Note: Descriptions are shown in the official language in which they were submitted.
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WO 90tl2008 PCI/US90/014~8
2 ~
URE:A BASED LIPOXYGENASE INHIBITING ICOMPOUNDS
os~-Refer~nce to ~l~ted A~Dlications
This application is a continuation-in-part of copending application Serial No.
331,566 filed March 30, 1989 which, in tum, is a continuation-in-part of application Serial
No. 04'~,491, filed April 24, 1987, (now abandoned) which is a contimlation-in-part of
application SeIial No. 856,725, filed April 25, 1986 (now abandoned).
Technical Field
This invention relates to compounds having pharmacological utility, to
pharrnaceutical compositions comprising the compounds, and to medical methods oftreatrnent. More particularly, this invention concerns compounds which inhibit
lipoxygenase enzymes, to methocls and compositions for inhibiting lipoxygenase enzyrnes
in human and other mammalian hosts in need of such treatrnent.
Back~ound of the Invention
5-Lipoxygenase is the first dedicated enzyme in ~he pathway leading to the
biosynthesis of leukotrienes (Samuelsson, B., Science, 120: 568 (1983); Hammarstrom,
S., Annual Review of Biochemistry, 52: 355 (1983)). This important enzyme has a
rather restricted distribution, being found predominantly in leukocytes and mast cells of
most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form;
however, when leukocytes respond to external stimuli, intracellular 5-lipoxygenase can be
rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids
with cis,cis-l,~pentadiene structures, converting them to 1 hydroperoxy-trans,cis-2,4-
pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotliene
products, is found in very low concentrations in mammalian cells and must first be
hydrolyzed from membrane phospholipids through the ac~ions of phospholipases in
response to extracellular stirnuli. The initial product of 5-lipoxygenase action on
arachidonate is S-hydroperoxyeicosatetraenoic acid (~-HPETE) which can be reduced to 5-
hydroxyeicosate~aenoic acid (~-HETE) or conver~ed to leukotriene A4 (~LTA4). This
reactive leukotnene inte~rnediate is enzyrnatically hydrated to Ll B4 or conjugated to the
~ipeptide glutathione to produce LTC4. LTA4 can also be hydrolyzed nonenzymatically ~o
form two isomers of Ll~34. Successive proteolytic cleavage steps convert LTC4 to LTD4
and LTE4.
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WO 90~12008 PCI/US90/01488
Other products resulting from further oxygenation steps have also been described(Serhan, C.N., Harnberg, M., and Sarnuelsson, B., Proceedings of the Na~ional Academy
of Sciences, USA, 81: 5335 (1985); Hansson, G., Lindgren, J.A., Dahlen, S.E.,
Hedqvist, P., and Samuelsson, B. PEBS Letters, 130: 107 (19~4)).
Products of the 5-lipoxygenase cascade are extremely potlent substances which
produce a wide variety of biological effects, often in the nanomol,ar to picomolar
concentration range. (Sirois, P., Advances in Lipid Research, R. Paoletti, D.
Kritchevesky, editors, Academic Press, 21: 79 (1985).
The remarkable potencies and diversity of actions of products of the S-lipoxygenase
pathway have led to the suggestion that ~hey play important roles in a variety of diseases.
Alterations in leukomene metabolism have been demonstrated in a number o~ disease
states. Examples of some of these are briefly discussed as follows:
1. Asthma. Slow reacting substance of anaphylaxis (SRS-A) has long been
recognized as a potentially important mediator of asthma and other allergic diseases
(Orange, R.P. and Austen, K.F., Advances in Irnrnunology, 10: 105, 1969). Upon
specific antigen challenge, dssues from allergic ar~mals and hurnans generate and release
SRS-A (Kellaway, C.H. and Tre~hewie, E.R., Qua~terly Journal of Experimen~al
Physiology~ 30: 121, 1940; Orange, R.P., Stechschulte, D.J., and Austen, K.F., Journal
of Immunology, 105: 1087, 1979; Lewis, R.A., Wasserman, S.I., Goetzl, E.J., and
Austen, K.F., Journal of Experimental Medicine, 140: 1133, 1974). It produces a slow
and sustained contracdon of airway smooth muscle preparations from a variety of species
in vitro, including man (Drazen, J.M., Lewis, R.A., Wassennan, S.I., Orange, R.P., and
.4usten, K.F., Journal of Clinical Investigation, 63: 1, 1979; Piper, P.J., Tippins, J.R.,
Morris, H.R., and Taylor, G.W., Advances in Prostaglandin and Thromboxane Research,
6: 121, 1980; Brocklehurst, W.E. Progress in Allergy, 6: 539, 1962; Berry, P.A. and
Collier, H.O.J., British Journal of Pha~nacology, 23: 201, 1964). Intravenous
administration of SRS-A to guinea pigs results in compromised respiration, primarily due
to constriction of small peripheral airways (l~razen, J.M. and Austen, K.F., Journal of
Clinical Investigation, 53: 1679, 1974). SRS-A also ~nduces vascular perrneability when
injected intracu~aneously in some species, including man (Orange, R.P., Stechschulte,
D.J., and Austen, K~., Federation Prcseedings, 28: 1710, 1969). The chernical identity
of SRS-A lemained ~ own until 1979 when it was found to be a rnixture of three
leukotrienes (LTC4, LTD4, and LTE4) (Murphy, R.C., Hamrnarstrom, S., and
Samuelsson, B. Proceedings of the National Academy of Sciences, USA, 76: 4275,
.
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WO 90/12008 2 ~ PCI/US90/01488
1979; Morris, H.R., Taylor, G.W., Piper, P.J., and Tippins, J.R., Nature, 28$: lOa"
1980). Since this discovery, leukotrienes have been shown to possess all the biological
properties descnbed for SRS-A (Lewis, R.A., Drazen, J.M., Austen, K.F., Clarlc, D.A.,
and Corey, E.J., Biochernical and Biophysical Research Cornmunications, 96: 271,1980). Moreover, human lung fragments from patients with exlrinsic asthma gen~ate
large amounts of leukotrienes when challenged in vitro (Lewis, R.A., Austen, K.F.,
Drazen, J.M., Clark, D.A., Marfat, A., and Corey, E.J., Proceedings of the National
Academy of Sciences, USA, 77: 3710, 1980.) and synthe~c leukotrienes are potent
constrictors of human aiIway smooth muscle in vitro (Dahlen, S.E., Hansson, C;.,Hedqvist, P., Bjorck, T., Granstrom, E., and Dahlen, ~3., Proceedings of the National
Academy of Sciences, USA, 80: 1712, 1983; Dahlen, S., Hedqvist, P., Hamrnarstrom,
S., and Sarnuelsson, B., Nature, 288: 484, 1980). Aerosolized leukotrienes administered
to normal human volunteers cause vigorous airway constnction (Hanna, C.J., Bach,M.K., Pare, P.D., and Schellenberg, R.R., Nature, 290: 343, 1981; Holroyde, M.C.,
Altounyan, R.E.C., Cole, M., Dixon, M., and Elliott, E.Y., The Lancet, 4: 17, 1981)
and LTC4 produces a preferential effect on the peripheral airways which is slow in onset
and long in duration (Weiss, J.W., Drazen, J.M., Coles, N., McFadden, E.R., Jr.,Weller, P.F., Corey, E.J., Lewis, R.A., and Austen, K.F., Science, 2I6: 186, 1982).
LTC4 levels were found to be elevated in the blood of children undergoing an acute
asthmatie attack (Schwartsburg, S.B., Shelov,S.P., and Van Praag, D. Prostaglandins
Leukotrienes and Medicine, 26: 143, 1987). Leukotrienes were also de~ected in sputurn
of patients with chronic bronchitis (Zakrezewski, J.T., Barnes, N.C., Piper, P.C.,
Costello, J.F. Prostaglandins, 33: 663, 1987). These pulmonary effects of LTC4 are
characteristic of those obselved in asthmatic patients following antigen inhalation and are
consistent with a major role for leukotrienes in allergic asthma (Lewis, R.A., Chest, 87:
SS, 1985).
2. Allergic Rhinitis. Nasal challenge with specific antigen of patients with allergic
rhinitis results in dose- and time-dependent elevadons of leuko~ienes in nasal washings
tShaw, R.J., Fitzharris, P., Cromwell, O., Wardlaw, A.J., and Kay, A.B., Allergy, 40:
1, 1985). Leukotrienes are proposed mediators of allergic rhinitis as they are st~mulators of
mucus secretion and vascular permeability (Schelhamer, J.H., Marom, Z., Sun, F., Bach,
M.K., and Kaliner, M., Chest, 81 ~Suppl): 36, 1982; Coles, S.J., Neill, K.H., Reid,
L.M., Austen, K.F., Nii, Y., Corey, E.J., and Lewis, R.A., Prostaglandins, 25: 155,
1983; Soter, N.A., Lewis, R.A., Corey, E.J., and Austen, K.F., The Journal of
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W~ 90/12008 PCr/US90/û1488
Investigative Dermatology, 80: 115, 1983), characteristic events in the pathophysiology ofthis disorder.
3. Rheumatoid Arthritis And Gout. Both LTB4 and 5-HE1[E stimulate
polymorphonuclear leukocyte (PMNL) chemotaxis. LTB4 is one of the most potent
chemotactic substances known (Srnith, M.J.H., ~3eneral Pharmacology, 12: 211, 1981).
By virtue of their abilides to attract P~NL, these products may contribute to the observed
accumulation of PMNL in synovial fluid of individuals with rheurnatoid arthritis and gou~
~-~TE and LTB4 have been identified in joint fluids from patients with rheumatoid
arthritis (Klickstein, L.B., Shapleigh, C., and Goetzl, E.J., Journal of Clinical
Investiga~ion, 66: 1166, 1980; Davidson, E.M., Rae, S.E., and Smith, M.J.H., Journal
of Pharmacy and Pharrnacology, 34: 410, 1982) and particularly high concentrations of
LTB4 have been found in synovial fluids from patients with gout (Rae, S.A., Davidson,
E.M., and Smith, M.J.H., The Lancet, 2: 1122, 1982).
4. Psoriasis. LTB4 is present in higher than normal levels in psoriadc lesions
(Brian, S.D., Camp, R., Dowd, P., Black, A., and Greaves, M., The Jnurnal of
Investigadve Dermatology, 83: 70, 1984) which have significantly elevated
5-lipoxygenase activity compared to uninvolved or normal skin (Ziboh, V.A., (: asebolt,
T.L., Marcelo, C.l.., and ~oorhees, J.J., The Journal of Investigative Dermatology, 83:
425, 1984). The neutrophil infiltrate that characterizes the early stages of this disease may
be due tu the chemoattractant properties of LTB4 which can induce rnicropustule forcnation
when applied topically ~VandeKerkhof, P.C.M., Bauer, F.W., and deGroud, R.M., The
Journal of Investigative Dermatology, 84: 450, 1985). LTC4 and LTD4 have also been
detected in psoriatic skin lesions (Brian, S.D., Camp, R.D.R., Black, A.K., Dowd, P.M.,
Greaves, M.W., Ford-Hutchinson, A.W., and Charleson, S., Prostaglandins, 29: 611,
1985). These rnediators act as ~rasodilators in human skin and may account for the
vasodilation and increased blood flow in psonatic lesions.
5. Adult Respiratory Distress Syndrome. The presence of elevated LTD4
concentrations in pulrnonary edema fluids has led to the suggestion that LTD4 contributes
to the pe~neabili~ defect in the alveolar-capillary balrier in patients with adult respiratory
dis~ess syndrome (Matthay, M.A., Eschenbacher, W.L., and Goetzl, E.J., Journal of
Clinical Immunology, 4: 479,1984).
6. InflammatoIy Bowel Disease. The colonic mucosa of patients with Crohn's
disease has an increased capacity to synthesiæ sulfidopeptide leukotriçnes compared to
normal mucosa when exposed to the calcium ionophore A-23187 (Peskar, B.M., Dreyling,
WO 90/1200~ PCr/US90/0148~ 1
5 2Q~,~79~
K.W., Hoppe, V., Schaarschrnidt, K., Goebell, H ., and Peskar, B.A., Gastroenterology,
88: 537, 1985). Elevated levels of 5-lipoxygenase products are found in colonic tissue
from patients with inflamrnatory bowel disease; sulfasalazine, a drug used in the treatment
of this disease, has been shown to be a weak 5-lipoxygenase inhibitor (Sharon, P. and
Stenson, W.F., Gastroenterology, 86: 453, 1984). These observations suggest thatincreased leukotriene forrnation may contribute to the characteristic mucosal inflammation
of this disorder.
7. Endotoxin Shock. Leukotrienes elicit many of the pathophysiologic syrnptoms
observed in endotoxin shock, such as cardiac depression, increased vascular penneability
leading to tissue ederna, and irlcreased leukocyte adhesion to endothelial surfaces
(Hagmann, W., Denzlinger, C., and Keppler, D. Production of peptide leukotrienes in
endotoxin-shock. FEBS Letters, 180: 309, 1985). Furtherrnore, endotoxins have been
shown to trigger the formation of leukotrienes. It has therefore been proposed that
leukotrienes play a key role in the lethal action of endotoxin (Konig, W., Scheffer, J.
Bremm, K.D., Hacker, J., and Goebel, W., International Archives of Allergy and Applied
Immunology, 77:1 1 8, 1985).
8. Ischemia-induced Myocardial Injury. The leukotrienes are potent constrictors of
coronary arteries and may play a role in regula~ing blood flow to the heart. LTC4 and
LTD4 exacerbate ischemia-induced myocardial injury in rabbits (Lefer, A.M. Eicosanoids
as Media~ors of Ischernia and Shock. Federa~ion Proceedings, 44: 275, 1985).
Furthermore, infarcted hearts, when reperfused, release larger quantities of leulcotnenes in
response to stimuli than hearts from sham-operated animals (Barst, S. and Mullane, K.,
Clinical Research, 33: A51~, 1985). These results implicate leukotrienes as potential
mediators of ischemia `~`
9. Central Nervous Pathophysiology. Leukotrienes are synthesized in greater
amounts in gerbil forebrains after ischemia and reperfusion (Moskowitz, M.A., Kiwak,
K.J., Hekimian, K., et al., Science, 224: 886, 1984)~ concussive injury, or subarachnoid
hemorrhage (subarachnoid injection of blood) (Kiwak, K.J., Moskowitz, M.A., and
Levine, L., Journa} of Neurosurgery, 62: 865, 1985). The formation of leukotrienes is
temporally associated with the cerebral vasospasm and other abnolmali~es resulting from
the insult. Thus a possible role can be suggested for leukotrienes in the pathophysiology
resulting from stroke or subarachnoid hemorrhage.
The enzyme 5-lipoxygenase catalyzes the first step leading to the biosyn~hesis of all
the leukotrienes and therefore inhibition of this enzyrne provides an approach to limit the
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WO 90/12008 PCr/US9~/014~8
effects of all the products of this pathway. Agents capable of abrogatmg the effects of
these potent mediators of pathophysiological processes represent a prornising class of
therapeutic agents (Brooks, D. W., Bell, R. L., and Carter, ~. W. Chapter 8. Pulmonary
and Antiallergy Agents, Annual Reports in ~edicinal Chemistry, Allen, R. C. ed.,Acadernic Press 1988.
SUmm~rv of the InvensQIl
The compounds of this invention possess activity as inhibitors of 5- and/or 12-
lipoxygenase and reduce the biosynthesis of leukotrienes LTB4, LTC4, LTD4 and LTE4.
The compounds and compositions containing these compounds are useful for the trea~ment
of disease states in rnammals which inYolve lipoxygenase enzymes or which involve the
leukotrienes Ll~34, LTC4, LTD4 and LTE4.
The novel compounds of this invention are the compounds of Formula I:
z
X
`N N R3
R2 OM
I
or a phannaceutically acceptable salt thereof, where Z is oxygen or sulfur,.
X is selected from alkylene of from one to six carbon atoms; aL~cenylene of fromtwo to six carbon atoms; and alkylene of from one to six carbon atoms or aL~cenylene of
from two tO SiX carbon atoms substituted by a group selected from hydroxy, halo, cyano,
alkoxy, arn~nocarbonyl, aLkylaminocarbonyl, diaLkylaminocarbonyl, carboxy and
aLkoxycarbonyl.
Rl and R2 are independently selected from hydrogen; hydroxy; alkyl of from one to
six carbon atoms; aLIcyl of from one to six carbon atoms substituted with a substituent
selected from hydroxy, halo, cyano, alkoxy, alkylthio, arIunocarbonyl, aL~cylanuno-
carbonyl, diaLIcylaminocarbonyl, carboxy and alkoxycarbonyl; carbocyclic aryl; and
carbocyclic aryl substituted with a substituent selected from hydroxy, halo, cyano, aL~coxy,
alkylthio, amino, alkylamino, dialkylam~no, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, carboxy and alkoxycarbonyl; with the proviso that Rl and R2 are
not simul~aneously hydroxy.
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WO 90/12008 PCr/US90/01488
~ ~ S ~
R3 is selected from the gIVup consisting of phenyl; naphthyl; ~hienyl; and phenyl,
naphthyl, or thienyl substituted by alkyl of from one to six carbon atoms, alkenyl of from
two to six carbon atoms, cycloalkyl of from ~ree to ten carbon atoms, alkoxy of from one
to six carbon atoms, aLlcylthio of from one to s~x carbon atorns, halo, nitro, hydroxy;
carbocyclic or heterocyclic aryl; carbocyclic or heterocyclic aryloxy; carbocyclic or
heterocyclic aroyl; carbocyclic or heterocyclic arylalkyl wheTein the alkyl portion contains
from one tO SiX carbon atoms, carbocyclic or heterocyclic arylaL~cenyl wherein the alkenyl
portion contains from two to six carbon atoms, carbocyclic or heterocyclic arylaL~cynyl
wherein the aLtcynyl portion contains from two to six carbon atoms, carbocyclic or
heterocyclic arylalkoxy wherein the alkoxy portion contains from one to six carbon atoms,
carbocyclic or heterocyclic arylalkylthio wherein the alkylthio portion contains from one to
six carbon atoms. In addition, the foregoing carbocyclic or heterocyclic aryl; carbocyclic or
heterocyclic aryloxy; carbocyclic or heterocyclic aroyl; carbocyclic or heterocyclic arylalkyl,
carbocyclic or heterocyclic arylaL'cenyl, carbocyclic or heterocyclic arylalkynyl, carbocyclic
or heterocyclic arylaL~coxy, and carbocyclic or heterocyclic arylalkylthio groups may be
optionally substituted by one, two, or three groups independently selected frorn the group
consis ing of halo, nitro, cyano, alkyl, alkoxy, and halosubstituted alkyl.
M is selected from the group consisting of hydrogen; a pharmaceudcally acceptable
cation; a metabolically cleavable group, carbocyclic aroyl; -Si(Rs)3 wherein Rs is
independently selected at each occurrence from alkyl of from one to six carbon atoms; -
C(O)R4; -CH20R4; -C(O)N(R4)2 or -C(O)OR4 wherein R4 is aLlcyl of one to six carbon
atoms.
e~ail~d Descri~tion
While, in the compounds of this invention, the group M can be hydrogen, a suitable
cation, or a group capable of being metabolically cleaved in vivo, in prefelred compounds
of the present invention M is hydrogen.
Sirnilarly, while R3 may be substituted or unsubstituted phenyl, naphthyl or
thienyl, preferred compounds of the present invention are those in which R3 is substituted
or unsubstituted thienyl.
Examples of compounds which are within the scope of the present invention and/orcan be used according to the me~ods of the present invenaon include, but are not limited
~o, the following:
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Wo 90/~2~08 PCr/lJS9û/0148X
p~ r~
N-hydroxy-N-(1-(4-butoxyphenyl)e~hyl) urea
N-hydroxy-N-(1-(3-butoxyphenyl)ethyl) urea
N-hydroxy-N-(1-(4-(2-methylpropyl)phenyl)ethyl) urea
N-hydroxy-N-(1-(4~yelohexyl)phenyl)ethyl) urea
N-hydroxy-N-(2-(~butoxyphenyl)ethyl) urea
N-hydroxy-N-(1-methyl-~-(4-butoxyphenyl)ethyl) urea
N-hydroxy-N-(3-(~butoxyphenyl)propyl) urea
N-hydroxy-N-(1-methyl-3-(4-butoxyphenyl)propyl) urea
N-hydroxy-N-(1-methyl-1-(4-butoxyphenyl)ethyl) urea
N-hydroxy-N-(1-(4-butoxyphenyl)-2-methylpropyl) urea
N-hydroxy-N-(3-nitro-~butoxyphenylmethyl) urea
N-hydroxy-N-(1-(4-(2~4,6 tnmethylphenyl)phenyl) ethyl urea
N-hydroxy-N~(1-(3-benzoylphenyl)ethyl) urea
N-hydroxy-N-(1-(4-(2-phenylethenyl)phenyl)ethyl) urea
N-hydroxy-N-(1-(4-(2-phenylethyl)phenyl)ethyl) urea
N-hydroxy-N- 1 -(4-bromophenyl)ethylurea
N-hydr~xy-N-1-(4-bromophenyl)ethyl-N'-methyl- urea.
N-hydroxy-N- 1 -(4-bromophenyl)ethyl-N'-(2-hydroxyethyl)-urea.
N-hydroxy-N-4-bromobenzylurea.
N-hydr~xy-N-4-bromobenzyl-N'-methyl urea
N-hydroxy-N-(1-(4-bromophenyl)propyl) urea
N-hydroxy-N-( 1-(4-bromophenyl)propyl)-N'-methylurea
N-hydroxy-N-( 1- (2,4-difluorophenyl) ethyl)-N'-methylurea
N-hydroxy-N-(1-(~(2-phenylethynyl) phenyl)ethyl) urea
N-hydroxy-N-(1-(4-(2-phenylethynyl) phenyl)ethyl)-N'-methyl urea
N-hydroxy-N-(1-(4-chlorophenyl)ethyl) urea
N-hydroxy-N-(1-(4-chlorophenyl)ethyl)-N'-methyl urea
N-hydroxy-N-(1-(4-fluoIophenyl)ethyl) urea
N-hydroxy-N-(1-(4-fluorophenyl)ethyl)-N'-methyl urea
N-hydroxy-N-(1-(~trifluoromethylphenyl) ethyl) urea
N-hydroxy-N-(l-(~trifluoromethylphenyl) ethyl)-N'-methylurea
N~hydroxy-N-(1-(4-methylphenyl~ethyl) urea
N-hydroxy-N-(1-(3-bromo~-fluorophenyl)e~yl)-N'-methyl urea
N-hydroxy-N-(1-(3-bromo-~methylphenyl)ethyl)-N'-methyl urea
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WO 90/12008 Prr/US90/01488
~5~7
N-hydroxy-N-(1-(~methoxyphenyl)ethyl) urea
N-hydroxy-N-(1-(~methoxyphenyl)ethyl)-N'-methyl urea
N-hydroxy-N-tl-t4-phenoxyphenyl)ethyl) urea
N-hydroxy-N-tl-t4-butoxyphenyl)ethyl) urea
N-hydroxy-N-(l-t4-biphenyl)ethyl) urea
N-hydroxy-N-t1-t4-bis-allylaminophenyl) ethyl) urea
N-hydroxy-N-t1-t3-bromo-4-fluorophenyl) ethyl) urea
N-hydroxy-N-tl-t4-chloro-3-methylphenyl~ ethyl) urea
N-hydroxy-N-~l-t4~hloro-3-methylphenyl) ethyl)-N'-methyl usea
N-hydroxy-N-tl-t4-chlor~3-methylphenyl) ethyl~ urea
N-hydroxy-N-t~methoxyphenyl)-N'-methyl urea
N-hydroxy-N-(1-t4-phenylmethoxyphenyl) ethyl) urea
N-hydroxy-N-1-t4-phenylmethoxyphenyl) ethyl N'-methyl urea
N-hydroxy-N-1-(4-phenylmethoxyphenyl) ethyl N'N'-dimethyl urea
N,N'-dihydroxy-N-tl-(4-phenylmethoxyphenyl) ethyl urea
N-hydroxy-N-t4-phenylrnethoxyphenylmethyl) urea
N-hydroxy-N-t4-phenylrnethoxyphenylmethyl)-N'-methyl-urea
N-hydroxy-N-tl-t4-phenylmethoxy-3,5-dimethoxy-phenyl)-ethyl) urea
N-hydroxy-N-tl-t4-(2-phenyl)ethoxyphenyl)ethyl) urea
N-hydroxy-N-tl-(4-phenoxyphenyl)e~hyl) urea
N-hydroxy-N-(l-t4-t4-fluorophenylmethoxy) phenyl)ethyl) urea
N-hydroxy-N-(l-t4-t~methoxyphenylmethoxy)phenyl) ethyl) urea
N-hydroxy-N-tl-t4-t~tIifluoromethylphenyl methoxy)-phenyl)ethyl) urea
N-hydroxy-N-tl-(4-phenylmethoxy-3,~-dichlorophenyl)ethyl) urea
N-hydroxy-N-t2-hydroxy-4-phenylmethoxyphenylmethyl) urea
N-hydroxy-N-t1-t4-phenylthiomethoxyphenyl)ethyl urea
N-hydroxy-tl-t4-phenylmethoxyphenyl)ethyl) urea sodium salt
N-hydroxy-tl-t4-phenylmethoxyphenyl)ethyl) urea potassium salt
N-hydroxy-tl-t4-phenylmethoxyphenyl)ethyl) urea arnmonium salt
N-hydroxy-tl-(4-phenylmethoxyphenyl)ethyl) urea triethylamrnonium salt
N-hydroxy-tl-t4-phenylmethoxyphenyl~ethyl) urea tetraethyl ammonium salt
N-bu~yryloxy-tl-(~phenylmethoxyphenyl)ethyl) urea
N-benzoyloxy-t1-(4-phenylmethoxyphenyl)ethyl) urea
N-hydroxy-N-tl-t2-naphthyl)ethyl) urea
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WO 90/12~08 PCI/US90/01488
N hydroxy-N-(1-(~butoxy-2-naphthyl)ethyl) urea
N-hydroxy-N-(1-(6-phenylmethoxy-2-naphthyl)e~hyl) urea
N-hydroxy-N-(l-(~methoxynaphthalen-2-yl)ethyl) urea
N-hydroxy-N-((6-methoxynaphthalen-2-yl)methyl) urea
N-hydroxy-N-(3-(~methoxynaphthalen-2-yl)propen-1-yl) urea
N,N'-dihydroxy-N-(1-(2-naphthyl)ethyl) urea
N-hydroxy-N-1-(5-methylthien-2-yl)ethyl urea.
N-hydroxy-N-(thien-2-yl)methyl uIea
N-hydroxy-N-1-(3-methylthien-2-yl)ethyl urea
N-hydroxy-N-(1-(5 pyrid-2-yl)thien-2-yl)ethyl urea
N-hydroxy-N-(1-thien-2-yl)ethyl urea
N-hydroxy-N-(3-methylthien-2-yl)methyl urea
N-hydroxy-N-(thien-2-yl)methyl-N'-methyl ~ea
N-hydroxy-N-(5-methylthien-2-yl)methyl urea
N-hydroxy-N-l -(5-methylthien-2-yl)methyl-N'-methyl urea
N-hydroxy-N-(1-(5-phenylthien-2-yl)methyl) urea
N-hydroxy-N-(l-(S-phenylthien-2-yl)methyl)-N'-rnethyl urea
N-hydroxy-N-(1-(5-(pyrid-2-yl)thien-2-yl)methyl) urea
N-hydroxy-N-(1-(5-phenylthien-2-yl)ethyl) urea
N-hydoxy-N-(1-(5-benzylthien-2-yl)ethyl) urea
N-hydroxy-N-(1-(5-(2-phenylethenyl)thien-2-yl)ethyl) urea
N-hydroxy-N-(1-(1-(5-methylthien-2-yl)-2-hydroxy)ethyl) urea
N-hydroxy-N-(1-(5-methylthien-2-yl)-5-car~oethoxypentyl) urea
N-hydroxy-N-(1-(5-methylthien-2-yl)-~carboxyamidohexyl) urea
N-hydroxy-N-(1-(1-(2-hydroxy))-5-methylthien-2-yl)propyl) urea
N'-methyl-N-hydroxy-N-(1-(1-(2-hydroxy))-5-(methylthien-2-yl)ethyl~ urea
N-hydroxy-N-1-(2,5-dimethylthien-3-yl)ethyl ure~
N-hydroxy-N-1-(thien-3-yl)ethyl urea
N-hydroxy-N-(thien-3-yl)methyl urea
N-hydroxy-N-(1-(2,5-dimethylthien-3-yl)ethyl)-N'-methylethoxycarbonyl urea
N-hydroxy-N-(1-(2,5-dimethylthien-3-yl)ethyl)-N'-(2-hydroxye~hyl) urea
N-hydroxy-N-(1-~hien-3-ylethyl)-N'-1-(4-carbomethoxybutyl) uuea
N-hydroxy-N-(1-thien-3-ylethyl-N'-(methylethoxycarbonyl) urea
N-hydroxy-N-(3-(1-thien-3-yl)propenyl) urea
- , .
, . . .
Wo 90/12~08 ~ S90/014~8
11
N-hydroxy-N-(3-(1-thien-3-yl)propyl) urea
N-hydroxy-N-(l-thien-3-ylethyl) Ihiourea
N-hydroxy-N-[1-(5-methylthien-2-yl) ethyl] thiourea
N-hydroxy-N-(2-(1-(S-me~hylthien-2-yl~) propyl) urea
N-hydroxy-N-4-~4,5,6,7-tetrahydrothianaphthalene) urea
N-hydroxy-N-[(4-bromothien-3-yl)methyl]urea
N-hydroxy-N-[l -(thien-3-yl)propen-2-yl]urea
N-hydroxy-N-(l -(5-(2-thien-2-ylethenyl)thien-2-yl)ethyl)-urea
N-hydroxy-N-( 1 -(5-(2-pyrid-2-ylethenyl)thien-2-yl)ethyl~-urea
N-hydroxy-N-(l -(5-(2-thien-3-ylethenyl)thien-2-yl)ethyl)-urea ;i.
N-hydroxy-N-(l -(5-(4-chlorophenylethen-2-yl)thien-2-yl)-ethyl)urea
N-hydroxy-N-(2-(1-thien-3-yl)propyl)urea
N-hydroxy-N- (2- ( 1 -thien-2-yl)propyl)urea
N-hydroxy-N-(2-(1-(5-pyrid-2-yl)thien-2-yl)propyl)urea
N-hydroxy-N-(2-( 1 -(5-phenylethen-2-yl)thien-2-yl)propyl)-urea
N-hydroxy-N-(2-(1 -(5-benzylthien-2-yl)propyl)urea
N-hydroxy-N-(thien-3-yl)methyl urea potassium salt
N-hydroxy N-(3-(1-thien-3-yl)propenyl) urea potassium salt
N-ethoxycarbonyloxy-N-tthien-3-yl)methy urea
N-ethoxycarbonyloxy-N-(3-(1-thien-3-yl)propenyl) urea
N-trimethylsilyloxy-N-(thien-3-yl)methyl urea
N-hydroxy-N-(thien-3-yl)methyl-N'-phenyl urea
N,N'-dihydroxy-N-(thien-3-yl)methyl-N'-methyl urea
N,N'-dihydroxy-N-l-(thien-3-yl)ethyl-N'-methyl urea
N,N'-dihydroxy-N- 1- (5-phenylthien-2-yl)ethyl urea
N-hydroxy-N-( 3-bromothien-2-yl)methyl urea
N-hydroxy-N-( 4-bromothien-2-yl)methyl urea
N-hydroxy-N-tS-chlorothien-2-yl)methyl urea
N-hydroxy-N-( 5-bromothien-2-yl)methyl urea
N-hydroxy-N-( S-bromothien~2-yl)methyl æetamide
N-hydroxy-N^[l-( 4-bromothien-2-yl)ethyl]urea
N-hydroxy-N-[l-( S-bromothien-2-yl)ethyl]uIea
N-hydroxy-N-[ 3-(phenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 5-(phenylthio)thien-2-yl~methyl urea
.
. .
WO 9~tl2008 PCr/US9û/01488
12
N-hydroxy-N-[ 4-(phenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ S-(phenylthio)thien-3-yl]methyl urea
N-hydroxy-N-[ 2-(phenylthio)thien-3-yl]methyl urea
N-hydsoxy-N- I 1-[ 5-(phenylthio)-thiell-2-yl]ethyl ) urea
N-hydroxy-N-[ 3-(4hydroxyphenylthio)thien-2-yl]methyl urea
N-hydroxy-N-~ 3-(~bromophenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 3-(~chlorophenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 3-(4-fluoqophenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 3-(~terlbutylphenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 3-(2-pyndylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 3-(2-furf 1rylmethylthio)thien-2-yl]methyl urea
N-hydroxy-N-l 3-(tert-butylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 5-(ter~-butylthio)thien-2-yl]methyl urea
N-hydroxy-N-[1-( 5-{~ert-butylthio)thien-2-yl)ethyl]urea
N-hydroxy-N-[ 5-(iso-propylthio)thien-2-yl]methyl urea
N-hydroxy-N-E1-( 5- l methylthio} thien-2-yl)ethyl]urea
N-hydroxy-N-3-[ 5-(phenylthio)thien-2-yl]propenyl urea
N-hydroxy-N-(3-[ 5-(phenylthio)thien-2-yl]butenyl urea
N-hydroxy N-3-[ S-(~er~-butylthio)thien-2-yl]propenyl urea
N-hydroxy-N-[ S-(phenoxy)thien-2-yl]methyl urea
N-hydroxy-N-~ 3-(phenoxy)thien-2-yl]methyl urea
N-hydroxy-N-[ 4-(phenoxy)thien-2-yl]me~hyl urea
N-hydroxy-N-[ 4-(~chlorophenoxy)thien-2-yl]methyl urea
Preferred compounds of the invention include, but are not limited to, the following
N-hydroxy-N- 1 -(4-bromophenyl)ethylurea
N-hydroxy-N-(1-(4-chlorophenyl)ethyl) urea
N-hydroxy-N-( S-bromothien-2-yl)methyl urea
N-hydroxy-N-[ 1-( S-bromothien-2-yl)ethyl] urea
N-hydroxy-N-[ 3-(phenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 5-(phenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ 4-(phenylthio)thien-2-yl]methyl urea
N-hydroxy-N-[ S-(phenylthio)lhien-3-yl]methyl urea
N-hydroxy-N-[ 2-(phenylthio)thien-3-yl3methyl urea
.
, . . , , ,:
..
- - :' : ~ -
WO 90/12008 PCM)S90/01488
2 ~
13
The term "alkylene" as used herein refers to a divalent straight or branched chain
group of from one to six carbon atoms including, but not limited to, -CH2-, -(CH2)2-,
-~CH2)3-, -CH(CH3)-, -CH(C2Hs)-, -CH(CH3)CH2-, and the like.
The term "alkenyl" as used herein refe~s to a monovalent straight or branched chain
radical of from tWO tO SiX carbon atoms contair~ing a carbon-carbon-double bond including, .i~
but not lirnited to, l-propenyl, 2-propenyl, 2-methyl-l-propenyl, l-butenyl, 2-butenyl and
~he like.
The term "aL~enylene" as used herein refers to a divalent straight or branched chain
group of frorn two tn six carbon atoms containing a carbon-carbon double bond, including,
but not lirnited to -CH=CH-, -CtCH3)=CH-, -CH=OEI-CH2-,
-CH=C(CH3)-CH2-, -CH2CH(CH=CH2)CH2- and the like.
The terrn "cycloaLkyl" as used herein refers tO monovalent saturated cyclic radicals,
preferably of three to eight carbon atoms, including, but not limited to cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The terms l'alkoxy" and "alkylthio" as used herein refer to alkyl groups as defined
above, linked to the parent molecular moiety through an oxygen atom or a sulfur atom,
respectively. Alkoxy and aL~cylthio groups include, for example, methoxy, ethoxy,
isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like, or the
corresponding sulfur analogues.
The term "alkylamino" as used herein refers to a monovalent group of the formula-NH-aL~yl where alkyl is as defined above.
The term "diaLkylamino" as used herein refers to a group of the fo~nula
-N(alkyl)(alkyl) where the two aLlcyl gr~ups are as defined above and may be the same or
di~ferent.
The term "aminocarbonyl" as used herein refers to a group of the formula
-C(O)NH2-
The term "alkylaminocarbonyl" as used herein refers ~o a group of the formula-C(O)NH(aLscyl) where alkyl is as defined above.
The term "dialkylarninocabonyl" as used herein refers to a group of the formula
-C(O)N(alkyl)(alkyl) where the two aL~cyl groups are as defined above and may be the sarne
or different.
The telm "carboxyl" refers to -COOH.
The tenn ''aLI~oxycarbonyl'' as used herein refers to an ester group of the formula
-C(O)O(alkyl) where alkyl is as defined above.
. . ,
: .
, . ... . :
WO 90/~20û8 PCr/US90/014~8
1 4
N-hydroxy-N-[ 1-( 5-(phenylthio)-thien-2-yl)ethyl]urea
N-hydroxy-N-E 3-(~chlorophenylthio)thien-2-yl]methyl urea
N-hydroxy-N-~ 3-(2-pyridylthio)thien-2-yUmethyl urea
N-hydroxy-N-3-[ 5-(phenylthio)thien-2-yl]propenyl urea
N-hydroxy-N-(3-[ 5-(phenylthio)thien-2-yl]butenyl urea
N-hydroxy-N-[ 4-(phenoxy)thien-2-yl]methyl urea
N-hydroxy-N-[ 4-(~chlorophenoxy)thien-2-yl]methyl urea
N-hydroxy-N-1-(5-methylthien-2-yl)ethyl urea;
N-hydroxy-N-(l-thien-2-yl)ethyl urea;
N-hydroxy-N-(l-(S-pyrid-2-yl)thien-2-yl)ethyl urea;
N-hydroxy-N-(3-methylthien-2-yl)methyl urea;
N-hydroxy-N-(1-(5-phenylthien-2-yl)methyl) urea;
N-hydroxy-N-(1-(5-phenyl-thien-2-yl)methyl-N'-methyl urea;
N-hydroxy-N-(1-(5-(pyrid-2-yl)thien-2-yl)methyl) urea;
N-hydroxy-N-(1-(5-phenylthien-2-yl)ethyl) urea;
N-hydroxy-N-(3-(1-thien-3-yl)propyl) urea;
N-hydroxy-N-(l-thien-3-ylethyl) thiourea;
N-hydroxy-N-(2-(1-(5-methylthien-2-yl))propyl) urea;
N-hydroxy-N-l-(thien-3-yl)ethyl urea;
N-hydroxy-N-(thien-3-yl)methyl urea;
N-hydroxy-N-(thien-2-yl)methyl urea; and
N-hydroxy-N-(3-(1-thien-3-yl)propenyl) urea.
N-hydroxy-N-1-(thien-3-yl)ethyl urea;
N-hydroxy-N-(thien-3-yl)methyl urea;
N-hydroxy-N-(thien-2-yl)methyl urea; and
N-hydroxy-N-(3-(1-thien-3-yl)propenyl) urea.
The term "aL1cyl" as used herein refers to a monovalent straight or branched chain
adical of from one to six carbon atoms, including, but not limited to methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-hexyl and the like.
The term "halosubstituted aLtcyl" as used herein refers to an aL~yl group a.. jUSt
defined, substituted by one, two, or ~hree halogen atoms selected from fluorine, chlorine
and bromine. Exarrlples of such groups include chloromethyl, bromoethyl,
trifluoromethyl, and the like.
:, .
., ,
, ~
WO 90/120~8 PCT/U~90/01488
The term "alkanoyl" as used herein refers to -C(O)H or -C(O)aL~cyl where alkyl is as
defined above. Examples of alkanoyl groups include, but are no~ L;mited to formyl, acetyl,
propionyl, butyryl, isobutyryl, pivaloyl, and the like.
The terrn " carbocyclic aryl" as used herein refers tO a monovalent substituted or
unsubstituted aromatic radical comprising a single ring of carbon atoms or two or three
fused rings of carbon atoms including, but not limited to, phenyl, 1- or 2-naphthyl, 1-, 2-,
or 9-anthracyl, and the like. Substituted carbocyclic aryl groups are groups as just defined,
substituted with one or two substinlents independently selected from hydroxy, halo,
aLIcoxy, aL~cylthio, aLlcyl, nitro, amino, aLkylarnino, dialkylarnino, haloaLlcyl, cyano,
carboxy, alkoxycar~onyl, aminocarbonyl, allcylaminocarbonyl and dialkyl~ninocarbonyl.
The term "heterocyclic aryl" refers to a monovalent 5- or 6-membered substituted or
unsubstituted aromatic radical containing one nitrogen, oxygen, or sulfur atom, one
nitrogen and one oxygen atom, one nitrogen and one sulfur atom, or one, two, or three
nitrogen atoms. "Heterocyclic aryl" is also meant to include 5- or 6-mernbered ring
systems as just defined, fused to a benzene ring. Specifically, as used herein, the term
heterocyclic aryl refers to substituted or unsubstituted furyl, benzofuranyl, thienyl,
benzoEblthienyl, pyridyl, indolyl, quinolyl, thiazolyl, benzothiazolyl, and pyrimidyl.
Substituted heterocyclic aryl groups are heterocydic aryl groups as just defined, substituted
with one or two substituents independently selected from hydroxy, halo, alkoxy, alkylthio,
alkyl of from one to six carbon atoms, nitro, a nino, aLtcylamino, diaL~cylarnino, haloalkyl,
cyano, carboxy, aLIcoxycarbonyl, arninocarbonyl, aL~cylaminocarbonyl and
dialkylarninocarbonyl.
The term "carbocyclic arylalkyl" as used herein refers to a carbocyclic aryl group as
defined above, attached to the parent molecular moiety through an alkylene group of from
one to six carbon atoms including, but not limited to, substituted or unsubsntuted
phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, l-naphthylrnethyl, 2-naphthylmethyl
groups and the like.
I he terrn "heterocyclic arylaL~cyl" as used herein refers tO a heterocyclic aryl group
as defined above, attached to the parent molecular moiety through an alkylene group of
from one to six carbon atoms including, but not limited to, as used herein refers to a
heterocyclic aryl group as defined above7 attached to the parent molecular moiety through
an alkylene group of from one to six carbon atoms including, but not limited to substituted
or unsubstituted 2-, 3-, or 4-pyridylmethyl, 2- or 3-thienylmethyl, 2- or 3-furanylmethyl,
2-, 3-, or ~quinolylmethyl groups and the lilce.
..
WO 90~12008 PCI/US90/01~8
16
The terrn "carbocyclic aIylalkenyl" as used herein refers to a carbocyclic aryl group,
as defined above, attached to the parent molecular moiety through a straight or branched
aL~cenylene group of from two to six carbon atoms. Such groups include, for excunple,
phenylethenyl, 3-pheDylpropen-l-yl, 3-phenylpropen-2-yl, 1-naphthylethenyl, cmd the
like.
The term "heterocyclic arylalkenyl sirnilarly refers to a heterocyclic aryl group as
defined above attached to the parent molecular moiety through a sllaight or branched
aL~cenylene group of from two to six carbon atoms. Such groups are exemplified by 3-
(pyrid-3-yl)propen-1-yl, 2-(thien-2-yl)ethenyl and the like.
The term "carbocyclic arylalkynyl" as used berein refers to a carbocyclic aryl group
as defined above, attached to the parent molecular moiety through a divalent straight or
branched chain hydrocarbon group of from two to six carbon atoms con~aining one carbon-
carbon triple bond. Such groups include, for example substituted and unsubsdtuted
phenylethynyl, 3-phenyl-propyn-1-yl, 1- or 2-naphthylethynyl, and the like.
The terms "carbocyclic aryloxy" and "carbocyclic arylthio" as used herein refer so a
carbocyclic aryl g~oup as defined above, attached to the parent molecular moiety through an
oxygen or sulfur atom, Iespectively. Such groups include, for example, substituted or
unsubstituted phenoxy, 1-naphthoxy, 2-naphthoxy groups, the sulfur analogues, and the
like.
The terms "heterocyclic aryloxy" and "heterocyclic arylthio" as used herein refer to
a heterocyclic aryl group as defined above, attached to the parent molecular moiety through
an oxygen or sulfur atom, respectively. Such ~oups include 2-, 3-, or 4-pyridyloxy, 2- or
3-thienyloxy, 2-, 3-, or 4-pyridylthio, and the like.
The teIms "carbocyclic arylalkoxy" and "carbocyclic arylalkylthio" as used herein
refer to monovalent radicals in which a carbocyclic arylaL~cyl group, as defined above, is
attached to the parent molecular moiety through an oxygen or sulfur atom, respectively.
Such groups include, for exa~nple, phenylmethoxy ~i.e., benzyloxy), 1-phenylethoxy, 2-
phenylethoxy, l-naphthylmethyloxy, 2-napthylmethyloxy and the like.
The terms "heterocyclic arylalkoxy" and "heterocyclic arylalkylthio" as used herein
refer to a heterocyclic a~lalkyl group as defined above, attached to the par~nt molecular
moiety through an oxygen or sulfur atom, respectively. Such groups include, for example
2-, 3-, or 4-pyndylmethoxy, 2-, 3-, or 4-pyridylmethylthio, 2- or 3-thienylmethoxy, 2- or
3-thienylmethyl~hio, and the like.
.
. , .
WO 90/12008 PCr/US90/014~
17 2~
The term "carbocyclic aroyl" as used herein refers to -C(O)-(carbocyclic aryl) where
carbocyclic aryl is as defined above. Carbocyclic aroyl groups include, for exarnple,
substituted and unsubstituted benzoyl, 1- or 2-naphthoyl and the like.
The teIms "halo" and "halogen" as used herein refer to radicals derived from theelements fluorine, chlorine, bromine, and iodine.
The term "halosubs~tuted aL1cyl" and "haloalkyl" as used herein refer to an alkyl
group, as defined above, in which one to three hydrogen atoms are substituted by a
halogen, including, but not limited to, chloromethyl, trifluoromethyl, 2,2,2-trichloroethyl,
and the like.
As used throughout this specifica~on and the appended claims, the term
"meta~olically cleavable group" denotes a moiety which is readily cleaved in vivo from the
compound bearing it, whlch compound after cleavage remains or becomes
pharmacologically active. Metabolically cleavable groups form a class of groups reactive
with the N-hydroxy group of the compounds of this invention (where Z is hydrogen) well
known to practitioners of the art. They include, but are not limited to such groups as
alkanoyl ~such as acetyl, pt~pionyl, butyryl and the l~ce), unsubstituted and substituted
aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl),
trialkylsilyl (such as trimethyl- and triethylsilyl), monoesters formed with dicarboxylic
acids (such as succinyl)~ and the like. Because of the ease with which the metabolically
cleavable groups of the compounds of this invention are cleaved in vivo, the compounds
bearing such groups act as pro-drugs of other lipoxygenase inhibitors. The compounds
bearing the metabolically cleavable groups have the advantage that they may exhibit
improved bioavailability as a result of enhanced solubility and/or rate of absorption
confeIred upon the parent compound by virtue of the presence of the metabolically
cleavable group.
In those instances where the compounds of the present invention possess an acidic
functional substituent such as carboxyl, the compounds are capable of forrning base
addition salts. In such instances, the terrn "phannaceutically acceptable salts" refers to the
relatively non-toxic, inorganic and organic base addition salts of compounds of the present
invention. These salts can be prepared in situ during the final isolation and purifica~on of
the compounds or by separately reacting the purified N-hydroxy urea compound with a
suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically
accep~able metal cation or with ammonia, or an organic primary, secondary, or tertiaIy
amine of sufficient basicity to foIm a salt with the N-hydroxy functional gTOUp of the
. ,
.
WO 90/12008 PCr/US90/01488
~ 18
compounds of this invention.
Representative aLcali or aL'kaline earth salts include the lithium, sodium, potassium,
calcium, magnesiurn and aluminum salts and the lilce. Representative organic amines
useful for the formation of base addition salts include ethylam~ne, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine, and ~he like. (See, for
example S. M. Berge, el al., "Pharmaceuhcal Salts," J, Pharrn. Sçi" 66: 1-19 (1977)
which is incorporated herein by reference.)
Sirnilarly, in those instances where the compounds of the present invention
comprise a basic substituent such as an arnino, aLlcylamino, or diaLI~ylamino group, the
compounds are capable of forming acid addition salts. In such cases, the terrn
l'pharmaceutically acceptable salts" refers tO the relatively non-toxic, inorganic and organic
acid addi~on salts of compounds of the present invention. These salts can be prepared ir
situ during the final isolation and purification of the compounds or by separately reac~ng
the purit-ied compound in its free base form with a suitable organic or inorganic acid Md
isolating the salt thus forrned. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate,
palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,
fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate,
laurylsulphonate salts and the like. (See, for example S. M. Berge, et al., "Pharmaceutical
Salts," J.~harm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.)
The terrn "pharmaceutically acceptable cation" refers tO non-toxic cations including
but not limited to those based on the aL~cali and aL~caline earth metals, such as sodium,
lithium, potassium, magnesium, aluminurn and the like, as well as nontoxic amrnonium,
quaternary amrnonium, and amine cations, derived from nitrogenous bases of suf~lcient
basicity to form salts with the N-hydroxy group of the compounds of this invention.
Certain compounds possess one or more chiral centers and may thus exist in
optically active fo~ns. Likewise, when the compounds contain an alkenyl or alkenylene
group, there exists the possibility of cis- and rrans-isomeric fo~ms of the compounds. The
R- and S-isomers and mixtures thereof, including ~acemic mibctures as well as ~x~xtures of
cis- and rrans-isomers, are contemplated by this invention. Additional asyrnme~ic carbon
atoms can be present in a substinlent group such as an alkyl group. All such isomers as
well as the mixo~res thereof are intended to be included in the invention. If a particular
stereoisomer is desired, it can be prepared by methods well known in the art by using
stereospecific reactions with starting matenals which contain the asyrnmetric centers and are
WO 90/12~08 P~/VS90/û1488
2 ~
19
akeady resolve d or, alternatively by methods which lead to rnixture s of the stereoisomers
and subsequent resolution by known methods.
Method o~Trç~ent
This invention provides a method of treatment of inhibiting 5- and/or l2-
lipoxygenase activity ;n a human or lower mamrnal host in need of such treatment, which
method comprises administration to the hurnan or lower marnmal host of a compound
previously described in an amount effective to inhibit lipoxygenase activity in the host. The
compounds of the present invention may be administered orally, parenterally or topically in
dosage unit formulations containing conventional nontoxic pharmaceutically acceptable
camers, adjuvants and vehicles as desired.
The term parenteral as used herein includes subcutaneous, intravenous, intraarterial
injection or infusion techniques, without limitation. The term "topically" encompasses
adm~nistration rectally and by inhalation spray, as well as by the more common routes of
the skin and the mucous membranes of the mouth and nose.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this
invention may be varied so as to admiIuster an amount of the active compound(s) that is
effective to achieve the desired therapeutic response for a particular patient, compositions,
and mode of adrninistration. The selected dosage leYel will depend upon the activity of the
par~cular compound, the route of adrninistration, the severi~ of the condition being
treated, and the condition and prior medical history of the patient being treated. However,
it is within the SKi]l of the art to start doses of the cornpound at levels lower than required
for to achieve the desired therapeutic effect and to gradually increase the dosage until the
desired effect is achieved. If desired, the effective daily dose may be divided into mul~iple
doses for purposes of ad ninistration, e.g. two to four separate doses per day.
Total daily dose of the compounds of this invention administered tO a host in single
or divided doses may be in amounts, for example, of from about O.OOl to about 10() mg/kg
body weight daily and more usually O.Ol to lO mg/kg/day. Dosage unit compositions may
contain such amounts of such submultiples thereof as may be used to make up the daily
dose.
It will be understood, however, that the specific dose level for any palticular
patient will depend upon a variety of factors including the body weigh~., general heal~h, sex,
diet, time and route of administration, rates of absorption and excretion, combination with
o~her drugs and the severity of the panicular ~isease 'oeing ~eated.
". - ~.
WO gû/12008 PCr/US9OtO1~8
3~
.~
FQrmUIatiOn Q~p~a~ç~caL5~g~ i~Qns
The present invention also provides pharmaceu~cal COrnpOSihons which comprise
one or more of the compounds of formula I above formulated together with one or more
non-toxic pharmaceutically acceptable carners. The pharmaceutica'l composinons may be
specially formulated f~r ~ral administration in solid or liquid forrn, for parenteral injectiont
or for rectal adrninistt~tion.
The pharmaceutical compositions of this invention can be adrninistered to hurnans
and other anirnals orally, rectally, parenterally, intrac~stemally9 intravaginally,
intrapelitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or
nasal spray. The terrn "parenteral" administration as used herein refers to modes of
adrninistradon which include intra~enous, intramuscular, intrapentoneal, intrasternal,
subcutaneous and in~aarticular injection and infusion.
Pharmaceutical compositions of this invendon for parenteral injection comprise
pharmaceudcally acceptable sterile aqueous or nonaqueous soludons, dispersions,
suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous
carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable rnixtures thereof,
vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper
fluidity can be maintained, for exarnple, by the use of coating matenals such as lecithin, by
the rna~ntenance of the required particle size in the case of dispersions, and by the use of
surfactants.
These compositions may also contain adjuvants such as preservative, wetting
agents, emulsifying agents, and dispersing agents. Prevention of the action of
microorganisms may be ensured by the inclusion of various antibacterial and antifungal
agents, for exarnple, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also
be desirable to include isotonic agents such as sugars, sodium chloride, and the like,
Prolonged absorption of the injectable pharmaceutical foIm may be brought about by the
inclusion of agents which delay absolption such as alurninum monostearate and gelatin.
In some cases, in order to prolong the effect of the dn~, it is desirable to slow the
absorption of the drug from subcutaneous or intramuscular injection. This may beaccomplished by the use Qf a liquid suspension of crystalline or arnorphous material with
poor water solubility. The rate of absorption of the drug then depends upon its rate of
dissolution which, in turn, may depend upon crystal size and crystalline forrn.
: . , :, . . ,, ~..
: .
WO 90/12008 PCr/U~901~148~
~ Q ~
21
Alternatively, delayed absorption of a parenterally adrninistered drug form is accomplished
by dissolving or suspending ~he drug in an oil vehicle.
Injectable depot forms are rnade by forming rnicroencapsule matIices of the drug in
biodegradable polyrners such as polylactide-polyglycolide. Depending upon the ratio of
drug to polymer and the nature of the particular polymer ernployed, the rate of drug release
can be controlled. Examples of other biodegradable polymers include poly(orthoesters)
and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the
drug in liposomes or rnicroemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for exarnple, by filtration through a
bacterial-reta~ning filter, or by incoIporating sterilizing agents in the form of sterile solid
cornpositions which can be dissolved or dispersed in sterile wate~ or other ste~ile injectable
medium just prior ~o use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders,
and granules. In such solid dosage forms, the active compound is mixed with at least one
inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as
glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents
such as paraffin, f) abso~ption accelerators such as quaternary amrnonium compounds, g)
wet~ng agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents
such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and rnixn~res
thereof. In the case of capsules, tablets and pills, the dosage form may also comprise
buffering agents.
Solid compositions of a sirnilar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or rnilk sugar as well as high
molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings and o~her coa~ings well known in
the phaImaceutical forrnulating ar~ They may optionally contain opacifying agents and can
also be of a composition ~hat they release the active ingredient(s) only, or preferentially, in
a certain part of the intestinal ~ac~ optionally, in a delayed manner. Exarnples of
.. ~ . . ............... .. .
.' .. ' :. .~:'' :.
: . ,. :. ;
WO 9~ 008 P~r/US90/Olq8
~ o~ 22
embedding compositions which can be used include polymeric substances and waxes.The active compounds can also be in micro-encapsulated ~orm, if appropriate, with
one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs. In addition to the activecompounds, the liquid dosage fvrms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents and ernulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formarnide, oils (in particular,
cottonseed, groundnut, com, germ, olive, castor, and sesarne oils), glycerol,
teLrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof~
Besides inert diluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming
agents.
Suspensions, in addition to the active compounds, may contain suspending agents
as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, and rnixtures thereof.
Compositions for rectal or vaginal adrninistration are preferably suppositories which
can be prepared by rnixing the compounds of this inven~ion with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which
are solid at room temperature but liquid at body temperature and therefore melt in the
rectum or vaginal cavity and release the active compound.
Dosage forms for topical administration of a compound of this invention include
powders, sprays, ointrnents and inhalants. The active compound is mixed under sterile
conditions with a phaImaceutically acceptable caTrier and any needed preservatives,
buffers, or propellants which may be required. Opthalrnic formulations, eye ointments,
powders and solutions are also contempla~ed as being within the scope of this invention.
W~ 90/1200~ PCr/US9~/0148~
23 2~ ~3~
Svnthesis of the CQm~Qun(ls
Compounds of this invention can be prepared according to the reaction sequence
described in Scheme 1. Al9,hough the sequence illustrates the compound of fomlula I
where Rl, R2, Yl and y2 are hydrogen, X is CHCH39 and R3 is phenyl, it will be seen
from the examples that other compounds of this invention can be prepared in the same
tnanner using the appropriate starting materials.
O NOH NHOH
E~ NH20H-HCI ~ 3~Pyr ~
~ O O
' N ~ Cl HO, N J1~NH
1. HCI ~ NH40
2. COC12 l~d _ ~J 5
Scheme l
Referring to reaction Scheme 1, acetophenone, 1~ is treated with hydroxylamine in
ethanoVpyridine to produce the oxime, 2. This is reduced to the hydroxylamine, 3, with
borane pyridine complex and then converted to the hydrochloride salt with HCl gas.
Treatrnent with phosgene yields carbamoyl chloride, 4, which is reacted without isolation
to yield the urea, 5. Other reagents may also be used to ca~Ty out the same
transforrnations. For example the oxime, 2, may be conve~ed to the correspondinghydroxylamine, 3, using borane dimethylamine or other borane amine complexes or with
sodium cyanoborohydride.
Compounds of formula I can also be prepared according to Scheme 2, below. The
sequence illus~ates the case where Rl, R2, yl and y2 are hydrogen and where R2 is
phenyl and X is CH(CH3), however it will be seen from the following examples that other
compounds of this invention can also be prepared in this manner.
-, , . ,. ., . , . ~
, .
WO 90/12008 PCr/US90/01488
o
NHOH HO~N J~NH
TMSNCO
3 5
Scheme 2
The hydroxylamine, 3, is treated wifh ~imethylsilyl isocyanate, followed by
arnmonium chloride workup to give the urea, 5.
In addition to the methods described above the compounds of this invention may
also be prepared according to the method of Scheme 3.
o
HO~ J~
NHOH N NH2
NaOCN ~
W ~
3 5
Scheme 3
The hydroxylarnine, 3, is dissolved in dilute hydrochloric acid and aqueous sodium
cyanate is added. The resulting urea, 5, precipitates from the reaction and is collected.
In addidon to the method described in Scheme 1, above hydroxylamine, 3, can
also be prepared according to the method of Scheme 4, below. The sequence illustrates the
case where Rl, R2, Yl and y2 are hydrogen and where R2 is phenyl and X is CH(CH3),
however it will be seen from the following examples that other compounds of thisinvention can also be prepared in this manner.
... . . . . . . .
,, , :: , : : ~
WO 90/l~008 PCr/US9~/01~g8
25 ~ ' 37
~r 1, n-BuLI ~U' ~~
2. ~F3-Et20 ~ H 8
6 3 ~ N 'I Pd/C
7 ~ H2
1~ ,1 N o H
~b 3 H
Scheme 4
Bromobenzene (6) is converted to phenyl lithium by trea~nent with n-butyl lithium
at -78C. Boron t~ifluoride etherate is then added and this is reacted with acetaldehyde O-
benzyl oxirne (7) to yield (8). The O-benzyl protecting group is removed by catalytic
hydrogenation. Other reagents may be substituted for those described above. For
example, phenyl lithium may be prepared by treatment w~th t-butyl lithium, sec-butyl
lithium, or lithium metal instead of n-butyl lithium. Other protecting groups may be used
for acetaldehyde oxime. For example, benzyloxymethoxy, methyloxymethoxy,
methoxybenzyl may be used instead of benzyl.
In an alternative method to this detailed above, compounds of this invention can be
prepared accordîng to the TeaCtiOn sequence descri~ed in Scheme 5.
1. EtNO2/MeOH CH3 l. BH3~HF/THF
R3-- CHO ~
2. n-Bu~yl Amine (cat.) R3~ NO2 2. NaBH4 (cat.)
HO 11
CH3 ~N~NH2
I TMSNCO~F
R9----NI lOH R~----CH3
Scheme 5
Scheme S outlines the reac~on of an aldehyde with ni~oethane in methanol with an
amine such as n-butylamine as a catalyst. The vinyl nitro compound obtained is then
, : ~ . . :, :
., .:, " . ;
WO 90/12008 PCr/USgO/0~4~8
26
reduced with borane:TH~ and a catalytic amount of NaBH4. This procedure is a modified
method frorn a published procedure (J. Org. Chem. 1985, 50, 133). The hydroxylamine
obtained is then reacted with an isocyanate to provide the colTesponding hydroxyurea
The following examples ~re provided to enable one skilled in the art to practice the
present invennon. These exarnples, however, are not to be read as limiting the scope of the
invention as it iS defined by the appended claims.
Example 1
e~aration of ~-hvdroxv-N-(1-(4-~henylm~thQ~ henyl~hyl)
a. 4-Phenylmethoxyacetophenone.
4-Hydroxyacetophenone (5.0 g, 3S.7 rnmole) was dissolved in dimethyl-sulfoxide
(50 rnL) and potassium t-buloxide (4.73 g, 42.2 mr,nole) was added. Twenty minutes later
benzyl bromide (7.85 g, 45.8 mmole) was added. After an additional hour, the reaction
mixture was poured into water and extracted with ether. The etner layer was dried with
magnesium sulfate and evaporated to give an off white solid which was carried on without
further purification.
b. 4-Phenylmethoxyacetophenone oxime. Using the method described in scheme
1, the material prepared as in part a, above and hydroxylamine hydrochloride (4.8 g, 0.70
mole) were dissolved in a mixture of ethanol (25 rrL) and pyridine 125rnL) and heated a~
50~ for 2 hours. Most of the solvent was removed in vacuo and the residue dissolved in
ether. After washing with 2N HCI (50 mL), the solu~ion was dried over MgSO4 and
evaporated. A white crystalline solid was obtained and was carried on without further
purification. An alternative work-up may also be used. The reaction tnixture is diluted
with water (300 rr~) and the product precipitates. It is filtered off and dried in vacuo.
c. 1-(4-Phenylmethoxyphenyl) ethyl hydroxyl amine. ~Phenylmethoxy
acetophenone oxime ~3.7 g, 15.3 mrnole), prepared as described in part b above, was
dissolved in ethanol (30 mL) and cooled to 0OC. Borane-pyr~dine complex (4.6 mL, 46
mmole) was added via syringe under nitrogen followed ten rninutes later by 6N HCl (15
rnI,). Within thirty rninutes the reaction was complete and was brought tO pH 9 with the
addi~on of solid sodium carbonate or 2N NaOH. The mixture was extracted into ether and
dried over MgSO4. After evaporation a white solid resulted which was carried on without
further puriflcation.
:. ,: ,,; : ,...., ~
-; . ". I. .
. .
WO g~/~2008 PCr~US90/014
27 ~ ~ 3 ~
d. N-hydroxy-N-(1-t4-phenylmethoxyphenyl)ethyl) urea.
Metkod a. Using the method of scheme 2, the material prepared as in part a above (2g, 8.2
mrnole) was refluxed for thirty minutes with ~imethylsilyl isocyanaee (0.95 g9 8.2 mmole)
in 30 rnL dioxane. The reaction nuxture was then washed with saturated NH4CI solution,
dried with MgSO4, and evaporated. The residue was washed with ether to give 1.33g of a
white solid.
Method b. Using the method of scheme 1, the material prepared as in part a above(4g, 16.4 rrLmole) was dissolved in toluene (100 rnL) and HCl gas was bubbled through
the rnixture at a moderate rate for about four rninutes. The solution was then heated to
reflux and phosgene was bubbled through for another four minutes. After an additional
one hour reflux, the mixture was allowed to cool to room temperatur~ and then added to
excess cold arnmonium hydroxide solu~ion. The precipitate was coLlected and recrystaLlized
from aqueous ethanol. mp: 132-1340C; NMR (300 MHz, DMSO-d6): 1.37 (d,3H); S.08
(s, 2H); 5.24 (q, lH); 6.25 (s, 2H); 6.92 (d, 2H); 7.25 (d, 2H); 7.30-7.50 (m, 5H); 8.90
(s, lH); Mass spectrum (EI): 286 M+, 269, 255, 243, 226, 211, 91.
Example 2
Preparation of N-hvdroxv-N-1-(4-~henylmethoxv~hen~ll) ethvl Nl-methvi urea
The title compound was prepared according tO the method of example 1, Method a,
except using methyl isocyanate instead of trimethylsilyl isocyanate. mp 125-1280C; NMR
~300 MHz, DMSO-d6): 1.37 (d, 3H); 2.57 (dd, 3H); 5.08 ~s, 2H); 5.20 (q, lH); 6.78 (q,
lH); 6.92 (d, 2H~; 7.20-7.50 (m, 7H); 8.90 (s, lH); IR (KBr): 34509 1630, 1610, 1520,
1250; Mass spectrum (EI): 300 M~, 283, 226, 211, 91.
Example 3
Preparation of N-hvdroxY-N-1-(4-phenYImethQxYphenyl) ethYI N'N'-dimethyl urea
a. N-hydroxy-N-~1-(4-phenylmethoxyphenyl)ethyl) urea, prepared as in example
1, (5.0g, 21 rnmole) was treated with dihydropyran (2.1 mL, 23 mrnole) and a few crystals
of p-toluene sulfonic acid in methylene chloride (200 rnL) for 6 hours. The mixture was
evaporated in v~cuo and chromatographed on silica gel eluting with ether to gi~e 3.5 g of a
colorless oil.
b. N-(2-tetrahydropyranoxy)-N-(1-(~phenylmethoxyphenyl~ ethyl) N'N'-dimethyl
urea. The material prepared in part a, above (3.5 g, 10.8 mmole) was dissolved in 1
(50 mL) and sodium hydride (60%, 432 mg, 10.8 mmole) was added. After hydrogen
:. .: .
..
' ~, . ' -~ : ' :
,~ '' ' , ,~., :: '
W~ 9~/12008 ~ a PCr/US9û/01488
28
evolution ceased, methyliodide (0.67 mL) was added and the rluxture stirred overni~ht.
The solvent was evaporated in vacuo and the residue chromatographed on silica gel eluting
with ether to obtain 1.8 g of the desired produc~.
c. N-hydroxy-N-(1-(4-phenylmethoxyphenyl)ethyl)N'N'-dimethylurea. The
material prepared as in part b above (1.8g) was dissolved in methanol (20 rnL) and a few
crystals of p-toluene sulfonic acid were added. The solvenl was evaporafed and the
mixture was par~tioned between safurated sodium bicarbonate solution and methylene
chloride. After dIying over MgSO4, concentration in vacuo gave a white solid (870 mg).
mp: 1?5-126C; NMR (DMSO-d6, 30~) MHz): 1.38 (d, 3H); 2.82 (s, 6H); 4.84 (q, lH),
5.09 (s, 2H); 6.90-7.00 (m, 2H); 7.20-7.48 (m, 7H); 8.51 (brs, lH); Mass spectrum (CI-
NH3): 315 (M~1)+, 299, 297, 211.
Example 4
Preparation s2f N N'-~ihvdrQxv-N-(1-(4-phenvlmethQxvDhenvl~ ethvl urea
The desired compound was prepared according to the method of example 1, method
a, except using hydroxylamine instead of arnrnonium hydroxide. mp: 157-1590C; NMR
(DMSO-d6, 3Q0 MHz): 1.46 (d, 3H); 5.03 (s, 2H); 5.14 (q, lH); 6.92 (m, 2H); 7.24 (m,
2H); 7.30-7.50 (m, SH); 8.31 (brs, lH); 8.88 ~brs, lH); 9.34 (brs, lH); Mass spec~um
(EI): 302, 286, 241, 211, 91, ~5.
Example S
Preparation of N-hydroxv-N-(4-phenvlmethoxy~nYlmethvl~ urea
The desired material was prepared according the method of example 1, except using
4-hydroxybenzaldehyde instead of ~hydroxyacetophenone. mp: 147-149OC; NMR
(DMSO-d6, 300 MHz): 4.42 (s, 2H); 5.08 (s, 2H); 6.31 (brs, 2H); 6.95 (m, 2H); 7.19
(m, 2H); 7.30-7.50 (m, SH); 9.27 (s, lH); Mass spectrum (CI-NH3): ~90 (M+NH4)-~,273 (M+1)+, 257, 230, 212.
Example 6
Preparation of N-hydroxv-N-(4~?henvlrnethoxyphenvlmethYl~N'-methyLurea
The ~itle compound was prepared according the method of exarnple 1, method a,
except using 4-hydroxybenzaldehyde instead of ~hydroxy-acetophenone and using
methylisocyanate in~stead of tnrnethylsilylisocyanate. inp: 150-153 C; NMR (DMSO-d6,
.. .. . ..
.. . ..
,
. ' ' , . ' ' ' '; ' ,: .
. . .
.
WO 9o/12008 P~r/l~so/ot488
2 ~
300 MHz): 2.60 (3H, d); 4.42 (2H, s); 5.û8 (2H, s); 6.86 (lH, q); 6.94 (2H, d); 7.19
(2H, d); 7.28-7.47 (SH, m); 9.19 (lH, s); Mass Spectrum (EI): 286 M+, 269, 197, 91.
Example 7
Preparation of N-hydroxy-N-(1-(4-phenylmethoxy-3,5-dimethoxyphenyl)ethyl) urea
The desired material was prepared according to the methocls of example 1, exceptusing 3,5-dimethoxy-4-hydroxyacetophenone instead of 4-hydroxyacetophenone. mp: 10~-
110OC; NMR t300 MHz, D~SO-d6): 1.40 (d, 3H); 3.76 (s, 6H); 4.85 (s, 2H); 5.23 (q,
lH); 6.36 (s, 2H); 6.65 (s, 2H); 7.29-7.50 (m, 5H); 9.06 (s, lH); Mass spectrum (EI):
346 M+, 336, 279, 91.
Example 8
Preparation of N-hvdroxv-N-(1-(4-(2-phenvl)ethoxyphenyl~ethvl~ urea
The desired matenal was prepared according to the methvd of example 1 except
using 2-phenethylbromide instead of benzyl bromide mp: 12~1280C; NMR (300 MHz,
DMSO-d6): 1.36 (d, 3H); 3.02 (d, 2H); 4.16 (d, 2H); 5.23 (q, lH); 6.25 (i~rs7 2H); 6.84
(m, 2H); 7.23 (m, 2H); 7.32 (m, SH); 8.98 (brs, lH); Mass spectrum (EI): No M+, 283
(M-OH)~, 225, 121, 105.
Example 9
Preparation of N-hvdroxv-N-L1-(2-naphthY12~hYI) urea
The desired rnatenal was prepared according to the method of exarnple 1, except
using 2-acetonaphthone instead of acetophenone. mp: 140-1420C, NMR (300 MHz,
DMSO-d6): 1.51 (d, 3H); 5.46 (q, lH); 6.34 (brs, 2H); 7.45-7.54 (m, 3H); 7.B1-7.90 (m,
4H); 9.11 (s, lH); Mass spectrum (EI): 230 M+, 213, 155, 127, llS, 77.
Example 10
Prepara~ion Qf ~.N':dihydroxY-N-(1-(2-1l~ht~vllethYl) ure~
a. O-benzyl 2-æetonaphthone oxime was prepared according to the method of
example 1 part b, except using 2-acetonaphthone instead of 4-phenylmethoxyacetophenone
and using ~benzylhydroxylamine instead of hydroxylamine.
b. N-benzyloxy-N'-hydroxy-N-(1-2-naphthyl)ethyl)urea. Thematerialprepared
as described in part a, (3.2g, l l.S mrnole) was dissolved in toluene and HCl gas was
: , ., . ~ : ,- .
: :, .. . ,. ; , ... .
~ . . ..... , : , .. : . . : :
WO gO/1~008 PCr/US90/01488
bubbled through at a moderate rate for about 3 minutes. The solution was heated to reflux
and phosgene was added over about 5 minutes. The insoluble hydrochlonde salt
dissolved. After refluxing for one hour the mixture was cooled and added to a solution of
hydroxylarnine hydrochloride ~960mg, 13.8 tnmole) and tliethylamine ~3.5gt 35mrnole) in
THF ~30mL~ and water (5mL). The n~ixhlre was poured into 2N HCl solution and ether
was added. The organic phase was dried over MgSO4 and evaporated. The residue was
chromatographed on silica gel, eluting with 75% ether in hexanes to yield a white solid.
c. N,N'-dihydroxy-N-(1-(2-naphthyl)ethyl) urea was prepared by catalytic
hydrogenation of the material prepared in part b, above, using 5% palladium on carbon in
ethanol. mp: 148-150OC; NMR t300 MHz, DMSO-d6): 1.51 (d, 3H); ~.37 (q, lH); 7.45-
7.54 (m, 4H); 7.81-7.90 (m, 4H); 8.34 (s, lH); 9.10 (s, lH3; 9.43 (s, lH); IR (KBr):
3220, 1620,147û; Mass spectrum (EI): 246 M+, 230, 155.
Example 11
Preparation of N-hvdroxY-N-tl-(4-butox~rphenyl)ethvll urea
The desired material was prepared according to the method of Example 1, except
using 1-bromobutane instead of benzyl bromide. NMR (300 MHz, CDCl3): 0.97 (t, 3H);
1.46 (m, 2H); 1.53 (d, 3H); 1.76 (m, 2H); 3.94 (t, 2H); 5.23 (brs, 2H); 5.42 (q, lH);
6.71 (s, lH); 6.85 (d, 2H); Mass spectrum (EI): 252 M+, 235, 192, 177, 121.
Example 12
Preparation of N-Hvdroxv-N-l-(5-methvlthien-2-yl)ethvl u~
a) To a stirred solution of 2-acetyl-5-methylthiophene (5.0 g, 35.7 rnmol) in
ethanoVpyridine (1:1) (30 mL) was added hydroxylamine hydrochloride (5.0 g, 71.9mmol). The reaction was stiIred for 1 h before evaporatmg the ethanol and diluting the
residue with water. The aqueous solution was extracted with ethyl acetate ~3xS0 mL),
dried over MgSO4 and evaporated. A quandtative yield of a yellow solid was obtained.
b) To a stirred soludon of the product obtained in part a (5.5 g, 35.7 mrnol) inethanol was added BH3 Pyridine (11.9 mL, 117.8 mmol). After 20 minutes, 10%
HCUEtOH (35 mL) was added slowly via dropping funnel. Two hours later the reac~ion
was complete and the ethanol was removed. The aqueous residue was diluted with water,
neutralized with 2N NaOH, extracted wilh ethyl acetate (3x50 mL3, dried over MgSO4 and
evaporated. The resulting oil was purified by chromatography (siJica gel, ether-hexane,
., .~,.
, ,
.,
.,
WO 90tl2008 PCI~JUS90/01488
31 2 ~
2:3) to yield 2.2 g of a clear oil.
c) To a stirred solution of ~he product obtained in part b ( 2.2 g, 14.0 mmol) in
THF was added trimethylsilyl-isocyanate (3.35 r~, 21.0 mmol). After 1 h, the reaction
was complete and saturated NH4Cl was added. The THF was evapora~ed and the residue
was ex~acted with ethyl ace~ate (3x50 mL), dried over MgSO4, and evaporated. Theresulting residue was purified by chromatography (silica gel, 7% methanol-methylene
chloride) to yield 1.7 g of a waxy solid.
NMR (300MHz, DMSO-d6~ 1.38 ~3H, t, J=7.5H~), 2.38 (3H, s), 5.39 (lH, q, J=7.5
Hz), 6.36 (2H, br s), 6.59 (lH, m), 6.70 (lH, m), 9.08 (lH, s); MS: (M+H)~ 201;
(M+NH4)~ 218
Example 13
Preparation of N-hvdroxv-N-(1-(3-butoxvphenvl)ethYI) urea
The desired material is prepared according to the method of Example 1, except
using 1-bromobutane instead of benzyl bromide and using 3-hydroxyacetophenone instead
of 4-hydroxyacetophenone.
Example 14
Preparanon of N-hvdroxv-N-(1-(~-~2-methvlpropvl)phenvl~ethvll urea
The desired material is prepared according to the method of Example 1, except
using ~isobutylacetophenone instead of 4-phenylrnethoxyacetophenone in part b.
Example 1~
Preparation of N-hvdroxy-N~ 4 cvclohexvl)phenv!)ethYI) urea
The desired rnaterial is prepared according to the method of Exarnple 1, except
using 4-cyclohexylacetophenone instead of ~phenylmethoxy-acetophenone in part b.
Example 16
eparatiQn of N-hydroxv-N-(2-(4-butoxyphçnvl)ethyllurea
a. 4-Butoxybenzaldehyde was prepared according to the method of Example 1,
part a, except using 1-bromobutane instead of benzylbromide and using 4-
hydroxybenzaldehyde instead of ~hydroxyacetophenone.
b. l-ni~o-2(-4-butoxyphenyl)ethene The material prepared as in part a above
(1.8g, 10 mmole), prepared as in Example 1, part a, and nitromethane (0.6g, 10 mmole)
,~ ,' . : ' '
:, , . ,.. , , .. ~ ; . .. ~
WO 90/12008 PCr/US90/01488
(~ 32
were dissolved in ethanol (30 rnL). Potassium hydroxide (1.3g, 20 mmole) in ethanol (10
mL) was added and a white solid mass formed. The rnixture was poured into 6N HCl (50
rnL) and the white mass turned to a yellow solid. This material was collec~ed by filtration
and dissolved in ether (100 mL). The solution was dried with MgSO4 and evaporated. A
yellow solid (l.Og, 45%) was obtained which was carned on without further purification.
c. N-hydroxy-2-(~1 butoxyphenyl)ethyl amine. The matenial prepared as described
above (6.0g, 27.1 mmole) in TH~; (80 rnL) was added to borane-'[HF (28.4 mmole) at Oo
C. Sodium borohydride (10 mg) was added. After stinring for 8 hours most of the yellow
color of the starnng material was gone. Water (75 mL) and 2N HCI were added and the
mibcture was heated to 600 for 45 minutes. The reaction rnixture was washed with ether
and then neutralized with 2N NaOH. The product was extracted into ether which was dried
over MgSO4 and evaporated. A white solid (2.2g) was obtained and carried on without
further purification.
d. N-hydroxy-N-(2-(~butoxyphenyl)ethyl) urea. The material described above is
converted to the desired compound using the method described in Example 1 p~rt d .
Example 17
Preparation of N-hydroxY-N-(I-methYl-2-(~butoxYphenYl)eth~l) urea
The desired material is prepared according to the method of Example 16, excep~
using nitroethane instead of nitromethane.
Example 18
Preparation of N-hvdroxv-N-(3-(4-butoxYQhenyl)pro~l) urea
a. Methyl ~butoxycinnamate was prepared according to the method of Example 1,
part a, excep~ using methyl 4-hydroxycinnamate instead of 4-hydroxyacetophenone and
using 1-bromobutane instead of benzylbromide.
b. Methyl 3-(~butoxyphenyl)propionate by catalytic hydrogenation of the materialprepared as in par~ a using 20% palladium on carbon.
c. 3-(4-Butoxyphenyl)-1-propanol. The material prepared as in part b (10 g, 42
mmole) was dissolved in THF (50 rnL) and lithium aluminum hydride (lM in T~, 42
rnL) was added ~apidly. Fifteen minutes later, 2N HCl was added to quench the reaction.
The organic layer was separated and dried with MgSO4 and evaporated to give a colorless
oil.
,
:
: ., ., , ,. .. :
WO 90/12008 PCI/US90/01488
3 3 ` ` j "' ~
d. 3-(4-Butoxyphenyl)propanal. The alcohol prepared as in par~ c (9g) was
dissolved in methylene chloride (100 mL) and pyridinium chlorochromate (18g, 84 mmole)
was added. Three hours later ether was added and the rnixture was filtered through silica
gel. The fil~rate was evaporated and the sesidue chromatographed on silica gel.
e. N-hydroxy-N-(3-(4-butoxyphenyl)propyl) urea is prepared according to the
methGd of Example 1, except using the material prepared as in part d above instead of
phenylmethoxyacetophenone.
Example 19
Pre~arationQf N-hv~EQxY~-(l-melhyl-~-(4-~utoxy~2henyl)~rQ~Yll~ea a. 4-(4-
Butoxyphenyl)-2-propanol. 3-~4-butoxyphenyl) propanal (5.0g, 24 rnrnole) prepared as
descri'oed in Example 18, part d, was dissolved in T~ and cooled to -780 C. Methyl
lithium in hexanes (27 mmole) was added. The reaction was allowed to walm to room
temperature and then was quenched with 2N HCl. The organic layer was separated, dried
over MgSOd and evaporated to give a colorless oil.
b. 4-(4-Butoxyphenyl)-2-propanone was prepared according to the method of
Exarnple 18, part d, except using the material prepared in part a above instead of 3-t4-
butoxyphenyl)- 1 -propanol.
c. N-hydroxy-N-(1-methyl-3-(4-butoxyphenyl)propyl) urea is prepared according
to the method of Example 1, except using the rnaterial prepared as in part b above instead of
acetophenone.
Example 20
Preparation of N-hvdroxv-N-(1-methvl-1-(4-butoxv~enYl~ethYl~rea
a. 4-Butoxyacetophenone was prepared as in Example 1, part a except using 1-
bromobutane instead of benzylbromide.
b. 1-Methyl-1-(4-butoxyphenyl)ethanol The material prepared as described above
(8.0g, 41.7 rnmole) was dissolved in ether (100 mL~ and cooled to Oo C. Methyl lithium
(1.2M in hexanes, 62.5 mrnole) was added and the mixture s~i~Ted for 30 minutes. HCl
(2N) was added and ~he ether layer was separated, dried over MgSO4 and concentrated in
v~c~o.
c. N-hydroxy-N-(l-Methyl-1-(~butoxyphenyl)) ethylamine. O-benzyl
hydroxylamine hydrochlolide (7.35 g, 46.1 mmole) was suspended in THF (200 mL).
Triethyl amine (6.5 mL, 46.1 mmo}e) was added and the mixrlre stirred for 1 hour. The
;:. :,: . -.. . .
.. . : ~ :: . .: : . ~ :, ~
, . . . . . . .. . .
.
WO 90/12008 PCT/US90/014g8
34
suspension was then filtered tO remove triethvl amine hydrochloride and the filtrate was
concentrated in vacuo. The residue was redissolved in benzene (20 mL) and added to a
stirred solution of the material prepared in paIt a (3.55g, 17.1 mIIlole) in benzene ~50 rnL).
Trifluoroacetic acid (1.3 mL, 16.9 rslmole) was added neat and the mixture stirred for 48
hours. At that time the rnixture was concentrated ~o dryness and then redissolved in ether
(150 rnL). This solution was dried over MgSO4 and evaporated to produce an oil which
was carried on immediately without purification.
d. N-hydroxy-N-(1-methyl-1-(4-butoxyphenyl)ethyl urea is prepared according to
the procedure of Example 1, except using the material prepared as in part c above instead of
4-phenylmethoxyacetophenone.
Example 21
e~ra~ion of ~-hvdroxv-N-fl-(~butox~heml)~2-rnethYlpropvl) ure~
a. 1-(4-Butoxyphenyl)-2-rnethyl-1-propanol. 4-Butoxy-benzaldehyde (l.Og, 5.6
rnmole), prepared as Aescribed in Exarnple 15, part a, was dissolved in ether (50 rnl,) and
cooled to -780 C. Isopropyl magnesium bromide in T~ (6.5 mmole) was added. The
reaction mixture was allowed to warm to room temperature and then quenched with water
(20 mL). The ether layer was separated, dried with MgSO4 and evaporated to give a liquid
(1.16g).
b. 4-Butoxyphenyl isopropyl ketone. The material prepared in part a (1.16g, 5.2
rnrnole) was dissolved in methylene chloride (2~ mL) and pyndinium chlorochromate
(2.82g, 13.1 mmole) was added. Three hours later ether (25 rnL) was added ~Lnd the
resulting mixture filtered through celite. The filtrate was dried over MgSO4 and evaporated
to afford 1.û7g of an oil.
c. N-hydroxy-N-(14-butoxyphenyl)-2-methylpropyl) urea is prepared according
the method of Example 1, except using the material prepared in paTt b above instead of 4-
phenylmethoxyacetophenone.
Example 22
Preparation of N-hydroxv-N-(I-(~butoxy-2-naphthvl)ethvl~ urea
a 2-Brom~butoxynaphthalene was prepared according to the method of
Example 1, part a, except using ~bromo-2-naphthol instead of 4-hydroxyacetophenone
and using 1-bromobutane instead of benzylbrornide. ;`
b. l-(~butoxy-2-naphthyl)-ethanol. The material prepared as above (11 g, 39.3
~ '; . :~. ' . '
W~ 9~/12008 P~r/US~0/0~48
2 ~
mmole) was dissolved in THF and cooled to -780 C. Tert-butyl lithium (1.7M in hexanes,
86.4 mrnole) was added and the mL~c~ure stirred for thirty minutes. Acetaldehyde (2.23 rnL,
40 mmole) was added and the n~ixture was snrx~d an additional th~rty minutes. The
reaction was quenched by the addition of NH4CI and the product extracted into ether. After
drying over MgS04 and concentrated in vacuo, the resulting residue was carried on without
purification.
c. 6-butoxy-2-acetonaphthone. The desired rnaterial was prepared according to ~he
method of Example 21, part b, except using the material prcpared accor~ing to part b above
instead of 1-(4-Butoxyphenyl~-2-methyl- l-propanol.
d. N-hydroxy-N-(1-(6-butoxy-2-naphthyl)ethyl urea is prepared according to the
method of Exarnple 1, except using the material prepared according to the method of part c
above instead of 4-phenylme~hoxyacetophenone (Rl, R2=H, R3=6-C~Hg-2-naphthyl,
X=CH(CH3)). mp: 135-1370C; ~MR (300 MHz, DMSO-d6): 0.92 (t, 3H); 1.50 (m,
4H); 1.75 (m, 2H); 2.03 (s, 3H); 4.08 (t, 3H); 5.75 (br m, lH); 7.10-7.8~ (m, 7H); 9.55
(s, lH); Mass Spectrum (EI): 301, 284, 242, 227, 171.
Example 23
Preparation of N-h~drox~-N-(l-(~phçn Im~Qxv-2-na~hthYI)elhYI~ urea
The desired material is prepared according to the met'nod of Example 22 except
using benzylbromide instead of l-bromobutane.
Example 24
Prep~ra~iQn oN-hy~xv-N-(1-(~4-fluoro~henylmethQxv~henYl~ethyl~ ul~a
The desired material is prepared according the method of Example 1, except usingfluoro'oenzylbromide instead of benzyl'oqomide.
Exa~slple 25
~reparanon of N-hvdroxv-~-(1-~4-L4-methox~?henylmethQxY~henvlLe~hyl) ure
The desired mateTial is prepared according the method of Example 1, except using 4-
methoxybenzyl'orornide instead of benzylbromide.
Example 26
Prepa~tion of N-hvdrQxv-N-(~-(4-L~ifluoromethyl~henYI methoxy~-~h~nvl~ethyl) urea
The desired mat~ial is prepared according ~e method of Example 1, except using 4-
. . .
. . ~ . .
..
.. ..
WO 90/12008 PCir/US90/01488
36trifluoromethylbenzylbromide instead of benzylbromide.
Example 27
Pre~aratio~of N-hydro~ (3-nitrQ 4-
The desired rnaterial is prepared according to the method of Example 1, exceptusing 3-nitro-4-hydroxybenzaldehyde instead of 4-hydroxyaeeto-phenone .
Example 28
PreparationQf ~-hvdroxv-N-(1-14-~henYln~thoxy-~5~dichloro~henvl~-
ethvU urea
a. 4-Phenylrnethoxy-3,5-dichlorobenzonitrile was prepared according to the
method of Example 1, part a, except using 3,5-dichloro-4-hydroxy benzonitrile instead of 4-
hydroxy-acetophenone.
b. 4-Phenylmethoxy-3,5-dichloroacetophenone. The material prepared as in part a
above (6.8g, 26 mmole) was dissolved in benzene (200 mL) and methyl magnesium
bromide (10 rnL, 3.0 M in ether) was added. The rnixture was refluxed for three hours,
cooled and 6N HC1 was added. The mixture was refluxed again for 2 hours and thenpoured into a saturated sodium bicarbonate solution. The organic layer was dried over
MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with 50%
ether in hexanes to give a 36~o yield of the desired product.
c. N-hydroxy-N-(1-(4-pbenylmethoxy-3,5-dichlorophenyl) ethyl) urea is prepared
according to the method of Example 1, except using the material prepared as in part b above
instead of 4-phenylmethoxyacetophenone.
Example ~9
eparangn of N-hYdrQ~-N-L2-hYdrQxy-4-~henvlmelh~x~henYlmethvl) urea
The desired material is prepared according to the method of Exarnple 1, except
using 2-hydroxy-~phenylmethoxy acetophenone instead of 4-
phenylmedloxyacetophenone.
Example 30
Prepar_~ion of N-hy~roxv-~-(l-(~pheny~hioFIçthoxyphenYl)ethyl urça
a. 4-Phenylthiomethoxyacetophenone. Benzyl phenyl sulfide (lO.Og, SOmmole)
was added at OoC to a soluqon of acetyl chloride (4.3g, 55 mmole) a~d alurninurn chlonde
. ,.. , ~., .
` ; ~ ~ ;, '' ,, ' .;
. ~:. , . . , , ...... ,:
WO ~Oll2008 PCI/US90/~1488
37
t28g, 204 mmole) in nitroethane (75mL). The mixture wa`s s~ti~or 3 hours at OoC and
then slowly poured over ice and 3N HCl. The resuldng mixture was extracted with ether,
which was then dried over MgSO4 and concentrated in vacllo. The residue was
chromatographed on silca gel eluting with 10% ethyl acetate in hexanes to give a white
solid (3.41 g).
b. N^hydroxy-N-(1-(~phenylthiomethoxyphenyl)ethyl urea is prepared according
to the method of Example 1, except using ~he material prepared as in part a, above, instead
of 4-phenylmethoxyacetophenone.
Example 31
Preparation of N-hvdroxY-N-ll-(4-(2~4~6-trimethYlphenyl)phenYI) e~hvl ur a
a. 4-(2,4,6-tTirnethylphenyl)acetophenone. Mesityl bromide ~6g, 30 mmole) was
dissolved in TEIF (60 mL)and cooled to -780 C. Tert butyl lithium (1.7M in hexanes, 63.3
rnrnole) was added and the mixture stiIred for 20 rninutes. In a separate flask, zinc chloride
(4.1 g, 30.1 mrnole) was suspended in THF (30 mL) and cooled to -780C. The lithium
reagent prepared above was added via cannula to the zinc suspension and the resul~ing
rnixture stirred for 60 rninutes. In another flask palladium
bis(triphenylphosphino)dichloride was dissolved in THF (40 mL), di-isobutylaluminum
hydride (l.OM in THF, 3.02 mrnole) was added, followed by 4-bromoacetophenone (5.39
g, 27.1 mmole) in THF (30 mL). The zinc reagent prepared above was transferred via
cannula to this solution and the mixture was stirred for two hours. The reaction mixture
was evaporated in vacuo and the residue dissolved in ether. This was then washed with
2N HC1 and dried over MgSO~I, and evaporated. The residue was chromatographed on 150
g silica gel, eluting with 12% ether in hexanes. A white solid t3.8 g) was obtained.
b. N-hydroxy-N-(1-(~(2,4,6-~rimethylphenyl)phenyl)ethylureaisprepared
according to the method of Exarnple 1, but using the material prepared as in part a above
instead of phenylmethoxyacetophenone.
Example 32
Preparanon of N-hydroxv-N-(1-(3-benzovlphenyl)ethy!~ urea
a. 3-Brom~benzophenone. 3-Bromobenzoyl chloride (33g) was dissolved in
benzene (125 mL) and alurninum chloride (30g) was added over 25 minutes. The mixture
was refluxed for one hour, cooled to room temperature and then added to ice (50g) and
con-~en~ated HCl (50mL). The organic layer was dried over MgSO~ and evaporated in
.' :: .' : ' ' `
:. , .:, ,
WO g~/12008 PCr/US90/014~8
~t'~
~ 38
vacuo to give a brown solid. This was then Kugelrohr distilled to give an off-whi~e solid
(39g).
b. 3-Bromobenzophenone ethylene glycol ketal. The material prepared as in par~ aabove (39g, 150 rnmole), ethylene g~ycol (42mL, 750 mmole), trimethyl orthoformate
(33raL, 300 mmole) and a few crystals of p-toluene sulfonic acid were heated to 60OC. for
24 hours. The rnixture was then poured into saturated NaH(: 03 solution and e~ctracted into
ether. The ether was dried over MgSO4 and evaporated. The residue was chromatogaphed
on silica gel eluting with 40% ether in hexanes to give a colorless oil (30g).
c. 3-Benzoylacetophenone ethylene glycol ketal. The material prepared as in part b
above (23.6g, 77.3 mmole) was dissolved in T~ (200 mL) and cooled to -780C. Tert-
butyl litni~n (lOOmL, 1.7M in hexanes) was added and then the mixture was stirred for 20
ninuteS N,O-dimethyl acetohydroxamic acid (15.9g, 154 mmole) in IHF (50 mL) was
added and the rnixture was stiITed for an additional thirty rninutes. The reaction was
quenched with pH 7 phosphate buffer and extracted into ether. The solvent was
evaporated, and the resulting residue chromatographed on silica gel, eluting with 40% ether
in hexanes.
d. N-hydroxy-N-(1-(3-benzoylphenyl)ethyl) urea is prepared according to the
method of Example 1, but using the material prepared as in part c above instead of
phenylmethoxyacetophenone.
Example 33
Prepara~on of N-hvdrox~LI-(4-12-phenylethenvl~phen~l)e~hyl) urea a. 4-(2-
Phenylethenyl)acetophenone is prepared according to the method of Example 21, parts a ;~
and b, except using 4-foImylstilbene instead of ~butoxy'oenzaldehyde and using methyl
magnesium bro,nide instead of isopropyl rnagnesium bromide.
b. N-hydroxy-N-(1-(4-(2-phenylethenyl)phenyl)ethyl ace~nide is prepared
according to the met'nod of Example 1, except using tne material prepared as described in
part a above instead of phenylmethoxyacetophenone
Example 34
eparation of N-h~droxv-N-(l-(4-!2-phenvlethyl)phenv!)ethyl) urea
a. 4-(2-Phenylethyl)benzaldehyde is prepare~l by catalytic hydrogenation of 4-
forrnylstilbene over 20% palladium on carbon in methanol.
b. N-hydroxy-N-(1-(4-(2-phenylethyl)phenyl)ethyl) aceta~ide is prepared
~ , , ,::
. .,
Wo 90/120~8 Pcr/u~9O/O~
39 2~9~
according to the method of Example 33, except using the material prepared as in part a
above instead of 4-formylstilbene .
Example 35
~reDara~ion~-h,Y~roxy-(1 -(4-~i~Ls~
The ma~erial prepared as in Example 1 is dissolved in te~ ydrofuran and one
equivalent of sodium hydride is added. After hydrogen evolution ceases, the solvent is
removed in vacuo to yield the desired product.
Example 36
The matenal prepared as in Example 1 is dissolved in tetrahydrofuran and one
equivalent of potassium hydride is added. After hydrogen evolution ceases, the solvent is
removed in vacuo to yield the desired product.
Example 37
Prepa~ation of ~:h,vdroxy-(l~L~henylmethox~henvl~ethvl)u~ea~oni~lt
The material prepared as in Example 1 is dissolved in tetrahydrofuran and ammonia
is bubbled through. The solvent is removed in vacz~ to yield the desired product.
Example 38
e~aralion of N~xv-(1-(4;~nylmethoxyQhçrlvl~hyl~ urea t~i~thv'l~nmQni~ ~alt
The materiial prepared as in Example 1 is dissolved in tetIahydrofuran and one
equivalent of tnethylarn~e is added. The solvent is removed in vacuo to yield the desired
product.
Example 39
Preparation of N-hvdroxv-fl-f4-phenYlmetho~yphenvl)ethyl~rea tetraethvl ammonium
The material prepared as in Example 1 is dissolved in te~ahydrofuran and one
equivalen~ of te~raethylammonil3m hydroxide is added. The solvent is removed in vacuo to
yield the desired product.
.. .
. .
. . . .. ~ .
WO 90/12~08 P~r/U~o/014P.8
3~ 40
Example 40
The material prepared as in Example 1 and 1.1 equivalent of tnethylan~ine are
dissolved in tetrahydrofuran and 1 equivalent of but,YrYl chloride is added. Ether is added
and the material is washed with 2N HCl, dried with MgS04 and then evaporated in vacuo
to yield the desired product.
Ex~mple 41
epar~tion of N-b~nzoyloxv-(1-(4-~henyl~netho2cyl2hçnvl)ethYI) ~r~a
The material prepared as in Example 2 and 1.1 es~uivalent of triethylamine are
dissolved in tetrahydrOfUraTI and 1 equivalent of benzoyl chloride is added. Ether is added
and 9.~he mate~ial is washed with 2N HCl, dried with MgS04 and ~hen evaporated in vacuo
to yield the desired product.
Example 42
Preparation of N-Hvdroxv-N-1-(2.5-dimethylthien-3-yl)ethvl urea
The desired compound was prepared by the same method as descnbed for Example
12 except using 3-acetyl-2,5-dirnethylthiophene instead of 2-acetyl-5-methylthiophene.
mp = 146-1470C; NMR (300MHz, DMS0-d6) 1.29 (3H, d, J = 7.5 Hz), 2.29 (3H, s),
2.32 (3H, s), 5.23 (lH, q, J = 7.5 Hz), 6.21 (2H, br s), 6.74 (lH, s), 9.02 (IH, s); MS:
(M+H)+= 215, (M+NH4)+= 23Z
Analysis Cal'd for CgHl4N202S: C, 50.45; H, 6.56; N, 13.93
Found: C, 50.44; H, 6.56; 13.91
Example 43
The desired compound was prepared by the same method as described for Exarnple
12 except using 3-acetylthiophene instead of 2-acetyl-5-methylthiophene.
mp. = 138.5-1400C, NMR (300MHz, DMS0-d6) 1.39 (3H, d, J = 7.5 Hz), 5.32 (lH, q,
J = 7.5 Hz), 6.33 (2H, br s), 7.05 (lH, m), 7.27 (lH, m), 7.42 (lH, m) 9.03 (lH, s);
MS: (M~H)t= 1879 (M~NH4)+= 204
.
.
Wo ~0/12008 PCr~US90/814P.8
41
Example 44
The desired compound was prepared by the same method as described ~or Example
12 except using 3 thiophene-car'ooxaldehye instead of 2-acetyl-5-methylthiophenlo.
mp. - 129-131C, NMR (300MHz, DMSO-d6) 4.48 (2H, s), 6.36 (2H, br s), 7.04 (lH,
m), 7.30 (lH, m), 7.45 (lH, m) 9.35 (lH, s); MS: ~M+H)+= 173, (M~NH4)+= 190
Analysis Cal'd for C6HgN2O2S: C,41.85; H, 4.68; N, 16.~7
Found: C, 41.61; H, 4.68, N, 16.27
Example 45
Preparadon of N-hydroxv-N-~thien-2-vl~methyl urea
a) 2-Thiophe lecar~oxaldoxime: To a solution of 2-t'niophene-car~oxaldehyde (3.0g, 26.8 mmole) in 10 rnL etnanol at room temperature was added pyridine (4.3 rnL, 53.5
mmole) and hydroxylamine hydrochloride (2.8 g, 40.1 mmole) witn stirring. After one
hour at room temperature the solution was dilu~ed with water and extracted with ethyl
acetate (3xS0 nL). The combined organic extracts were washed with 2M HCl (60 mL),
and brine (60 rnL), dried over MgS04, filtered and concentrated to yield 1.09 g of a white
solid (m.p. = 1230 C).
b) Thien-2-ylrnethyl hydroxyla~une: The oxime from part a (3.4 g, 26.8 rr~nol)
was dissolved in 50 r~ ethanol at room temperature and borane pyridine complex (8.1
rnL, 80.3 rnmol) was added. The solution was stirred one hour at room temperature and
was then cooled to Oo C at which time 6N HCl (80 mL) was slowly added. When the heat
of the reaction subsided, the flasls was warrned to room temperature and allowed to stir
approximately one hour. Then the solution was diluted with water and neutralized with
solid sodiurn carbonate. The aqueous layer was extracted with ethyl acetate (3x 50 mL)
and the combined organic layers were washed with brine and dried (MgSO4), filtered and
evaporated from toluene to remove the excess pyridine to give 3.4 g of product as a white
solid.
c) N-Hydroxy-N-(l-thien-2-ylmethyl) urea: To a solution of
trimethylsilylisocyanate (3.1 mL, 23.2 rnmole) in 10 mL THF at room temperature was
added the above hydroxylamine (1.5 g, 11.6 rnmole) in 10 mL of THF with s~rring. Afler
thirty minutes the reaction was quenched with saturated ammonium chlonde solution (10
mL). The aqueous layer was saturated with sodium chloride and extracted with ethyl
acetate (3x, 25 mL). The c~mbined organic ex~act was dned over MgS04, filtered and
WO 90/12~8 PCr/US9OtOI~I~
42
concentrated. T,he resultant solid was washed with ether and the c~ystals were collected to
yield 0.82 g (41 %) of the desired product as a white solid. m.p. = 1120 C; IH NMR (300
MHz, DMSO-d6~ 9.41 (br s, lH), 7.40 (dd, J = 2.4, 5.6 Hz, lH), 6.95 (m, ~H), 6.40
(br s, 2H), 4.63 (br s, 2H); MS (M~H)+ = 173; (M+NH4)+ = 190.
Analysis calc'd for C6HgN2O2S: C, 41.85; H, 4.68; N, 16.27. Found: C, 41.55; H,
4.58; N, 16.15.
Example 46
reparation of N-hvdroxv-N-1-(3-methylthien-2-vl)ethyl urea
The same me~hod as descIibed for Example 45 was used substituting 2-acetyl-3-
methylthiophene instead of 2-thiophenecarboxaldehyde to provide the desired product.
m.p. = 1310 C; lH NMR (300 MHz, DMSO-d6) 9.16 (bs, lH), 7.25 (d, J = 5.97 Hz,
lH), 6.78 (d, J = 5.90 Hz, lH), 6.30 (bs, 2H), 5.09 (q, J = 6.00 Hz, 13.21 Hz, lH),
2.16 (s, 3H), 1.35 (d, J = 6.91 Hz, 3H); MS (M+H)~ = 201; (M+NH4)+ = 218.
Analysis calc'd for CgHI2N202S: C, 47.98; H, 6.04; N, 13.99. Found: C, 47.79; H,5.96; N, 13.94.
Example 47
Preparation of,N-hydroxy-N-(1-thien-2-vl)ethy~ rea
The same method as described for Example 45 was used substitu~ng 2-
acetylthiophene instead of 2-thiophenecarboxaldehyde to provide the desired product. m.p.
= 129.50 C; IH NMR (300 MHz, DMSO-d6) 9.13 (br s, lH), 7.36 (dd, J = 6.3, 13.8
Hz, lH), 6.94 (m, 2H), 6.38 (br s, 2H), 5.49 (q, J = 6.3, 13.8 Hz, lH), 1.42 (d, J =
7.00 Hz, 3H). MS (M+H)+ = 187.
Analysis calc'd for C7HloN202S: C, 45.1S; H, 5.41; N, 15.04; Found: C, 45.00; H,5.35; N, 15.04.
Example 48
PreparatQn of N-hydroxv-N-(1-(5-pvrid:2-yl)thien-2-vl)ethvl urea
a) 2-Pyrid-2-ylthiophene. To a solu~on of thiophene (4.7 rnL, 59.4 mrnole) at OoC was added 25 M n-but,vllithium (24 rnL, 59.4 mmole) dropwise via syringe. The
solution was stiTred 3 h and was then transfeIred via cannula into a stirred solution of zinc
chloride (8.6 g, 63.4 mmole) in 60 mL THF at TOOID temperature. This solution was
.
.' : - ' , . .
.
.
W~ 90/~2008 PCr/U~90/01488
~3 ~
stirred ~or 1 h and was then transferred via cannula in~ a stirred solution of 2-
bromopyridine (3.8 rnL, 39.6 mmole) and tetrakistriphenylphosphine palladium ( 0.22 g,
0.20 mmole) in 100 mL of THF. After st*ing ovemight at room ternperaturç the rnixture
was quenched wi~h saturated ammoniurn chloride solution (100 mL) and extractçd with
ether (3xlO0 mL). The combined ether extract was washed with brine (lxlO0 mL), dried
over MgS04, filtered and concentrated in vacuo to yield 8.4 g of crude residue. The
material was chrornatographed (silica gel,10% ether/hexanes) tO yield 5.0 g (78%) of a pale
yellow solid.
b) 2-Acetyl-5-(pyrid-2-yl)thiophene. To a solution of 2-pyrid-2-ylthiophene frompart a (1.0 g, 6.2 mmole) in 20 mL of THF at -780 C was added n-butyllithium (2.6 mL,
6.5 mmole, 2.5 M solu~on in hexanes). The solution was stirred for 30 min and then N-
methoxy-N-methylacetamide (0.7 g, 6.8 mmole) was added via synnge. After
approximately 2 h at -780 C the material was quenched with saturated amrnonium chloride
solution ( 15 mL) and extracted with ethyl acetate (3x20 mL). The combined organic
extract was washed with brine, dried with MgS04, filtered and concentrated.
Chromatography (silica gel, 40% ether/hexanes) afforded 0.72 g (55 %) of product.
c) N-hydroxy-N-(1-(5-pyrid-2-yl)thien-2-yl)ethyl urea. The same method as
described for Example 45 was used substituting 2-acetyl-5-(2-pyridyl)thiophene from part
b instead of 2-thiophenecarboxaldehyde to provide the desiled product. lH NMR (300
MHz, DMSO-d6) 9.20 ~br s, lH), 8.49 (m, lH), 7.81 Im, 2H), 7.60 (d, 3.2 Hz, lH),7.23 (m, lH), 6.96 (d, J = 7.5, 14.4 Hz, lH), 1.46 (d, J = 7.2 Hz, 3H); MS (M~H)+ =
264.
Analysis calc'd for ClzH12N30 ~S: C, 54.74; H, 4.9&; N, 15.96. Found: C, 52.93; H,
4.87; N, 14.81.
Example 49
Preparation of ~-hvdroxv-N-(3-methvlthien-2-Yl~m~hvl~
The same method as described for Exarnple 45 was used substituting 3-methylthien-
2-ylcarboxaldehyde instead of 2-thiophenecarboxaldehyde to provide the desired prcduct.
m.p. = 11~ C; IH NMR (300 MHz, DMSO-d6) 9.38 (br s, lH), 7.28 (d, J = 8.2 MHz,
lH), 6.81 (d, J ~ 5.76 Hz, lH), 6.35 (bs, 2H), 4.56 (br s, 2H), 2.17 ts, 3H); MS(M+H)+ - 187; (M+NHq)+ = 204.
Analysis calc'd for C'7HIoN202S: C, 45.15; H, 5.41; N, 15.04. Found: C, 45.30; H,
.
. . .
Wo 90/12~8 PCr/U~9~0148
r~
5.46; N, 14.76.
Example 50
epara~on of ~-b~d~xv-?~-(thien-2-yl~meth,Yl-N'-~nçthYl urea
The same method as descIibed for Exarnple 45 was used substituting
me~ylisocyanate for ~nethylsilylisocyanate to provlde the desired product. m.p. = 108
oC; lH NMR(300 MHZ7 DMSO-d6): 9.35 (br s, lH), 7.39 (dd, J = 2.2, 5.4 H~, lH),
6.99-6.87 (m, 3H), 4.62 (br s, 2H), 2.58 (d, J = 4.~ Hz); MS (M+H)+ = 187,
~M+NH4)+ = 204. `~`
Analysis calc'd for C7HloN202S: C, 45.15; H, 5.41; N, 15.04. Found: C, 45.û8; H,5.38; N, 15.00.
Example 51
Pr~paration of N-hvdroxv-N-(5 methvlthien-2-vl)methyl urea
The same method as described for Example 45 was used substituting 5-methylthien-2-yl carboxaldehyde instead of 2-thiophenecarboxaldehyde to provide thc desiIed product.
m.p. = 1340 C; IH NMR (300 MHz, DMSO-d6): 9.36 (bs, lH), 6.74 (d, J = 3.3 Hz,
lH), 6.61 (m, lH), 6.35 (bs, 2H), 4.52 (bs, 2H), 2.38 (s, 3H); MS (M+H)+ = 187,
(M+NH4)+ = 204.
Analysis calc'd for C7HloN2O2S: C, 45.15; H, 5.41; N, 15.04; Found: C, 45.37; H,5.33; N, 14.94.
Example 52
Pre~aration_ f N-hvdroxv-~-1-(5-met~lthien-2-vlknethvl-N'-rnethvl urea
Formula I, Rl = H, R2 = OEI3, R3 = 5-methylthien-2-yl, X = CH2.
The same method as described for Example 45 was used substituting 5-methyl-2-
thien-2-yl carboxaldehyde for 2-thiophenecar~xaldehyde and methylisocyanate for
trimethylsilylisocyanate to provide the desired product. m.p. = 1200 C; IH NMR (300
MHz, DMS0-d6): 9.30 (br s, lH), 6.89 (m, lH), 6.73 (d, J = 3.1 Hz, lH), 6.61 (m,lH), 4.52 (br s, 2H), 2.58 (d, J = 4.5 Hz, 3H), 2.38 (s, 3H); MS (M+H)+ = 201,
(M+NH4)+ - 218.
Analysis calc'd for C8HI2N202S: C, 47.98; H, 6.04; N, 13.99. Found: C, 47.91; H,5.96; N, 13.92.
.
WO 90/12~08 Pcr/u~90/~ 8
.
Example 53
P~eparanon of N-hvdr~x~v-~-(1-~5-~hen~ylthien-2--YUmethvl~ lre~
a. 2-Phenylthiophene. To a solution of thiophene (9.5 mL, 0.12 mole) in 100 mL
tetrahydrofuran at Oo C was added 2M n-butyllithiurn (48 mL, 0.12 mole) dropwise. The
solution was stirred 2.5 h and was then added via cannula to a stirr~d solution of
anhydrous zinc chloride (26 g, 0.19 mole) in 100 rnL of TE~ at room ternperature. After 1
h this soludon was transferred via cannula into a solution of bromobenzene (8.4 mL, 0.08
mole) and tetrakis triphenylphosphine palladium (0.2 g) in 100 mL, of THF. The solution
was warmed to reflux overnight. The solution was cooled to room temperature and
quenched with saturated ammonium chloride solution The mixture was extracted with ether
(3xSO rnL). The ether extracts were washed with brine, dried {MgS04), filtered and
concentrated. The material was distilled (20 mm Hg) to yield 7.5 g (60%) of desired
product, b.p. = 1500 C~.
b. 5-Phenylthien-2-ylcarboxaldehyde. To a solution of dimethylforrnamide (13
rnL, 0.17 mole) at Oo 5 was added POCI3 (4.4 mL, 0.05 mole) dropwise. To this was
added 2-phenylthiophene (7.5 g, 0.05 mole) neat. The solution was warmed to 800 C and
allowed to stir overnight. The soludon was cooled to room temperature and neutralized
u~th salurated sodium acetate solution (100 mL). The rnixture was washed with ether
(3xSO mL). The ether ex~acts were washed with brine, dried (MgSO4), filtered andconcentrated. The resultant solid was recIystallized from hexanes tO yield 5.03 g (57%) of
the aldehyde.
c. N-hydroxy-N-l-(5-phenylthien-2-yl)methyl urea. The same method as
described for Example 45 was used substituting 5-phenyl-2-thien-2-ylcarboxaldehyde for 2-
thiophenecarboxaldehyde to give the desired product. m.p. = 1740 C; IH NMR (300
MH~, DMSO-d6) 9.50 (br s, lH), 7.61 (m, 2H), 7.43-7.27 tm, 4H)9 6.98 (d, J = 3.3Hz, lH), 6.45 (br s, 2H), 4.63 (br s, 2H); MS: (M+H)+ = 249, (M~NH4)l = 266.
Analysis calc'd for ( l2HI2N202S: C, 58.05; lH, 4.87; N, 11.28. Found: C, 57.55; H,
4.88; N, 11.14.
Example 54
Preparation of N-hvdroxv-N-(I-~-~envlt_ien 2 yl~methyLN'-methvl urea
The same method as described for Ex~nple 45 was used substituting 5-phenylthien-2-ylcarboxaldehyde for 2-thiophenecarboxaldehyde and methylisocyanate ~or
t
'''
,, ,' . ", ' `: '' ''
:':, '' ' '' ' " ' ' ~' '
:, '` ...
WO 90/12008 P~r/US90/014B~
~ j 46
trimethylsilylisocyanate to provide the desired product. m.p. = 1690 C; IH Nh~R ~300
MHz, DMSO-d6) 9.43 (br s, lH), 7.60 (m, 2H), 7.43-7.26 (m, 4H), 6~98 (m, 2H), 4.63
(br s, 2H), 2.58 (d, J = 5.5 Hz, 3H); MS (M+H)+ = 2S3, (M~NH4)~ - 280.
Analysis calc'd for Cl3HI4N2O2S: C, 59.52; H, 5.38; N, 10.68. Found: C, 58.35; H,
5.30; N, 10.46.
E~cample 5~
Preparation of N-hydroxY^N-(1-(5-(pyrid-2-vl)thien-2-vl)methyl) urea
a) 2-Pyrid-2-ylthiophene. To a solution of thiophene (4.7 rnL,59.4 mmole) at Oo
C was added 2.5 M n-butyllithium (24 mL, 59.4 mmole) dropwise via syringe. The
solution was sti~Ted 3 h and was transferred via cannula into a stirred solution of zinc
chloride (8.6 g, 63.4 mmole) in 60 rnL THF at room temperature. This solution was
stirred for 1 h and was transferred via cannula into a stirred solution of 2-bromopyridine
(3.8 rnL, 39.6 mmole) and tetrakis-triphenylphosphine palladium ( 0.22 g, 0.2 mmole) in
100 mL of THF. The solution was stirred oYernight at roorn temperature and was then
quenched with saturate ammoniurn chlonde solution (100 mL) and extracted with ether
(3xlO0 rnL). The ether extracts were washed with brine (lxlO0 rnL), dried over MgSO4,
filtered and concentrated to yield 8.4 g of crude residue. The material was
chromatographed (silica gel,10% ether/hexanes) to yield 5.0 g (78%) of a pale yellow
solid.
b) 5-(2-Pyridyl)thien-2-ylcarboxaldehyde. To a solution of 2-(2-pyIidyl)thiophene
(2.0 g, 12.4 mmole) in 20 mL THF at -20O C was added 2.5 M n-butyllithium (6.0 mL,
15.0 mmole) and the bright red solution was sti~red 1 h. To this solution was added
d;,rnethylforrnarnide (4.8 rnL, 62 mmole) and the solution was sdrred 1 h. The reaction
was quenched with saturated ammoniurn chloride soludon (25 ~iL) and ext~acted with ethyl
acetate ~3x20 mL). The ethyl acetate extracts were washed with brine (lx30 mL), dried
(MgS04), filtered and concentrated. The ;esultant red solid was ch~matoglaphed over
silica gel (5% ether in dichloromethane) to give 1.4 g of the desired aldehyde.
c) N-hydroxy-N-(1-(5-pyIid-2-ylthien-2-yl)methyl) urea. The same method as
described for Example 4j was used subs~ituting 5-(pyrid-2-yl)thien-2-ylcarboxaldehyde for
2-thiophenecarboxaldehyde to provide the desired product. m.p. = 168O C; IH NMR (300
MHz, DMSO-d6) 9.49 ~br s, lH), 8.49 (m, lH), 7.82 (m, 2H), 7.61 (d, J = 3.45 Hz,lH), 7.23 (m, lH), 6.99 (d, J = 3.5 Hz, lH), 6.42 (br s, 2H), 4.62 (br s, 2H), MS
WO 9~ 008 Pcr/lJ~so/ol4~8
47 ~ 9~
(M+H)~ = 250. Analysis calc'd for CIlHllN3O2S: C, 53.00; H, 4.45; N, 16.86.
Found: C, 52.59; H, 4.45; N, 16.S8.
Example 56
Preparation of N-hvdroxv-N-(I-(S-phenylthien-2-vl)ethvl) ur~a
a) 2-Acetyl-S-phenylthiophene. To a solution of 2-phenylthiophene (1.85 g, l l.Ssnmol) and acetyl chloride (0.9 g, 11.5 mmol) in benzene (20 mL) a~ OoC was added SnC4 r
(3.0 g, 11.5 m~nol) dropwise. The rnixture was stiITred for 1 h and allowed to warm to
room temperature after which it was poured into cold 10% aqueous HCI. The mixture was
extracted with ether. The organic extract was washed with bnne, dried over MgS04,
filtered, and concen~ated to provide a solid which was puIified by chromatography (silica
gel, 1:3, ether, hexane) to give 1.8 g of a white powder.
b) The desired product was prepared by the same method described for Example
12, except using 2-acetyl-5-phenylthiophene instead of 2-acetyl-5-methylthiophene. m.p.
150-151.5 oC; IH NMR (300 MHz, DMSO-d6) 1.46 (d, 3H, J = 7.5 Hz), 5.49 (dd, lH,
J = lS, 7.5 Hz), 6.43 (br s 2H), 5.95 (m, lH), 7.30 (m, 2H), 7.40 (m, 2H), 7.60 (m,
'~H), 9.21 (s, lH); MS (M+H)+ = 263, (M+ NH4)+= 280.
Example 57
_ eparation of N-hvdoxv-~5-benzvlthien-2~ ethyl) urea
a) 2-Benzylthiophene. Thiophene (10 g, 120 mmol) was dissolved in THF (100
mL) and cooled to OoC. n-BuLi (2.5 M in hexane, 48 mL, 120 rnmol) was added
dropwise and the mixture was s~red fo 1 h at OoC. This solution was added via cannula tO
a soludon of benzyl brornide (14 g, 79 mrnol) and [(C6Hs)3P~4 Pd (0.46 g, 0.4 mrnol) in
THF (100 rnL) at OoC. The rnix~ure was stilred at room temperature overnight, ~hen pured
into 10% aqueous HCl and extracted with ether. The organic extract was washed with
brine, dried over MgS04, filtered, and concentrated. The residue was filtered through
silica gel (lOOg) with hexane as eluent and concentration gave a residue which was distilled
to give 8 g of liquid, bp 88-92 oC at 0.1 mm Hg.
b) The desired product was prepared according to the method described for
Example 12 except using 2-acetyl-S-benzylthiophene which was in ~rn prepared according
to the method descnbed for 2-acetyl -5-phenylthiophene. m.p. 117-120 oC; lH NMR
(300 MHz, DMSO-d6) 1.37 (d, 3H, J = 7.5 Hz), 4.06 (s, 2H), 5.39 (dd, lH, J = 15, 7.5
WO 90tl2008 PCI/US90/01488
2~
48 "''`
Hz), 6~43 (br s 2H), 6.71 (m, 2H), 7.27 (m, SH), 9.10 (s, lH); MS (M+H)+ = 277, (M+
NHi4)~= 294.
Analysis calc'd for Cl4Hl6N202S: C, 60.85; H, 5.84; N, 10.14. Found: C, 60.~8; H,
5.90; N, 9.78.
Example 58
Preparahon of N-hvdroxv-N-(1-(5-(2-~henvlethenvl)thien-2-~ ethyl~ urea
a) Trans2-phenyl-1-(thien-2-yl)ethene. Ben~yldiethylphosphonate(5.7g,25
mmol) was dissolved in THF (50 r~sL) and cooled to -780C and nBuLi (2.5 M in hexane,
25 mmol) was added dropwise and the mixmre was stilTed for 30 min. Then a solu~ion of
thiophene-2-carboxaldehyde ~2.8 g,25 mmol) in T~F (10 mL) was added dropwise at -
780C. The cold bath was removed and the reaction was warmed to room temperature,heated for 2 h at reflux and the reaction was t'nen cooled and saturated aqueous NH4Cl was
added. I'he nixture was diluted with water and extracted with ether. The organic extract
was washed with brine, dried over MgSO4, filtered, and concentrated to provide a solid
which was purified by recrystallization from hexane to give 2.6 g of intermediate.
b) Acetylation was accomplished according to the method used in Example 56.
This interrnediate was then converted to the desired compound according to ~he method
described for Exarnple 12. m.p. 16û.5-1630C; IH NMR (3ûû MHz, D~ISO-d6) 1.44 (d,3H, J = 7.5 Hz), 5.46 (dd, lH, J = 15, 7.5 Hz), 6.42 (br s 2H), 6.84 (d, lH, J = 12 Hz),
6.87 (m, lH), 7.01 (m, lH), 7.24 (m, lH), 7.36 (m, 3H), 7.55 (m, 2H), 9.20 (s, lH);
MS (M+H)+ = 289, (M~ NH4)+= 306.
Analysis calc'd for ClsHl6N2o2s: C, 62.4B; H, 5.59; N, 9.71. Found: C, 62.73; H,5.60; N, 9.43.
Example 59
Preparation of N-hvdroxv-N-(1-(2.5-dimethvlthien-3-vl)e~hvl~-N'-methvlethoxvcarbonYI
urea
To a s~red solu~ion of 1-(2,5-dimethylthien-3-yl)etnylhydroxyla~nine (5.5 g, 32
mrnol) in THF (25 mL) was added ethyl isocyanatoacetate (4.0 g, 31 rnmol) dropwise
under dry nikogen. After s~iIring for one hour, thie reaction was concenh ai~ed, the residue
was dissolved in ethyl acetate (200 mL) and washed widl 5% aqueous ci~ric acid (100 ml).
~e organic layer was dried over MgSO4 and concen~ted. The resulting residue was
WO 90/12008 PCr/US90/01488
2 ~
~ ,9
purified by chromatography (silica gel, ethyl acetate-hexanes, 25:75, 40:60) followed by
crystallization from ethyl acetate-hexanes to provide the desired product (5.03 g, 16.75
rnmol) as white needles. m.p = 111-112.50C; NMR (300MHz, DMSO-d6) 1.17 (3H, ~, J= 7.0 Hz), 1.31 (3H, d, J = 7.0 Hz), 2.27 (3H, s), 2.32 (3H, s), 3.73 (2H, rn), 4.06
(2H,q,J=7.0Hz),5.23 (lH,q,J=7.0Hz),6.74 (lH,m),7.13 (lH, t,J=6.1 Hz),
9.16 (lH, s); MS: (M+H)~ 301
Analysis Calc'd for C13H20N204S: C, 51.98; H, 6.71; N, 9.33. Found: C, 51.89; H,.65; N, 9.22
Example 60
eparation Qf N-hvdrox~r-N-LI-t2,5-dimethylthien-3 yl~ethyl)-N'-(2-hvdroxyethvl) ure_
To a stirred solution of ester from Example 59 (1.84 g, 6.13 mmol) in dry TH F (15
mL) was added 2M lithium borohydride in THF (5.0 mL, 10.0 mmol) dropwise under
nitrogen. The solution was stiIred overnight, then quenched by the dropwise adclition of
rne~hanol (25 rnL) and stirred 4 h. The reaction was concentrated, poured into 10%
aqueous citric acid (100 mL), and extracted with ethyl acetate (3 X 100 rnL). The
combined organic extract was dried over MgS04 and concentrated. The resulting residue
was pulified by chromatography (silica gel, ethyl acetate-hexanes, 50:50,75:25), followed
by crystallization from ethyl acetate-hexanes to provide the desired produc~ (510 mg). m.p
= 122 - 123.50C; NMR (300MHz, DMSO-d6) 1.29 (3H, d, J = 7.0 Hz), 2.28 (3H, s),
2.32 (3H, s), 3.08 (2H, m), 3.35 (2H, m), 4.65 (lH, t, J = 5.3 Hz), 5.23 (lH, q, J = 7.0
Hz), 6.70 (lH, t, J = 5.9 ~), 6.73 (lH, m), 9.03 (lH, s); MS: (M-~H)+= 259
Analysis Calc'd for C1lH1gN203S: C, 51.14; H, 7.02; N, 10.84.
Found: C, 51.07; H, 6.88; N, 10.63
Example 61
Prel2ar ion of N-hydroxv-N-(l-thien-3~ylethy~ ~-1-~4-carbornethoxYbutYI) urea
To a sti~ed solution of the mono-methyl ester of glutaric acid (2.0 ~L,15.2 rnmol)
in benzene(100 rnL), ~iethylamine (2.23 mL, 16.0 trlmol) and diphenylphosphoryl azide
(3.37 mL, 15.2 mmol) were added. Afterrefluxing lh, N-(1-thien-3-ylethyl)
hydroxylarnine (2.20 g, 15.4 mmol) was added. After 30 min the reaction was cooled to
room temperature and poured into 10% HCl and extracted with EtOAc (2x). The combined
organic extract was washed with H20 and 'oline, dried (MgSO4), and concentrated in
.. . . .. . . .
WO 90/12008 PCr/US90/014B8
3~
vacuo. Purification by chromatography (silica gel, EtOAc/llexanes) followed by
recrys~allization from EtOAc/hexanes, gave 400 mg of desired product as a white solid.
m.p. 84.5-85.5C; NMR (300 MHz, DMSO-d6) 1.38 (3H, d, 7.0 Hz), 1.65 (2H,
quintet, J = 7.5 Hz), 2.25 (2H, t, J = 7.5 Hz), 3.05 (2H, q, J = 7.5 Hz), 3.58 (3H, s),
5.28 t1H, q, J = 7.0 Hz), 7.03 ~2H, m), 7.26 (lH, m), 7.40 (lH, m), 8.98 (lH, s); MS
(M+H)~= 287.
Analysis Cale'd for Cl2H1gN204S: C, 50.33; H, 6.34; N, 9.78.
Found: C, 50.16; H, 6.22; N, 9.78.
Example 62
Prepalation of N-hvdroxy-N-~1-thien-3-vlethyl-N'-(methylethoxycaTbonyl)urea
To a stirred solution of the 1-thien-3-ylethylhydroxylamine (1.43 g, 10 mmol) inTE~ (12 mL) was added ethyl isocyanatoacetate (1.44 g, 11.1 mmol) dropwise under dry
nitrogen. Workup as desc~ibed above for Example 59, purification by chromato~aphy
(silica gel, ethyl acetate-hexanes, 25:75,40:60) followed by crystallization frorn ethyl
acetate-hexanes provided the desired product (2.68 g, 9.84 mmol) as white crystals. m.p.
= 86.5-880C; NMR (300MHz, DMSO-d6) 1.19 (3H, t, J = 7.0 Hz), 1.41 (3H, d, J = 7.0
Hz), 3.73 (2H, d, J = 6.3 Hz), 4.09 (2H, q, J = 7.0 Hz), 5.3û (lH, q, J = 7.0 Hz), 7.06
(lH,dd,J=5.1, 1.3Hz),7.29(2H,m),7.42(1H,dd,J=5.1,2.9Hz),9.17(1H,s);
MS: (M+H)~ 273
Analysis Calc'd for CIlHl6N204S: C, 48.52; H, 5.92; N, 10.2g.
Found: C, 48.4; H, 6.01; N, 10.19.
Example 63
Preparation of N-hydroxv-N-(1-(1-(5-methvlthien-2-vl)-2-hvdroxv~ethvl) urea
a) 1-(5-Methylthien-2-yl)-2-hydroxyethanone. To a stirred solulion of
diisopropylamine (3.18 g, 31.4 mmol) at -780C in 150 mL THF, was added dropwise n-
butyllithium (12.56 mL of a 2.5 M solution in hexanes, 31.4 mmol). After complete
addition, the solution was shrred for 30 mins at that temperature. A sample of 2-acetyl-5-
me~hylthiophene (4.00 g, 28.6 mmol) in 10 mL THF was then added and the reaction was
sti~red for an additional 30 mins at -780C. Chlorotrimethylsilane (3.41 g,31.4 mmol) was
L~len added, the mixture was stirred 30 mins at -780C and then diluted wi~h aqueous sat'd
NaHCO3 (lSO mL) and extracted with ethylacetate (3 x 150 mL). The combine~ organic
. ~ ~
WO 90/12008 PCI/US90/01488
51 2 ~
extracts were dried with MgS04 and concentrated.
The resulting residue from above was taken up in 100 mL CH2CI2 containing 50
mL aqueous sat'd NaHC03, and cooled to OoC and m-chloroperoxybenzoic acid t6.17 g,
80% purity, 28.6 mmol) was added and the mixture was stirred for 45 mins at OoC. It was
then diluted with aqueous. sat'd NaHC03 (50 rnL) and extracted with CH2CI2 (3 x 150
mL). The combined organic extract was dried with MgS04 and soncentrated to a volume
of 150 snL. To this was added 4 spatulas of Amberlyst-15 ion exchange resin and the
heterogeneous mixture was st Ired for 1 hr. It was then filtered and concentrated. The
resulting residue was purified by chromatography (silica gel, ether-hexanes, 3:7) to provide
2.91 g of the desired product.
b) N-hydroxy-N-(l-(1-(5-methylthien-2-yl)-2-hydroxy)ethyl) urea. The same
method as described for Exarnple 45 was used substituting 1-(5-me~hylthien-2-yl)-2-
h,vdroxyethanone instead of 2-thiophene-carboxaldehyde to provide the desired product.
mp.=140.0- 141.50C; NMR (300 MHz, DMSO-d6) 2.38 (s, 3H), 3.59 (m, lH), 3.75 (m,
lH), 4.64 (dd, lH, J = ~ Hz), 5.26 (dd, lH, J = 6 Hz), 6.32 (s, 2H), 6.61 (dd, lH, J = 2
Hz), 6.71 (d, lH, J = 3.5 Hz), 9.08 (s, lH); MS: M+=217.
Analysis Calc'd for CgHl2N203S: C, 44.43; H, 5.60; N, 12.96.
Found: C, 44.33; H, 5.50; N, 12.85
Example 64
PreparatiQn of N-hvdroxv-N-(l-t5-methYlthien-2~1)-5-c~r~oçthoxY~ntvl~ urea
a) Adipoyl chloride monoethyl ester. To a stiITed solution of adipic acid monoethyl
ester (3.14 g, 18.0 mmol), was added dropwise oxalyl chloride (2.51 g, 19.8 mmol) and
the resulting mixture was stirred for 18 h and then concentrated and used as follows.
b) Ethyl ~keto-(5-rnethylthien-2-yl)hexanoate. To a stirred solution of 2-
methylthiophene (1.767 g, 18.0 mmol) in 90 mL THF at -780C, was added n-butyllithium
(7.20 mL of a 2.5 M solution in hexanes, 18.0 mrnol) dropwise. The resulting mixture
was stilred for 30 snin., then MnI2 (5.7B g, 18.72 rnrnol) was added (preparation
according to G. Friour, G. Cahiez, J.F. Norrnant, Svnthe~, 1984, 37). The cooling bath
was withdrawn and the reaction allowed to warm to room temperature and stiIred for 30
mins. It was then cooled to OoC and adipoyl chloride monoethyl ester from above (18.0
mmol) was added as a solution in 10 mL THF. The cooling bath was withdrawn and the
reaction allowed to warrn to room temperature and sti~ed for 3 h. The mixn re was diluted
W~ 90/1200X PCr/US90/0148S
u r ~ 52
with aqueous sat'd NaHCO3 (90 mL) and extrac~ed with ethyl acetate (3 x 90 mL). The
combined organic extract was dried with ~A[gSO4 and concentrated. I he resulting residue
was purified by chromatography (silica gel, ether-hexanes, 15:85) to afford 2.84 g of the
desired product as an oil.
c) N-hydroxy-N-(1-(5-methylthien-2-yl)-5-carboethoxypentyl) urea. The same
method as described for Example 45 was used substituting ethyl 6-(S methylthien-2-yl)-6-
keto-hexanoate instead of 2-thiophene-carboxaldehyde to provide the desired product.
mp.= 106-1070C; NMR (300 MHz, DMSO-d6) 1.14-1.42 (m, 2H), 1.48-1.59 (m, 2H),
1.62-1.76 (m, lH), 1.77-1.90 (m, lH), 2.28 (t, 2H, J = 7.5 Hz), 2.37 (s, 3H), 3.57 (s,
3H), 5.19 (t, lH, J = 7.5 Hz), 6.30 (br s, 2H), 6.59 (m, lH), 6.69 (d, lH, J - 3.5 Hz),
9.07 (s, lH); MS: M+=301.
Example 65
Preparation of N-hvdroxv-N-(1 -(5-methvlthien-2-vl)-~ca b_xvamidohex~ ~ urea
a) A solution of ethyl 6-oxo-6-(5-methylthien-2-yl)hexanoate (1.45 g, 5.5 mmol)
in 30 mL 1:1 aqueous lN LiOH: THF was sti~red for 5 h. The mixture was diluted with
water (10 rnL) and washed with ethyl acetate (2 x 25 mL). The aqueous layer was acidified
to pH2 with aqueous 6N HCl and extracted with ethylacetate (3 x 25 mL). These last
organic extracts were combined, dried with MgS04, and concentrated to afford 1.08 g
(87%) of the desired inte~rnediate.
b) To a st*ed solution of the intermediate from part a) (1.07 g, 4.7 mrnol) in 23
mL CH2C12, was added oxalyl chloride (721 mg, 5.7 mmol). After sti~ing for 72 h, the
reaction was concentrated in vac~o. The resulting residue was taken up in a minimum
arnount of THF and was added dropwise to a solution of 10% aqueous NH4OH (20 mL)I he reaction was stiIred for 1 h., diluted with brine (10 mL) and extracted with ethylacetate
(3 x 30 mL). The combined organic extract was dried with MgSO4 and concentrated to
afford 1.02 g of interrnediate amide.
c) The same method as described for Example 45 was used substituting 6-oxo-6-(5-methylthien-2-yl)hexam~de instead of 2-thiophene-carboxaldehyde to provide the desired
product.
mp.=1720C (dec); NMR (300 MHz, DMSO-d6) 1.11-1.25 (m, lH), 1.25-1.39 (m, lH),
1.49 (m, 2H), 1.62-1.75 (m, lH), 1.75-1.90 (m, lH), 2.01 (t, 2H, J = 8 Hz), 2.3O (s,
3H), 5.19 (t, lH, J = 7.5 Hz), 6.59 (m, lH), 6.69 (d, lH, J = 3.5 Hz); MS: M+=286.
.
::
.,
: : ~ : , . . .
wo so/l2aos Pcr/usgo/0l488
53 ~ 0
Analysis Calc'd for Cl2HlgN303S: C, 50.51; H, 6.71; N, 14.73
Found: C, ~0.41; H, 6.68; N, 14.S9
lE:xample 66
Pre~aration Q N-hvdr_ ~Ib2myvlLur~
a) l-(5-Methylthien-2-yl)-1-propanol. To a solution of 5-rnethylthien-2-
ylcarboxaldehyde (2.52 g, 20 mmol) in 100 mL ether at ûoC, was added ethylmagnesium
bromide (8.00 mL of a 3.0 M solution in ether, 24 mmol) dropwise. The cooling bath was
withdrawn and the reaction was allowed to wa~n to room temperatureafter which it was
que~lched with aqueous sat'd NH4Cl (100 mL) and extracted vith ethylacetate (3 x 100
rnL). The combined organic extreact was dried with MgS04 and concentrated to afford the
desired product.
b) l-(5-Methylthien-2-yl)propanone. Asolutionof 1-(5-methylthien-2-yl)propanol
from above (20 mmol) and pyridinium dichromate (9.03 g, 24 rnrnol) in 10() mL (:H2Cl2
was stirred for 18 h. The reaction was then f;ltered through Celite and the filtrate was
concentrated. The resulting residue was purified by chromatography (silica gel, ether-
hexanes, 1:9) to afford 1.86 g (60% over the two steps~ of the desired product.
c) N-hydroxy-N-(1-(1-(5-methylthien-2-yl))-2-hydroxypropyl) urea. The same
method as described for Exarnple 12 was used substituting 1-(5-methylthien-2-yl)-
propanone instead of 2-acetyl-5-methylthiophene to provide the desired product. Upon
purification by chromatography (silica gel, ether-methanol, 9:1) separation of the two
diastereomers were achieved. mp.=160-1610C; NMR (300 MHz, DMSO-d6) 0.92 (d,
3H, J = 6.5 Hz), 2.38 (s, 3H), 3.94 (m, 1H), 4.37 (d, 1H, J = 5 Hz), 4.92 (d, 1H, J - 9
Hz), 6.31 (bs, 2H), 6.61 (dd, lH, J = 2 Hz), 6.71 (d, lH, J = 3.5 Hz), 9.01 (s, lH);
MS: M+=231
Analysis Calc'd for CgHl~lN203S: C, ~6.94; H, 6.13; N, 12.17
Found: C, 47.16; H, 6.23; N, 12.15
Example 67
Prepa~tion of N'-methy]-N-hvdroxv-N-(1-(1-(2-hYdroxY~?-5-(methvlthien-2-vl?ethvl)
urea
The same method as described for Example 66 was used substitu~ing methyl
isocyanate for tlimethylsilyl isocyanate. mp.=1ûO.5-102.00C; NMR (300 MHz, DMS0-
: :: . . : : . .:, :: :: :
,. . .. . ..
WO 90/12008 PCr/US90/01488
k). 2.56 (d, 3H, J = 4.5 Hz), 3.53-3.63 (m, lH), 3.71-3.81 (rn, lH), 4.62
~d, lH,J=6Hz,J=7Hz),5.74(t,1H,J=7.~Hz),6.6û(m,1H),6.70(d,1H,J=4
Hz), 6.84 (q, lH, J = 4 Hz), 9.02 (s, lH); MS: M+=231.
Analysis Calc'd for CgH14N2O3S l/2H2O: C, 45.17; H, 6.32; N, 11.71
Found: C, 45.02; H, 6.37; N, 11.67
Example 68
Preparation~o N-hydroxv-N-(3-(1-thien-3-vl)p~openY!)urea
a) 3-tThien-2-yl)acrolein. To a solution of 2N NaOH (99 mL, 11.2 mmole) at
r~om temperature was added dropwise 3-thiophene-carboxaldehycle (3.9 mL,44.6
mmole). The solu~on was sti~red until homogeneous (10 min), cooled to Oo C and
acetaldehyde (2.7 mL, 49.0 rnmole) in 5 mL water was added slowly. After 30 min ~he
solution was extracted with ether (3xS0 mL). The ether extracts were washed with brine
and dried over MgSO4, filtered and concentrated tO yield a crude yellow oil. The material
was chromatographed ~silica gel, 30% ether/hexanes) to yield 1.65 g (27%) of pure
material and 1.91 g of a 3:1 mixture of desired product and diene aldehyde.
b) N-hydroxy-N-(3-(1-thien-3-yl)propenyl) urea . The same meullod as described
for Exarnple 45 was used substituting 3-thien-2-yl acrolein for 2-thiophenecarboxaldehyde
to provide the desired product. m.p. = lSlo C.; IH NMR (300 MHz, DMSO-d6) 9.30 (br
s, lH), 7.50 (m, lH), 7.42 (m, lH), 7.30 tm, lH), 6.56 (d, J - 15.3 Hz, lH), 6.35 (br
s, 2H), 6.09 (m, lH), 4.03 (m, 2H); MS (M+H)+ = 199, (M~NH4)+ = 216.
Analysis calc'd for C8H~oN202S: C, 48.47; H, 5.08; N,14.13. Found: C, 48.29; H,
5.11; N, 13.99.
Example 69
Pre~ara~ion o~-hvd~x~ th;en~l~l~
To a stirred solution of 10% Pd/C (0.36 g) in 50 rnL of ethyl acetate was added N-
hydroxy-N-3~ tthien-3-yl)propenyl) urea (0.26 g, 1.31 rnmole) in 50 mL of me~hanol.
The solution was hydrogenated at room ternperature under hydrogen (4 atm) for 2.5 h.
The solution was then filtered, concentrated and the cmde solid was recrys~allized from
ethyl ace~ate/hexanes to yield white c}ystalline product. m.p. = 97.5O C; IH NMR (300
MHZ7 DMSO-d6) 9.24 (br s, lH), 7.44 (m, lH), 7.13 Im, lH), 6.99 (m, 1~1), 6.23 tbr s,
2H), 3.33 tt, J = 6.6Hz, 14.6 Hz, 2H), 2.S7 (t, J = 7.3Hz, 15.3 Hz, 2H), 1.78 tm, 2H).
- , . . .:, , . .,. , : "
WO 90/12û~8 PCT/US90/01488
Analysis calc'd for CgH12N202S: C, 47.98; H, 6.04; N, 13.99. Found: C, 47.50;;H,5.83; N, 13.78.
Example 70
e~ar~Qn of N-Hv~roxv-~-Ll-t~ien-3-Ylethyl) ~g~
The same method as described for Example 43 was used except
tsimethylsilylisothiocyanate was used instead of trimes~ylsilylisocyanate. mp. =1580C
Dec., NMR (300MHz, DMS0-d6) 1.46 (3H, d, J = 7.5 Hz), 6.55 (lH, q, J=7.5 Hz),
7.10 (lH, m), 7.32 (lH, m), 7.45(1H, m~, 7.8 (2H, brs), 9.58 (lH, brs); MS:
~M+H)~ 203, ~M~NH4)~= 220
Example 71
Preparation of N-Hydrox~-~ -methylthien-2-yl) ethYlLthiourea
The same method as described for Example 12 except ~nethylsilylisothiocyanate
was used instead of tnrnethylsilylisocyanate. mp. = 155C Dec., NMR (300MHz, DMS0- -~
dfi) 1.46 (3H, d, J = 7.5 Hz), 2.38 (3H, s), 6.63 (2H, m), 6.29 (lH, m), 7.32 (lH, m),
7.42 ~lH,brs), 7.82 (lH, brs), 9.62 (lH, brs); MS: (M+H)+= 217, (M~NH4)+- 234
Example 72
_paration of N-Hv=droxv-N-(2-(1-(5-methvlthien-2-vl)~propvl) urea
a) To a stirred solution of 5-methyl-2-thiophenecarboxaldehyde (10 g, 79.4 rnmol)
in methanol was added nitroethane (6.8 mL, 95.2 rnmol9 1.2 eq), followed by a catalytic
arnount of n-butylarnine. The reaction was heated to reflux for four days. Xhe reaction
was cooled, the solvent was evaporated, and the residue was partitioned 90en~veen water and
CH2CI2. The organic layer was dried over MgS04 and evaporated. Yhe resulting residue
was puIifued by Chromatography (silica gel, 10% ethyl acetate-hexane) yielding 4.5 g of a
yellow solid.
b) To a flamed dried, nitrogen flushed 250 mL flask, equipped with a magnetic stir
bar, and a reflux condenser ae at OoC, was added BH3THF (lM, 11.2 mmol, 11.2 mL).
The product obtained in a (1.9 g, 11.2 mrnol, in 20 rnL THF) was added slowly via
syringe. The cold ba~h was removed and a catalytic amount of NaBH4 was added. After 2
hours passed 100 mL of ice-water was added followed by 20 mL of 10% HCI. The
reaction was heated to 650C for 2 hours before cooling to room ~emperanlre. The acidic
. . .. , , . .. ,.:., . ,.... ,, . :
WO 90/12008 PCI/US90/01~.'8
56
solution was washed with etner (3x5a rnL) and the hydroxylamine was liberated from the
aqueous layer with 2N NaOH. Extraction of the neut aliæd solution with ethyl acetate,
drying of the combined organic layers with MgSO4, and evaporation gave a clean, clear oil
(558 mg).
c) The fonnation of the urea was pe~fomed as in Example 12. Purification of the
produet was done using radial chromatography (4 rr~n plate, 3% methanol-methylene
chloride). 300 mg of a solid was obtained.
mp. = 96-980C, IH NMR (300 MHz, DMSO-d6) 0.98 (3H, d), 2.37 (3H, s), 2.80 (2H,
m), 4.25 (lH, m), 6.30 (2H, br s) 6.62 (2H, m), 8.98 (lH, s); MS~ H)+= 215,
(M+NH4)+= 232.
Example 73
Preparation of N-hvdroxv-N-4-(4.5.6.7-tetrahvdro-thianaphthalene) urea
To a stirred solution of 4-keto-4,5,6,7,-tetrahydrothianaphthalene (5.0 g, 32.8
nrnole) in ethanoVpyridine ( 1:1, 50 mL) was added hydroxylarMne hydrochloride (4.5 g,
65.7 rr~nole). The reaction was stirred 24 h at room temperature and diluted with 3N HCl.
The resulting solid was collected and washed thoroughly with water and dried lo give 3.86
g of the corresponding oxime as a white solid. This ;naterial was used without further
purification.
To a stirred solution of oxi ne (3.68 g, 22.7 nmole) in ethanol was added
borane.pyridine (5.27 g, 56.7 rmnole) followed by 6N HCl (25 nL) via a dropping funnel
at a rate to maintain a gende reflux. After the addition tne nixture was stirred 5 h at room
temperature and then concentrated in vacuo. I he residue was neutralized with 3N NaOH
(- pH 10~ . The resulting solid was collected by flt.ation, washed thoroughly with water
and dried to give 3.22 g of the corresponding hydroxylamine as a white solid.
To a stirred solution of the hydroxylamine from above (3.0 g, 17.7 mmole) in THF(50 mL) was added trirnethylsilylisocyanate (2.55 g, 22.16 mmole). The reaction was
stirred 2 h at room temperature and poured into saturated arnmonium chloride solution and
the m~x~,ure was extracted with ethyl ace~ate (3x20 rnL). The combined organic layer was
washed with brine, dried (MgS04), filtered and concentrated. I'he resulting solid was
recrystal~ised from ethyl acetate to give 2.25 g ~f desired product as A white so~id: mp 165-
167O C; IH NhIR (300 MHz) ~DMSO-d6) d 1.65-1.89 (m, 3H), 1.97-2.10 (m, lH), 2.68(m, 2H), 5.18 (m, 2H), 6.41 (bs, 2H), 6.74 (d, lH, J=6 Hz), 7.20 (d, lH, J=6 Hz), 8.95
;,i " ~ " ~, " ~ , :
WO 90/12û~8 PCr/US90/014X8
57
(s, lH); MS m / e 242 ( M+ NH4)+, 225 (M+H)~.
Example 74
Preparatio~o~-hydroxv~L(~brorrlo-thien-~-yl~mçthvl`lurea
To a - 78 oC stiITed solution of 3,4-dibromothiophene (10 g, 41.33 mmole) in THF(25 rr~) was added n-BuL i (45.5 mmole, 2.5 M in hexanes). The reaction was stirred S
rnin. and cannulated into a cold (-78 oC) s~red solution of DMF ~4.35 g, 62 rnmole) in
TH~ (20 mL). The reaction was allowed to stir overnight at room temperature, poured into
dilute HCl and extracted with ethyl acetate. The combined organic layers were washed with
water, dried (MgS04~ and concentrated to give a brown oil. Distillation yielded 2.31 g (29
%) of 4-bromothien-3-yl carboxaldehyde as a liquid (bp: 65o, O.Smm Hg).
To a sdrred solution of the aldehyde from above (2.31 g, 12.15 mmole) in
ethanol/pyridine ~1:1, 40 rnL) was added hydroxylamine hydrochloride (1.67 g, 24.32
snrnole). The reacdon was s~irred 2 h at room temperature, concentrated and diluted with
3N HCl. The mixture was extracted with ethyl acetate (3x75 rnL) and dried (MgS04).
Concentration gave an oil that crystallised upon addition of ethyl acetate / hexane. The
crystals were collected to give 0.68 g of the corTesponding oxime.
To a sdu~ed solution of oxirne from above (0.65 g, 3.17 mmole) in ethanol was
added borane.pyridine (0.59 g, 6.34 IIamole) followed by 6N HCl (7 rnL) via a dropping
funnel at a rate to maintain a gentle reflux. After the addition the mixture was s~rred5 h at
room temperature and then concentrated in vacuo. The residue was neutralized with 3N
NaOH (~ pH 10) and ex~acted with ethyl acetate. The combined organic layers werewashed with water, dried (MgSO4) and coneen~ated to give 0.68 g of the co~esponding
hydroxylan~ine.
To a sti~d solution of the hydroxylarnine from above (0.54 g, 2.22 rnmole) in
T~IF (25 mL) was added trimethylsilylisocyanate (0.45 g, 3.33 mrnole). The reaction was
st~ned 2 h at room temperature and poured into saturated ammonium c'nloride solution and
the mixture was extracted with ethyl acetate (3x20 mL). The organic layer was washed
with brine, dTied ~MgSO4), filtered and concentrated. The resulting solid was purifled by
chromatography (5 % MeOH / CH2CI2)to give 0.32 g of the desired product as a white
solid: mp 134-135.50 C; lH NMR (300 MHz) (DMSO-d6) d 4.63 (s, 2H), 6.48 (bs, 2H),
7.02 (d, 1H, J= 6 Hz), 7.58 (d, lH, J= 6 Hz), 9.53 (s, lH); MS m / e 268 ( M~
NH4)+, 251 (M+H)+.
'' : ''', ' " ., "`........ ' " '.".. " ~'' , ~ 'i'~: '.'
: : . - . : . . ..
WO 90~12008 PCI/US90/01488
7.~
Example 75
Pleyaratic~n of N-hYdl:oxv~ thiçn:3-Yl)~ en-2-~lh~.
In a 100 mL round bottom flask equipped with a dropping funnel under an argon
atmosphere were dissolved 1-(thien-3-yl)l-hydroxy-2-propene (1.01 g, 7.20 mmole),
triphenylphosphine (1.82 g, 9.0 mmole), and N,O-bis benzyloxycarbonyl hydroxylamine
(2.38 g, 7.921 rnmole) in T~ (50 rslL). To this stirred cooled (-lSo C) solution was
added slowly over a period of 30 min a l~IF (15 mL) solution of
diisopropylazodicarboxylate (2.36 g, 9.00 mmole) via a dropping funnel. After the
addition was complete the reaction was stirred an additional 15 min and then concentrated
in vacuo. The residue was dissolved in 50% ethyl acetate / hexane (-10 mL) and loaded
onto a short silica gel column and eluted l,vith 33% ethyl acetate / hexane. The fractions
containing the product were combined and reconcentrated. The residue was loaded onto
another flash column and eluted with 5% ethyl acetate / hexane to give 0.97 g of the di(',BZ
hydroxylarnine derivative.
To a 0 oC stilred solution of the diCbz derivative (3.10 g, 7.3 mrnole) in CH2C12
(150 mL) was added trimethylsilyl iodide (4.39 g, 22 mmole) via syringe. The ice bath
was removed and the reaction allowed to s~r for 2 h at room temperature. The reaction was
then poured into ice / sodiurn bicarbonate and the layers separated. The aqueous layer was
washed with CH2Cl2 (3x 50 mL); the organic layers were combined, washed with water,
dr~ed(MgSO4) and concentrated. The residue was purified by flash column
chromotography; eluting f~st with CH2Cl2 (to remove benzyliodide) then 5% MeOH /CH2CI2 to afford 0.61 g of the corresponding hydroxylamine as a brown solid
To a stirred solution of hydroxylamine (0.6 g, 3.87 mmole) in THF (10 mL) was
added trimethylisocyanate (0.56 g, 4.87 mrnole). The reaction was stirred 2 h at room
temperature and 5 drops of water were added. The mixture was concentrated to dryness
and ~he residue was ~imrated with ether to provide a tan solid which was collected by
filtration and washed with ether. 'I he resul~ng solid was recrystallised from ethyl acetate /
hexanes to give 0.190 g of the desired product. mp 165-167O C; IH NMR (300 MHz)
(DMSO-d6) d 5.20-5.35 (m, 2H), 5.74 (d, lH, J=6Hz ), S.08-6.22 (m, lH), 6.40 ~bs,
2H), 7.03 (dd, lH), 7.28 (m, lH), 7.45 (dd, lH), 9.20 (s, lH); MS m / e 216 ( M+NH4)+, 199 (M+H)+, 123.
:, . ............................... ., , . :
. .
.. ;. .. . . .
WO 90~2008 PCrtUS90/0148X
59
Example 76
Pre~a~non nf N-hvdroxv-N-(k(5-(2-~hien-2-y!~h~nvl')~hien-2-yl)çth,Yl~L~a
The desired material is prepared in a sirnilar manner as Examlple 58 substituting
benzyldiethylphosphonate with thien-2-ylrnethyldiethyl-phosphonate.
Example 77
Preparation QN-h,v~xv-N-(1-(5-(2-~vnd-2-vlethenyl)thien-2-yl)~,th,vl)-ur~a
The desired material is prepared in a sirnilar manner as Example 58 subs~tuting
benzyldiethylphosphonate with pyrid-2-ylmethyldiethyl-phosphonate.
Example 78
PreyaratiQn of N-hvdmxv-N-f,1:~5-L2 th~en-3-vl~thenvl)thien-2-vl~ethvl)-urça
The desired material is prepared in a similar manner as Example 58 substituting
benzyldiethylphosphonate with thien-3-ylmethyldiethylphos-phonate.
Example 79
Preparation of N-hvdroxv-N-( I - (5-(4-çhlorophenylethen-2-Yl)thien-2~1-ethy~e~
The desired material is prepared in a sirnilar manner as Exarnple 58 substituting
benzyldiethylphosphonate with 4-chlorobenzyldie~hylphos-phonate.
Example 80
PreparatiQn of N-hydroxY-N-(2-(l-thien-~vl,~?vl)urea
The desired matenal is prepared in a similar m~ner as Example 72 substituting 5-methylthien-2-yl carboxaldehyde with thien-3-yl carbox-aldehyde.
Example 81
Prepa~tion of N-h~cdroxY-N-(2-(l-thien-2-vl)propYl)urea
The desired matenal is prepared in a similar manner as Example 72 substituting S-
methylthien-2-yl carboxaldehyde with thien-2-yl carboxaldehyde.
Example 82
The desired material is prepared in a similar manner as Example 72 subs~ituting 5-
methylthien-2-yl carboxaldehyde with (5-pyrid-2-yl)thien-3-yl carboxaldehyde.
~, , : . ,; ; . .. .: , , :
WO 90/12008 PCr/US90/~1~88
Example 83
Pre~aratiQ~Qf N-hydroxy-N-(2-(L-(~-~henvlethen-2-vl)thien-2^yl)~rQ~!~Eç
The desired rnaterial is prepared in a sirnilar manner as Example 72 substituting S-
methylthien-2-yl carboxaldehyde with (5-phenylethen-2-yl)thien-2-yl carboxaldehyde.
Example 84
~enaratiQn of N-hvcirox~-N-(~-(1-(5-'~e~zvlthiell-2-vllprol2yl~
The desired matenal is prepared in a similar manner as Example 72 substituting 5-
methylthien-2-yl carboxaldehyde with 5-'~en~ylthien-3-yl carboxaldehyde.
Example 85
Preparati~7n of N-~vdr~xv-N-(thiçn-~-yl~methvl urça ~otas~iurn salt
The material prepared as in example 44 is dissolved in tetrahydrofuran and one
equivalent of potassium hydride is added. After hydrogen evolution ceases, the solvent is
removed in vacuo to yield the desired product.
Example 86
epaT~ion of N-hvdroxv-N-(3-(1-thie~-3-vl)proD~ urea potassium salt
The material prepared as in example 68 is dissolved in telrahydrofuran and one
equivalent of potassium hydride is added. After hydrogen evolution ceases, the solvent is
removed in vacuo to yield the desired product.
Example 87
Preparation of N-ethoxvcarbonyloxY-N-(thien-3-vl)methv urea
The material prepared as in Example 44 is dissolved in dichloromethane and treated
with triethylamine and ethoxycarbonylchloride. Aqueous workup and evaporation of the
organic extract provides the desired product.
Example 88
Preparation of N-ethoxvcarbonYloxv-N-(3-~1-thien-3-vl)propenvl~ urea
The material prepared as in Exarnple 68 is dissolved in dichloromethane and treated
with triethylamine and ethoxycarbonylchloride. Aqueous workup and e~raporalion of the
organic extract provides the des~red product.
..
:: ,. : , , . ~
:~ . . . . . . .
: ~: : . ~ - ,,
WO 90/1~008 Pcr~us9o/ol488
61
Example 89
The material prepared as in Example 44 is dissolved in dichlo~romethane and treated
with trimethylsilyl-~midazole. Evaporation of mixture and addition of ether precipitates
imidazole which is filtered. Evaporation of the ether provides the desired product.
Example 90
P~a~atio~of ~-HvdrQ~y:N-(thien-3-v~me~hvl-N'-~henyl urea
The desired compound is prepared by the same method as descIibed for Example 44
except using phenylisocyanate instead of tTimethylsilylisocyanate. 1
Example 91
Preparation of N~N'-dihydroxv-N-(thien-3-~!!)methyl-N'-methyl urça
The desired material is prepared in a similar rnanner as descTibed for Example 10,
except using thien-3-yl carboxyaldehyde instead of 2-acetonaphthone in part a. and
methylhydroxylamine hydrochloride instead of hydroxylamine hydrochloride in part b.
Example 92
~e~ara~i~n of N.N'-dihyd~xv-N~ t~e~yl~etbYI-~-m~thyl ~rea
The desired rnaterial is prepared in a similar manner as described for Example 10,
except using 3-acetylthiophene instead of 2-acetonaphthone in part a. and
me~hylhydroxylamine hydrochloride instead of hydroxylamine hydrochloride in part b.
Example 93
PreQaration of N.N'-dihydroxY-N-1-(5-phenvlthien-2-~l)ethyl urea
The desired mateIial is pIepared in a similar manner as descnbed for Example 10,except using 2-acety1-5-phenylthiophene instead of 2-acetonaphthone in part a.
Example 94
Preparation of N~HYdroxy-N-1-(6-methoxynaphthalen-2-vl)ethvl urea
The desired material is p}epared in a similar manner as described for Example 1 except
using ~methoxy-2-acetonaphthone instead of acetophenone.
.. .. . .~.
.: ,,- . ;
... ..
WO 90/12008 pcr/usso/o1488
62
Example 95
~naranQn of ~-HYdroxy:N-(Ç-rne~h~xyn~hthal~n-2:Y12methYI ~rea
The des~red material is prepared in a similar manner as descnbed for Example 1 except
using 6-methoxy-naphthalen-2-yl carboxyaldehyde instead of acetophenone.
Example 96
~reparaion of N-H~roxv-N-3-(1-(6-methoxYna~h~halen-2-vl)nT~Den~rea
The desired matenal is prepared in a similar manner as described for Exarnple 68except using ~methoxynaphthalen-2-yl carboxyaldehyde instead of 3-thiophene
carboxyaldehyde.
Example 97
Preparation of N-HYdrox~-N-1-(4-bromo~envl)ethylurea
To a solution of 3.90 g (20 mmol) of p-bromoacetophenone in 40 rnL of methanol
under nitrogen at room was added a solution of 1.64 g (23.6 rnmol) of hydroxylarnine
hydrochloride and 3.34 g (24.6 mrnol) of sodium acetate ~ihydrate in 20 mL of water.
After 2 h, evaporate the methanol, add more water, extract with 3 x 35 mL of ether, dry
over magnesium sul~ate, ISlter and evaporate to give 4.27 g of a mixture of oxime geornetric
isomers. IR (CDC13) 3580, 33û0, 1590, 1490, 1010, 825 ~m~ H NMR (CDC13) 2.28
(s, 3), 7.49 (m, 4) ppm; mass spectrum mle (rel intensity) 231 and 233 (35, M++NH4~,
214 and 216 (lO0, M~+H).
To a soluhon of 2.9 g (13.6 mmol) of the crude hydroxylamine from above in 70 mLof ethanol was added 3.0 mL (29.7 mmol) of borane pyridine complex. After stirring
under nitrogen at ~om temperature for 30 min there was added 54 mL (32.7 mmol) of S N
HCl and the resulting solution was allowed to stir ovemight. After 18 h the solution was
basified with 1 N KOH, diluted with brine, extracted with 2 x 100 rnL of methylene
chloried, dried over magnesium sulfate, filtered, evaporated, and crystallized. Column
chromatography with 4/1 hexane~ether elution gave 1.75 g of the desired hydroxylamine.
IR (CDCI3) 3580, 3280, 2980, 1595, 1487 cm~ H NMR (CDC13) 1.34 td, 3, J = 7 Hz),4.08(q, 1,J=7Hz),5.45(brs,2),7.21 (d,2,J=8Hz~,7.46(d,2,J=8Hz)ppm;
mass spectrum mle (rel intensity) 233 and 235 (12, M++NH4), 216 and 218 (100, M++H),
200 and 202 (40, M+-Me), 183 and 185 (60), 104 (85).
,. , . . ,, ~ . ~ :
WO 90/12008 P~r/US90/01488
2 ~
63
To a solution of 1.7 g (7.9 mrnol) of the hydroxylarnine from above in 40 rnL of drS
THF was added under nitrogen at room temperature 1.3 mL (9.6 mmol) of 85%
tnmethylsilylisocyanate. After 2 h there was added 25 mL of saturated aqueous ammonium
chloride and after stirring for 30 rnin the reaction was diluted with 25 mL of w~ter,
extracted with 3 x S0 mL of ethyl acetate, dried over magnesium sulfate, filtered,
evaporated, and recrystallized from ether (using a small amount of THF and acetonitrile as
cosolvent) to give 0.30 g of the title compound. mp 138-40C; IR (CDC13) 3445, 3240,
1660, 1575, 1490, 1430 cm-l; lH NMR (d6 Me2SO) 1.40 (d, 3, J = 7 Hz), ~.26 (q, 1, J =
7 Hz~7 6.31 ~br s, 2), 7.29 (d, 2, J = 8 Hz), 7.49 (d, 2, J = 8 Hz), 9.1U (s, 1) ppm; mass
spectrum mle (rel intensity) 276 and 278 (70, M+~NH4), 259 and 261 (100, M+~H), 243
and 245 (18), 200 ~90). Analysis calculated for CgHIIBrN202: C, 41.72, H, 4.28, N,
10.81; found: C, 41.67, H, 4.31, N, 10.77.
Example 98
Preparation of N-Hvdroxv-N-1-(4-bromophenvl)ethvl-N'-meth~Ll~ea.
The compound was prepared using the method of Exarnple 97 except for the
substitution of methylisocyanate for trimethylsilylisocyanate. mp 129-30'C; IR (CDCI3)
3400, 3200, 1650, 1600, 1535 cm-l; IH NMR (d6 Me2SO) 1.39 (d, 3, J = 7 Hz), 2.57 (d,
3,J=4Hz),5.22(q,1,J=7Hz),6.82(brs,1),7.27(d,2,J=8Hz),7.48(d,2,J=8
Hz), 9.00 (s, 1) ppm; mass spectrum mle (rel intensity) 2.90 and 2.92 (70, M++N4), 274
and 276 (100, M++NH4-O), 273 and 275 (35, M~H), 257 and 259 (80, M+-Me).
Analysis calculated for CloHI3BrN2O2: C, 43.98, H, 4.80, N, 10.26; found: C, 43.98,
H, 7.78, N, 10.26.
Example 99
PreR~tiQns~-HYdrQxv-N~ 4-br~ henyl)eIhy~ ~-hydrQxyethvl~rea~
The compound was prepared using the method of Example 97 substituting ethyl
isocyanatoacetate for trimethylsilyl isocyanate to provide 1.7 g of the ethyl ester. mp 131-
5 C; IR (CDC13) 3690, 3530, 3440, 2980, 1740, 1670, 1520, 1210 cm~ H NMR (d6
Me2SO) 1.19 (t, 3, J = 7 Hz), 1.90 (d, 3, J = 7 Hz), 3.70 (dd, 1, J = 6, 18 Hz), 3.78 (dd,
1, J = 6, 18 Hz), 4.06 (q, 2, J = 7 Hz), 5.23 (q, 1, J = 7 Hz), 7.25 (t, 1, J = 6 Hz), 7.29
(d, 2, J = 9 Hz) 7.48 (d, 2, J = 9 Hz) 9.27 (s, 1) ppm; mass spec~um mle (rel in~ensity)
362 and 364 (10, M++NH4), 345 and 347 (100, M++H), 200 (25), 183 and 185 (22), 163
. . ,: :
" : ~
...: ,....
WO 90/12008 PCr/US90/01488
~, h4
(18), 104 (85).
To a solution of 1.7 g t4.9 mmol) of the ester frorn above in 10 mL of THF at room
temperatu~e under ni~ogen was added 3.5 mL (7 rnrnol) of 2 M lithium borohydride in
T~. After 3 h the rea~ion was poured into 25 mL of saturated amrnonium chloride
soludon, extracted with 3 x 50 mL of methylene chloride, dried of ver magnesium sulfate,
filtered, evaporated and recrystall~zed from THF/hexane to give 1.0 g of the desired
compound. mp 117-9-C; IR (KBr) 3320, 2925, 1625, 1525 cm-l; lH NMR (d6 Me2SO)
1.38 (d, 3, J = 7 Hz), 3.08 tm, 4), 4.63 tm. 1), 5.23 (q, 1, J = 7 Hz), 6.80 (m, 1), 7.28
(d, 2, J = 8 Hz), 7.49 (d, 2, J = 8 Hz), 9.10 tbr s, 1) ppm; mass spectrum mle (rel
intensity) 303 and 305 (50, M++NH4), 287 and 289 (7), 216 and 218 (18), 200 (28), 183
and 185 (22), 145 (21), 105 (100). Analysis calculated for CIlHlsBrN2o2: C, 43.58, H,
4.99, N, 9.24; found: C, 44.30, H, 5.13, N, 9.05.
Example 100
Preparation of N-H~roxv-N-4-bromobenzvlurea.
The compound was prepared using the method of Exarnple 97 substituting p-
bromobenzal~ehyde forp-bromoacetophenone. mp 157-9-C; IR (KBr) 3420,3140, 2880,
1645, 1545 cm-l; IH NMR (d6 Me2SO) 4.48 (s, 2), 6.38 (br s, 2), 7.23 (d, 2, J = 8 Hz)
7.50 (d, 2, ~ = 8 Hz) 9.38 (s, 1) ppm; mass spectrum mle (rel intensity) 262 and 264 (35,
M++NH4), 245 and 247 (100, M++H), 229 ~32), 186 (40), 169 and 171 (18), 106 (30).
Analysis calculated for CgHgBrN2O2: C, 39.21, H, 3.70, N, 11.43; found: C, 39.48, H,
3.69, N, 11.34.
Examlple 101
eparation of N-HvdroxY-N-4-br~mobenzvl-N'-methvl urea
The compound was prepared using the method of Exarnple 97 substituting p-
bromobenzaldehyde forp-bromoacetophenone, and substituting methyl isocyanate fortrimethylsilyl isocyanate. mp 165-7-C; IR tCDCl3) 3480, 3180, 2900, 1660, 1620, 1580
cm l; lH NMR (ds Me2SO) 2.61 (d, 3, f = 5 Hz), 4.47 (s, 2), 6.90 (q, 1, J = S Hz), 7.22
(d, 2, J = 8 Hz), 7.50 (d, 2, J = 8 Hz), 9.30 (s, 1) ppm; mass spectrum mle (rel intensity)
276 and 278 (20, M++NH4), 259 and 261 (100, M++H), 243 (60), 241 (45~, 186 (35),106 (40). Analysis calculated for CgHl1BrN2O2: C, 41.72, H, 7,28, N, 10.81; found:
C, 41.77, H, 4.21, N, 10.79.
.. . . .
:. .
.. , , ., . ~ ..
~ . .
WO 90/~2008 PCr/US90/01488
~ ~S ~
Example 102
Preparation of N-~ydrQxv-~:LI-~4-bromQ~h~nYl)~ro~ u~ea
The compound was prepared us~ng the method of Example 97 substituting 4-bromo^
propiophenone for 4-bromoacetophenone. mp 139-41UC; IR (KBr) 3490,3325, 3160,
1640, 1560, 1485 cm~ H NMR (d6 Me2SO) 0.88 (t, 3, J = 7 Elz), 1.70 - 2.00 (m, 2),
4.97 (dd, 1, J = 6, 9 Hz), 6.25 (s, 2), 7.27 (d, 2, J = 8 ~), 7.46 (d, 2, J = 8 Hz), 9.lO
(s, 1) ppm; mass spectrum mle (rel intensity) 290 and 292 (20, M++NH4), 273 and 275
(100, M+~H), 257 (10),214 (15), 197 and 199 (15). Analysis calculated for
CloHl3BrN2O2: C, 43.97, H, 4.80, N, 10.26; found: C, 43.96, H, 4.84, N, 10.18.
Example 103
eparation of N-HYdroxv N-(1-(4-bromophenvl)propyl)-N'-methvlurea
The compound was prepared using the method of Example 97 substituting p-
bromopropiophenone forp-bromoacetophenone, and subsdtuting methyl isocyanate formmethylsilyl isocyanate. mp 110-2 C; IR t~CBr) 3400, 3170, 1640, 1620, 1535 cm-l; lH
NMR (d6 Me2SO) 0.87 (t, 3, J = 7 Hz), 1.70 - 2.00 (m, 2), 2.55 (d, 3, J = 7 Hz), 4.94
(dd, 1,J=6,9Hz),6.79(q,1,J=7Hz),7.25(d,2,J=8Hz),7.46(d,2,J=8Hz),
9.00 (s, 1) ppm; mass spectrum mle (rel intensity) 304 and 306 (10, M++NH4), 287 and
289 (100, M++H), 271 (14). Analysis calculated for CIlHl5BrN2O2: C, 46.01, H, 5.27,
N, 9.76; found: C, 45.92, H, 5.16, N, 9.76.
Example 104
Preparation of N-Hvdroxv-N-fl-(2.4-difluorophenvU ethYI)-N'-methvlurea
The compound was prepared using the method of Example 97 substituting 2,~
difluoroacetophenone forp-bromoacetophenone, and substituting methyl isocyanate for
tnmethylsilyl isocyanate. mp 125-34-C; IR (KBr) 3460, 3140, 1635, 1535, l5Q0 cm-l;
lH NMR (d6 Me2SO) 1.38 (d, 3, J = 7 Hz), 2.58 (d, 3, J = 4.5 Hz), 5.49 (q, 1, J = 7
Hz), 6.90 (q, 1, J = 4.5 Hz), 7.03 (ddt, 1, J = 1,2,9 Hz), 7.14 (dt, 1, J = 2, 9 Hz), 7.54
(dt, 1, J - 6, 9 Hz), 9.10 (s, 1) ppm; mass speclrum mle (rel intensity) 248 (100,
M++N~), 231 ~50, M++H~, 215 (20), 213 ~18). Analysis calculated for C~ 2F2N2O2:C, 52.17, H, 5.25, N, 12.17; found: C, 51.81, H, 5.29, 12.21.
WO 90/12~08 PCr/lUS90/~1488
.. .
~ Example 10S
Pr~Far~tinn of N-H,Y.droxv-N-(I-t4-t2-~h~nvlethvnYI~ yh~,vl)ethvl
The compound was prepared using the method of Example 97 substituting 4-(2-
phenylethynyl)acetophenone forp-bromoacetophenone. mp 144-6C; IR (KBr) 3450,
1650 cm-l; IH NMR (d6 Me2SO) 1.42 (d, 3, J = 7 Hz), 5.30 ~q, 1, J = 7 Hz), 6.33 (s, 2),
7.30 - 7.60 (m, 9), 9.13 (s, 1) ppm; rnass spectrum mle (rel intensity) 298 (20, M~+NH4),
281 (100, M++H), 263 (12), 205 (75). Analysis calculated for Cl7Hl6N2O2: C, 72.84,
H, 5.75, N, 10.00; found: C, 72.49, H, 5.73, N, 9.99.
Example 106
Preparation of N-Hvdroxv-N-(1-(4-(2-phenvlethynvl) phenvl)ethYI)-N'-methvl urea
The compound was prepared using the method of Example 97 substituting 4-(2-
phenylethynyl)acetophenone forp-bromoacetophenone, and substituting methyl isocyanate
for trimethylsilyl isocyanate. mp 138-41-C; IR (KBr) 3400, 3160, 2880, 1630, 1535 cm
l; IH NMR td6 Me2SO) 1.42 (d, 3, J = 7 Hz), 2.60 (d, 3, J = S Hz), 5.29 (q, 1, J = 7
Hz), 6.85 (q, 1, J = S Hz), 7.30 - 7.60 (m, 9), 9.02 (s, 1) ppm; mass spectrum mle (rel
intensity) 312 (10, M~+NH4), 295 (100, M++H), 279 (8), 277 (8), 205 (45). Analysis
calculated for C~8HIgN2O2: C, 73.44, H, 6.16, N, 9.52; found: C, 73.14, H, 6.18,9.57.
Example 107
Preparation of N-Hvdro~-N-~I-t4-chlorophenvl~ethyl~urea
The compound was prepared using the method of Example 97 substituting p-
chloroacetophenone forp-bromoacetophenone. mp 125-8 C; :[R (KBr) 3480, 3300, 2900,
1660, 1630, 1490 cm-l; IH NMR (d6 Me2SO) 1.39 (d, 3, J = 7 Hz), 5.27 (q, 1, J = 7
H~), 6.31 (br s, 2,~, 7.33 (s, 4), 9.10 (s, 1) ppm; mass spectrum mle (rel intensity) 232
(83, M~+NH4), 215 (100, M++H), 199 (20), 197 (15), 156 (38), 154 (25). Analysis
calculated for CgH11ClN2O2: C, 50.36, H, 5.17, N, 13.05; found: C, 50.39, H, 5.18,
N, 13.02.
Example 10S
Preparation of N-HvdrQxv-N-(1-(4-chlorophenvl)ethvl)-N'-methvl urea
The compound was prepared using the method of Exarnple 97 substituting p-
chloroacetophenone forp-bromoacetophenone, and subs~tuting methyl isocyanate for
~ ,~ ~, . . . . . . .
,. ~: ., . :
.
WO 90/12008 PCr/US90/0148
67
trimethylsilyl isocyanate. mp 117-20 C; IR (KBr) 3400, 3200, 1630, 1530 cm~ H
NMR (d6 Me2SO) 1.38 (d, 3, J = 7 ~)t 2.58 (br s, 3), 5.23 (q, 1, J = 7 Hz), 6.3~ (br s,
1), 7.32 (s, 4), 9.00 (s, 1) ppm; mass spectrum m/e (rel intensity) 248 (35, M~+NH4),
246 (100, M++NH4), 2~9 (8, M++H). Analysis calculated for CloHI3ClN2O~: C, 52.52,
H, 5.73, N, 12.25; found: C, 51.87, H, ~.40, N, 12.11.
Example lQ9
Preparation of N-HvdroxY-N~ (4-fluorophenvl~ethyl) urea
The compound was prepared using the method of Example 97 subsatutingp-
Sluoroacetophenone forp-bromoacetophenone. mp 127-9-C; IR (KBr) 3480, 3345,3120,2880, 1620, lS10, 122S cm-l; lH NMR (d6 Me2SO) 1.40 (d, 3, J = 7 Hz), 5.28 (q, 1, J =
7 Hz), 6.31 (s, 2), 7.11 (t, 2, J = 9 Hz), 7.37 (dd, 2, J = 6, 9 Hz), 9.07 (s,l) ppm; mass
spectrum mle (rel intensity) 216 (90, M++NH4), 199 (100, M++H), 183 (14), 181 (11),
156 (8), 140 (18), 138 (19), 1~3 (7). Analysis calculated for CgHllFN2O2: C, 54.S4, H,
5.59, N, 14.13; found: C, 54.40, H, 5.58, N, 14.12.
Example 110
Preparation of N-HYdroxy:l~-fl-(4-fluorophen~!~ethvl)-N'-methYI urea
The compound was prepared using the method of Example 97 substituting p-
fluoroacetophenone for p-bromoacetophenone, and substituting methyl isocyanate for
trimethylsilyl isocyanate. mp 130-3-C; IR (KBr) 3380, 3250, 1645, 1510 cm-l; IH NMR
(d6 Me2SO) 1.39 (d, 3, J = 7 Hz), 2.55 (br s, 3), 5.25 (q, 1, J = 7 Hz), 6.82 (br s, 1),
7.10 (br t, 2, J = 8 Hz), 7.35 (br t, 2, J = 6 Hz)7 8.96 (br s, 1) ppm; mass spectrum mle
(rel intensity) 230 (100, M++NH4) 214 (38), 213 (8, M+~H), 197 (S), 157 (8), lSS (3),
138 (11). Analysis calculated for CloHI3FN2O2: C, 56.60, H, 6.17, N, 13.20; found:
C, 56.04, H, 5.84, N, 12.97.
Example llI
Preparation of N-HvdroxY-N-tl-(4-trifluoromethvlphenyl) ethvl) urea
The compound was prepared using the method of Example 97 subs~tu~ing p-
trifluoromethylacetophenone forp-bromoacetophenone. mp 133-5'C; IR (KBr) 3470,
3280, 2900, 1670, 1635, 1330, 1120 cm-l; lH NMR (d6 Me2SO) 1.43 (d, 3, J = 7 Hz),
5.36 (q, 1, J = 7 Hz), 6.38 (s, 2), 7.SS (d, 2, J = 8 Hz), 7.66 (d, 2, J = 8 Hz), 9.19 (s, 1)
-,; . ., . ~ . .
WO 90/12008 PCr/VS90/01488
'?.'~3~
ppm; mass spectrum mle ~rel intensity) 266 (100, M++NH~), 249 (60, M++H), 233 (13),
231 (20), 207 (18), 206 (17), 190 (40), 188 (35). Analysis calculated for CloHllF3N2o2:
C, 48.39, H, 4.47, N, 11.29; found: C, 48.44, H, 4.50, N, 11.31.
Example 112
Preparation of N-Hvdroxy-N-(1-(4-trifluoromethy!phenvl~ ethvl)-N'-methvl urea
The compound was prepared using the method of Example 97 substituting p-
trifluoromethylacetophenone ~orp-bromoacetophenone, and subs~ituting methyl isocyana~e
for trimethylsilyl isocyanate. mp 124-S-C; IR (KBr) 3420, 3380, 3240, 2900, 1660,
1605, 1535, 1325, 1334, 1170, 1130, 1120 1070 cm-l; IH NMR (d6 Me2SC)) 1.42 (d, 3,
J=7Hz),2.59 (d,3,J=5Hz),5.33 (q, 1,J=7Hz),6.90(q, 1,J=5Hz),7.55 (d,2,
J = 9 Hz), 7.66 (d, 2, J = 9 Hz), 9.10 (s, 1) ppm; mass spectrum mle ~rel intensity) 280
(60, M++NH4), 263 (100, M+*H), 247 (38), 245 (50), 190 (25), 188 (30). Analys;s
calculated for CllHl3F3N2O2: C, 50.39, H, S.00, 10.68; found: C, 50.21, H, 4.91, N,
10.65.
Example 113
Preparahon of N-Hydroxv-N-(1-~4-methvlphenvl)ethylLurea
The compound was prepared using the method of Example 97 substituting p-
methylacetophenone forp-bromoacetophenone. mp 134-5C; IR ~KBr) 3460, 3180, 2880,
1660, 1570, 1480 cm~ H NMR (d6 Me2SO) 1.38 (d, 3, J = 7 Hz), 2.26 (s, 3), 5.25, (q,
1, J = 7 Hz), 6.27 (s, 2), 7.09 (d, 2, J = 8 Hz), 7.21 (d, 2, J = 8 Hz), 9.00 (s, 1) ppm;
mass spectrum mle (rel intensity) 212 (40, M++NH4), l9S (100, M++H), 179 (18), 177
(13), 136 (30), 134 (43), 119 (26). Analysis calculated for CloHI4N2O2: C, 61.84, H,
7.26, N, 14.42.
Example 114
Preparation of N-Hvdroxy-N-~1-(3-bromo-4-fluorophenvl)ethyl)-N'-methvl urea
The compound was prepared using the method of Example 97 substituting 3-bromo-4-fluoroacetophenone forp-bromoacetophenone, and substituting methyl isocyanate for
tr~nethylsilyl isocyanate. mp 137-8C; IR (KBr) 3370, 3240, 1640, 1530, 1495 cm-l; IH
NMR (d6 Me2SO) 1.38 (d, 3, J = 7 Hz), 2.57 (d, 3, J = 4.S Hz), 5.26 (q, 1, J = 7 Hz),
6.91 (q, 1, J = 4.5 Hz), 7.30 (t, 1, J = 8 Hz), 7.33 (ddt, 1, J = 2, S, 9 Hz), 7.61 (dd, 1, J
. , , . . i ., , ",
W~ 90/12008 PCr/US90/014X8
.2 ~ 3 ~1
69
= 2, 7 Hz), 9.09 (s, 1) ppm; mass spectrum mle (rel intensity) 308 and 310 (43,
Mt~ ), 294 (85), 292 (100), 275 (60). Analysis calculated for C~ 2BrFN2O~: C,41.26, H, 4.15, N, 9.62; found: C, 41.46, H, 4.12, N, 9.68.
Example 11~
Preparation of N-HvdroxY-N-f 1-(3-brom~methvlphçnyl~ethv!)-N'-methyl urea
The compound was prepared using the method of Example 97 substituting 3-bromo-4-methylace~ophenone forp-bromoacetophenone, and subsamting methyl isocyanate for
trimethylsilyl isocyanate. mp 107-8-C; IR (KBr) 3460, 3180, 1640, 1515 cm-l; lH NMR
(d6 Me2SO) 1.37 (d, 3, J = 7 Hz), 2.31 (s, 3), ~.57 (d, 3, J = 4 Hz), 5.22 (q, 1, J = 7
Hz), 6.87 (q, 1, J = 4 Hz), 7.22 (dd, 1, J = }.S, 8 Hz), 7.27 (d, 1, J = 8 Hz), 750 (cl, 1,
J = 1.5 Hz), 9.û4 (s, 1) ppm; mass spectrum mle (rel intensity) 304 and 306 tlOO,
M++NH4),288 and 290 (35), 287 and 289 (38, M+~H), 271 (35). Analysis calculated for
CllHlsBrN2o2: C, 46.01, H, 5.26, N, 9.75; found: C, 45.29, H, 5.19, N, 9.58.
Example 116
Preparation of N-Hvdrox -N-(1-(4-methoxYphenyl)ethvl) urea
The compound was prepared using the method of Exarnple 97 substinlting p-
methoxyacetophenone forp-bromoacetophenone. mp 132-4-C; IR (KBr) 3440, 3200,
1660, 1580, lS20, 1455, 1445, 1245 cm~ H NMR (d6 Me2SO) 1.37 (d, 3, J = 7 Hz),
3.73 (s,3),5.24(q, 1,J=7Hz),6.25(s,2),6.85(d,2,J=8Hz),7.25(d,2,J=8
Hz), 8.98 (s, 1) ppm; mass spectrum mle (rel intensity) 228 (100, M++N~), 212 (36),
211 (35, M~+H), 135 (12). Analysis calculated for CloHl4N203: C, 57.13, H, 6.71, N,
13.32; found: C, 57.29, H, 6.71, N, 13.41.
Example 117
Prçparation of N-~vdroxY-N-~1-(4-methoxyphenyl)ethvl)-N'-methYI urea
The compound was prepared using the method of Example 97 substituting p- .. ~`?
methoxyacetophenone forp-bromoacetophenone, and substitut;ng methyl isocyanate for
trimethylsilyl isocyanate. mp 102.5-4-C; IR (CDC13) 3540,3460, 3200, 2940, 1670,
151~, 1250 cm~ H NMR (d6 Me2SO) 1.36 (d, 3, J - 7 Hz), 2.56 (d, 3, J = 4 Hz), 5.22
(q, 1, J = 7 Hz), 6.78 (q, 1, J = 4 Hz), 6.84 (d, 2, J = 8 Hz), 7.24 (d, 2, J = 8 Hz), 8.88
(s, 1) ppm; mass spectrum m/e (rel intensity) 242 (100), M+~NH4), 226 (100), 225 (70,
,~
; ,, : - ~ ~ .... : . -. . . .
WO 90/120~8 P~r/uS9O/~14
M++H), 209 (75), 207 (100). Analysis calculated for C"H~6N2O3: C, 58.91, H, 7.19,
N, 12.49; found: C, 58.91, H, 7.18, N, 12.57.
Example 118
Preparation of N-Hvdroxy-N-(1-(4phenoxypIIenvl~ethYl) urea
A solution of p-phenoxybromobenzene (4.98 g, 20 ~nol) at -780C in dly ~IF (50
rnL) was treated under nitrogen with n-BuLi ~8 mL, 2.5M in hexanes, 20 rnrnol) and the
rnixnlre was s~ed for 30 rnin. A solunon of nio one (prepared by modification of the
method reported in Ac~a. Chim. Aca~l. Sc~. ~ung. 1958, 14, 333, by the treatment of 5-
hydroxypentanal oxime (3.5 g, 30 mrnol3 with acetaldehyde (3.4 mL, 60 mrnol) in the
presence of CaCl2 (17.4 g, 130 rmnol) at 0C in dichloromethane for 6 h, filtered, and
dichloromethane evapo~ated in vacuo at O C) in l~IF precooled to 0C (50 mL) was added
to the cold anion (-78'C) and stirred for 30 min after removal of the cold bath. Ethanol (50
mL) and 6N HCl (5 mL) was added and the mixture was stined for 1.5 h at 40DC and at
room temperature overnight. Concentrate, add 150 mL of water, wash with ether, basify
with sodium carbonate, extract with 2 x 100 mL of ether, dry over magnesium sulfate,
filter, and evaporate to provide the cmde hydroxlyamirle which was acylated using
tnmethylsilyl isocyantate as described in Example 98. mp 118-9-C; IH NMR (d6 Me2SO)
1.40 (d, 3, J = 7 Hz), 5.28 (q, 1, J = 7 Hz), 6.31 (s, 1), 6.96 ~m, 4), 7.22 (t, 1, J = 7
Hz), 7.35 ~m, 4), 9.05 (s, 1) ppm; mass spec~rum mle 290 (M~+NH4), 273 (M~+H).
Analysis calculated for Cl5HI6N2O3: C, 66.15~ H, S.92, N, 10.29; found: C, 62.57, H,
6.20, N, 9.96.
Example 119
Prep~ration of N-HvdrQ7qY-N-(1-~4-buto~henYI)ethYlLllre~
The compound was prepared using the method of Example 97 subsntuting p-
butoxyacetophenone forp-bromoacetophenone. mp 137-8.5-C; IH NMR (CDCl3) 0.97 (t,3, J = 7 Hz), 1.46 (m, 2), 1.53 (d, 3, J = 7 Hz), 1.76 (m, 2), 3.94 (t, 2, J = 7 Hz), 5.23
(br s, 2), 5.42 (q, 1, J ~ 7 Hz), 6.71 (s, 1), 6.85 (d, 2, J = 8 Hz), 7.32 (d, 2, J = 8 Hz)
ppm; rnass spec~um mle 252, 235, 192, 177, 121.
WO gO/12008 PCr/US90/0148
71
Example 120
Preparation Qf N-~lvdroxY-N-(1-(4 binhenvl)ethYl) u~
The compound was prepared using the method of Example 98 substitutingp-
phenylacetophenone for p-bromoacetophenone. After the hydrox ylarnine had bee prepared
it was acylated in toluene by preparing the hydrochlonde salt (HC'l gas), heating to reflux,
gassing with phsgene for about three minutes, continue to reflux for about one hour, then
cool ~nd pour into cold ammonium hydroxide. The crude material thus obt ined waspresumed to be diacylated, therefore, it was treated with about 2.S equivalents of lithium
hydroxide in isopropanol. After work-up and recrystallization from ethanoVwater there
was obtained a 32% yield of ~he desired hydroxy urea. mp 157-8C; IH NMR (d6
Me2SO) 1.44 (d, 3, J = 7.5 Hz), 5.33 (q, 1, 3 = 7.5 Hz), 6.34 (br s, 2), 7.50 (m, 9), 9.12
(br s, 1,~ ppm; mass spectrum mle 274 (M++NH4), 257 (, M++H).
Example 121
Preparation of N-Hvdroxy-N-(1-(4-bis allvlamino~henyll~thyl) urea
The compound was prepared using the method of Example 98 substi~uting p-(bis-
allylamino)acetophenone forp-bromoacetophenone. mp 112-4C; IH NI~R (d6 Me2SO)
1.33 (d, 3, J = 7 Hz), 3.89 (m, 4), 5.09 - 5.22 (m, 5), 5.76 - 5.9û (m, 2), 6.28 (br s, 2),
6.~8 (m, 2), 7.10 (m, 2), 8.88 (s, 1) ppm; mass spec~um mle 276 (M++H), 200.
Example 122 .
Preparation of N-Hvdroxy-N-(1-(3-bromo-4-iluorophenvl) ethvl~ urea
The compound was prepared using the method of Example 97 substituting 3-bromo-4-fluoroacetophenone forp-bromoacetophenone. mp 125-7C; IR (KBr) 3460, 3300,
1660, 1630, 1495 cm-l; lH NMR (d6 Me2SO) 1.39 (d, 3, J = 7 Hz), 5.28 (q, 1, J = 7 ,~
Hz), 6.39 (bs, 2), 7.30 (t, 1, J = 8 Hz), 7.34 (dt, 1, J = 2, 8 Hz), 7.62 (dd, 1, J = 2, 7
Hz), 9.18 (s, 1) ppm; mass spec~um mle 294 and 296 (M+~NH4), 278 and 280 (M~H).
Analysis calculated for CgHloBrFN2O2: C, 39.01, H 3.64, N, 10.11; found: C, 39.14,
H, 3.68, N, 10.15.
:. ~, . , .::
, .... .. . .. . . .
WO 90/12008 pcr~us9o/o1488
2~S0~ 72
Example 123
Pr~ranQnQf ~Hydroxv-N-(1-14 çhlQro--3-~~ ph~vl~Ih~l) u~
The compound was prepared using the method of Example 97 substitu~ng 4-chloro-3-methylacetophenone forp-bromoacetophenone. mp 129-31C; IR ~KBr) 3460, 3300,
1630, 1560, 1480, 1440 cm-l; IH NMR (d6 Me2SO) 1.38 (d, 3, J = 7 Hz), 2.31 (s, 3),
S.25 (q, 1, J = 7 Hz), 6.33 (bs, 2), 7.17 (m, 1), 7.33 (m, 2), 9.08 (s, 1) ppm; mass
speclrum m/e (rel intensity) 229 and 231 (100 and 40, M++H), 170 (78), 153 (75).Analysis calculated for CloHI3ClN2O2: C, 52.52, H, 5.73, N, 12.25; found: C, 52.72,
H, 5.71, N, 12.27.
Example 124
Preparation of N-Hvdroxy-N~ (4-chloro-3-methvlpheml)ethvl)-N'-rnethvl urea
The compound was prepared using the method of Example 97 substituting 4-chloro-3-
methylacetophenone forp-brornoacetophenone, and substituting methyl isccyanate for
trimethylsilyl isocyanate. mp 99 102C; IR (KBr) 3440, 3200, 1640, 1535 cm-l; IH
NMR (d6 Me2SO) 1.37 (d, 3, J = 7 Hz), 2.30 (s, 3), 2.57 (d, 3, J = 4 Hz?, 5.22 (q, 1, J =
7 Hz), 6.85 (bq, 1, J = 4.5 Hz), 7.16 (dd, 1, J = 2, 8 Hz), 7.3û (d, 1, J = 2 Hz), 7.32 (d,
1, J = 8 Hz), 8.98 (s, 1) ppm; mass spec~um mle (rel intensity) 260 and 262 (50 and 18,
M++NH~,), 243 and 245 (100 and 35, M++H). Analysis calculated for CIlHlsclN2o2:
C,54.44, H, 6.23, N, 11.54; ~ound: C, 54.33, H, 6.30, N, 11.54.
Example 12~
Preparation of N-Hvdroxy-N-(1-(4-chloro-3-methvlphenvl) ethvl) ure_
The compound was prepared using the method of Example 97
substituting 3-phenoxybenzaldehyde forp-bromoacetophenone. mp 155-6C; JR (KBr)
3480, 3200, 1660, lS20, 1590, 1490, 1450, 1260 cm~ H NMR (d6 Me2SO) 4.51 (s,
2), 6.39 fs9 2), 6.32 - 7.42 (m, 9), 9.39 (s, lj ppm; mass spectrum mle (Tel intensity~ 276
(25, M++NH4), 259 (100, M+~H), 216 (28), 200 (40), 183 (38). Analysis calculated for
Cl4HI4N2O3: C, 65.11, H, 5.46, N, 10.85; found: C, 64.53, H, 5.42, N, 10.81.
: .... . .
.: :
WO 9û/12008 PCI/US90/0148B
73
Example 126
~non of N-HYclrQx~-N-lL(4-chlor~n~eth~ henvl)ethYl-N~
The compound was prepared using the method of Exarnple 97 substituting 3-
phenoxybenzaldehyde forp-bromoacetophenone, and substituting me~hyl isocyanate for
trimethylsilyl isocyanate. mp 124-6C; IR (KBr) 3340, 3180, 1630, 1575, 1S45, 1485,
1220 cm-l; IH NMR (d6 Me2SO) 2.59 (d, 3, J - S Hz), 4.50 (s, 2), 6.84 - 7.41 (m, 10),
9.30 (s, 1) ppm; mass spectrum mle (rel mtensity) 290 (lS, M*+NH~), 273 (100, M++H),
257 (60), 198 (40), 183 (40). Analysis calculated for ClsHI6N203: C, 66.16, H, 5.92,
N9 10.29; found: C, 66.16, H, 5.94, N, 10.27.
Example 127
paration of N-hydroxv-N-( 3-bromothien-2-vl~methvl urea
Br 1. nBuLi Br
sr . MF ~ S ~ CHO
Br HCL-H~ OH ~ Br BH~
~_ PY / ElOH S ~1 6N HCI
N- OH
~ ~ ~ HO
a) Preparation of 3-bromothiophene-2-carboxaldehyde.
To a cold (-78~ C, dry ice / acetone) solution of 2,3-dibrornothiophene (lOg, 41.3
mMol ) in ether (75 mL ) was added n-butylli~ium ( 19.35 mL, 48.36 mMol, 2.5 M in
hexanes). The reaction was stiIred for S min and cannul ated into a cold stir~ed solution of
N,N-dimethylformamide ( 4.53g, 61.99 mMol ) in ether t25 mL ). The reaction was stirred
- . .
WO 90/12008 PCr/US90/01488
J~
74
1 h at -780C and then allowed to warm to room temperature. Water (S rnL) was added
cautiously while stirring. The reaction rnixture was diluted with ether and washed with
water (100 rnL). The aqueous layer was washed with ether and the organic layer~
combined, washed with brine, dried ( MgSO4), and concentrated. Purification by flash
chroma-tography ( SiO2, eluted with 3% ethylaceta~e / hexanes ) afforded 3-bromo-
thiophene-2-carboxaldehyde ( 5.6g, 71% ) as a slightly yellow liquid that solidified upon
refIigeration.
The aldehyde ( 1.0g, 4.5 mMol) obtained above was dissolved in 1:1 pyridine, ethanol
(15 mL). To this stirred solution was added hydroxylarnine hydrochlo~ide ( .63g, 9.3
mMol). The reaction was allowed to stirr overnight at room temperature and then
concentTated. The residue was pamtioned between ether (100 mL) and cold 10% HCl (50
rnL). The organic layer was washed with brine and dried (MgSO~). Concentration
afforded the oxime intermediate ( 1.1 g ) as a yellow liquid that was used without further
.
purificatlon.
The oxime ~ l.lg, 5.4 mMol) obtained above was dissolved in ethanol (25 rnL) andborane pyridine ( 1.26g, 13.5 rrlMol) was added via syringe. The reaction flask was
equipped with a dropping funnel and charged with 6N HCI (14 mL). The HCI solution was
added at a rate to maintain a gentle reflux. The solution was allowed to stir lh at room
temperature and concentrated. The resulting reside was neutralized with 3N NaOH, and
extracted with ethylacetate ~3X50 rnL). The combined organics were washed with water
(50 rnL) and dried (MgSO~,). Concentration afforded the hydroxylamine interrnediate
(l.lg) as a white solid and it was used without further pu~ification.
To a stirred THF (15 mL) solution of the hydroxylamine ( l.lg, 5.3 rnMol) obtained
abo~e was added trimethylsilylisocyanate ( .98g, 8.5 rnMol). The solution was stirred lh
at room temperature and poured into sat'd NH4Cl / ice. The THF was removed and the
resulting aqueous residue thoroughly extracted with ethylacetate. The combined organic
layer was dried (MgSO4) and concentrated to give a white solid. Recrystalization from
ethylacetate / hexanes afforded the title compound ( .8g, 71% from aldehyde) as a white
solid. mp: 138-139.5C; NMR (300MHz, DMSO-d6) ~ 4.65 (2H, s), 6.43 (2H, bs),
7.03 (lH, d, J=lHz), 7.57 (lH, d, J=lHz), 9.50 (lH, s); MS m/e (DCI / NH3) 268
(M~ )+, 251 (M+H)~; Anal. Calcd for C6H7BrN2O2S: C, 28.70; H, 2.81; N, 11.16.
Found: C, 28.62; H, 2.81; N, 11.12.
. .: :;
. : .
, , ~ , . ~ , .', .. ,. . ; .. ; ,
WO 90/12008 PCr~90/01148~.
Example 128
Pr~paration of N-hvdrQxv-~-( 4-bromnthien-2-vl)methvl urea
The ti~le compound was prepared according to ~he method of Example 127 using 4-
bromothiophene-2-carboxaldehyde instead of 3-bromothiophene-2- carboxaldehyde. mp:
162-163.5C; NMR (300MHz, DMSO-d6) o 4.61 (2H, s), 6.47 (2H, bs), 6.98 (lH, d,
J=lHz), 7.54 (lH, d, J=lHz), 9.52 (lH, s); MS rnle (fab) 251 (M+H)-~; Anal. Calcd for
C6H7BrN2O2S: C, 28.70; H, 2.81; N, 11.16. Found: C, 28.95; H, 2.81; N, 11.20.
Example 129
Preparation of N-hvdroxv-N-(5-chlorothien-2-yl)methvl urea
The ~itle compound was prepared according to the method of Example 127 using 5-
chlorothiophene-2-carboxaldehyde instead of 3-bromothiophene-2-carboxaldehyde. mp:
138.5-140C; NMR (300MHz, DMSO-d6) ~ 4.55 (2H, s), 6.46 (2H, bs), 6.85 (lH, d,
J=3.5Hz), 6.95 (lH, d, J=3.5~1z), 9.51 (lH, s); MS m/e (I)CI / isobutane) 207 (M+H)+; ;~
Anal. Calcd for C6H7ClN2O2S: C, 34.87; H, 3.41; N, 13.56. Found: C, 3~.96; H, 3.46;
N, 13.44.
Example 130
Pre~ration of N-hvdroxv-N-~ romolhien-2-vl~methvl urea
The title compound was prepared according to the method of Example 127 using 5-
bromothiophene-2-carboxaldehyde instead of 3-bromothiophene-2-carboxaldehyde.rnp:
145-147C; NMR (300MHz, DMSO-d6) o 4.57 (2H, s), 6.47 (2H, bs), 6.83 (lH, d,
J=4Hz), 7.05 (lH, d, J-4Hz), 9.52 (lH, s); MS rn/e tDCI / NH3) 268 (M+N~,)+, 251
(M+H)+.
Example 131
Preparation of y-hvdroxv-N-( 5-bromothien-2-vl)methvl-N'-methvlurea
The title compound is preparecl from t5-bromothien-2-yl)methyl hydroxylarnine from
Exarnple 127 by reaction with methyl isocyanate instead of trimethylsilylisocyanate.
:. "
;: : : : ; :
WO 90/12008 PCr/US90/014~8
76
Example 132
e~ar~tiQn of ~-hvdroxY-N-~-( ~kromothi~n-2~1~byllur~
The title compound was prepared according to the method of Exarnple 127 us~ng 4-bromo-2-acetylthiophene ;nstead of 3-bromothiophene-2-carbox-aldehyde. mp: 154-157C
(dec); NMR (300MHz, DMSO-d6) o 1.42 (3H, d, J=7Hz), 5.46 (lH, q, J=7Hz), 6.47
(2H, bs), 6.94 (lH, m), 7.52 (lH, d, J=lHz), 9.25 (lH, s); MS m/e (DCI-NH3) 282
(M+NH4)+, 265 (M+H)+; Arlal. Calcd for C7H9BrN202S: C, 31.71; H, 3.42; N, 10.57
Found: C, 31.41; H, 3.35; N, 10.40.
Example 133
Preparation of N-hvdroxv-N-rl-( 5-bromothien-2-vl~ethyllurea
The title compound was prepared according to the method of Example 127 using 5-
bromo-2-acetylhiophene instead of 3-bromothiophene-2-carboxaldehyde. mp: 147-149C
(dec); NMR (300MHz, DMSO-d6) ~ 1.39 (3H, d, J=4Hz), 5.42 (lH, q, J=7Hz), 6.46
(2H, bs), 6.78 (lH, m), 7.03 (lH, d, J=3Hz), 9.26 (lH, s); MS m/e (DCI-NH3) 282
(M+NH4)-~.
Example 134
Prep~ration of N-hvdroxy-N-r 3-(phenylthio)thien-2-vllmethvl urea
SPh
SPh HCI H2NOH ~ sH3-PY
CHO PY / EtOH S ~l 6N HCI
N--OH
,: - . ~ ~,
... , . ~
WO 90/1200B PCI/l lS90~01488
2~5~
SPh
~h TMSNCO
HN~ OH HO ~
a) Preparation of 3-(phenylthio)thiophene-2-carboxaldehyde. To a stirred solution
of 3-bromothiophene-2-carboxaldehyde ( l.9g, 10 rnMol) in ethanol (15 mL) is added
thiophenol (2.2g, 20 mMol) and powdered potassium carbonate (3.04g, 22 mMol). The
mixture is stirred oven~ight and concen~ated. The residue is pa~tioned between water and
edler. The aqueous layer is washed with ether and the organics combined, dried(MgSO4) ;;
and concentrated. Purification by flash col~nn ( SiO2, eluted with 3% ethylacetate /
hexanes) afforded the desired aldehyde (2.02g, 92%) as a yellow liquid.
The tide compound was prepared according to the method of Example 127 using 3-
(phenylthio)~hiophene-2-carboxaldehyde ( prepared above ) instead of 3-bromothiophene-2- -
carboxaldehyde. mp: 99-100.5C NMR (300MHz, DMSO-d6) ~ 4.77 (2H, s), 6.47 (2H,
bs), 6.95 (lH, d, J=6Hz), 7.10-7.21(3H, m), 7.24-7.33 (2H, m), 7.59 (lH, d, J=6Hz),
9.51 (lH, s); MS rn/e (I)CI / NH3) 298 (M~ ,)+, 281 (M+H)+.
Example 135
Preparation of N-hvdroxv-N-~ 5-(phenvlthio)thien-2-vllmethyl urea
5-~Phenylthio)thiophene-2-carboxaldehyde was prepared as described in Exarnple 134
using 5-bromothiophene-2-carboxaldehyde instead of 3-bromothiophene-2-carboxaldehyde
I he tide compound was prepared according to the method of Exarnple 127 using 5-(phenyldlio)thiophene-2-carboxaldehyde instead of 3-bromothio-phene-2-carboxaldehyde.
mp: 126-128C (dec); NMR (300MHz, DMSO-d6) ~ 4.63 (2H, s), 6.47 (2H, bs), 7.02
(lH, d, J=4Hz), 7.27-7.37 (6H, m), 9.53 ~lH, s); MS m/e (DCI / NH3) 298
(M+NH4)+, 281 (M~H)+.
Example 136
Preparation of N-hvdroxY-N-~ 4-(~heny!thioLthien-2-vllmethvl urea
Br Br~
HOCH~CH20H ¢~ 1. nB~
~S~ TsOH/PhH S~ 2. PhSSPh
o
WC~ 90/1200~ PCI'/US9~/01488
. .
6~ ' d~ 7~3
PhS PhS
~ ~3 ~ BH3-PY
S ~ ~ 2. HCI-H2NOH S ~1
O_J N~ OH
PhS PhS
l'MSNCO ~3
HN_OH HO
Preparation of 4-(phenylthio)thiophene-2-carboxaldehyde
a) 2 (4-bromo-2-thienyl)- 1,3-dioxolane. In a 100 rnL roundbottom flask equippedwith a dean stark trap and a reflux condenser, 4-bromothiophene-2-carboxaldehyde (25g,
131 rnMol) and a catalytic arnount of p-toluenesulfonic acid were dissolved in benzene (50
rnL). The mixture was heated to reflux overnight. The reaction was cooled, washed with
sae'd sodium bicarbonate, water, dried (MgSO4) and concentrated. Purification byfractional distillation ( 80-900C, O.5mm Hg) afforded 24.23 g (72~) of the desired
dioxolane as a clear liquid.
b) 2-[ (4-phenylthio)thien-2-yl]-1,3-dioxolane. To a cold (-780C, dry ice / acetone)
sti~ed solution of the bromothienyl dioxolane ( 8 g, 34mMol) prepared above in ether (150
mL) was added n-butyl lithium (15 rnL, 37.4 mMol, 2.5M in hexanes). The reaction was
stilTed for 10 min and diphenyldisulflde ( o.2g, 37.4 mMol) added as a solid. The ice bath
was removed and the reaction allowed to walm to room temperature. Water was added and
the layers separated.The organic layer was dried (MgSO4) and concentrated. Purification
by flash column chromotography ( SiO2, eluted with 10% ethylacetate / hexanes ) afforded
6.05g (67%) of the desired dioxolane as an oil.
c) 4~phenylthio)thiophene-2-carboxaldehyde. To a seirred solution of the
phenythiosubseituted thienyl-dioxolane ( 6.05g, 23mMol) prepared abo~/e in dioxane (45
mL) was added 10% HCI (45 mL). The reaction was stirred 20 min ae room temperature
and the dioxane removed removed by rotory evaporator. The resulting residue was
extIacted thoroughly with ethyl acetate. The combined organic layer washed with sat'd
NaHCO3, water ,dried (MgSO4). Concen~a~on afforded 5.06 g of the desired aldehyde as
.' . "' . ' ' ;, '' ' ' ' ' '. " ' ' "
' " '; " ~ ' '''" ', ,; , ' ' " ~ .;
Wo 90/12~08 pcr/usso/o148x
'ç~
79
a clear oil.
The title compound was prepared according to ~he method of :Example 127 using 4-(phenylthio)thiophene-2-carboxaldehyde ( prepared above ) instead of 3-bromo~hiophene-2-
carboxaldehyde. mp: 111-113C ~dec~; NMR (300MHz, DMSO-d6) ~ 4.62 (2H, s), 6.46
(2H, bs), 6.94 (lH, d, J=lHz), 7.16-7.25 (3H, m), 7.28-7.36 (2H, m), 7.63 (lH, d, ;~
J=lHz), 9.50 (1H, s); MS m/e (DCI / NH3) 298 (M+NH4)~, 281 (M+H)+.
Example 137
Pre~Eation of N-hyd~oxv-N-~ 5-(~envlthio~thien~3-yllmethyl urea
HOCH2CH~OH ~ 1. nBuLi
STsOH / PhH S 2. TMSCI
O_\ O~\
~ o~ 1. nBuLi ~ O/ DIOXANE
// \\2. PhSSPh // \\ HCI
S ~~ TMS PhS S
CHO I HCL-H2NOH ~ N~OH
PhS S TMS 2. BH3-PY PhS S
a) 2-(3-thienyl) 1,3-dioxolane . In a 100 mL roundbottom flask equipped with a dean
stark trap and a reflux condenser, thiophene-3-carboxaldehyde and p-toluenesulfonic acid
were dissolved in benzene (50 rf~L). The mixture was heated to reflux overni~,ht. The
reaction was cooled, washed with sat'd sodium bicarbonate, water, dried ~MgS04) and
concen~ated. Purification by fractional distillation ( 93-950C, 7.5mm Hg) afforded 45.3g
~72%,` of the desired dioxolane as a clear liquid.
b) 2-~(2-trimethylsilyl)thien-3-yl]-1,3-dioxolane. To a OoC sti~ed solution of the 3-
. , , ., ;,; :
,- .. , :, ~ . ,
. .
, . . . ~
- ~ . . : , ; . - ~ . ... . .
WO 90/12008 PCrtUS9û/01488
thienyl dioxolane ( 5 g, 32.1 mMol) prepared above in ether (100 mL) was added n-butyl
lithium (14.1 tnL, 35.2 mMol, 2.5M in hexanes). The reaction was stirred for 10 min and
trimethylsilyl chloride ( 3.83 g, 35.3 mMol) added via syringe. The ice bath was removed
and the reaction allowed to warrn to room temperature. Sat'd ammonium chloride was
added and the layers separated The organic layer was dried (MgSO4) and concentrated.
Purification by flash column chromotography (SiO2, eluted with 5% ethylacetate / hexanes)
afforded 4.0 g (55%) of the desired dioxolane as an oil.
c)2-[(S-phenylthio-2-trimethylsilyl)thien-3-yl]-1,3-dioxolane. Toa~C stirred
solution of the 2-trimethylsilylthien-3-yl dioxolane ( 4 g, 17.5 mMol) prepared above in
ether (100 mL) was added n-butyl lithium (7.7 mL, 19.3 rnMol, 2.5M in hexanes). The
reaction was stirred for 15 min and diphenyl disulfide ( 4.2g, 19.3 mMol) added as a solid.
The ice bath was removed and the reaction allowed to warm to room temperature. Water
was added and the layers separated.The organic layer was dried (MgSO4) and
concentrated. This crude dioxolane was used without further purification.
d) 5-phenylthio-2-trirnethylsilylthiophene-3-carboxaldehyde. To a stirred solu~ion of
the crude phenythiosubstituted thienyl-dioxolane ( 3.8g, prepared above in dioxane (20
mL) was added 1û% HCI (20 mL). The reaction was stirred 20 min at room temperature
and the dioxane removed removed by rotory evaporator. The resulting residue was
extracted thoroughly with ethyl acetate. The combined organic layer washed with sat'd
NaHCO3, water ,dried (MgSO4).and concentrated. Purification by flash column
chromotography ( SiO2, eluted with 5% ethylacetate / hexanes ) afforded 1.16 g of the
pure aldehyde as an oil.
e) [(5-phenylthio)thien-3-yl]methyl hydroxylamine. The aldehyde ( 1.0g, 3.7 mMol)
obtained above was dissolved in 1:1 pyridine, ethanol (10 mL). To this stirred solution was
added hydroxylamine hydrochloride ~ lg, 14 mMol). The reaction was allowed to stir
ovemight at room temperature and then concentrated. The residue was partitioned between
ether (100 rnL) and cold 10% HCl (50 mL). The orgaluc layer was washed with brine and
dried (MgSO4). Concentration afforded the oxime intermediate ( l.lg ) as a yellow liquid
that was used without fu~ther purifica~ion.
The oxime obtained above was dissolved in ethanol (25 mL) and borane py~idine (
1.26g, 13.5 mMol) was added via synnge. The reaction flask was equipped with a
dropping fuMel and charged with 6N HCI (14 mL). The HCI solution was added at a rate
to maintain a gentle reflux. The solution was allowed to stir 1 h at room temperature and
concentrated. The resulting reside was neutralized with 3N NaOH, and extracted with
,; . , : . .: .,:,.. . . ..
WO 90/120Q8 PCr/US90/01488
81
ethylacetate (3X50 mL). The combined organics were washed with water (50 mL) and .
dried (MgSO4). Concentration afforded the desilylated hydroxylamine intermediate.
The title compound was prep~red from the hydroxylamine described above by standard
treatment with trimethylsilyl isocyanate. mp: 113-114C; NMR (300MHz, DMSO-d6)
4.47 (2H, s), 6.44 (2H, bs), 7.17-7.26 (3H, m), 7.28-7.38 (3H, m), 7.56 (lH, d,
J=lHz), 9.45 (lH, s); MS m/e (DCI / NH3) 298 (M+NH4)+, 231 (M+H)~; Anal. Calcd
for C12H12N2O2S2: C, 51.41; H, 4.31; N, 9.99 Found: C, 51.16; H, 4.27; N, 9.91.
Example 138
Br 2 PhSSPh CHO
~ P~r 4 DMF ~--SPh
Preparation of(2-phenylthio)thiophene-3-carboxaldehyde.
To a OoC solution of 2,3-dibromothiophene ~Sg, 20 mMol ) in e~her (25 mL ) was added n-
butyllithium ( 8 mL, 20 mMol, 2.5 M in hexanes). The reac~ion was stirred for 20 min and
diphenyl disulfide (4.36g, 20 mMol) was added as a solid.. The reaction was stirred O.5h
and then cooled to -780C. n-Butyl lithiurn (8 mL, 20 mMol, 2.5 M in hexanes) was added
and the reaction stiIIed an additional l5rnin. To the cold reaction rr~ixture was added DIvlF
(SmL) and the reaction allowed to warm to room temperature. Water (5 rnL) was added
cautiously while stirring. The reaction mixture was diluted with ether and washed with
water (100 mL). The aqueous layer was washed with ether and the organic layers
combined, washed with bnne, dried ( MgS04), and concentrated. Purification by flash
chromatography ( SiO2, eluted with 10% ethylacetate / hexanes ) afforded (2-
phenylthio)thiophene-3-carboxaldehyde ( 2.8g, 63% ) as a slightly yellow oil.
The title compound was prepared according to the method of Example 127 using (2-phenylthio)thiophene-3-~arboxaldehyde ( prepared above ) instead of 3-bromothiophene-2-
carboxaldehyde. mp: 120-122C; NMR (300MHz, DMSO-d6) ~ 4.56 (2H, s), 6.43(2H,
bs), 7.12-7.23 (4H, m), 7.26-7.34 (2H, m), 7.76 (lH, d, J=4Hz), 9.43 (lH, s); MS mle
, , ,: ,,;.: " ' ' - .. :~ :
, ~ , . . " . : ,: : , - ~ : .
.. . .
WO 90/12008 pcrius9o/o1488
(DCI I NH3) 298 (M+NH~,)+, 281 (M+H)+.
Example 139
Preparation of N-hvdroxv-N~ 5-rphenvltnio)-thien-2-Yl)ethyllurea
5-(Phenylthio)-2-acetylthiophene was prepared as described in Example 136 using 5-
bromo-2-acetylthiophenethiophene f~repared in Example 131) instead of 3-bromothiophene-
2-car'ooxaldehyde
The ~itle compound was prepared according to the method of Example 127 using 5-
~phenylihio)-2-acetylthiophene instead of 3-'oromothiophene-2-car~oxaldehyde. mp: 151 C
(dec); NMR (300MHz, DMSO-d6) ~ 1.43 (3H, d, J=7Hz), 5.48 (lH, q, J=7Hz), 6.46
(2H, bs), 6.98 (lH, m), 7.16-7.26 (4H, m), 7.34 (2H, m), 9.26 (lH, s); MS m/e (DCI-
NH3) 312 (M+NH4)+, 219.
Example 14û
Preparation of N-hvdroxv-N-~ 3-(4-hYdroxyphenYlthio)thien-2-YIlmethvl urea
The title compound was prepared according to the method of Example 134 using 4-
hydroxythiophenol instead of thiophenol. mp: 145C (dec); NMR (300~Hz, DMSO-d6) ~
4.78 (2H, s), 6.45 (2H, bs), 6.71 (2H, m), 6.81 (lH, d, J=6Hz), 7.25 (2H, m), 7.46
(lH, d, J~ 6Hz), 9.50 (}H, s), 9.61(1H, s); MS m/e (DCI / NH3) 314 (M+NH4)+, 297(M+H)+.
Exarnple 141
Prepara~ion Qf N-hvdroxy-N-L~ romophenYIthiQllhien-2-Yllmethyl urea
Tbe title compound was prepared according ~o the method of Example 134 using 4-
bromothiophenol instead of thiophenol. mp: 124-126C NMR (300MHz, DMSO-d6) ~
4.76 (2H, s), 6.48 (2H, bs), 6.98(1H, d, J-6Hz), 7.05 (2H, m), 7.47 (2H, m), 7.62
(lH, d, J=6Hz), 9.52 t1H, s); MS m/e (DCI / NH3) 376 (M+NH4)+, 359 (M+H)+.
Example 142
The title compound was prepared according to the method of Example 134 using 4-
chlorothiophenol instead of thiophenol. mp: 111-113C NMR (300MHz, DMSC)-d~)
:. .
. .. .
, ,, ~, . ... . . . .
.... . , . , : ". . ., ~.
WO ~0/12008 PCr/US90/01488
83
4.75 (2H, s), 6.48 (2H, bs), 6.97(1H, d, J=6Hz), 7.12 (2H, m), 7.34 (2H, m), 7.62
(lH, d, J=6Hz), 9.52 (lH, s); MS rn/e (DCI / NH3) 332 (M+NH4)~, 315 ~M+H)+.
Example 143
Preparation of N-hYdroxy-N-r 3-(4-fluorophenylthiokhien-2-vllmethvl urea
The title compound was prepared according to the method of Example 134 using 4-
fluorothiophenol instead of thiophenol. mp: 101-103C NMR (300MHz, DMSO-d6)
4.78 (2H, s), 6.48 (2H, bs)t 6.94 (lH, d, J=6Hz), 7.10-7.26~4H, m), 7.58 (lH, d,J-6Hz), 9.53 (lH, s); MS mJe (DCI/NH3~ 316 (M~NH~ , 299 (M+H)i.
Example 144
Preparation of N-hvdroxv-N-r 3-(4-tertbutvlph~nvlthiQ~hien-2-yllme~hyl ure~
The title compound was prepared according to the method of Example 134 using 4-tert-
butylthiophenol instead of thiophenol. mp: 144-146C; NMR ~300MHz, DMSO-d6)
1.24 (9H, s), 4.78 (2H, s), 6.48 t2H, bs), 6.93 (lH, d, J=6Hz), 7.08 (2H, m), 7.31
(2H, m), 7.56 (lH, d, J=6Hz), 9.52 (lH, s); MS m/e (FAB) 337 (M+H)+.
Example 145
The title compound was prepared according to the method of Example 134 using 2-
mercaptopyridine instead of thiophenol. mp: 80C (dec); NMR (300MHz, DMSO-d6) ~
4.75 (2H, s), 6.46 (2H, bs), 6.81 (lH, d, J=8Hz), 7.08 (lH, d, J-6Hz), 7.13 (lH, m),
7.60 (lH, m), 7.65 (lH, d, J=6Hz), 8.38 (lH, m), 9.49 (lH, s); MS m/e (DCI l NH3)
282 (M+H)+, 266.
Example 146
P~eparation of N-hvdroxv-N-r 3-(2-~filIYlrtlethYlthiQ~thien-2-vllmethvl ~rea
The title compound was prepared according to the method of Example 134 using
furfurylmercaptan instead of thiophenol. mp: 93-95C; NMR (300MHz, DMSQ-d6)
4.20 (2H, s), 4.62 (2H, s), 6.05 (lH,m), 6.34 (lH, m), 6.43 (2H, bs), 6.94(1H, d,
J=6Hz), 7.46 (lH, d, J=6Hz), 7.57 (lH, m), 9.45 (lH, s); MS m/e (DCI / NH3) 302
(M+NH4)+, 285 (M+H)+, 209.
WO 90/12008 PCrtU~0/0148
Example 147
eFaration of ~-hYd~xY-~ ertbu Ithiolthien 2-vllmethyl urea
The title compound was prepared according to the method of Exatnple 134 using 4 tert-
butylthiophenol instead of thiophenol mp: 145-146C; NMR (SOOMHz, DMSO-d6)
1.23(9H, s), 4.83 (2H, s), 6.39 (2H, bs~, 6.99 (lH, d, J=SHz), 7.48 (lH, d, J=SHz),
9.42 (lH, s); ~fS m/e (I)CI / NH3) 278 (M+NH4)+, 261 (M+H)+.
Example 148
Preparation of N-hydroxv-N-~ 5-(~ertbutvlthio)thiçn-2-yllmethyl urea
The title compound was prepared according to the method of Example 135 using tert-
butylmercaptan instead of thiophenol. mp: 101-103C NMR (500MHz, DMSO-d6)
1.26 (9H, s), 4.61 (2H, s), 6.45 (2H, bs), 6.96 (lH, d, J=3Hz), 7.03 (lH, d, J=3Hz),
9.49 (lH, s); MS m/e (DCI / NH3) 278 tM+NH4)+, 261 (M+H)+, 185.
Example 149
Preparation of N-h~droxv-N-~l-( 5-Jtertbutvlthiolthien-2-vl~ethvllurea
The title compound was prepared according to the method of Example 148 using 5-
bromo-2-acetylthiophene instead of 5-bromothiophene-2-carboxaldehyde. mp: 135-136C;
NMR (300MHz, DMSO-d6) ~ 1.25 (9H, s), 1.42 (3H, d, J=7Hz), 5.46 (lH, q, J=7Hz)),
6.44 (2H, bs), 6.92 (lH, m), 7.01 (lH, d, J=3Hz), 9.22 (lH, s); MS m/e (DCI-NH3)292 (M+NH~)+, 274 (M+H)+, 199.
Example 150
Preparation of N-hvdroxv-N-~ 5-(isopropvlthio)thien-~vllmetl~YL~
The title compound was prepared according to the m;ethod of Example 135 using
isopropylmercaptan instead of thiophenol as an off white powder. This matenal contained
appToximately 10% of the 5-bromocompound (Exarnple 131): NMR (500MHz, DMSO-
d6) ~ 1.21 (6H, d, J=7Hz), 3.13 (lH, hept, J=7Hz), 4.59 (2H, s), 6.44 (2H, bs), 6.92
(lH, d, J=4Hz), 7.02 (lH, d, J=4Hz), 9.48 (lH, s); MS m/e (DCI / NH3) 264
(M+NH4)+, 247 (M+H)+.
WO 90/12008 ~ pcr/usso/o1488
Example 151
Preparation_of N-~lydroxv-~-[ 1-( ~- ~ methvlthiQl thlen-2-vllethvllurea
The title compound was prepared according to the method of Example 127 using 5-
methylthio-2-acetylthiophene instead of 3-bromothiophene-2-carboxaldehyde. mp: 125.5-
126.5C (dec); MMR (300MH~, DMSO-d6) o 1.40 (3H, d, J=7Hz), 2.45 (3H, S), 5.42
(lH, q, J=7Hz), 6.40 (2H, bs), 6.83 (lH, d, J=3Hz), 6.94 (1~, d, J=3H~), 9.28 (lH, s);
MS rn/e (DCI-NH3) 250 (M+NHO~, 233 (M~H)~.
Example 152
PreparatiQn of N-hvdroxY-N-3-~ 5-(phenvlthio)thien-2-yllpropenvl urea
1. (cOc1)2
'' 11 J~ (HO2C)2CH2 ~ - ' - ~--
! ~ ,~ ~ 2. MeONHMe
S ~ S ~ CHO PYR~INE PhS S CO2H
PhS ~ NMe DIBAL hS ~ H
O O
Preparation of 3-~ 5-(phenylthio)thien-2-yll acrolein
a) 3-~ 5-(phenythio)thien-2-yl] acrylic acid. To a stirred solution of (5-
thiophenyl)thiophene-2-carboxaldehyde (11.6g, 60.4 mMol) (from Example 135) in
pyridine (75 mL) was added malonic acid (12.6g, 120 rnMol) and morpholine (0.5 mL).
The rnixture was heated to reflux and stirred overnight. The mixture was cooled and poured
into 10% HCl / ice. The tan solid was collected, washed and dried to give 11.36g of the
desired acid that was used without fllrther purification.
b) N,O,dimethyl-3-~ 5-(phenythio)thien-2-yl] acrylamide. The acid (11.36g, 43.36rnMol) obtained above was dissolved in dry methylene chloride (lO()mL). To this stirred
solution was added oxalyl chloride (7.96g, 65 mMol) and DMF ( -l mL). The rnixlure was
stirred for 3h and concentrated to dryness. The residue was dissolved in fresh dry
me~hylene chloride ( 100 rnL) and to this stirred solution was added pyridine ( 1 lg, 131
rnMol) and N,O-dimethylhydroxylamine hydrochloride (6.3g~ 65 mMol). The reac~ion was
stirred for 2h and concentrated. The resulting reside was partitioned between water and
ethylacetate . The aqueous layer was washed with ethylacetate and the organic layers
WV 90/12008 P~r/US90/01~188
combined, dried (MgSO4) and concentrated. The residue was purified by flash column
chromotography (SiO2, eluted with 2:1 hexanes / ethylacetate) to a~ford 10.Sg (79%) of the
unsaturated amide as an off white solid.
c) 3-[ (5-phenylthio)thien-2-yl] acrolein. The unsaturated arrude obtained above was
treated with 1.5 equivalents of DIBAL in methylene chloride at -780C. The reaction was
poured into 10% HCI and extractive work up gave crude aldehyde that was used without
further purification
The crude aldehyde obtained in this manner was converted to the title compound by the
rnethod described for Example 1 to afford a white crystaline solid. mp: 152-154C; NMR
(300MHz, DMSO-d6) o 4.05 (2H, m), 6.02 (lH, m), 6.48 (2H, bs), 6.71 (lH, d,
J=16Hz), 7.09 (lH, d, J=4Hz), 7.19-7.26 (3H, m), 7.28-7.38 (3H, m), 9.36 (lH, s);
MS m/e (DCI / NH3) 324 (M+NH4)~, 307 (M~H)+; Anal. Calcd for C14HI4N2O2S2: C,
54.88; H, 4.61; N, 9.14. Found: C, 54.04; H, 4.65; N, 9.04.
Example 153
Preparation of N-hvdrQxY-N-~3-~ 5-(.~benYlthio~thien-2-YllbutenY~ea
Methylmagnesium bromide was added to an ether soluion of the N~O,dimethyl-3-[ 5-(phenythio)thien-2-yl] acrylamide intermediate from Example 152. The crude ketone
obtained after aqueous work up was converted to the title compound by the me~hoddescribed for Exarnple 1, to afford an off white powder that contains approximately 10% of
the saturated N-hydroxy-N-3-~5-(phenylthio)thien-2-yl]butyl urea.
NMR (300MHz, DMSO-d6) o 1.19 (3H, d, J=7Hz), 4.78 (lH, m), 6.06 (lH, dd,
J=16Hz,J=7Hz), 6.48 (2H, bs), 6.65 (lH, m), 7.08 (lH, d, J=16Hz), 7.15-7.48 (6H,m), 9.07 (lH, s); MS ~D/e (DCI / NH3) 338 (M+NH4)+, 321 (M+H)~, 245; Anal. Calcdfor ClsHl6N2O2S2: C, 56.23; H, 5.03; N, 8.74. Found: C, 55.65; H, 5.15; N, 8.64.
Example 154
Preparation of N-hvdroxv-N-3-~ 5-(tert~t~lthiQ)thien-2-~llpro~enyl urea
The desired product was prep~red according to the method of Example 152 using 5-tert-
butylthiophene-2-carboxaldehyde instead of 5-(thiophenyl)thiophene-2-carboxaldehyde.
mp: 111-113C NMR ~300MHz, DMSO-d6) ~ 1.27 (9H, s), 4.05 (2H, m), 6.03 (lH,
m), 6.38 (2H, bs), 6.67 (lH, d, J=lSHz), 7.04 (lH, d, J=4Hz), 7.08 (lH, d, J-4Hz),
,~. .;, , .:.,,::," :: ~ ;
. : .................... . ~ ., i : ... , : . ~
WV 90/12008 PCrtUS90/01488
,
87 2 ~ ? 3 ~7
9 35 tlH, s); MS m/e (I)CI / NH3) 304 (M+NH4)+, 287 ~M+H)+.
Example lSS
Preparation of N-hydroxv-N-~ S-(phenoxv)thien-2-yllmethyl urea
02N ~ NaH / DMSo ~ o~ CHO
a) 5-phenoxythiophene-2-carboxaldehyde. To a stirred suspension of sodium hydride
(1.05g, 35 mMol, 80% oil dispersion) in DMSO (lOOmL) is added phenol (3.3g, 35
mMol). The rnixture was stirred .S h at room temperanlre and a DMSO (3~nL) solution of
5-nitrothiophene-2-carboxaldehyde ( 5g, 32 mMol) was added dropwise. The reaction was
stilTed .Sh and poured into water. The rnixture was thoroughly exsacted with ether and the
combined organics rewashed with brine. The organics were then dried (MgSO~) and
concentrated to give crude aldehyde.
The crude aldehyde prepared in this manner was converted to the title compound
according to the method of Example 127. mp: 114-116C; NMR (300MHz, DMSO d6
4.53 ~2H, s), 6.42 (2H, bs), 6.50 (lH, d, J=4Hz), 6.74 (lH, d, J=4Hz), 7.13 (3H, m),
7.40 (2H, m), 9.45 (lH, s); MS m/e (DCI / NH3) 282 (M+NH4)+, 265 (M+H)+, 189.
Example 156
Preparation of N-hydroxY-N-~ 3-(phenoxy)thien-2-Yllmethyl urea
~3 P~NOL ~~
S CU K2C03 2. DMF
0~
S C~O 3
Wo 90~1200~ Pcr/vsso/~ 8
Preparation of 3-phenoxythiophene-2-carboxaldehyde
a) 3-phenoxythiophene. A mixture of 3-bromothiophene (100g, 610 rnMol), phenol
(61.2g, 650 rnMol), copper bronze ( S g) and potassium carbonate (30 g, 220 rnMol) was
heated to lSOoC.. After heating for 7 days the n~ixture was cooled, diluted with 300 mL of
chloroform and filtered. The solids were thoroughly washed with chloroform and the
filtrates combined. The combined organics were washed with lO~o NaOH ( 2x 300 rnL),
water (300mL), dried ~MgSO4) and concentrated. The residue was factionally distilled to
afford 31 g(29%) (80oC, 3rnrn) of the desired ether as a clear liquid.
b) 3-phenoxythiophene-2-carboxaldehyde. To a 0OC solu~ion of 3-phenoxyth;ophene
(2 g, 11.4 rnMol ) in ether ~50 mL ) was added n-butyllithium ( 5 rnL, 12.5 mMol, 2.5 M
in hexanes). The reaction was stilred for 15 min and N,N-dimethylformamide (3 mL) was
added. The reaction was allowed to wa~n to room temperature. Water (5 mL) was added
cautiously while stirring. The reaction mixn~e was diluted with ether and washed with
water (100 mL). The aqueous layer was washed with ether and the organic layer combined,
washed with brine, dried ( MgSO4), and concentrated. The residue was punfied by flash
colurnn chromotography ( SiO2, eluted with 10% ethylacetate / hexanes) tO afford 1.74 g
(75%) of the desired aldehyde as a clear oil.
The title compound was prepared according to the method of Example 127 using 3-
phenoxythiophene-2-earboxaldehyde ( prepared above ) instead of 3-bromothiophene-2-
carboxaldehyde. mp: 132-133.5C; NMR (300MHz, DMSO-d6) ~ 4.55 (2H, s), 6.43
(2H, bs), 6.72 (lH, d, J=6Hz), 6.95 (2H, m),7.06 (lH, m), 7.33 (2H, m), 7.46 (lH, d,
J=6Hz), 9.44 (lH, s); MS m/e ~DCI / NH3) 282 (M~NH4)+, 265 (M+H)+; Anal. Calcd
for Cl2Hl2N2O3S: C, 54.53; H, 4.58; N, 10.60 Found: C, 53.73; H, 4.39; N, 10.43.
.. .. .. .. . ... .
Wo 90/~2008 Pcr/usso/~)l4x8
~9
Example 1~7
Prep~aiQn Qf N-hvdrQxy-N-~ 4-~henoxv~thien-2-Yll~thvl ~re~
~C3 1. nBuLi /
Br o TMSCI
~ PHENOL
S CU~ K2CO3
~ '.
TMS S CHO
a) 4-phenoxy-5-trimethylsilylthiophene-2-carboxaldehyde. To a OoC solution of 3-phenoxythiophene (9.5 g, 53.9 mMol ) in ether (200 rnL ) was added n-butyllithiurn ( 24
mL, 60 mMol, 2.5 M in hexanes). The reaction was sdIred for lS min and trimethylsilyl
chloride (6.45 g, 59.4 ~ol) was added via syringe.. The reaction was s~irred 15 min and
addidonal n-butyllithium ( 24 mL, 60 mMol, 2.5 M in hexanes) was added and the reaction
stirred l5min. To the cold reaction mixture is added DMF (14 mL) and the reaction
allowed to warm to room temperah~re over night. Water (5 rnL) was added cautiously while
stirring The reacdon rnixture was diluted with ether and washed with water . The aqueous
layer was washed with ether and the organic layer combined, washed with brine, dried (
MgSO4), and concen~ated. Purification by flash chromatography ( SiO2, eluted with 5%
ether/ hexanes ) afforded ~phenoxy-5-trimethylsilylthiophene-2-carboxaldehyde ( 12.1 g,
83% ) as a slightly yellow oil.
The title compound was prepared as described in Example 137 except using 4-phenoxy-
5-trimethylsilylthiophene-2-carboxaldehyde described above instead of 5-phenylthio-2-
trimethylsilylthiophene-3-carboxaldehyde. rnp: 120-122C; NMR (300MHz, DMSO d6)
4.57 (2H, s), 6.4~ (2H, bs), 6.78 (2H, s ), 7.03 (2H, m), 7.12 (lH, m), 7.38 (2H, m),
9.49 (lH, s); MS m/e (I)CI / NH3) 282 (M+NH~)+, 265 (M+H)+.
Example 158
Prepara~ion of N-hvdIpxv-N-r ~(4-chlorQ~enoxy)thien-2-vllmethyL~Eea
The ~tle compound was prepared as described in Example 157 except using 4-
Wo 90/1200B PCr/US90/OJ488
'' I .
'3~ 90
c~lorophenol instead of phenol. mp: 141-142C; NMR (300MHz, DMSO d6) ~ 4.58
(2H, s), 6.47t2H, bs), 6.79 (lH, d, J=lHz), 6.85 (lH, d, J=lHz), 7.05 (2H, m), 7.43
(2H, m), 9.48 (lH, s); MS rn/e (DCI / NH3) 316 (M~NH4)+, 299 (M-~H)+.
I
Lipoxy~enase Inhib tion Determinahon
Assays to determine 5-lipoxygenase inhibitory activity were perforrned in 20~
incubations containing the 20,000xg supernatant from 1.5 million homogenized RBL- 1
cells and various concentrations of the test compound. Reactions were initiated by addi~ion
of radiolabeled arachidonic acid and terminated by acidification and ether extraction.
Reaction products were separated from nonconverted substrate by thin layer
chromatography and measured by liquid scintillation spectroscopy. All incubations are
performed in triplicate. Lnhibition of 5-lipoxygenase activity was calculated as the ratio of
the amount of product ~o~ned in the presence and absence of inhibitor. ICso values
(concentration of compound producing 50% enzyme inhibition) were calculated by linear
regression analysis of percentage inhibition versus log inhibitor concentration plots. (Dyer,
R.D.; Haviv, F.; Hanel, A. M.; Bornernier, D. A.; Carter, G. W. Fed. Proc., Fed. Am.
Soc. Exp. Biol. 1984, 43, 1462A). Results for compounds of the foregoing examples are
indicated in Table 1.
T~ble 1
In Vitro Inhibitory Potencies of Compounds of this Inven~on Against
5-Lipoxygenase ~om RBL- 1 20,000xg Supernatant
=====================_=======_==============================_
Example I~so (l0-6M) Examp~e ICsO ~10-6M)
0.43 108 0.4
2 0.37 109 1.8
3 0.68 110 2.3
4 0.50 113 0.3
0.61 1 14 0.9
6 0.54 1 lS 0.6
7 1.4 116 4.4
8 0.33 1 17 4.43
. .. . . .
.;
, ,,: ,; ' ~ ' ' . :, . . ; - -
; . ....... .. . .... .
~ ~ ~ . . , .. 1 ., , , :
.. . . . . . ..
WO 90~12008 PCr/lJS9û/01488
f~
91 ~,
(Table 1 con~nued)
0.87 1 19 0.53
1 1 1 . 1 120 0.57
12 0.53 121 0.74
13 2.8 122 0.80
4~ 1.5 123 0.50
43 3.5 124 0.60
44 4.9 125 0.40
6.~ 126 0.80
46 2. 1 127 1 ~2
~7 3.7 128 2.~
48 1.7 129 2.0
49 3.1 130 0.9
6.7 132 0.9
51 0.2 133 0.9
52 3.9 134 0.3
53 0.~ 135 0.2
54 0.31 137 0.4
2.1 139 0-4
56 0.4 1~0 0.4
57 0.42 141 0.2
58 0.15 142 0.3
59 0.99 143 0.3
3.5 144 0.2
61 2.1 145 1.5
62 4.2 146 0.7
68 1.9 147 3.7
69 1.5 148 0.3
72 0.8 149 0.8
97 0.2 154 0.2
98 1.1 155 0.7
99 0.3
1()0 0.8 156 1.0
101 0.3 157 0.5
., . ~. .. .. .
- .. : . : . ~ :
; . . .,: . ; :. ;
WO 90/12008 PCr/US90/014~ ,
, I
s~ 92
(Table 1 concluded)
104 3.9 158 0.4
107 0.6
=======_============_=_============_========================= , :
I_
Inhibi~ion of the biosynthesis of leukotrienes in vivo after oral administration of
compound was detennined using a Iat pentoneal anaphylaxis model in a similar malmer as
that described by Young and coworkers (Young, P. R.; Dyer, RD.; Carter, G. W. Fed.
Proc., Fed. Am. Soc. Exp. Biol. 1985, 44, 1185). In this model rats were injected
in¢aperitoneally (ip~ with rabbit antibody to bovine serum alburnin (BSA) and three hours
later injected ip with BSA to induce an antgen-antibody response. Rats were sacrificed 15
minutes after this challenge and the peritoneal fluids were collected and analyzed for
leukotTiene levels. Test compounds were administered by gavage one hour prior to the
antigen challenge. Percent inhibition values were determined by compa~ing the trestrnent
group to the mean of the control group. From the results of this assay, presented in Table
2, it is demonstrated that compounds of this invention are orally effective in preventing the
in vivo biosynthesis of leukomenes.
Table 2
In Vivo Inhibition of LeukotIiene Biosynthesis
Percent Inhibition at 200 ~rnollkg Oral Dose
====_=====================================================.==
Example %Inhibition Example % Inhibi~ion
_ _ _
58 55 71
4 63 56 89
74 68 93
7 88 97 94
9 69 99 84
12 94 1~0 95
42 64 101 93
43 66 102 85
44 87 103 88
'~ '. ' ' ~:::. ' ' ' ':';'' . '.. .~ ,, '' .: ' : : :.,, .
WO 90~1~0~ P~r/usso/ol488
~ 9~7
93
(Table 2 concluded)
4S 97 107 99
47 94 109 98
49 9~ 1 1 1 97
113 94
51 94 120 77
===============================_===_==_===================_==
- . ~ . .. : ... : : : : -
