Note: Descriptions are shown in the official language in which they were submitted.
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WO 96/21654 PCTJ~S96JDlD94
NOVEL COMPOUNDS
This invention relates to a novel group of imidazole compounds, processes for
the preparation thereof, the use thereof in treating cytokine mediated diseases and
10 pharmaceutical compositions for use in such therapy.
~3ACKGROUND OF TH~ INVENTION
Interleukin-l (IL-l) and Tumor Necrosis Factor (TNF) are biological substances
produced by a variety of cells, such as monocytes or macrophages. IL- 1 has been15 demonstrated to mediate a variety of biological activities thought to be important in
immunoregulation and other physiological conditions such as infl:~mm~tion [See, e.g.,
Dinarello et al., Rev. Infect. Disease. 6, 51 (1984)]. The myriad of known biological
activities of IL-I include the activation of T helper cells, induction of fever, stimulation
of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute
20 phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL- 1 productionis implicated in exacerbating and/or causing the disease. These include rheumatoid
arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or
chronic infl~mm~tory disease states such as the infl~mm~tory reaction induced by25 endotoxin or infl~mm~tory bowel disease; tuberculosis, atherosclerosis, muscle
degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout,
traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL- 1
activity to diabetes and pancreatic 13 cells.
Dinarello, J. Clinical Immunology. 5 (5), 287-297 (1985), reviews the biological30 activities which have been attributed to IL-1. It should be noted that some of these
effects have been described by others as indirect effects of IL-l.
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WO 96/21654 PCT/US96/01094
- 2 -
Excessive or unregulated TNF production has been implicated in mediating or
exacerbating a number of diseases including rheumatoid arthritis, rheumatoid
spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic
shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory O
S distress syndrome, cerebral m~ , chronic pulmonary infl~mm~tory disease, silicosis,
pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host
reaction, allograft rejections, fever and myalgias due to infection, such as influenza,
cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune
deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation,
10 scar tissue forrnation, Crohn's disease, ulcerative colitis, or pyresis.
AIDS results from the infection of T Iymphocytes with Human
Immunodeficiency Virus (HIV). At least three types or strains of HIV have been
identified. i.e., HIV- 1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell
mediated immunity is impaired and infected individuals manifest severe opportunistic
15 infec~ions and/or unusual neoplasms. HIV entry into the T lymphocyte requires T
lymphocyte activation. Other viruses, such as HIV-l, HIV-2 infect T lymphocytes after
T Cell aclivation and such virus protein expression and/or replication is mediated or
m~int~ined by such T cell activation. Once an activated T lymphocyte is infected with
HIV, the T lymphocyte must continue to be maintained in an activated state to permit
20 HIV gene expression and/or HIV replication. Monokines, specifically TNF, are
implicated in activated T-cell mediated HIV protein expression and/or virus replication
by playing a role in maintaining T lymphocyte activation. Therefore, interference with
monokine activity such as by inhibition of monokine production, notably TNF, in an
HIV-infected individual aids in limiting the maintenance of T cell activation, thereby
25 reducing the progression of HIV infectivity to previously uninfected cells which results
in a slowing or elimination of the progression of immune dysfunction caused by HIV
infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells,
have also been implicated in maintenance of the HIV infection. These cells, likeT-cells, are targets for viral replication and the level of viral replication is dependent
30 upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis
of HIV Infection, Advances in Immunology, Vol. 57, (1989)]. Monokines, such as
TNF, have been shown to activate HIV replication in monocytes and/or macrophages[See Poli. et al.. Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of
monokine production or activity aids in limiting HIV progression as stated above for
35 T-cells.
TNF has also been implicated in various roles with other viral infections, such as
the cytomegalia virus (CMV), influenza virus. and the herpes virus for similar reasons
as those noted.
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WO 96/216~4 PCTIUS96101094
- 3 -
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in
1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts,
endothelial cells, and keratinocytes. Its production from endothelial cells is induced by
IL-l, TNF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse,
Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have been applied to
IL-8, such as neutrophil attractant/activation protein-l (NAP-l), monocyte derived
neutrophil chemotactic factor (MDNCF). neutrophil activating factor (NAF), and T-cell
lymphocyte chemotactic factor.
IL-8 stimulates a number of functions in vitro. It has been shown to have
10 chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it
induces histamine release from basophils from both normal and atopic individuals as
well as lyso~omal enzyme release and respiratory burst from neutrophils. IL-8 has also
been shown to increase the surface expression of Mac-l (CDl lb/CDl 8) on neutrophils
without de novo protein synthesis, this may contribute to increased adhesion of the
15 neutrophils to vascular endothelial cells. Many diseases are characterized by massive
neutrophil infiltration. Conditions associated with an increased in IL-8 production
(which is responsible for chemota~cis of neutrophil into the infl~mm~lory site) would
benefit by compounds which are suppressive of IL-8 production.
IL-I and TNF affect a wide variety of cells and tissues and these cytokines as
20 well as other leukocyte derived cytokines are important and critical infl~mmatory
mediators of a wide variety of disease states and conditions. The inhibition of these
cytokines is of benefit in controlling, reducing and alleviating many of these disease
states.
There remains a need for treatment, in this field, for compounds which are
25 cytokine suppressive anti-infl~mm~tory drugs, i.e. compounds which are capable of
inhibiting cytokines, such as IL-l,IL-6,IL-8 and TNF.
SUMMARY OF THE INVENTION
This invention relates to the novel compounds of Formula (I) and
30 ph~rmaceutical compositions comprising a compound of Formula (I) and a
pharrnaceutically acceptable diluent or carrier.
This invention also relates to a method of inhibiting cytokines and the treatment
of a cytokine mediated disease, in a m~mm~l in need thereof, which comprises
a~lministering to said m~mm~l an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production
of IL-l in a m~mm~l in need thereof which comprises admini.~tering to said m~mm~l an
effective amount of a compound of Formula (I).
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WO 96/21654 PCT/US96/0109 1
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This invention more specifically relates to a method of inhibiting the production
of IL-8 in a m~mm~l in need thereof which comprises ~tlmini.~tering to said mammal an
effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production
S of TNF in a m:~mm~l in need thereof which comprises a(1mini.ctering to said m~mm~l an
effective amount of a compound of Formula (I).
Accordingly, the present invention provides for a compound of the Formula:
1 2
Rl N
~>
R--N
4 (I)
wherein
Rl is 4-pyridyl, pyrimidinyl, (luinolyl, isoquinolinyl, quinazolin-4-yl, I-imidazolyl or
l-benzimidazolyl, which ring is optionally substituted with one or two substituents
each of which is independently selected from C 1-4 alkyl, halogen, hydroxyl, C 1-4
alkoxy, C1 4 alkylthio, Cl 4 alkylsulfinyl, CH2OR12, amino, mono and di- C1-6
alkyl substituted amino, N(R1o)C(O)Rc or an N-heterocyclyl ring which ring has
from 5 to 7 members and optionally contains an additional heteroatom selected from
oxygen, sulfur or NR15;
R4 is phenyl, naphth- I -yl or naphth-2-yl, or a heteroaryl, which is optionally substituted
by one or two substituents, each of which is independently selected, and which, for a
4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substitiuent, is halogen,
cyano, nitro, -C(Z)NR7R 17, -C(Z)OR 16, -(CR 1 oR20)VCOR 12, -SRs, -SORs,
-OR 12. halo-substituted-C 1-4 alkyl, C 1-4 alkyl, -ZC(Z)R 12, -NR I oC(Z)R 16, or
-(CRloR20)vNR IoR2o and which, for other positions of substitution, is halogen,
cyano, -C(Z)NR13R14, -C(Z)OR3, -(CRloR2o)m~coR3~ -S(O)mR3, -OR3, halo-
substituted-Cl 4alkyl,-C1 4alkyl,-(CRloR2o)mllNRloc(z)R37-NRlos(o)m~Rg,
-NRlos(o)m~NR7Rl7. -ZC(Z)R3 ~r-(CRl0R20)m''NR13R14;
v is 0, or an integer having a value of I or 2;
m is 0, or the integer I or 2;
m' is an integer having a value of 1 or 2,
m" is 0, or an integer having a value of I to 5;
Rc is hydrogen, C1 ~ alkyl, C3 7 cycloalkyl, aryl, arylCI 1 alkyl, heteroaryl,
heteroarylC 1 4alkyl, heterocyclyl, or heterocyclylC I 4alkyl C 1-4 alkyl;
R2 is an optionally substituted C3 7 cycloalkyl, or C3 7cycloalkylCl lo alkyl;
R3 is heterocyclyl, heterocyclylCl lo alkyl or R8;
Rs is hydrogen, C 1-4 alkyl, C2 4 alkenyl, C2 4 alkynyl or NR7R 17, excluding the
moeities -SRs being -SNR7R17 and -SORs being -SOH;
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R7 and R 17 is each independently selected from hydrogen or C 1-4 alkyl or R7 and R 17
together with the nitrogen to which they are attached form a heterocyclic ring of 5 to
7 members which ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NR 15;
R8 is C 1 l o alkyl, halo-substituted C 1- l o alkyl, C2- 10 aL~enyl, C2 l o alkynyl, C3 7
cycloalkyl, C5 7 cycloalkenyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylCl lo
alkyl, (CR10R20)noRl 1, (cRloR2o)ns(o)mRl8~ (CRl0R20)nNHS(O)2R18~
(CRloR20)nNR13R14; wherein the aryl, arylaL~yl, heteroaryl, heteroaryl alkyl maybe optionally substituted;
n is an integer having a value of 1 to 10;
Rg is hydrogen, -C(Z)Rl 1 or optionally substituted Cl lo alkyl, S(O)2Rlg, optionally
substituted aryl or optionally substituted aryl-C1 4 alkyl;
R 10 and R20 is each independently selected from hydro~en or C 1-4 alkyl;
Rl 1 is hydrogen. or R18;
Rl2 is hydrogen or R16;
R1 3 and R14 is each independently selected from hydrogen or optionally substituted
C 1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 aL~yl, or
together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7
members which ring optionally contains an additional heteroatom selected from
oxygen, sulfur or NRg;
Rlsishydrogen. Cl 4alkylorC(Z)-Cl 4alkyl;
R 16 is C 1_4 alkyl, halo-substituted-C 1-4 alkyl, or C3 7 cycloalkyl;
R1g is ~I lo alkyl, C3 7 cycloalkyl, heterocyclyl, aryl, arylC1 1o alkyl, heterocyclyl,
heterocyclyl-C 1-1 oalkyl, heteroaryl or heteroarylalkyl;
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRTPTION OF THE INVENTION
The novel compounds of Formula (I) may also be used in association with the
veterinary treatment of m~mm~l.c, other than humans, in need of inhibition of cytokine
inhibition or production. In particular, cytokine mediated diseases for treatment,
therapeutically or prophylactically, in animals include disease states such as those noted
herein in the Methods of Treatment section, but in particular viral infections. Examples of
such viruses include. but are not limited to, lentivirus infections such as, equine infectious
anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections,
such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency
virus, or canine immunodeficiency virus or other retroviral infections.
In Formula (I). suitable R 1 moieties includes 4-pyridyl, 4-pyrimidinyl, 4-
quinolyl, 6-isoquinolinyl, 4-quinazolinyl, l-imidazolyl and l-benzimidazolyl, of which
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- 6 -
the 4-pyridyl, 4-pyrimidinyl and 4-quinolyl are preferred. More preferred is an
optionally substituted 4-pyrimidinyl or optionally substituted 4-pyridyl moiety, and
most preferred is an optionally substituted 4-pyrimidinyl ring.
Suitable substituents for the R I heteroaryl rings are C 1-4 alkyl, halo, OH, C 1-4
alkoxy, Cl 4 alkylthio, Cl 4 alkylsulfinyl, CH2OR12, amino, mono and di-Cl 6 alkyl
substituted amino, N(Rlo)C(O)Rc, or an N-heterocyclyl ring which ring has from 5 to
7 members and optionally contains an additional heteroatom selected from oxygen,sulfur or NRls. A preferred substituent for all the Rl moieties is Cl 4 alkyl, in
particular methyl, amino, and mono- and di-C 1-6 alkylsubstituted amino, preferably
10 where the amino group is mono-substituted, more preferably with methyl. The alkyl
group in the mono- and di-Cl 6 alkylsubstituted moiety may be halo substituted, such
as in trifluoro- i.e., trifluoromethyl or trifluroethyl.
When the R1 optional substituent is N(Rlo)C(O) Rc, wherein Rc is hydrogen,
C 1-6 alkyl, C3 7 cycloalkyl, aryl, arylCI~ alkyl, heteroaryl, heteroarylC 1 4aL~yl,
15 heterocyclyl, or heterocyclylC 1 4aL~yl C 1-4 alkyl, Rc is preferably C 1-6 alkyl;
prelerably R I () is hydrogen. It is also recognized that the Rc moieties, in particular the
C 1-6 alkyl group may be optionally substituted, preferably from one to three times,
prel'erably with halogen, such as fluorine, as in trifluoromethyl or trifluroethyl.
Preferably, the preferred substituent for R I is the amino or mono C 1-6 alkyl
substituted moiety. A preferred ring placement of the R I substituent on the 4-pyridyl
derivative is the 2-position, such as 2-methyl-4-pyridyl. A preferred ring placement on
the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methyl-pyrimidinyl, 2-
amino pyrimidinyl or 2-methylaminopyrimidinyl.
Suitably, R4 is phenyl, naphth- I-yl or naphth-2-yl, or a heteroaryl, which is
optionally substituted by one or two substituents. More preferably R4 is a phenyl or
naphthyl ring. Suitable substitutions for R4 when this is a 4-phenyl, 4-naphth-1-yl, 5-
naphth-2-yl or 6-naphth-2-yl moiety are one or two substituents each of which are
independently selected from halogen, -SRs, -SORs, -OR12, CF3, or
-(CRloR20)VNR loR20, and for other positions ol substitution on these rings preferred
substitution is halogen, -s(o)mR3~ -OR3, CF3, -(CRl0R20)m"NR13R14,
-NR1oC(Z)R3 and -NRloS(O)m~R~. Preferred substituents for the 4-position in phenyl
and naphth- I-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro
and chloro and -SRs and -SORs wherein Rs is preferably a C1 2 alkyl, more preferably
methyl: of which the nuoro and chloro is more preferred, and most especially preferred is
nuoro. Preferred substituents for the 3-position in phenyl and naphth-l-yl rings include:
halogen, especially fluoro and chloro; -OR3, especially Cl 4 aL~oxy; CF3, NRloR20,
such as amino; -NRloC(Z)R3, especially -NHCO(Cl l() alkyl); -NRlos(o)m~Rg~
especially -NHSO2(C1 1o alkyl), and -SR3 and -SOR3 wherein R3 is preferably a C1 2
CA 02210322 1997-07-10
WO 961216S4 PCTllJ$96J0109
-- 7 --
aLkyl, more preferably methyl. When the phenyl ring is disubstituted preferably it is two
independent halogen moieties, such as fluoro and chloro, preferably di-chloro and more
preferably in the 3, 4-position. It is also preferred that for the 3-position of both the
-OR3 and -ZC(Z)R3 moietites, R3 may also include hydrogen.
Preferably, the R4 moiety is an unsubstituted or substituted phenyl moiety.
More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and/or
substituted at the 3-position with fluoro, chloro, C 1-4 alkoxy, methane-sulfonamido or
acetamido, or R4 is a phenyl di-substituted at the 3,4-position independently with chloro
or fluoro, more preferably chloro. Most preferably, R4 is a 4-fluorophenyl.
In Formula (I), Z is suitably oxygen.
Suitably, R2 is an optionally substituted C3 7cycloalkyl, or an optionally
substituted C3 7cycloalkyl Cl lo alkyl. Preferably R2 is a C3 7cycloalkyl, of which
the cycloalkyl group is preferably a C4-7 ring, more preférably a C4 or C6 ring, most
preferably a C6 ring, which ring is optionally substituted.
The C3 7cycloalkyl ring may substituted one to three times independently by
halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C 1- l o aL~oxy, such as
methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1, or 2, such as methyl thio,
methylsulfinyl or methyl sulfonyl; S(O)m aryl; cyano; nitro; amino, mono & di-
substituted amino, such as in the NR7R17 group, wherein R7 and Rl7 are as defined in
Formula (I); or where the R7R17 may cyclize together with the nitrogen to which they
are attached to form a S to 7 membered ring which optionally includes an additional
heteroatom selected from oxygen, sulfur or NRls (and Rls is as defined for Formula
(I)): N(Rlo)C(O)Xl(wherein Rlo is as defined for Formula (I)), and Xl is Cl 4 alkyl,
aryl or arylC1 4alkyl); N(R1o)C(O) aryl; C1-10 alkyl, such as methyl, ethyl, propyl,
isopropyl, or t-butyl; optionally substituted alkyl wherein the substituents are halogen,
(such as CF3), hydroxy, nitro, cyano, amino, mono & di-substituted amino, such as in
the NR7R17 group, S(O)m alkyl and S(O)m aryl, wherein m is 0, 1 or 2; optionallysubstituted Cl loalkylene, such as ethylene or propylene; optionally substituted Cl lo
alkyne; SUGh as aGet-ylene (ethynyl) or !-propyny!; C(O)ORl 1 (wherein R1; is asdefined in Formula (I)), such as the free acid or methyl ester derivative; the group Ra;
-C(O)H; =O; =N-ORl l; -N(H)-OH (or substituted alkyl or aryl derivatives thereof on
the nitrogen or the oxime moiety); -N(ORb)-C(O)-R6; oxirane; an optionally substituted
aryl, such as phenyl; an optionally substituted arylCl 41kyl, such as benzyl or
phenethyl; an optionally substituted heterocycle or heterocyclic C 1 4alkyl, and further
these aryl, arylalkyl, heterocyclic, and heterocyclic alkyl moieties are optionally
substituted one to two times by halogen, hydroxy, Cl lo alkoxy, S(O)m alkyl, cyano,
nitro, amino, mono & di-substituted amino, such as in the NR7Rl7 group~ an alkyl,
halosubstituted alkyl.
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Suitably Ra is a 1,3-dioxyalkylene group of the formula -O-(CH2)S-O-~ wherein
s is I to 3, preferably s is 2 yielding a 1,3-dioxyethylene moiety.
Suitably Rb is hydrogen, a pharmaceutically acceptable cation, aroyl or a Cl lo
alkanoyl group.
Suitably R6 is NRlgR21; alkyl 1-6; halosubstituted alkyl 1-6; hydroxy
substituted alkyl 1-6; alkenyl 2-6; aryl or heteroaryl optionally substituted by halogen,
alkyl 1-6, halosubstituted alkyl 1-6. hydroxyl, or alkoxy 1-6-
Suitably Rlg is H or alkY11-6.
Suitably R2 1 is H, aLkyl 1-6~ aryl, benzyl, heteroaryl, alkyl substituted by
halogen or hydroxyl, or phenyl substituted by a member selected from the group
consisting of halo, cyano, alkyll l2, alkoxy 1-6~ halosubstituted alkyl 1-6. alkylthio,
alkylsulphonyl, or alkylsulfinyl; or Rlg and R21 may together with the nitrogen to
which they are attached form a ring having 5 to 7 members, which members may be
optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen. The ring
may be saturated or contain more than one unsaturated bond. Preferably R6 is
NR 1 gR2 1 and R I S~ and R2 1 are preferably hydrogen.
When the R2 moiety is substituted by NR7R17 group, or NR7R17 Cl lo alkyl
group, and the R7 and R17 areas defined in Formula (I), the substituent is preferably an
amino, amino alkyl, or an optionally substitued pyrrolidinyl moiety.
A preferred ring placement on the cyclohexyl ring, particularly when it is a C6
ring, is the 4-position.
When the cyclohexyl ring is disubstituted it is preferably disubstituted at the 4
position, such as in:
R~YR2'
S~ .
wherein R I and R2 are independently the optional substitutents indicated above for R2.
Preferably, R I and R2 are hydrogen, hydroxy, alkyl, substituted alkyl, optionally
substituted alkynyl, aryl, arylalkyl, NR7R17, and N(Rlo)C(O)Rl 1 Suitably, alkyl is
Cl 4 alkyl, such as methyl, ethyl, or isopropyl; NR7R17 and NR7R17 alkyl, such as
amino, methylamino, aminomethyl, aminoethyl; substituted alkyl such as in
cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; optionally substituted alkynyl, such
as propynyl or ethynyl; aryl such as in phenyl; arylalkyl, such as in benzyl; or together
R 1 and R2 are a keto functionality.
As used herein, "optionally substituted" unless specifically defined herein, shall
mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy;
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WO 96/21654 PCTJUS96JD109
_ 9 _
hydroxy substituted Cl loalkyl; Cl-10 alkoxy, such as methoxy or ethoxy; S(O)m
alkyl, wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl;
amino, mono & di-substituted amino, such as in the NR7R17 group; or where the
R7R 17 may together with the nitrogen to which they are attached cyclize to form a 5 to
7 membered ring which optionally includes an additional heteroatom selected fromO/N/S; C1-10 alkyl, cycloalkyl, or cycloaLkyl aLkyl group, such as methyl, ethyl,
propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C l- l o alkyl, such
CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted
arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be
substituted one to two times by halogen; hydroxy; hydroxy substituted aLkyl; Cl lo
alkoxy; S(O)m alkyl; amino, mono & di-substituted amino, such as in the NR7R17
group; alkyl, or CF3.
In a preferred sub~enus of compounds of Formula (I), Rl is 4-pyridyl, 2-alkyl-4-pyridyl, 4-pyrimidinyl, 2-amino-4-pyrimidinyl or 2-methylamino-4-pyrimidinyl; R2 is an
optionally substiuted C4 or C6 cycloaLkyl and R4 is phenyl or optionally substituted
phenyl. In a more preferred subgenus R4 is phenyl or phenyl substituted one or two
times by fluoro. chloro, C1 4 alkoxy, -S(O)m alkyl, methanesulfonamido or acetamido;
R2 is cyclohexyl substituted by methyl, phenyl, benzyl, amino, acetamide, aminomethyl,
aminoethyl, cyanomethyl, cyanoethyl, hydroxy, nitroethyl, pyrrolidinyl, ethynyl,l-propynyl, =O, O-(CH2)2O-, =NOR1 1, wherein R I I is hydrogen, alkyl or aryl, NHOH,
or M(OH)-C(O)-NH2; and R I is a 4-pyrimidinyl moiety, optionally substituted by
amino, or methylamino; or R I is a 4-pyridyl optionally substituted by methyl.
Suitable pharmaceutically acceptable salts are well known to those skilled in the
art and include basic salts of inorganic and organic acids, such as hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane
sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid
and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of
Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance,
if a substituent group comprises a carboxy moiety. Suitable pharmaceutically
acceptable cations are well known to those skilled in the art and include alk~line,
~lk~line earth. ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
~ "halo" or "halogens", include the halogens: chloro, fluoro, bromo and iodo.
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WO 96/21651 PCT/US96/0109
- 10-
~ ''Cl loalkyl'' or "alkyl" - both straight and branched chain radicals of I to 10
carbon atoms, unless the chain length is otherwise limited, including, but not limited to,
methyl, ethyl"1-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and
the like.
~ The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to
8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the
like.
~ The term "cycloalkenyl" is used herein to mean cyclic radicals, preferably of 5
to ~ carbons, which have at least one bond including but not limited to cyclopentenyl,
cyclohexenyl, and the like.
~ The term "alkenyl" is used herein at all occurrences to mean straight or
branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto,
including, but not limited to ethenyl, I -propenyl, 2-propenyl, 2-methyl- 1 -propenyl, 1-
butenyl. 2-butenyl and the like.
~ "aryl" - phenyl and naphthyl;
~ "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or
"heteroaryl aL~yl") - a 5-10 membered aromatic ring system in which one or more rings
contain one or more heteroatoms selected from the group consisting of N, O or S, such
as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline,
quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thi~ 7ole, triazole, imidazole, or
benzimidazole.
~ "heterocyclic" (on its own or in any combination, such as "heterocyclylalkyl")- a saturated or partially unsaturated 4-1() membered ring system in which one or more
rin~s contain one or more heteroatoms selected from the group consisting of N, O, or S;
such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine,
tetrahydropyran, or imidazolidine.
~ The term "aralkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to
mean C 1 4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety
as also defined herein unless otherwise indicate.
~ "sullïnyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers
to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety.
~ "aroyl" - a C(O)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkyl derivative
such as defined above, such group include but are note limited to benzyl and phenethyl.
~ "alkanoyl" - a C(O)CI lo aL~cyl wherein the alkyl is as defined above.
It is recognized that the compounds of the present invention may contain one or
more asymmetric carbon atoms and may exist in racemic and optically active forms.
All ol' these compounds are included within the scope of the present invention.
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wa 96/21654 PCT/US96J~)ln9
- 11 -
E;xemplified compounds of Formula (I) include:
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-(1,3-dioxycyclopentyl) cyclohexyl)
imidazole;
5 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1-(4-ketocyclohexyl)imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-cyclohexyl oxime) imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1-(4-cyclohexyl hydroxylamine)
imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(trans-4-hydroxyurea) imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(cis-4-hydroxyurea) imidazole;
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-hydroxycyclohexyl)imidazole;5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-ketocyclohexyl)-
imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(traMs-4-hydroxy-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4- fluorophenyl)- I-(cis -4-hydroxy-
cyclohexyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -[4-(cis-pyrrolidinyl)- cyclohexyl]imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-[4-(trans--1-pyrrolidinyl)-
cyclohexyl]imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-ethynyl-4-hydroxy-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-(1 -propynyl)-4-
hydroxycyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-amino-4-methyl-
cyclohexyl)imidazole;
5-[4-~2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-acetamido-4-methyl-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-methyl-
cyclohexyl)imidazole;
5-[4-~2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-oxiranyl-
cyclohexyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-cyanomethyl-4-
hydroxycyclohexyl)imidazole;
5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-
hydroxymethylcyclohexly)imidazole;
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- 12-
5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -[4-hydroxy-4-( 1 -propynyl)-
cyclohexyl]imidazole;
5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-methyl-
cyclohexyl)imidazole
s
Additional compounds within the scope of Formula (I) include:
5-[4-(2-N-methylamino)pyrimidinyl]~(4-fluorophenyl)- 1 -(4-hydroxy-4-isopropyl-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-phenyl-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-benzyl-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-hydroxy-4-cyanomethyl
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-(2-
cyanoethyl)cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-(2-
aminoethyl)cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-hydroxy-4-(2-nitroethyl)-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxymethyl-4-amino-
cyclohexyl)imidazole.
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-amino-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-amino-
cyclohexyl)imidazole.
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-thiomethyl
cyclohexyl)imidazole.
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-hydroxy
methylcyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-aminomethyl-
cyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-amino-4-methyl-
cyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-methyl-
cyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-oxiranyl-
cyclohexyl)imidazole.
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- 13-
Exemplified and additional compounds of Formula (I) included herein include the
2-methylamino-4-pyrimidinyl derivatives of the 2-aminopyriminid-4-yl compounds
noted above noted compounds and the 2-amino-4-pyrimidinyl derivatives of the 2-
methylaminopyriminid-4-yl compounds noted above where not where not explicitly
described.
The compounds of Formula (I) may be obtained by applying synthetic
procedures, some of which are illustrated in Schemes I to XI below. The synthesis
provided for in these Schemes is applicable for the producing compounds of Formula (I)
having a variety of different R I, R2, and R4 groups which are reacted, employing
optional substituents which are suitably protected, to achieve compatibility with the
reactions outlined herein. Subsequent deprotection, in those cases, then affordscom~ounds of the nature generally disclosed. Once the imidazole nucleus has beenestablished, further compounds of Formula (I) may be prepared by applying standard
techni~lues for functional group interconversion, well known in the art.
For instance: -C(O)NR13R14 from -C02CH3 by heating with or without
catalytic metal cyanide, e.g. NaCN, and HNR13R14 in CH30H; -OC(O)R3 from -OH
with e.g., CIC(O)R3 in pyridine; -NRIo-C(S)NRl3Rl4 from -NHRlo with an
alkylisothiocyante or thiocyanic acid; NR6C(O)OR6 from -NHR6 with the aLtcyl
chloroformate: -NRloC(O)NR13R14 from -NHRIo by treatment with an isocyanate,
e.g. HN=C=O or RloN=C=O; -NRlo-c(o)R8 from -NHRIo by treatment with Cl-
C(O)R3 in pyridine: -C(=NRlo)NR13R14 from -C(NR13R14)SR3 with H3NR3+0Ac-
by heating in alcohol; -C(NR13R14)SR3 from -C(S)NR13R14 with R6-I in an inert
solvent, e.~. acetone: -C(S)NR13R14 (where R13 or R14 is not hydrogen) from
-C(S)NH2 with HNR13R14-C(=NCN)-NR13R14 from -C(=NR13R14)-SR3 with
NH2CN by heatin~ in anhydrous alcohol, alternatively from -C(=NH)-NR13R14 by
treatment with BrCN and NaOEt in EtOH; -NR10-c(=NcN)sR8 from -NHR1o by
treatment with (RgS)2C=NCN; -NRloso2R3 from -NHRIo by treatment with
ClS02R3 by heatin~ in pyridine; -NRIoC(S)R3 from -NRloC(O)Rg by treatment with
Lawesson's reac~ent [2,4-bis(4-methoxyphenyl)- 1 ,3,2,4-dithiadiphosphetane-2,4-disulfide]; -NRloso2cF3 from -NHR6 with triflic anhydride and base wherein R3, R6,
Rlo, R13 and R14 are as defined in Formula (I) herein.
In a further aspect the present invention provides for compounds of the Formula
(II) havin~ the structure:
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WO 96/21654 PCT/US96/01094
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Ar--S(~)r
(II)
R4/~ NC
wherein p is 0, or 2; R4 is as defined for Formula (I) and Ar is an optionally
substituted aryl as defined herein. Suitably, Ar is phenyl optionally substituted by
Cl 4alkyl, Cl 4 alkoxy or halo. Preferably Ar is phenyl or 4-methylphenyl, i.e. a tosyl
5 derivative. Compounds of Formula (II) are belived novel, provided than when Ar is
tosyl, and p is O or 2, then R4 is not an unsubstituted phenyl.
Precursors of the groups R 1, R2 and R4 can be other Rl, R2 and R4 groups
which can be interconverted by applying standard techniques for functional groupinterconversion. For example a compound of the formula (I) wherein R2 is halo
10 -substituted Cl 1o alkyl can be converted to the corresponding Cl lo alkylN3
derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced
to the corresponding C l loalkylNH2 compound. which in turn can be reacted with
RI~S(0)2X wherein X is halo (e.g., chloro) to yield the corresponding
C 1-10alkYlNHs(0)2Rl 8 compound.
Alternatively a compound of the formula (I) where R2 is halo-substituted
Cl lo-aLkyl can be reacted with an amine R13R14NH to yield the corresponding
Cl lo-alkylNRl3Rl4 compound, or can be reacted with an alkali metal salt of RlgSH
to yield the corresponding Cl loalkylSRlg compound.
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- 15-
R4CHO ( V) + Ar S(O)p H R4CH2NH2 (VIII)
\ ~ormylatin~ agent
H2NCHO CHCI3 \~
- NaOHR4CH2NHCHO
CH2CI2
H20, PrC ~ k,Ly~ lg agent
Ar--S(O)p R4CH2NC (VI)
/~ Ar S(0)2LI (VII)/
R4 NHCHO
wherem p =2 /
RICHO + R2NH2
dehydrating agent
Ar--S(O)p R1~NR2
/~ H (III)
R4 NC
~/
~ ~2
R.
(I)
ScHEMF~ I
Referring to Scheme I the compounds of Formula (I) are suitably prepared by
5 reacting a compound of the Formula (II) with a compound of the Formula (III) wherein p
is 0 or 2, R1, R2 and R4 are as defined herein, for Formula (I), or are precursors of the
groups R 1, R2 and R4, and Ar is an optionally substituted phenyl group, and thereafter if
necessary converting a precursor of R 1~ R2 and R4 to a group R1, R2 and R4. It is
recognized that R2NH2 which is reacted with RICHO to form the imine, Formula (III)
10 the R2 moiety when it contains a reactive functional group, such as a primary or
secondary amine, an alcohol, or thiol compound the group must be suitably protected.
Suitable protecting groups may be found in, Protecting Groups in Organic Synthesis,
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WO 96/21654 PCTIUS9610109 1
- 16-
Greene T W, Wiley-lnterscience, New York, 1981, whose disclosure is incorporatedherein by reference. For instance, when R2 is contains as a substituent group a
heterocyclic ring, such as a piperidine ring, the nitrogen is protected with groups such as
t-Boc, CO2RI~, or a substitued arylalkyl moiety.
s
Suitably, the reaction is performed at ambient temperature or with cooling (e.g.-50~ to 10~) or heating in an inert solvent such as methylene chloride, DMF,
tetrahydrofuran, toluene, acetonitrile, or dimethoxyethane in the presence of anappropriate base such as 1,8-diazabicyclo [5.4Ø] undec-7-ene (DBU) or a guanidine
base such as 1,5,7-triaza-bicyclo [4.4.0] dec-5-ene (TBD). The intermediates of formula
(II) have been found to be very stable and capable of storage for a long time. Preferably,
p is 2.
Reaction a compound of the Formula (II) wherein p = 2, with a compound of
the Formula (III)-Scheme I gives consistently higher yields of compounds of Formula
(I) than when p=0. In addition, the reaction of Formula (II) compounds wherein p = 2
is more environmentally and economically attractive. When p=0, the preferred solvent
used is methylene chloride, which is environmentally unattractive for large scale
processing, and the preferred base, TBD, is also expensive, and produces some
byproducts and impurities, than when using the commercially attractive synthesis (p=2)
as further described herein.
As noted, Scheme I utilizes the 1 ,3-dipolar cycloadditions of an anion of a
substituted aryl thiomethylisocyanide (when p=0) to an imine. More specifically,this reaction requires a strong base, such as an amine base, to be used for the
deprotonation step. The commercially available TBD is preferred although t-
butoxide, Li+ or Na+, or K+ hexamethyldisilazide may also be used. While
methylene chloride is the prefered solvent, other halogenated solvents, such as
chloroform or carbon tetrachloride; ethers, such as THF, DME, DMF, diethylether,t-butyl methyl ether; as well as acetonitrile, toluene or mixtures thereof can be
utiltized. The reaction may take place from about -20~C to about; 40~C, preferably
from about 0~C to about 23~C, more preferably from about 0~C to about 10~C, and
most preferably about 4~C for reactions involving an Rl group of pyrimidine. Forcompounds wherein R I is pyridine, it is recognized that varying the reations
conditions of both temperature and solvent may be necessary, such as decreasing
temperatures to about -50~C or changing the solvent to THF.
In a further process, compounds of Formula (I) may be prepared by coupling a
suitable derivative of a compound of Formula (IX):
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WO 96/21654 PCT/l~S96J~)lU
- 17 -
R2
1~N
Il /--H
T N
4 (IX)
wherein Tl is hydrogen and T4 is R4, or alte,-natively Tl is Rl and T4 is H in which
Rl, R2 and R4 are as hereinbefore defined; with: (i) when Tl is hydrogen, a suitable
derivative of the heteroaryl ring R 1 H, under ring coupling conditions, to effect
coupling of the heteroaryl ring Rl to the imidazole nucleus at position 5; (ii) when T4
is hydrogen, a suitable derivative of the aryl ring R4H, under ring coupling conditions,
to effect coupling of the aryl ring E~4 to the imidazole nucleus at position 4.
Such aryllheteroaryl coupling reactions are well known to those skilled in the
art. In general. an organometallic synthetic equivalent of an anion of one component is
coupled with a reactive derivative of the second component, in the presence of asuitable catalys~. The anion equivalent may be formed from either the imidazole of
Formula (IX), in which case the aryUheteroaryl compound provides the reactive
derivative, or the aryl/heteroaryl compound in which case the imi~ 7Ole provides the
1~ reactive derivative. Accordingly, suitable derivatives of the compound of Formula (IX)
or the aryVheteroaryl rings include organometallic derivatives such as
organomagnesium, organozinc, organostannane and boronic acid derivatives and
suitable reactive derivatives include the bromo, iodo, fluorosulfonate and
trifluoromethanesulphonate derivatives. Suitable procedures are described in WO
91/19497, the disclosure of which is incorporated by reference herein.
Suitable organomagnesium and organozinc derivatives of a compound of
Formula (IX) may be reacted with a halogen, fluorosulfonate or triflate derivative of
the heteroaryl or aryl ring, in the presence of a ring coupling catalyst, such as a
p~ dillm (O) or palladium (II) catalyst, following the procedure of Kumada et al.,
Tetrahedron Letters, 22, 5319 (1981). Suitable such catalysts include tetrakis-
(triphenylphosphine)palladium and PdC12[1,4-bis-(diphenylphosphino)-butane],
optionally in the presence of lithium chloride and a base, such as triethylamine. In
addition, a nic~el (II) catalyst, such as Ni(II)cl2(l72-biphenylphosphino)ethane7 may
also be used for coupling an aryl ring, following the procedure of Pridgen et al., J. Org.
Chem, 1982, 47, 4319. Suitable reaction solvents include hexamethylphosphor-amide.
When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4-
iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine.Similarly, suitable derivatives for when the aryl ring is phenyl include the bromo,
fluorosulfonate, triflate and, preferably, the iodo-derivatives. Suitable
organom~gnesium and organozinc derivatives may be obtained by treating a compound
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WO 96/21654 PCT/US96/01091
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of Formula (IX) or the bromo derivative thereof with an aL~yllithium compound toyield the corresponding lithium reagent by deprotonation or transmetallation,
respectively. This lithium intermediate may then be treated with an excess of a
magnesium halide or zinc halide to yield the corresponding organometallic reagent.
~ trialkyltin derivative of the compound of Formula (IX) may be treated with a
bromide, fluorosulfonate, triflate, or, preferably, iodide derivative of an aryl or
heteroaryl ring compound, in an inert solvent such as tetrahydrofuran, preferably
containin~ 10% hexamethylphosphoramide, in the presence of a suitable coupling
catalyst, such as a palladium (0) catalyst, for instance tetrakis-(triphenylphosphine)-
10 p~ linm, by the method described in by Stille, J. Amer. Chem. Soc, 1987, 109, 5478,
US Patents 4,719,218 and 5,002,942, or by using a palladium (II) catalyst in thepresence of lithium chloride optionally with an added base such as triethylamine, in an
inert solvent such as dimethyl formamide. Trialkyltin derivatives may be conveniently
obtained by metallation of the corresponding compound of Formula (IX) with a
15 lithiating a~ent! such as s-butyl-lithium or ~I-butyllithium, in an ethereal solvent, such
as tetrahydrofuran, or treatment of the bromo derivative of the corresponding
compound of Formula (IX) with an alkyl lithium, followed, in each case, by treatment
with a trialkyltin halide. Alternatively, the bromo- derivative of a compound ofFormula (IX) may be treated with a suitable heteroaryl or aryl trialkyl tin compound in
20 the presence of a catalyst such as tetrakis-(triphenyl-phosphine)-palladium, under
conditions similar to those described above.
Boronic acid derivatives are also useful. Hence, a suitable derivative of a
compound of Formula (~), such as the bromo, iodo, triflate or fluorosulphonate
derivative, may be reacted with a heteroaryl- or aryl-boronic acid, in the presence of a
25 palladium catalyst such as tetrakis-(triphenylphosphine)-palladium or PdC12[1,4-bis-
(diphenyl-phosphino)-butane] in the presence of a base such as sodium bicarbonate,
under reflux conditions, in a solvent such as dimethoxyethane (see Fischer and
Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439, 1965, Snieckus, V., Tetrahedron Lett.,
29, 2135, 1988 and Ter~himi~, M., Chem. Pharm. Bull., 11, 4755, 1985). Non-
30 aqueous conditions, for instance, a solvent such as DMF, at a temperature of about
100~C, in the prescnce of a Pd(II) catalyst may also be employed (see Thompson W J
et al. J Ore Chem, 49, 5237, 1984). Suitable boronic acid derivatives may be prepared
by treatin~r the m~nesium or lithium derivative with a triaL~ylborate ester, such as
triethyl, tri-iso-propyl or tributylborate, according to standard procedures.
In such coupling reactions, it will be readily appreciated that due regard must be
exercised with respect to functional groups present in the compounds of Formula (IX).
Thus. in general. amino and sulfur substituents should be non-oxidised or protected.
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Compounds of Formula (IX) are imidazoles and may be obtained by any of the
procedures herein before described for preparin~ compounds of Formula (I). In
particular, an a-halo-ketone or other suitably activated ketones R4COCH2Hal (forcompounds of Formula (IX) in which Tl is hydrogen) or RlCOCH2Hal (for
5 compounds of Formula (IX) in which T4 is hydrogen) may be reacted with an amidine
of the formula R2NH-C=NH, wherein R2 is as defined in Formula (I), or a salt thereof,
in an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform,
at a moderately elevated temperature. and, if necessary, in the presence of a suitable
condensation agent such as a base. The preparation of suitable oc-halo-ketones is
described in WO 91/19497. Suitable reactive esters include esters of strong organic
acids such as a lower alkane sulphonic or aryl sulphonic acid, for instance, methane or
p-toluene sulphonic acid. The amidine is prel'erably used as the salt, suitably the
hydrochloride salt, which may then be converted into the free amidine in situ, by
employing a two phase system in which the reactive ester is in an inert organic solvent
15 such as chloroform, and the salt is in an aqueous phase to which a solution of an
aqueous base is slowly added, in dimolar amount, with vigorous stirring. Suitable
amidines may be obtained by standard methods, see for instance, Garigipati R,
Tetrahedron Letters, 190, 31, 1989.
Compounds of Formula (I) may also be prepared by a process which comprises
20 reacting a compound of Formula (IX), wherein Tl is hydrogen, with an N-acyl
heteroaryl salt, according to the method disclosed in US patent 4,803,279; US patent
4,719,218 and US patent 5,002,942, to give an intermediate in which the heteroaryl
ring is attached to the imidazole nucleus and is present as a 1,4-dihydro derivative
thereof, which intermediate may then be subjected to oxidative-deacylation conditions
25 (Scheme II). The heteroaryl salt, for instance a pyridinium salt, may be either
preformed or, more preferably, prepared in situ by adding a substituted carbonyl halide
(such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or, preferably,
an alkyl haloformate ester, such as acetyl bromide, benzoylchloride, benzyl
chloroformate, or, preferably, ethyl chloroformate) to a solution of the compound of
30 Forrnula (IX) in the heteroaryl compound R 1 H or in an inert solvent such as methylene
chloride to which thc heteroaryl compound has been added. Suitable deacylating and
oxidising conditions are described in U.S. Patent Nos. 4,803,279, 4,719,218 and
5,002,942, which references are hereby incorporated by reference in their entirety.
Suitable oxidizing systems include sulfur in an inert solvent or solvent mixture, such as
35 decalin, decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions,
or, preferably, potassium t-butoxide in t-butanol with dry air or oxygen.
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W O96/216S4 PCT~US9610109
-20-
RX4~ Ij-~2 ~¢N,~ pyridin~/R,COCI ~ S/de~calin,~ or 1~N>
SCHEME II
S In a further process, illustrated in Scheme III below, compounds of Formula (I)
may be prepared by treating a compound of Formula (X) thermally or with the aid of a
cyclising agent such as phosphorus oxychloride or phosphorus pentachloride (see
Engel and Steglich, Liebigs Ann Chem, 1978,1916 and Strzybny etal., J Org Chem,
1963,28,3381). Compounds of Formula (X) may be obtained, for instance, by
acylating the corresponding a-keto-amine with an activated formate derivative such as
the corresponding anhydride, under standard acylating conditions followed by
formation of the imine with R2NH2. The aminoketone may be derived from the parent
ketone by ox~min~tion and reduction and the requisite ketone may in turn be prepared
by decarboxylation of the beta-ketoester obtained from the condensation of an aryl
(heteroaryl) acetic ester with the R1COX component.
R~O
X 2 ) HCI Rt)~~ 1 )NaNO HCI H O R1~o HJ~OJlMe, ~ ~ POCI R~)~N
R4~bP R4 2.) reduce R NH2 2 )NH2R2- -H20 R N~ R~ N
formula (X)
SCHEME III
In Scheme IV illustrated below, two (2) different routes which use ketone
(formula XI) for preparing a compound of Formula (I). A heterocyclic ketone (XI) is
prepared by adding the anion of the alkyl heterocycle such as 4-methyl-quinoline(prepared by treatment thereof with an alkyl lithium, such as M-butyl lithium) to an N-
25 alkyl-O-alkoxybenzamide, ester, or any other suitably activated derivative of the same
oxidation state. Alternatively, the anion may be condensed with a benzaldehyde, to
~ive an alcohol which is then oxidised to the ketone (XI).
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wo 96/21654 PCTIUS96101094
- 21 -
R, ~,N H R2 R ~ r H
4 R4 ~
(XI) HN
R4 R4 R4 ~I R~
SCH~ME~ IV
In a further process, N-substituted compounds of Formula (I) may be prepared
by treating the anion of an amide of Formula (XII):
RlCH2NR2COH (XII)
wherein R I and R2 with:
(a) a nitrile of the Formula (XIII):
R4CN (XIII)
wherein R4 is as hereinbefore defined, or
(b) an excess of an acyl halide, for instance an acyl chloride, of the Formula
(XIV):
R4COHal (XIV)
15 wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding
anhydride, to give a bis-acylated intermediate which is then treated with a source of
ammonia, such as ammonium acetate.
R2HN~ base R1 CI~ R~ N2 1.) Lh -N(i-Pr)2 R R2
o /~ H R4~C N R4 N
(Xll)
SCHEME V
One v ariation of this approach is illustrated in Scheme V above. A primary
amine (R2NH ) is treated with a halomethyl heterocycle of Formula RICH2X to givethe secondary amine which is then converted to the amide by standard techniques.25 Alternativel~ the amide may be prepared as illustrated in scheme V by alkylation of the
formamide with RICH2X. Deprotonation of this amide with a strong amide base, such
as lithium di-is(~-propyl amide or sodium bis-(trimethylsilyl)amide, followed by
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WO 96/21654 PCT/US96/01094
- 22 -
addition of an excess of an aroyl chloride yields the bis-acylated compound which is
then closed to an imid~7O1e compound of Formula (I), by heating in acetic acid
containing ammonium acetate. Alternatively, the anion of the amide may be reacted
with a substituted aryl nitrile to produce the imidazole of Formula (I) directly.
s
The following description and schemes are further exemplification of the processas previously described above in Scheme I. Various pyrimidine aldehyde derivatives 6, 7
and 8 as depicted in scheme VI below, can be prepared by modification of the procedures
of Bredereck et al. (Chem. Ber. 1964, 97, 3407) whose disclosure is incorporated by
10 reference herein. These pyrimidine aldehydes are then utilized as intermediates in the
synthesis as further described herein. The unprotected amino aldehyde derivative, e.g. 8,
can 'ne somewhat unstable. Use of an acetolysis procedure, as described in Scheme VI,
wherein the aldehyde 7 is isolated as the acetamide derivative, (compound 3 is converted
to 7, via the intermediate 4) and leads to a more stable compound for use in the15 cycloaddition reaction to make compounds of Formula (I).
General acetolysis conditions, for such a reaction are employed and are well
known to those of skill in the art. Suitable conditions are exemplified, for instance in
Example 83. In greater detail, the reaction employs heating the 2-amino pyrimidine
diaLkoxy acetal with acetic anhydride in the presence of a catalytic amount of
20 concentrated sulfuric acid, which simultaneously acetylates the amine and leads to the
exchange of one of the alkoxy groups for an acetoxy group. The resultant compound is
converted to the aldehyde by deacetylation with a catalytic amount of an alkoxide salt
and the corresponding alcohol solvent, e.g. Na+ methoxide and methanol. Alternatively,
higher yields can be obtained by first acetylating the amine with acetic anhydride and
25 then affecting exchange by subsequent addition of concentrated sulfuric acid.
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MeO
O >--NMe2 0
MeO ~ MeO MeO ~ N
MeO 1 MeO 2
1. thiourea
NaOEt/EtOH / \ NH
" ~ 2.Mel \ 11 ~HX
~ H20 \ H2N J~NHR
H3CS ~ N~ R=H,al~l
~ HaC ~ AC20 YN~
4 ¦ H2S04
AcOH MeO OAc MeO OMe
H2SO4
NaOMe HCI
MeOH THF / H20
H3CS
6 ~H~ H~C ~ ~ ~N'~ RHN ~N~
H H
SCHEME VI
The reaction of imines with tosylmethyl isonitriles was first reported by van
Leusen (van Leusen, et al., J. Org. Chem. 1977, 42, 1153.) Reported were the following
5 conditions: tert butyl amine(tBuNH2) in dimethoxyethane (DME), K2C03 in MeOH,
and NaH in DME. Upon re-ex~min~tion of these conditions each was found produce low
yields. A second pathway involving amine exchange to produce the t-butyl imine
followed by reaction with the isocyanide to produce a l-tBu imidazole was also
operating. This will likely occur using any primary amine as a base. The secondary
10 amines, while not preferred may be used, but may also decompose the isonitrile slowly.
Reactions will likely require about 3 equivalents of amine to go to completion, resulting
in approximately 50% isolated yields. Hindered secondary amines (diisopropylamine)
while usable are very slow and generally not too effective. Use of tertiary and aromatic
amines, such as pyridine, and triethylamine gave no reaction under certain test
15 conditions, but more basic types such as DBU, and 4-dimethylamino pyridine (DMAP)
while slow, did produce some yields and hence may be suitable for use herein.
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WO 96/21654 PCTIUS96/0109 1
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As depicted in Schemes VII and VIII below. the pyrimidine aldehydes of Scheme
VI, can be condensed with a primary amine, to generate an imine, which may suitably be
isolated or reacted in situ, with the desired isonitrile in the presence of a variety of
suitable bases, and solvents as described herein to afford the 5-(4-pyrimidinyl)-
5 imidazoles, wherein R2 and R4 are as defined herein for Formula (I) compounds.One preferred method for preparing compounds of Formula (I) is shown below inScheme VII. The imines, prepared and isolated in a separate step where often tars. which
were hard to handle. The black color was also often carried over into the final product.
The yields, for making the imines varied, and environmentally less-acceptable solvents,
10 such as CH2C12 were often used in their preparation.
This reaction, wherein p=2 requires a suitable base for the reaction to proceed.The reaction requires a base strong enough to deprotonate the isonitrile. Suitable bases
include an amine, a carbonate, a hydride, or an alkyl or aryl lithium reagent; or mixtures
thereof. Bases include, but are not limited to, potassium carbonate, sodium carbonate,
15 primary and secondary amines, such as t-butylamine, diisopropyl amine, morpholine,
piperidine, pyrrolidine, and other non-nucleophilic bases, such as DBU, DMAP and 1,4-
diazabicyclo[2.2.2]octane (DABCO).
Suitable solvents for use herein, include but are not limited to N,N-dimethyl-
formamide (DMF), MeCN, halogenated solvents, such as methylene chloride or
20 chloroform, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, such as
methanol or ethanol, benzene, toluene, DME or EtOAc.. Preferably the solvent is DMF,
DME, THF, or MeCN, more preferably DMF. Product isolation may generally be
accomplished by adding water and filtering the product as a clean compound. The
mixture is non-nucleophilic, thus no isonitrile decomposition occurs.
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Me
SO2Tol ~/ t-BUNH2 N I~/N~
F N--C ~ 25 ~C, 2~ h 1~ ¦ ~N~
N~ N ~d
NHMe F
t-BuNH2
~tBu 1 MeHN ~ N~
N~ N ~ N
NHMe
SCHEME VII
While not convenient for large scale work, addition of NaH, instead of t-
butylamine. to the isonitrile, perhaps with temperatures lower than 25 ~C (in THF) are
S likely needed. Additionally, BuLi has also been reported to be an effective base for
deprotonatin~ tosyl benzylisonitriles at -50 ~C. (DiSanto, R.; Costi, R.; Massa, S.; Artico,
M. Synth. Commu~l. 1995, 25, 795).
Various temperature conditions may be utilized depending upon the preferred
base. For instance, tBuNH2/DME, K2CO3/MeOH, K2CO3 in DMF, at temperatures
above 40 ~C. the yields may drop to about 20% but little difference is expected between
0~C and 25 ~C. Consequently, temperature ranges below 0 ~C, and above 80 ~C are
contemplated as also being within the scope of this invention. Preferably, the temperature
ranges are from about 0 ~C to about 25 ~C. For purposes herein, room tempature, which
is depicted as 25~C, but it is recognized that this may vary from 20~C to 30~C.
As shown in Scheme VIII below, the imine is preferably formed in situ in a
solvent. This preferred synthesis, is a process which occurs as a one-pot synthesis.
Suitably, when the primary amine is utilized as a salt, such as in the dihydrochloride
salt in the Examples, the reaction may further include a base, such as potassiumcarbonate prior to the addition of the isonitrile. Alternatively, the piperidine nitrogen
- 20 may be required to be protected as shown below. Reaction conditions, such as
solvents, bases, temperatures, etc. are similar to those illustrated and discussed above
for the isolated imine as shown in Scheme VIII. One skilled in the art would readily
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recognize that under some circumstances, the in situ formation of the imine may
require dehydrating conditions, or may require acid catalysis.
N~ BOC
BOC /~/
~CHO ~ D5MhF ~ N
NHMeNH2 N~s N
NHMe
KD2MCFO3 N 3N HCI MeHN ~N~N
M HN ~ j~ N
Tol ~ N F
SCHEME VIII
s
Another method for preparing compounds of Formula (I) is shown below in
Scheme VIIIa. To avoid the difficulty associated with isolating the pyrimidine
aldehyde 8. it is possible to hydrolyze the acetal 3 to aldehyde 8 as described herein.
The aldehyde 8, formed in situ, can be treated sequentially with a primary amine, ethyl
10 acetate, and NaHCO3 to form the corresponding imine in situ, which is extracted into
the ethyl acetate. Addition of the isonitrile, a carbonate base and DMF allows for the
formation of the 5-(4-pyrimidinyl)-imidazoles, wherein R2 and R4 are as defined
herein for Formula (I) compounds.
While it is recognized that Schemes VII, VIII, and VIII(a) are shown using a
piperidine ring in the R2 position this is for illustration purposes only and any suitable
R2 as defined herein may be utilized.
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OMo N ~ N P EtOAc
NHMe
NHMe _ ~ NH2
N,,PG N~PG
~/ DMF MeHNl~N~
N~ _ F/~NC ~N
SCHEME VIIIa
The preferred method of synthesis for compounds of Formula (I) also provides
for a suitable and reliable method for introduction of an S(O)maLkyl moiety on the
pyrimidine (R 1 group) by using, for instance, the 2-methylthio pyrimidine aldehyde
derivative, as is also described in the Examples section.
In scheme IX below (X=S Methyl), compound 1, while a final product may also
be used as a precursor, as previously noted to make further compounds of formula (I). In
this particular instance the methylthio moiety is oxidized to the methyl sulfinyl moiety
which may additionally be l'urther modified to a substituted amino group.
R2
R2 N
for X = SCH3 for X = NRAc
HCI
H3C(O)S ~ Ac02H / H20
R~N RHN~
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ScHF~MF IX
Another embodiment of the present invention is the novel hydrolysis of 2-
thiomethylpyrimidine acetal to 2-thiomethylpyrimidine aldehyde, as shown in Scheme X
below. Hydrolysis of the acetal to aldehyde using various known reaction conditions,
5 such as formic acid, did not produce a satisfactory yield of the aldehyde, <13%) was
obtained. The preferred synthesis involves the use of AcOH (fresh) as solvent and
concentrated H2SO4 under heating conditions, preferably a catalytic amount of sulfuric
acid. Heating conditions include tempcratures from about 60 to 85~C, preferably from
about 70~ to about 80~C as higher temperatures show a darkening of the reaction mixture.
I() After the reaction is completed the mixture is cooled to about room temperature and the
acetic acid is removed. An alternative procedure to this involves heating the acetal in
3N HCL at 40~C for about 18 hours, cooling and extracting the bicarbonate neutralized
solution into EtOAc.
OMe
N~AcOH/conc. H2SO4 ~H
SMe
1 5 SMe
SCHEME X
The final 2-aminopyrimidin-4-yl imidazole compounds of Formula (I), as well as
similar pyridinc containing compounds can be prepared by one of three methods: 1 )
direct reaction of the 2-aminopyrimidine imine with the isonitrile; 2) condensation of the
20 2-acetamidopyrimidine imine with the isonitrile followed by removal of the acetamido
group and 3) oxidation of the 2-methylthiopyrimidine derivative to the corresponding
sulfoxide followed by displacement with the desired amine.
While these schemes herein are presented, for instance, with an optionally
substituted piperidine moiety for the resultant R2 position, or a 4-fluoro phenyl for R4,
25 any suitable R2 moiety or R4 moiety may be added in this manner if it can be prepared on
the primary amine. Similarly, any suitable R4 can be added via the isonitrile route.
The compounds of Formula (II), in Scheme I, may be prepared by the methods of
Van Leusen et al., supra. For example a compound of the Formula (II) may be prepared
by dehydrating a compound of the Formula (IV)-Scheme L wherein Ar, R4 and p are as
30 defined herein.
Suitablc dehydrating agents include phosphorus oxychloride, oxalyl chloride,
thionyl chloride, phosgene, or tosyl chloride in the presence of a suitable base such as
triethylamine or diisopropylethylamine, or similar bases, etc. such as pyridine. Suitable
solvents are dimethoxy ether, tetrahydrofuran, or halogenated solvents, preferably THF.
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The reaction is most efficent when the reaction temperatures are kept between -10~C and
0~C. At lower temperatures incomplete reaction occurs and at higher temperatures, the
solution turns dark and the product yield drops.
The compounds of formula (IV)-Scheme I may be prepared by reacting a
compound of the forrnula (V)-Scheme I, R4CHO where R4 is as defined herein, withArS(O)pH and formamide with or without water removal, preferably under dehydrating
conditions, at ambient or elevated temperature e.g. 30~ to 150~, conveniently at reflux,
optionally in the presence of an acid catalyst. Alternatively trimethysilylchloride can be
used in place of the acid catalyst. Examples of acid catalysts include carnphor-10-
10 sulphonic acid. formic acid, p-toluenesulphonic acid, hydrogen chloride or sulphuric
acid.
An optimal method of making an isonitrile of Formula (II) is illustrated below, in
Scheme XI.
fu~ al~id~ NHCHO SO2Tol
F~ MeCN ~ NHCHO 2 > ~ NHCHO
50 ~C 2 3
SO2Tol 0.5 M THF SO2Tol
. POCI3
~NHCHO Et3N ~ NC
~ J -10toO~C D
F~ ~ 30 min F~----
70% yield 4
SCHEME XI
The conversion of the substituted aldehyde to the tosylbenzyl forrn~mi(~e may beaccomplished by heating the aldehyde, l-Scheme XI, with an acid, such as p-toluene-
sulfonic acid, formic acid or camphorsulfonic acid; with formamide and p-toluene-
sulfinic acid [under reaction conditions of about 60~C for about 24 hours]. Preferably, no
20 solvent is used. The reaction, may give poor yields (< 30%) when solvents, such as
DMF, DMSO. toluene, acetonitrile, or excess formamide are used. Temperatures less
than 60~C are ~enerally poor at producing the desired product, and temperatures in
excess of fi()~C may produce a product which decomposes, or obtain a benzylic bis-
formamide, 2-Scheme XI. In Example 23 (a), described in WO 95/02591, Adams et al.,
25 synthesizes 4-Fluorophenyl-tosylmethylformarnide. a compound of Formula (IV)
-Scheme I, wherein p = 2. This procedure differs from that presently described herein by
the following conditions, using the sodium salt of toluene sulfinic acid, neat which
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process results in uneven heating, lower yields and lower reproduceability then the
present invention, as described herein which uses sulfinic acid and allows for use of non-
aqueous conditions.
Conditions for making a-(p-Toluenesulfonyl)-4-fluorobenzylisonitrileas
described in Example 23 (b), of WO 95/02591, Adams et al., used as a solvent MeCI to
extract the product and DME as solvent. The present invention improves upon thisprocess by utiizing less expensive solvents, such as THF and EtOAc to extract. Further
higher yields are obtained by recrystalizing with an alcohol, such as 1-propanol, although
other alcohols, such as methanol, ethanol and butanols are acceptable. Previously, the
10 compound was partially purifed using chromatography techniques, and hazardous solvents for additional purifications.
Another embodiment of the present invention is the synthesis of the tosyl benzylformamide compound, achieved by reacting the hisformamide intermediate, 2-Scheme15 XI. with p-toluenesulfinic acid. In this preferred route, preparation of the bis-formamide
from the aldehyde is accomplished by heating the aldehyde with formamide, in a suitable
solvent with acid catalysis. Suitable solvents are toluene, acetonitrile, DMF, and DMSO
or mixtures thereof. Acid catalysts, are those well known in the art, and include but are
not limited to hydrogen chloride, p-toluenesulfonic acid, camphorsulfonic acid, and other
20 anhydrous acids. The reaction can be conducted at temperatures ranging from about
25~C to 110~C, preferably about 50~C, suitably for about 4 to about 5 hours, longer
reaction times are also acceptable. Product decomposition and lower yields may be
observed at higher temperatures (~70~C) at prolonged reactions times. Complete
conversion of the product generally requires water removal from the reaction mixture.
Preferred conditions for converting a bis-formamide derivative to the tosyl
benzyl formamide are accomplished by heating the bisformamide in a suitable solvenl
with an acid catalyst and p-toluenesulfinic acid. Solvents for use in this reaction
include but are not limited to toluene, and acetonitrile or mixtures thereof. Additional
mixtures of these solvents with DMF, or DMSO may also be used but may result in
30 lower yields. Temperatures may range from about 30~C to about 100~C. Temperatures
lower than 40~C and higher than 60~C are not prel'erred as the yield and rate decreases.
Preferably the range is from about 4() to 60~C, most preferably about 50~C. The
optimal time is about 4 to 5 hours, although it may be longer. Preferably, acids used
include but are not limited ~o, toluenesulfonic acid, camphorsulfonic acid, and
35 hydrogen chloride and other anhydrous acids. Most preferably the bisform~mide is
heated in toluene:acetonitrile in a 1:1 ratio, with p-toluenesulfinic acid and hydrogen
chloride.
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Another embodiment of the present invention is the preferred synthetic route l'or
synthesis of the tosylbenzyl formamide compound which is accomplished using a one-pot
procedure. This process first converts the aldehyde to the bis-formamide derivative and
subsequently reacts the bis-fonnamide derivative with toluenesulfinic acid. Thisprocedure combines the optimized conditions into a single, efficient process. High yields,
>90% of the aryl benzylformamide may be obtained in such a manner.
Preferred reaction conditions employ a catalyst, such as trimethylsilyl chloride(TMSCl), in a preferred solvent, toluene:acetonitrile, preferably in a 1:1 ratio. A reagent,
such as TMSCl, is preferred which reacts with water produced therein and at the same
10 time produces hydrogen chloride to catalyze the reaction. Also preferred is use of
hydrogen chloride and p-toluenesulfonic acid. Therefore, three suitable reactionconditions for use herein include 1) use of a dehydrating agent which also provides
hydro~en chloride, such as TMSCl; or by 2) use ol a suitable dehydrating agent and a
suitable source of acid source, such as but not limited to, camphorsulfonic acid~ hydrogen
15 chloride or toluenesulfonic acid; and 3~ alternative dehydrating conditions, such as the
azeokopic removal of water, and using an acid catalyst and p-toluene sulfinic acid.
Compounds of the l~ormula (II) where p is 2 may also be prepared by reacting in
the presence of a strong base a compound of the formula (VI) -Scheme I, R4CH2NC
20 with a compound of the formula (VII)-Scheme I, ArSO2Ll wherein R4 and Ar are as
defined herein and Ll is a leaving group such as halo, e.g. fluoro. Suitable strong
bases include, but are not limited to, alkyl lithiums such as butyl lithium or lithium
diisopropylamide (van Leusen Çt al., Tetrahedron Letters. No. 23, 2367-68 (1972)).
The compounds of formula (VI)-Scheme I may be prepared by reacting a
25 compound of the formula (VIII)-Scheme I, R4CH2NH2 with an alkyl formate (e.g.ethylformate) to yield an intermediate amide which can be converted to the desired
isonitrile by reacting with well known dehydrating agent, such as but not limited to
oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable
base such as triethylamine.
Alternatively a compound of the formula (VIII) - Scheme I may be converted to
a compound of the formula (VI)- Scheme I by reaction with chloroform and sodium
hydroxide in aqueous dichloromethane under phase transfer catalysis.
The compounds of the formula (III) - Scheme I may be prepared by reacting a
compound of the formula RlCHO with a primary amine R2NH2.
The amino compounds of the formula (VIII) - Scheme I are known or can be
prepared from the corresponding alcohols, oximes or amides using standard functional
group interconversions.
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In Scheme XII below, the compound 5-Scheme 12 is shown in the Examples
section as Example 2, the compound 6-Scheme 12 as Example 4; compound 7-Scheme 12
as Example 5; 8-Scheme 12 as Example 6: and compound 9-Scheme 12 as Example 7.
o o
I I I I ~
~~~ a ~ b ~IJ
O H2N ~
2 H N~NJ 3
NOH NHOH
F--~ F~ 3
HO'NJ~ NH
9 ~ 5
N
Conditions: a) i. NH20H-HCI, Na2CO3, H20; ii. Raney Ni, H2; b) 2-aminopyrimidinyl~-carboxaldhyde, CH2CI2
c) 4-tluc,,u?he,,jl tolythiomethyisocyanide, TBD, CH2CI2; d) i. HCI, H20; ii. Na2CO3, H20; e) NH20H-HCI,
5 Na2CO3, H20; f. NaCNBH3, MeOH; g) KNCO, DMF, H20, HOAC.
SCHEME XII
Cycloalkanones such as l-Scheme XII (available from Aldrich Chemical Co.,
10 Milwaukee, Wi) may be converted to cycloalkylamines such as 2-Scheme XII by
conventional procedures for reductive amination such as oxime formation with
hydroxylamine in H20 followed by reduction of the oxime to the amine by standardconditions such as catalytic hydrogenation with Raney Ni in an H2 atmosphere. The
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- 33 -
resulting cycloaL~ylamines such as 2-Schcme XII may be reacted with aryl aldehydes
such as 2-aminopyrimidinyl-4-carboxaldhyde in non-hydroxylic organic solvents toform imines such as 3-Scheme XII. Depending on the degree of activation of the
aldehydes towards imine formation, catalytic acid (such as toluenesulfonic acid) and
dehydrating conditions (such as azeotropic removal of water in refluxing benzene) may
or may not be needed. Imines such as 3-Scheme XII may be converted to 1,4 diarylimidazoles alkylated with cycloalkyl groups by reaction with isonitriles such as 4-
fluorophenyl-tolylthiomethylisocyanide in the presence of a base such as 1,5,7-
triazabicyclo[4.4.0]-dec-5-ene (TBD) in organic solvents such as CH2CI2. In this way
3-Scheme XII was converted to 5-Scheme XII. Cycloalkyl ketal substituted imidazoles
such as 5-Scheme XII are hydrolyzed with aqueous acids (such as aqueous HCl)
follo~ved by neutralization with base (such as aqueous Na2CO3) to afford ketones such
as 6-Scheme VI. 6-Scheme XII is converted to the oxime 7-Scheme XII with
hydroxylamine in H2O. 7-Scheme XII is converted to the hydroxylamine 8-Scheme XII
by reduction with sodium cyano borohydride in methanol. 8-Scheme X is converted to
the hydroxyureas 9-Scheme XII by the procedure of Adams et al (WO 91/14674
published 3 October 1991).
NaBH~,CH30H ~ ~ H
6 lo
SCHEME XIII
In the above noted Scheme, the alcohol 10-Scheme 13 may be prepared by
reducing the ketone of 6-Scheme 13 with a suitable reducing agent, such as NaBH4.
In formula XI below, Rl is may be an optionally substituted alkyl, aryl or a
25 heteroaryl group and R2 is either an OH, NH2 or SH, or Rl and R2 togethercan form a
C3 7 cycloal~yl ring, such as, for example a pyrrolidine or piperdine ring. Some
representative examples of such compounds are illustrated in scheme XIV below.
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F1 R2
N~N
, I ~
~--N
F ~ (XI)
SCHEME XIV
The ketone 1 can be reacted with any organomettalic reagent (RlM) to afford the
corresponding alcohol 2 ( wherein Rl can be hydrogen or any optionally susbtituted alkyl
5 aryl, arylalkyl, heteocyclic, heterocyclic alkyl, etc. moiety). The alcohol 2 can be
converted to the neopentyl amine 3, by using the classical Ritter reaction well l~nown by
those of skill in th art. The amine 3 can be acylated or sulfonylated. The ketone 1 can be
can be transformed into an spirooxirane 4 by reagents such as dimethylsulfonium
methylide and dimethyl sulfoxonium methylide. The oxirane 4 can be ring opened with a
10 plethora of nucleophiles such as hydroxides, thiolates, amines, organometallic reagents
(such as the well known organo-cuprate or organo-aluminum reagents, etc.).
F ~ F~X 1
2, R1 = H, Alkyl, Aryl, HeterocyHcO 3, R2 = H, COAlk, COAr
~,o ~,,R1
HN~ HN~Ç)
F~--N N
4 5, R1 = CH20H,CH2SH,cH2NH2.
Optionally subst. Alkyl or Aryl
SCHEME XIV
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- 35 -
The ketone 1 -Scheme XV may also be subjected to reductive amination by any
primary or secondary amines to afford amines 6-Scheme XV.
o N'
HN ~N ~ HN ~N
N ~ l N Rl R2NHI EtOH N ~ N
,~ orMeOH, NaCNBH3 ~ ,~
~N ~ N
R1 and P2 can be any alkyl or aryl
group,R1 and R2 can also be a part of a ring
SCHEME XV
s
Suitable protecting groups for use with hydroxyl groups and the imidazole
nitrogen are well known in the art and described in many references, for instance,
Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York,
1981. Suitable examples of hydroxyl protecting groups include silyl ethers, such as t-
10 butyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl connected by an
alkyl chain of variable link, (CRloR20)n. Suitable examples of imidazole nitrogen
protectin~ groups include tetrahydropyranyl.
Pharmaceutically acid addition salts of compounds of Formula (I) may be
obtained in known manner, for example by treatment thereof with an appropriate
15 amount of acid in the presence of a suitable solvent.
MFTHODS OF TREATMENT
The compounds of Formula (I) or a pharmaceutically acceptable salt thereof can
be used in the manufacture of a medicament for the prophylactic or therapeutic
20 treatment of any disease state in a human, or other m~mm~l, which is exacerbated or
caused by excessive or unregulated cytokine production by such m~mmAl's cell, such as
but not limited to monocytes and/or macrophages.
Compounds of Formula (I) are capable of inhibiting proinfl~mm~tQry cytokines,
such as IL- 1, IL-6, IL-8 and TNF and are therefore of use in therapy. IL- 1, IL-6, IL-8
25 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other
leukocyte-derived cytokines, are important and critical inl~:lmm~tory medi~tors of a
wide variety of disease states and conditions. The inhibition of these pro-infl~mm~tory
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cytokines is of benefit in controlling, reducing and alleviating many of these disease
states.
Compounds of Formula (I) are capable of inhibiting inducible proinflammatory
proteins, such as COX-2, also referred to by many other names such as prostaglandin
endoperoxide synthase-2 (PGHS-2) and are therefore of use in therapy. These
proinflamm~ory lipid mediators of the cyclooxygenase (CO) pathway are produced by
the inducible COX-2 enzyme. Regulation, therefore of COX-2 which is responsible for
the these products derived from arachidonic acid, such as prostaglandins affect a wide
variety of cells and tissues are important and critical inflammatory mediators of a wide
lO variety of disease states and conditions. Expression of COX-l is not effected by
compounds of Formula (I). This selective inhibition of COX-2 may alleviate or spare
ulcerogenic liability associated with inhibition of COX- l thereby inhibiting
prostoglandins essential for cytoprotective effects. Thus inhibition of these pro-
infl~mm~tory mediators is of benefit in controlling, reducing and alleviating many of
15 these disease states. Most notably these inflammatory mediators, in particular
prostaglandins, have been implicated in pain, such as in the sensitization of pain
receptors, or edema. This aspect of pain management therefore includes treatment of
neuromuscular pain, headache, cancer pain, and arthritis pain. Compounds of Formula
(I) or a ph~rmaceutically acceptable salt thereof, are of use in the prophylaxis or
20 therapy in a human, or other m~mma1, by inhibition of the synthesis of the COX-2
enzyme.
Accordingly, the present invention provides a method of inhibiting the synthesisof COX-2 which comprises arlmini~tering an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof. The present invention also
25 provides for a method of prophylaxis treatment in a human, or other m~mma,1, by
inhibition of the synthesis of the COX-2 enzyme.
Accordingly, the present invention provides a method of treating a cytokine-
mediated diseasc which comprises ~rlmini~t~ring an effective cytokine-interfering
amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In particular, compounds of Formula (I) or a pharmaceutically acceptable salt
thereof are of use in the prophylaxis or therapy of any disease state in a human, or other
m~mma1, which is exacerbated by or caused by excessive or unregulated IL-l, IL-8 or
TNF production by such m~mma1's cell, such as, but not limited to, monocytes and/or
macrophages.
Accordingly. in another aspect, this invention relates to a method of inhibitingthe production of IL- l in a mamma1 in need thereof which comprises administering to
said mamma1 an efi'ective amount of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof.
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Wo 96/21654 PCT/US96~109
- 37 -
There are many disease states in which excessive or unregulated IL- l productionis implicated in exacerbating and/or causing the disease. These include rheumatoid
arthritis, osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, other acute or
chronic infiammAtory disease states such as the infl~mmAtory reaction induced by5 endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscledegeneration, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, Reiter's
syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute
synovitis. Recent evidence also links IL- 1 activity to diabetes, pancreatic 13 cells and
Alzheimer's disease.
In a further aspect, this invention relates to a method of inhibiting the production
of TNF in a mamm~l in need thereof which comprises a~mini.ctering to said mammal an
effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
Excessive or unregulated TNF production has been implicated in mediating or
exacerbating a number of diseases including rheumatoid arthritis, rheumatoid
spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic
shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory
distress syndrome, stroke, cerebral malaria, chronic pulmonary inflAmmAtory disease,
silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis,
reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to
infection, such as influenza, cachexia secondary to infection or malignancy, cachexia
secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS relatedcomplex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and
pyresis.
Compounds of Formula (I) are also useful in the treatment of viral infections,
where such viruses are sensitive to upregulation hy TNF or will elicit TNF production in
vivo. The viruses contemplated for treatment herein are those that produce TNF as a
result of infection. or those which are sensitive to inhibition, such as by decreased
replication, directly or indirectly, by the TNF inhibiting-compounds of Formula (1).
Such viruses include, but are not limited to HIV- 1, HIV-2 and HIV-3, Cytomegalovirus
(CMV), Influenza, adenovirus and the Herpes group of viruses, such as but not limited
to, Herpes Zoster and Herpes Simplex. Accordingly, in a further aspect, this invention
relates to a method of treating a mAmmAl afflicted with a human immunodeficiencyvirus (HIV) which comprises Acimini.~tering to such mAmmAl an effective TNF
inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt
thereof.
Compounds of Formula (I) may also be used in association with the veterinary
treatment of mamm~ , other than in humans, in need of inhibition of TNF production.
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TNF mediated diseases for treatment, therapeutically or prophylactically. in animals
include disease states such as those noted above, but in particular viral infections.
Examples of such viruses include, but are not limited to, lentivirus infections such as,
equine infectious ~n~l~.mia virus, caprine arthritis virus, visna virus, or maedi virus or
retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV),
bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral
infections.
The compounds of Formula (I) may also be used topically in the treatment or
prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine
production, such as by IL- 1 or TNF respectively, such as inflamed joints. eczema,
psoriasis and other infl~mmatory skin conditions such as sunburn; infl~mm~ory eye
conditions including conjunctivitis; pyresis, pain and other conditions associated with
in~mm~tion.
Compounds of Formula (I) have also been shown to inhibit the production of IL-
8 (Interleukin-8, NAP). Accordingly, in a further aspect, this invenlion relates to a
method of inhibiting the production of IL-8 in a m~mm~l in need thereof which
comprises ~(lministering to said m~mm~l an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof.
There are many disease states in which excessive or unregulated IL-8 production
is implicated in exacerbating and/or causing the disease. These diseases are
characterized by massive neutrophil infiltration such as, psoriasis, infl~mm~tory bowel
disease, asthma, cardiac and renal reperfusion in.jury, adult respiratory distress
syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with
increased IL-8 production which is responsible for the chemotaxis of neutrophils into
the infl~mm~tory site. In contrast to other inflamm~tory cytokines (IL-l, TNF, and IL-
6), IL-8 has the unique property of promoting neutrophil chemotaxis and activation.
Therefore, the inhibition of IL-8 production would lead to a direct reduction in the
neutrophil infiltration.
The compounds of Formula (I) are ~dministered in an amount sufficient to
inhibit cytokine, in particular IL-l, IL-6, IL-8 or TNF, production such that it is
regulated down to normal levels, or in some case to subnormal levels, so as to
ameliorate or prevent the disease state. Abnormal levels of IL- 1, IL-6, IL-8 or TNF, for
instance in the context of the present invention. constitute: (i) levels of free (not cell
bound) IL-l, IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell
associated IL- 1, IL-6, IL-8 or TNF; or (iii) the presence of IL- 1, IL-6, IL-8 or TNF
mRNA above basal levels in cells or tissues in which IL- 1, IL-6, IL-8 or TNF,
respectively, is produced.
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The discovery that the compounds of Formula (I) are inhibitors of cytokines,
specifically IL- 1, IL-6, IL-8 and TNF is based upon the effects of the compounds of
~ormulas (I) on the production of the IL- 1, IL-8 and TNF in in vitro assays which are
described herein.
As used herein, the term "inhibitin~ the production of IL-1 (IL-6, IL-8 or TNF)"refers to:
a) a decrease of excessive iM vivo levels of the cytokine (IL- 1, IL-6, IL-8 or
TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of
the cytokine by all cells, including but not limited to monocytes or macrophages;
b) a down regulation, at the genomic level, of excessive in vivo levels of the
cytokine (IL- 1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels:
c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL- 1,
IL-6. IL-8 or TNF) as a postranslational event; or
d) a down regulation, at the translational level, of excessive iM vivo levels of the
cytolcine (IL- 1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels.
As used herein, the term "TNF mediated disease or disease state" reters to any
and all disease states in which TNF plays a role, either by production of TNF itself, or
by TNF causing another monokine to be released, such as but not limited to IL-I, IL-6
or IL-8. A disease state in which, for instance, IL- 1 is a major component, and whose
production or action, is exacerbated or secreted in response to TNF, would therefore be
considered a disease stated mediated by TNF.
As used herein, the term "cytokine" refers to any secreted polypeptide that
affects the functions of cells and is a molecule which modulates interactions between
cells in the immune, infl~mm~tory or hematopoietic response. A cytokine includes, but
is not limited to, monokines and lymphokines, regardless of which cells produce them.
For instance, a monokine is generally referred to as being produced and secreted by a
mononuclear cell, such as a macrophage and/or monocyte. Many other cells howeveralso produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils,
endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and
B-lymphocytes. Lymphokines are generally referred to as being produced by
lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin- I
(IL- I ), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-oc)
and Tumor Necrosis Factor beta (TNF-13).
As used herein, the term "cytokine interfering" or "cytokine suppressive
amount" refers to an effective amount of a compound of Formula (I) which will cause a
decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given
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to a patient for the prophylaxis or treatment of a disease state which is exacerbated hy,
or caused by, excessive or unregulated cytokine production.
As used herein, the cytokine referred to in the phrase "inhibition of a cytokine,
for use in the treatment of a HIV-infected human" is a cytokine which is implicated in
(a) the initiation and/or maintenance of T cell activation and/or activated T cell-
mediated HIV gene expression and/or replication and/or (b) any cytokine-mediateddisease associated problem such as cachexia or muscle degeneration.
As TNF-13 (also known as lymphotoxin) has close structural homology with
TNF-oc (also known as cachectin) and since each induces similar biologic responses and
10 binds to the same cellular receptor, both TNF-a and TNF-~ are inhibited by the
compounds of tbe present invention and thus are herein referred to collectively as
"TNF" unless specifically delineated otherwise.
A new member of the MAP kinase family, alternatively termed CSBP, p38, or
RK, has been identified independently by several laboratories recently. Activation of
15 this novel protein kinase via dual phosphorylation has been observed in different cell
systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress
and treatment with lipopolysaccharide or proinfl~mm~ory cytokines such as interleukin-
1 and tumor necrosis f'actor. The cytokine biosynthesis inhibitors, of the present
invention, compounds of Formula (I), have been determined to be potent and selective
20 inhibitors of CSBP/p38/RK kinase activity. These inhibitors are of aid in determining
the signaling pathways involvement in infl~mm~tory responses. In particular, for the
first time a definitive signal transduction pathway can be prescribed to the action of
lipopolysaccharide in cytokine production in macrophages.
The cytokine inhibitors were subsequently tested in a number of animal models
25 for anti-in~l~mm~tory activity. Model systems were chosen that were relatively
insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of
cytokine suppressive agents. The inhibitors exhibited significant activity in many such
in vivo studies. Most notable are its effectiveness in the collagen-induced arthritis
model and inhibition of TNF production in the endotoxic shock model. In the latter
30 study, the reduction in plasma level of TNF correlated with survival and protection
from endotoxic shock related mortality. Also of great importance are the compounds
effectiveness in inhibiting bone resorption in a rat fetal long bone organ culture system.
Griswold et al., (1988) Arth~itis Rhe~m. 31:1406-1412; Badger, et al., (1989) circ.
Sh~7c~27,51-61;Vottaetal., (1994)invitro.Bone 15,533-538;Leeetal., (1993).B
35 An~l. N. Y. Acad. Sci. 696, 149- 170.
In order to usc a compound of Formula (I) or a pharmaceutically acceptable salt
thereof in therapy, il will normally be Formulated into a pharmaceutical composition in
accordance with standard pharmaceutical practice. This invention, therefore, also
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relates to a pharmaceutical composition comprising an effective, non-toxic amount of a
compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
Compounds of Formula (I), pharmaceutically acceptable salts thereof and
phannaceutical compositions incorporating such may conveniently be administered by
any of the routes conventionally used for drug administration, for instance, orally,
topically, parenterally or by inhalation. The compounds of Formula (I) may be
administered in conventional dosage forms prepared by combining a compound of
Formula (I) with standard pharmaceutical carriers according to conventional procedures.
The compounds of Formula (I) may also be administered in conventional dosages in10 combination with a known, second therapeutically active compound. These procedures
may involve mixing, granulating and compressing or dissolving the ingredients asappropriate to the desired preparation. It will be appreciated that the form and character
of the pharmaceutically acceptable character or diluent is dictated by the amount of
active ingredient with which it is to be combined, the route of ~dministration and other
15 well-known variables. The carrier(s) must bc "acceptable" in the sense of being
compatible with the other ingredients of the Formulation and not deleterious to the
recipient thereof.
The pharmaceutical carrier employed may be, for example, either a solid or
liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar,
20 pectin, acacia, m~nesium stearate, stearic acid and the like. Exemplary of liquid
carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or
diluent may include time delay material well known to the art, such as glyceryl mono-
stearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid
25 carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in
powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier
will vary widely but preferably will be from ahout 25mg. to about lg. When a liquid
carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin
capsule, sterile injectable li~yuid such as an ampule or nonaqueous liquid suspension.
Compounds of Formula (I) may be administered topically, that is by non-
systemic administration. This includes the application of a compound of Formula (I)
externally to the epidermis or the buccal cavity and the instillation of such a compound
into the ear~ eye and nose, such that the compound does not significantly enter the blood
stream. In contrast, systemic ~ministration refers to oraL intravenous, intraperitoneal
35 and intramuscular aclmini.stration.
Formulations suitable for topical a(lministration include li4uid or semi-liquid
preparations suitable for penetration through the skin to the site of infl~mmation such as
linirnents, lotions, creams, ointments or pastes~ and drops suitable for ~-~minictration to
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the eye, ear or nose. The active ingredient may comprise, for topical ~ mini~tration~
from 0.001~ to 10% w/w, for instance from 1% to 2% by weight of the Formulation. I
may however comprise as much as 10% w/w but preferably will comprise less than 5w/w, more preferably from 0.1% to 1% w/w of the Formulation.
Lotions according to the present invention include those suitable for application
to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally
containing a bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skin may also include
an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a
moisturizer such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the present invention are semi-solid
Formulations of the active ingredient for external application. They may be made by
mixing the active ingredient in finely-divided or powdered form, alone or in solution or
suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with
a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or
liquid paraflin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin
such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty
acid such as steric or oleic acid together with an alcohol such as propylene glycol or a
macrogel. The Formulation may incorporate any suitable surface active agent such as
an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene
derivative thereof. Suspending agents such as natural gums, cellulose derivatives or
inorganic materials such as silicaceous silicas, and other ingredients such as lanolin,
may also be included.
Drops according to the present invention may comprise sterile aqueous or oily
solutions or suspensions and may be prepared by dissolving the active ingredient in a
suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other
suitable preservative, and preferably including a surface active agent. The resulting
solution may then be clarified by filtration, transferred to a suitable container which is
then sealed and sterilized by autoclaving or maintaining at 98-100" C. for half an hour.
Alternatively, the solution may be sterilized by filtration and transferred to the container
by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for
inclusion in the drops are phenylmercuric nitrate or acetate (0.002%)? benzalkonium
chloride (0.01 %) and chlorhexidine acetate (0.01%). Suitable solvents for the
preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Compounds of formula (I) may be administered parenterally, that is by
intravenous~ intramuscular, subcutaneous intranasal, intrarectal, intravaginal or
intraperitoneal ~clmini.ctration. The subcutaneous and intramuscular forms of parenteral
administration are generally preferrcd. Appropriate dosage forms for such
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~minictration may be prepared by conventional techni~ues. Compounds of Formula (I)
may also be a~mini.~tered by inhalation, that is by intranasal and oral inhalation
~mini~tration. Appropriate dosage forms for such ~lmini.stration, such as an aerosol
Formulation or a metered dose inhaler, may be prepared by conventional techniques.
For all methods of use disclosed herein for the compounds of Formula (I), the
daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total
body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg
to 15mg. The daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total
body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from
about 0.5 mg to 15mg/kg. The daily topical dosage regimen will preferably be from 0.1
mg to 150 mg, administered one to four, preferably two or three times daily. The daily
inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg
per day. It will also be recognized by one of skill in the art that the optimal quantity and
spacing of individual dosages of a compound of Formula (I) or a pharmaceuticallylS acceptable salt thereof will be determined by the nature and extent of the condition
being treated, the form, route and site of ;~lmini~tration, and the particular patient being
treated, and that such optimums can be determined by conventional techniques. It will
also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the
number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt
thereof given per day for a defined number of days, can be ascertained by those skilled
in the art using conventional course of treatment determination tests.
The invention will now be described by reference to the following biological
exarnples which are merely illustrative and are not to be construed as a limitation of the
scope of the present invention.
BIOLOGICAL EXAMPJ F.~C.
The cytokine-inhibiting effects of compounds of the present invention were
determined by the following in vitr(7 assays:
lnterleukin- 1 (IL-l)
Human peripheral blood monocytes are isolated and purified from either fresh
blood preparations from volunteer donors, or from blood bank buffy coats, according to
the procedure of Colotta et al, J Immunol, 132, 936 (1984). These monocytes (lx106)
are plated in 24-well plates at a concentration of 1-2 million/ml per well. The cells are
allowed to adhere for 2 hours, after which time non-adherent cells are removed by
gentle washing. Test compounds are then added to the cells for about lhour before the
addition of lipopolysaccharide (50 ng/ml), and the cultures are incubated at 37~C for an
additional 24 hours. At the end of this period, culture super-natants are removed and
clarified of cells and all debris. Culture supernatants are then immediately assayed for
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IL-I biological activity, either by the method of Simon et al., J. Immunol. Methods. 84,
85, (1985) (based on ability of IL-I to stimulate a Interleukin 2 producing cell line (EL-
4) to secrete IL-2, in concert with A23187 ionophore) or the method of Lee et al., J.
ImmunoTherapy, 6 (1), 1 - 12 (1990) (ELISA assay).
S
Tumour Necrosis Factor (TNF):
Human peripheral blood monocytes are isolated and purified from either blood
bank buffy coats or plateletpheresis residues, according to the procedure of Colotta, R.
et al., J Immunol, 132(2), 936 (1984). The monocytes are plated at a density of lx106
cells/ml medium/well in 24-well multi-dishes. The cells are allowed to adhere for 1
hour after which time the supernatant is aspirated and fresh medium (lml, RPMI-1640,
Whitaker Biomedical Products, Whitaker, C~) containing 1 % fetal calf serum pluspenicillin and streptomycin (I() units/ml) added. The cells are incubated for 45 minutes
in the presence or absence of a test compound at 1 nM- I OmM dose ranges (compounds
are solubilized in dimethyl sulfoxide/ethanol, such that the final solvent concentration in
the culture medium is 0.5% dimethyl sulfoxide/0.5% ethanol). Bacterial lipopoly-saccharide (E. coli 055:B5 [LPS] from Sigma Chemicals Co.) is then added (100 ng/ml
in 10 ml phosphate buffered saline) and cultures incubated for 16- 18 hours at 37~C in a
5% C~2 incubator. At the end of the incubation period, culture supernatants are
removed from the cells, centrifuged at 3000 rpm to remove cell debris. The supernatant
is then assayed for TNF activity using either a radio-immuno or an ELISA assay, as
described in WO 92/10190 and by Becker et al., J Immunol, 1991, 147, 4307.
IL-I and TNF inhibitory activity does not seem to correlate with the property ofthe compounds of Formula (I) in mediating arachidonic acid metabolism inhibition.
Further the ability to inhibit production of prostaglandin and/or leukotriene synthesis, by
nonsteroidal anti-infl~mm~tory drugs with potent cyclooxygenase and/or lipoxygenase
inhibitory activity does not mean that the compound will necessarily also inhibit TNF or
IL-l production, at non-toxic doses.
lnterleukin -8 (IL-8 ):
Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems,
Kirland, Wa) are m~in~ined in culture medium supplemented with 15% fetal bovine
serum and I ~ CS-HBGF consisting of aFGF and heparin. The cells are then diluted20-fold before being plated (250,ul) into gelating coated 96-well plates. Prior to use,
culture medium are replaced with fresh medium (200~1). Buffer or test compound
(25~1, at concentrations between I and IOIlM) is then added to each well in
quadruplicate wells and the plates incubated for 6h in a humidified incubator at 37~C in
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- 45 -
an atmosphere of 5% CO2. At the end of the incubation period, supernatant is removed
and a~.sayed for IL-8 concentration usin~ an IL-8 ELISA kit obtained from R&D
Systems (Minneapolis, MN). All data is presented as mean value (ng/ml) of multiple
samples based on the standard curve. ICso's where appropriate are generated by non-
5 linear regression analysis.
Cytokine Specific Binding Protein Assay
A radiocompetitive binding assay was developed to provide a highly reproducibleprimary screen for structure-activity studies. This assay provides many advantages over
10 the conventional bioassays which utilize freshly isolated human monocytes as a source of
cytokines and ELISA assays to quantify them. Besides being a much more facile assay,
the binding assay has been extensively validated to highly correlate with the results of
the bioassay. A specific and reproducible cytokine inhibitor binding assay was developed
using soluble cystosolic fraction from THP. 1 cells and a radiolabeled compound. Patent
Application USSN 08/123175 Lee et al., filed September 1993, USSN; Lee et al., PCT
94/10529 filed 16 September 1994 and Lee et al., Natu~-e 300, n(72), 739-746 (Dec.
1994) whose disclosures are incorporated by reference herein in its entirety describes the
above noted method for screening drugs to identify compounds which interact with and
bind to the cytokine specific binding protein (hereinafter CSBP). However, for purposes
20 herein the binding protein may be in isolated form in solution, or in immobilized form, or
may be genetically engineered to be expressed on the surface of recombinant host cells
such as in phage display system or as fusion proteins. Alternatively, whole cells or
cytosolic fractions comprising the CSBP may be employed in the creening protocol.
Regardless ol the form of the binding protein, a plurality of compounds are contacted
25 with the binding protein under conditions sufficient to form a compound/ binding protein
complex and compound capable of forming, enhancing or interfering with said
complexes are detected.
Representative final compounds of Formula (I), of Formula (I), Examples 4, 7,
8, 10 to 21 have all demonstrated positive inhibitory activity in this binding assay.
Prostog1~nrlin endoperoxide synthase-2 (PGHS-2) assay.
The following assay describes a method for determining the inhibitory effects ofcompounds of Formula (I) on human PGHS-2 protein expression in LPS stimulated
human monocytes
35 Method:
Human peripheal blood monocytes were isolated from buffy coats by centrifugationthrough Ficoll and Pcrcoll gradients. Cells were seeded at 2 X 106/well in 24 well plates
and allowed to adhere for 1 hour in RPMI supplemented with 1% human A13 serum,
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20mM L-glutamine, Penicillin-Streptomycin and lOmM HEPES. Compounds were
added at various concentrations and incubated at 37~C for 10 minutes. LPS was added at
50 ng/well (to induce enzyme expression) and incubated overnight at 37~C. The
supernatant was removed and cells washed once in cold PBS. The cells were lysed in
100~11 of cold lysis buffer(SOmM Tris/HCI pH 7.5, 150mM NaCl, 1% NP40, 0.5%
sodium deoxycholate, 0.1 % SDS, 300ug/ml DNAse, 0.1 % TRITON X- 100, 1 mM PMSF,
lmM leupeptin, lmM pepstatin). The Iysate was centrifuged (10,000 ~ g for 10 min. at
4~C) to remove debris and the soluble fraction was subjected to SDS PAGE. analysis
(12~ gel). Protein separated on the gel were transferred onto nitrocellulose membrane
by electrophoretic means for 2 hours at 60 volts. The membrane was pretreated for one
hour in PBS/O. l ~ Tween 20 with 5% non-fat dry milk. After washing 3 times in
PBS/Tween buffer, the membrane was incubated with a 1 :2000 dilution of a
monospecific antiserum to PGHS-2 or a 1:1000 dilution of an antiserum to PGHs-l in
PBS/Tween with 1 % BSA for one hour with continuous shaking. The membrane was
washed 3X in PBS/Tween and then incubated with a 1 :3000 dilution of horseradishperoxidase conjugated donkey antiserum to rabbit Ig (Amersham) in PBS/Tween with1% BSA for one hour with continuous shaking. The membrane was then washed 3X in
PBS/Tween and the ECL immunodetection system (Amersham) was used to detect the
level of expression of prostaglandin endoperoxide synthases-2.
RESULTS:
The following compounds were tested and found to be active (inhibited
LPS induced PGHS-2 protein expression in rank order potency similar to that for
inhibiting cytokine production as noted in assays indicated):
6-(4-Fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo~2,1-b]thiazole and
Dexamethasone
Several compounds were tested and found to be inactive (up to lOuM):
2-(~Methylsulfinylphenyl)-3-(4-pyridyl)-6~7-dihydro-(SH)-pyrrolo[1,2-a]imidazolerolipram, phenidone and NDGA.
None of the compounds tested was found to inhibit PGHS-l or cPLA2
protein levels in similar experiments.
SYN l ll~; l lC EXAMPLES
The invention will now be described by reference to the following examples
which are merely illustrative and are not to be construed as a limitation of the scope of
the present invention. All temperatures are given in degrees centigrade, all solvents are
highes~i available purity and all reactions run under anydrous conditions in an argon
atmosphere unless otherwise indicated.
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In the Examples, all temperatures are in degrees Centigrade (~C). Mass spectra
were performed upon a VG Zab mass spectrometer using fast atom bombardment,
unless otherwise indicated. lH-NMR (hereinafter "NMR") spectra were recorded at
250 MHz using a Bruker AM 250 or Am 400 spectrometer. Multiplicities indicated are:
5 s=singlet, d-doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal.
Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of
reagent relative to the principal reactant.
Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh).
Example I
I -r~-(4-Morpholinyl)propyll-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole
a) 4-fluorophenyl-tolylthiomethylformamide
A solution of p-fluorobenzaldehyde (13.1 milliliters (hereinafter mL), 122
millimoles (hereinafter mmol) thiocresol (16.64 grams (hereinafter g), 122 mmol),
formamide (15.0 mL, 445 mmol), and toluene (300 mL) were combined and heated to
toluene reflux with azeotropic removal of H2O for 18 h. The cooled reaction was
diluted with EtOAc (500 mL) and washed with satd aq Na2CO3(3 x 100 mL), satd aq
NaCl (100 mL), dried (Na2SO4), and concentrated. The residue was triturated withpetroleum ether, f1ltered and dried in vacuo to afford 28.50 g of the title compound as a
white solid (85 %). melting point (hereinafter mp) = 119 - 120~.
b) 4-fluorophenyl-tolylthiomethylisocyanide
The compound of example l(a) (25 g, 91 mmol) in CH2C12 (300 mL) was
cooled to -30~ and with mechanical stirring POC13 (11 mL, 110 mmol) was added
dropwise followed by the dropwise addition of Et3N (45 mL, 320 mmol) with the
temperature maintained below -30~. Stirred at -30~ for 30 min and 5~ for 2 h, diluted
with CH2C12 (300 mL) and washed with 5% aq Na2CO3 (3 x 100 mL), dried (Na2SO4)
and concentrated to 500 mL. This solution was filtered through a 12 x 16 cm cylinder of
silica in a large sintered glass funnel with CH2C12 to afford 12.5 g (53%) of purified
isonitrile as a light brown, waxy solid. IR (CH2C12) 2130 cm~l.
c) Pyridine-4-carhoxaldehyde ~4-Morpholinylprop-3-yllimine
Pyridine-4-carhoxaldehyde (2.14 g, 20 mmoL), 4-(3-aminopropyl)morpholine
(2.88 g, 20 mmol), toluene (50 mL) and MgSO4 (2 g) were combined and stirred under
argon for 18 h. The MgSO4 was filtered off and the filtrate was concentrated and the
residue was reconcentrated from CH2C12 to afford 4.52 g (97%) of the title compound
as a yellow oil containing less than 5% of aldehyde based on IH NMR. lH NMR
(CD3Cl): d 8.69 (d, J = 4.5 Hz, 2H), 8.28 (s, lH), 7.58 (d, J = 4.5 Hz, 2H), 3.84 (m,
6H), 2.44 (m, 6H), 1.91 (m, 2H).
d) l-r3-(4-Morl~holinyl~propyl]-4-(4-fluorophenyl)-5-(4-pyridyl~imidazQle
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The compound of example I (b) (1.41 g, 5.5 mmol), and the compound of
example l(c) (1.17 g, 5.0 mmol) and CH2C12 (10 mL) were cooled to 5 ~C. 1.5.7-
triazabicyclo[4.4.0]dec-5-ene, henceforth referred to as TBD, (0.71 g 5.0 mmol) was
added and the reaction was kept at 5 ~C for 16 h, diluted with EtOAc (80 mL) andwashed with satd aq Na2CO3 (2 x 15 mL). The ~tOAc was extracted with 1 N HCl (3
x 15 mL), and the acid phases were washed with EtOAc (2 x 25 mL), layered with
EtOAc (25 mL) and made basic by the addition o~solid K2co3 til pH 8.0 and then 10%
NaOH til pH 10. The phases were separated and the aq was extracted with additional
EtOAc (3 x 25 mL). The extracts were dried (K2C03) concentrated and the residue was
crystalized from acetone/hexane to afford 0.94 g (51%) of the title compound. mp =
149 - 150 ~.
Fxample 2
5-(2-amino-4-pyrimidinyl)-4-(4-flu~rophenyl)- 1 -(4-(1.3-dioxycyclopentyl) cyclohexyl)
I S imidazole
a) I-Amino-4-(1.3-dioxycylopentyl)cyclohexane 1,4-Cyclohexanedione
monoethylene ketal (15.6 g, 0.10 mol) H2O (170 mL) and Na2CO3 (27.8 g) were
combined and NH2OH ~ HCl (27.8 g, 0.40 mol) was added in small portions. The
resulting mixture was stirred for 30 min. Extraction with EtOAc, drying (Na2SO4) and
concentration afforded 17. Ig (100%) of 4-(1,3-dioxycylopentyl)-cyclohexanone oxime.
The oxime (6.0 g, 35 mmol), Raney Ni (ca 3 mL as a suspension in pH 7.0 H2O)
and EtOH (abs) were combined and shaken at 50 psi H2 for 16 h. The catalyst was
filtered off and the filtrate was concentrated and distilled to afford 2.4 g (60%) of the
title compound (bp = 68~, 0.18 mm).
b) 2-Aminopyrimidine-4-carhoxaldehyde (4-ethylene ketal-l-cyclohexyl) imine
The product of the previous step 2 (a), and the product of Example 3 (b),
prepared below, were reacted by the procedure of 1 (c) except that the solvent was
CH2C12 and no drying agent (MgSO4) was required to afford the title compound as a
yellow oil.
c) 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-dioxycyclohexyl)imidazoleFollowing the procedure of example 1 (d) except using the compound of the
previous step as the imine afforded the title compound. ESI mass spectrum MH+ = 396.
Fxample 3
2-Aminopyrimidinc-4-carhoxaldehyde
a) 2-Aminopyrimidine-4-carhnxaldehyde dimethyl acetal
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Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvic aldehyde
dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100~ Ior about 18
hours. Methanol was removed in vacuo to afford an oil.
A solution of NaOH (18 g, 0.45 mol) in H2O (50 mL) was added to guanidine
HCI (43 g, 0.45 mol) in H2O (100 mL), and the resulting solution was added to the
above described oil. The resulting mixture was stirred at 23~ for 48 h. Filtration
afforded 25g (50%) of the title compound.
b) 2-Aminopyrimidine-4-carboxaldehyde
The compound of the previous step (1.69 g, 10 mmol) and 3N HCI (7.3 mL, 22
mmol) were combined and heated to 48~ for 14h, cooled, layered with EtOAc (50 mL)
and neutralized by the addition of NaHCO3 (2. lg, 25 mmol) in small portions. The aq
phase was extracted with EtOAc (5 x 50 mL) and the extracts were dried (Na2SO4)and
concentrated to afford 0.793 g (64%) of the title compound.
F.xam~le 4
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-ketocyclohexyl)imidazole
The product of example 2 (1.27 g, 3.22 mmol) and 3 N HCL (12.4 mL) were
combined and stirred at 23~ for 16 h, combined with 10% aq Na2CO3 (50 mL) and
extracted with EtOAc. The extracts were dried (Na2SO4) and concentrated and flash
chromatographed (0 - 4% MeOH) to afford 0.72 g (64~,) of the title compound as awhite solid. ESI mass spectrum MH+ = 352.
Fx~mple 5
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-cyclohexyl oxime) imidazole
The product of example 4 (351 g, 1.0 mmol), NH2OH ~ HCI (278 mg, 4.0
mmol), H2O (6 mL), and CH30H, (2 mL) were combined, Na2CO3 (278 mg, 2.6
mmol) was added in small portions. The mixture was stirred for 24 h, aq NaHCO3 was
added and the mixture was extracted with CH2C12, concentrated and flash
chromatographed with 0 - 8% MeOH to afford 0.248 g (67~c) of the title compound.
~ F~rnple 6
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-cyclohexyl hydroxylamine)
imi~7ole
The product of example 5 (250 mg, 0.68 mmol), NaCNBH3 (42 mg, 0.68 mmol)
and MeOH (2.5 mL) were combined. Methanolic HCI (several drops) was added (pH <
3) and the mixture was stirred for I h, diluted with 10% aq NaOH and extracted with
EtOAc. The extracts were dried (Na2SO4) concentrated and flash chromatographed (0 -
8% MeOH in CH2C12) to afford 160mg (64%). E~I mass spectrum MH+ = 369.
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F~ample 7
5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)- I -(trans-4-hydroxyl-rea) imidazole and
5-(2-~mino-4-pyrimiflinyl)-4-(4-fluorophenyl)-1-(ci.S-4-hydroxyurea) imi~701e
The product of example 6 was reacted by the procedure of Adams et al (WO
91/1~674 published 3 October 1991) to afford a mixture of cis and trans cyclohexyl
hydroxyurea isomers. Trituration of the mixture with CH2C12 selectively dissolved the
cis isomer (based on nmr). The solid was filtered off. l~he filtrate was concentrated to
afford 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(cis-4-hydroxyurea) imidazole
10 SB 223768. containing ca 20% of the trans isomer based on nmr. mp = 1 gS - 245 (dec).
The solid obtained above was redissolved in CH2C12/MeOH and concentrated
til precipitation began. Filtration afforded pure 5-(2-amino-4-pyrimidinyl)-4-(4-
fluorophenyl)-l-(trans-4-hydroxyurea) imidazole. mp = 188 - 190~.
Example 8
5-(2-arnino-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(~ran.~-4-hydroxycyclohexyl)
idazole
The product of example 4 (0.61 g, 1.74 mmol) and lM NaBH4 in CH30H were
combined in CH30H / THF (1: 1, 7 mL) and stirred for 10 min, the reaction was poured
20 into 10~c aq Na2C03 (25 mL), extracted with EtOAc (4 x 50 mL) and dried (Na2S04).
Flash chromatography (O - 8% CH30H in CH2cl2) afforded 0.52 g (85%) of the titlecompound.
In methods analagous to those described above and in the schematics herein the
25 following compound may be prepared:
F.x~mple 9: 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-
aminocyclohexyl)imidazole.
Fxample 10
30 5-r4-(2-~-methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-ketocyclohexyl)imid~ole
a) 2-N-methylaminopyrimidine-4-carhoxaldehyde
The title compound was prepared as described in Example 3 using methyl
gll~ni~line-HCI. lH NMR (CDC13, 400 MHz): ~ 9.95 (s, lH), 8.88 (d, IH), 7.50 (, IH),
3.54 (s. 3H), 2.54 (s, 3H).
35 b) 2-N-methylamino,~yrimidine-4-carboxaldehyde-(4-ethyleneketal- 1 -
cyclohexyl)imine
The compound of example lO(a) (.8 g, 5.8 mmol) and the compound of example
2(a) (.8 g, 5.1 mmol) were stirred for 18 h. in DMF (12 mL). Concentration under
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vaccuum afforded the title compound as a yellow oil. lH NMR (400 MHz, CDC13):
8.34 (d, IH), 8.15 (s, lH), 7.13 (d, lH), 5.25 (d,lH), 3.39 (m, lH), 3.03 (d, 3H), 1.90
(m, 7H), 1.79 (m, 2H), 1.65 (m, 2H).
c) 4-fluorophenyl-tolylsulfonylmethvl formamide
Concentrated HCI (15 mL) was added dropwise to a suspension of p-toluene
~ sulfinic acid sodium salt (30 g) in H2O (100 mL) and ter~-butyl methyl ether (50 mL).
After stirring for 15 min., the organic phase was removed and the aqueous phase was
extracted with tert-butyl methyl ether. The organic phases were combined, dried
(Na2SO4), and concentrated almost to dryness. Hexane was added and the resulting10 solid was filtered to give the free acid (22.06 g). The free acid (140.6 mmol) was
combined with p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL, 503
mmol) and camphor sulfonic acid (4 g, 17.3 mmol) and stirred at 60 ~C for 18 h. The
resulting solid was broken up and stirred with methanol (35 mL), and hexane (82 mL).
The mixture was filtered. The large chunks were crushed and the resulting solid was
lS stirred vigorously .S h. in methanol/hexane (200 mL, 1:3). The suspension was filtered
to afford the title compound (27.08 g, 62.7% yield). lH NMR (400 MHz, CDC13):
8.13 (s, lH), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.35 (d, lH), 2.45
(s, 3H).
d) 4-fluoro-tolvlsulfonvlmethyl isocvanide
A mixture of the compound from example 10(c) (2.01 g, 6.52 mmol) in ethylene
glycol dimethyl ether (DME) (32 mL) was cooled to -10~C. Added dropwise was
POC13 (1.52 mL, 16.30 mmol) dissolved in DME (3 mL) keeping the internal
temperature below -5~C. After stirring at -5~C for I h., the reaction was quenched with
H2O and the product was extracted with EtOAc followed by an aqueous saturated
NaHCO3 wash. The organic phase was dried (Na2SO4) and concentrated. The residue
was triturated with petroleum ether and filtered affording the title compound ( 1.70 g,
90% yield) as an orange brown solid. IR (CH2C12) 2135 cm~l.
e) S-r4-(2-N-methylamino)pyrimidinyll-4-(4-fluorophenyl)-1-r4-(1.3-
dioxycyclopentyl)cyclohexyllimidazole
The compound from example 10(b) (1.6 g, 5.84 mmol) was combined with the
compound from example 10(d) (2 g, 6.9 mmol) and powdered K2CO3 (1.2 g, 8.7
mmol) in DMF (12 mL) at 0~C for 3 h. The mixture was slowly warmed to room
temperature and stirred an additional 18 h. EtOAc was added and the mixture was
filtered, concentrated and taken up in H20/EtOAc. The resulting yellow solid wasfiltered and purified hy flash chromatography (silica gel) eluting with 5%
MeOH/CH2C12 to afford the title compound (.50 g, 29% yield) 1H NMR (400 MHz,
CDC13): ~ 8.16 (d, IH), 7.78 (s, IH), 7.45 (q, 2H), 6.99 (t, 2H), 6.40 (d, lH), 5.70 (m,
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IH), 4.74 (m, lH), 3.99 (s, 4H), 3.05 (d, 3H), 2.20 (M, 2H), 2.04 (q, 2H), 1.89 (dd. 2H),
1.68 (m, 3H).
~1 5-r4-~2-N-methylamino)pyrimidinyl~-4-(4-fluorophenyl)- 1-(4-
ketocyclohexyl)imidazole
Following the procedure of example 4 except using the compound of example
10(e) (.50 g, .22 mmol), the title compound was obtained (.37 g, 78% yield). mp 232.5
- 233.5~C. IH NMR (400 MHz, CDC13): ~ 7.97 (d, lH), 7.69 (s, lH), 6.89 (t, 2H),
6.24 (d, IH), 5.08 (m, IH), 3.25 (s, IH), 2.91 (d, 3H), 2.39 (d, 5H), 2.08 (m, 2H), 1.92
(m, lH).
Example 11
5-r4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(trans-4-
hydroxvcyclohexyl)imidazole
The title compound was prepared following the procedure of example 8 except
using the compound from example l l(f) (.451 g, 1.34 mmol) and recrystalizing from
EtOH/H20 to afford white crystals (.38 g, 77% yield). mp 230 - 231~c. lH NMR (400
MHz, CDC13): ~ 8.08 (m, IH), 7.70 (s, lH), 7.37 (q, 2H), 6.98 (t, 2H), 6.32 (d, lH),
4.67 (m, lH), 3.67 (m, lH), 3.00 (s, 3H), 2.18 (m, 2H), 2.07 (m, 2H), 1.75 (m, 2H), 1.37
(m, 2H).
Using an analagous methods to Example I I the cis isomer was also obtained: 5-[4-(2-
N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(tis 4-hydroxycyclohexyl)imidazole
Fxample 12
5-l4-(2-~-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -14-(ci~-
pyrrolidinyl)cyclohexyllimidazole and 5-~4-(2-N-methylamino)pyrimidinyll-4-(4-
fluorophenyl)- I -14-(trans-- 1 -pyrrolidinyl)cyclohexyllimidazole
To a solution of pyrrolidine (.3 mL, 3.6 mmol) in MeOH (3 mL) was added 5%
ethanolic HC1 (.25 mL). The compound of example 10(f) (.50 g, 1.26 mmol) was added
followed by sodium cyanoborohydride (.05 g, 1.30 mmol). After stirring for 2 days, the
mixture was concentrated and the residue was suspended in H2O and brine and thenextracted wtih EtOAc. The organic phase was dried (Na2SO4) and concentrated. Theproducts were purilied by flash chromatography (silica gel) eluting with 5% - 20~
MeOH/CH2C12 with the cis- isomer eluting from the column first to afford the title
compounds 5-[4(2-N-methylamino)pyrimidinyl]-4-(r-fluorophenyl)-1-[4-cis-
pyrrolidinyl)cyclohesyl]imidazole, mp 192 - 193~C, lH NMR (400 MHz, CDC13):
8.04 (s, lH), 7.95 (s. lH), 7.35 (q, 2H), 6.95 (t, 2H), 6.30 (d, lH), 4.59 (s, lH), 3.40 (m,
lH), 2.97 (s, 3H), 2.58 (s, 4H), 2.13 (q, 2H), 2.00 (d, 2H), 1.84 (m, 6H), 1.50 (t, 2H), and
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-[4-(trans- l-pyrrolidinyl)-
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cyclohexyl]imidazole, mp 1 SS - 156~C, 1 E I NMR (400 MHz. CDC13): ~ 8.03 (d, 1 H),
7.69 (s, IH), 7.35 (q, 2H), 6.95 (t, 2H), 6.28 (d, lH), 4.61 (t, lH), 3.12 (s, lH), 2.96 (s,
3H), 2.58 (s, 4H), 2.25-2.05 (m, 4H), 1.78 (s, 4H), 1.70 (m, 2H), 1.35 (t, 2H).
S ~xample 13
~ 5-r4-(2-N-methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-ethynyl-4-
hydroxycyclohexyl)imidazole
The compound from example 10(f) (.50 g, 1.37 mmol) was suspended in dry
THF (5 mL) and cooled to -78~C. Ethynylm~gne~ium bromide (13.4 mL, 6.17 mmol, .SM in THF) was added and the mixture was stirred for 2 h. The reaction was quenched
with saturated aqueous NH4CI and the product was extracted with EtOAc. The organic
phase was dried (Na2S04) and concentrated. The product was purified by flash
chromatography (silica gel) elutin~ with 2% MeOH/CH2C12 to afford the title
compound. mp 233.5 - 234.5~C. 1H NMR (400 MHz, CDC13): ~ 8.08 (d, lH), 7.77 (s,
lH), 7.38 (q. 2H), 6.97 (t, 2H), 6.31 (d, lH), 4.68 (s, IH), 2.76 (s, 3H), 2.62 (s, lH),
2.10 (m, 6H). 1.63 (q, 2H).
Example 14
S-r4-~2-N-methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-amino-4-
mçthylcyclohexyl)imidazole
a) 5-14-(2-N-methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-
methylcyclohexyl)imidazole
Following the procedure of example 13 except using methylm~gnesillm
bromide, the title compound was obtained (7fi% yield) as a 1: 1 mixture of cis- and
trans- isomers. 1H NMR (400 MHz, CDC13): â 8.13 (s, lH), 7.79 (s, .S H), 7.72 (s,
.SH), 7.43 (m, 2H), 6.96 (m, 2H), 6.38 (m, lH), 5.45 (m, lH), 4.68 (m, .SH), 4.52 (m,
.SH), 3.00 (d, 3H), 2.30-1.40 (m, 8H), 1.36 (s, l.S H), 1.25 (s, l.SH).
b) 5-14-(2-N-methvlamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-amino-4-
methylcyclohexyl)imidazole
A mixture of the compound from example 14(a) (.28 g, .75 mmol), sodium
cyanide (.03 g) and H2SO4 (.S mL) was stirred for 1 ~ h. After diluting with H2O and
adding 50~ NaOH, the mixture was refluxed for 4 h., then cooled and extracted with
EtOAc. The a4ueous phase was made basic with 50% NaOH and was extracted with
EtOAc. The organic phase was dried (Na2S04) and concentrated. The residue was
purified by flash chromatography (silica gel) eluting with MeOH/CH2C12/H2O
(20:80:2) to alford the title compound. mp 186 - 192~C.
Example IS
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~-~4-(2-N-methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-acet~mido-4-
metllylcyclohexyl)imi~701e
A mixture of the compound of example 14(b) (.02 g, .05 mmol) and DMAP
(.0012 g, .01 mmol) in pyridine (1 mL) was cooled to 0~C. Acetic anhydride (.009 mL)
S was added and the mixture was warmed to room temperature. After stirring for 18 h.,
the mixture was diluted with H2O and the product was extracted with EtOAc. The
organic phase was dried (Na2SO4) and concentrated. Flash chromatohraphy (silica gel)
eluting with 0% - 5% MeOH/CH2C12 afforded the title compound (.019 g, 90% yield).
mp 175 - 176~C. IH NMR (400 MHz, CDC13): ~ 8.14 (d, lH), 7.77 (s, lH), 7.43 (4,
2H), 7.00 (t, 2H), 6.40 (d, lH), 4.58 (m, lH), 3.03 (d, 3H), 2.41 (d, 2H), 2.09 (m, 2H),
2.02 (s, 3H), 1.82 (m, 2H), 1.40 (c, 3H), 1.37 (m, 2H).
In methods analagous to Examples I to 15 above the following compounds may be
made:
Example 16: 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-
methylcyclohexyl)imidazole; m.p. 160- 161 ~C.
Example 17: 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-oxiranyl-
cyclohexyl)imidazole; m.p. 229-230~C
Ex~rnple 18
5-r4-(2-N-Methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-cyanomethyl-4-
l~ydroxycyclohexyl)imidazole
a) 4-Fluorophenyl-tolylsulfonomethylformamide
To a suspension of p-toluenesulfinic acid sodium salt (30 g) in H2O (100
mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of
conc. HCI (15 mL). After stirring S min., the organic phase was removed and the
aqueous phase was extracted with methyl ~-butyl ether. The organic phase was
dried (Na2SO4) and concentrated to near dryness. Hexane was added and the free
acid was filtered.
The p-toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22
mL, 206 mmol), formamide (20 mL, 503 mmol) and camphor sulphonic acid (4 g,
17.3 mmol) were combined and stirred at 60~C I 8 h. The resulting solid was
broken up and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) then
liltered. The solid was resuspended in MeOH/hexane ( I :3, 200 mL) and stirred
vigorously to break up remaining chunks. Filtration afforded the title compound
(27 g, 62 % yield). IH NMR (400 MHz, CDCI3): ~ 8.13 (s, lH), 7.71 (d, 2H),
7.43 (dd, 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d, lH), 2.45 (s, 3H).
b) 4-Fluorophenyl-tolylslllfonomethylisocyanide
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The compound in the previous step (2.01g, 6.25 mmol) in DME (32 mL)
was cooled to -10~C. POCI3 (1.52 mL, 16.3 mmol) was added followed by the
dropwise addition of triethylamine (4.6 mL~ 32.6 mmol) in DME (3mL) keeping
the internal temperature below -5~C. The mixture was gradually warmed over 1
h., quenched in H2O and extracted with EtOAc. The organic phase was washed
with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated. The resulting
residue was triturated with petroleum ether and filtered to afford the title
compound (1.7 g, 90% yield). IH NMR (CDCl3): ~ 7.63 (d, 2H), 7.33 (m, 4H),
7.10 (t, 2H), 5.60 (s, lH), 2.50 (s, 3H)
c) 1 -Amino-4-(1 ~3-dioxycyclopentyl)cyclohexane
To a mixture of 1,4-cyclohexanedione monoethylene ketal (27.6 g, 177
mmol) and hydroxylamine hydrochloride (49.2 g, 708 mmol) in H2O (250 mL)
was added portionwise Na2CO~ (49.2 g, 547 mmol). After stirring I h, the mixturewas extracted with EtOAc. The organic phase was dried (Na2SO4) and
concentrated affording 4-(1,3-dioxycyclopentyl)-cyclohexanone oxime (27.5 g,
90% yield).
The oxime (27.5 g, 161 mmol), Raney Ni (ca 13.5 mL as a suspension in
EtOH) and EtOH (200 mL) were combined and shaken at 50 psi H2 for 4 h. The
catalyst was filtered off and the filtrate was concentrated to afford the title
compound as a colorless oil (23.6 g, 93% yield). 'H NMR (CDCI3): â 2.64 (m,
lH), 1.75 - 1.25 (m, 12 H).
d) 2-N-Methylaminopyrimidine-4-carboxyaldehyde dimethyl acetal
Pyruvic aldehyde dimethyl acetal (277 mL, 2.3 mol) and N,N-dimelthyl
formamide dimethyl acetal (304 mL, 2.3 mol) were stirred together at 100~C for
18 h. The mixture was cooled and concentrated.
This crude product was added to a well stirred solution of methyl guanidine
hydrochloride (112 g) and NaOEt (74 g) and the resulting mixture was refluxed for
24 h, then cooled, filtered, and concentrated. The resulting residue was triturated
with hot EtOAc and filtered over celite. The filtrate was concentrated affording the
title compound as a brown oil. IH NMR (CDCl3): ~ 8.33 (d, IH), 6.75 (d, lH),
5.10 (s, lH), 3.40 (s, 6H), 3.00 (s, 3H).
e) 2-N-Methylaminopyrimidine-4-carboxaldehyde
A mixture of thc compound from the previous step (10.04 g, 55 mmol) in
3N HCl (45 mL) was stirred at 47~C for 24 h. After cooling EtOAc was added
followed by the addition of solid NaHCO3. The aqueous phase was extracted with
EtOAc (4 x 100 mL). The organic phases were combined, dried (Na2SO4), and
contrated to afford the title compound as a yellow foam.~H NMR (CDCl3): â 9.88
(s, lH), 7.13 (d, lH). 7.01 (d, lH), 2.05 (s, 3H).
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f) 2-N-Methylamino-4-carboxaldehyde(4-ethylene ketal cyclohexyl)imine
A mixture of the compound from the previous step (9.5 g, 6.9 mmol) and
l-amino-4-(1,3-dioxycyclopentyl)cyclohexane prepared in example 18 (c) (10.8 g.
6.9 mmol) were stirred in DMF (150 mL) 18 h. The title compound was used
without any purification. IH NMR (CDCI3): ~ 8.34 (d, lH), 8.15 (s, lH), 7.13 (d.lH), 5.25 (d, lH), 3.39 (m, lH), 3.03 (d, 3H), 1.90 (m, 7H0, 1.79 (m, 2H), 1.65
(m, 2H).
g) 5-~-(2-N-Methylaminopyrimidinlyll-4-(4-fluorophenyl)- 1-(4-ethvlene
k~l cvclohexyl)imidazole
To the crude product from the previous example in DMF cooled to 0~C
was added 4-fluorophenyl-tollylsulfonomethylisocyanide prepared in example 1
(b) (20 g, 69 mmol) and K~CO3 (12 g, 87 mmol). The mixture was stirred at 0~C
for 3 h. then gradually warmed to room temp. and stirred for 18 h. EtOAc was
added and the mixture was filtered washing the solid with EtOAc. H~O was added
to the filtrate and the organic phase was separated, dried (Na2SO4), and
concentrated. The residue was purified by flash chromatography (Silica gel, 2~
MeOH/CH2CI2) to afford the title compound as a yellow solid (10.7 g, 38% yield).H NMR (CDCI3): ~ 8.16 (d, lH), 7.78 (s, lH), 7.45 (q, 2H), 6.99 (t, 2H), 6.40 (d,
lH), 5.70 (m,lH), 4.74 (m, lH), 3.99 (s, 4H), 3.05 (d, 3H), 2.20 (m, 2H), 2.04 (dq,
2H), 1.89 (dd, 2H), 1.68 (m, 2H).
h) 5-[4-(2-N-Methylamino)r)yrimidinyll-4-(4-fluorophenyl)-1-(4-
oxocyclohexyl)imidazole
A mixture of the compound from the previous step (10.73 g, 26.23 mmol)
in 3N HCl (150 mL) was stirred 36 h. then neutralized with saturated aqueous
25 Na2CO3 and filtered. The solid was washed with water and the aqueous mixture
was extracted with EtOAc. The organic phase was dried (Na2SO4) and
concentrated giving the title compound as a pale yellow solid (7.9 g, 77% yield)mp 232.5 - 233.5~C.
i) 5-~4-(2-N-Methylamino)pyrimidinyl~-4-(4-fluorophenyl)-1-(4-
30 ~xir~nylcyclohexyl)imirl~7nle
To a suspension of sodium hydride (0.07 g, 1.18 mmol, 60% suspension inmineral oil) in DMSO (1.2 mL) was added trimethylsulfoxonium iodide (0.39 g,
1.78 mmol). The mixture was stirred until gas evolution ceased. Added to this
was the compound from the previous step (0.50 g, 1.4 mmol) in dry THF (5 mL).
35 The resulting mixture was stirred 4 h. then poured into H2O and filtered. Theresulting solid was triturated with acetone/hexane to afford the title compound
(.4117 g, 77~ yield). mp 229 - 230~C.
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j) S-r4-~2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-
cyanomethyl-4-hydroxycyclohexyl)imidazole
To a solution of the compound of from the previous step in dry THF (10
mL) was added diethylaluminum cyanide (2 mL, lM in toluene). After stirring at
70~C for 1 h., the mixture was cooled and quenched with 10% NaOH and
decanted. The organic phase was decanted then concentrated. The residue was
purified by flash chromatography (silica gel, 5% MeOH/CH2C12) and the product
was recrystalized from EtOH/H20 affording the title compound as white crystale.
mp 152 - 154~C.
Fxample 19
5-r4-(2-N-Methylamino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-
hvdroxymethylcyclohexly)imidazole
a) A solution of the compound in example 18 (i) (0.084 g, .22 mmol) and
15 88% formic acid (3 mL) was stirred I h. The mixture was concentrated and the
residue was dissolved in MeOH. Excess Et3N was added and the mixture was
stirred 24 h. The mixture was concentrated and purified by flash chromatography
(silica gel, 25~ - 10% MeOH/CH2CI2). The resulting white solid was triturated
with acetone/hexane to afford the title compound as a mixture of cis and trans
20 isomers (0.047 g, 53% yield). mp 1~5 - 130~C.
Example 20
5-~4-(2-Amino)pyrimidinyll-4-(4-fluorophenyl)- I -[4-hydroxy-4-(1 -
25 prop,vnyl)cyclohexyl]imidazole
a) 2-Amino-4-cari~oxaldehyde(4-ethylene ketal cyclohexyl)imine
Following the procedure of example 18 (f) substituting 2-
aminopyrimidine-4-carboxaldehyde (prepared in Example 3) afforded the title
compound. IH NMR (CDCl3): â 8.36 (d, lH), 8.16 (s, lH), 7.21 (d, lH), 5,13 (m,
30 lH), 3.98 (s! 4H), 2.00 - 1.40 (m, 8H).
b) S-r4-(2-amino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-ethylene kt~t~l
cyclohexyl)imidazole
Following the procedure of example 18(g) using the compound from the
previous step afforded the title compound. 'H NMR (CDCI3): ~ 8.29 (d, lH), 7.77
35 (s, lH), 7.45 (q, 2H), 7.00 (t, 2H), 6.5() (d, lH), 5.12 (s. 2H), 4.63 (m, lH), 4.00 (s,
4H), 2.17 (m, 2H), 2.05 (m, 2H), 1.9() (m, 2H), 1.73 (m. 2H).
c) ~-~4-(2-Amino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4
oxocyclohexyl)imi-l~701e
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Following the procedure of example 1 (h) except using the from the
previous step afforded the title compound as a white solid. IH NMR (CDCl3):
8.02 (d, lH), 7.74 (s, lH), 7 32 (q, 2H), 6.94 (t, 2H), 6.28 (d, lH), 5.10 (m, lH),
2.93 (s, 3H), 2.44 (m, 6H), 2.12 (m, 2H).
d) 5-(Amino)pyrimidinyl]-4-(4-fluoro~henyl)-1-r4-hydroxy-2-
propynyl)cyclohexyllimidazole
To a suspension of the compound from the previous step (0.49 g, 1.4
mmol) in dry THF (30 mL) at -7813C was added propynyl m~gne.~ium bromide [15
mL, lM sln. in THF, obtained by bubbling propyne gas (4 g) into dry THF (75
10 mL) followed by the addition of methyl m~gnesium bromide (26 mL, 78 mmol,
3M in Et,O) and stirring the mixture until gas evolution ceases]. The resulting
mixture was gradually warmed to room temperature. After quenching with
saturated aueous NH4Cl, the mixture was extracted with EtOAc. The organic
phase was dried (Na2SO4) and concentrated. The resulting residue was purified by15 flash chromatography (silica gel, 5% MeOH/CH2CI2) affording the title compound
(0.068 g~ 12~ yield) as a white solid. mp 231 - 232~C.
Example 21
5-r4-(2-Amino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-metllyl-
20 cyclohexyl)imidazole
a) 5-r4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-
oxiranylcyclohexyl)imidazole
Following the procedure of example I 8 (i) except using 5-[4-(2-
amino)pyrimidinyl] -4-(4-fluorophenyl)- 1 -(4-oxocyclohexyl)imidazole prepared in
25 example 20 (c) afforded the title compound as a yellow solid. IH NMR (CDCl3):~ 8.11 (d, lH), 7.78 (s, lH), 7.38 (q, 2H), 6.99 (t, 2H), 6.43 (d, lH), 4.65 (m, lH),
2.71 (s, 2H), 2.26 (m, 2H), 2.03 (m, 4H), 1.39 (m, 2H).
b) 5-~4-(2-Amino)pyrimidinyll-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-
~ethylcyclohexyl)imidazole
To a suspension of the compound from the previous step (1.24 g, 3.39
mmol) in dry THF (40 mL) was added lithium aluminum hydride (5 mL, 5 mmol,
IM in THF). The resulting mixture was refluxed I h. then poured into 3N HCI
(200 mL) and made basic with solid NaHCO3. After extracting with EtOAc, the
organic phase was dried (Na2SO4) and concentrated. The resulting residue was
35 purified hy flash chromatography (silica gel, 5% MeOH/CHzClz) then crystalized
~rom EtOH/H,O to afford the title compound as a white solid (0.06 g, 4.8 % yield).
mp 110- 111~C.
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In methods analagous to Examples 1 to 18 above the following compounds may be
made:
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-hydroxy-4-isopropyl- cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-hydroxy-4-phenyl-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-Quorophenyl)- I -(4-hydroxy-4-benzyl-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-cyanomethyl
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-(2-
cyanoethyl)cyclohexyl)imidazole;
5-~4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-(2-
aminoethyl)cyclohexyl)imidazole;
lS 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-hydroxy-4-(2-nitroethyl)-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxymethyl-4-amino-
cyclohexyl)imidazole .
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-hydroxy-4-amino-
cyclohexyl)imidazole;
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1-(4-amino-
cyclohexyl)imidazole .
5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-thiomethyl
cyclohexyl)imidazole .
25 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-hydroxy
methylcyclohexyl)imidazole;
5-[4-~2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-aminomethyl-
cyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-amino-4-methyl-
cyclohexyl)imidazole;
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-hydroxy-4-methyl-
cyclohexyl)imidazole:
5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)- 1 -(4-oxiranyl-
cyclohexyl)imidazole.
The above description fully discloses the invention including preferred
embodiments thereof. Modifications and improvements of the embodiments
specifically disclosed herein are within the scope of the following claims. Without
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further elaboration, it is believed that one skilled in the are can, using the preceding
description, utilize the present invention to its fullest extent. Therefore the Examples
herein are to be construed as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in which an exclusive
5 propcrty or privilege is claimed are defined as follows.
.
