Note: Descriptions are shown in the official language in which they were submitted.
WO 92/07567 PCr/US91/08229
--1--
209~2~
1 0 IM~AZOLII)TNONE COlvlPOUNDS
Field of Invention
The present invention relates to novel compounds, pharmaceutical compositions
containing these compounds and their use in treating allergic and inflammatory diseases
and for inhibiting the production of Tumor Necrosis Factor (TN~3.
1 5 Back~round of the Invention
Bronchial asthma is a complex, multifactorial disease characterized by
reversible narrowing of the airway and hyperreacdvity of the respiratory tract to external
stimuli.
Identification of novel therapeutic agents for asthma is made difficult by
2 0 the fact that multiple mediators are responsible for thc development of the disease. Thus,
it seems unlilcely that climinating the effects of a single mediator will havc a substantial
effect on all three components of chronic asthma. An alternative to the "mediator
approach" is to regulate the activity of the cells responsible for the pathophysiology of the
disease
2 5 One such way is by elevating levels of cAMP tadenosine cyclic 3',5'-
monophosphate). Cyclic AMP has been shown to be a second messenger mediating thebiologic responses to a wide range of hormones, neurotransmitters and drugs; Krebs
Endocrinology Proceedings of the 4th International Congress ExceIpta Medica, pgs 17-
29, 1973). When the appropAate agonist binds to specific cell surfacc receptors,3 0 adenylate cyclase is activated which conveTts Mg+2-ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the acdvity of most, if not all, of the cells that
contAbute to the pathophysiology of extrinsic (allergic) asthma As such, an elevation of
cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation,
2) inhibition of mast cell mediator release, 3) suppression of neutrophil de-granulation, 4)
3 5 inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage
activation. Hence, compounds that acdvate adenylate cyclase or inhibit PDE should be
effective in suppressing the inappropriate activation of airway smooth muscle and a vide
valiety of inflarnmatory cells. The plincipal cellular mechanism foq ~e inactivation of
cAMP is hydrolysis of the 3'-phosphodiester bond by one or more of a family of
4 0 isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
- SUBSTITUTE SHEET
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It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE)
isozyme, PDE IV, is responsible for cyclic AMP breakdown in airway smooth muscleand inflammatory cells. (Torphy, "Phosphodiesterase Isozymes:Potential Targets for
Novel Anti-asthmatic Agents" in New Drugs for Asthma, Bames, ed. IBC Technical
5 Services Ltd. (1989)). Research indicates that inhibition of this enzyme not only
produces airway smooth muscle relaxation, but also suppresses degranulation of mast
cells, basophils and neutrophils along with inhibiting the activation of monocytes and
neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly
potentiated when adenylate cyclase activity of target cells is elevated by appropriate
1 0 hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be
effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin
(activators of adenylate cyclase) are elevated. Such compounds would offer a unique
approach toward the pharmacotherapy of bronchial asthma and possess significant
therapeutic advantages over agents currently on the market.
1 5 The compounds of this invendon also inhibit the in vivo production of
Tumor Necrosis Factor (INP), a serum glycoprotein. Excessive or unregulated TNF
production is implicated in mediating or exacerbating a number of diseases including
rheumatoid arthrids, rheumatoid spondylids, osteoarthrids, gouty arlhritis and other
arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic
2 0 shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic
pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption
diseases, reperfusion injury, graft vs host reacdon, allograft rejections, fever and
myalgias due to infection, such as influenza, cachexia secondary to infecdon or
malîgnancy, cachexia, secondary to acquired immune deficiency syndrome ~AlI)S),
2 5 AIDS, ARC (AIDS related complex), keloid formation, scar dssue formation, Crohn's
disease, ulceradve colitis, or pyresis.
AIDS results from the infectdon of T lymphocytes with Human
Immunodeficiency Virus (HIV) At least three types or strains of ~V have been
identified, i e, HIV-1, HIV-2 and HIV-3 As a conse~uence of HIV infection, T-cel~
3 0 mediated immunity is impaired and infected individuals manifest severe opponunistic
infections and/or unusual neoplasms HIY entry into the T lymphocyte requires T
lymphocyte activation Odler viruses, such as HIV- 1, HIV-2 infect T lymphocytes after T
Cell activation and such virus protein expression and/Qr replication is mediated or
maintained by such T cell activation Once an activated T Iymphocyte is infected with
3 5 HIY, ~he T lymphocyte must continue to be maintained in an activated state to permit H~V
gene expression and/or HlV replication Monokines, specifically TNF, are implicated in
activa~ed T-cell mediated H~V protein expression andJor virus replication by playing a role
SUBSTITUTE SHEET
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WO 92t07567 2 ~ 9 ~ ~ 2 9 PCI/US9l/08229
in maintaining T Iymphocyte activation. Therefore, interference with monokine activity
such as by inhibition of monokine production, notably TNF, in an H~V-infected
individual aids in limiting the rnaintenance of T cell activation, thereby reducing the
progression of HIV infectivity to previously uninfected cells which results in a slowing or
S elimination of the progression of immunc 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, like T-cells, are targets for
viral replication and the level of viral replication is dependent upon the activation state of
the cells. [See Rosenberg et ah, The Immunopathogenesis of HIV Infection, Advances in
1 0 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 produc~ion or activity aids in
limiting ~V progression as stated above for T-cells.
TNF has also been implicated in various roles with other viral infections,
1 5 such as the cytomegalia virus (CMV), influenza virus, and the heIpes virus for similar
reasons as those noted.
The ability to control the adverse effects of TNF is furthered by the use of
the compounds which inhibit TNF in mammals who are in need of such use. There
remains a need for compounds which are useful in treating TNF mediated disease states
2 0 which are exacerbated or caused by the excessive andlor unregulated production of TNF.
Summarv of the Invention
This invention relates to the novel compounds of Formula (I), as shown
below, having Tumor Necrosis Factor inhibitory activity. This invention also relates to
2 5 the pharmaceutical compositions comprising a compound of Formula (I), or
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or
diluent.
This invention also relates to a method of inhibiting TNF production in a
mammal, including humans, which method comprises administering to a mammal in need
3 0 of such treatment, an effective TNF inhibiting amount of a compound of Fonnula a).
This method may be used for the prophylactic treatment or prevention of certain TNF
mediated disease states arnenable thereto.
This invention also relates to a method of treating a human afflicted with a
human immunodeficiency ViTUS a~l), which comprises administering to such human an
3 5 effective TNF inhibiting amount of a compound of Formula a)
The compounds of Fo~mula a) are also useful in the treatment of
additional viral infections, where such viruses are sensitive to upregulation by TNF or
SUBSTITUTE SHEET
.
WO 92/07~6, 2 ~ 2 9 4 PCr/US9l/08~29
will elicit TNF production in vivo. The viruses contemplated for treatrnent herein are
those which are sensitive to inhibition, such as by decreased replication, directly or
indirectly, by the TNF inhibitors of Forrnula (I). Such viruses include, but are not
limited to; HIV-l, HIV-2 and HIV-3 as noted above, Cytomegalovirus (CMV),
5 Influenza, and the Herpes family of viruses, such as Herpes Simplex & Herpes Zoster.
This invcntion also relates to the novel compounds and pharmaceutical
compositions, of Formula (Ia), a sub-genus of the compounds of Formula (I) having
TNF activity but also are useful in the mediation or inhibition of phosphodiesterase IV
(PDE IV).
1 0 The invendon also relates to a method of inhibiting phosphodiesterase IV
in a mammal, including humans, which comprises administering to an mammal in need
thereof an effective amount of a compound of Formula (Ia), as shown below.
The invention further provides a method for the treatment of allergic and
inflammatory disease which comprises administering to a mammal in need thereof, an
1 5 effective amount of a compound of Formula (Ia).
The invention also provides a method for the treatment of asthma which
comprises administering to an a mammal in need thereof, an effective amount of acompound of Formula (Ia).
The compounds of Forrnula a) are represented by the structure:
R4~N~N,R5
R~O~
2 0 X (I)
wherein:
Rl is- (cR9Rlo)n- (c(o)o)r-(cR9Rlo)m-R8~ -(CR9RlO)n-
(C(O)NR6)r -(CR9Rlo)m-Rg~ or- (CRgRlo)n- ()s -(CRgRlo)m-R8 wherein the
alkyl moieties may be optionally substituted with one or more halogens;
2 5 n is a number having a value of 0 to 4;
m is a number having a value of 0 to 2;
r is a number having a value of 0 or 1;
s is a number having a value of 0 or 1;
Rg and Rlo are independently selected from hydrogen or a Cl-2 alkyl;
3 0 R8 is hydrogen, methyl, hydroxyl, tetrahydrofuran, tetrahydropyran,
tetrahydrothiophene, tetrahydrothiopyran, C3-6 cycloalkyl, or a C4-6 cycloalkyl
containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclicmoieties may be optionally substituted by l to 3 methyl groups or one ethyl group;
SUBSTITUTE SHEET
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WO 92/07s67 PCI/US91/0822~
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provided ~hat
a) when r is l, n is l to 4; or
b) when s is l, n is 2 to 4; or
c) when R8 is hydroxyl, r is l, and n is l to 4, then m is 2; or
d) when R8 is hydroxyl, and r or s is 0, then the sum of n + m is 2 to 6; or
e) when m is 0, r is l in -(CR9Rlo)n- (C(O)O)r -(CRgRlo)m-R8~ then n is l to
4; or
f) when R8 is a 2-tetrahydropyran or 2-tetrahydrothiopyran, 2-tetrahydrofuran or2-tetrahydrothiophene, and r or s is 0. then the sum of n + m is 1 to 6; or
1 0 g) when R8 is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or
2-tetrahydrothiophene, n is l to 4, and r is l, then m must be 1 to 2; or
h) when R8 is a 2-tetrahydropyran, 2-tetrahydrothiopyran, 2-tetrahydrofuran or
2-tetrahydrothiophene, n is 2 to 4, and s is l, then m must be l to 2;
X is YR2, halogen, nitro, NR6R7, or formyl amine;
1 5 Yis OorS(O)m';
m' is a number having a value of 0 to 2;
R2 is -CH3 or -GH2CH3 opdonally subsdtuted by 1 or more halogens;
R3 is ~1, CH3, CN, CH2F, CHF2, or CF3;
R4 is H, Cl-C4 alkyl, OH, OCH3, OCH2CH3, or OAc;
2 0 Rs is H, OH, -(CH2)qAr, or C1 6 alkyl whcrcin thc (CH2)qAr or C1 6
alkyl group is optionally substituted one or more times by F, Br, Cl, -N02, -NR6R7,
-C02R6, -OE~6, -0C(O)R6, C(O)R6, CN, -C(O)-NR6R7, -C(S)-NR6R7,
-NR6-C(O)-NR6R7, - NR6-C(S)-NR6R7, - NR6-C(O)-R6, - NR6-C(S)-R6,
-NR6-C(O)-OR6, C(=NR6)-NR6R7, -C(=NCN)-NR6R7, -C(=NCN)-SR6,
2 5 -NR6-C(=NCN)-SR6, - NR6-c(=NcN)-NR6R7~ -C(--NR6R7)SR6.
-NR6-S(0)2 R6, - S(O)m~-R6, -NR6S02-CF3, - NR6C(O)-C(O)-NR6R7,
-NR6-C(O)-C(O)-OR6, 1-imidazolyl, or l-(NR6)-2-imidazolyl;
Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, 4- or ~-
thiazolyl, triazolyl, 2- or 3- thienyl, 2-thiaphene, or phenyl;
3 0 R6 and R7 are independently hydrogen, or Cl 4 alkyl optionally substituted by
one or more halogens;
q is a number having a value of 0 to 2;
and the phaTmaceutically acceptable salts thereof.
3 5 Detailed Description of the Invention
The compounds of Formula (Ia) are represented by the structure:
SU~STITUTE SHEET
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wo g2/0~s67 2 ~ 9 ~ 4 2 9 - 6 - PCI/US91/08229
o
R4~N~N_R5
R~O~/
X (Ia~
wherein
Rl is -CH2-C3 cyclic aLkyl, -CH2-C5 6 cyclic aL~cyl, C4-6 cyclic aLIcyl,
S tetrahydrofuran, cyclopentenyl,-Cl 7 alkyl optionally substituted by l or more
fluorines,
-(CH2)2 4 OH, -(CH2)n-C(O)O(CH2)m-CH3, - (CH2)p-O-(CH2)mCH3, all of which -
may be optionally substituted by one to three methyl groups or one ethyl group;
m is a number having a value of 0 to 2;
I 0 n is a number having a value of l to 3;
p is a number having a value of 2 or 3;
X is YR2;
YisOorS;
R2 is -CH3 or CH2CH3 optional.ly substituted by l or more fluorines;
1 5 R3 is H, CH3, CN, CH2F, CHF2 or CF3;
R4 is H, Cl 4 alkyl, OH, OCH3, OCH2CH3, or OAc;
R5 is H, OH, -tCH2)q Ar, C1 6 allcyl; whe~ein Ar and Cl-6 alkyl may
be unsubstituted or substituted by one or more of the following:
F, Br, Cl, NO2, NR6R7, CO2R6, -NH-C(=NCN)-SCH3, -NHC(O)-
2 0 NR6R7, -C(O)NR6R7, -NHC(O)CH3, -NH-(----NCN)-NR6R7, -NHC(O)C(O)r
NR6R7.
-NHS02CH3, -S(O)mCH3, -NHC(O)C(O)-OR6, -OR6, -CN, -C(--NR6)-NR6R7,
N~NR8 or--N~=~N
. -NHS02CF3, \=/ ~ ;
Ar is 2-, 3- or 4-pyridyl, pyrimidyl, pyrazyl, imidazolyl, morpholino, or
2 5 phenyl;
R6 and R7 arv independently hydrogen~ or Cl 4 alkyl;
q is a numbeT havmg a value of 0 to 2;
or a pharmaceutically acceptable salt theleof.
3 0 Another aspect of the present in-~endon is the novel coqnpounds of
Formula (II), also a sub-genus of Fonnula (I) having activity as an inhibitor of TNF.
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W o 92/07567 2 ~ 9 ~ ~ 2 9 PC~r/US9~/08229
The compounds of Formula (II) are represented by the stTucture:
o
R4~NJ~N,R5
R,O ~
X, (II)
wherein:
S R1, n, m, r, s, q, R8, R3, R4, Rs, Ar, R6, and R7 are as defined for
Formula (I);
X1 is halogen, nitro, NR6R7, or formyl amine; and
pharrnaceutically acceptable salts thereof.
1 0 When Rl for the compounds of Formula (I) and (II) is an aL~yl substituted
by 1 or more halogens, the halogens are preferably fluorine and chlorine, more
preferably a C14 alkyl substituted by 1 or more fluorines, morc preferably 1 or more
times by fluorine. The most preferred chain length is one or two carbons, and most
preferred is a -CF3, CH2F, -CHF2, -CP2CHF2, CH2CF3, or -CH2CHF2 moiety.
1 5 More preferred are those compounds in which R1 is cyclopentyl,
CH2~ CH2~ ~,
-CF3, -CHF2, or CH3. The R1 term contains the moiety (CRgR10) wherein the Rg
and Rlo are independendy hydrogen or alkyl. This allows for branching of the
individual methylene units æ (CRgRIo)n or (CRgR1o)m; each repeating methylene unit
2 0 is independent of the other, e.g. (CRgRlo)n wherein n is 2 can be -CH2CH(CH3)-, for
instance. The individual hydrogen atoms of the repeating methylene unit or the
branching hydrocarbon can be substituted by fluorine independent of each other to yield,
for instance, the prefe~ed R1 substitutions, as noted above.
Preferred Rl groups for the compounds of Formula (Ia) are -CH2-C3
2 5 eyclo- aL1~yl, -CH2-C~ 6 cycloaL~cyl, C~6 cycloaL~cyl, tetrahydrofuran, cyclopentenyl, -
Cl 7 aLkyl optionally substituted by 1 or more fluorines, and -(OEI2)24 OH. When R
is a Cl 7 alkyl optionally substituted by fluorine the more preferred groups are -CF3, -
CH2F, CH~2,
-CF2CHF2, CH2CF3, or -CH2CHF2
3 0 Pref~red X groups for both Formulas (I) and (la) are those wherein X isYR2, Y is oxygen. Preferred R2 groups for the compounds of both Formula (I) and (~),
and (Ia) where applicable is a Cl-2 alkyl optionally substituted by 1 or more halogens.
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WO 92/0756~ 8 - pcr/us9l/o8229
The halogens aloms are preferably fluorine and chlorine, more preferably fluorine. More
preferred R2 groups those wherein R2 is methyl, or the fluoro-substituted alkyls,
specif~cally a Cl-2 alkyl, such as a -CF3, CHF2, or -CH2CHF2 moiety. Most preferred
are the CHF2 and CH3 moieties.
Preferred Rs groups are the optionally substituted -(CH2)qAr moiety,
wherein q is preferably 1, or an optionally substituted Cl-6 alkyl, more preferably when
Rs is an alkyl and more preferred when Rs is a C3 5 allcyl . Preferred substituent
groups on the alkyl and aryl moieties are F, Br, Cl, N02, NR6R7, C02R6, -NH-
C(=NCN)-SCH3,
-NHC(O)-NR6R7, -C(O)NR6R7, -NHC(O)CH3 , -NH-(=NCN)-NR6R7,
-NHC(O)C(O)-NR6R7, -NHso2cH3~ -s(o)mcH3~ -NHc(o)c(o)-oR6~ -OR6, -
CN,
N~NR~; or--N N
-C(=NR6)-NR6R7,-NHS02CF3, \=/, \=/ .
More preferred substituent groups are -NH2, -N(CH3)2,-S(O)mCH3, -
NH-C(O)-CH3, -CO2CH3, OCH3, CO2H, NO2,-NH-C(=NCN)-SCH3, -NH-
C(=NCN)-NH2, -NH-C(O)-NH2, -NH-C(O)-C(O)-OR6 or NH-C(O)-C(O)-NR6R7.
Preferably, the Ar moiety is phenyl.
Preferred R4 substituents for the compounds of Formulas (I), (Ia) and (II)
are H, C1 2 alkyl or OCH3.
2 0 Preferred are those compounds of Formula (I) and (Ia) wherein Rs is an
optionally substituted-(cH2)qAr~ q is 0 or 1 or an optionally substituted C3 5 aL~cyl; R
is -CH2-C3 cyclic alkyl, -CH2-Cs 6 cyclic aL~yl, C4-6 cyclic aL~cyl, tetrahydrofuran,
cyclopentenyl, -Cl 7 alkyl optionally substituted by 1 or more fluorines, and -(CH2)24
OH; R2 is methyl or fluro substituted alkyl, R3 is CN, CHF2~ CF3, or H; R4 is H, C
2 5 4 alkyl or OCH3; Y is oxygen.
More preferred compounds are those R1, R2, and Y are as desdbed
above, and Rs is ~r is optionally substituted -(CH2)qAr, q is 1 and Ar is phenyl; R3, is
H, CN, methyl or CHF2 and R4 is H or Cl 4 aL~cyl. The optional substituents are
selected from
3 0 -NH-C(O)-CH3, -NH-C(=NCN)-SCH3, -NH-C(--NCN)-NH2, -NH-C(O)-NH2, -
NH2, -N(CH3)2, -NH-C(O)-C(O)-NH2, or-NHC(O)CO2CH3 group.
Most preferred are those compounds wherein Rl is cylopentyl, methyl or CF2H,
R3 is H, CN or CH3, R4 is hydrogen, X is YR2, Y is oxygen, R2 is CF2H or methyl,and R~
SU ~STITUTE SHEET
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wo 92/07s67 2 ~ 9 ~ PCr/US91~08229
is bcnzyl substituted by a -NH-C(O)-CH3, -NH-C(=NCN)-SCH3, -NH-C(=NCN)-
NH2, -NH-C(O)-NH2, -NH2, -N(CH3)2, -NH-C(O)-C(O)-NH2, or-
NHC(O)C02CH3 group.
Especially preferred are the following compounds:
1-(4-Aminobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-
imidazolidinone;
1-(4-Aminobenzyl)4-(3-cyclopentyloxy~methoxyphenyl)-3-methyl-2-
irnidazolidinone;
4-(3-Cyclopentyloxy4-methoxyphenyl)-1-(4-dimethylaminobenzyl)-2-
1 0 imidazolidinone;
4-(3-Cyclopentyloxy4-methoxyphenyl)-2-imidazolidinone;
1-(4Acetarnidobenzyl)~l (3-cyclopentyloxy-4-methoxyphenyl)-2-
imidazolidinone;
R-(-)4-(3-Cyclopentyloxy4-methoxyphenyl)-2-imidazolidinone
1 5 S-(+)4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone
S-(-)-1-(4-Aminobenzyl)-4-(3-cyclopentyloxy4-methoxyphenyl)-2-
imidazolidinone;
R-(+)-1-(4-Aminobenzyl)~(3-cyclopentyloxy-4-methoxyphenyl)-2-
irnidazolidinone;
2 0 S-(-)-1-(4-BenzylpyIidyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-
irnidazolidinone;
R-(+)-1-(4-Benzylpyridyl)-4-(3-cyclopentyloxy~methoxyphenyl)-2-
imidazolidinone;
S-(-)-1-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy~methoxyphenyl)-2-
2 5 imidazolidinone;
R-(+)-1-(4-Acetamidobenzyl)-4-(3-cyclopentyloxy-4methoxyphenyl)-
2-imidazolidinone;
S-(-)-1-(4-Oxamidobenzyl)-4-(3-cyclopentyloxy~methoxyphenyl)-2-
irnidazolidinone;
3 0 R-(+)-1-(4-Oxamidobenzyl)-~(3-cyclopentyloxy-~methoxyphenyl)-2-
imidazolidinone;
R-(+)-l -(4-Forrnamidobenzyl)-4-(3-cyclopentyloxy~methoxyphenyl~
2-imidazolidinone;
S-(-)-1-(4-Fo~mamidobenzyl)~(3-cyclopen~yloxy-4me~oxyphenyl)-
3 5 2-imidazolidinone;
1 -(4Acetamido-3-pyridylmethyl)~(3-cyclopentyloxy-4-
methoxyphenyl)-2-imidazolidinone;
SUBSTITUTE SHEFT
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~, W O 92/07567 PC~r/US91/08229
2 o 9 ~
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S-(-)-4-(3-Cyclopentyloxy-4-methoxyphcnyl)- 1-(2,4-diaminobenzyl)-2-
imidazolidinone;
S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-
diacetamidobenzyl)-2-imidazolidinone;
R-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-diarninobenzyl)-
2-imidazolidinone; or
R-(+)-4-(3-Cyclopentyloxy-~methoxyphenyl)- 1-(2,4-
diacetamidobenzyl)-2-imidazolidinone.
1 0 Another aspect are the novel intermediates used herein, in particular
Forrnulas (5) and (6). Preferred exemplified compounds of Fonnula t5) are (2R)- and
(2S)-l-Benzyloxycarbonylamino-2-(3-cyclopentyloxy 1 methoxyphenyl)-2-[(-)-
menthyloxycarbonylamino]ethane.
The compounds of the present invention may contain one or more
1 5 asymmetric carbon atoms and may exist in racemic and optically active forms. All of
these compounds are contemplated to be within the scope of the present invention.
By the term "Cl 7alkyl" or "alkyl" groups as used herein is meant to
include both straight or branched chain Tadicals of 1 to 7 carbon atoms, unless the chain
length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopTopyl,
2 0 n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
By the tenn "alkenyl" as used herein is meant to include, but not limited
to vinyl, l-propenyl, 2-propenyl, 2-propinyl or 3-methyl-2-propenyl.
By the tenm "cycloalkyl" or "cycloaLkyl alkyl" as used herein is meant to
include groups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl,
2 5 cyclopentyl or cyclohexyl.
By the term "aryl" or "araL~cyl", unless speciffed otherwise, as used
herein is meant an aromatic ring or ring system of 6-10 carbon atoms, preferablymonocycle, such as phenyl, benzyl, phenethyl or naphthyl.
By the term "halo" as used herein is meant all halogens, i.e., chloro,
3 0 fluoro, bromo and iodo.
By the terrn "l-(NR6)-2-imid~zolyl or l-imidazolyl" or is meant
N~N - R6 --N~N
, or \=/ respectively.
By the term "inhibiting the production of IL- 1" or "inhibiting the
3 5 production of TNF" is meant
SUBSTITUTF SH~ET
WO 92/07~67 PCrfUS91/08229
11 2Q9~2~
a) a decrease of excessive in vivo IL-1 or TNF levels, respcctively, in a
human to normal levels or below normal levels by inhibidon of the ~ vivo release of IL~ 1
by all cells, including but not limited to monocytes or macrophages;
b) a down regulation, at the translational or transcription level, of
S excessive in vivo IL- 1 or TNF levcls, respectively, in a human to normal levels or below
normal leveJs; or
c) a down reguladon, by inhibition of the direct synthesis of IL-1 or TNF
levels as a postranslational event.
1 0 ~y the term ' TNF mediated disease or disease states" is meant any and all
disease states in which TNF plays a role, either by production of TNF itself, or by TNF
causing another cytokine to be released, such as but not limited to IL-l, or IL 6. A
disease state in which IL-1, for instance is a major component, and whose production or
action, is exacerbatcd or secreted in response to TNF, would therefore be considered a
1 5 disease state mediated by TNF. As TNF-B (also known as Iyrnphotoxin) has close
structural homology with TNF-a (also known as cachectin) and since each induces
similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-
B are inhibited by the compounds of the present invention and thus are herein referred to
collectively as "TNF" unless specifically delineated otherwise. Preferably TNF-a is
2 0 inhibited.
By the term "cytokine" as used herein is meant any secrvted polypeptide
that affects the functions of cells, and is a molecule which modulates interactions between
cells in the immune or inflammato~y response A cytokine includes, but is not limited to
monokines and lymphokines regardless of which cells produce them. For instance, a
2 5 monokine is generally referred to as being produced and secreted by a mononuclear cell,
such as a macrophage and/or monocyte but many other cells produce monokines, such as
natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes,
bone marrow stromal cells, epideral keratinocytes, and B- Iymphocytes. Lymphokines are
generally referred to as being produced by lymphoctye cells. Examples of cytokines for
3 0 the present invention include, but are not limited to, Interleukin-1 (IL 1~, Interleukin-6
(IL 6), Lnterleukin-8 (IL 8), Tumor Necrosis Factor-alpha (INF-a) and Tumor Necrosis
Factor beta (INF~
The inhibition of a cytokine, contemplated by the present invention, for
use in the treatment of a HlV-infected human, must be a cytoldne which is irnplicated in
3 5 (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated
H~V gene expression and/orreplication, and/or (b) any cytokine-mediated disease
5UBSTITlJTE SHEET
; . ~ : : ~ . . .. -
WO 92/07567 ~ 3 12 PCI/US9t/08229
associated problern such as cachexia or muscle degeneration. The cytokine specifically
desired to be inhibited is TNF-.
All of the compounds of Formula (I) are useful in the method of inhibiting
the production of TNF, preferably by macrophages, monocytes or macrophages and
monocytes in a human in need thereof. All of the compounds of Formula (la) are useful in
the method of inhibiting PDE IV and in treatment of disease states mediated thereby.
The mammal is preferably a human, afflicted with a disease state selected
from endotoxic shock, adult respiratory distress syndrome, cachexia secondary toinfection or malignancy, cachexia secondary to acute immune deficiency syndrome
1 0 (AIDS), AIDS, reperfusion injury, pulmonary inflammatory disease, cerebral malaria,
graft vs. host reaction, bone resorption diseases, rheumatoid arthritis, rheumatoid
spondylitis, osteoarthritis, gouty arthritis, eczema, psoriasis, sunburn, conjunctivitis, or
pyresls.
1 5 METHODS OF PREPARATION:
Preparation of the compounds of Formula tI) can be carried out by one of
skill in the art according to the procedures outlined in the Examples, infra. The
preparation of any remaining compounds of Fo~nula (I) not described theIein may be
prepared by the analogous processes disclosed herein which comprise:
2 0 For compounds wherein R3 is other than CN and X is other than Br, I,
NO2, amine, formyl amine or S(O)m' when m' is 1 or 2, reacting a compound of theFormula (2)
O .,
X (2)
2 5 wherein Rl represents Rl as defined in relation to a compound of Formula (1) or a group
convertible to Rl and X represents X as defined in relation to a compound of Formula
(I) or a group conver~ble to X, with t imethylsilyl cyanide and a suitable catalyst, such
as anhydrous zinc iodide, either neat or in the presence of a suitaUe non-reacting
solvent, such as a halocarbon, at ambient temperature under an inert atmosphere. Upon
3 0 complete formation of the intermediate trimethylsilyl cyanohydlin, the solvent, if
present, is removed and the residue is reacted with the amine (NH2R4), in which R4
represents R4 as defined in relation to a compound of Forrnula (I) or a gr~up convertible
to R4, in a suitable solvent, such as an alcohol, at about 40C under an inert atmosphere
in a sealed vessel to provide a compound of the Formula (3)
SUBSTITllTE SHEET
W092t07~i67 2~9~.2~
R4HN CN
R~0~3X
X (3)
which may be converted to an appropriate acid salt form, such as a hydrochloride.
Alternatively, compounds of Formula (3) may be prepared by a Strecker synthesis in
which a compound of Formula (2) is r~acted with sodium cyanide and the amine as its
5 hydrochloride sal~ in an appropriate non-reacting solvent, such as an alcohol, at ambient
temperature. Reaction of a compound of Formula (3) or its salt with a suitable allcyl or
aralkyl haloformate, such as ethyl, benzyl or menthyl chloroformate, in a non-reacting
solvent, such as methylene chloride, in the presence of an appropriate acid scavenger,
such as saturated aqueous sodium bicarbonate, provides a compound of the Formula t4)
1 0 in which R8 is alkyl, optionally substituted benzyl, or (-)-menthyl.
N OR8
I~CN
R1 0~\ (4~
Reduction of the nitrile of a compound of Formula (4), uvherein R8 is not
opdonally substituted benzyl, with, for exarnple, hydrogen and a catalyst, such as Raney
nickel catalyst in the presence of excess ammonia, provides a compound of Formula (5)
1 5 in which Rs is H.
~N R8
R~ 0~_ NHR5
X (S)
Cyclization of a compound of Forrnula (5) wherein R5 is H in the
presence of an appropriate base, such as aqueous sodium hydroxide, in an appropriate
2 0 solvent, such as an alcohol or dimethyl sulfoxide (DMSO), then provides a compound
of Formula (I) wherein Rs is H and R3 is other than CN.
Alternatively, these compounds may be obtained by ~duction of the
nitrile of a compound of the Formula (3) with an appropriate reductant, such as lithium
aluminum hydride in a non-reacting solvent, such as ethyl ether, THF, or hydrogen in
SUBSTITIJTE SHEET
:, . - ,: ` ;
. . : ;
: . - - : .
- ~ : . : -
.
. ~ . ~ . .. .
WO 92/07567 2 0 9 ~ 4 2 9 14 - PCr/US9ltO8229
the presence of a suitable catalyst, such as a noble metal or Raney nickel, in an alcoholic
solvent to provide a diamine of the Forrnula (6) in which Rs is H.
NH
R,O~__NH-R5
X (6)
Reacdon of a diamine of Formùla (6) in which Rs is H, with phosgene in
S a solvent, such as toluene, at reduced temperature in the presence of an acid scavenger,
such as saturated aqueous sodium bicarbonate, then provides these compounds of
Forrnula (I) wherein Rs is H and R3 is other than CN; altematively, use of N,N'-carbonyldumidazole or 1,1-carbonyl-di-1,2,4-triazole in an appropriate solvent avoids
the use of phosgene and acid scavenger to provide these compounds in comparable
1 0 quantities.
Altematively, selective protection of the o~-NH in a compound of the
Forrnula (6) wherein Rs is H, and R3 is not CN, with, for example, a t-butyloxy
carbonyl or benzyloxy carbonyl group, followed by imine formation with the
appropriate aldehyde and imine or irnminium ion reduction as described below, followed
1 5 by ol-N protecting group removal, provides a compound of Formula (6) in which R5 is
other than H and R3 is other than CN.
Reaction of the diamine of the compound of Fo~mula (6) when Rs is
other then H, as described above for the compound of Formula (6) when R5 is H, then
provides the compound of Formula (I), in which Rs is other then H.
2 0 For compounds of Formula (I) wherein Rs is OH are prepared by
oxidation of the corresponding Fommula (5) compound where R5 is H to an aldehydeoxime with, e.g., sodium tungstate and hydrogen peroxide at 0C followed by reduction
of the oxime intermediate with, e.g., sodium cyanoborohydride in presence of acid to
give the corresponding Formula (5) compound wherein Rs is hydroxyl.
2 5 Compounds of Fonnula (I) wherein R3 is CF3, CHF2 or CH2F, are
prepared from the corresponding Formula (2) compounds using the methods described
below. The Formula (2) compounds where R3 is CF3 are obtained by the method of
Shono et al., J. Or~. Chem., Vol. 56, pages 204 (1991) electrochemically from the
Forrnula (2) compounds where R3 is H.
3 0 Formula (2) compounds where R3 is CF3 or CHF2, aTe obtained by
treatment of the Fo~mula (2a) compound with a metalling agent at -78C followed by
~ifluoroacetic acid or difluoroacetic acid by the method of Nad et al., Izvest, (1959)
page f~nula (2a) compound with a metalling agent at -78 C followed by trifluroacetic
SUBSTITUTI~: SHEET
, . . ..
. .
.. . .. .
.
. . ~. . , - ,
.
. - . .
.
WO 92/07s67 PCrtUS91/08229
2~9~29
- 15-
acid or difluroacetic acid by the method of Nad et al., Izvest, (1959) page 71; Chem.
Abstract., Vol. 53, No. 14877; and Vol. 53, No. 17933 (1959).
R1O~o~Br ~r I
X Fonnula (2a)
Formula (2) compound where R3 is CH2F are obtained by treatment of
5 the Formula (2) compounds where R3 is CH3 according to the method of Rozen et al.,
Synthesis (6) 665, (1985).
Fonnula (2) compounds where X is R2S and R3 is H are prepared by
alkylation of 3-hydroxy 4-nitrobenzaldehyde with the desired Rl-halide, where R1 is as
described above, followed by treatment with sodium SR2 in DMF.
1 0 Formula (2) compounds wherein X is F or Cl and R3 is H are prepared
by aL~cylation of the (2-fluoro or chloro)-5-methyl phenol with the desired Rl-halide,
followed by formation of the benzyl bromide with N-bromo succinimide and subsequent
transformation tQ the required aldehyde with 2-nitropropane and sodium ethoxide in
ethanol
1 5 Novel Formula ~2) compounds where R3 is CH3 can be made by
addition of a methyl metal to the Formula (2) compounds where R3 is hydrogen,
followed by oxidation, e.g, with pyridinium dichromate.
For compounds of Formula (I) wherein R10 and X are as described in
Formula (I) are prepared by alkylation of the corresponding Formula (2) compounds
2 0 where either both of R1 and R2 (where X is YR2) are hydrogen with a base, e.g. a
metal carbonate, metal hydroxide, metal hydride, and an alkylating agent Q-L, where Q
is R1 or R2 as described above and L is an appropriate leaving group known in the art,
e.g. Cl, Br, I, tosyl, mesyl, or triflyl or with a fluorinated ethylene, e.g.
tetrafluoroethylene.
2 5 Alternatively the Formula (I) compounds may be prepared from otherFormula (I) compounds where Rl and/or R2 are protecting groups, such as benzyl or
med~oxymethyl, ethoxymethyl or acetonide, and are removed by methods well known in
dhe art and subsequendy alkylated as described above for the Formula (2) compounds.
For compounds of Formula O wherein X is arnine, monoakylamine or formylamine,
3 0 such aL~cylation is performed on Pormula (2) orprotected R1/R2 Formula a)
compounds, where X is nitro or a protected amine, e.g., a mono-or di-N-t-
butoxycarbonyl or a mono- or di-N-benzyloxycarbonyl, and the protec~ng group
removed subsequen~dy by methods known to those skilled in the art.
For those compounds of the Fo~nula (I) in which R3 is other than CN,
3 5 when X is other than Br, I, N02, amine, fonnyl amine or S(O)m' and m' is 1 or 2, and
SUBSTITUTE SHEET
, . : `............ .. . - . ;
-..
wo s2/07s67 PCr/US9l/08229
2 0 9 ~ 1 ; i3 16 -
Rs is other than H, reaction of an arnine of the Formula (5) wherein Rs is H with a
suitably substituted aryl or alkyl aldehyde in a suitable solvent, such as chloroform at
reflux temperature, followed by suitable acid salt fomnation, such as a hydrochloride or
acetate, and reduction of the iminium salt with, for example, sodium cyanoborohydride
S in methanol, provides a compound of the Formula (5) in which R3 is other than CN and
Rs is other than H; altematively nobel metal catalytic reduction of the imine or iminium
function may also be employed. For most of these compounds, cyclization as described
above provides compounds of Formula (I) in which Rs is other than H. In the case of
certain compounds of Fommula (5) which contain a base-sensitive functionality in Rs,
1 0 such as a nitro group, conversion to a base stable functionality, such as an amine, is
conducted prior to cyclization; such amines may then be functionalized as desired.
For those compounds of Formula (I) in which R3 is CN, and X is other
than Br, I, NO2 or forrnyl amine, a sequence beginning with reaction of a compound of
the Forrnula (2) wherein R3 is H with a lithium halide and a silyl halide in an appropriate
1 5 solvent followed by reduction with an appropriate reductant, such as a siloxane,
provides a compound of the Formula (7) wherein X1 is a halide. Alternatively,
reduction of a compound of the Forrnula (2) wherein R3 is H with a suitable reductant,
such as sodium borohydride, provides a compound of the Formula (7) wherein X1 isOH. Reaction of such a compound of the Formula (7) with, for example, phosphorous
2 0 trichloride, thionyl chloride, phosphorous tribromide, cupric bromide or carbon
tetrabromide and triphenylphosphine, also provides a compound of the Forrnula (7)
wherein ~1 is a halide;
R,OX~ X,
X (7)
halide displacement by cyanide provides a compound of the Formula (8) wherein R3 and
Rgis H
L~ Rs
X (8)
which is allowed to react with a strong base, such as LDA or an alkyl lithium or lithium
3 0 hexamethyldisilazide, at reduced temperature under an inert atrnosphere followed by
reaction with, for exarnple, trirnethylsilyl isocyanate and appropriate workup to pr~duce
a compound of Formula (8) wherein R3 is CONH2 and Rg is H; or followed by reaction
with for example an alkyl or aryl halofonnate, such as methyl chlorofonnate, to produce
SUBSTITUTE SHEET
.. .. : ..... ... .
~, :
., .
WO 92/0756~ PCr/US91/08229
- 17- 2~9~2~
a compound of Formula (8) wherein R3 is COORg and Rg is H; this COORg group of
such a compound may be transformed either at this stage or at a later stage to a CONH2
group by any of the standard techniques well known to those skilled in the art.
Alternatively, a compound of Formula (8) whcrein R3 is COORg and Rg is H may also
be obtained by reaction of a compound of Formula (8) wherein R3 and Rg are H with a
rnetal hydride, such as sodium or potassium hydride, at ambient or elevated temperature
under an inert atrnosphere in the presence of an alkyl or aryl dicarbonate, for example
methyl dicarbonate. Also a compound of Formula (2) wherein R3 is H may be
homologated to a compound of the For nula (7) wherein Xl is COOR4 by any number
l 0 of known processes, such as reaction with a methyl methyl sulfinylmethyl sulfide and a
base, such as sodium hydroxide, followed by treatment with, for example, alcoholic
acid; generation of an anion of a compound of Formula (7) wherein X1 is COOR4 with
a suitable base, followed by reaction with, for exarnple, cyanogen chloride or 2-
chlorobenzyl thiocyanate, provides a compound of Formula (8) wherein R3 is COOR4l 5 andRgisH.
Generation of a third anion with the appropriate base in an appropriate
solvent followed by reaction with, e.g. 2,4,6-triisopropyl-benzenesulfonyl azide or
other electrophilic source of azide, produces a compound of the Formula (8) wherein R3
is CONH2 and Rg is N3 Reduction of both the azido and nitrile moieties by, for
2 0 example, hydrogenation with a noble metal or Raney nickel catalyst provides a
compound of the Formula (6) wherein R4 is H and R3 is CONH2. Cyclization of thisdiarnine as described above followed by arnide dehydration, with for example,
trifluoroacetic anhydride provides a compound of the Formula (I) wherein R4 and Rs
are H and R3 is CN
2 5 Alternatively, for a compoand of the Formula (8) wherein R3 is CONH2
and Rg is N3, selective reduction of the azido moiety to an arnine, using e.g, catalydc
hydrogenation with 10% palladium on carbon and one equivalen~ of acetic acid or
alternatively t~iphenyl phosphine in a suitable solvent such as tetrhydrofuranJwater,
followed by reaction with a suitable alkyl or aralkyl haloformate as described above
3 0 produces a compound of the Formula (4) wherein R4 is H and R3 is CONH2. Nitrile
reduction as described above provides a compound of the Formula (5) wherein R4 and
Rs are H and R3 is CONH2 Cyclization of the ring and dehydration of the R3 amide to
a nitrile then provides a compound of the Formula I wherein R4 and Rs are H and R3 is
CN
3 5 Alternatively, the amino moie~,r of a compound ~f the Fonnula (5)wherein R4 and Rs are H and R3 is CONH2 may be suitably protected, e.g. with a
carbobenzyloxy or t-butyloxycarbonyl group, prepared as known in the art, dehydration
SUBSTiTUTE SHEET
. -
,
wo 92J07567 2 ~ g 5 ~ 3 PCI/US9l/08229
- 18- ~ ;:
of the R3 amide to the nitrile is conducted, and the amine deprotected, by methods well
known to those skilled in the art, to provide a compound of the Formula (5) wherein R4
and Rs are H and R3 is CN. The amine moiety of such a compound of Formula (5)
rnay be homologated as described above to provide a compound of the Formula (5)
S wherein Rs is other than H. Cyclizadon followed by any appropriate funcdonal group
rnanipulations (such as reductions, acyladons, deprotections, oxidadons, etc.) then
provides a compound of the Formula (I) wherein R3 is CN, R4 is H and Rs is otherthan H.
Compounds of Formula (I) may be prepared from other Formula (I)
1 0 compounds and functionally modified, as known in the art, e.g. where R4 is O-acetate,
by acetylation from R4 as hydroxyl. Compounds where Rs is (CH2)qAr or C2 6 alkylsubstituted by: N02 from the NH2 derivadve by oxidation, e.g. with a peracid;
C(O)NR6R7 from the -C02CH3 by heating with or without catalytic metal cyanide, e.g.
NaCN, and HNR6R7 in CH30H; -OC(O)R6 from the -OH with e.g.,ClC(O)R6 in
1 5 pyridine; -NR6-C(S)NR6R7 fTom -NHR6 with an alkylisothiocyante or thiocyanic acid;
NR6C(O)OR6 from -NHR6 with the allcyl chloqoformate; -NR6C(O)NR6R7 from the -
NHR6 by treatment with an isocyanate, e.g. HN=C=O or R6N=C=O; -NR6-C(O)R6
from the -NHR6 by treatment with Cl-C(O)R6 in pyridine; -C(=NR6)NR6R7 from -
C(NE~6R7)SR6 with H3NR6+0Ac- by heating in alcohol; -C(NR6R7)SR6 from -
2 0 C(S~NR6R7 with R6-I in an inert solvent, e.g. acetone; -C(S)NR6R7 where R6 or R7 is
not hydrogen from C(S)NH2 with HNR6R7, C(=NCN)-NR6R7 from -C(=NR6R7)-
SR6 with NH2CN by heating in anhydrous alcohol, alternatively from C(=NH)-NR6R7
by treatment with Br-CN and NaEtO- in EtOH; NR6-C(=NCN)SR6 from NHR6 by
treatment with (R6S)2C=NCN; -NR6S02R6 from NHR6 by treatment with ClS02R6 by
2 5 heating in pyridine; -NR6C(S)R6 from -NR6C(O)R6 by treatment with Lawesson'sreagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide]; -
NR6S02CF3 from NHR6 with triflic anhydride and base; NR6C(O)-C(O)-OR6 from -
NHR6 with, e.g. methyloxalyl chloride and a base such as triethylamine;
-NR6C(O)-C(O)-NR6R7 from -NR6C(O)-C(O~OR6 with HNR6R7; 1-(NR6)-2-
3 0 imidazolyl from -C(=NH)NHR6 by heating with 2-chloroacetaldehyde in chlorofo~rn.
For compounds wherein X is S(O)m~-C1 6 alkyl, and m is 1 or 2 the final
compound is made from the -S-Cl 6 alkyl moiety by oxidizing the inteImediate -S-alkyl
product with, e.g. a peracid such as 3-chloroperbenzoic acid, under condidons well
known those skilled in the art, after the CONH2 moiety in synthesis step (c) is dehydrated
3 5 to the cyano moiety. For compounds wherein X is Br, I, N02, amine or formyl amine
synthesis of these compounds is accomplished by any of the steps described abo~e using
a suitably protected amine. Such protecting groups are h~own to those slcilled in the art
SUBSTITUTE SHEET
.. .. . .
:
; .
' . ~ ' ' . - ' ' '
.
wo ~2/07s67 PCr/US91/08229
- 19 - 2 ~ 2 ~
and are readily disclosed in Greene, T., Protective Groups in Or,eanic Svnthesis, Wiley
Publishers, NY (1981), the contents of which are hereby incorporated by reference.
In particular, for Compounds of Formula (I) wherein X is formyl amine
are formed at the last step, by formylating a compound wherein X is NH2, obtained by
S removal of a protecting group from the amine functionality. Use of the deprotected
amine in many instances allows for appropriately acylating the moiety to the NHCHO
moiety, or oxidizing it to the NO2 moiety; diazotization and displacement by methods
well known to those skilled in the art produces the desired Br or I moiety. For instance,
compounds of Formula (I) wherein X is Br or I may be prepared using the techniques of
1 0 PCT/US91/0479~ on a similarly deprotected amine, diazotization of the arnine, and
diazonium displacement; or for compounds of Formula (I) wherein X is N02 may be
prepared using the techniques of PCT/US91/04795 on a similarly deprotected amine by
oxidation of the amine to the nitro group.
1 5 METHODS OF TREATMENT
In order to use a compound of the Forrnula (I) or a pharmaceutically
acceptable salt thereof for the treatment of humans and other mammals it is normally
formulated in accordance with standard pharmaceutical practice as a pharmaceutical
composition.
2 0 The compounds of Formula (I) or a pharmaceutically acceptable salt
thereof can be used in the manufacture of a medicarnent for the prophylactic or therapeutic
treatment of any disease state in a human, or other mammal, which is exacerbated or
caused by TNF production by such human's cell, such as but not limited to monocytes
and/or macrophages, especially caused by excessive or unregulated TNF production. The
2 5 compounds of Forrnula (I) are administered in an amount sufficient to inhibit TNP
production such that it is regulated down to normal levels, or in some case to subnorrnal
levels, so as to ameliorate or prevent the disease state. Abnormal levels of TNF, for the
present invention, constitute levels of 1) free (not cell bound) TNF, greater than or equal
to 1 picogram per ml; 2) any cell associated TNF; or 3) the presence of TNF mRNA3 0 above basal levels in cells or tissues in which TNF is produced.
The compounds of Forrnula (Ia), or a pharmaceutically acceptable salt
thereof can be used in the manufacture of a medicament for the prophylatic or therapeutic
treatment of any disease state, in a human, or other mammal, which is mediated by
inhibition of PDE IV, such as but not limited to asthma, allergic or inflammatory diseases.
3 5 The compounds of Formula (Ia) are administered in an amount sufficient to treat such a
disease in a human or other mammal.
~IJBSTITUTE SHEET
,
', . ,. ` : .
. .
- ` : . : , -
W O 92/07567 2 0 ~ ~ ~ 2 9 PC~r/US91/08229
-20- ''
No unacceptable toxicological effects are expected when compounds of
the invention are administered in accordance with the present invention.
The compounds of Formula (I) may be used in the treatment of any disease
states mediated by excessive or unregulated TNF producdon, such as but not limited to
5 rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other
arthritic condidons; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic
shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic
pulmonary inflam natory disease, silicosis, pulmonary sarcoisosis, bone resorption
diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and
1 0 myalgias due to infection, such as influenza, cachexia secondary to infec~on or
malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS),
AIDS, ARC (AIDS related complex), keloid formation, scar dssue forrnation, Crohn's
disease, ulcerative colids, pyresis, AIDS and other viral infecdons, such as cytomegalia
virus (CMV), influenza virus, and the herpes family of viruses.
1 5 The compounds of Formula (I) may also be used topically as well in the
treatment or prophylaxis of inflammatory topical disease states mediated or exacerbated by
excessive TNF producdon respectively, such as for rheumatoid arthritis, rheumatoid
spondylitis, osteoarthritis, gouty arthrids and other arthritic conditions, inflamed joints,
eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflarnmatory
2 0 eye conditions including conjuncdvids; pyresis, pain and other condidons associated with
inflammation
The compounds of Formula a) may also be used in associadon with the
veterinary field for treatment of INF mediated diseases such as viral infecdons
Examples of such viruses include but are not limited to, feline immunodeficiency virus
2 5 (FIV) or other retroviral infecdon such as equine infecdous anaemia virus, caprine arthrids
virus, visna virus, maedi virus and other lentiviruses.
It further appears that among the cytokines, while TNF producdon
precedes and augments the funcdon of IL 1 and other cytokines, there is no clear data on
how the relationship among these molecules contributes to inflammation-related disease
3 0 states. The present invention attributes many of the biological disease states attributable to
interleukin-1 (~1) activity as being attributable to that of TNF activity as well. A
comprehensive listing of IL 1 activides can be found in Dinarello, J. Clinical
Immunolo~v, 5 (5), 287-297 (1985). It should be noted that some of these effects have
been described by others as indirect effects of IL-1. The myriad of known biological
3 5 activities of IL-1 include the activadon of T helper cells, induction of fever, sdmuladon of
prostaglandin or collagenase production, neutrophil chemotaxis, inducdon of acute phase
proteins and the suppression of plasma iron levels. These disease states are also
SUB5TITlJTE SHET
.
.
wo 92/07567 PCr/US9l/08229
-21- 209~;~29
considered appropriatc disease states of TNF activity and hence compounds of Formula
(I) are also useful in their treatment as well, and the use of the compounds of Forrnula (I)
should not be considered solely limited to the specifically described TNF mediated disease
states herein. The compounds of Forrnula (I) should be efficacious in an IL-I mediated
S disease state as TNF and IL- 1 act in a synergistic manner. TNF as well mediates the
release, in some instances, of IL 1, therefore à reduction in the levels of TNF may be
useful in the treatmcnt of a discasc state whcrein IL- 1 is a major componcnt. The prescnt
invcntion relates thereforc, to an cffecdvc, TNF producdon inhibidng arnount of a
compound of Forrnula a) or a pharmaceutically acceptablc salt thereof is useful in
1 0 treating, prophylactically or therapeutically, any disease state in a human which is
exaccrbatcd or caused by cxcessive or unregulated IL-l production, i.e., where IL-1 is a
major component, by such human's monocytes and/or macrophages.
The method of treatment and monitoring for an HIV-infected human
manifesting immune dysfunction or cytokine-mediated disease associated problems is
1 5 taught in Hanna, WO 90/15534, December 27, 1990. In general, an initial treatment
regimen can be copied froTn that known to be effective in interfering with TNF activity for
other TNF mediated disease states by the compounds of Formula (1). Treated individuals
will be regularly checked for T cell numbers and T4tT8 ra~os and/or measures of viremia
such as levels of reverse transcriptase or viral proteins, and/or for progression of
2 0 monokine-mediated disease associated problems such as cachexia or muscle degcneration.
If no effect is seen follo ving the normal treatment regimen, then the amount of the
monokine activity interfering agent administered is increased, e,g" by fifty percent per
week.
The compounds of Formula (I) may be administered oTally (when active
2 5 by this route), topically, parenterally or by inhalation in conventional dosage forms
prepared by combining such agent with standard pharmaceutical carIiers according to
convendonal procedures in an amount sufficient to produce the desired therapeutic acdvity
for treatrnent of a TNF mediated disease state or in the case of a compound of Formula
(Ia) in their use as a PDE IV inhibitor.
3 0 In order to use a compound of the Formula (I) or a pharmaceutically
- acceptable salt thereof for the treatment of humans and other mammals it is normally
formulated in accordance with standard pharmaceutical practice as a phannaceutical
composition,
The pharmaceutical composition of the present invention will comprising
3 5 an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically
acceptable carrier or diluent, The compounds of Formula (I) are administered in
conventional dosage forms prepared by combining a compound of Formula (I) in an
SUBSTITUTE SHE1'
.. . . -, . ~ . . . . . . .
: ~ : : . . . . .
WO 92/07s67 PCr/US91/08229
2095~ 22- ~
amount sufficient to produce TNF production inhibiting activity, respectively, with
standard pharmaceutical carriers according to conventional procedu~es. These
procedures may involve mixing, granulating and compressing or dissolving the
ingredients as appropriate to the desired preparation.
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,
pectin, acacia, magnesium stearate, stcaric acid and the lilce. Exemplary of liquid
carriers are syrup, peanut cil, olive oil, water and the like. Similarly, the carrier or
diluent may include time delay material well known to the art, such as glyceryl
1 0 monostearate or glyceryl distearate alone or with a wax.
Compounds of Forrnula (I) and their pharmaceutically acceptable salts
(when possible), some of which are orally active, can be employed in a wide variety of
pharmaceutical farms. The preparation of a pharmaceutically acceptable salt will be
determined by the nature of the compound itself, and can be prepared by conventional
1 5 techniques readily available to one skilled in the art. Thus, if a solid camer is used, the
preparation can be tableted, placed in a hard gelatin capsule in pawder or pellet form or
in the forrn of a trache or lozenge. The amount of solid carrier will vary widely but
preferably will be from about 25 mg ~o about 1 gram. When a liquid carrier is used, the
preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile
2 0 injectable liquid such as an ampule or nonaqueous liquid suspension. Where the
composition is in the form of a capsule, any routine encapsulatdon is suitaUe, for
example using the aforementioned carriers in a hard gelatin capsule shell. Where the
composidon is in the form of a soft gelatin shell capsule any pharmaceutical carrier
routinely used for preparing dispersions or suspensions may be considered, for example
2 5 aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule
shell. A syrup formuladon will generally consist of a suspension or solution of the
compound or salt in a liquid carrier for example, ethanol, glycerine or water with a
flavouring or colouring agent.
The amount of a compound of Formula (I) required for therapeutic effect
3 0 on topical administra~on will, of course, vary with the compound chosen, the nature and
severity of the condition and the animal undergoing treatrnent, and is ultimately at the
discretion of the physician.
By systemic administration is meant o~al, intravenous, intraperitoneal and
intramuscular administration.
3 5 By topical administradon is meant non-systemic administration and
includes the application of a compound externally to the epidermis, to the buccal cavity
SUBSTITUTE SHEET
WO 92/0756~ PCr/US91/08229
f - 23 - 2 0 9 ~ 4 2 ~
and instillaion of such a compound into the ear, eye and nose, and where the compound
does not significantly enter the blood stream.
The term 'parenteral' as used herein includes intravenous, intramuscular,
subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administraion. The
5 subcutaneous and intrarnuscular forms of parenteral administration are generally
preferred. Appropriate dosage forms for such administration may be prepared by
conventional techniques.
Typical parenteral compositions consist of a solution or suspension of the
compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a
1 0 parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone,
lecithin, arachis oil, or sesarne oil. The daily dosage regimen for inhibition of TNF
production, via parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg,
for example about 0.001 mg/Kg to 40 mgl'Kg, of a compound of the Formula (I) or a
pharmaceutically acceptable salt thereof calculated as the free base.
1 5 The compounds of Formula (I) may be administered orally. Each dosageunit for oral administration contains suitably from 1 mg to 100 mg, and preferably from
10 mg to 30 mg of a compound of Formula (I) or a pharmaceutically acceptable salt
thereof calculated as the free base,
The daily dosage regimen for oral administration is suitably about .001
2 0 mg/lcg to lOOmg~cg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula
(I) or a pharmaceutically acceptable salt thereof calculated as the free base. The active
ingredient may be administered from 1 to 6 times a day, sufficient to exhibit acdvity.
The compounds of Fonnula (I) may also be administered by inhalation.
By "inhalation" is meant intranasal and oral inhalation administration. Appropriate
2 5 dosage forms for such adrninistration, such as an aerosol for nulation or a metered dose
inhaler, may be prepared by conventional techniques. The daily dosage regimen for a
compound of Fonnula (I) for intranasal administradon and oral inhalation is suitably
about 10 to about 1200 mg.
Typical compositions for inhala~ion are in the form of a solution,
3 0 suspension or emulsion that may be administered as a dry powder or in the fonn of an
aerosol using a conventional propellant such as dichlorodifluoromethane or
trichlorofluoromethane.
Preferably the composition is in unit dosage fo¢m, for exarnple a tablet,
capsule or metered aerosol dose, so that the patient may administer to himself a single
3 5 dose.
The compounds of Formula (I) may also be administered topically.
Thus, the compounds of FoTmula (I) may be adrninistered topically in the treatment or
SUBS~ITUTE SHFE'r
` . ~... . . ~ . .
. - . - . ~ .
.. . . . , --
. .
WO 92~07567 PCr/US9l/08229
209~l~29 -24- ~
prophylaxis of inflarnmatory topical disease states mediated or exacerbated by excessive
TNF production, respectively, such as rheumatoid arthritis, rheurnatoid spondylitis,
osteoarthritis, gouty arthritis and other arthritic conditions, inflamed joints, ecæma,
psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye
5 conclitions including conjunctivitis; pyresis, pain and other conditions associated with
inflammation.
A suitable dose of a TNF production inhibiting compound of Formula (I)
is from about .01 mg to about 100 mg of base for topical adrninistration, the most
preferred dosage being about .01 mg to about 30 mg, for example, .003 mg to 10 mg
1 0 administered two or three times daily.
While it is possible for an active ingredient to be administered alone as
the raw chemical, it is preferable to present it as a pharmaceutical formulation. The
active ingredient may comprise, for topical administration, from 0.001% to 10% w/w,
e.g. from 1% to 2% by weight of the formulation although it may comprise as much as
1 5 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1%
w/w of the forrnulation.
The formulations of the present invention comprise an active ingredient
together with one or rnore acceptable carrier(s) therefor and optionally any other
therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sensc of being
2 0 compatible with the other ingredients of the forrnulation and not deleterious to the
recipient thereof.
Formulations suitable for topical administration include liquid or semi-
liquid preparations suitable for penetration through the skin to the site of inflammation
such as liniments, lotions, creams, ointments or pastes, and drops suitable for
2 5 administration to the eye, ear or nose.
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
3 0 solution may then be clarified by filtration, transferred to a suitable container which is
then sealed and sterilized by autoclaving or maintaining at 98-100C.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%), benzaLtconium
3 5 chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the
preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
SUBSTITUTE SHEET
: . . :- - .
,: .
.
WO 92t07s67 PCr/US91/08229
- 25 - 2 ~ 9 3 ~ ~ ~
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 sirnilar to those for
thle preparation of drops. Lotions or liniments for application to the skin may also
S 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.
Crearns, ointrnents 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
1 0 or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery,
with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard,
soft or liquid paraffin, 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 prolylene glycol or
1 5 macrogols. The formulation may incorporate any suitable surface acdve agent such as
an anionic, cadonic or non-ionic sulfactant such as sorbitan esters or polyoxyethylene
derivatives thereof. Suspending agents such as natural gums, cellulose derivadves or
inorganic materials such as silicaceous silicas, and other ing~dients such as lanolin, may
also be included.
2 0 It will be recognized by one of skill in the art that the fo~n and character
of the pharrnaceutically acceptable carrier or diluent is dictated by the arnount of actdve
ingredient, with which it is to be combined, the route of administration and other well-
known variables.
It will be recognized by one of skill in the art that the optimal quantity and
2 5 spacing of individual dosages of a compound of Formula (I) or a pharmaceutically
acceptable salt thereof will be determined by the nature and extent of the condition being
treated, the form, route and site of administration, and the particular patient being
treated, and that such opdmums can be determined by conventdonal techniques. It will
also be appreciated by one of skill in the art that the optimal course of treatrnent, i.e., the
3 0 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 sldlled
in the art using convendonal course of treatment determinadon tests.
I~'IlLlTY EXAMPLES
3 5 Example A
Inhibitory Effect of compounds of Fo~nula ~I) on
in vitro TNF production by Human Monocytes
.
SUBSTITUTE SHE~
-
,
WO 92t07567 ~ ~ ~ r ~ 26 - PCI/US91/08229
The inhibitory effect of compounds of Forrnula (I) on in vitro TNF
production by Human Monocytes can be determined by the protocol as described in
]Badger et al., EPO published Application 0 411 754 A2, February 6, I991, and inHanna, WO 90/15534, December 27, 1990. The compounds of Formula (I) displayed
S an ICso value of 0.01- to about >3.0 for Lnhibition of LPS-Induced Human Monocyte
TNF Production in the above noted assay. For instance, 4-(3-cyclopentyloxy4-
methoxyphenyl)-2-imidazolidinone demonstrated an ICso of .2~,1M in the in-vitro assay
system described above.
1 0 I~IILl~Y EXAMPLE B
MODEL A
Two models of endotoxin shock have been utilized to determine in vivo TNF
activity for the compounds of Formula (1). The protocol used in these models is
described in Badger et al., EPO published Application 0 411 754 A2, February 6,
1 5 1991, and in Hanna, WO 90/15534, December 27, 1990.
4-(3-cyclopentyloxy-4-methoxyphenyl)-2-imidazolidinone demonstrated a
positive in-vivo response of about 57 % reduction in serum levels of TNF which were
induced by the injection of endotoxin.
The data shown herein demonstrate that the compounds of thc present invention
2 0 inhibit TNF production in a mammal. Therefore, the compounds of Formula (I) are
useful in inhibiting the production of tumor necrosis factor ( INP) by monocytes or
macrophages in a human.
I~'IILITY MODEL B
- 2 5 The phosphodiesterase inhibitory activity and selectivity of the compounds of
Formula (Ia) can be determined using a battery of five distinct PDE isozymes. The
tissues used as sources of the different isoymes are as follows: 1) PDE Ia, canine
trachealis; 2) PDE Ib, porcine aorta; 3) PDE Ic, guinea-pig heart; 4) PDE m, guinca-pig
heart; and 5) PDE IV, human monocyte. PDEs Ia, Ib, Ic and m are partially purified
3 0 using standard chromatographic techniques (Torphy and Cieslinski, Mol. Pharmacol. 37:
206 214, 1990). PDE IV is pu~ified to kinetic homogeneity by the sequential use of
anion-exchange followed by heparin-Sepharose chromatography (White et al" FASEB J.
4: A1987 1990).
Phosphodiesterase activity is assayed as described in the protocol of
3 ~ Torphy and Cieslinski, Mol. Pharmacol. 37: 20~214, 1990. ICso's for compounds of
Forrnula (Ia) range from 0.1 llM to 3011M.
SUBSTITUTE SHEE~
.~ .
WO 92/07567 PCI/US91/08229
20~29
- 27 -
UTLITY MODE__
The ability of selected PDE IV inhibitors to increase cAMP accumulation in
intact tissues is assessed using U-937 cells, a human monocyte cell line that has been
shown to contain a large amount of PDE IV. To assess the activity of PDE IV
inhibition in intact cells, nondifferentiated U-937 cells (approximately 105 cellslreaction
tube) were incubated with various concentrations (0.01-100 ~lM) of PDE inhibitors for
one minute and lllM prostaglandin E2 for an additional four minutes. Five minutes
after initiating the reaction, cells were Iysed by the addition of 17.5% perchloric acid,
the pH was neutralized by the addition of lM potassium carbonate and cAMP content
1 0 was assessed by RIA . A general protocol for this assay is described in Brooker et al.,
Radioimmunassay of cyclic AMP and cyclic GMP., Adv. Cyclic Nucleotide Res.,
10:1-33, 1979. ECso's for compounds of Formula (Ia) range from 0.3 ~LM to >10
IlM.
1 5 SYNTHETIC EXAMPLES
The following examples are illustrative and are not limiting of the
compounds of this invention.
~AMPLE 1
2 0 4-(3-ÇyclopentYloxy-4-methoxYphenvl)-2-imidazolidinone
A) 2-Amino-2-(3-cvclopentvloxy-4-methoxvphenYl)acetonitrile hvdrochl~ide.
A mixture of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.0 g, 45.4 mmol),
trimethylsilylcyanide (7.6 ml,57 mmol) and a trace of anhydrous zinc iodide under an
2 5 argon atmosphere was stirred at room temperature. After 30 min, a cold solution of
anhydrous ammonia in methanol (6.2 M, 36 ml, 223 mmol) was added and the mixturewas heated in a sealed reaction vessel at 40C for 3 hours. The vessel was vented and
the liquids were removed in vacuo. The resulting oil was redissolved in methanol,
concentrated hydrochloric acid (5 ml, 60 mmol) and ether were added to produce a solid,
3 0 which was washed well with ether and dried to produce the hydrochloride salt of 2-
amino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile as an off-white powder (11.8
g, 92%):
m.p. 164-166C (dec).
Analvsis Calc. for C14H1gN2O2.HC1: C 59.47,
3 5 H 6.77, N 9.91; found:- C 59.30, H 6.91, N 9.87.
SUBSTITUTE SHEET
.:
..
. ~ .
WO 92/07~67 q PCr/US~1/08229
2 ~ 9 ~ 28 -
B) 2-Ethoxvcarbonvlamino-2-(3-cvclopentvloxv-4-methoxy-phenvl)acetonitrile.
2-Am~no-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile hydrochloride (2.83
g, lO mmol) was suspended in saturated aqueous sodium bicarbonate (25 ml) and
methylene chloride (25 ml) was added. The mixture was stirred vigorously under an
5 argon atmosphere until all solid dissolved and then ethyl chloroformate (1.9 ml, 19.9
mmol) was added in one portion. Additional ethyl chloroformate (0.5 ml,5.2 mmol)was added at 1, 2 and 3 hours. After 4 hours, the mixture was partitioned, the
methylene chloride was washed with dilute hydrochloric acid and dried (potassiumcarbonate). Recrystallization from ether/hexanes provided a solid of the tide compound
1 0 (3.0 g, 93%): m.p. 100-101C.
Analysis Calc. for C17H22N2O4: C 64.13, -
H 6.97, N 8.80; found: C 63.89, H 7.04, N 8.72.
C) 2-Ethoxvcarbonv!amino-2-(3-cvclopentvloxv-4-methoxyphenvl)ethvlamine.
1 5 2-Ethoxycarbonylamino-2-(3-cyclopentyloxy-4-rnethoxyphenyl)acetonitTile (3.0
g,9.4 mmol) and concentTated ammonium hydroxide (2.5 ml) were added to a
suspension of Raney nickel (3.0 ml of 50% suspension in water, washed three times
with ethanol) in ethanol (70 ml). The mixture was hydrogenated at 60 psi for 3 hours,
diluted with methylene chloride, filtered through celite and evaporated. The residue was
2 0 partitioned bet~veell methylene chloride and dilute aqueous hydrochloIic acid and the
organic layer was discarded. The aqueous layer was basifled with saturated aqueous
sodium carbonate, extracted with methylene chloride and dried (potassiurn carbonate).
Solvent evaporation provided 2-ethoxycarbonylamino-2-(3-cyclopentyloxy4-
methoxyphenyl)ethylamine (3.0 g, 100%): m.p. 79-84C.
2 5 Analysis Calc. for C17H26N2O4 1/8 Hp: C 62.89, H 8.15, N 8.63; found: C
62.70, H 8.17, N 8.47.
D) 4-(3-Cvclopentvloxv~methoxyphenvl~-2-imidazolidinone.
A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy~methoxyphenyl)-
3 0 ethylamine (40 mg, 0.12 mmol) in ethanol (1 ml) and aqueous sodium hydroxide (2.5
N, 0.5 ml) under an argon atmosphere was heated at reflux for 5 hours. The mixture
was cooled and partitioned between ether and water. The ether layer was washed with
dilute acid, dried (potassium carbonate) and evap~ated to a solid of 4-(3-
cyclopentyloxy~methoxyphenyl)-2-imidazolidinone (16 mg,48%): m.p. 116-118C.
AnalvsisCalc.forC1sH20N2O3: C65.20,
H 7.30, N 10.14; found: C 65.04, H 7.19, N 10.28.
SIJBSTITUTE SHEET
... . . . - - .
, : , - . . . ~, ~
- ~' ,' , . .
.. .
wo 92~07~67 PCr/US9l/08229
-29- 209~429
EXAMPLE 2
I -(4-AminobenzYl~-4-(3-cvclopentvloxv-4-methoxyphenYl)-2-imidazolidinone
A) 2-EthoxycarbonvlaTnino-2-(3-cYclopentYloxv-4-methoxvphenyl)- 1-(4-
5 n~robenzylaminQ!-ç-3ha~e~
A solution of 2-ethoxycarbonylamino-2-(3-cyclopcntyloxy-4-methoxyphenyl)ethylamine
(1.25 g, 3.9 mmol), prepared as in Example 1, and 4-nitrobenzaldchyde (0.59 g, 3.9
mrnol) in chloroform under an argon atmosphere was heated at reflux for 2 hours. The
mixture was cooled, the solvent was removed in vacuo and a solution of anhydrous1 0 hydrochloric acid in ether (1 0 M, 4 ml) was added. The solution was evaporated to
dryness, the residue was redissolved in absolute methanol and sodium
cyanoborohydride (0.25 g, 4.0 mmol) was added. The mixture was stirred at room
temperature for 2 hours, partitioned between methylene chloride and saturated sodium
bicarbonate and the organic layer dried (potassium carbonate) The residue was purified
1 S by flash chromatography, eluting with ether to provide a solid of 2-
ethoxycarbonylamino-2-(3-cyclopentyloxy-~methoxyphenyl)-1-(4-
nitrobenzylarnino)ethane
(0.7 g, 40%~: m.p. 112-113C.
2 0 B) 1~ Aminobenzvl)4-(3-cvclopentyloxY-4-methoxyphenYI)-2-imidazolidinone.
A solution of 2-ethoxycarbonylarnino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4-
nitro-benzylamino)ethane (0.4 g, 0.9 mmol) in acetic acid (2.5 ml) and water (2.5 ml)
was treated with an aqueous solution of titanium trichloride (20%, 4.5 ml). After 15
min, concentrated ammonium hydroxide (6 ml) and 9:1 methylene chloride/methanol
2 5 were added and the mixture was filtered through a glass fiber filter. The methylene
chloride layer was separated and dried (sodium sulfate). The solvent was evaporated.
The residue (0.31 g) in ethanol (10 ml) and aqueous sodium hydroxide (2.5 M, 5 ml)
was heated at reflux for 5 hours. The mixture was cooled, partitioned between
methylene chloride and water and the aqueous layer extracted with both methylene3 0 chloqide and ether. The combined organic layers were dried (potassium carbonate) and
evaporated. The residue wæ purified by recTystallization from methylene chloride/ether
to provide a solid of 1-(~aminobenzyl)~-(3-cyclopentyloxy-~methoxyphenyl~2-
imidazolidinone (0.22 g, 66%):
m.p. 127-128C.
3 ~ Analysis Calc. for C22H27N303: C 69.27,
H 7.13, N 11.02; found: C 69.51, H 7.23, N 11.16.
SUBSTITUTE SHEET
.
'.
W O 92t0756~ PC~r/US91/08Z29
2095`~ 2~ - 30 - ~
EX A~IPLE 3
4-~3-CyclopentYloxv-4-methoxvphenvl~-1-(4_imethvlaminobenzyl)-2-imidazolidinone.
A) 2-Ethoxvcarbonvlamino-2-(3-cvclopentvloxy-4-methoxY-phenyl~-1-(4-
S dirnethvlaminobenzvlamino)ethane.
A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-
methoxyphenyl)ethylaminc, prepared as in Example 1, (0.725 g, 2.25 mmol) and 4-
dimethylamino-benzaldehyde (0.34 g, 2.25 mmol) in chloroform under an argon
atmosphere was heated at reflux for 2 hours and the solvent was removed by distillation.
1 0 Additional chlorofo~rn (10 ml) was added and reflux was continued for an additional
hour. The mixture was cooled, the solvent was removed in vacuo, the residue was
redissolved in tetrahydrofuran (15 ml) and a solution of anhydrous hydrochl~ic acid in
ether (1.0 M, 5 ml) was added. The solution was evaporated to dryness, the residue
was redissolved in absolute methanol (10 ml), cooled to 0C and sodium
1 5 cyanoborohydride (0.28 g, 4.5 mmol) was added. The mixture was allowed to warm to
room temperature and stirred overnight. The colorless mixture was partitioned between
methylene chloride and 10% sodium hydroxide and the organic layer dried (potassium
carbonate). The residue was purified by flash chromatography, eluting first with ether
and then with 5% methanoVether to provide a solid of the title compound (0.82 g, 805/o):
2 0 m.p. 94-96C.
B) 4-(3-CvclopentYloxY4-methoxYphenYl)-l-(4-dimethylaminobenz)/l)-2
imidazolidinone.
A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4-
2 5 dimethylaminobenzylamino)ethane (0 40 g, 0.88 mmol) in ethanol (10 ml) and aqueous
sodium hydroxide (2.5 M, 1 ml) was heated at reflux under an argon atmosphere foQ 6
hours. The mixture was cooled, partitioned between methylene chloride and water and
the aqueous layer extracted with methylene chloride. The organic layer was dried(potassiurn carbonate) and evaporated. The residue was purified by flash
3 0 chromatography, eluting with 2% methanoUmethylene chloride, and the resulting solid
was purified by recrystallization from chlorofoIm/ether to provide a solid of the ~tle
compound (0.29 g, 80%):
m.p. 171-172C.
Analysis Calc. for C24H31N303 3/8 H20:
3 5 C 69.25, H 7.69, N 10.09; found: C 69.29, H 7.50,
N 9.9~.
SUBSTiTUTE SHE~T
,
WO 92~07567 PCI`/US91J08229
-. -31- 2~95429
EXAMPLE 4
I -(4-Acetamidobenzvl~(3-cvclopentvloxY-4-methoxv~henvl~-2-imidazolidinone
A) 1-(4-Acetamidobenzvlamino)-2-(3-cvclopentyloxv-4-methox~yI2hç_y]L2-
,(ethoxvcarbonvlarnino)ethane.
A soludon of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)ethylamine
prepared as in Example 1 (0.725 g, 2.25 mmol) and 4-acetamidobenzaldehyde (0.37 g,
2.25 mmol) in chloroform (15 ml) under an argon atmosphere was hea~ed at reflux for 3
hours and the solvent was removed by distillation. Addidonal chloroform (10 ml) was
1 0 added and reflux was continued for an additional hour. The mixture was cooled, the
solvent was removed in vacuo. the residue was redissolved in tetrahydrofuran (15 ml)
and a solution of anhydrous hydrochloric acid in ether (1.0 M, 2.5 ml) was added. The
solution was evaporated to dryness, the residue was redissolved in absolute methanol
(10 ml), cooled to 0C and sodium cyanoborohydride (0.28 g, 4.5 mmol) in methanol (5
1 5 ml) was added. The mixture was allowed to warm to room temperature and stirred
overnight. The colorless mixture was partitioned between methylene chloride and 10%
sodium hydroxide and the organic layer dried (potassium carbonate). The residue was
purified by flash chromatography, eluting with 3% methanoVmethylene chloride to
provide a foam of the title compound (0.84 g, 80%).
B) 1-(4-Acetamidobenzvll~(3-cvclopentvloxv4-methoxyphenvl)-2-
imidazolidinone.
A solution of 2-ethoxycarbonylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(4-
acetamidobenzylamino)ethane (0.08 g, Q17 mmol) in ethanol (3 ml) and aqueous
2 5 sodium hydroxide (2.5 M, 0.2 ml) was heated at reflux under an argon atmosphere for
48 hours. The mixture was cooled, partitioned between methylene chloride and water
and the aqueous layer extracted with methylene chloride. The organic layer wæ dried
(potassium carbonate) and evaporatcd. The residue was purified by flæh
chromatography, eluting with a gradient of 2-5% methanol/chloroform, and the resulting
3 0 solid was purified by recrystallizadon from chlorofo~n/ether to provide a solid of the
title compound (0.05 g, 65%): m.p. 191C.
- Anal~sis Calc. for C24H2gN3O4: C 68.06,
H 6.90, N 9.92; found: C 67.90, H 7.21, N 9.86.
3 5 EXAMPLE S
l-(~Aminobenzvl) 4 (3-cvclopentvloxv-4-me~oxyphenvl)-3-methv!-2-imidazolidinone
SUBSTITUTE SHEET
,,. . . : :
~' ' . ~ . ,, ' .: ,
--
WO 92/07s67 PCr/USs1/08229
2095~2~ -32-
A) 2-(3-Cvclopentvloxv-4-methoxyphenx1)-2-mçthylaminoacetoni~ilç
hydrochloride~
A mixture of 3-cyclopentyloxy-4- methoxybenzaldehyde (5.5 g,25 mmol),
tnmethylsilyl-cyanide (4.2 mL, 31.3 mmol) and a trace of anhydrous zinc iodide under
5 an argon atmosphere was stirred at room temperature. After 30 min, a cold solution of
anhydrous methylamine in methanol (5 M, 25 mL, 125 mmol) was added and the
mixture was heated in a sealed reaction vessel at 40C for 3 hours. The vessel was
vented and the liquids were removed m vacuo. The resulting oil was redissolved in
methanol, concentrated hydrochloric acid (2.3 mL, 27 mmol) and ether were added to
1 0 produce a solid, which was washed well with ether and dried to produce the
hydrochloride salt as an off-white powder (6.5 g, 85%): m.p. 123 - 127C (dec).
Analysis Calc. for C14H1gN2O2.HCl: C 59.47, H 6.77,
N 9.91; found: C 59.30, H 6.91, N 9.87.
1 5 B) 2-LthoxYcarbonYlmethvlamino-2-(3-cvclopentvloxY-4-
methoxvphenvl~acetonitrile
.
2-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylaminoacetonitrile hydrochloride (2.0 g,
6.7 mmol) was suspended in saturated aqueous sodium bicarbonate (15 mL) and
methylene chloride (25 mL) was added. Thé mixture was stirred vigorously under an
2 0 argon atmosphere until all solid dissolved and then ethyl chloroformate (1.35 mL, 14
mmol) was added in one portion. After 3 h at room temperature, the mixture was
partitioned, the methylene chloride was dried (potassium carbonate) and the solvent
removed in vacuo to provide an oil (2.6 g, 100%).
2 5 C) 2-Ethoxvcarbonvlmethvlamino-2-(3-cvclopentyloxY-~
methoxyphenyl)ethvlamine.
2-Ethoxycarbonyl-methylamino-2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (2.4
g, 7.2 mmol) and concentrated ammonium hydroxide (2 mL) were added to a
suspension of Raney nickel (2.4 mL of 50% suspension in water, washed three times
3 0 with ethanol) in ethanol ~70 mL). The mixture was hydrogenated at 60 psi for 3 h,
diluted with methylene chlo~ide, filteTed through celite and evaporated ~o an oil. The
residue was partitioned between methylene chlo~ide and dilute aqueous hydrochl~ic acid
and the organic layer was discarded. The aqueous layer was basified with saturated
aqueous sodium carbonate, extracted with methylene chloride and dried (potassium3 5 carbonate). Solvent evaporation provided the amine (3.0 g, 100%): m.p. 79 - 84C.
Analvsis Calc. for C17H26N2O4 1/8 H2O:
C 62.89, H 8.15, N 8.63; found: C 62.70, H 8.17, N 8.47.
SUBSTITUTE SHEEr
.
.
. ' .' :
.
WO 92/07~67 2 0 ~ ~ 4 2 9 PC~/US91/08229
- 33 -
D) 2-EthoxYcarbonvlmethvlamino-2-f3-cvclopentvloxv-4-methoxvphenv1)-1-(4-
nitl obenzvlamino~ethane.
A solution of 2-ethoxycarbonylmethylamino-2-(3-cyclopentyloxy-4-
methoxyphenylhthylamine (1.88 g, 5.6 mmol) and 4-nitrobenzaldehyde (0.89 g, 5.9
S mmol) in chloroforrn (25 mL) under an argon atmosphere was heated at reflux for 6 h.
Thc mixture was cooled, the solvent was removed in vacuo and a solution of anhydrous
hydrochloric acid in ether (1 M, 5.7 mL) was added. The soludon was evaporated to
dryness, the residue was redissolved in absolute methanol (25 mL) and sodium
cyanoborohydride (0.71 g, 11.3 mmol) was added. The mixture was stirred at room
1 0 temperature for 2 h, partitioned between ethyl acetate and ten percent aqueous sodium
hydroxide and the organic layer dried (sodium sulfate). The residue was purified by
flash chromatography, eluting with 50% hexanes/ethylacetate to provide the amine (1.11
g, 42%).
1 S E) 1-(4Aminobenzvl~-4-~3-cvclopentvloxv-4-methoxvphenvl)-3-methvl-2-
imidazolidinone.
A solution of 2-ethoxycarbonylmethylamino-2-(3-cyclopentyloxy-4methoxy-
phenyl)-1-(4-nitrobenzylamino)ethane (1.11 g, 2.4 mmol) in acetic acid (6.5 mL) and
water (6.5 mL) was treated with an aqueous solution of titanium tnchloride (20%, 12.2
2 0 mL). After 30 min, concentrated ammonium hydroxide (16 mL) and 97:3 methylene
chloride/methanol were added and the mixture was f;iltered through a glass fiber filter.
The methylene chloride layer was separated and dried (sodium sulfate). The solvent was
evaporated. Tne residue (0.99 g, 2.1 mmol) in ethanol (55 mL) and aqueous sodiumhydroxide (2.5 M, 2.6 mL) was heated at reflux for 48 h. The mixture was cooled,2 5 partitioned between ethyl acetate and water ~nd the aqueous layer extracted with both
ethyl acetate and ether. The combined organic layers were dried (sodium sulfate) and
evaporated. The residue was purified by flash ch~l~matog;aphy, duting with 10%
ether/methylene chloride, followed by recrystallizadon f.~m methylene chloride/ether, to
provide a solid of 1-(~aminobenzyl)-14-(3-cyclopentyloxy~methoxyphenyl)-3-
3 0 methyl-2-irnidazolidinone (0.7 g, 88%): m.p. 143C.
Analvsis Calc. for C23H2gN3O3: C 69.85,
H 7.39, N 10.62; found: C 69.82, H 7.46, N 10.52.
EXAMPLES 6 and 7
3 5 (2R)- and (2S)-l-Benzvlox-~carbon~lamin~2-(3-cvclopentvloxv-4-methoxyphenv!~-2-
~(-)-menthvloxvcarbonYlarninolethane
SUBSTITUTE SHEET
. .
-
-.
WO 92/07567 PCr/US91/08229
2 0 9 ~ 34 - ~
A~! 2-(3-Cvclopentvloxv-4-methoxv~henvl)-2-r(-)-menthvloxvcarbonvl-
aminolacetonitrile
A solution of 2-amino-2-(3-cyclopentyloxy~methoxyphenyl)acetonitrile
hydrochloride (as prepared in Example 1, part A) (39 g, 137.9 mmol) in methylencchloride (450 mL) was treated with saturated aqueous sodium bicarbonatc (350 mL)and st~ed under argon until the amine had dissolved. To the mixture was added (-)-
menthyl chlorofolmate (44.4 mL, 206.9 mmol) and the mixture was sti~ed vigorously
for 18 h. The organic layer was separated, dried (potassium carbonate) and evapo~ated.
The product was recrystallized from methylene chloride and hexanes, washing the
1 0 filtered solid with 9: 1 hexanes/ether (34.7 g, 59%): m.p. 124 - 141C. The mother
liquor was evaporated and purified by flash chromatography, eluting with 6:1:2
hexanes/ether/methylene chloride, to provide a solid (21.2 g, 36%): m.p. 114 - 125C.
Analvsis Calc. for C2sH36N2O4-1/10H2O: C 69.77, H 8.48, N 6.51; found: C
70.14, H 8.41, N 6.66.
B) 2-(3-Cvclopentvloxv-4-methoxvphenvl~-2-~ -menthvloxYcarbonvl-
aminolethylamine
A solution of 2-(3-cyclopentyloxy4-methoxyphenyl)-2-[(-)-
menthyloxycarbonyl-arnino]acetoni~ile (27.5 g, 64.2 mmol) in hot ethanol (650 mL)
2 0 was treated with Raney nickel (28 mL of a 50% suspension washed three times with
ethanol) and concentrated ammonium hydroxide (30 mL). The mixture was
hydrogenated at 50 psi for 2 h and filtered through celite washing with methylene
chloride. The solvent was evaporated in vacuo to provide a solid (27.5 g, 99%).
Analvsis Calc. for C2sH40N2o4: C 69.41, H 9.32, N 6.48;
2 5 found: C 68.21, H 9.73, N 5.06.
C) l-Benzvloxvcarbonvlamino-2-(3-cvclopentyloxv~-methoxvphenvl)-2-r(-!-
menthvloxvcarbonvlaminolethane
To a solution of 2-(3-cyclopentyloxy-~methoxyphenyl)-2-[(-)-
3 0 menthyloxycarbonylamino]ethylamine (27.2 g, 62.9 mmol) in methylene chloride (500
mL) was treated with tnethylamine (9.2 mL, 66.2 mmol) under an argon atmosphere,and cooled to 0C. Over a period of 10 min, benzyl chloroformate (9.1 mL, 63.7
mmol) was added, and the reaction was stirred for 16 h, slowly coming to room
temperature. The mixture was partitioned between methylene chlonde and dilute
3 5 hydrochloric acid. The organic extracts were dried (magnesium sulfa~e) and
evapo~ated. Purification by flash chromatography, eluting with 97:3 methylene
SUBSTITUTE SHEET
.
. .
, . ~ ,- . ,.
.:
wo 92tO75b7 2 0 9 5 ~ 2 ~ PCr/US91/08229
chlonde/ether, provided a solid which was recrystallized from methylene
chloride/ether/hexanes to provide a solid (27.1 g, 76%): m.p. 154-164C.
D) (2R)- and (25)-1-Benzvloxvcarbonvlamino-2-(3-cvclopentvloxv4
rnethox~henvl)-2-r(-)-menthvloxvcarbonvlarninolethane
Diastereomeric separation of 1-benzyloxycarbonylamino-2-(3-cyclopentyloxy-
4-rnethoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane was accomplished with
preparative HPLC conditions using a JY-100 chromatospac apparatus equipped with a
8cm x lOOcm column packed with 1.8 kg YMC sperical silica gel (15-30~). The
mobile phase of 95:5 methylene chlo~idelether eluted at a flow rate of 200 mL/min and a
1 0 load of 13 g per run. The total amount of mixed sample run was 51 g (54% 2R, 46%
2S). Refractive index detection of the eluting product was employed. Recovery of the
2R-isomer was 25.2 g (92%); 99.9% HPLC, and recovery of the 2S-isomer was 20.7
g (88%); 99.3% HPLC: m.p. (2R): 178-li9C; (2S): 167-169C.
Analvsis Calc. for C33H46N206: C 69.94, H 8.18, N 4.94;
1 5 found: 2R: C 69.95, H 8.19, N 4~92; 2S: C 69.55, H 7.89, N 4.84.
2R: [a]D5 (0.5, methanol) =-67.2
2S: ~a]D (0-5, methanol) = +9.2
EXAMPLE 8
2 0 R~ 4-r3-CYclopentvloxv-4-methoxvphenvl)-2-imidizolidinone
A) (2R~-2-(3-Cvclopentvloxv-~methoxvphenvl)-2-~(-)-menthvloxycarbonyl-
aminolethvlamine
A soludon of (2R)-1-benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-
2 5 methoxyphenylj-2-[(-)-menthyloxycarbonylamino]ethane ( 293 mg, 0.52 mmol) in
methanol (20 mL) was treated with 10% palladium on carbon (306g) and ammonium
formate (168 mg, 2.6 mmol). The reacdon was allowed to stir at 50-55C for 0.5 h,
basided with concentrated ammonium hydroxide and then filtered through Celite. The
solvent was removed in vacuo and the residue was partitioned between 95:5 methylene
3 0 chloride/methanol and water. The organic extracts were dried (sodium sulfate) and
evaporated to a white solid (222 mg, 99%).
B) R-(-)-4-(3-Cyclopentvloxv-4-methoxvphenvl)-2-imidazolidinone
A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-
3 ~ menthyloxycarbonylamino]ethylamine (149 mg, 0.34 mmol) in dimethylsulfoxide (3
mL) was treated with 10% aqueous sodium hydroxide (0.15 L, 0.41 mmol) and stirred
SUBSTlTlJTE 5~1EEl~
... .
W O 92/07567 PC~r/US91/08229
209~4~9 -36 -
under an argon atmosphere for 1.5 h. The mixture was diluted with ethyl acetate and
the pH was adjusted to - 6 with arnmonium chloride. The aqueous phase was extracted
with ethyl acetate, and the combined organic extracts were washed five times with
water. The organic extracts were dried tsodium sulfate) and evaporated. Purification
5 by flash chromatography, eluting with 97:3 methylene chloride/methanol, provided a
white solid (70 mg,74%): m.p. 135-137C.
AnalYsis Calc. for C15H20N2o3: C 65.20, H 7.30, N 10.14;
found: C 65.26, H 7.39, N 10.14.
la]D (1.13, methanol) = -25.2
1 0 EXAMPLE 9
S -(+)4-(3-Cvclopentvloxv4-methoxvphenYI)-2-irnidiazolidinone
A) (2S)-2-(3-Cvclo~entvloxv~methoxvphenvl)-2-r(-)-menthvloxv-
carbonvlarninolethvlamine
1 5 A solution of (2S)-l-benzyloxycarbonylamino-2-(3-cyclopentyloxy-4-methoxy-
henyl)-2-[(-)-menthyloxycarbonylamino]ethane (1.65 g, 2.91 mmol) in methanol (lûO
mL) was treated with 10% palladium on carbon (1.65 g) and ammonium formatc (1.0
g, 15.8 mmol). The rcaction was allowed to stir at 50-55C for 0.25 h and then filtercd
through Cclitc. Thc solvcnt was rcmovcd in vacuo and thc rcsiduc was partitioned2 0 between gS:5 methylene chloridc/methanol and 95:5 watcr/concentrated ammonium
hydroxide. The organic extracts were dried (sodium sulfate) and evaporated to a whitc
solid (1.21 g, 96%).
B) S-(+)-4-(3-Cvclopentvloxv 1 methoxvphenvl)-2-imidazolidinone
2 5 A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl~2-[(-)-menthyl-oxycarbonylamino]ethylamine (147.3 mg, 0.34 mmol) in dimethylsulfoxidc (3 mL)
was treated with lO~o aqueous sodium hydroxide (0.15 mL, 0.41 mmol) and stirred
under an argon atmosphere for 1.5 h. The mixture was diluted with ethyl acetate and
the pH was adjusted to ~ 6 with ammoniurn chloride. The aqueous phase was extracted
3 0 with ethyl acetate, and the combined organic extracts were washed 5 times with water.
The organic extracts were dried (sodium sulfate) and evaporated. Purification by flash
chromatography, eluting with 97:3 methylene chlo~ide/methanol, p~ovided a white solid
(80.4 mg, 84%~: m.p. 134-136C.
Analvsis Calc. for C15H20N2o3-5l4H2o: C 60.28, H 6.75, N 9.37; found:
3 5 C 60.35, H 6.60, N 9.42.
[a]D5 (1.30, methanol) = +22
SUBSTITUTE SHEET
. ..
`.
;., . - ~ :
.
. ' ,
wo 92/07~67 PCr/US91/08229
- 37 - ~ 2 9
EXAMPLE 10
-)-1-(4-Aminobenzvl)-4-(3-cvclopentvloxv-4-methoxyphenvl)-2-imid 701idinone
(A) (2S)- 1 -(4-Nitrobenzvlamino)-2-(3-cyclopentvloxv-4-methoxyphenvl)-2-r(-)-
5 ms nthvloxYcarbonvlaminolethane
A solution of (2S)-2-t3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxyc-
arbonylamino3ethylamine (553 mg, 1.27 mmol) and 4-nitrobenzaldehyde (202 mg,
1.33 mmol) in chloroform (10 mL) under an argon atmosphere was stirred for 8 h at
reflux and for 18 h at room temperature. The solvent was removed in vacuo and the
1 0 residue was redissolved in tetrahydrofuran (10 mL) and methanol (15 mL). Sodium
cyanoborohydride (242 mg, 3.85 mmol) was added and the solution was stirred for 0.5
h. Addition of aceic acid (150 IlL, 2.5 mmol) was followed by stirring at room
temperature for 2 h under an argon atmosphere. Aqueous sodium bicarbonate was
added, and the solution was evaporated to dryness. The residue was partiioned
1 5 between methylene chloride/methanol and water several times, and the organic extracts
were dried (potassium carbonate) and evaporated. Purification by flash
chromatography, eluting with 25:75 ethyl acetate/hexanes, provided a yellow solid (293
mg, 41%): m.p. 76-77.5C.
2 0 B) (2S)-1-(4-Aminobenzvlarnino)-2-(3-cYclopentYloxv-4-methoxYphenv!)-2-r(
menthyloxvcarbonylaminolethane
A solution of (2S)-1-(4-nitroben_ylamino)-2-(3-cyclopentyloxy~
methoxyphenyl)-2-(-)-menthyloxycarbonylamino]ethane (270 mg, 0.5 mmol~ in
methanol (1.5 mL) was treated with acetic acid (1.45 mL), water (1.45 mL) and
2 5 titanium trichloride (2.6 mL of a 20% aqueous solution). The reaction was stim~d for
15 min, at which time water (1.45 mL) and concentrated ammonium hydroxide (3.5
mL) were added. The reaction was diluted with 1:1:2 aqueous sodium
carbonate/methanoVmethylene chloride (100 mL) and stirred for 1 h. The mixture was
filtered through Celite, washing well with 5%methanoVmethylene chloride and
3 0 evaporated. The n~sidue was partitioned between water and methylene chloride, and the
organic extracts were dried (potassium carbonate) and evaporated to provide a yellow
solid (237 mg, 93%): m.p. 74-75C.
C) S-(-)- 1 -(4-Aminobenzvl)-4-(3-o,vclopentY!oxY4-methoxyphenY11-2-
3 5 imidazolidinone
A solution of (2S)-l-(~aminobenzylamino)-2-(3~yclopentyloxy~
methoxyphenyl)-2-[(-)-menthyloxycarbonylamino3ethane (232 mg, 0.43 mmol) in
SUBSTITUTE SHEET
wo 92/07s67 ~ ~) 9 S ~ h 9 Pcr/ussl/o~229
- 38 -
dime~hylsulfoxide (5 mL) was treated with 10% sodium hydroxide t210 IlL, 0.54
mmol) and stirred for 1 h under an argon atmosphere at 80-85C. The reaction mixture
was cooled and extracted twice with ethyl acetate. The organic extracts were washed 5
times with water, dried (potassium carbonate) and evaporate~ Purification by flash
5 chromatography, first eluting with 7:3 ethyl acetate/hexanes, then a second column,
elùting with 98.5: 1.5 methylene chloride/methanol, provided a off-white solid (119 mg,
63%): m.p. 72-74C.
AnalYsis Calc, for C22H27N3O3-1/4H2O: C 68.46, H 7.18, N 10.89; found: C
68.35, H 7.07, N 10.52.
1 0 [a]DS (0.99, methanol) = -85
EXAMPLE 11
R-(+)-1-(4-Aminobenzvl)-4-(3-cvclo~entvloxv~methoxv,phen~1)-2-imidazolidinone
1 5 A) (2R)-1-(~Nitrobenzvlamino)-2-(3-cyclopentyloxy-4-methoxvphenvl)-2-r(-)-
menthvloxvcarbonvlaminolethane
A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyl-
oxycarbonylamino]ethylamine (843 mg, 1.95 mmol) and 4-nitrobenzaldehyde (311 mg,2.04 mmol) in chlorofonn (15 mL) under an argon atmosphere was sti~ed for 18 h at
2 0 reflux. The solvent was removed in vacuo and the residue was redissolved in
tetrahydrofuran (10 mL) and methanol (10 mL). Sodium cyanoborohydride (371 mg,
5.8 mmol) was added and the solution was stirred for 1 h. Addition of acetic acid (225
L,3.7 mmol) was followed by stirring at room temperature for 48 h under an argonatmosphere. Aqueous sodium bicarbonate was added, and the solution was evaporated
2 5 to dryness. The residue was partitioned between methylene chloIide/methanol and
water several times, and the organic extracts were dried (potassium carbonate) and
evaporated. Purification by flash chromatography, eluting with 3:7 ethyl
acetate/hexanes, provided a yellow solid (7M mg, 64%): m.p. 62-64C.
3 0 B) (2R)-1-(4-Aminobenz!amino-2-(3-cvclopentvloxv-4-methoxvphenv!)-2-r(-)-
menthylo%vcarbonvlarninolethane
A solution of (2R)-1-(4-nitrobenylamino-2-(3-cyclopentyloxy-4-
methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane (683 mg, 1.2 mmol~ in
methanol (5 mL) was treated with acetic acid (4.5 mL), water (4.5 mL) and titanium
3 5 trichloride (7.8 mL of a 20% aqueous solution). The reaction was stirred for 15 min, at
which tirne water (4.5 mL) and concentrated ammonium hydroxide (10.5 mL) were
added. The reaction was diluted with 1:1:2 aqueous sodium
SUBSTITUTE SHEET
:
. .
, ~ .
,:
wo 92/0~s67 39 2 0 ~ ~ ~ 2 ~ PcrJUs9l/08229
carbona~e/methanoVmethylene chloride (300 mL) and stirred for l.S h. The mixturewas filtered through Celite, washing well with 5% methanoVmethylene chloride andevaporated. The residue was partitioned between water and methylene chloride, and the
organic extracts were dried (potassium carbonate) and evaporated to provide a yellow
S solid (625 mg, 97%): m.p. 71-73C.
C) R-(+)- 1-(4-Aminobenzvl)4-(3-cvclopentvloxY-4-methoxvphenvl)-2-
imidazolidinone
A solution of (2R)-1-(4-aminobenzylamino)-2-(3-cyclopentyloxy~methoxy-
1 0 phenyl)-2-[(-)-menthyloxycarbonylamino]ethane (615 mg, 1.2 mmol) in
d~methylsulfoxide (3 mL) was treated with 10% sodium hydroxide (600 IlL, 2.5 mmol)
and stirred for 2 h under an argon atmosphere at 85-90C. The reacdon was cooled,
water added and extracted twice with ethyl acetate. The organic extracts were washed 5
times with water, dried (potassium carbonate) and evaporated. Pu~ification by flash
1 5 chromatography, first eluting with 98.5:1.5 methylene chloride/methanol, then a second
column, eluting wi~h 98:2 methylene chloride/methanol, provided a yellow solid (310
mg, 68%): m.p. 71-73C.
Analysis Calc. for (~22H27N3O3-5/8H2O: C 67.28, H 7.25, N 10.70, found: C
67.24, H 7.02, N 10.34.
2 0 La]25 (1.12, methanol) = ~80
~AMPLE 12
S-(-)- 1 -(4-Benzvlpvridvl)-4-t3-cvclopentyloxv-4-methoxyphenvl)-2-imidazolidinone
2 5 A) f2S)-1-~4-Benzvlpvridylarnino)-2-(3-cvclopentvloxv-4-methox~henYI)-2-
r(-!-menthyloxvcarbonvlaminolethane
A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyl-
oxycarbonylarnino]ethylamine (444 mg, 1.03 mmol) and 4-pyridine-carboxaldehyde
(105 ~L, 1.08 mmol) in chloroform (10 mL) under an argon atsnosphere was s~ed for
3 0 4.5 h at reflux and then allowed to stir at room temperature for 18 h. The solvent was
removed in vacuo and the sesidue was redissolved in tetrahydrofuran (8 mL) and
methanol (5 mL). 5Odiurn cyanoborohydride (198 mg, 3.1 mmol) was added and the
solution was stirred for 0.5 h. Addition of acetic acid (120 ,uL, 2.1 mmol) was
followed by stirring at room temperatuse for 2 h under an argon atmosphese. Aqueous
3 5 sodium bicarbonate was added, and the solution was evaporated to dryness. The
residue was partitioned between methylene chloride/methanol and water, and the
orgar.ic layer was dried (potassium carbonate) and evapoTated. Purification by flash
~UE3STITUTE SHEET
'.
W O 92J07567 PC~r/US91/08229
2095~2 3 40 - ~ `
chroma~ography, elu~ng with 98:2 methanoVmethylene chloride, provided the product
(353 mg, 66%).
B) S-(-)-1-(4-Benzyl~YridYI)-4-t3-cYclopentYloxy-4-methox~henvl)-2
imidazolidinone
A solution of (2S)-1-(4-benzylpyridylamino)-2-(3-cyclopentyloxy4-methoxy-
phenyl)-2-[(-)-menthyloxycarbonylamino]ethane (322 mg, 0.62 mmol) in
dimethylsulfoxide (5 mL) was treated with 10% sodium hydroxide (300 ,uL, 0.74
mmol) and stirred for 0.5 h under an argon atmosphere at 100-105C. The reaction1 0 was cooled and extracted twice with ethyl acetate. The organic extracts were washed 5
times with water, dried (potassium carbonate) and evaporated. Purification by flash
chromatography, eluting with 97.5:2.5 methylene chloride/methanol, provided a pale
yellow solid (162 mg,71%), which was triturated with ether and dried (143 mg):
m.p.146-147C.
1 5 Analvsis Calc. for C21H25N3O3-3/8H2O: C 67.40, H 6.94, N 11.23; found: C
67.71, H 6.82, N 11.05.
[a]D (0 95, methanol) = -64.6
E~AMPLE 13
2 0 R-~+~-1-(~Benzvlp~idYI~-4-(3-cvclopentvloxv4-methoxvphenvl)-2-imidazolidinone
A) (2R)-1-(4-Benzvlpvridvlamino)-2-(3-cvclopentvloxv4-methoxvphenvl)-2-r(-)-
menthvloxvcarbonvlaminolethane
A solution of (2R)-2-(3-cyclopentyloxy4-methoxyphenyl)-2-[(-)-menthyl-
2 5 oxycarbonylamino]ethylamine (358 mg, 0.83 mmol) and 4-pyndinecarboxaldehyde (85
~L, 0.87 mmol) in chloroform (8 mL) under an argon atrnosphere was stirred for 6 h at
reflux and then allowed to stir at room temperature for 18 h. The solvent was removed
in vacuo and the residue was redissolved in tetrahyd~ofuran (5 rnL) and methanol (5
mL). Sodium cyanoborohydride (161 mg, 2.5 mmol) was added and the solution was
3 0 stirred for 1 h. Addition of acetic acid (95 ~lL, 1.7 mmol) was followed by stirring at
room temperat~e for 18 h under an argon atmosphere. Aqueous sodium bicarbonate
was added, and the solution was evaporated to dryness. The residue was partitioned
between methylene chloride/methanol and water, and the organic layer was dried
(potassium carbonate) and evaporated. Purification by flash chromatography, first
3 5 eluting with 97:3 methanoVmethylene chloride, followed by a second separation using
flash chromatography, eluting with 98:2 methanoVmethylene chlcride, provided theproduct (120 mg, 28%).
SlJfi~STITUTE SHEET
, .: ~ . . ~ . - . :
..
,, : ~ : . . ; . .. .
- ~
- ,
.
: ~
wo 92/07567 PCr/US91/08229
4~ 2 9
B) R-(+)- 1 -(4-Benzvlpvridvl)-4-(3-cvclnpentvloxY-4-methox!~phenvl)-2-
imidazolidinone
A soluion of (2R)-1-(4-benzylpyridylamino)-2-(3-cyclopentyloxy4-
methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane (112 mg, 0.21 mmol) in
S dimethylsulfoxide (3 mL) was treated with 10% sodium hydroxide (110 ~LL, 0.26
mmol) and sdrred for 1 h under an argon atmosphere at 80-85C. The reactdon was
cooled, water added and extracted twice with ethyl acetate. The organic extracts were
washed 5 times with water, dried (potassium carbonate) and evaporated. Purificadon
by flash chromatography, eluting with 97:3 methylene chloride/methanol, provided a
1 0 white solid (41 mg, 52%): m.p. 135-137C.
Analvsis Calc. for C21H2sN3O3-0.55SiO2: C 60.33, H 6.03, N 10.05; found:
C 60.32, H 6.14, N 9.92.
EXAMPLE 14
1 5 S-(-l-l-t4-Acetamidobenzvl)-4-(3-cvclopentvloxv-4-methoxvphenvll-2-
imidæolidinone
A) S-f-~-l-t4-Acetamidobenzvl)-4-(3-cvclopentvloxv-4-methoxvphenvl~-2-
imidazolidinone
2 0 To S-(-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy~methoxyphcnyl)-2-
imidazolidinone (50 mg, 0.13 mmol) was added a solution of acetic anhydride (37 IlL,
0.39 mmol) and pyndine (one-half drop) in methylene chloride (1 mL) and the mixture
was stirred at ambient temperature for 0.5 h under an argon atmosphere. The reaction
mixtu~e was purifiled by flash chromatogra~hy, eluting with 98:2 mcthylene
2 5 chloride/methanol, to provide a white solid (51 mg, 93%): m.p. 98-100C.
Analysis Calc. for C24H29N3O4-1/2H2O: C 66.65, H 6.99, N 9.72; found: C
66.94,H6.89,N9.58.
[C]D (0-90. methanol) = -72 9
3 0 EXA~LE 15
R-(+)-l -(4-Acetamidobenzvl~(3-cvclopentvloxY-4-methoxvphenvl)-2-
imidazolidinone
R-(+1-1-(4-Acetamidobenzvl) 1 ~3-cvclopentvloxv-4-methoxyphenYI)-2-
3 5 imidazolidinone
To R-(~)-1-(4-aminobenzyl)-~t3-cyclopentyloxy~methoxyphényl)-2-imidazolidinone
(50 mgt 0.13 mmol) was added a solution of acetic anhydride (37 ~IL, 0.39 mmol) and
~UBSTITUTE SHEET
:
.. - . .
. .~ ` .
wo 9t/07~67 2 0 ~ ~ ~ 2 ~ P~r/us91/08229
-42-
pyridine (one-half drop) in methylene chloride (1 mL).and the mixture was stirred at
arnbient temperature for 0.5 h under an argon am~osphere. The reaction mixture was
purified by flash chromatography, eluting with 98:2 methylene chloride/methanol, to
provide a white solid (51 mg, 93%): m.p. 99-102C.
Analvsis Calc. for C24H29N3O4-1/2H2O: C 66.65, H 6.99, N 9.72; found: C
6fi.8g, H 6.60, N 9.38.
1~]D (0-99. methanol) = +75.6
EXAMPLE 16
1 0 S-t-~-1-(4-Oxamidobenzvl)4-(3-cvclopentyloxv-4-methoxvphenvl)-2-imidazolidinone
S-(-)-l -(4-Oxamidobenzvl)-4-(3-cvclopentyloxy-4-methoxyphenvl)-2-irnidazolidinone
To a solution of S-(-)-1-(4-aminobenzyl)-4-~3-cyclopentyloxy~
methoxyphenyl)-2-imidazolidinone (76 mg, 0.2 mmol) in methylene chloride (1.5 mL)
1 5 at 0C under an argon atmosphere was added triethylamine (0.03 mL, 0.22 mmol) and
methyl oxalyl chloride (0.04 mL, o.æ mmol). After 0.5 h, aqueous ammonium
chlo~ide was added, the mixture was poured into water and extracted three times with
methylene chlo~ide. The organic extracts were dried (potassium carbonate) and
evaporated. Purification by flash chromatography, eluting with 4:1 ethyl
2 0 acetate/hexanes, provided a white foamy solid (89 mg, 93%): m.p. 77-80C. This
methyl oxamate (89 mg, 0.19 mmol) in methanol (1 mL) in a pressure tube under anargon atmosphere was cooled to -78C and anhydrous ammonia (3 mL) was condensed
into the tube. The tube was sealed and the mixture was allowed to come to ambient
temperature. After 20 h, the tube was cooled to -78C, unsealcd and allowed to come
2 5 to ambient temperature under a stream sf argon. The residue was disso]ved, ~Itered
and evaporated. Trituration with me~hylene chloride provided a white solid ~79 mg,
91%): m.p. 191-193C.
Analvsis Calc. for C24H2gN4O5-0.6H2O: C 62.22, H 6.35, N 12.09; found:
C 62.25, H 6.22, N 11.97.
3 0 [~]D5 (0.99, dimethylsulfoxide) = -47.7
EXAMP~E 17
R-(+)-1 -(4-~xamidobenzyl~-4-(3-cvclopentvloxv~methoxvphenvl)-2-~midazolidinone
3 5 R-(+)-1-(4-Oxamidobenzvl)-4-(3-cvclopentvloxv~methoxvphenv!~-2-imidazolidinone
, .
. , . . : ~ ,,, ,....... : .
, . .
- ~ . .: .
,, , , : . ::
wo 92/07~67 Pcr/ussl/o8229
43 209~9
To R-(+)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy-~methoxyphenyl)-2-
imidazolidinone (5 l mg, 0.13 mmol) at 0C under an argon atmosphere was added asolution of triethylarnine (0.02 mL, 0.14 mmol) in methylene chloride (0.5 mL) and a
solution of methyl oxalyl chloride (0.014 mL, 0.14 mmol) in methylene chloride (0.5
S mL). After 0.5 h, aqueous ammonium chloride was added, the mixture was poured
into water and extracted three times with methylene chloride. The organic extracts were
dried (potassium carbonate) and evaporated. Purification by flash chromatography,
eluting with 3:1 ethyl acetate/hexanes, provided a sticky white solid (58 mg, 96%):
m.p. 127-131C. This methyl oxamate (58 mg, 0.12 mmol) in methanol (1 mL) in a
1 0 pressure tube under an argon atmosphere was cooled to -78C and anhydrous ammonia
(2 mL) was condensed into the tube. The tube was sealed and the mixture was allowed
to come to ambient temperature. After 18 h, the tube was cooled to -78C, unsealed
and allowed to come to ambient temperature under a stream of argon. The residue was
dissolved, filtered and evaporated. Trituradon with methylene chloride provided a
1 5 white solid (35 mg, 61%): m.p. 192-193C.
Analvsis Calc. for C24H2gN4O5-1/3H2O: C 62.88, H 6.30, N 12.22; found:
C 63.23, H 6.27, N 11.78. [a]D5 (0.99, dimethylsulfoxide) = ~49.1
EXAMPLE 18
2 0 R-(+~ (4-Formamidobenzvl)-4-(3-cvclopent!oxv-4-methoxyphenvl)-2-
imidazolidinone
R-t+)- 1 -(4-Formamidobenzvl)-4-(3-cvclopentvloxv-4-methoxYphenv!)-2-
imidazolidinone Acetic formic anhydnde was prepared by heating a mixture of
2 5 acetic anhydride (5.0 mL, 53 mmol) and formic acid (2.1 mL, 56 mmol) at 4045C for
3 h. To acetic formic anhydride (37 IIL,0.39 mmol) at 0C under an argon atmosphere
was added dropwise a solution of R-(+)-l-(~aminobenzyl)-4-(3-cyclopentyloxy-4-
methoxyphenyl)-2-imidazolidinone (66 mg, 0.17 m~nol) in dry tetrahydrofuran (1.5rnL), the mixture was allowed to wann to ambient temperature and stir ed for 18 h.
3 0 The reaction mixture was par~tioned between methylene chloride and aqueous sodium
bicarbonate, the organic extracts were washed with water, dried and evaporated.
Pur~lcation by flash chromatography, eluting with 98:2 methylene chlo~ide/methanol,
provided a white solid (57 mg, 82%): m.p. 92-95C.
Analysis Calc. for C23H27N3O4: C 67.46, H 6.65, N 10.26; found: C 67.09, H
3 ~ 6.64, N 10.06.
[a]D5 (0.90, methanol) = +89.3
SuE~TlTuTE SHEET
.
~, ' , , .
wo 92t07567 PCr/US91/082Z9
2095~2~ 44 ~
EXAMPLE 19
S-(-)- I -(4-FormamidobenzYI)-~(3-cvclopentvloxv-4-methoxyphenvl)-2-
imidazolidinone
S S-(-)-1-(4-FormamidobenzYI)-4-(3-cYclopenlvloxv-4-methoxvphenyl)-2-
imidazolidinone Acetic formic anhydride was prepared by heating a mixture of
acetic anhydride (5.0 mL, 53 mmol) and formic acid (2.1 mL, 56 mmol) at 40-45C for
3 h. To acetic formic anhydride (25 ~lL, 0.27 mmol) at 0C under an argon atmosphere
was added dropwise a solution of S-(-)-1-(4-aminobenzyl)-4-(3-cyclopentyloxy4-
1 0 methoxyphenyl)-2-imidazolidinone (65 mg, 0.17 mmol) in dry tetrahydrofuran (1.5
mL), the mixture was allowed to warm to ambient temperature and stirred for 18 h.
The reaction mixture was partitioned between methylene chloride and aqueous sodium
bicarbonate, the organic extracts were washed with water, dried and evaporated.
Puriflca~on by flash chromatography, elu~ing with 98:2 methylene chloride/methanol,
1 5 provided a foamy white solid (43 mg, 62%): m.p. 103-106C.
Analysis Calc. for C23H27N3O4-1.1H20: C 64.35, H 6.86, N 9.79; found: C
64.72, H 6.53, N 9.31.
[a]D (0-90. methanol) = -90.6
2 0 EXAMPLE 20
1 -(4-Acetamido-3-pvridvlmethvl~-4-(3-cvclopentyloxy-4-methoxyphenyl)-2-
imidazolidinone
A) l-(~Acetamido-3-pyridvlmethylamino)~(3-cyclQ~entyloxY-4-
2 5 methoxvphenvl~-2-imidazolidinone
A solution of (2R,2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-
menthyloxycarbonylamino]ethylamine (409 mg, 0.95 mmol) and 4-pyridine-
carboxaldehyde (155 mg, 0.95 mmol) in chloroform (15 mL) under an argon
atmosphere was stirred for 4 h at reflux and cooled. The solvent was removed in vac~o
3 0 and a portion of the residue (195 mg, 0.34 mmoles) was redissolved in tetrahydrofuran
(2 mL) and methanol (2 mL). Sodium cyanoborohydride (65 mg, 1.0 mmol) was
added and the solution was stirred for 0.5 h. Addition of acetic acid (40 IlL, 0.7 mmol)
was followed by stirnng at room temperature for 1 h under an argon atmosphere.
Aqueous sodium bicarbonate was added, and the solution was evaporated to dryness.
3 5 The residue was parti~oned between methylene chloride/methanol and water, and the
organic layer was dried (potassium carbonate) and evaporate~ Purification by flash
SlJBSTlTUTE SHEE~
.
WO 92/07567 PCr/US91/08229
-45- 2n9~2!~
chromatography, first eluting with 3:97 methano}/methylene chloride, provided Ihe
amine (128 mg, 65%): m.p. 78-81C.
B) 1-(4-Amino-3-~vridvlmethvl)-4-(3-cvclopentvloxv-4-methoxyphenyl)-2-
S in~Lidazolidinone
A solution of 1-(4-acetamido-3-pyridylmethylamino)-4-(3-cyclopentyloxy-4-
methoxyphenyl)-2-imidazolidinone (121 mg, 0.21 mmol) in dimethylsulfoxide (3 mL)was treated with 10% sodium hydroxide (0.42 mL, 1.05 mmol) and sti~ed for 2.5 h
under an argon atmosphere at 90-95C. The reaction was cooled, water added and
1 0 extracted twice with ethyl acetate. The or~anic extracts were washed S times with
water, dried (potassium carbonate) and evaporated. Purification by flash
chromatography, eluting with 96:4 methylene chloride/methanol, provided a white solid
(63 mg, 79%): m.p. 69-71C.
Analvsis Calc. for C21H26N4O3-0.5H2O: C 64.43, H 6.95, N 14.31; found: C
1 5 64.30, H 6.86, N 14.05.
C) 1-(4-Acetamido-3-pvridvlmethvl3~(3-cvclopentvloxY-4-methoxvphenYI)-2-
imidazolidinone
A solution of 1-(4~amino-3-pyridylmethyl)-4-(3-cyclopentyloxy~methoxy-
2 0 henyl)-2-imidazolidinone (36 mg, 0.09 mmol) in pyridine (2 mL) was ~reated with a
solution of acetyl chlonde (0.0075 mL, 0.11 mmol) in methylene chloride (0.5 mL) and
the mixturc was s~red for 1 h under an argon atrnosphere at ambient temperature. An
additional aliquot of acetyl chloride (0.0075 mL, 0.11 mmol) in methylene chloride (0.5
mL)was added and stir ing was continued for 1.5 h. Water was added and the mixture
2 5 was extracted three times with methylenc chloride. The organic cxtracts dried (sodium
sulfate) and cvapo~ated. Purification by flash chromatography, eluting with 96:4methylene chloride/methanol, provided an off-white solid (39 mg, 99%): m.p. 184-187C. the solid was triturated with methylene chloride and ether to provide a white
solid (10 mg).
3 0 Analvsis Calc. for C23H2gN4O4-0.65H2O: C 63.33, H 6.77, N 12.84; found: C
63.34, H 6.52, N 12.44.
EXAMPLE 21
S-(-3-4-(3-Cvclopentvloxv~methoxvphenvl3-1-(2.4-diaminobenzv!)-2-
3 ~ imidazolidinone
SLIBSTITUTE SHEET
.
:- , . . .- .
.
. ~ . . ~ , . .
wo 92/07567 2 0 9 ~ 4 2 9 PCr/US91/08~29
- 46 -
A) (2S~-2-(3-Cvclopentvloxv-4-methoxvphenvl~-1-(2~4-Dinitrobenzylamino~-2-r(-
)-menthvloxvcarbonvlarninolethane
A solution of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-men~hyloxycarbonyl-
arnino]ethylamine, obtained as described above from (2S)-l-benzyloxycarbonylamino-
2-(3-cyclopentyloxy-4-methoxyphenyl)-2-[(-)-menthyloxycarbonylamino]ethane (2.00g, 3.53 mmol), and 2,4-dinitrobenzaldehyde (762 mg, 3.88 mmol) in chloroform (40mL) under an argon atmosphere was stirred for 5 h at reflux. The solvent was removed
in vau o and the residue was redissolved in tetrahydrofuran (38 mL) and methanol (40
mL) under an argon atmosphere. Sodium cyanoborohydride (664 mg, 10.6 mmol) was
1 0 added and the solution was stirred for 1 h. Addition of acetic acid (404 t~L, 7.1 mmol)
was followed by stirring at room temperature for 72 h . Aqueous sodium bicarbonate
was added, and the mixture was evaporated to dryness. The residue was partitioned
between methylene chloride and water, and the organic extract was dried (sodium
sulfate) and evaporated in vac~o. Purification by flash chromatography, eluting with
1 5 from 40 to 60% ethyl acetate in hexane, provided a semi-solid (1.7 g,79%).
B) (2Sl-2-(3-Cvclopentvloxv-4-methoxvphenvl)-1-(2.4-diaminobenzvlamino)-2-
,r(-)-menthvloxvcarbonvlaminolethane
A soludon of (2S)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4-
2 0 dinitrobenzyl)-2-[(-)-menthyloxycarbonylamino]ethane (1.7 g, 2.8 mmol) in methanol
(16.6 mL) containing acetic acid (16.6 mL), was treated with water (16.6 mL) andtitanium trichloride (35 mL of a 20% aqueous soludon). The reaction was sdrred for 90
min, chilled in an ice bath and a solution of water (24 mL) and concentrated ammonium
hydroxide (47 mL) were added. The reaction was diluted with 5% sodium
2 5 carbonate/methanoVmethylene chl~ide (1:1:2) and sdrred for 1 h. The mixture was
separated and the aqueous phase extracted with methylene chloride. The organic extract
was dried f~potassium carbonate) and evaporated in vacuo. Purification by flash
chromatography, eluting the product with chloroform (saturated with ammonium
hydroxide and dried) provided a solid (1.04 g, 68%): m.p. 150-154C.
C) S-(-)-~f3-CvclopentyloxY-4-methoxYphenvl)-1-~2.~diaminobenzvl)-2-
imidazolidinone
A solution of (2S)-2-(3-cyclopentyloxy-~methoxyphenyl)-1-(2,4 diamino-
benzylamino)-2-[(-)-menthyloxycarbonylamino]ethane (1.0 g, 1.81 mmol) in
3 5 dimethylsulfoxide (8 mL) was treated with 10% sodium hydroxide (1.0 mL, 2.5 mmol)
and stirred for 3 h under an argon atmosphere at 80-85C. The reaction mixture was
cooled, partitioned between cold water and ethyl acetate, and the organic extract was
SUBSTITUTE SHE~T
. . ,
. ~ ., ........ . ~ . ~.................... ; -
. , , , , - .
W O 92/07567 PC~r/US91/08229
47 2~9~2~
washed with water, dried (sodium sulfate) and evaporated in vacuo. Purification by
flash chromatography, eluting the product with. chloroform (satura~cd with ammonium
hydroxide and dried) containing 0.5 to 2% methanol, provided a granular resin (459
mg, 64%): [a]D t0.609, methanol) = -83.6.
~ Calc. for C22H28N4o3: C 66.65, H 7.12, N 14.13; found: C 66.40, H
7.û4, N 13.96.
EXAMPLE 22
,S-(-)-4-(3-Cyclo~enivloxv 4-methoxv~henvl)-1-(2.4-diacetamidobenzyl)-2-
1 0 imidazolidinone.
To a solution of S-(-)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-
diaminobenzyl)-2-imidazolidinone (240 mg, 0.605 mmol) in anhydrous pyridine (5 ml)
was added acetic anhydride (340 ~L, 3.60 mmol) and the mixture was stirred at
ambient temperature for 18 h under an argon atmosphere. The reaction mixture was1 5 concentrated in vacuo and the residue partitioned between cold 3N HCI and ethyl
acetate. The organic extract was washed with water, 5% aqueous sodium bicarbonate,
water, dried over sodium sulfate and concentrated in vacuo. Purification by flash
chromatography,eluting the product with chloroform (saturated with ammonium
hydroxide and dried) containing 1 to 2% methanol, provided a resin (180mg, 62%):2 0 ~a]DS (0.600, methanol) = -61.
Analvsis Calc. for C26H32N4o5-ll4H2o: C 64.38, H 6.75, N 11.55; found: C
64.61, H 6.77, N 11.38.
EXAMPl F 23
2 5 R-(~!-4-(3-Cvclopentvloxv4-methoxvphenvl~-1-(2.4-diaminobenzvl)-2-
~ imidazolidinone
.
A) (2R)-2-(3-CvclopentvloxY-~methoxvphenvl)-1-(2A-dinitrobenzvlamino)-2-r(-
)-menthyloxYcarbonYlaminolethane
3 0 A solution of (2R)-2-(3-cyclopen~yloxy-4-methoxyphenyl)-2-~ menthyloxy-
carbonylarnino3ethylamine, obtained as described above from (2R)-l-
benzyloxycarbonyl-arnino-2-(3-cyclopentyloxy-4-methoxyphenyl~2-((-)-
menthyloxycarbonylamino)ethane (2.00 g, 3.53 mmol), and 2,4dinitrobenzaldehyde
~762 mg, 3.88 mmol) in chloroform (40 mL) under an argon atmosphere was s~red
3 5 for ~ h at reflux. The solvent was removed in vacuo and the residue was redissolved
in te~ahydrofuran (10 mL) and methanol (15 mL). Sodium cyanoborohydride (665
SUBSTITUTE SHEET
: . .
:
:. . . ~ , ,
wo 9t/07567 PCr/US91/08229
2 ~1 9 ~ 48 ~
mg, 10.6 mmol) was added and the solution was stirred for 1 h. Addition of acetic acid
(405 IlL, 7.1 mmol) was followed by sti~Ting at room temperature for 72 h under an
argon atmosphere. Aqueous sodium bicarbonate was added, and the solution was
evaporated to dryness. The residue was partitioned between methylene chloride and
S watcr, and the organic extract was dried (sodium sulfate) and evaporated in vacuo.
Purification by flash chromatography, eluting with from 30 to 50% ethyl acetate in
hexane, provided an orange solid (~.25 g, 62%), mp 119-125C.
B) (2R)-2-(3-Cvclopentvloxv-4-methoxvphenvl)-1-(2~4-diaminobenzvlamino)-2-
r(-)-menthvloxYcarbonvlarninolethane
1 0 A solution of (2R)-2-(3-cyclopentyloxy-4-methoxyphenyl)-1-(2,4dinitro-
benzylamino)-2-[(-)-menthyloxycarbonylamino]ethane (1.2 g,2.0 mmol) in methanol
(12 mL) contain~ng acetic acid (12 mL), was treated with water (10 mL) and dtanium
trichloride (20.8 mL of a 20~o aqueous solution). The reaction was stirred for 60 min,
chilled in an ice bath and a solution of water (12 mL) and concentrated ammonium1 5 hydroxide (28 mL) were added. The reaction was diluted with 5% sodium
carbonate/methanoVmethylene chloride (1:1:2) and stirred for 1 h. The mixture was
separated, the aqueous phase extracted with methylene chloride containing 5% methanol
and the combined organic extracts were washed with water, dried (potassium
carbonate), and evaporated in vacuo. Purification by flash chromatography, eluting
2 0 with chloroform (saturated with ammonium hydroxide and dried) provided a tan solid
(0.59 g, 54%): m.p. 139-143C.
C) R-(+)-4-(3-CyclopentYloxv4-me~oxvphenvl~ (2.4-diaminobenzyl)-2-
imidazolidinone
2 5 A solution of (2R)-2-(3-cyclopentyloxy4-methoxyphenyl)-1-(2,4-
diaminobenzylamino)-2-[(-)-menthyloxycarbonylamino]ethane (0.59 g, 1.07 mmol) indimethylsulfoxide (4 mL) was treated with 10% sodium hydroxide (0.53 mL, 1.3
mmol) and stirred for 3.5 h under an argon atmosphere at 80-85C. The reaction
mixture was cooled, partitioned between cold water and ethyl acetate, and the organic
3 0 extract was washed with water, dried (potassium carbonate) and evaporated in vacuo.
Purification by flash chromatography, eluting the p~duct with chloroform (saturated
with ammonium hydroxide and dried) containing 1 to 2% methanol, provided a resin(352 mg, 83%): [a]D (0.564, methanol) = ~84.
Analysis Calc. for C22H2gN4O3: C 66.65, H 7.12, N 14.13;
3 5 found: C 66.43, H 7.03, N 14.11.
5UBSTITIJTE SHEET
. . ... . . . .
. .
.. . . : ~
.~. . . : - .
WO 92/07s67 PCr/US91/0822~
~ ` 49 2 0 ~
EXAMPLE 24
R-(+)-4-(3-Cvclo~entvloxY-4-methoxyphenvl)- 1 -(2~4-diacetamidobenzyl)-2-
imidazolidinone.
To a solution of R-(+)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,4-
S diaminobenzyl)-2-imidazolidinone (176 mg, 0.44 mmol) in anhydrous pyridine (4 ml)
was added acetic anhydride (250 ~L, 2.64 mmol) and the mixture was stirred at
ambient temperature for 18 h under an argon atmosphere. The reaction mixture wasconcentrated in vacuo, and the residue partitioned between cold 3N HCl and ethylacetate. The organic extract was washed with water,2% aqueous sodium carbonate,
1 0 water, dried over sodium sulfate and concentrated in vacuo. Purification by flash
chromatography,eluting the product with chloroform (saturated with ammonium
hydroxide and dried) containing 1 to 2% methanol, prwided a resin (140 mg, 66%):[a]D (0.591, methanol) - 59.
Analysis Calc. for C26H32N405-1/4H20: C 64.38, H 6.75, N 11.55; found: C
1 S 64.20, H 6.70, N 11.43.
By the methods given above, the following compounds may be prepared:
Example No. Compound
1-~4-Cyanobenzyl)-~(3-cyclopentyloxy-4-
2 0 methoxyphenyl)-2-imidazolidinone
26 1-(4-Amidinobenzyl)~(3-cyclopentyloxy-4
methoxyphenyl)2-imidazolidinone
27 4-(3-Cyclopentyloxy~methylphenyl)-1-[4-(2-
imidazo)benzyl] -2-imidazolidinone
2 S 28 4-(3-Cyclopentyloxy-~methoxyphenyl)-2-
imidazolidinone
29 4-(3-Cyclopentyloxy-4-methoxyphenyl)-1-[4-(1-
imidazo)benyl] -2-imidzolidinone
4-(3-t4-Butoxy]~methoxyphenyV-2-irnidazolidinone
EXAMPLE 31
Formulations for pharmaceudcal use incorporating compounds of the present
invention can be prepared in various forms and with numerous excipients. Examples of
such formulations are given below.
3 5 Inhalant Formulation
A compound of Formula (I), (l,ug to 100 mg) is aerosoliæd from a metered dose
inhaler to deliver the desired amount of d~ug per use.
SUBSTITUTE SHEET
WO 92/07567 PCI/US91/08229
209~429 so ~--~
Tablets/Ingredients Per Tablet
1. Active Ingredients
(cpd. of Formula (I) 40 mg
2. Corn Starch 20 mg
3. AlginicAcid 20 mg
4. Sodium Alginate 20 mg
5. MgStearate 1.3 m~
101.3 mg
EXAMPLE 32
1 0 A pharmaceudcal composition for parenteral administradon is prepared
by dissolving an appropriate amount of a compound of Formula (I) in polyethyleneglycol with heating. This solution is then diluted with water for injecdon (to lOOml).
The soludon is then sterilized by filtradon through a 0.22 micron membrane filter and
sealed in sterile containers.
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 further
elaboratdon, it is believed that one skilled in the are can, using the preceding dcscription,
2 0 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 invcntion
in any way. The embodiments of the invention in which an exclusivc propcrty o¢
privilege is claimed are defined as follows.
Sui3sTlTuTE SHEET
~, .. . ., - . ,, . - . .
- - .
~ ' . ' . : ' ~
.
.
