.2CH.sub.2--) and ethylethylene (--CH
(CH.sub.2CH.sub.3)CH.sub.2--).
[0052] "Metabolically cleavable derivatives" are frequently
referred to by the term "prodrugs" which refers to compound forms
which are rapidly transformed in vivo to the parent compound
according to the invention, for example, by hydrolysis in blood.
Thus, prodrugs are compounds bearing groups which are removed by
biotransformation prior to exhibiting their pharmacological action.
Such groups include moieties which are readily cleaved in vivo from
the compound bearing it, which compound after cleavage remains or
becomes pharmacologically active. Such metabolically cleavable
groups form a class well known to practitioners of the art. They
include, but are not limited to such groups as alkanoyl (i.e.
acetyl, propionyl, butyryl, and the like), unsubstituted and
substituted carbocyclic aroyl (such as benzoyl, substituted benzoyl
and 1- and 2-naphthoyl), alkoxycarbonyl (such as ethoxycarbonyl),
trialklysilyl (such as trimethyl- and triethylsilyl), monoesters
formed with dicarboxylic acids (such as succinyl), phosphate,
sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compounds
bearing the metabolically cleavable groups have the advantage that
they may exhibit improved bioavailability as a result of enhanced
solubility and/or rate of absorption conferred upon the parent
compound by virtue of the presence of the metabolically cleavable
group. (T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery
System", Vol. 14 of the A.C.S. Symposium Series; "Bioreversible
Carriers in Drug Design", ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987).
[0053] Examples of such compounds include the following:
[0054]
(5R)-4-acetyl-1-(4-chloro-2-fluorophenyl)-5-cyclohexyl-2-oxo-2,5-di-
hydro-1H-pyrrol-3-yl ethyl carbonate m.p. 74.degree. C. (compound
P1=compound no. 125 in which hydroxy is replaced by
ethoxycarbonyloxy);
[0055]
4-acetyl-5-cyclohexyl-1-(4-methylphenyl)-2-oxo-2,5-dihydro-1H-pyrro-
l-3-yl benzoate (MS 418) (compound P2=compound no. 10 in which
hydroxy is replaced by benzoyloxy).
[0056] As used herein, the term "pharmaceutically acceptable salts"
refers to salts that retain the desired biological activity of the
above-identified compounds and exhibit minimal or no undesired
toxicological effects. Examples of such salts include, but are not
limited to acid addition salts formed with inorganic acids (for
example, hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid, and the like), and salts formed with
organic acids such as citric acid, acetic acid, oxalic acid,
tartaric acid, succinic acid, malic acid, fumaric acid, ascorbic
acid, benzoic acid, tannic acid, palmoic acid, alginic acid,
polyglutamic acid, napthalenesulfonic acid, napthalenedisulfonic,
and polygalacturonic acid as well as base addition salts such as
those formed with alkali- and alkaline earth metals such as sodium,
potassium and calcium The compounds can also be administered as
pharmaceutically acceptable quaternary salts known by those skilled
in the art, which specifically include, but not limiting to the
quaternary ammonium salt of the formula --NR.sup.+Z.sup.-, wherein
R is hydrogen, alkyl, or benzyl, and Z is a counterion, including
chloride, bromide, iodide, --O-- alkyl, toluenesulfonate,
methylsulfonate, sulfonate, phosphate, or carboxylate (such as
fumarate, benzoate, succinate, acetate, glycolate, maleate, malate,
fumarate, citrate, tartrate, ascorbate, benzoate, cinnamoate,
mandeloate, benzyloate, and diphenylacetate).
[0057] In accordance with the invention all stereoisomeric forms
such as enantiomeric and diastereoisomeric forms of the compounds
of formula I or mixtures thereof (including all possible mixtures
of stereoisomers and racemates) are included. Typically one of the
enantiomeric forms (eutomer) will be more therapeutically
attractive than the other (distomer). In the case of the compounds
according to the invention it is the (-)-- form which is the
eutomer and thus preferred. In compounds where the carbon atom at
position 5 in the pyrrolidinone or pyrrolidine-thione ring is
assymetric it is typically the "R" enantiomer which is preferred.
X-Ray analysis has confirmed that in the present case the "R" and
"-" enantiomers correspond.
[0058] Furthermore certain compounds of formula I which contain
alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers.
In each instance, the invention includes both mixture and separate
individual isomers.
[0059] Multiple substituents on the scaffold ring can also stand in
either cis or trais relationship to each other with respect to the
plane of the ring. In each instance, the invention includes both
mixture and separate individual forms.
[0060] Some of the compounds of formula I may also exist in
tautomeric forms. Such forms although not explicity indicated in
the above formula are intended to be included within the scope of
the present invention.
[0061] With respect to the present invention reference to a
compound is intended to encompass that compound in each of its
possible forms including geometrical isomers, enantiomers,
diastereomers, and mixtures thereof (racemates) unless the
particular isomeric form is referred to specifically.
[0062] The substituents the compounds of formula I preferably have
the following meanings:
[0063] for Y, oxygen;
[0064] for G and G', together with the bond linking them,
C.dbd.C;
[0065] for V,
[0066] a) aryl, especially phenyl, benzyl, naphthyl,
naphthylmethyl, indenyl, dihydro indenyl; heterocycle especially
pyridyl;
[0067] b) phenyl, benzyl or dihydroindenyl;
[0068] c) phenyl or dihydroindenyl;
[0069] d) phenyl or benzyl;
[0070] e) phenyl;
[0071] for Z,
[0072] a) halogen, alkyl, alkoxy, OH, NO.sub.2 or NH.sub.2;
[0073] b) halogen, alkyl, alkoxy, NO.sub.2 or NH.sub.2;
[0074] c) fluoro, chloro, bromo, iodo, C.sub.1-4-alkyl,
C.sub.1-4alkoxy, especially methoxy, trifluoromethyl, NO.sub.2 or
NH.sub.2;
[0075] d) fluoro, chloro, bromo, C.sub.1-4-alkyl, C.sub.1-4 alkoxy,
especially methoxy, trifluoromethyl, NO.sub.2 or NH.sub.2;
[0076] e) fluoro, chloro, bromo, iodo, C.sub.1-4 alklyl especially
methyl or ethyl;
[0077] f) fluoro, chloro, bromo, C.sub.1-4 alkyl especially methyl
or ethyl;
[0078] for t, 0, 1, 2 or 3 especially 0, 1 or 2;
[0079] for R.sup.1,
[0080] a) alkyl, in particular C.sub.1-10, especially C.sub.1-8
alkyl, cycloalkyl, especially C.sub.3-10 cycloalkyl, cycloalkenyl,
especially C.sub.6-8 cycloalkenyl, phenyl or heterocycle;
[0081] b) C.sub.1-8 alkyl, especially, methyl, ethyl, propyl,
i-propyl, 3,3,3-trifluoropropyl, i-butyl, t-butyl, pentyl,
1-ethylpropyl, neo-pentyl, 1,2-dimethylbutyl or 1-propylbutyl
particularly 1-ethylpropyl, C.sub.3-10 cycloalkyl especially
cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,
cycloheptyl, cyclooctyl, adamantyl or noradamantyl, particularly
cyclopentyl or cyclohexyl, notably cyclohexyl, C.sub.6-8
cycloalkenyl especially 2-cyclohexenyl or
bicyclo[2.2.1]hept-5-enyl, particularly the latter, furyl, thienyl
or phenyl, optionally substituted by one or more alkyl, especially
methyl, halogen, especially fluoro, chloro or bromo or cyano;
[0082] for R.sup.2, hydrogen;
[0083] for R.sup.3, --C(O)R.sup.3a wherein R.sup.3a is alkyl, aryl
or heterocycle, especially preferred as R.sup.3a are
C.sub.1-5-alkyl, phenyl, benzyl, phenethyl, or thienyl with methyl
being most preferred;
[0084] for R.sup.4, hydroxy.
[0085] Combinations of the above preferred substituent meanings are
especially preferred.
[0086] Particularly preferred compounds of formula I are those
wherein Y is oxygen, R.sup.4 is hydroxy, G and G', together with
the bond linking them, are C.dbd.C and the remaining substituents
are as variously defined above and pharmaceutically acceptable
salts thereof (compounds IA).
[0087] Within compounds IA those compounds are particularly
preferred wherein R.sup.3 is acetyl and R.sup.2 is hydrogen and
pharmaceutically acceptable salts thereof (compounds IB).
[0088] Preferred individual compounds are nos. 10, 13, 17, 18, 24,
25, 51, 53, 54, 56, 63, 65, 69, 70, 72, 79, 118, 119, 120, 121,
125, 127, 129, 135, 137, 139, 140, 141, 142, 144, 148, 149, 150,
151, 153, 154, 155, 156, 157 and 169 as hereinafter described
whereby compounds 10, 17, 18, 24, 51, 53, 54, 69, 72, 118, 119,
120, 121, 125, 127, 129, 135, 137, 139, 140, 141, 142, 144, 148,
149, 150, 151, 153, 154, 155, 156, 157 and 169 are especially
preferred, with 51, 125, 129, 140, 144, 148, 149, 155 and 156 being
most preferred.
[0089] Within the compounds of formula I certain compounds are
novel and may be defined as follows with respect to the individual
substituent meanings:
[0090] for Y, sulfur (compounds IIA);
[0091] for R.sup.1 and R.sup.2,
[0092] a) R.sup.1 is hydrogen, halogen, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl or heterocycle and R.sup.2 is hydroxy
(compounds IIB); or
[0093] b) R.sup.1 is as defined above except for hydrogen,
C.sub.1-7-alkyl, phenyl, C.sub.3-5-cycloalkyl, or methylene
(C.sub.3-5-cycloalkyl) wherein each alkyl or phenyl group may be
substituted with one or two methyl, methoxy, ethyl or
trifluoromethyl, or up to three halogens and R.sup.2 is hydrogen
(compounds IIC);
[0094] c) one of R.sup.1 and R.sup.2 is other than hydrogen
(compounds IID);
[0095] for R.sup.3, as defined above except for --C(O)R.sup.3c
wherein R.sup.3c is hydrogen, C.sub.1-7-alkyl, C.sub.2-3-alkenyl,
phenyl, C.sub.3-5-cycloalkyl, or methylene (C.sub.3-5-cycloalkyl)
wherein each alkyl, phenyl or alkenyl group may be substituted with
one nitro, methoxy or ethoxy, with one or two methyl, ethyl or
trifluoromethyl, or with up to three halogens (compounds IIE);
[0096] and, in each case the remaining substituents are as defined
above.
[0097] Compounds of formula I in fully or partially resolved
isomeric form (compounds IIF) are also novel as are all individual
compounds in the table set forth hereinafter with the exception of
compounds nos. 1, 2, 3, 4, 5, 9 and 122 (compounds IIG).
[0098] The novel compound groups IIA to IIG also form part of the
invention
[0099] The present invention concerns also a process for preparing
the compounds having general formula I.
[0100] The synthetic scheme set forth below illustrates how
compounds according to the invention can be made. Those skilled in
the art will be able to routinely modify and/or adapt the following
scheme to synthesize any compound of the invention covered by
formula I. 2
[0101] Compounds of formula 1 may be obtained by the condensation
of an amine of formula V(Z).sub.t--NH.sub.2 and two carbonylic
compounds of formulae R.sup.1C(O)R.sup.2 and R.sup.3C(O)C(O)OEt in
acidic conditions.
[0102] Several analogues can be obtained from compound 1. For
example compound 2 can be obtained by reduction of compound 1 with
a suitable reducing agent. The carbonylic group in position 2 can
be converted to the corresponding thio group after submission to
Lawesson's reagent (phosphorus pentasulfide). The enolic function
can be converted to the corresponding amine after reaction in the
presence of ammonium formate. Compound 5 can be prepared by
conversion of compound 1 to the corresponding methoxy compound in
the presence of trimethylsilyldiazometh- ane and then convertion to
the sulfanyl analog in the presence of sodium hydrosulfide.
[0103] As will be evident to those skilled in the art, individual
isomeric forms can be obtained by separation of mixtures thereof in
conventional manner.
[0104] For example, in the case of geometric isomers,
chromatographic separation may be employed.
[0105] For separation of individual optical isomers from racemic
forms for example the racemic mixture of an enolic parent compound
can be derivatised and resolved by SMB (simulated moving bed)
chromatography and then cleaved back to the single enantiomers at
the enol function.
[0106] Alternatively separation can be achieved by fractional
crystalisation of diastereomeric salts.
Utility
[0107] As mentioned above, the compounds of the invention possess
CCR2 antagonist activity and are therefore indicated for use in
treating a variety of conditions in which there is likely to be a
component involving MCP-1, CCR2 or the interaction between these
two such as asthma, seasonal and perennial allergic rhinitis,
sinusitus, conjunctivitis, food allergy, scombroid poisoning,
psoriasis, urticaria, pruritus, eczema, inflammatory bowel disease,
chronic obstructive pulmonary disease, thrombotic disease, otitis
media, neuroinflammatory diseases such as multiple sclerosis,
atherosclerosis, other inflammatory diseases such as rheumatoid
arthritis and nephritis, liver cirrhosis, cardiac disease,
pulmonary fibrosis, restenosis such as vascular restenosis,
Alzheimer's. disease, sepsis, systemic sclerosis, ulcerative
colitis, atopic dermatitis, stroke, acute nerve injury,
sarcoidosis, hepatitis, endometriosis, HIV infection, AIDS,
autoimmune disease and cancer.
[0108] In addition certain compounds of the invention exhibit cross
reactivity with other chemokine receptors especially CCR1 and
CCR5.
[0109] As described below, several disease models have been used to
demonstrate the efficacy of inhibiting the interaction between
MCP-1 and CCR2. In addition, clinical studies have provided
evidence of the strong correlation between MCP-1 and CCR2
expression and the incidence and severity of human diseases.
[0110] Several studies have linked CCR2 with the pathogenesis of
asthma. In mouse models of lung inflammation and hyperreactivity,
inhibition of MCP-1 with a monoclonal antibody significantly
decreases allergen-induced infiltration of leukocytes into the lung
and also decreases airway hyperreactivity (Lukacs, N. et al (1997)
J. Immunol. 158: 4398; Gonzalo, J. et al (1998), J. Exp. Med. 188:
157). The effect of blocking MCP-1 was greater than that of
blocking other chemokines, such as eotaxin, MIP-1.alpha., and
RANTES. In CCR2 knockout mice, allergen-induced hyperreactivity was
also decreased, as was the release of histamine into the lung
(Campbell, E. et al (1999), Immunol. 163: 2160). In human studies,
it has been shown that MCP-1 in both bronchoalveolar lavage and
bronchial tissue is significantly increased in asthmatics (Sousa,
A. et al (1994), Am. J. Respir. Cell Mol. Biol. 10: 142; Alam, R.
et al (1996), Am. J. Respir. Crit. Care Med. 153: 1398; Holgate, S.
et al (1997), A. J. Respir. Crit. Care Med. 156: 1377). In
addition, levels of MCP-1 are correlated with the incidence of
attacks and the severity of symptoms (Sousa, A. et al (1994), Am.
J. Respir. Cell Mol. Biol. 10: 142; Alam, R. et al (1996), Am. J.
Respir. Crit. Care Med. 153: 1398; Holgate, S. et al (1997), A. J.
Respir. Crit. Care Med. 156: 1377; Lummus, Z. et al (1998), J.
Allergy Clin. Immunol. 102: 265; Jahnz-Rozyk, K. et al (1997),
Immunol. Lett. 58: 47). Asthmatic patients who respond positively
to immunotherapy also show a reduction in plasma levels of MCP-1.
(Hsieh, K. et al (1996), J. Allergy Clin Immunol. 98: 580).
[0111] MCP-1 has also been shown to be elevated in the lung tissues
and secretions of patients with other respiratory diseases such as
chronic obstructive pulnonary disease (COPD)(Capelli, A. et al
(1999), Eur. Resp. J. 14: 160; de Boer, W. et al (2000), J. Pathol.
190: 619), allergic rhinitis (Kimura et al (1998), Lab. Invest.
78:571; Fujikura et al (2001), J. Allergy Clin. Immunol 107:123),
and pulmonary fibrosis (Antoniades, H. et al (1992), Proc. Nat.
Acad. Sci. 89:5371; Iyonaga, K. et al (1994), Hum. Pathol. 25:455;
Hasegawa, M. et al (1999), Clin Exp. Immunol. 117:159). In an
animal model of pulmonary fibrosis using CCR2-deficient (knockout)
mice, it was shown that lung damage was significantly decreased in
the knockout mice (Moore et al (2001), J. Immunol. 167:4368).
[0112] Several studies have demonstrated an association of MCP-1
and CCR2 with the neuroinflammatory disease multiple sclerosis
(MS). Experimental autoimmune encephalomyelitis (EAE), which is an
animal model of MS, is initiated by an autoimmune T cell response
to myelin followed by infiltration of macrophages into the CNS
which brings about demyelination and paralysis. Studies with the
EAE model have shown MCP-1 levels in the CNS of mice to be
correlated with the severity of relapses (Kennedy, K. et al (1998),
J. Neuroimmunol. 92: 98). In addition, treatment with an anti-MCP-1
antibody reduced the clinical severity of the relapsing disease.
Knockout mice lacking either MCP-1 (Huang, D. et al (2001), J. Exp.
Med. 193: 713) or CCR2 (Fife, B. et al (2000), J. Exp. Med. 192:
899; Izikson, L. et al (2000), J. Exp. Med. 192: 1075) show a
significantly increased resistance to EAE compared to wild-type
mice. In studies with post-mortem human brain tissue, it has been
demonstrated that MCP-1 is elevated in demyelinating MS lesions
(Simpson, J. et al (1998), J. Neuroimmunol. 84: 238; Van der Voorn,
P. et al (1999), Am. J. Path. 154: 45).
[0113] Atherosclerosis is a disease whereby hypercholesterolemia
induces an influx of monocytes into the subendothelium, which
subsequently differentiate into foam cells which grow into
atherosclerotic plaques. Studies in animals and humans have shown
MCP-1 to be involved in the pathogenesis of this disease. In
hypercholesterolemic (Apo E deficient) mice, the expression of both
MCP-1 and CCR2 is elevated in atherosclerotic lesions (Rayner, K.
et al (2000), J. Vasc. Res. 37: 93). Overexpression of MCP-1 in
transgenic mice results in an increase in the incidence of
atherosclerosis in animals (Aiello, R. et al (1999), Arterioscler.
Tromb. Vasc. Biol. 19: 1518). Knockout mice which lack either MCP-1
(Gu, L. et al (1998), Mol. Cell 2: 275; Gosling, J. et al (1999),
J. Clin. Invest. 103: 773) or CCR2 (Boring, L. et al (1998), Nature
394: 894; Dawson, T. et al (1999), Atherosclerosis 143: 205) show a
significant reduction in atherosclerotic lesions. In humans, it has
been shown that CCR2 expression in blood monocytes is increased in
hypercholesterolemic patients and that this correlates with
increased responsiveness to MCP-1 (Han, K. et al (1999), J. Lipid
Res. 40: 1053).
[0114] Plasma levels of MCP-1 have been shown to increase
significantly in patients after angioplasty and has been correlated
with the incidence of vascular restenosis (Hokimoto et al (2000),
Japan Circ. J. 64:83 1; Cipollone et al (2000), Arter. Throm. Vasc.
Biol. 21:327; Economou et al (2001), Int. J. Cardiol. 80:55).
Similar results have been observed after stent implantation (Oshima
et al (2001) Japan Circ. J. 65:261). Studies with blocking
anti-MCP-1 antibodies have shown decreased incidence and severity
of neointimal thickening in animal models (Furukawa et al (1999),
Circ. Res. 84:306; Koyanagi et al (2000), Circulation 102:2243).
Decreased neointimal hyperplasia has also been demonstrated in a
CCR2 knockout mouse model (Egashira et al (2002), Circ. Res.
90:1167).
[0115] Studies have linked MCP-1 to two other inflammatory
diseases, rheumatoid arthritis (RA) and nephritis. In animal models
of arthritis, a neutralizing anti-MCP-1 antibody (Ogata, H. et al
(1997), J. Pathol. 182: 106) and a mutated MCP-1 peptide antagonist
to CCR2 (Gong, J. et al (1997), J. Exp. Med. 186: 131) were both
found to inhibit disease. Human studies have shown MCP-1 to be
elevated in both the blood and synovial fluid from RA patients
(Benedetti, F. et al (1999), J. Rheumatol. 26: 425; Ross, E. et al
(2000), J. Rheumatol. 27: 2432; Ellingsen, T. et al (2001), J.
Rheumatol. 28: 41). Levels of MCP-1 in the synovium correlates with
severity of the disease. Animal models of glomerulonephritis have
demonstrated that MCP-1 is elevated during the disease, and this is
correlated with increased macrophage infiltration into the kidney
as well as proteinuria. Several experiments have shown that
blocking MCP-1 with antibody results in decreased severity of the
disease (Tang, W. et al (1996), Kidney Int. 50: 665; Wada, T. et al
(1996), FASEB J. 10: 1418; Fujinaka, H. et al (1997), J. Am. Soc.
Nephrol. 8: 1174; Lloyd, C. et al (1997), J. Exp. Med. 185: 1371).
MCP-1 knockout mice also show a reduction in tubular injury (Tesch,
G. et al (1999), J. Clin. Invest. 103: 73). In human nephropathies,
MCP-1 is elevated in the kidney and the urine, and levels of the
chemokine are correlated with disease activity (Yokoyama, H. et al
(1998), J. Leuk. Biol. 63: 493; Saitoh, A. et al (1998), J. Clin.
Lab. Anal. 12: 1).
[0116] Several additional studies in both animals and humans have
demonstrated the association of MCP-1 with various other diseases.
These include stroke (Haro et al (1996), Spine 21:1647; Umehara et
al (1996), Acta Neuropathol. 91:343), skin diseases such as atopic
dermatitis (Kaburagi, Y. et al (2000), Arch. Dermato. Res. 293:350)
and psoriasis (Deleuran, M. et al (1996), J. Dermatol. Sci. 13:
228), liver cirrhosis (Marra, F. et al (1998), Am. J. Pathol. 152:
423; Fisher, N. et al (1999), Gut 45: 416; Tsuneyama, K. et al
(2001), J. Pathol. 193: 102), alcoholic hepatitis (Fisher, N. et al
(1999), Gut 45:416), sarcoidosis (Hashimoto, S. et al (1998), Clin.
Exp. Immunol. 111: 604; lyonaga, K. et al (1998), Sarcoidosis Vasc.
Diffuse Lung Dis. 15: 165), cardiac diseases (Nishiyama, K. et al
(1998), Jpn. Circ. J. 62: 710; Ono, K. et al (1999), Lab. Invest.
79: 195; Damas, J. et al (2000), Cardiovasc. Res. 47: 778), sepsis
(Hogaboam, C. et al (1998), Infect. Immun. 66: 650; Neumann, B. et
al (1999), Int. Immunol. 11: 217), Alzheimer's disease (Grammas et
al (2001), Neurobiol. Aging 22:837), systemic sclerosis (Hasegawa,
M. et al (1999), Clin. Exp. Immunol. 117: 159) inflammatory bowel
diseases such as ulcerative colitis (Ugoccioni, M. et al (1999),
Am. J. Pathol. 155: 331) and Crohn's disease (McCormack, G. et al
(2001), Inflamm. Res. 50:491), and endometriosis (Akoum et al
(1996), Fertil. Steril. 66:17). Numerous studies with neutralizing
anti-MCP-1 antibodies have shown improvements in disease symptoms
in animal models of myocardial infarction (Ono, K. et al (1999),
Lab. Invest. 79: 195), stroke (Galasso et al (2000), Neuroscience
101:737), dermatitis (Gordon, J. et al (2000), J. Allergy Clin.
Immunol. 106:110) and sarcoidosis (Ichiyasu et al (2001), Microsc.
Res. Tech. 53:288).
[0117] Treatment or prevention can be carried out by administering
to the patient an effective amount of one or more compounds
according to the invention in a pharmaceutically acceptable carrier
or diluent. The active materials can be administered by any
appropriate route, for example, orally, parenterally,
intravenously, intradermally, subcutaneously, intramuscularly or
topically, in liquid, cream, gel or solid form, via a buccal or
nasal spray, or aerosol.
[0118] The active compound is included in the pharmaceutically
acceptable carrier or diluent in an amount sufficient to deliver to
a patient a therapeutically effective amount without causing
serious toxic effects in the patient treated. A preferred dose of
the active compound for all of the above-mentioned conditions is in
the range from about 0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg
per day, more generally 0.5 to about 25 mg per kilogram body weight
of the recipient per day. A typical topical dosage will range from
0.01-3% wt/wt in a suitable carrier. The effective dosage range of
the pharmaceutically acceptable derivatives can be calculated based
on the weight of the parent compound to be delivered. If the
derivative exhibits activity in itself, the effective dosage can be
estimated as above using the weight of the derivative, or by other
means known to those skilled in the art.
[0119] The methods of the invention comprise administration to a
mammal (preferably human) suffering from a MCP-1 or CCR2 mediated
condition (preferably, asthma or rhinitis) a pharmaceutical
composition according to the invention in an amount sufficient to
alleviate the condition. The compound is conveniently administered
in any suitable unit dosage form, including but not limited to one
containing 1 to 3000 mg, preferably 5 to 500 mg of active
ingredient per unit dosage form. An oral dosage of 1-500,
preferably 10-250, more preferably 25-250 mg is usually
convenient.
[0120] The active ingredient should be administered to achieve peak
plasma concentrations of the active compound of about 0.001-30
.mu.M, preferably about 0.01-10 .mu.M. This may be achieved, for
example, by the intravenous injection of a solution or formulation
of the active ingredient, optionally in saline, or an aqueous
medium or administered as a bolus of the active ingredient.
[0121] The concentration of active compound in the drug composition
will depend on absorption, distribution inactivation, and excretion
rates of the drug as well as other factors known to those of skill
in the art. It is to be noted that dosage values will also vary
with the severity of the condition to be alleviated. It is to be
further understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
composition. The active ingredient may be administered at once, or
may be divided into a number of smaller doses to be administered at
varying intervals of time.
[0122] Oral compositions will generally include an inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches or capsules.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition.
[0123] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a dispersing
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterores; a lidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharine;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring. When the dosage unit form is a capsule, it can
contain in addition to material of the above type, a liquid carrier
such as fatty oil. In addition, dosage unit forms can contain
various other materials which modify the physical form of the
dosage unit, for example, coatings of sugar, shellac, or enteric
agents.
[0124] The active compound or pharmaceutically acceptable salt or
derivative thereof can be administered as a component of an elixir,
suspension, syrup, wafer, chewing gum or the like. A syrup may
contain, in addition to the active compounds, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
[0125] Other components used in oral or topical compositions
include emulsifying agents or penetration enhancers such as oleic
acid and stabilising or solubilising agents such as
cyclodextrins.
[0126] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerin, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl parabens; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parental preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic.
[0127] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[0128] In one embodiment, the active compounds are prepared with
carriers that will protect the compound against rapid elimination
from the body, such as a controlled release formulation, including
implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. The materials can also be
obtained commercially from Alza Corporation (CA) and Guilford
Pharmaceuticals (Baltimore, Md.). Liposomal suspensions may also be
pharmaceutically acceptable carriers. These may be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811 (which is
incorporated herein by reference in its entirety). For example,
liposome formulations may be prepared by dissolving appropriate
lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl
phosphatidylcholine, arachadoyl phosphatidylcholine and
cholesterol) in an organic solvent that is then evaporated, leaving
behind a thin film of dried lipid on the surface of the container.
An aqueous solution of the active compound or its monophosphate,
diphosphate, and/or triphosphate derivatives are then introduced
into the container. The container is then swirled by hand to free
lipid material from the sides of the container and to disperse
lipid aggregates, thereby forming the liposomal suspension.
[0129] The active compound or pharmaceutically acceptable salt or
derivative thereof can also be mixed with other active materials
that do not impair the desired action, or with materials that
supplement the desired action, such as adrenergic agonists like
pseudoephedrine, antibiotics, antifungals, other
anti-inflammatories, or antiviral compounds.
[0130] The present invention concerns also a method of treating or
preventing conditions mediated by CCR2, MCP-1 or the interaction
thereof, the method comprising administering to a patient an amount
of a compound having the formula I or a pharmaceutically active
derivative or salt thereof sufficient to prevent, reduce or
eliminate the condition.
[0131] The method is particularly useful in the treatment or
prevention of a condition selected from asthma, seasonal and
perennial allergic rhinitis, sinusitus, conjunctivitis, food
allergy, scombroid poisoning, psoriasis, urticaria, pruritus,
eczema, inflammatory bowel disease, chronic obstructive pulmonary
disease, thrombotic disease, otitis media, neuroinflammatory
diseases such as multiple sclerosis, atherosclerosis, other
inflammatory diseases such as rheumatoid arthritis and nephritis,
liver cirrhosis, cardiac disease, pulmonary fibrosis, restenosis
such as vascular restenosis, Alzheimer's disease, sepsis, systemic
sclerosis,ulcerative colitis, atopic dermatitis, stroke, acute
nerve injury, sarcoidosis, hepatitis, endometriosis, HIV infection,
AIDS, autoimmune diseases and cancer.
[0132] The method is particularly useful in the treatment or
prevention of asthma, atherosclerosis, multiple sclerosis and
rheumatoid arthritis.
[0133] The present invention concerns also the use of a compound
having general formula I, or a pharmaceutically active derivative
or salt thereof for the manufacture of a medicament for a
therapeutic application.
[0134] The present invention concerns also a method for
manufacturing a medicament intended for therapeutic application,
wherein a compound having general formula I or a pharmaceutically
active derivative or salt thereof is used.
[0135] The following Examples are provided for illustrative
purposes only and are not intended, nor should they be construed,
as limiting the invention by any other manner. Those skilled in the
art will appreciate that routine variations and modifications of
the following Examples can be made without exceeding the scope of
the invention.
EXAMPLE 1
[0136] Preparation of
4-acetyl-5-cyclohexyl-3-hydroxy-1-(4-methylphenyl)-1-
,5-dihydro-2H-pyrrol-2-one (compound 10).
[0137] To a stirring solution of p-toluidine (430 mg, 4.0 mmol) in
4 ml of acetic acid at room temperature, are added cyclohexane
carboxaldehyde (450 mg, 4.0 mmol) and ethyl acetopyruvate (640 mg,
4.0 mmol). The reaction mixture is heated to 95.degree. C., stirred
for 120 minutes, cooled to room temperature and the solvent removed
under reduced pressure. Diethyl ether (10 ml) is added to the
residue and the mixture stirred for 30 minutes whereupon a white
precipitate forms. The fmal compound is collected after filtration
as a white crystalline solid mp 222.degree. C. The filtrate may be
concentrated to give additional compound.
[0138] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 0.80-1.20 (m,
5H), .delta. 1.40-1.79 (m, 5H), .delta. 1.96 (m, 1H) .delta. 2.41
(s, 3H), .delta. 2.56 (s, 3H), 4.97 (d, 1H, J=0.9 Hz), 7.29 (m,
4H), 8.90 (s, br, 1H) ppm.
[0139] The racemic mixture can be resolved on a chiral HPLC column
(Chiral Cel OD-H) using a mixture of isopropyl alcohol (15)/hexanes
(85) and 0.1% TFA, flow rate 0.5 ml/min, or it can be resolved by
using a chiral auxiliary.
EXAMPLE 2
[0140] Preparation of
1-(4-chlorophenyl)-5-cyclohexyl-3-hydroxy-4-[3-(4-hy-
droxyphenyl)propanoyl]-1,5-dihydro-2H-pyrrol-2-one (Compound
67)
[0141] To a stirring solution of 4-hydroxy benzyl acetone in 40 mL
of dry DMF at room temperature, are added 0.96 g (40 mmol) of
sodium hydride. The reaction mixture turns deep yellow and after 30
minutes diethyl oxalate (5.43 ml, 40 mmol) is added. The mixture is
stirred overnight at room temperature, then quenched with HCl 10%
and extracted with ethyl acetate. The organic layers are washed
with water, dried over magnesium sulfate, filtered and the solvent
is evaporated under reduced pressure. The formation of the desired
ethyl 6-(4-hydroxyphenyl)-2,4-dioxohexanoate is checked by
H.sup.1-NMR before being used further without purification.
[0142] To a stirring solution of p-chloraniline (320 mg, 2.5 mmol)
in 2.5 mL of acetic acid at room temperature, are added cyclohexane
carboxaldehyde (0.30 mL, 2.5 mmol) and ethyl
6-(4-hydroxyphenyl)-2,4-diox- ohexanoate (618 mg, 2.5 mmol). The
reaction mixture is stirred at room temperature. After 30 minutes a
white precipitate is formed. The solvent is removed under reduced
pressure and the crude material recrystallized from a mixture of
ether/methanol. The final compound is collected after filtration as
a white crystalline solid m.p. 259.degree. C.
[0143] .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 0.80-1.20 (m,
5H), .delta. 1.40-1.79 (m, 5H), .delta. 2.80 (t, 2H), .delta.
3.0-3.2 (m, 2H), .delta. 5.05 (s, 1H), .delta. 6.65 (d, 2H),
.delta. 7.0 (d, 2H), .delta. 7.55 (q, 2H), .delta. 917 (s, 1H),
.delta. 12.1 (s, br, 1H) ppm.
EXAMPLE 3
[0144] Preparation of
4-acetyl-5-cyclohexyl-3-amino-1-(4-methylphenyl)-1,5-
-dihydro-2H-pyrrol-2-one (compound 61).
[0145] A reaction mixture of
4-acetyl-5-cyclohexyl-3-hydroxy-1-(4-methylph-
enyl)-1,5-dihydro-2H-pyrrol-2-one (139 mg, 0.44 mmol) and ammonium
formate (342 mg, 4.44 mmol) in ethanol (0.2M, 2.2 ml) is heated at
reflux for 16 hours. The solvent is removed in vacuo to give a
white residue. Water is added to the residue to dissolve some of
the white solid leaving a sandy-coloured precipitate. This mixture
is then filtered, washed with a small amount of diethyl ether and
dried under high vacuum at room temperature to give a pale brown
solid.
[0146] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 10.07 (s, br,
1H), 7.36 (d, 2H), 7.22 (d,2H), 6.41 (s, br, 1H), 4.83 (d, 1H),
2.36 (s, 3H), 2.19 (s, 3H), 1.80-0.96 (m, 9H).
EXAMPLE 4
[0147] Preparation and enantiomeric resolution of
4-acetyl-1-(4-chloro-2-f-
luorophenyl)-5-cyclohexyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one.
[0148] A. Preparation of
4-acetyl-1-(4-chloro-2-fluorophenyl)-5-cyclohexyl-
-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (compound 72).
[0149] To a stirred solution of 4-chloro-2-fluoroaniline (727 mg,
5.0 mmol) in THF (10 ml) at room temperature is added dropwise
cyclohexanecarboxaldehyde (0.6 ml, 5.0 mmol). The reaction mixture
is stirred for 12 hours at room temperature. Then, ethyl
2,4-dioxovalerate (0.7 ml, 5.0 mmol) is added dropwise at room
temperature and the reaction is stirred for another 12 hours. The
solvent is removed under reduced pressure and the black residue is
dissolved in acetonitrile. The mixture is stirred for 15 minutes,
filtered and dried under high vacuum to yield the product as a
white solid (220 mg).
[0150] .sup.1H NMR (CDCl.sub.3) .delta. 0.63 (dq, 1H), 0.82-1.18
(m, 4H), 1.42-1.78 (m, 5H), 1.93 (tq, 1H), 2.51 (s, 3H), 4.96 (d,
1H), 7.23-7.26 (m, 2H), 7.36 (dt, 1H). IR (NaCl) 3151, 2929, 1689,
1643, 1501, 1220. MS (ES+) 352.1 (M.sup.+).
[0151] B. Preparation of methyl
(2R)-{[4-acetyl-1-(4-chlorophenyl)-5-cyclo-
hexyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]oxy }(phenyl)ethanoate
[0152] To a cooled (0.degree. C.) mixture of
4-acetyl-1-(4-chloro-2-fluoro-
phenyl)-5-cyclohexyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (2.05 g,
5.84 mmol), methyl (S)-mandelate (1.36 g, 8.18 mmol) and
triphenylphosphine (2.0 g, 7.6 mmol) in THF (50 ml) is added
dropwise DIAD (1.6 ml, 7.6 mmol). The reaction is then left to warm
to room temperature and is stirred for 12 hours. The solvent is
removed under vacuum and the oily residue is plugged through a pad
of silica gel (eluent 1/1 hexanes/ethyl acetate). The solvent is
removed and the residual oil is purified by radial chromatography
(eluent 9/1 hexanes/ethyl acetate) to yield each diastereomer (1 g)
as a white foam.
[0153] C. Preparation of
(5R)-4-acetyl-1-(4-chloro-2-fluorophenyl)-5-cyclo-
hexyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (compound 125).
[0154] To a stirred solution of methyl
(2R)-{[4-acetyl-1-(4-chlorophenyl)--
(5R)-cyclohexyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]oxy
}(phenyl)ethanoate (diastereomer eluting first) (10 g, 2.0 mmol) in
1,4-dioxane (20 ml) is added by portions 10% Pd/C (300 mg). The
reaction vessel is flushed with hydrogen and a balloon filled with
H.sub.2 is fitted to the flask. The reaction is monitored by thin
layer chromatography. Upon completion, the reaction mixture is
filtered through cotton and the solvent is removed under vacuum.
The residue is purified by reverse-phase chromatography
(acetonitrile/water 20% ACN to 100% ACN over 8 mns). The solvent is
removed under high vacuum to yield the product as a white foam (364
mg).
[0155] .sup.1H NMR (CDCl.sub.3) .delta. 0.63 (dq, 1H), 0.82-1.18
(m, 4H), 1.42-1.78 (m, 5H), 1.93 (tq, 1H), 2.51 (s, 3H), 4.96 (d,
1H), 7.23-7.26 (m, 2H), 7.36 (dt, 1H). IR (NaCl) 3151, 2929, 1689,
1643, 1501, 1220. MS (ES+) 352.1 (M.sup.+)."
[0156] The following compounds may be prepared analogously. As used
herein RACEMATE refers to a mixture of all enantiomers, MIXTURE
refers to a mixture of diastereoisomers and CHIRAL refers to a pure
enantiomer.
1TABLE 1 melting point in .degree. C. Cpd. stereo- or (mass No.
Name chemistry spec) 1 4-acetyl-1-benzyl-5-(4- RACEMATE 207
bromophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 2
4-acetyl-5-(4-bromophenyl)- RACEMATE 258 1-(5-bromopyridin-2-yl)--
3- hydroxy-1,5-dihydro-2H- pyrrol-2-one 3 4-acetyl-1-benzyl-5-(2-
RACEMATE 234 fluorophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 4
4-acetyl-1-benzyl-5-(4- RACEMATE 262 chlorophenyl)-3-hydroxy-1,5-
dihydro-2H-pyrrol-2-one 5 4-acetyl-1-benzyl-3-hydroxy- RACEMATE 188
5-phenyl-1,5-dihydro-2H- pyrrol-2-one 6 4-acetyl-1-benzyl-5-(4-
RACEMATE (326) fluorophenyl)-3-hydroxy-1,- 5-
dihydro-2H-pyrrol-2-one 7 4-acetyl-1-benzyl-5- RACEMATE (314)
cyclohexyl-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 8
4-acetyl-1-benzyl-5-(2- RACEMATE 174 furyl)-3-hydroxy-1,5-dihydro-
2H-pyrrol-2-one 9 4-acetyl-1,5-bis(4- RACEMATE 132
bromophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 10
4-acetyl-5-cyclohexyl-3- RACEMATE 222 hydroxy-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-o- ne 11 4-acetyl-3-hydroxy-5- RACEMATE
(274) isopropyl-1-(4-methylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 12
4-acetyl-5-tert-butyl-3- RACEMATE 189 hydroxy-1-(4-methylpheny- l)-
1,5-dihydro-2H-pyrrol-2-one 13 4-acetyl-5-(1-ethylpropy- l)-
RACEMATE 146 3-hydroxy-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-one 14 4-acetyl-5-cyclohexyl-3- RACEMATE
194 hydroxy-1-(4-methoxyphenyl)- 1,5-dihydro-2H-pyrrol-2-- one 15
4-acetyl-5-(4-chlorophenyl)- RACEMATE 197
3-hydroxy-1-(4-methylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 16
4-acetyl-5-cyclohexyl-3- RACEMATE 204 hydroxy-1-(3-methylpheny- l)-
1,5-dihydro-2H-pyrrol-2-one 17 4-acetyl-1-(4-bromopheny- l)-
RACEMATE 229 5-cyclohexyl-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 18
(R)-4-acetyl-5-cyclohexyl-3- CHIRAL (314)
hydroxy-1-(4-methylphenyl)- (Racemate = 1,5-dihydro-2H-pyrrol-2-one
no. 10) 19 4-acetyl-5-(1,2- MIXTURE 176 dimethylbutyl)-3-hydroxy-1-
(4-methylphenyl)-1,5- dihydro-2H-pyrrol-2-one 20
4-acetyl-5-(4-bromophenyl)- RACEMATE 206
3-hydroxy-1-(4-methylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 21
4-acetyl-5-cyclopropyl-3- RACEMATE 198 hydroxy-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-o- ne 22 5-cyclohexyl-3-hydroxy-1-(4-
RACEMATE 218 methylphenyl)-4-(thien-2- ylcarbonyl)-1,5-dihydro-2H-
pyrrol-2-one 23 4-acetyl-5-cyclohexyl-3- RACEMATE 220
hydroxy-1-phenyl-1,5- dihydro-2H-pyrrol-2-one 24
4-acetyl-1-(4-chlorophenyl)- RACEMATE 229 5-cyclohexyl-3-hydroxy--
1,5- dihydro-2H-pyrrol-2-one 25 4-acetyl-5-cyclohexyl-1-(4-
RACEMATE 214 fluorophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one
26 4-acetyl-5-(4-fluorophenyl)- RACEMATE (340.2)
3-hydroxy-1-(4-methylbenzyl)- 1,5-dihydro-2H-pyrrol-2-one 27
4-acetyl-5-(4-bromophenyl)- RACEMATE (400.2)
3-hydroxy-1-(4-methylbenzyl)- 1,5-dihydro-2H-pyrrol-2-one 28
4-acetyl-1-benzyl-3-hydroxy-5- RACEMATE (322.2)
(4-methylphenyl)-1,5-dihydro- 2H-pyrrol-2-one 29
4-acetyl-5-(4-fluorophenyl)-3- RACEMATE (376.2)
hydroxy-1-(1-naphthylmethyl)- 1,5-dihydro-2H-pyrrol-2-one 30
4-acetyl-5-(4-bromophenyl)-3- RACEMATE (436.2)
hydroxy-1-(1-naphthylmethyl)- 1,5-dihydro-2H-pyrrol-2-one 31
4-acetyl-5-(4-fluorophenyl)- RACEMATE (394.2) 3-hydroxy-1-[4-
(trifluoromethyl)benzyl]- 1,5-dihydro-2H-pyrrol-2-one 32
4-acetyl-5-(4-bromophenyl)-1- RACEMATE (422.2)
(3,5-difluorobenzyl)-3- hydroxy-1,5-dihydro-2H- pyrrol-2-one 33
4-acetyl-1-benzyl-3-hydroxy- RACEMATE (274.2)
5-propyl-1,5-dihydro-2H- pyrrol-2-one 34
4-acetyl-1-benzyl-3-hydroxy- RACEMATE (288.2)
5-isobutyl-1,5-dihydro-2H- pyrrol-2-one 35 4-acetyl-5-cyclohexyl-3-
RACEMATE (382.2) hydroxy-1-[4- (trifluoromethyl)benzyl]-
1,5-dihydro-2H-pyrrol-2-one 36 4-acetyl-5-(2-furyl)-3- RACEMATE
(366.2) hydroxy-1-[4- (trifluoromethyl)benzyl]-
1,5-dihydro-2H-pyrrol-2-one 37 4-acetyl-5-cyclohexyl-1-(3,5-
RACEMATE (350.2) difluorobenzyl)-3-hydroxy-
1,5-dihydro-2H-pyrrol-2-one 38 4-acetyl-1-(3,5- RACEMATE (334.2)
difluorobenzyl)-5-(2-furyl)- 3-hydroxy-1,5-dihydro-2H- pyrrol-2-one
39 4-acetyl-3-hydroxy-1-(4- RACEMATE 189 methylphenyl)-5-(1-
propylbutyl)-1,5-dihydro-2H- pyrrol-2-one 40 4-acetyl-3-hydroxy-5-
RACEMATE 153 isobutyl-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-one 41 5-cyclohexyl-4-(2,2- RACEMATE 188
dimethylpropanoyl)-3-hydroxy- 1-(4-methylphenyl)-1,5-
dihydro-2H-pyrrol-2-one 42 1-benzyl-5-(4-bromophenyl)-4-(2- ,2-
RACEMATE 198 dimethylpropanoyl)-3-hydroxy-
1,5-dihydro-2H-pyrrol-2-one 43 4-acetyl-1-(3-chlorophenyl)-
RACEMATE 230 5-cyclohexyl-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 44
4-acetyl-1-(3-bromophenyl)- RACEMATE 239
5-cyclohexyl-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 45
4-acetyl-5-cyclohexyl-1-(2- RACEMATE 238
fluorophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 46
4-butyryl-1-(4-chlorophenyl)- RACEMATE 197
5-cyclohexyl-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 47
4-acetyl-5-cyclohexyl-1-(3- RACEMATE 203 fluoro-4-methylphenyl)-3-
- hydroxy-1,5-dihydro-2H- pyrrol-2-one 48
4-acetyl-5-cyclohexyl-1-(3,4- RACEMATE 228
dichlorophenyl)-3-hydroxy- 1,5-dihydro-2H-pyrrol-2-one 49
4-acetyl-5-cyclohexyl-3- RACEMATE 235 hydroxy-1-[4-
(trifluoromethyl)phenyl]- 1,5-dihydro-2H-pyrrol-2-one 50
4-acetyl-5-(cyclohex-2-en- MIXTURE 226 1-yl)-3-hydroxy-1-(4-
methylphenyl)-1,5-dihydro- 2H-pyrrol-2-one 51 (R)-4-acetyl-1-(4-
CHIRAL (334) chlorophenyl)-5-cyclohexyl- (Racemate =
3-hydroxy-1,5-dihydro-2H- no. 24) pyrrol-2-one 52
4-acetyl-5-cyclohexyl-3- RACEMATE 227
hydroxy-1-(4-isopropylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 53
4-acetyl-1-(4-chloro-3- RACEMATE 217 methylphenyl)-5-cyclohexy- l-
3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 54
4-acetyl-5-cyclohexyl-1-(2- RACEMATE 205 fluoro-4-methylphenyl)-3-
- hydroxy-1,5-dihydro-2H- pyrrol-2-one 55 4-acetyl-1-[4-chloro-3-
RACEMATE 230 (trifluoromethyl)phenyl]- 5-cyclohexyl-3-hydroxy-1,5-
dihydro-2H-pyrrol-2-one 56 4-acetyl-5-cyclopentyl-3- RACEMATE 186
hydroxy-1-(4-methylphen- yl)- 1,5-dihydro-2H-pyrrol-2-one 57
4-acetyl-5-cyclooctyl-3- - RACEMATE 287 hydroxy-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-one 58 4-acetyl-5-(1-adamantyl)-3- RACEMATE
251 hydroxy-1-(4-methylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 59
4-acetyl-1-(3-chloro-4- RACEMATE (348.1)
methylphenyl)-5-cyclohexyl-3- hydroxy-1,5-dihydro-2H-pyrrol- 2-one
60 4-acetyl-5-cyclohexyl-3- RACEMATE (402) hydroxy-1-(3,4,5-
trichlorophenyl)-1,5-dihydro- 2H-pyrrol-2-one 61
4-acetyl-3-amino-5-cyclohexyl- RACEMATE (313)
1-(4-methylphenyl)-1,5- dihydro-2H-pyrrol-2-one 62
4-acetyl-5-cyclohexyl-1-(2,4- RACEMATE (336.1)
difluorophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 63
4-acetyl-5-cyclohexyl-1-(2,3- RACEMATE 210
dihydro-1H-inden-5-yl)-3- hydroxy-1,5-dihydro- 2H-pyrrol-2-one 64
4-acetyl-5-cyclohexyl-1-(4- RACEMATE 220 fluoro-3-methylphenyl)-3-
hydroxy-1,5-dihydro-2H- pyrrol-2-one 65
4-acetyl-5-cyclohexyl-1-(3,4- RACEMATE 205
dimethylphenyl)-3-hydroxy- 1,5-dihydro-2H-pyrrol-2-one 66
4-acetyl-1-(4-chloro-3- RACEMATE (379.1) nitrophenyl)-5-cyclohexyl-
3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 67 1-(4-chlorophenyl)-5-
RACEMATE 259 cyclohexyl-3-hydroxy-4-[3-
(4-hydroxyphenyl)propanoyl]- 1,5-dihydro-2H-pyrrol-2-one 68
4-acetyl-5-cycloheptyl-3- RACEMATE 214 hydroxy-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-o- ne 69 4-acetyl-1-(4-chloro-3- RACEMATE
199 methylphenyl)-5-cyclopentyl- 3-hydroxy-1,5-dihydro-2H-
pyrrol-2-one 70 4-acetyl-1-(4-chloro-3- RACEMATE 225
ethylphenyl)-5-cyclohexyl- 3-hydroxy-1,5-dihydro-2H- pyrrol-2-one
71 4-acetyl-1-(3-amino-4- RACEMATE 162 chlorophenyl)-5-cyclohexyl-
3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 72 4-acetyl-1-(4-chloro-2-
RACEMATE (352.1) fluorophenyl)-5-cyclohexyl-
3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 73 4-acetyl-1-(3-bromo-4-
RACEMATE (392) methylphenyl)-5-cyclohexyl- 3-hydroxy-1,5-dihydro-
2H-pyrrol-2-one 74 4-acetyl-1-(3,4- RACEMATE (288)
dimethylphenyl)-3-hydroxy- 5-propyl-1,5-dihydro-2H- pyrrol-2-one 75
4-acetyl-1-(3,4- RACEMATE (316) dimethylphenyl)-3-hydroxy-
5-pentyl-1,5-dihydro-2H- pyrrol-2-one 76 4-acetyl-1-(3-chloro-4-
RACEMATE (308) methylphenyl)-3-hydroxy-5- propyl-1,5-dihydro-2H-
pyrrol-2-one 77 4-acetyl-5-cyclohexyl-1-(4- RACEMATE (328)
ethylphenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 78
4-acetyl-3-hydroxy-1-(4- RACEMATE (302) methylphenyl)-5-neopentyl-
- 1,5-dihydro-2H-pyrrol-2-one 79 4-acetyl-5- MIXTURE (324)
bicyclo[2.2.1]hept- 5-en-2-yl-3-hydroxy-1-(4-
methylphenyl)-1,5-dihydro- 2H-pyrrol-2-one 80
4-acetyl-1-(3-bromo-4- RACEMATE (392) methylphenyl)-3-hydroxy-
5-thien-3-yl-1,5-dihydro- 2H-pyrrol-2-one 81 4-acetyl-1-benzyl-5-
RACEMATE 196 (cyclohexylmethyl)-3- hydroxy-1,5-dihydro-
2H-pyrrol-2-one 82 4-acetyl-3-hydroxy-1-(4- RACEMATE (322)
methylbenzyl)-5-phenyl- 1,5-dihydro-2H-pyrrol-2-one 83
4-acetyl-3-hydroxy-1-(4- RACEMATE (336) methylbenzyl)-5-(4-
methylphenyl)-1,5-dihydro- 2H-pyrrol-2-one 84
4-[3-acetyl-4-hydroxy- RACEMATE (347) 1-(4-methylbenzyl)-5-oxo-
2,5-dihydro-1H-pyrrol-2- yl]benzonitrile 85
4-acetyl-3-hydroxy-1-(1- RACEMATE (358) naphthylmethyl)-5-phenyl-
1,5-dihydro-2H-pyrrol-2- one 86 4-acetyl-3-hydroxy-5-(4- RACEMATE
(372) methylphenyl)-1-(1- naphthylmethyl)-1,5-
dihydro-2H-pyrrol-2-one 87 4-acetyl-1-(3,5- RACEMATE (394)
dichlorobenzyl)-5-(4- fluorophenyl)-3-hydroxy-
1,5-dihydro-2H-pyrrol-2-one 88 4-acetyl-3-hydroxy-5- RACEMATE (376)
phenyl-1-[4- (trifluoromethyl)benzyl]- 1,5-dihydro-2H-pyrrol-2-one
89 4-acetyl-5-(4-bromophenyl)- RACEMATE (454) 3-hydroxy-1-[4-
(trifluoromethyl)benzyl]- 1,5-dihydro-2H-pyrrol-2-one 90
4-acetyl-5-(4-fluorophenyl)- RACEMATE (356) 3-hydroxy-1-(3-
methoxybenzyl)-1,5-dihydro- 2H-pyrrol-2-one 91
4-acetyl-5-(4-bromophenyl)- RACEMATE (416)
3-hydroxy-1-(3-methoxybenzyl)- 1,5-dihydro-2H-pyrrol-2-one 92
4-acetyl-1-(3,5-difluorobenzyl)- RACEMATE (344)
3-hydroxy-5-phenyl-1,5-dihydro- 2H-pyrrol-2-one 93
4-acetyl-1-(3,5-difluorobenzyl)- RACEMATE (362)
5-(4-fluorophenyl)-3-hydroxy- 1,5-dihydro-2H-pyrrol-2-one 94
4-acetyl-1-(3,5-difluorobenzyl)- RACEMATE (358)
3-hydroxy-5-(4-methylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 95
4-acetyl-1-benzyl-3-hydroxy- RACEMATE (302)
5-neopentyl-1,5-dihydro-2H- pyrrol-2-one 96
4-acetyl-1-benzyl-3-hydroxy-5- RACEMATE (328)
(3,3,3-trifluoropropyl)-1,5- dihydro-2H-pyrrol-2-one 97
4-acetyl-5-cyclohexyl-1-(3- RACEMATE 210 fluorophenyl)-3-hydroxy--
1,5- dihydro-2H-pyrrol-2-one 98 4-butyryl-5-cyclohexyl-3- RACEMATE
237 hydroxy-1-(4-methylphenyl)- 1,5-dihydro-2H-pyrrol-2-one 99
4-acetyl-1-cyclohexyl-3- RACEMATE 210 hydroxy-5-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-o- ne 100 5-cyclohexyl-4-hexanoyl-3-
RACEMATE 213 hydroxy-1-(4-methylphenyl)-
1,5-dihydro-2H-pyrrol-2-one 101 1-(4-chlorophenyl)-5- RACEMATE 227
cyclohexyl-3-hydroxy-4-(3- phenylpropanoyl)-1,5-
dihydro-2H-pyrrol-2-one 102 1-(4-bromophenyl)-5-cyclohexyl-
RACEMATE 244 3-hydroxy-4-(3-phenylpropanoyl)-
1,5-dihydro-2H-pyrrol-2-one 103 1-(4-chlorophenyl)-5- RACEMATE 211
cyclohexyl-4-hexanoyl-3- hydroxy-1,5-dihydro-2H-pyrrol- 2-one 104
1-(4-chlorophenyl)-5- RACEMATE 121 cyclohexyl-3-hydroxy-4-
pentanoyl-1,5-dihydro-2H- pyrrol-2-one 105
4-acetyl-5-cyclohexyl-1-(4- RACEMATE 254 fluoro-3-nitrophenyl)-3-
hydroxy-1,5-dihydro-2H-pyrrol- 2-one 106 4-acetyl-3-hydroxy-1-(4-
RACEMATE 241 methylphenyl)-5-(thien-3-yl- )-
1,5-dihydro-2H-pyrrol-2-one 107 4-acetyl-(3-bromo-4- RACEMATE (352)
methylphenyl)-3-hydroxy-5- propyl-1,5-dihydro-2H-pyrrol- 2-one 108
4-acetyl-1-(3,4- RACEMATE (302) dimethylphenyl)-3-hydroxy-5-
isobutyl-1,5-dihydro-2H- pyrrol-2-one 109 4-acetyl-1-(3-fluoro-4-
RACEMATE (292) methylphenyl)-3-hydroxy-5- propyl-1,5-dihydro-2H-
pyrrol-2-one 110 4-acetyl-1-(3-fluoro-4- RACEMATE (320)
methylphenyl)-3-hydroxy- 5-pentyl-1,5-dihydro-2H- pyrrol-2-one 111
4-acetyl-1-(3-chloro-4- RACEMATE (336) methylphenyl)-3-hydroxy-
5-pentyl-1,5-dihydro-2H- pyrrol-2-one 112 4-acetyl-1-(3-chloro-4-
RACEMATE (322) methylphenyl)-3-hydroxy-5- isobutyl-1,5-dihydro-2H-
pyrrol-2-one 113 4-acetyl-1-(2,3-dihydro-1H- RACEMATE (328)
inden-5-yl)-3-hydroxy-5- pentyl-1,5-dihydro-2H-pyrrol- 2-one 114
4-acetyl-3-hydroxy-1-(3- RACEMATE (302)
methylphenyl)-5-neopentyl-1,5- dihydro-2H-pyrrol-2-one 115
4-acetyl-1-(3-bromo-4- RACEMATE (406) methylphenyl)-3-hydroxy-5-
(3,3,3-trifluoropropyl)- 1,5-dihydro-2H-pyrrol-2-one 116
4-acetyl-1-(3,4- RACEMATE (316) dimethylphenyl)-3-hydroxy-5- -
neopentyl-1,5-dihydro-2H- pyrrol-2-one 117 4-acetyl-1-(3,4-
RACEMATE (328) dimethylphenyl)-3-hydroxy-5-
(thien-3-yl)-1,5-dihydro- 2H-pyrrol-2-one 118
4-acetyl-1-(4-chlorophenyl)-5- RACEMATE 182
cyclopentyl-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 119
4-acetyl-1-(4-chloro-2- RACEMATE 194 fluorophenyl)-5-cyclopentyl--
3- hydroxy-1,5-dihydro-2H-pyrrol- 2-one 120
4-acetyl-1-(4-chloro-2,6- RACEMATE (370) difluorophenyl)-5-cycloh-
exyl- 3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 121 4-acetyl-5-
MIXTURE 196 bicyclo[2.2.1]hept- 5-en-2-yl-1-(4-chlorophenyl)-
3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 122 4-benzoyl-1-benzyl-3,5-
RACEMATE 114 dihydroxy-5-phenyl-1,5- dihydro-2H-pyrrol-2-one 123
4-acetyl-1-benzyl-5-ethyl- RACEMATE 182 3-hydroxy-1,5-dihydro-2H-
pyrrol-2-one 124 4-acetyl-1-benzyl-5-(2,4- RACEMATE 198
dichlorophenyl)-3-hydroxy- 1,5-dihydro-2H-pyrrol-2-one 125
(R)-4-acetyl-1-(4-chloro-2- CHIRAL (352)
fluorophenyl)-5-cyclohexyl- (Racemate = 3-hydroxy-1,5-dihydro-2H-
no. 72) pyrrol-2-one 126 2-cyclohexyl-4-hydroxy-N- RACEMATE (329)
methyl-1-(4-methylphenyl)- 5-oxo-2,5-dihydro-1H-pyrrole-
3-carboxamide 127 4-acetyl-1-(4-chlorophenyl)- RACEMATE 195
3-hydroxy-5-(4- methylenecyclohexyl)-1,5- dihydro-2H-pyrrol-2-one
128 1-(4-chlorophenyl)-5- RACEMATE 120 cyclohexyl-3-hydroxy-4-
(methylthio)-1,5-dihydro- 2H-pyrrol-2-one 129
(R)-4-acetyl-1-(4-chloro-2- CHIRAL 186 fluorophenyl)-5-cyclopenty-
l- (Racemate = 3-hydroxy-1,5-dihydro-2H- no. 119) pyrrol-2-one 130
(S)-4-acetyl-1-(4-chloro-2- CHIRAL 188 fluorophenyl)-5-cyclopentyl-
(Racemate = 3-hydroxy-1,5-dihydro-2H- - no. 119) pyrrol-2-one 131
2-cyclohexyl-4-hydroxy-1-(4- RACEMATE (314)
methylphenyl)-5-oxo-2,5- dihydro-1H-pyrrole-3- carboxamide 132
4-acetyl-1-(4-chlorophenyl)- RACEMATE 233 3-hydroxy-5-(4-
methoxycyclohexyl)-1,5- dihydro-2H-pyrrol-2-one 133
5-cyclohexyl-3-hydroxy-1-(4- RACEMATE (353)
methylphenyl)-4-pent-4-enoyl- 1,5-dihydro-2H-pyrrol-2-one 134
4-acetyl-1-(4-chlorophenyl)-5- RACEMATE 209
(cyclopentylmethyl)-3-hydroxy- 1,5-dihydro-2H-pyrrol-2-one 135
(R)-4-acetyl-1-(4-chloro-3- CHIRAL 135 methylphenyl)-5-cyclopentyl-
(Racemate = 3-hydroxy-1,5-dihydro-2H- - no. 69) pyrrol-2-one 136
4-acetyl-1-(4-chlorophenyl)- RACEMATE (364) 3-hydroxy-5-(4-
methoxycyclohexyl)-1,5- dihydro-2H-pyrrol-2-one 137
(R)-4-acetyl-5-cyclopentyl-1- CHIRAL 118
(4-fluorophenyl)-3-hydroxy- 1,5-dihydro-2H-pyrrol-2-one 138
4-acetyl-1-(4-chlorophenyl)- RACEMATE 196
5-(1,4-dioxaspiro[4.5]dec- 8-yl)-3-hydroxy-1,5-dihydro-
2H-pyrrol-2-one 139 (R)-4-acetyl-5-cyclohexyl-1- CHIRAL 160
(4-fluorophenyl)-3-hydrox- y- (Racemate =
1,5-dihydro-2H-pyrrol-2-one no. 25) 140
(R)-4-acetyl-1-(4-bromophenyl)- CHIRAL 98
5-cyclohexyl-3-hydroxy-1,5- (Racemate = dihydro-2H-pyrrol-2-one no.
17) 141 4-acetyl-1-(4-chlorophenyl)- RACEMATE 230
3-hydroxy-5-(3-noradamantyl)- 1,5-dihydro-2H-pyrrol-2-one 142
4-acetyl-1-(4-bromo-2- RACEMATE 228 fluorophenyl)-5-cyclohexy- l-
3-hydroxy-1,5-dihydro-2H- pyrrol-2-one 143
5-cyclohexyl-3-hydroxy-1-(4- RACEMATE (513) methylphenyl)-4-[5-(5-
methyl-2-phenyl-1,3-oxazol- 4-yl)pentanoyl]-1,5-
dihydro-2H-pyrrol-2-one 144 (R)-4-acetyl-1-(4- CHIRAL (318)
chlorophenyl)-5-cyclopentyl- (Racemate = 3-hydroxy-1,5-dihydro-2H-
no. 118) pyrrol-2-one 145 4-acetyl-1-(4-chlorophenyl)- RACEMATE
(390) 3-hydroxy-5-(3,3,5,5- tetramethylcyclohexyl)-1,5-
dihydro-2H-pyrrol-2-one 146 5-cyclohexyl-3-hydroxy-1-(4- RACEMATE
185 methylphenyl)-4-[(4E)-5- (5-methyl-2-phenyl-1,3-
oxazol-4-yl)pent-4-enoyl]- 1,5-dihydro-2H-pyrrol-2-one 147
(S)-4-acetyl-1-(4-chloro-2,6- CHIRAL (368)
difluorophenyl)-5-cyclohexyl- (Racemate = 3-hydroxy-1,5-dihydro-2-
H- no. 120) pyrrol-2-one 148 (R)-4-acetyl-1-(4-chloro-2,6- CHIRAL
90 difluorophenyl)-5-cyclohexyl- (Racemate =
3-hydroxy-1,5-dihydro-2H- no. 120) pyrrol-2-one 149
(R)-4-acetyl-1-(4-bromo-2- CHIRAL 96 fluorophenyl)-5-cyclohexyl-
(Racemate = 3-hydroxy-1,5-dihydro-2H- no. 142) pyrrol-2-one 150
4-acetyl-1-(4-chlorophenyl)- RACEMATE 186 3-hydroxy-5-(4-
methylcyclohexyl)-1,5- dihydro-2H-pyrrol-2-one 151
4-acetyl-1-(4-chloro-2- RACEMATE 246 fluorophenyl)-3-hydroxy-5-
(3-noradamantyl)-1,5-dihydro- 2H-pyrrol-2-one 152
4-acetyl-5-(4-tert- RACEMATE 188 butylcyclohexyl)-1-(4-
chlorophenyl)-3-hydroxy-1,5- dihydro-2H-pyrrol-2-one 153
4-acetyl-1-(4-chloro-2- RACEMATE 182 fluorophenyl)-3-hydroxy-5-
(4-methylenecyclohexyl)-1,5- dihydro-2H-pyrrol-2-one 154
4-acetyl-1-(4-bromo-2,6- RACEMATE 170 difluorophenyl)-5-cyclohexyl-
3-hydroxy-1,5-dihydro-2- H- pyrrol-2-one 155
(R)-4-acetyl-1-(4-bromo-2,6- CHIRAL 91
difluorophenyl)-5-cyclohexyl- (Racemate = 3-hydroxy-1,5-dihydro-2H-
no. 154) pyrrol-2-one 156 (R)-4-acetyl-1-(4- CHIRAL 178
chlorophenyl)-3-hydroxy-5- (Racemate =
tricyclo[3.3.1.0.about.3,7.about.]non- no. 141)
3-yl-1,5-dihydro-2H-pyrrol- 2-one 157 4-acetyl-1-(4- RACEMATE 126
chlorophenyl)-5-cyclohexyl- 3-mercapto-1,5-dihydro-2H- pyrrol-2-one
158 1-(4-chlorophenyl)-4- RACEMATE (318) (cyclohexylcarbonyl)-
3-hydroxy-1,5-dihydro- 2H-pyrrol-2-one 159
4-acetyl-5-(4-fluorophenyl)- RACEMATE 232 3-hydroxy-1-(4-methylph-
enyl)- 1,5-dihydro-2H-pyrrol-2-one 160 4-acetyl-3-hydroxy-1-(4-
RACEMATE 220 methylphenyl)-5-phenyl-1,5- dihydro-2H-pyrrol-2-one
161 (S)-4-acetyl-5-cyclohexyl- CHIRAL (314)
3-hydroxy-1-(4-methylphenyl)- (Racemate =
1,5-dihydro-2H-pyrrol-2-one no. 10) 162 methyl 2-cyclohexyl-4-
RACEMATE 254 hydroxy-1-(4-methylphenyl)-5-
oxo-2,5-dihydro-1H-pyrrole- 3-carboxylate 163 (S)-4-acetyl-1-(4-
CHIRAL (334) chlorophenyl)-5-cyclohexyl- (Racemate =
3-hydroxy-1,5-dihydro-2H- no. 24) pyrrol-2-one 164
1-(4-bromophenyl)-5- RACEMATE 218 cyclohexyl-4-hexanoyl-3-
hydroxy-1,5-dihydro-2H- pyrrol-2-one 165 ethyl
2-cyclohexyl-4-hydroxy- RACEMATE (344)
1-(4-methylphenyl)-5-oxo-2,5- dihydro-1H-pyrrole-3- carboxylate 166
N-(3-chlorophenyl)-2- RACEMATE (425) cyclohexyl-4-hydroxy-1-(4-
methylphenyl)-5-oxo-2,5- dihydro-1H-pyrrole-3- carboxamide 167
N-butyl-2-cyclohexyl-4- RACEMATE (369) hydroxy-1-(4-methylphenyl)-
- 5-oxo-2,5-dihydro-1H-pyrrole- 3-carboxamide 168
2-cyclohexyl-4-hydroxy-1-(4- RACEMATE (314)
methylphenyl)-5-oxo-2,5- dihydro-1H-pyrrole-3- carboxamide 169
4-acetyl-1-(4-chloro-2- RACEMATE 66 fluorophenyl)-5-cyclohexyl-
3-sulfanyl-1,5-dihydro-2H- pyrrol-2-one 170 4-acetyl-1-(5-chloro-2-
RACEMATE 226 thienyl)-5-cyclohexyl-3- hydroxy-1,5-dihydro-2H-
pyrrol-2-one 171 4-acetyl-1-(6-chloro-3- RACEMATE 224
pyridinyl)-5-cyclohexyl-3- hydroxy-1,5-dihydro-2H- pyrrol-2-one 172
4-acetyl-1-(5-chloro-2- RACEMATE 214 pyridinyl)-5-cyclohexyl-3-
hydroxy-1,5-dihydro-2H- pyrrol-2-one
EXAMPLE 4
[0157] Binding Assay
[0158] Antagonism of the CCR2 receptor is determined by a binding
assay using the human monocytic cell line THP-1. Cells are
suspended in assay buffer (RPMI+1% BSA+25 mM HEPES) at
3.times.10.sup.6 cells/ml and an aliquot (180 .mu.l) added to a 0.5
ml siliconized Eppendorf tube. Compound (10 .mu.l) is added at
various concentrations to the cell suspension and 10 .mu.l of
.sup.125I-MCP-1 added to give a final concentration of 0.1 nM.
After incubation for 1 hr at room temperature, the cell suspension
is centrifuged through oil and the cell pellets counted to
quantitate cell-bound ligand. Nonspecific (NS) binding of
radioligand is determined by the addition of 100 nM cold MCP-1.
Control binding is determined by the addition of buffer without
compound. Inhibition of .sup.125I-MCP-1 binding to THP-1 cells was
determined as an IC50Compounds nos. 7, 8, 9, 10, 13, 14, 16, 17,
18, 19, 20, 23, 24, 25, 39, 40, 41, 43, 44, 47, 48, 49, 50, 51, 52,
53, 54, 55, 56, 58, 59, 61, 62, 63, 64, 65, 66, 68, 69, 70, 71, 72,
73, 74, 76, 77, 78, 79, 116, 118, 119, 120, 121, 125, 126, 127,
128, 129, 131, 132, 134, 135, 136, 137, 139, 140, 141, 142, 144,
145, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 168, 169,
170 and 172 exhibited an IC50 of 5 .mu.M or less.
EXAMPLE 5
[0159] Chemotaxis Assay
[0160] Antagonism of CCR2 function is determined by a chemotaxis
assay. MCP-1 is prepared in buffer (Hanks+0.1% human serum albumin)
at 3 nM concentration and aliquoted into the bottom chambers of a
96-well chemotaxis plate (Neuroprobe). THP-1 cells are suspended in
the same buffer at 1.times.10.sup.7 cells /ml and compound added at
various concentrations to the aliquots of cells. The cell and
compound mixture is added to the top of the polycarbonate membrane
(5 .mu.m pore diameter) and the chemotaxis plate incubated at
37.degree. C. for 2 hr. After the unmigrated cells are scraped off
the top of the filter, the plate is gently centrifuged and the
membrane removed. Cells which migrate to the bottom chamber are
quantitated by counting with a hemacytometer. Spontaneous
chemotaxis is determined by measuring cell migration in the absence
of chemokine. Chemotaxis of a positive control is determined by
measuring cell migration without compound. Inhibition of cell
chemotaxis is determined as an IC50.
[0161] Compounds nos. 10, 24, 51, 53, 69, 72, 125, and 156
exhibited an IC50 of 5 .mu.M or less.
* * * * *