Note: Descriptions are shown in the official language in which they were submitted.
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
HYDANTOIN COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS
Related Inventions
This application claims the benefit of US application Serial Nos.
s 60/250,486 and 60/250,653, both filed December 1, 2000, and US application
Serial No: 60/272,165, filed February 28, 2001, the contents of which are
incorporated herein by reference.
Field of the Invention
1o The present invention relates to hydantoin compounds, pharmaceutical
compositions containing them, and methods of using such compounds in
treating inflammatory or immune disease.
Background of the Invention
Is Cells adhere to other cells and to substrates through specific, regulated
processes that are critical to various biological functions. The proper
functioning of the immune system, for example, is dependent upon adhesive
interactions and cell migration. A key event in an immune response involves
the migration of leukocytes to a disease site. During an inflammatory
2o response, leukocytes are recruited to the site of injury and extravasated
by a
series of cellular interactions involving cell-cell and cell-substrate
adhesion.
One family of molecules that serve an important adhesive function are
integrins. Integrins are expressed on cell surfaces and function in cell-cell
and cell-substrate adhesion. Integrins are alpha-beta heterodimers: each
2s integrin has an alpha (a) subunit non-covalently binded to a beta (~i)
~subunit:
When activated, integrins bind to extracellular ligands and induce adhesion
(the expression of integrins on a cell surface alone is.inadequate for
adhesion
-1-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
- they must be activated to become adhesive). The integrin activation state is
transient, such that there is a rapid flux between adhesive and non-adhesive
states which is important for cell movement, e.g., a cell is endowed with the
ability to rapidly adhere to various cell surfaces and matrices and to migrate
s among cells and tissue.
There are four known integrins having a X32 or CD18 subunit which
comprise the CD11/CD18 integrin sub-family, namely, Lymphocyte Function-
associated Antigen 1 (LFA-1 ) (CD11 a/CD18 or a~~i2); Macrophage Antigen 1
(Mac-1) (CD11b/CD18 or aM~3~); p150,95 (CD11c/CD18 or aXa2); and ap~2.
to The CD11/CD18 family of integrins are also referred to as Leukointegrins as
they are expressed on the surface of various leukocyte cells, and they
mediate a number of inflammation-related cellular interactions. See Diamond
et al., "The Dynamic Regulation of Integrin Adhesiveness," Current Biology,
Vol. 4 (1994) at pp. 506-532.
is Ligands to LFA-1 and Mac-1 comprise the intercellular adhesion
molecule (ICAM) ICAM-1. LFA-1, the primary CD11/CD18 integrin, also binds
with ICAM-2 and ICAM-3. ICAMs are found on endothelium cells, leukocytes,
and other cell types, and their interaction with CD11/CD18 integrins is
critical
to immune system function. The interaction between the CD18 integrins,
2o particularly LFA-1, and ICAMs mediates antigen presentation, T-cell
proliferation, and adhesion between the endothelium and activated leukocytes
which is necessary for leukocytes to migrate from the circulatory system into
tissue. A condition termed "Leukocyte Adhesion Deficiency" has been
identified in patients having a severe deficiency in CD18 integrins. These
2s patients are unable to mount a normal inflammatory or immune response;
they suffer from disorders such as recurrent infections, poor wound healing,
granufocytosis, progressive periodontitis, and umbilical cord separation. See
-2-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Anderson et aL, "Leukocyte LFA-1, OKMI, p150,95 Deficiency Syndrome:
Functional and Biosynthesis Studies of Three Kindreds," Fed. Proc., Vol. 44
(1985), pp. 2671-2677.
While sufficient levels of CD18 integrins interacting with ICAMs are
s needed to mount a normal immune response, significant cellular and tissue
injury can result in chronic inflammatory states where there is an
inappropriate
influx of leukocytes to the disease site. Continuous recruitment of leukocytes
from blood vessels into inflamed tissue, as in chronic inflammatory states,
can
perpetuate tissue injury and lead to excessive fibrous repair and autoimmune
io disease. Thus, inhibition of the interaction between LFA-1 and/or Mac-1 and
their ICAMs can be advantageous in treating inflammatory or immune
disease. For example, monoclonal antibody blockade of either ICAM or LFA-
1 has been shown to prevent the migration of leukocytes into tissue and the
subsequent development of inflammatory disease in animal models of
is rheumatoid arthritis, inflammatory bowel disease, and pulmonary
inflammation
(e.g., asthma). Knockout mice deficient in ICAMs have reduced susceptibility
to induced arthritis, ischemia injury, impaired lung inflammatory responses,
and increased tolerance to transplantations (e.g. heart grafts). See Anderson,
supra. Antibodies blocking the ICAM-LFA-1 interaction reportedly suppress
2o cardiac allograft rejection and islet cell xenograft rejection in animal
models.
See Gorski, "The Role of Cell Adhesion Molecules in Immunopathology,"
Immunology Today, Vol. 15 (1994), at pp. 251-255.
Compounds inhibiting CD18 integrins, ICAMs, or the LFA-1:ICAM
interaction could potentially demonstrate a wide range of utilities in
treating
2s inflammatory or immune diseases. Blocking LFA-1 reportedly inhibits the
influx of leukocytes in almost every system, including the skin, peritoneum,
synovium, lung, kidney and heart, and blocking ICAM-1 would be expected to
-3-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
have similar effects. Also, present therapies for many inflammatory or
immune diseases have drawbacks. For example, current treatments for
asthma include ~2-agonists, inhaled corticosteroids, and LTD4 antagonists.
However, ~2-agonists have limited efficacy and inhaled corticosteroids raise
s safety concerns. To treat psoriasis, current therapies include PUVA,
methotrexate, cyclosporin A, and topical treatments. The first three of those
therapies raise toxicity issues over long-term (6-9 month) use, whereas
topical
treatments have limited efficacy. Additionally, these treatments typically are
applied only in response to flares and not as a prophylaxis measure. There is
~o a need for pharmaceuticals having increased effectiveness and fewer side
effects.
Accordingly, there is interest in developing Leukointegrin or ICAM
antibodies and antagonists of Leukointegrins and/or ICAMs. Thiadiazole-
based compounds reportedly inhibit LFA-1 and Mac-1 binding with ICAM-1
is and are claimed to be useful as anti-inflammatory agents. See intern. Pub.
No. WO 99/20,618, "Thiadiazole Amides Useful as Anti-Inflammatory Agents"
filed by Pharmacia & Upjohn Co. (See also WO 99/20,617, also to Pharmacia
and Upjohn.) Thiazole compounds linked to phenyl and pyrazole rings are
claimed to be active LFA-1/ICAM inhibitors. Sanfilippo et al., "Novel Thiazole
2o Based Heterocycles as Inhibitors of LFA-1/ICAM-1 Mediated Cell Adhesion,"
J. Med. Chem. Vol. 38 (19.95) at pp.1057-1059. A series of small molecules
comprising 1-(3,5 dichlorophenyl) imidazolidines are claimed to be
antagonists to the binding of ICAMs with CD18 integrins. See Intern. Pub.
No. WO 98/39303, "Small Molecules Useful in the Treatment of Inflammatory
2s Disease," filed by Boehringer Ingelheim Pharmaceuticals, Inc. (See also
Boehringer patent applications WO 01/07052, WO 01/07048, WO 01/07044,
WO 01/06984, and WO 01/07440). A series of compounds comprising
_4_
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
various benzylamines and 2-brorr~obenzoyl-tryptophan are claimed to be
antagonists to LFA-1/ICAM-1 receptor binding. See Intern. Pub. No.
W099/49,856, "Antagonists for Treatment of GD11/CD18 Adhesion Receptor
Mediafed Disorders," filed by Genentech, Inc. See also Intern. Pub. No. WO
s 00/21,920, "Diaminopropionic Acid Derivatives," filed by Hoffmann-La Roche
Inc., disclosing a series of compounds claimed to block ICAM activity and
have particular utility in treating reperfusion injury following acute
myocardial
infarction.
As may be appreciated, those in the field of pharmaceutical research
io continue to seek to develop new compounds and compositions for treating
inflammatory or immune disease such as inhibitors of Leukointegrins andlor
ICAMs. Particularly in the area of immune response, many individuals
respond differently to different drugs. Thus, there is an interest in
providing
consumers not only with pharmaceutical compounds and compositions
~5 demonstrating increased effectiveness and reduced side-effects but also
different structures or mechanisms of action to provide consumers with a
choice of options. The instant invention is directed to hydantoin compounds
that are effective as antagonists of Leukointegrins and/or ICAMs. Hydantoin
compounds are disclosed in European patent application Serial No. 0 272 594
2o A2 to Hoechst Aktiengesellschaft for use as herbicides; in US Pat. No.
5,605,877 to Schafer et al. for use as herbicides; and in European patent
application Serial No. EP 1 004 583 A2 and Intern. Pub. No. WO 98/58,947
both to Pfizer Inc., for use as intermediates in making growth hormone
secretagogues. Hydantoin compounds are disclosed in Intern. Pub. No. WO
25 01/30781 A2 (published May 3, 2001) to Tanabe Seiyaku Co. Ltd, "Inhibitors
of a~~2 Mediated Cell Adhesion."
-5-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Each of the patents, patent applications and publications referenced
above and hereinafter is incorporated herein by reference.
Summary of the Invention
s The present invention provides compounds useful for treating
inflammatory or immune disease having the formula (I):
R4b
\ L
Z
R4a .
~r
s~~1
C s)r, (I)
and pharmaceutically-acceptable salts thereof, in which:
io L and K, taken independently, are O or S;.
M is N or CH;
Y is CH or N;
Z is hydrogen, alkyl, or substituted alkyl, provided that Z may be
selected from arylalkyl and heteroarylalkyl only when M is CH and/or when
~s ring A has a second ring fused thereto;
T is nitrogen, CH, or a carbon atom substituted with an R3 group;
R1 is Q-aryl or Q-heteroaryl, wherein (a) when T is not nitrogen, Q is
selected from a bond, -O-, -NRIO-, -S-, -C(=O)-, -C02-, -OC(=O)-, -
NRIOC(=O)-, -C(=O)NRIO-, -NR1oC02-, C1_4alkylene, C1_4substituted alkylene,
2o C1_4alkenylene, C1_4substituted alkenylene, and optionally-substituted
bivalent
C1_~alkoxy, C1_4alkylthio, C1_4alkylamino, C1_4aminoalkyl, Co_4alkylsulfonyl,
Co_
4alkylsulfonamide, Cl~acyl, or Co_4alkoxycarbonyl, or when Z is arylalkyl or
heteroarylalkyl, R1 may join with an R3 group to form a fused carbocyclic or
-6-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
heterocyclic ring; or (b) when T is nitrogen, then Q is selected from a bond, -
C(=O)-, -C02-, -OC(=Q)-, -C~_4alkylene, C~_4substituted alkylene, C~_
4alkenylene, C~_4substituted alkenylene, or optionally-substituted bivalent
C~_
4alkoxy, C~_4alkylthio, C~_4aminoalkyl, Co_4alkylsulfonyl,
Co_4alkylsulfonamide,
s C~_4acyl, or C~_4alkoxycarbonyl, provided that when M is N, T is N, r is 1,
and s
is 2 such that ring A is piperazine, R~ is not an amine-protecting group;
R3 is selected from at least one of (i) a substituent R3, wherein each
substituent R3 is individually attached to any available carbon or nitrogen
atom
of ring A and at each occurrence is selected independently of each other R3
io from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano,
OR8,
NR$R9, C02R8, (C=O)R8, C(=O)NR8R9, NR$C(=O)R9, NR$C(=O)OR9,
OC(=O)R8, OC(=O)NR$R9, SR8, S(O)qRsa, NR$S02R9, S02NRsR9, aryl,
heteroaryl, heterocyclo, and cycloalkyl, and when attached to an atom of ring
A other than T, R3 is optionally keto (=O), provided that when R3 is attached
to
Is the atom designated as the C-5 atom of ring A, then R3 is not aryl or
heteroaryl; and (ii) a first group R3 and a second group Rs, wherein the first
group R3 and the second group R3 are attached to two adjacent atoms of ring
A and together form an optionally-substituted carbocyclic or heterocyclic ring
fused to ring A;
2o R4a and R4b are selected independently of each other from the group
consisting of hydrogen, halogen, alkyl, substituted alkyl, alkenyl, alkynyl,
nitro,
cyano, hydroxy, alkoxy, substituted alkoxy, phenyloxy, benzyloxy, CO2H,
C(=O)H, amino, alkylamino, substituted alkylamino, C02alkyl, (C=O)alkyl, and
alkylthio;
'2s R8 and R9 (i) selected independently of each other are hydrogen, alkyl,
substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or
heterocyclo; or (ii) taken together form a heterocyclo ring;
R8a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo;
R~o is hydrogen, alkyl, or substituted alkyl;
_7_
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
n is 0, 1, or 2;
q is 1, 2, or 3;
r is 1 or 2; and
s is 0, 1, or 2.
s
Detailed Description of the Invention
The following are definitions of terms used in this specification and
appended claims. The initial definition provided for a group or term herein
applies to that group or term throughout the specification and claims,
io individually or as part of another group, unless otherwise indicated.
The term "alkyl" refers to straight or branched chain hydrocarbon
groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower
alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most
preferred.
When numbers appear in a subscript after the symbol "C", the subscript
is defines with more specificity the number of carbon atoms that a particular
group may contain. For example, "C~_6alkyl" refers to straight and branched
chain alkyl groups with one to six carbon atoms, such as methyl, ethyl, n-
propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and so forth.
The term "substituted alkyl" refers to an alkyl group as defined above
2o having one, two, or three substituents selected from the group consisting
of
halo, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, -
NHS02,
-N(alkyl)S02, -NHS02(alkyl), -NHS02(aryl), -N(alkyl)S02(alkyl), -
N(alkyl)S02(aryl), -S02(alkyl), -S02(aryl), -S02N(aryl)(alkyl), -SO2N(alkyl)Z,
-
NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -C02H, -C(=O)H, -C02-alkyl, -
2s (C=O)alkyl, -(C=O)NH2, -(C=O)NH(alkyl), -(C=O)NH(cycloalkyl), -
(C=O)N(alkyl)2, -NH-CH2-C02H, -NH-CH2-C02-alkyl, keto (=O), =N-OH, =N-
O-alkyl, aryl, heteroaryl, heterocyclo, and cycloalkyl, including phenyl,
benzyl,
phenylethyl, phenyloxy, and phenylthio. When a substituted alkyl includes an
_g_
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
aryl, heterocyclo, heteroaryl, or cycloalkyl substituent, said ringed systems
are
as defined below and thus may have zero, one, two, or three substituents,
also as defined below.
The term "alkenyl" refers to straight or branched chain hydrocarbon
s groups having 2 to 12 carbon atoms and at least one double bond. Alkenyl
groups of 2 to 6 carbon atoms and having one double bond are most
preferred.
The term "alkynyl" refers to straight or branched chain hydrocarbon
groups having 2 to 12 carbon atoms and. at least one triple bond. Alkynyl
io groups of 2 to 6 carbon atoms and having one triple bond are most
preferred.
The term "alkylene" refers to bivalent straight or branched chain
hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon
atoms, e.g., {-CH2-Vin, wherein n is 1 to 12, preferably 1-8. Lower alkylene
groups, that is, alkylene groups of 1 to 4 carbon atoms, are most preferred.
is The terms "alkenylene" and "alkynylene" refer to bivalent radicals of
alkenyl
and alknyl groups, respectively, as defined above.
The term "alkoxy" refers to an alkyl group as defined above having a
carbon atom replaced by one or more oxygen atoms. For example, the term
"alkoxy" includes the groups -O-C~_~2alkyl, -C~_6alkylene-O-C~_salkyl, and so
2o forth.
The term "alkylthio" refers to an alkyl group as defined above having a
carbon atom replaced by one or more sulfur (-S-) atoms. For example, the
term "alkylthio" includes the groups -S-C~_~Zalkyl, -C~_salkylene-S-C~_salkyl,
etc.
2s The term "alkylamino" refers to an alkyl group as defined above
bonded through one or more nitrogen atoms (e.g., -NR- groups). For example,
the term "alkylamino" includes the groups -NH-C~_~2alkyl, -NH-C~_6alkylene-
NH-C~_6alkyl, etc. The term alkylamino refers to straight and branched chain
_g_
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
groups and thus, for example, includes the groups -NH(C~_~2alkyl) and -N(C~_
6alkyl)2. When a subscript is used with reference to an alkoxy, alkylthio or
alkylamino, the subscript refers to the number of carbon atoms that the group
may contain in addition to heteroatoms. Thus, for example, monovalent C~_
s 2alkylamino includes the groups -NH-CH3, -NH-CH2-CH3, and -N-(CH3)2 .
When reference is made to a substituted alkoxy, substituted alkylthio,
or substituted alkylamino group, the alkyl portion of the alkoxy, alkylthio
and
alkylamino groups may have one to three substituents selected from those
recited above for substituted alkyl. The nitrogen atom of the alkylamino group
to may optionally be substituted with a group selected from alkyl, substituted
alkyl, alkenyl, alkynyl, cyano, -S02(alkyl), -SO~(aryl), -C02H, -C(=O)H, -C02-
alkyl, -(C=O)alkyl, aryl, heteroaryl, heterocyclo, and cycloalkyl.
The alkoxy, alkylthio, or alkylamino groups may be monovalent or
bivalent. By "monovalent" it is meant that the group has a valency (i.e.,
power
~s to combine with another group), of one, and by "bivalent" it is meant that
the
group has a valency of two.
When the term "alkyl" is used as a suffix in conjunction with a second
group, such as in "arylalkyl," "aminoalkyl," or "cycloalkylalkyl", it is meant
that
an alkyl group is used as a linker to the second group. Thus, for example, the
2o term arylalkyl includes benzyl, phenylethyl, etc., and aminoalkyl includes
the
group -CH2-CH2-NH2. In such a case, the referenced second group (e.g., aryl
in arylalkyl) is as defined herein and thus may be substituted as set forth in
these definitions.
The term "halogen" includes chloro, bromo, fluoro, and iodo.
2s The term "haloalkyl" means an alkyl having one or more halo
substituents, e.g., including trifluoromethyl.
The term "haloalkoxy" means an alkoxy group having one or more halo
substituents. For example, "haloalkoxy" includes -OCF3.
-10-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
O
The term "acyl" refers to a carbonyl group (-~-) linked to an organic
radical including an alkyl, alkenyl, alkynyl, substituted alkyl, substituted
alkenyl, or substituted alkynyl, as defined above. The organic radical to
which
the carbonyl group is attached may be monovalent (e.g., -C(=O)-alkyl), or
s bivalent (e.g., -C(=O)alkylene, etc.)
The term "alkoxycarbonyl" refers to a carboxy or ester group
0
(-c-o-) linked to an organic radical including an alkyl, alkenyl, alkynyl,
substituted alkyl, substituted alkenyl, or substituted alkynyl, as defined
above.
The organic radical to which the carboxy group is attached may be
io monovalent (e.g., -C02-alkyl), or bivalent (e.g., -C02-alkylene, etc.)
The term "carbamyl" refers to -NR'-C(=O)R" or -C(=O)NR'R", wherein
R' and R" may be hydrogen, alkyl, substituted alkyl; or cycloalkyl, as defined
above. ,
The term "sulfonyl" refers to a sulphoxide group (i.e., -S(O)~_2-) linked
is to an organic radical including an alkyl, alkenyl, alkynyl, substituted
alkyl,
substituted alkenyl, or substituted alkynyl group, as defined above. The
organic radical to which the sulphoxide group is attached may be monovalent
(e.g., -S02-alkyl), or bivalent (e.g., -S02-alkylene, etc.)
The term "sulfonamide" refers to the group -S(O)2NR'R", wherein R'
2o and R" may be hydrogen or alkyl, alkenyl, alkynyl, substituted alkyl,
substituted alkenyl, or substituted alkynyl, as defined above. R' and R" may
be
monovalent or bivalent (e.g., -SO2-NH-alkylene, etc.)
The term "cycloalkyl" refers to optionally-substituted fully saturated and
partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon
2s atoms. The term "cycloalkyl" includes such rings having zero, one, two, or
three substituents, preferably zero or one, selected from the group consisting
of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, amino,
hydroxy,
alkoxy, alkylthio, -NHS02, -N(alkyl)S02, -NHS02(alkyl), -NHS02(aryl), -
-11-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
N(alkyl)S02(alkyl), -N(alkyl)S02(aryl), -S02(alkyl), -S02(aryl), -
S02N(aryl)(alkyl), -S02N(alkyl)2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2,
-C02H, -C(=.O)H, -C02-alkyl, -(C=O)alkyl, -(C=O)NH2, -(C=O)NH(alkyl), -
(C=O)NH(cycloalkyl), -(C=O)N(alkyl)2, -NH-CH2-C02H, -NH-CH2-C02-alkyl,
s keto, =N-OH, =N-O-alkyl, aryl, heteroaryl, heterocyclo, and a five or six
membered ketal, i.e.1,3-dioxolane or 1,3-dioxane. The term "cycloalkyl" also
includes such rings having a bridge of 3 to 4 carbon atoms.
The term "aryl" refers to phenyl, biphenyl, 1-naphthyl and 2-naphthyl,
with phenyl being preferred. The term "aryl" includes such rings having from
io zero, one, two or three substituents selected from the group consisting of
halo, alkyl, substituted alkyl, alkenyl, alkynyl, vitro, cyano, amino,
hydroxy,
alkoxy, alkylthio, -NHS02, -N(alkyl)S02, -NHS02(alkyl), -NHS02(aryl), -
N(alkyl)S02(alkyl), -N(alkyl)S02(aryl), -S02(alkyl), -S02(aryl), -
S02N(aryl)(alkyl), -S02N(alkyl)2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2,
is -C02H, -C(=O)H, -C02-alkyl, -(C=O)alkyl, -(C=O)NH2, -(C=O)NH(alkyl), -
(C=O)NH(cycioalkyl), -(C=O)N(alkyl)2, -NH-CH2-C02H, -NH-CH2-C02-alkyl,
phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, heterocyclo,
and heteroaryl.
When the term "aryl" is used with a hypen following another group, as
2o in -O-Co_2alkylene-aryl, -S-Co_2alkylene-aryl, -N-Co_2alkylene-aryl, acyl-
aryl,
alkoxy-carbonyl-aryl, or sulfonamide-aryl, it is meant that the hypenated
group
or groups serve as a linker to the aryl. In such a case, the aryl may be
unsubstituted or substituted with one to three groups, as defined above.
The term "heterocyclo" refers to substituted and unsubstituted non-
2s aromatic 3 membered monocyclic groups,to membered bicyclic
to 7 7 11
groups, and 10 to 15 membered tricyclic whichhave at least
groups one
heteroatom (O, S or N) in at least one rings.Each ring of
of the the
heterocyclo group containing a heteroatom can contain one or two oxygen or
sulfur atoms and/or from one to four nitrogen atoms provided that the total
-12-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
number of heteroatoms in each ring is four or less, and further provided that
the ring contains at least one carbon atom. The fused rings completing the
bicyclic and tricyclic groups may contain only carbon atoms and may be
saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms
s may optionally be oxidized and the nitrogen atoms may optionally be
quaternized. The heterocyclo group may be attached at any available nitrogen
or carbon atom. The heterocyclo ring may contain zero, one, two or three
substituents selected from the group consisting of halo, alkyl, substituted
alkyl, alkenyl, alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, -
NHS02,
io -N(alkyl)S02, -NHS02(alkyl), -NHSOZ(aryl), -N(alkyl)S02(alkyl), -
N(alkyl)S02(aryl), -SO2(alkyl), -S02(aryl), -SO2N(aryl)(alkyl), -S02N(alkyl)2,
-
NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -C02H, -C(=O)H, -CO~-alkyl, -
(C=O)alkyl, -(C=O)NH2, -(C=O)NH(alkyl), -(C=O)NH(cycloalkyl), -
(C=O)N(alkyl)2, -NH-CH2-C02H, -NH-CH2-CO2-alkyl, aryl, heteroaryl,
Is heterocyclo, cycloalkyl, keto, =N-OH, =N-O-alkyl, and a five or six
membered
ketal, i.e., 1,3-dioxolane or 1,3-dioxane.
Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl,
imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-
oxopiperidinyl,
20 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyf,
tetrahydropyranyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl
sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplary
bicyclic heterocyclo groups include quinuclidinyl.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5
2s or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11
to 14 membered tricyclic groups which have at least one heteroatom (O, S or
N) in at least one of the rings. Each ring of the heteroaryl group containing
a
heteroatom can contain one or two oxygen or sulfur atoms and/or from one to
four nitrogen atoms provided that the total number of heteroatoms in each ring
3o is four or less and each ring has at least one carbon atom. The fused rings
-13-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
completing the bicyclic and tricyclic groups may contain only carbon atoms
and may be saturated, partially saturated, or unsaturated. The nitrogen and
sulfur atoms may optionally be oxidized and the nitrogen atoms may
optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic
s must include at least one fully aromatic ring but the other fused ring or
rings
may be aromatic or non-aromatic. The heteroaryl group may be attached at
any available nitrogen or carbon atom of any ring. The aromatic portion of the
heteroaryl ring system may contain zero, one, two or three substituents
selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl,
to alkynyl, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, -NHS02, -
N(alkyl)S02,
-NHS02(alkyl), -NHS02(aryl), -N(alkyl)S02(alkyl), -N(alkyl)S02(aryl), -
S02(alkyl), -S02(aryl), -S02N(aryl)(alkyl), -SOZN(alkyl)2, -NH(alkyl), -
NH(cycloalkyl), -N(alkyl)2, -C02H, -C(=O)H, -C02-alkyl, -(C=O)alkyl, -
(C=O)NH2, -(C=O)NH(alkyl), -(C=O)NH(cycloalkyl), -(C=O)N(alkyl)2, -NH-CH2-
is C02H, -NH-CH2-C02-alkyl, phenyl, benzyl, phenylethyl, phenyloxy,
phenylthio, cycloalkyl, heterocyclo, and heteroaryl. The non-aromatic portion
of the heteroaryl ring may contain one or more of the above-referenced
substituents as well as keto (=O), =N-OH, =N-O-alkyl, and the like.
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,
2o pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,
isothiazolyl,
furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl
and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,
benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,
tetrahydroisoquinolinyl,
2s isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,
chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, iridazolyl,
pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the
like.
-14-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,
phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term "carbocyclic" refers to optionally substituted aromatic or non
aromatic 3 to 7 membered monocyclic and 7 to 11 membered bicyclic groups,
s in which all atoms of the ring or rings are carbon atoms.
When the term "unsaturated" is used herein to refer to a ring or group,
the ring or group may be fully unsaturated or partially unsaturated.
Throughout the specification, groups and substituents thereof may be
chosen by one skilled in the field to provide stable moieties and compounds.
io Thus, for example, in compounds of formula (I), the substituent R3 may be
attached to any available carbon atom of the "A" ring, including the atom T to
which the group R~ is attached. For ease of reference, this atom may be
referred to as the "R~ substituted atom." When R~ comprises a heteroatom
directly attached to ring A, advantageously any R3 group attached to T does
is not comprise a heteroatom directly attached to ring A, and vice-versa.
In compounds of formula (I), wherein R~ and/or R3 is attached to the 4-
position atom of a piperazine ring (i.e., wherein M is N, A is a six-membered
ring, and the fourth atom on the ring A [where M=atom 1] is a nitrogen atom),
these groups preferably do not comprise "amine-protecting groups." More
~'\N~Ra
yN/~ J
2o particularly, where ring A is \R3 , R~ preferably is not an amine-
protecting group. The term "amine-protecting group" as used herein refers to
those groups that one skilled in the field would readily recognize as being
suitable to protect the 4-position amine of a piperazinyl ring and which may
be
removed under typical deprotection conditions well known to those skilled in
2s the field as set forth in Greene and Wuts, Protecting Groups in 'Organic
S nthesis (John Wiley & Sons, New York 1991 ). For example, "amine-
protecting group" includes those protecting groups disclosed in EP 1 004 583
-15-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
A2, incorporated herein by reference, namely, Boc, CBZ, FMOC, benzyl, and
ethyloxycarbonyl. The term "amine-protecting group" as used herein does not
include -C2_4alkyl; -C~_4alkyl or C3_~cycloalkyl substituted with -C02H, -
S02H,
H
-~N~Ij . or C2_4alkyl substituted with
aryl, heteroaryl, or tetrazole, i.e., ~~
s alkoxy, N(alkyl)2, or heterocycle. The term "end-product substituent" means
a
substituent other than hydrogen that one skilled in the field would recognize
is
not an amine-protecting group as defined above. Thus, an "end-product
substituent" includes -C2_4alkyl; -C~_4alkyl substituted with -C02H, -S02H,
aryl,
heteroaryl, or tetrazole; or C2_4alkyl substituted with alkoxy, N(alkyl)2, or
1o heterocycle.
The compounds of formula (I) form salts which are also within the
scope of this invention. Unless otherwise indicated, reference to an inventive
compound is understood to include reference to salts thereof. The term
"salt(s)" denotes acidic and/or basic salts formed with inorganic and/or
organic
Is acids and bases. fn addition, the term "salt(s) may include zwitterions
(inner
salts), e.g., when a compound of formula (I) contains both a basic moiety,
such as an amine or a pyridine or imidazole ring, and an acidic moiety, such
as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic,
physiologically acceptable) salts are preferred, such as, for example,
2o acceptable metal and amine salts in which the cation does not contribute
significantly to the toxicity or biological activity of the salt. However,
other salts
may be useful, e.g., in isolation or purification steps which may be employed
during preparation, and thus, are contemplated within the scope of the
invention. Salts of the compounds of the formula (I) may be formed, for
2s example, by reacting a compound of the formula (I) with an amount of acid
or
base, such as an equivalent amount, in a medium such as one in which the
salt precipitates or in an aqueous medium followed by lyophilization.
-16-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Exemplary acid addition salts include acetates (such as those formed
with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid),
adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates,
bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates,
s cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates,
fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides
(formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates,
lactates, maleates (formed with malefic acid), methanesulfonates (formed with
io methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,
oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as those
formed
with sulfuric acid), sulfonates (such as those mentioned herein), tartrates,
thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the
is like.
Exemplary basic salts include ammonium salts, alkali metal salts such
as sodium, lithium, and potassium salts; alkaline earth metal salts such as
calcium and magnesium salts; barium, zinc, and aluminum salts; salts with
organic bases (for example, organic amines) such as trialkylamines such as
2o triethylamine, procaine, dibenzylamine, N-benzyl-(i-phenethylamine, 1-
ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-
ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically
acceptable amines and salts with amino acids such as arginine, lysine and the
like. Basic nitrogen-containing groups may be quaternized with agents such
2s as lower alkyl halides (e.g;, methyl, ethyl, propyl, and butyl chlorides,
bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and
diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyi and
stearyl
chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl
bromides), and others. Preferred salts include monohydrochloride,
3o hydrogensulfate, methanesulfonate, phosphate or nitrate.
-17-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Prodrugs and solvates of the inventive compounds are also
contemplated. The term "prodrug" denotes a compound which, upon
administration to a subject, undergoes chemical conversion by metabolic or
chemical processes to yield a compound of the formula (I), and/or a salt
s and/or solvate thereof. For example, compounds containing a carboxy group
can form physiologically hydrolyzable esters which serve as prodrugs by
being hydrolyzed in the body to yield formula (I) compounds per se. Such
prodrugs are preferably administered orally since hydrolysis in many
instances occurs principally under the influence of the digestive enzymes.
io Parenteral administration may be used where the ester per se is active, or
in
those instances where hydrolysis occurs in the blood. Examples of
physiologically hydrolyzable esters of compounds of formula (I) include C~_
6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C~_
6alkanoyloxy-C~_6alkyl, e.g. acetoxymethyl, pivaloyloxymethyl or
Is propionyloxymethyl, C~_salkoxycarbonyloxy-C~_6alkyl, e.g. methoxycarbonyl-
oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,
phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other
well known physiologically hydrolyzable esters used, for example, in the
penicillin and cephalosporin arts. Such esters may be prepared by
2o conventional techniques known in the art.
Compounds of the formula (I) and salts thereof may exist in their
tautomeric form, in which hydrogen atoms are transposed to other parts of the
molecules and the chemical bonds between the atoms of the molecules are
consequently rearranged. It should be understood that the all tautomeric
2s forms, insofar as they may exist, are included within the invention.
Additionally, inventive compounds may have traps and cis isomers and may
contain one or more chiral centers, therefore existing in enantiomeric and
diastereomeric forms. The invention includes all such isomers, as well as
mixtures of cis and traps isomers, mixtures of diastereomers and racemic
3o mixtures of enantiomers (optical isomers). When no specific mention is made
-18-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
of the configuration (cis, trans or R or S) of a compound (or of an asymmetric
carbon), then any one of the isomers or a mixture of more than one isomer is
intended. The processes for preparation can use racemates, enantiomers or
diastereomers as starting materials. When enantiomeric or diastereomeric
s products are prepared, they can be separated by conventional methods for
example, chromatographic or fractional crystallization. The inventive
compounds may be in the free or hydrate form.
Preferred Compounds
to Preferred compounds are those of formula (I) and/or pharmaceutically
acceptable salts thereof:
R4b
Y \ L
Z
R4a N
~ 5 ~r
~~M A
~~~R,
( s)r, (I)
wherein
Is A is a saturated, 4 to 7-membered monocyclic cycloalkyl or
heterocyclo;
Y is CH;
M is N or CH;
L and K are O;
2o Z is alkyl or substituted alkyl except when M is N, Z is not aryfalkyl or
heteroarylalkyl;
either T is CH and R~ is -Co_2alkylene-aryl, -O-Co_2alkylene-aryl, -S-Co_
2alkylene-aryl, -NR~o-Co_2alkylene-aryl, acyl-aryl, oxy-carbonyl-aryl, or
sulfonamide-aryl, or T is nitrogen and R~ is -Co_2alkylene-aryl, acyl-aryl, or
2s alkoxycarbonyl-aryl;
-19-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
R3 is alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, substituted
alkoxy, amino, alkylamino, acyl, alkoxycarbonyl, carbamyl, sulfonyl, or
sulfonamide;
R4a and R4b are each halogen;
s Rio is hydrogen, alkyl, or substituted alkyl;
nis0or1;
r is 1 or 2; and
s is 0, 1 or 2.
to More preferred are compounds where n is 0 such that R3 is absent.
Advantageously, in compounds of formula (I), where A is piperazine
and R~ is attached to the 4-position nitrogen atom of ring A (i.e., M is N, T
is
N, r is 1 and s is 2), R~ is preferably -C2alkylene-aryl; R~ is not an amine
is protecting group and thus is not benzyl or Boc.
More preferred compounds are those having formula (I), above, in
which
A is a saturated, 5 membered monocyclic ring (i.e., r and s are both 1) ;
2o M is N or CH;
L and K are both O;
Y is CH;
Z is hydrogen, lower alkyl, or lower alkyl substituted with hydroxy, lower
alkoxy, or halogen,
2s T is CH and R~ is -Co_2alkylphenyl, -O-Co_2alkylene-phenyl, -S-Co_
2alkylene-phenyl, -NR~o-Co_2alkylene-phenyl, acyl-phenyl, oxycarbonyl-phenyl,
or sulfonamide-phenyl, or T is N and R~ is -Co_2alkylene-phenyl, acyl-phenyl,
or alkoxycarbonyl-phenyl, and said R~ phenyl group has zero or one
-20-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
substituent selected from halogen, C~_4alkyl, nitro, cyano, hydroxy,
C1_4alkoxy,
-C02H, -C(=O)H, amino, and alkylamino; and
R4a and R4b are each chloro;
R1o is hydrogen or lower alkyl; and
s
to
n is 0 such that R3 is absent;
Most preferred compounds are (i) those having formula (la):
c1
I\ o
CI N
C ~N~R (la)
1
In WhICh
R1 is selected from
R11 ~ ~ R11 ~ ~ ~ R11
1$
and
(ii) those having the formula (1b):
CI
/
CI
(1b)
~o in which R1 is selected from:
-21-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
-O
R11 \ / R11
s
s
-S -NRIo
R11 ~ ~ ~ ~ R11
.
R11 ~
a
wherein in each of the compounds of formula (la) and (1b), R~~ is
selected from bromo, chloro, cyano, and methoxy, and Rio is selected from
s hydrogen and alkyl.
Methods of Pre~~aration
The compounds of the invention may be prepared by the exemplary
processes described in the following reaction schemes A to J. Exemplary
to reagents and procedures for these reactions appear hereinafter. Starting
materials are commercially available or can be readily prepared by one of
ordinary skill in the art, and/or modifications can be made to the methods of
Schemes A to J by one skilled in the art, using known methods. In the
schemes, the groups R~, R3, K and Z are defined as recited in the claims.
Is The group "R2" is used for ease of reference to describe the left-hand
phenyl
ring recited in the claims. Groups designated R', R", Z, P', and P" as well as
solvents, temperatures, pressures, and other reaction conditions, may readily
be selected as appropriate by one of ordinary skill in the art.
-22-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Scheme A
0 0
RZ NHZ * p~ ~ Rz N
O O O H
1 a 3 Rz-N N-R~
O H
SiMe3 Me3Si-~
HZN-R~ ~ CH- R~ ----~ ~ -R~
Me0
4 5 6
In Scheme A, an amine of formula 1 is reacted with malefic anhydride
2, as described for example in Org. Synth. (1961), 41, 93-5, to yield
s maleimide 3. An amine 4 is reacted with chloromethyltrimethylsilane to give
trimethylsilylmethylamine 5. This procedure can be conveniently carried out in
acetonitrile or in an alcohol in the presence of a base such as TEA, potassium
or sodium carbonate. Amine 5 is then condensed with formaldehyde in the
presence of MeOH to give methoxymethylamine 6. The latter can be
to condensed with maleimide 3 under acidic catalysis to give tetrahydro-
pyrrolo[3,4-c]pyrrole-1,3-dione of formula (lc). This reaction is carried out
advantageously using a catalytic amount of TFA in DCM.
20
-23-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Scheme B
O H O H O H
Rz-N N ~ Rz-N~NH ~ Rz-N~N--R~
O H ~ ~ O HH O HH
Ic (with R~ = Bn) 7 (lc)
O O H
O'~
Rz-N I + ~N-CPh3 ~ Rz-N' I ,N-CPh3
~O
O O H
3 8 9
In Scheme B, compound of formula (lc) where R~ is a benzyl group can
be debenzylated to give the N-unsubstituted molecule 7. Depending on the
nature of the group R2, this step can be carried out through a catalytic
s hydrogenation over Pd/C ~ in acetic acid or in alcohol, or by reaction with
1-
chloroethyl chloroformate in DCM. Compound 7 can also be obtained by
reaction of maleimide 3 with oxazolidinone 8 in refluxing toluene yielding 9
which is deprotected under acidic conditions, as described in Bull. Chem. Soc.
Jan. Vol. 60 (1987), at pp. 4079-89. Compound 9 can then be substituted by
io various electrophiles such as alkyl halides, alkyl mesylates or tosylates,
acyl
chlorides, or sulfonyl chlorides to yield the desired compounds of formula
(lc).
This compound can also be obtained by reductive amination of 7 with a
suitably functionalized aldehyde or ketone in the presence of a reducing agent
such as sodium triacetoxyborohydride in DCM or sodium cyanoborohydride in
Is acetonitrile.
-24-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Scheme C
O O R3"
HO C NH O
Rz-N~ + z a + Ra-N~~H
\//jj~ Rs Rs, Rs" //~/ (\H
O O Rs, Rs
11 14
R3~,
O O
HO C NH O
Rz-N 1 + a z + Ra-N~~-R~
IJ R3" R3 R3 J ~~~''~
O O R3, Rs
3 12 13 (~d)
Substituted tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione of formula (Id)
s can be obtained as depicted in Scheme C. Thus reaction of maleimide 3 with
an aminoacid 10 and an aldehyde 11 in a solvent such as acetonitrile gives
14. This transformation is described in J. Org. Chem. Vo. 53 (1988), pp. 1384-
91, and Tetrahedron Vol. 44 (1988), at 1523-34. The nitrogen atom of 14 can
then be substituted under classical conditions to give the desired compound
io of formula (Id). The same type of substitution pattern can also be obtained
by
the reaction of maleimide 3 with an aminoacide 12 and a ketone 13 in DMF at
100°C as described in Tetrahedron Lett. (1989), 30, at pp. 2841-44 or
Bull.
Chem. Soc. Jpn. (1987), 60, at pp. 4079-90.
Scheme D
O O O R
R O
Rz-N' I + N-R~ Ra-N N-R~
O Rs
R3
3 15 (1e)
Tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione of formula (1e) substituted by
a carbonyl group can be obtained by reacting maleimide 3 with aziridine 15 in
toluene or xylene (Scheme D), as described in J. Org. Chem. (1988), 53,
1882-7 or in Can. J. Chem. (1970), 48, 2215-26.
-25-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Scheme E
o
Me0 C .P RzN=C=K ,p
Z H~N ~ RZ-N~N
K-OorS
(R3)n ~ (R3)n
16 17
O O
Deprotection RZ_N~NH ~NiR~
~N~ ~ Rz-N/~~N
K (R3)n K (R3)n
18
Compounds having the formula (If) can be prepared as described in
s Scheme E. The monoprotected piperazine carboxylic acid ester 16 (see, e.g.,
Hu et al. Bioorg. Med. Chem. Lett. (1999), 9, at pp. 1121-6) is reacted with
either an isocyanate or an isothiocyanate in a solvent such as methylene
chloride or DMF in the presence of a base such as potassium carbonate,
sodium carbonate or TEA, to yield the hydantoin 17. The protecting group is
io removed to yield 1 ~, which can then be further substituted by reaction
with an
electrophile (allcylation, acylation, reaction with a sulfonyl chloride, etc.)
or by
reductive amination to yield the desired compound of formula (If).
Scheme F
OH OR'
BOC,N~ B-ITH~ . BOC.N
or
Me0 C Me0 C
DEADIPPh3 , R'OH z
19 20
OR' O OR'
H+ HN~~ RZN=C=K ~N
RZ ~N
MeO2C K = O or S K
21 (1g)
-26-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Protected hydroxy proline of formula 19 can be alkylated with R'X in
the presence of a base such as NaH in THF (as described for example in J.
Med. Chem., [1988], 31 (4), at pp. 875-885) or reacted with R'OH under
Mitsunobu conditions (as described for example in J. Med. Chem., [1988],
s 31 (6), pp. 1148-1160) to give 20. Deprotection of 20 under acidic
conditions
yields 21, which is then cyclized with an isocyanate R2NC0 or an
isothiocyanate R2NCS in the presence of a base such as K2C03 in a solvent
such as DCM or DMF (as described for example in Eur. J. Med. Chem.,
(1996), 31, pp. 717-713) to yield compounds of formula (1g).
io
Scheme G
OH OMs
BOC,N MsCI BOC, ~~
B-ITHF, R'SH
MeOZC DCM/TEA MeO~C
22 23
SR' SR' O SR'
BOC~ ~~ . HN ~N
RZN=C=K RZ ~N
Me0 C Deprotection Me0 C
K=OorS K
24 25 (1h)
Protected hydroxy proline of formula 22 can be esterified with mesyl
is chloride then reacted with a thiol of formula R'SH in the presence of a
base
such as NaH in THF (as described for example in J. Med. Chem. (1988),
31 (4), at pp. 875-885) to .give the thioether 24. Thioether 24 is deprotected
under acidic conditions to give 25. Cyclization of 25 with an isocyanate
R~NCO or an isothiocyanate RZNCS in the presence of a base such as K2C03
2o in a solvent such as DCM or DMF gives compounds of formula (1h).
-27-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Scheme H
0
H ~OH ~N OH
RzN=C=K
-N
Me02C ~ R2 27
K=OorS
26
oxidation
O,
H ~O RzN=C=K N O R~ ~N NR,R"
-~ R2~N + HN~ -
N
MeO2C K = O or S K R" Rz ' (i')
28 29 30 K
Hydroxy proline methyl ester of formula 26 can be cyclized with an
s isocyanate R2NC0 or an isothiocyanate R2NCS in the presence of a base
such as K2CO3 in a solvent such as DCM or DMF to give 27. Compound 27 is
oxidized in the presence of an oxidant such as pyridinium dichromate or
Dess-Martin periodinane in DCM to give 29. Alternatively, oxo proline methyl
ester of formula 28 (see for example, Bose, D. et al. Tetrahedron Lett.; 31;
47
io [1990] at pp. 6903-6906) can be cyclized with an isocyanate R2NCO or an
isothiocyanate R2NCS in the presence of a base such as K2CO3 in a solvent
such as DCM or DMF to give the oxohydantoin 29. Reductive amination of 29
with an amine of formula 30 in the presence of a reducing agent such as
sodium triacetoxyborohydride in DCM or sodium cyanoborohydride in
is acetonitrile under dehydrating conditions yields compounds of formula (Ii).
Scheme I
boc~ ~O OH OR"
~~~--'j' R'MgX boc~N~( R ~B_ boc,
R
.~ ~R'
MeOzC MeO2C/ MeOZC
_31 _32 33
OR" ~ OR"
H+ HN~( RzN=C=K N
--.-~ ~R' ~ R2-N R
Me02C/ K = O or S
K (1j)
34
-28-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Protected oxo proline methyl ester of formula 31 (see for example,
Barralough, P., et al., Tetrahedron (1995), 51 (14), at pp. 4195-4212) can be
reacted with a Grignard Reagent R'MgX (see for example, Tamaki M., et al.,
J. Org. Chem. (2001), 66, at pp. 3593-3596), to give 32. Compound 32 can
s be alkylated with R"X in the presence of a base to give 33, which is
deprotected to give 34. Cyclization of 34 with an isocyanate R2NC0 or an
isothiocyanate R~NCS in the presence of a base such as K2C03 in a solvent
such as DCM or DMF gives compounds of formula (1j).
Scheme J
OR ,
BOC,N OR BOC,N OR
H ~~
B-ITHF, ZX ~ H+
MeO2C ' MeOZC a MeO2C Z
20 35 _36
RzN=C=K
K=OorS
OR' O OR'
N B-ITHF, ZX ~N
Rz ~N ~ Rz
~N
K
K z
dig) (1k)
Scheme K
Z
ROzC' ~N,P' 1) Base ROzC~N~P~ Deprotection ROZC z ,P'
2) zX ~N~ --~ N
(Rs)~ P,. 3 H
(R )n
_16 _37 3$ ~R3)~
RzN=C=O
16
. P' Z . P'
Rz- ~N 1) Base Rz- ~N ~ z- ~N~R
~N~ 2) ZX ~N~ -~ R N~N
O (R3)n ~ O ~R3)n O ~h'3)n
17 39 (1k')
Protected substituted proline of formula 20 (Scheme J) can be
alkylated with R'X in the presence of a base such as LDA or LiHMDS in THF
-29-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
(as described, for example, in Khalil, Ehab M. et al., J. Med.Chem.; [1999],
42(4), pp628 - 637) to give 35. After deprotection under acidic conditions, 36
is cyclized with an isocyanate R2NC0 or an isothiocyanate R2NCS in the
presence of a base such as K2C03 in a solvent such as DCM or DMF (as
s described, for example, in Eur. J. Med. Chem., (1996), 31, pp. 717-713) to
yield compounds of formula (1k).
Alternatively, monocyclic compounds such as 16 (Scheme K) can be
substituted with Z groups other than hydrogen prior to cyclization, e.g., by
treatment at low temperature (-78°C) in a solvent such as THF with a
strong
io base such as LDA, potassium, lithium or sodium bis(trimethylsilyl)amide
(KHMDS, LiHMDS, NaHIVrDS) to generate enolates which can be reacted with
an electrophile ZX to give compounds having the desired Z groups.
The alkylation of other hydantoins to produce compounds of formula
(1k) or (1k') wherein Z is other than hydrogen can be performed as described
in
is Scheme J and K, e.g., with an alkyl halide in the presence of base such as
LDA or LiHMDS in THF. See also Seebach et al., J. Am Chem. Soc., Vol.
105(16) (1983) at pp. 5390-5398.
Each of the documents referenced above in the reactions schemes and
2o hereinafter (e.g, in the Examples) is incorporated herein by reference.
~Yennpi ~c
The following Examples illustrate embodiments of the inventive
2s compounds and starting materials, and are not intended to limit the scope
of
the claims. For ease of reference, the following abbreviations are used
herein.
Abbreviations
Me = methyl
MeOH = methanol
3o Et = ethyl
EtOH = ethanol
Bn = benzyl
t-Bu = tent-butyl
-30-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Boc = tert-butoxycarbonyl
CBZ = carbobenzyloxy
CDI = 1,1'-carbonyldiimidazole
DCM = dichloromethane
s DEAD = diethyl azodicarboxylate
DIAD = diisopropyl azodicarboxylate
DMF = dimethyl formamide
DMSO = dimethylsulfoxide
EDC (or EDC.HCI) or EDCI (or EDCI.HCI) or EDAC . 3-ethyl-3'
io (dimethylamino)propyl- carbodiimide hydrochloride (or 1-(3
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)
EtOAc = ethyl acetate
FMOC = 9-fluorenylmethyl carbamate
HOBT = 1-hydroxybenzotriazole hydrate
is HYP = trans-L-4-hydroxy-proline
ICHMDS = potassium bis(trimethylsilyl)amide
LDA = lithium diisopropylamide
LiHMDS = lithium hexamethyldisilazane
NaBH(OAc)3 = sodium triacetoxyborohydride
2o PDC = pyridinium dichromate
Pet. = petroleum
Ph = phenyl
Ph3P = triphenylphosphine
TEA = triethylamine
2s TFA = trifluoroacetic acid
THF = tetrahydrofuran
L = liter
mL = milliliter
~.L = microliter
3o g = grams)
mg = milligrams)
RT = room temperature
HPLC = high performance liquid chromatography
Mp = melting point
3s
Preparation 1
Trans-1-(3,5-dichloro-phenylcarbamoyl)-4-hydroxy-L-proline (2S,4R)
-31-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
OH
CI I ~ N N
,COON
CI
To a solution of HYP (1 g) (0.0076 mol) and KOH (1.05 g) (1 eq.) in 10
mL of water was added 3,5-dichlorophenyl isocyanate (1.42 g) (1 eq.) in
s portions. The reaction was stirred overnight and the insoluble material
removed by filtration. The aqueous phase was acidified with dilute NCI and
extracted with EtOAc. The combined organic extracts were washed with
water, dried over MgSO4, and evaporated under reduced pressure to afford
the above-titled compound as a white solid (1.8 g). NMR (CDCI3, 200MHz):
8.7 (1 H,NH), 7.65 (2H,d), 7.15 (1 H,m), 5.2 (1 H,OH), 4.25-4.45 (2H,m), 3.65
(1 H,dd), 3.42 (1 H,d), 2.05-2.25 (1 H,m), 1.85-2.05 (1 H,m).
Preparation 2
(7aS,6R)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro
~s pyrrolo[1,2-c]imidazole-1,3-dione
CI
O~
w ~ N~~..s
CI ~-N
O ~OH
1-(3,5-dichloro-phenylcarbamoyl)-4-hydroxy-L-proline (6.8 g) (0.021
mol) (Preparation 1) was combined with 35 mL of 1 N NCI and refluxed for 11
hrs. The organic oil was separated from the reaction mixture and dissolved in
EtOAc. The organic layer was washed with water, dried over MgS04, and
evaporated under reduced pressure. The resulting residue was purified on a
Si02 column (eluent: DCM/acetone-90/10) to afford the titled compound as a
white solid (3.2 g). NMR (CDC13, 200MHz): 7.4 (2H,d), 7.35 (1 H,m), 4.75
-32-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
(1 H,m), 4.60 (1 H,dd), 3.95 (1 H,dd), 3.35 (1 H,d), 2.75 (1 H,m,OH), 2.40
(1 H,dd), 1.80-1.95 (1 H,m).
Preparation 3
s (7aS,6S)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-
pyrrolo[1,2-c~imidazole-1,3-dione
CI
O
N~~-
CI ~-N~~~, OH
O
To a solution of cis-4-hydroxy-L-proline methyl ester (0.53 g) (0.0036
to mol) in 10 mL of DMF cooled at 0°C was added K2CO3 (0.52 g) (1.1
eq.), then
3,5-dichlorophenyl isocyanate (0.75 g) (1.1 eq.). The reaction was stirred
overnight at RT and the insoluble material removed by filtration. The solution
was concentrated under vacuum and the residue dissolved in DCM. The
organic layer was washed with water, dried over MgS04, and evaporated
is under reduced pressure. The resulting residue was purified on a Si02 column
(eluent: DCM/acetone-95/5) to afford the titled compound as a white solid
(0.25 g). NMR (CDC13, 200MHz): 7.35 (3H,s), 4.45 (1 H,m), 4.30 (1 H,dd), 4.0
(1 H,d), 3.1 (1 H,dd), 2.35-2.2 (2H,m), 1.95 (1 H,bs,OH).
' Preparation 4
2o Cis-4-(4-bromo-phenoxy)-L-proline methyl ester (4S,2S)
Br
O
HN
COOMe
-33-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
To a solution of trans-1-(Boc)-4-hydroxy-L-proline methyl ester (0.5 g)
(2 mmol), 4-bromophenol (0.52 g) (1.5 eq.) and Ph3P (0.78 g) (1.5 eq.) in 10
mL of dry THF at 0°C was added DEAD (0.47 mL) in a minimal volume of
THF. The reaction mixture was warmed to RT overnight. The solvent was
s removed in vacuo and the resulting residue suspended in ether. The solids
were removed by filtration and the solvent evaporated under reduced
pressure to afford after Si02 chromatography (eluent: cyclohexane/EtOAc -
9/1), cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester as a colorless
oil
(0.54 g). NMR (CDC13, 200MHz): 7.37 (2H,d), 6.70 (2H,d), 4.85 (1 H,m), 4.37-
io 4.6 (1 H,m), 3.6-3.85 (SH,m), 2.35-2.50 (2H,m), 1.4-1.5(9H). To a solution
of
cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester (0.54 g) in 8 mL of
DCM at 0°C was added 2.5 mL of TFA. The reaction mixture was
stirred at
0°C for 1 h and warmed to RT for an additional hour. The solvents were
evaporated in vacuo. The resulting residue was dissolved in water and the
is aqueous layer basified with aqueous NaHCO3 and extracted with EtOAc. The
combined organic extracts were washed with water, dried over MgS04, and
the solvent was evaporated under reduced pressure to afford the titled
compound as a colorless oil which solidified upon standing (0.39 g).
NMR (CDC13,200MHz): 7.35 (2H,d), 6.70 (2H,d), 4.8 (1 H,m), 3.92 (1 H,dd),
20 3.72 (3H,s), 3.35 (1 H,d), 3.1 (1 H,dd) 2.25-2.55 (2H,m).
Preparation 5
Trans-4-(4-bromo-benzyloxy)-L-proline methyl ester (2S,4R)
2s
R'
~i
O
HN
COOMe (p5)
The compound of formula (P5), wherein R' is 4-Bromo and the bonds
linking the benzyloxy and methyl ester groups (depicted in P5 as wavy bonds)
-34-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
define the traps, L-proline configuration (2S,4R) was prepared as follows. To
a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry
THF was added traps-N-Boc-4-hydroxy-L-proline methyl ester (0.5 g) in 5 mL
of dry THF. The reaction mixture was stirred for 45 minutes and a solution of
s 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The
reaction mixture was refluxed for 3 hours. After cooling to RT, the reaction
mixture was diluted with water and extracted with EtOAc. The aqueous layer
was acidified and extracted with DCM. The combined organic extracts were
washed with water, dried over MgS04, and evaporated under reduced
1o pressure to afford traps-N-Boc-4-(4-bromo-benzyloxy)-L-proline (0.25 g).
NMR (CDC13, 200MHz): 7.47 (2H,d), 7.2 (2H,d), 4.50-4.30 (3H,m), 4.25-4.1
(1 H,m), 3.75 (3H,s), 3.8-3.5 (2H,m), 2.5-2.3 (1 H,m), 2.15-1.95 (1 H,m), 1.5-
1.35 (9H).
SOC12 (0.27 ) was carefully added dropwise to 2.7 mL of MeOH at -
is 5°C. To this mixture was added traps-N-Boc-4-(4-bromo-benzyloxy)-L-
proline
(0.25 g) in 2.7 mL of MeOH. The reaction mixture was allowed to warm to
20°C and stirred overnight. The solvent was evaporated under reduced
pressure and the residue dissolved in DCM. The organic layer was washed
with water, dried over MgSO4, and evaporated in vacuo to afFord the above-
2o titled compound (60 mg). NMR (CDC13, 200MHz): 7.45 (2H,d), 7.2 (2H,d),
4.44 (2H,s), 4.15-4.05 (1 H,m), 4.0 (1 H,t), 3.7 (3H,s), 3.2-3.05 (2H,m), 2.27
(1 H,dd), 2.05-1.9 (1 H,m).
Preparations 6-8
2s Compounds having the above formula (P5), wherein R' has the values
listed in Table 1 and the wavy bonds linking the benzyloxy and methyl ester
groups define the isomers identified in Table 1, were produced using the
same or similar method as for Preparation 5.
TABLE 1
-35-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Example Stereo
No. R' isomer NMR (CDC13, 200MHz)
6 4-Br Cis,L 7.35 (2H,d)~ 7.05 (2H,d), 4.3 (2H,s),
4.15-3.9
(2S,4S) (1 H,m), 3.72 (1 H,t), 3.65 (3H,s),
3.15 (1 H,d),
2.85 (1 H,dd), 2.25-2.1 (2H,m).
7 4-(2-CN Cis,L 7.7-7.3 (BH,m), 4.4 (2H,s), 4.1-3.95
(1 H,m),
Phe) (2S,4S) 3.70 (1 H,dd), 3.60 (3H,s), 3.5 (NH),
3.20 (1 H,d),
2.4 (1 H,dd), 2.10-2.30 (2H,m)
8 3-Br Cis,L 7.5-7.35 (2H,m), 7.25-7.15 (2H,m),4.4
(2H,s),
(2S,4S) 4.1-4.0 (1 H,m), 3.35-3.2 (4H,m),
3.25 (1 H,d),
2.90 (1 H,dd), 2.6 (NH), 2.3-2.2
(2H,m)
Preparation 9
Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (2S,4R)
S02Me
;,,,0
Boc~N
Me00C
To a solution of trans-N-Boc-4-hydroxy proline methyl ester (17.6 g)
(0.072 mot) and TEA (12.5 mL) (0.09 mol) in 100 mL of DCM at 0°C was
slowly added methanesulfonyl chloride (7 mL) (0.09 mol). The temperature
was allowed to warm to 20°C, and the mixture was stirred overnight.
Insoluble
to material was removed by~ filtration and the organic layer washed with
water,
dried over MgS~4, and evaporated in vacuo to afford the above-titled
compound as an oil which solidified upon standing (24 g).
NMR (CDC13,200MHz): 5.22 (1 H,m), 4.32-4.5 (1 H,m), 3.5-3.9 (SH,m), 3.05
(3H,s), 2.5-2.73 (1 H,m), 2.15-2.35 (1 H,m), 1.35-1.5 (9H).
is
Preparation 10
Cis-4-(4-bromobenzyl thio)-L-proline methyl ester (2S,4S)
-36- '
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Br
S
HN
Me00C
To a solution of Na (0.25 g) (0.011 mol) in 3 mL of MeOH was added 4-
bromobenzyl mercaptan (2.2 g) (0.011 mol). The reaction mixture was stirred
for 1 h. Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (1.2 g)
s (0.0037mo1) (Preparation 9) was added and the mixture refluxed for 18 hrs.
Upon cooling to RT, 40 mL of water was added and the mixture was extracted
with EtOAc. The aqueous layer was acidified with 1 N HCI and extracted with
DCM. The combined organic extracts were washed with water, dried over
MgS04, and the solvent evaporated in vacuo to afford cis-N-Boc-4-(4-
io bromobenzyl thio)-L-proline (1.08 g). NMR (CDC13, 200MHz): 10.65
(1 H,COOH), 7.4 (2H,d), 7.15 (2H,d), 4.15-4.35 (1 H,m), 3.65 (2H,s), 2.95-3.35
(2H,m), 2.4-2.6 (1 H,m), 1.85-2.2 (1 H,m), 1.3-1.5 (9H). To a solution of cis-
N-
Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g) in 10 mL of MeOH was added
dropwise SOCK (0.2 mL), and the mixture was stirred for 72 hrs at RT. The
15 solvent was evaporated under reduced pressure and the residue dissolved in
DCM. The organic layer was washed with dilute aqueous NaHC03, water, and
dried over MgS04. The solvent was evaporated in vacuo to afford cis-4-(4-
bromo-benzylthio)-L-proline methyl ester (0.6 g).
2o Preparation 11
4-Chloro-N-[(trimethylsilyl)methyllbenzeneethanamine
I N
n
(P11)
The compound of formula (P11), wherein n = 2 and R" is chloro, was
2s prepared from a mixture of chloromethyltrimethylsilane (3.7 mL, 42.8 mmol),
-37-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
2-(4-chlorophenyl)ethylamine (10 g, 64.25 mmol), and K2C03 (4 g, 28.9 mmol)
in acetonitrile (80 mL). The reaction mixture was refluxed for 13 h and after
cooling, the precipitate was filtered off and the filtrate concentrated under
vacuum. The resulting oil was chromatographed over silica gel
s (CH2C12/MeOH/Et3N: 97/2/1 ) to yield the above-referenced compound as a
colorless oil (5.17 g). ~H NMR (CDC13): 7.25 (2H, d, J= 8.3 Hz), 7.12 (2H, d,
J
= 8.3 Hz), 2.7-2.9 (4H, m), 2.08 (3H, s), 0.95 (1 H, br s), 0.02 (9H,s).
Preparations 12-13
Compounds having the formula (P11), wherein n = 1 and R" has the
io values listed in Table 2, were produced using the same or similar method as
for Preparation 11, starting with an appropriately-substituted benzylamine.
TABLE 2
is
PreparationR" 'H NMR (CDC13)
No.~
12 OMe 7.23 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J
= 8.6 Hz), 3.80
(3H, s), 3.73 (2H, s), 2.03 (2H, s), 1.42
(1 H, br s), 0.03
(9H, s).
13 Br 7.40 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J
= 8.4 Hz), 3.70
(2H, s), 1.97 (2H, s), 1.22 (1 H, br s),
0.02 (9H, s).
Preparation 14
4-Chloro-N-(methoxymethyl) -N
[(trimethylsilyl)methyl]benzeneethanamine
home
R ~ ~ N~Si~
(P14)
The compound of formula (P14), in which n = 2 and R" is chloro, was
prepared from 4-chloro-N-[(trimethylsilyl)methyl]benzeneethanamine (5.17 g,
21.38 mmol) (Preparation 11), added dropwise to ice-cooled aqueous
2s formaldehyde (37% w/v, 2.3 g, 28.34 mmol). After 10 min., MeOH (3 mL, 74
-38-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
mmol) was added and the mixture stirred at 0°C for 3 h. Anhydrous K2C03
(1
g) was then added and the mixture stirred for 30 min at 0°C. The layers
were
separated and the aqueous phase extracted with t Bu methyl ether. The
combined organic layers were dried over MgS04 and concentrated to yield the
s titled compound as a pale yellow oil (6.35 g).'H NMR (CDC13): 7.21 (2H, d, J
= 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 4.03 (2H, s), 3.21 (3H, s), 2.8-2.9 (2H,
m),
2.65-2.8 (2H, m), 2.22 (2H, s), 0.03 (9H, s).
Preparations 15-16
~o Compounds having the formula (P14), wherein n = 1 and R" has the
values listed in Table 3, were produced using the same or similar method as
for Preparation 14, starting with an appropriately-substituted N-
[(trimethylsilyl)methyl]benzylamine.
TABLE 3
1s
PreparationR" 'H NMR (CDC13)
No.
15 OMe 7.24 (2H, d, J = 8.4 Hz), 6.85 (2H, d,
J = 8.4 Hz), 3.99
(2H, s), 3.80 (3H, s), 3.23 (3H, s), 2.18
(2H, s), 0.05
(9H, s).
16 Br 7.40 (2H, d, J = 8.4 Hz), 7.15 (2H, d,
J = 8.4 Hz), 3.96
(2H, s), 3.68 (2H, s), 3.20 (3H, s), 2.12
(2H, s), 0.02
(9H, s).
Preparation 17
20 2-(3,5-dichlorophenyl)-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3(2H,3a1~-dione
CI O H
N~NH
CI O HH
A solution of 5-benzyl-2-(3,5-dichlorophenyl)-tetrahydro-pyrrolo[3,4-
c]pyrrole-1,3(2H,3a1-~-dione (1.13 g, 3 mmol) in acetic acid (20 mL) was
-39-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
hydrogenated at atmospheric pressure over platinum oxide for 4h. The
catalyst was filtered off and the filtrate was poured into an ammonium
hydroxide solution. The aqueous solution was extracted twice with methylene
chloride. The organic layer was dried over sodium sulfate and concentrated in
s vacuo to give an oil (0.86 g) which was chromatographed over silica gel
(CH2C12/MeOH/NH40H: 90/9/1) to yield the above compound as a white solid
(0.53 g). Mp = 170°C. ~H NMR (DMSO-d6): 7.73 (1H, m), 7.47 (2H, m), 3.2-
3.5 (4H, m), 2.8-2.9 (2H,m).
to , Preparation 18
2-(3,5-Dichlorophenyl)-1,3-dioxo-hexahydro-imidazo[1,5-a]pyrazine-7
carboxylic acid tart butyl ester
ci
/ \ N,BOc
N NJ
15 C~ O
3,5-Dichlorophenyl isocyanate (2.85 g, 15.2 mmol) was added
portionwise to a mixture of piperazine-1,3-dicarboxylic acid 1-tart butyl
ester
3-ethyl ester (2.61 g, 10.1 mmol, prepared as described in Bioorg. Med.
2o ahem. Lett. 1999, 9, 1121-6) and potassium carbonate (1.68 g, 12.1 mmol) in
DCM (30 mL) at 5°C. After 30 min at 5°C, the reaction mixture
was stirred at
20°C for 48 h. The white precipitate was discarded and the filtrate
concentrated in vacuo to give an oil (5.5 g) which was chromatographed over
silica gel (CH2C12), to yield the above compound (2.77 g) as a white solid. Mp
25 = 144°C.
Preparation 19
2-(3,5-Dichlorophenyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione.
ci o
N~NH
~NJ
ci o
-40-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Methanesulfonic acid (2.1 mL, 32.7 mmol) was added to an ice-cold
solution of 2-(3,5-Dichlorophenyl)-1,3-dioxo-hexahydro-imidazo[1,5-
a]pyrazine-7-carboxylic acid tent butyl ester (2.62 g, 6.54 mmol, Prep. 18) in
methylene chloride (50 mL). After 1 h at RT, TEA (5mL, 36 mmol) was added.
s The reaction mixture was washed twice with water, dried over sodium sulfate
and concentrated in vacuo to yield the above compound (1.7 g) as a white
solid. Mp = 134 °C (crystallized from diethyl ether).
Preparation 20
io (7aS)-2-(3,5-dichloro-phenyl)-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3,6-trione
ci
O
N ~~~ee~
~V __0
To a solution of (7aS,6R)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione (11.3 g) (0.038 mol) (Preparation 2), in 185
is mL of DCM was added molecular sieves 3A (18 g) then PDC (33.5g) (0.093
mol). The reaction mixture was stirred for 72 h at RT, then the insoluble
material eliminated. After evaporating the solvent, the residue was purified
by
SiO2 chromatography (eluent: DCM/EtOAc 95/5) to afford the titled compound
as a white solid (7.3). NMR (CDC13, 200MHz): 7.45-7.35 (3H,m), 4.65
20 (1 H,dd), 4.25 (1 H,dd), 3.12 (1 H,dd), 2.97 (1 H,dd), 2.65 (1 H,dd).
Preparation 21
(2S,4S)-4-[(4-cyanophenyl)methoxy]-1,2-pyrrolidine-dicarboxylic acid 1
tert-butyl 2-methyl ester
2s
Me00C,,
boc~N~""~O w
~CN
-41-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
To a solution of trans-N-Boc-4-hydroxy-L-proline methyl ester (1.0 g)
(4mmol) and 4-bromomethyl benzonitrile (0.8 g) (4 mmol) in 20 mL of dry
DMSO was added powdered KOH (0.23 g) (4.5 mmol) in portions. The
mixture was stirred 4 hours at RT then poured in 100 mL of water and
s extracted with 150 mL of EtOAc. The organic layer was washed twice with
water, dried over sodium sulfate and concentrated in vacuo to yield an oily
residue (1.4 g) which was purified by Si02 chromatography (eluent:
DCM/MeOH 95/5) to afford the titled compound (0.4 g). NMR (CDC13,
200MHz): 7.6 (2H,d), 7.4 (2H,d), 4.55 (2H,s), 4.4 (1 H,m), 4.15 (1 H,m), 3.7-
3.55 (SH,s+m), 2.5-2.25 (2H,m), 1.5-1.4 (9H). The compound was
thensolubilized in 10 mL of DCM and treated with 0.8 mL of TFA at 0°C.
The
mixture was. stirred overnight at RT then washed with a dilute aqueous
solution of NaHCO3, then water, dried over sodium sulfate and concentrated
in vacuo to afford the titled compound (0.26 g) as an oil. NMR (CDC13,
is 200MHz): 7.55 (2H,d), 7.3 (2H,d), 4.45 (2H,s), 4.0 (1 H,m), 3.6 (3H,s),
3.25-3.1
(1 H,m), 2.9-2.7 (2H,m), 2.25-2.1 (2H,m).
Preparation 22
(S)-2-(3,5-diChloro-phenyl)-10,10x-dihydro-5H-imidazo-
[1,5-b]isoquinoline-1,3-dione
0
c1 ~ "", \
N N
O
CI
2s To a solution of L-tetrahydroisoquinoline-3-carboxylic acid,
hydrochloride (0.5 g) (2.3 mmol) and K2C03 (0.65 g) (2 eq.) in water (20 mL)
was added finely powdered 3,5-dichlorophenyl isocyanate (0.44 g) (1 eq.).
The reaction mixture was stirred for 48 h at RT, extracted with t-Bu methyl
-42-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
ether, and acidified with 1 N HCI. The resulting solid was filtrated, washed
with water, then dried to give 0.44 g of 1-(3,5-dichloro-phenylcarbamoyl)- L-
tetrahydroisoquinoline-3-carboxylic acid. (Mp = 234°C, NMR: CHC13,
200MHz, 8.6 (1 H,NH), 7.6 (2H,d), 7.2 (4H,m), 6.95 (1 H,m), 5.25 (1 H,m), 4.8
s (2H,dd), 3.1-3.45 (2H,m)). The carboxylic acid (0.44 g) was suspended in dry
toluene and conc. HZS04 (0.1 mL) added. The resulting reaction mixture was
heated to reflux until a clear solution was obtained. Insoluble material was
removed by filtration and the solution cooled to precipitate the cyclized
compound. The solid was collected by filtration to afford the titled compound
to (0.37 g). Mp = 243°C, NMR (CHC13, 200MHz): 7.45 (2H,d), 7.35 (1
H,m), 7.25
(4H,m), 5.1 (1 H,d), 4.5 (1 H,d), 4.25 (1 H,dd), 3.35 (1 H,dd), 3.0 (1 H,dd).
Preparation 23
is (2S,4R)-4-(4-Bromobenzyloxy)-2-methyl-proline methyl ester
Br
HN ,,,, O ~ I
~'s
MeOOC CH3
To a suspension of sodium hydride (60°!° in oil) (0.12 g)
(1.5 eq.) in 5
2o mL of dry THF was added (2S,4R)-N-Boc-4-hydroxy-2-methyl-proline methyl
ester (0.55 g) in 5 mL of dry THF. The reaction mixture was stirred for 45
min., and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5mL of dry
THF was added. The reaction mixture was refluxed for 3 h. After cooling to
RT, the reaction mixture was diluted with water and extracted with EtOAc.
2s The aqueous layer was acidified and extracted with DCM. The combined
organic extracts were washed with water, dried over MgS04 and evaporated
under reduced pressure to afford (2S,4R)-N-Boc-4-(4-bromo-benzyloxy)-2-
methyl-proline (0.25 g).
-43-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
SOC12 (0.27 mL) was carefully added dropwise to 2.7 mL of MeOH at
-5°C. To this mixture was added (2S,4R)- N-Boc-4-(4-Bromobenzyloxy)-2-
methyl-proline (0.25 g) in 2.7 mL of MeOH. The reaction mixture was allowed
to warm to 20°C and stirred overnight. The solvent was evaporated under
s reduced pressure and the residue dissolved in DCM. The organic layer was
washed with water, dried over MgS04, and evaporated in vacuo to afford the
titled compound (85 mg).
EXAMPIF1
to (7aS,6S)-2-(3,5-dichloro-phenyl)-6-(4-bromophenoxy)-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione
CI
O
Nil,,,
CI O~-N~, u0
~ Br
To a solution of (7aS,6R)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione (0.5 g) (1.67mmol) (Preparation 2), Ph3P
is (0.44 g) (1eq.) and 4-bromophenol (0.29 g) (1eq.) in 5 mL of dry THF at
0°C
was added DIAD (0.337 g) in a minimal volume of THF. The reaction mixture
was warmed to RT overnight. After evaporating the solvent, the residue was
dissolved in DCM, washed with NaHC03 solution, water, dried over MgS04,
and the solvent was evaporated under reduced pressure, to afford after Si02
2o chromatography (eluent: DCM) the titled compound as a white solid (50 mg).
Mp = 116°C. NMR (DMSO, 200MHz): 7.75 (1 H,m), 7.5-7.4 (4H,d+d),
6.85
(2H,d), 5.1 (1 H,m), 4.6 (1 H,dd), 3.95 (1 H,dd), 3.35 (1 H,dd), 2.7-2.5 (1
H,m),
2.25 (1 H,bd).
25 EXAMPLE 2
(7aS,6S)-2-(3,5-dichloro-phenyl)-6-(4-bromophenoxy)-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione
-44-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
CI
O
N ~ ,
CI ' ~-- N'~
O- ~v(CH2),r, II
()
The compound of formula (II), wherein R~~ is 4-bromo, m is 0, W = O,
and the bonds depicted as wavy bonds define the 7aS,6S stereoisomer, was
prepared as follows. To a solution of cis-4-(4-bromo-phenoxy)-L-proline
s methyl ester (0.2 g) (0.66 mmol) (Preparation 4) and K2C03 (0.09 g) (1 eq.)
in
mL of DMF at 0°C was added 3,5-dichlorophenyl isocyanate (0.12 g) (1
eq.). The reaction mixture was allowed to warm to 20°C and was stirred
overnight. After adding water, the mixture was extracted with EtOAc. The
combined organic extracts were washed with water, dried over MgS04, and
io evaporated under reduced pressure to afford after Si02 chromatography
(eluent: DCM), the above-titled compound (60 mg). Mp - 116°C.
NMR (DMSO, 200MHz): .7.75 (1 H,m), 7.5-7.4 (4H,d+d), 6.85 (2H,d), 5.1
(1 H,m), 4.6 (1 H,dd), 3.95 (1 H,dd), 3.35 (1 H,dd), 2.7-2.5 (1 H,m), 2.25 (1
H,bd).
~s EXAMPLES 3-9
Compounds having the formula (II), above, wherein m, R~~, and W .
have the values listed in Table 4 and the bonds depicted as wavy bonds
define the isomers identified in Table 4, were produced using the same or
similar method as for Example 2, starting with an appropriate methyl ester.
TABLE 4
Example R~~ W m Stereo-Mp NMR (CDC13, 200MHz)
No. .Isomer(C)
3 H O 1 7aR,6R 82 7.4-7.05 (BH,m), 4.5-4.2 (4H,m+dd),
4.1 (1 H,m), 3.05 (1 H,dd),
2.45-2.15
(2H,m)
4 4-Br S 1 7aS,6S 136 7.45 (2H,d), 7.35 (3H,m), 7.2
(2H,d),
4.32 (1 H,dd), 4.0-4.1 (1 H,m),
3.70
-45-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
(2H,s), 3.25-3.4 (2H,m), 2.45-2.65
(1 H,m), 2.0-2.15 (1 H,m)
4-Br O 1 7aS,6S 134 7.4 (2H,d), 7.35 (1 H,m),
7.0-7.15
(4H,m), 4.25-4.50 (4H,m),
4.15
(1 H,m), 3.05 (1 H,dd), 2.25-2.55
(2H,m)
6 4-Br O 1 7aR,6R 135 7.4 (2H,d), 7.35 (1 H,m),
7.0-7.15
(4H,m), 4.25-4.50 (4H,m),
4.15
(1 H,m), 3.05 (1 H,dd), 2.25-2.55
(2H,m)
7 4-CN O 1 7aS,6S 210 7.56 (2H,d), 7.34 (1 H,m),
7.30 (2H,d),
7.06 (2H,d), 4.55-4.30 (4H,dd+m),
4.20 (1 H,m), 3.10 (1 H,dd),
2.52-2.28
(2H,m)
8 3-Br O 1 7aS,6S Nd 7.5-7.35 (3H,m), 7.2-7.1 (4H,m),
4.5-
4.25 (4H,m), 4.2-4.1 (1 H,m),
3.06
(1 H,dd), 2.55-2.25 (2H,m)
9 4-(2- O 1 7aS,6S Nd 7.75 (1 H,d), 7.77.6 (1 H,m),
7.55-7.4
CN (4H,m), 7.4-7.2 (6H,m), 4.56
(1 H,d),
Ph) 4.45-4.3 (3H,m), 4.25-4.15
(1 H,m), 3.1
(1 H,dd), 2.55-2.25 (2H,m)
EXAMPLE 10
(7aS,6S)-2-(3,5-dichloro-phenyl)-6-(6-isoquinolinyl methoxy)-tetrahydro
pyrrolo[1,2-c]imidazole-1,3-dione
s
c1 o
N N~,"~~p
~N
CI
Using the same procedure as in Example 2, (7aS,6S)-2-(3,5-dichloro-
phenyl)-6-(6-isoquinolinyl methoxy)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-
to dione was obtained starting with the appropriate methyl ester. Mp =
144°C,
NMR (CDC13, 200MHz) 8.9 (1 H,dd), 7.95-8.05 (2H,m), 7.65-7.5 (2H,m), 7.37
(1 H,dd), 7.22 (1 H,m), 7.08 (2H,m), 4.65 (1 H,d), 4.53 (1 H,d), 4.45-4.3
(2H,m),
4.25 (1 H,m), 3.1 (1 H,dd), 2.6-2.25 (2H,m).
1s EXAMPLE 11
5-[2-(4-Chlorophenyl)ethyl]-2-(3,5-dichlorophenyl)tetrahydropyrrolo[3,4
c]pyrrole-1,3(2H,3ah~-dione
-46-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
CI
O
R1~
CI
O H ~l m _ (lm)
To prepare the compound of formula (lm), wherein R~~ is chloro and m
s is 2, TFA (32 p1, 0.41 mmol) was added to an ice-cooled mixture of 4-chloro-
N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzeneethanamine (1.5 g, 5.25
mmol) (Preparation 14) and N-(3,5-dichlorophenyl)succinimide (1 g, 4.13
mmol, prepared according to Fujinami et al., Agr. Biol. Chem. [1972], p. 318,
incorporated herein by reference) in methylene chloride (10 mL). The reaction
io mixture was allowed to warm to RT over 3 h. The solution was washed with
ammonium hydroxide. The organic layer was dried over MgS04 and
concentrated in vacuo to afford after chromatography over silica gel (CH2C12)
the above-referenced compound as a white solid (1.56 g). Mp = 115°C. ~H
NMR (CDC13): 7.40 (1 H, br s), 7.15-7.35 (4H, m), 7.07 (2H, d, J = 8.3 Hz),
3.4
is 3.5 (2H, m), 3.3-3.4 (2H, m), 2.55-2.8 (4H, m), 2.35-2.5 (2H, m).
EXAMPLES 12-14
Compounds having the formula (lm), above, wherein m is 1 and R~~
has the values listed in Table 5 were produced using the same or similar
2o method as for Example 11, starting with an appropriately-substituted N-
(methoxymethyl)-N-[(trimethylsilyl)methyl]benzenemethanamine.
TABLE 5
Example R~~ ~H NMR (CDC13) Mp (C)
No.
12 H 7.40 (1 H, m), 7.2-7.35 (7H, m), 145
3.63 (2H, s),
3.39 (2H, d, J = 9.9 Hz), 3.2-3.35
(2H, m), 2.4-
2.55 (2H, m).
13 OMe 7.41 (1 H, br s), 7.27 (2H, br s), 82
7.14 (2H, d, J =
8.4 Hz), 6.85 (2H, d , J = 8.4 Hz),
3.80 (3H, s),
-47-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
3.57 (2H, s), 3.25-3.45 (4H, m), 2.46
(2H, br t).
14 Br 7.35-7.55 (3H, m), 7.27 (2H, br s), 152
7.10 (2H, d,
J = 8.3 Hz), 3.57 (2H, s), 3.25-3.5
(4H, m),
2.35-2.55 (2H, m).
EXAMPLE 15
s 7-[2-(4-Bromophenyl)ethyl]-2-(3,5-dichlorophenyl)-tetrahydro-
imidazo[1,5-a]pyrazine-1,3-dione
/Br
CI
N
N NJ
CI
~o A mixture of 1-bromo-4-(2-bromoethyl)benzene (101 mg, 0.38 mmol,
prepared as described in Synth.Commun [1996], 26, pp. 1467-1472), 2-(3,5-
dichlorophenyl)-tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione (100 mg, 0.33
mmol, Prep. 19), potassium carbonate (48 mg, 0.35 mmol) and sodium iodide
(10 mg, 0.06 mmol) in methyl isopropyl ketone (2 mL) was heated at
100°C
is for 48 h. The precipitate was discarded and the filtrate was concentrated
under vacuum and chromatographed over silica gel (CH2C12). The obtained oil
was treated with Et20/HCI to yield the hydrochloride of 7-[2-(4-
bromophenyl)ethyl]-2-(3,5-dichlorophenyl)-tetrahydro-imidazo[1,5-a]pyrazine-
1,3-dione as a white solid (60 mg). ~H NMR (CDC13) of the free base: 7.25-7.4
20 (5H, m), 7.00 (2H, d, J = 8.3 Hz), 4-4.15 (2H, m), 3.32 (1 H, dd, J~ = 4.1
Hz, J2
= 11.1 Hz), 3.09 (1 H, dt), 2.87 (1 H, br d), 2.5-2.8 (4H, m), 1.95-2.15 (2H,
m).
EXAMPLE 16
2s 7-[2-(4-Bromophenyl)'-1-methyl-2-oxo-ethyl]-2-(3,5-dichlorophenyl)-
tetrahydro-imidazo[1,5-a]pyrazine-1,3-dione
Br
CI O
~N
N~N J O
CI //O
-48-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Using the same procedure as in Example 15, 7-[2-(4-bromophenyl)-1-
methyl-2-oxo-ethyl]-2-(3,5-dichlorophenyl)-tetrahydro-imidazo[1,5-a]pyrazine-
1,3-dione was obtained. ~H NMR (CDC13): 7.85-8.0 (2H, m), 7.62 (2H, d), 7.3-
s 7.5 (3H, m), 4-4.4 (3H, m),, 3.4-3.55 (1 H, m), 2.9-3.3 (2H, m), 2.6-2.8 (1
H, m),
2.3-2.5 (1 H, m), 1.25-1.4 (3H, m). Hydrochloride: Mp = 230-235 °C.
EXAMPLE 17
to (7aS,6S)-4-~[2-(3,5-dichloro-phenyl)-1,3-dioxo-hexahydro-pyrrolo[1,2-
c]imidazol-6-ylamino~-methyl}-benzonitrile
CI
O
C I ~--N ,"", W ~ i R11
(CH2)m (In)
The compound of formula (In), wherein R~~ is 4-cyano, m is 1, W = NH,
is and the bonds depicted as wavy bonds define the 7aS,6S stereoisomer, was
prepared as follows. To a solution of (7aS)-2-(3,5-dichloro-phenyl)-
tetrahydro-pyrrolo[1,2-c]imidazole-1,3,6-trione (0.5 g) (0.0017mo1)
(Preparation 20), in 50 mL of DCM was added molecular sieves 4A, 4-
cyanobenzyl amine (0.27 g) (0.002 mol), then NaBH(OAc)3 (0.54 g) (0.00255
2o mol.). The reaction mixture was stirred overnight at RT and then the
insoluble
material eliminated. After evaporating the solvent, the residue was purified
by
SiO2 chromatography (eluent: DCM/MeOH 98/2) to afford the titled compound
and its stereoisomer. 7aS,6S stereoisomer (70mg). NMR (CDC13, 200MHz):
7.45 (2H,d), 7.3 (1 H,m), 7.2-7.1 (4H,m), 4.25 (1 H,dd), 4.05 (1 H,d), 3.65
2s (2H,dd), 3.4(1 H,m), 3.02 (1 H,dd), 2.35-2.2 (1 H,m), 2.0 (1 H,bd).
EXAMPLES 18-22
Compounds having the formula (In), above, wherein m, R11, and W
have the values listed in Table 6 and the bonds depicted as wavy bonds
-49-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
define the isomers identified in Table 6, were produced using the same or
similar method as for Example 17, starting with an appropriate amine.
TABLE 6
Example R~~ W m Stereo- NMR (CDC13, 200MHz)
No. Isomer
18 4-Br NMe 1 7aS,6S 7.41-7.34 (SH,m), 7.08 (2H,d),
4.31
(1 H,dd), 4.05 (1 H,d), 3.45 (2H,s),
3.35-
3.15 (2H,m), 2.43-2.05 (2H,m),
2.1 (3H,s)
19 4-Br NH 2 7aS,6S 7.40-7.35 (SH,m), _7.0 (2H,d),4.25
(1 H,dd),
4.0 (1 H,d), 3.35(1 H,m), 3.05
(1 H,dd),
2.85-2.5 (4H,m), 2.35-2.2 (1 H,m),
2.0
(1 H,bd).
20 4-Br NH 3 7aS,6S 7.45-7.35 (SH,m), 6.97 (2H,d),4.28
(1 H,dd), 3.95 (1 H,d), 3.35(1
H,m), 3.05
(1 H,dd), 2.65-2.45 (4H,m), 2.35-2.2
(1 H,m), 2.0 (1 H,bd), 1.75-1.55
(2H,m).
21 4-CN NEt 1 7aS,6S 7.55 (2H,d), 7.4-7.3 (SH,m), 4.3
(1 H,t), 3.9
(1 H,dd), 3.7-3.55 (4H,s+m), 3.37
(1 H,dd),
2.65-2.5 (2H,m), 2.45-2.3 (1 H,m),
2.15-2.0
(1 H,m), 1.0 (3H,t)
22 4-CN NPr 1 7aS,6S 7.55 (2H,d), 7.45-7.3 (SH,m),
4.25 (1 H,t),
3.85-3.6 (4H,s+m), 3.4 (1 H,dd),
2.5-2.3
(2H,m), 2.05-1.9 (1 H,m), 2.15-2.0
(1 H,m),
1.5-1.3 (2H,m), 0.8 (3H,t)
s
EXAMPLE 23
(7aS,6S)-N-(4-cyano-benzyl)-N-[2-(3,5-dichloro-phenyl)-1,3-dioxo
hexahydro-pyrrolo[1,2-c]imidazol-6-yl]-acetamide
CI
O
1 NJ~I.e,
CI ~N~,,,N ' w
O '~CN
1 o Ac
To a solution of (7aS,6S)-4-{[2-(3,5-dichloro-phenyl)-1,3-dioxo-
hexahydro -pyrrolo[1,2-e]imidazol-6-ylamino]-methyl)-benzonitrile (13 mg)
(0.0313 mmol) (Ex. 17) in 0.5 mL of DCM was added 10 p1 (2.2 eq.) of TEA,
~s then 6 pi of acetyl chloride (2eq.) at RT and the mixture stirred 1 h. The
organic layer was washed with water, dried over MgS04, and evaporated in
vacuo to afford the above-titled compound as an oily residue (6 mg).
-50-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
NMR (CDCI3,200MHz): 7.69 (2H,d), 7.45 (2H,m), 7.35 (1 H,m), 7.29 (2H,d),
4.57 (2H,s), 4.35-4.2 (2H,m), 3.9 (1 H,dd), 3.45 (1 H,dd), 2.5-2.3 (2H,m), 2.1
(3H,s)
EXAMPLE 24
(6R,7aS)- [6-(4-bromobenzyloxy)-2-(3,5-dichlorophenyl)-1,3-dioxo-
tetrahydro-pyrrolo[1,2-c]imidazol-7a-yl]-acetic acid methyl ester
Br
ci ~~~~~''''o
~ N~N
I IO
C! (lo)
The compound of formula (lo), wherein Z is methoxycarbonylmethyl
and the bonds depicted as wavy bonds define the 7aS,6R stereoisomer, was
prepared as follows. 1.65 mL of a solution of LDA (1 M) in THF (1.5 eq.) was
added to a solution of (7aR,6R)-2-(3,5-dichloro-phenyl)-6-(4-
is bromobenzyloxy)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (500 mg) (1.1
mmol) (Ex. 6) in 5 mL of dry THF cooled to -65°C under nitrogen. The
reaction mixture was stirred for 1 h then treated with a solution of methyl
bromoacetate (340 mg) (2 eq.) in 3 mL of THF. After 1 h at -65°C, the
reaction
mixture was allowed to warm to -20°C, stirred for 2 h, and then poured
in a
2o mixture of water/EtOAc (1:1, 2 0 mL). The organic layer was washed with
water, dried over MgSOa, and evaporated under reduced pressure. The
resulting oily residue was purified over Si02 column (25 g) (eluent
EtOAc/cyclohexane 3/7) to afford the above-titled compound (28.8 mg) as a
foam. NMR (CDC13, 200MHz): 7.43 (2H,d), 7.35 (1 H,m), 7.15-7.0 (4H,m), 4.4-
2s 4.2 (3H,dd+m), 4.15 (1 H,m), 3.7 (3H,s), 3.2-3.0 (2H,dd+d), 2.75 (1 H,d),
2.52
(1 H,dd), 2.05 (1 H,dd).
EXAMPLES 25-26
-51-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
Compounds having the formula (lo), above, wherein Z has the values
listed in Table 7 and the bonds depicted as wavy bonds define the isomers
identified in Table 7 were produced using the same or similar method as for
Example 24 starting with an appropriate alkylating agent.
TABLE 7
Example Z Stereo-H NMR (CDC13)
No. Isomer
25 Me 7aR,6R 7.4 (2H,d), 7.33 (1H,m),_7.15-7.05
(4H,d+d),
4.45-4.2 (3H,dd+m), 4.15 (1 H,m),
3.1 (1 H,dd),
2.55 (1 H,dd), 1.93 (1 H,dd), 1.55
(3H,s)
26 CH20H 7aR,6S 7.45 (2H,d), 7.35 (2H,m), 7.15 (2H,d),
7.05
(1 H,m), 6.95 (OH), 4.65-4.5 (2H,m),
4.35 (1 H,d),
4.25 (1 H,m), 3.75-3.55 (2H,m), 2.9-2.7
(1 H,m),
2.3-2.1 (1 H,m)
EXAMPLES 27
io 5-[2-(4-Bromophenyl)-2-oxoethyl]-2-(3,5-dichlorophenyl)-
tetrahydropyrrolo(3,4-c]pyrrole-1,3-dione
CI
N \N
Br
CI O H O
is To a suspension of 2-(3,5-dichlorophenyl)-tetrahydro-pyrrolo[3,4-
c]pyrrole-1,3(2H,3a1~-dione hydrochloride (100 mg, 0.31 mmol) (Preparation
17) in ' DCM (2 mL) was added TEA (150 p1), followed by 2-4'-
dibromoacetophenone (95 mg, 0.34 mmol) in DCM (2 mL). After 24h at RT,
the solvent was removed and the residue chromatographed over silica gel
20 (eluent: DCM/acetone 95/5). The resulting oil was crystallized in ether to
yield
the above compound as a white solid (38 mg), Mp = 150°C.
EXAMPLE 28
2s 2-(3,5-Dichlorophenyl)-5-naphthalen-2-ylmethyl-tetrahydropyrrolo[3,4-
c]pyrrole-1,3-dione
-52-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
CI O
CI O
NaBH(OAc)3 (25.4 mg, 0.12 mmol) in DCM (1 mL) was added to a
solution of Preparation 17 (17.1 mg, 0.06 mmol) and 2-naphthaldehyde (14
s mg, 0.09 mmol) in DCM (0.4 mL). After 24h at RT, the product was purified
over an SCX cartridge to yield Example 29 above (20.5 mg). LC Mass:
retention time 2.58 min, MW: 466 (M+41, M+CH3CN).
EXAMPLE 29
io
(7aS,6S)-2-(3,5-dichloro-phenyl)-6-(4-bromobenzoyloxy)-tetrahydro-
pyrrolo[1,2-c~imidazole-1,3-dione
c1
0
0
c1
~' Br
is To a solution of (7aS,6S)-2-(3,5-dichloro-phenyl)-6-hydroxy-tetrahydro-
pyrrolo[1,2-c]imidazole-1,3-dione (0.6 g) (0.002 mol) (Preparation 3) and TEA
(0.2 mL) (0.002 mol) in 10 mL of DCM at 0°C was slowly added 4-
bromobenzoyl chloride (0.44 g) (0.09 mol) in 5 mL of DCM. The temperature
was allowed to warm to 20°C, and the mixture was stirred overnight. The
20 organic layer was washed with water, NaHC03 solution, water, dried over
MgS04, and evaporated in vacuo to afford after Si02 chromatography (eluent:
DCM/Pet.Ether - 50/50) the above-titled compound as a white solid (0.24 g).
NMR (CDCI3,200MHz): 7.68 (2H,d), 7.50 (2H,d), 7.38 (1H,m), 7.25 (2H,d),
5.55 (1 H,m), 4.46 (1 H,dd), 4.36 (1 H,d), 3.38 (1 H,dd), 2.65-2.59 (2H,m).
EXAMPLE 30
10a-(4-Bromo-benzyl)-2-(3,5-dichloro-phenyl)-10,10a-dihydro-5H
-53-
CA 02436943 2003-05-30
WO 02/44181 PCT/USO1/45540
imidazo[1,5-b]isoquinotine-1,3-dione
c~
s To a solution of (S)-2-(3,5-dichloro-phenyl)-10,10a-dihydro-5H-
imidazo[1,5-b]isoquinoline-1,3-dione (100 mg) (0.1 mmol) (Prep. 22) in 2.5 mL
of dry THF at -4.0°C was added a 1 M solution of LiHMDS (0.5 mL) in
THF.
The reaction mixture was stirred for 15 min. at -4.0°C and a
solution of 4-
bromobenzyl bromide (70 mg) in 1 mL of dry THF was added. The reaction
to mixture was stirred at~-50 °C for 30 min., allowed to warm to RT,
stirred
overnight, then partitioned between brine and t-Bu methyl ether. The organic
layer was dried over MgS04, concentrated in vacuo, and the residue purified
by HPLC to afford the above compound (34.5 mg). NMR (CDC13, 200MHz):
7.45 (2H,d), 7.25-7.35 (SH,m), 6.95-7.0 (4H,d+d), 5.15 (1 H,d), 4.55 (1 H,d),
1s 3.25 (2H,s), 3.20 (1 H,d), 2.95 (1 H,d).
-54-