III USOO5143928A

United States Patent (19) 11 Patent Number: 5,143,928

Cetenko et al. 45) Date of Patent: Sep. 1, 1992
(54) 3,5-DI-TERTIARYBUTYL-4-HYDROXY FOREIGN PATENT DOCUMENTS
PHENYLMETHYLENE DERVATIVES OF
2-SUBSTITUTED THIAZOLIDINONES, 0037480 10/1981 European Pat. Off. .
OXAZOLIDINONES, AND 343643 11/1984 European Pat. Off. ............ 548/184
MDAZOLONONES AS 861062495 12/1986 European Pat. Off. .
ANTNFLAMMATORY AGENTS 211670 2/1987 European Pat. Off. ............ 548/184
0211670 2/1987 European Pat. Off. .
75 Inventors: Wiaczeslaw A. Cetenko; David T. 863.061347 2/1987 European Pat. Off. .
Connor; Jagadish C. Sircar; Roderick 0304493 3/1989 European Pat. Off. .
0343643 11/1989 European Pat. Off. .
J. Sorenson; Paul C. Unangst, all of 0391644 10/1990 European Pat. Off. .
Ann Arbor, Mich. 62-29570 2/1987 Japan.
62-29579 2/1987 Japan ................................... 548/84
73 Assignee: Warner-Lambert Company, Morris 2078218A 1/1982 United Kingdom.
Plains, N.J. 8807035 9/1988 World Int. Prop. O. .......... 548/84
21 Appl. No.: 640,711 OTHER PUBLICATIONS
Derwent AbStr. No. 86-059.691AO9.
22 Filed: Jan. 18, 1991 Derwent Abstr. No. 4601OU-B.
Derwent Abstr. No. 88-178973/26.
Related U.S. Application Data Derwent Abstr. No. 87-076383/1.
63 Continuation-in-part of Ser. No. 499,937, Mar. 27, Derwent Abstr. No. 87-076379/11.
1990, abandoned. Derwent Abstr, No. 87-087608/3.
Derwent Abstr. No. 86-295746/45.
51 Int. Cl................... C07D 277/54; CO7D 277/36; Derwent Abstr. No. 88-99351A29.
A6K 3/415 Chemical Abstracts, vol. 105, No. 11, Sep. 15, 1986.
52 U.S.C. .................................... 514/369; 548/183; Katsumi I., et al. "Studies on Styrene Derivatives...'
548/184: 548/185; 548/187; 548/225; 548/226; Chen. Abstract No. 90791X.
548/301; 548/313 Primary Examiner-Robert Gerstl
58) Field of Search ............... 548/184, 183, 185, 187; Attorney, Agent, or Firm-Joan Thierstein
514/369
57 ABSTRACT
56). References Cited The novel 3,5-ditertiarybutyl-4-hydroxy-phenylmethy
U.S. PATENT DOCUMENTS lene derivative of 2-substituted thiazolidinones, ox
4,241,073 12/1980 Jamieson et al. . azolidinones, and imidazolidinones as antiinflammatory
4,345,072 8/1982 Kleenann et al. . agents having inhibiting activity for 5-lipoxygenase,
4,582,903 4/1986 Miruiss . cyclooxygenase, or both.
4,650,876 3/1987 Miruiss .
4,971,996 9/1988 Shiraishi .............................. 548/181 46 Claims, No Drawings
 5,143,928
1. 2
or NR7COR6
3,5-DI-TERTIARYBUTYL-4-HYDROXYPHENYL wherein
METHYLENE DERVATIVES OF 2-SUBSTITUTED Z is O, S, NH, NCN
THIAZOLIDINONES, OXAZOLIDINONES, AND W is CO2R, wherein R is as defined herein,
MIDAZOLD NONES AS ANTNFLAMMATORY
AGENTS CHCO2H,
This is a continuation-in-part of U.S. application Ser. CH3
No. 07/499,937, filed Mar. 27, 1990, now abandoned.
O (CH2)CO2H, (CH2)OH, C(CH2OH)3,
BACKGROUND OF THE INVENTION n is 1, 2, 3 and
3,5-Di-tertiarybutyl-4-hydroxyphenyl derivatives m is 1 to 5;
imidazolidinones are disclosed as a moiety in a variety R1,R2 are independently H, lower alkyl, arylalkyl, or
of compounds. (CH2)NR6R7
For example, U.S. application Ser. No. 07/198,528, 15 R3 is H, alkyl or aryl;
filed May 25, 1988, now abandoned; U.S. application R4 is H or alkyl;
Ser. No. 07/334,346, filed Apr. 10, 1989, now aban R5 is alkyl, aryl, or CF3;
doned; and U.S. application Ser. No. 07/375,794, filed R6 is H or lower alkyl; and
Jul. 5, 1989 disclose thiazolidinones, imidazolidinones, R7 is lower alkyl.
and oxazolidinones including 3,5-di-t-butyl-4-phenol. In 20 The present invention is also a novel compound of
fact, the disclosures in the Background of the Invention the formula II
of U.S. application Ser. No. 07/198,528, filed May 25,
1988, now abandoned; U.S. application Ser. No. II
07/334,346, filed Apr. 10, 1989, now abandoned; and 25
(CH3)3C
U.S. application Ser. No. 07/375,794, filed Jul. 5, 1989
cites other disclosures and therefore they are incorpo
rated here by reference. However, the present com HO
pounds differ from this disclosure by the 2-substituent C(CH3)3
of each of the thiazolidinone, oxazolidinone, or
imidazolidinone ring systems. 30
Other references disclose compounds having the or a pharmaceutically acceptable base or acid addition
2-substituents of the present invention with various salt thereof; wherein X is S, O, NH or N-loweralkyl;
and Yl is OH or SH.
other rings such as thiadiazoles, oxadiazoles or triazoles. The present invention is also a pharmaceutical com
See U.S. application Ser. No. 07/277,171, filed Nov. 29, 35 position for treating a disease or condition, such as
1988, now abandoned, and U.S. application Ser. No. rheumatoid arthritis, osteoarthritis, other inflammatory
07/426,814, filed Oct. 30, 1989, now pending. However, conditions, psoriasis, allergic diseases, inflammatory
such references differ from the present invention in both bowel disease, GI ulcers, cardiovascular conditions
the heteroaryl ring moiety and the substituent between
the heteroaryl ring and the 3,5-ditertiarybutyl-4- including ischemic heart disease and atherosclerosis,
hydroxyphenyl moiety. The present invention is limited and ischemia-induced cell damage, particularly brain
to rings linked by a methylene moiety. damage caused by stroke, preferably an inflammatory
disease or condition, comprising an antiinflammatory,
SUMMARY OF THE INVENTION antipsoriatic, antiallergy, antiulcer, antiischemic, antia
The present invention is a novel compound of the therosclerotic, or cytoprotective amount of the com
formula I 45 pound of the formula I or II or a pharmaceutically
acceptable salt of I or II as defined above and a pharma
ceutically acceptable carrier.
The present invention is also a method of treating a
Me3C N N disease or condition as noted above in a mammal, partic
A.
50 ularly a human, suffering therefrom which comprises
HO x- Y
administering a compound of the formula I or II or salt
of I or II as defined above in unit dosage form.
CMe3 The invention also provides for use of any such com
pound of formula I or II or salt of Ior II in the manufac
and a pharmaceutically acceptable base or acid addition 55 ture of a medical therapeutic agent.
salt thereof; in which The pharmaceutical composition or method of treat
Me is methyl; ing which is the present invention is meant to include
X is S, O, NH or N-lower alkyl; what is understood to be prophylactic to one of a fore
R8 is hydrogen or methyl; going named disease or condition.
Y is SCH3, SOCH3, SO2CH3, NRR2, NHCN, The compounds of the formula I or II have activity as
inhibitors of 5-lipoxygenase, cyclooxygenase or both
enzymes to provide the use for the pharmaceutical com
f i
NHCNHR3 NHNHCNH2, NHNHCNH2,
position and methods of the present invention.
A preferred compound of the formula I is 5-3,5-
65 Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2-
CH3 inino-4-thiazolidinone, (Z)-, methanesulfonate (1:1)
N(OH)CORs, NRW, CHCO2R4, salt, 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)-
methylene-2-(methoxymethylamino)-4-(5H)-thiazo
 5,143,928
3 4.
lone, monohydrochloride, (Z)-, 5-3,5-bis(1,1-dime use of the acid or free base form. Appropriate pharma
thylethyl)-4-hydroxyphenyl)methylene)-2,4-thiazoli ceutically acceptable salts within the scope of the inven
dinedione, 2-oxime (Z)-, 5-3,5-Bis(1,1-dimethylethyl)- tion are those derived from mineral acids such as hydro
4-hydroxyphenyl)methylene)-2-(methylthio)-4-(5H)- chloric acid and sulfuric acid; and organic acids such as
thiazolone, (Z)-, 5-3,5-Bis(1,1-dimethylethyl)-4- methanesulfonic acid, benzenesulfonic acid, p-toluene
hydroxyphenyl)methylene-2-hydroxy(1 -methylethyl sulfonic acid, and the like, giving the hydrochloride,
)amino)-4-(5H)-thiazolone, (Z)-, 5-3,5-Bis(1,1-dime sulfamate, methanesulfonate, benzenesulfonate, p-tol
thylethyl)-4-hydroxyphenyl)methylene)-4,5-dihydro-4- uenesulfonate, and the like, respectively or those de
oxo-2-thiazolyl)cyanamide, choline salt, 5-3,5-Bis(1,1- rived from bases such as suitable organic and inorganic
dimethylethyl)-4-hydroxyphenyl)methylene-2-(me O bases. Examples of suitable inorganic bases for the for
thylthio)-4(5H)-oxazolone, 5-3,5-Bis(1,1-dimethyle
thyl)-4-hydroxyphenyl)methylene)-4,5-dihydro-4-oxo mation of salts of compounds of this invention include
2-oxazolylcyanamide and 5-3,5-Bis(1,1-dimethyle the hydroxides, carbonates, and bicarbonates of ammo
thyl)-4-hydroxyphenyl)methylene)-4,5-dihydro-1-meth nia, sodium, lithium, potassium, calcium, magnesium,
yl-4-oxo-lH-imidazol-2-yl-cyanamide. 5
aluminum, zinc, and the like.
More preferred is 5-3,5-Bis(1,1-dimethylethyl)-4- Salts may also be formed with suitable organic bases.
hydroxyphenyl)methylene-2-imino-4-thiazolidinone, Bases suitable for the formation of pharmaceutically
(Z)-, methanesulfonate (1:1) salt, 5-3,5-Bis(1,1-dime acceptable base addition salts with compounds of the
thylethyl)-4-hydroxyphenyl)methylene)-2-(methox present invention include organic bases which are non
ymethylamino)-4(5H)-thiazolone, monohydrochloride, 20 toxic and strong enough to form such salts. These or
(Z)-, 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)- ganic bases form a class whose limits are readily under
methylene-2-hydroxy(1-methylethyl)aminol-4(5H)- stood by those skilled in the art. Merely for purposes of
thiazolone, (Z)- and 5-3,5-Bis(1,1-dimethylethyl)-4- illustration, the class may be said to include mono-, di-,
hydroxyphenyl)methylenel-4,5-dihydro-4-oxo-2- and trialkylamines, such as methylamine, dimethylam
thiazolylcyanamide, choline salt. 25 ine, and triethylamine; mono-, di-, or trihydroxyalkyla
Most preferred is 5-3,5-Bis(1,1-dimethylethyl)-4- mines such as mono-, di-, and triethanolamine; amino
hydroxyphenyl)methylene-2-imino-4-thiazolidinone, acids such as arginine, and lysine; choline; guanidine;
(Z)-, methanesulfonate (1:1) salt and 5-3,5-Bis(1,1- N-methylglucosamine; N-methylpiperazine; morpho
dimethylethyl)-4-hydroxyphenylmethylene-2-(me line; ethylenediamine; N-benzylphenethylamine; tris(-
thoxymethylamino)-4-(5H)-thiazolone, monohydrochlo hydroxymethyl) aminomethane; and the like. (See, for
ride, (Z)-. example, "Pharmaceutical Salts,” J. Pharm. Sci, 66(1),
A DETAILED DESCRIPTION OF THE 1-19 (1977).)
INVENTION The acid addition salts of said basic compounds are
prepared either by dissolving the free base of compound
In the present invention "lower alkyl' is alkyl of from 35 I in aqueous or aqueous alcohol solution or other suit
one to six carbons, inclusive, and means methyl, ethyl, able solvents containing the appropriate acid or base
propyl, butyl, pentyl, or hexyl and isomers thereof. and isolating the salt by evaporating the solution, or be
Halogen is chloro, iodo, bromo or fluoro. reacting the free base of compound I with an acid as
Aryl is phenyl unsubstituted or substituted by one, well as reacting compound I having an acid group
two or three substituents of one or more of each of alkyl thereon with a base such that the reactions are in an
of one to four carbons, inclusive, OR4 wherein R4 is organic solvent, in which case the salt separates directly
independently as defined above, SR4 wherein R4 is inde or can be obtained by concentration of the solution.
pendently as defined above,
The base salts of compounds of formula I or II de
O
scribed above are prepared by reacting the appropriate
45 base with a stoichiometric equivalent of the acid com
pounds of formula I to obtain pharmacologically ac
ceptable base salts thereof.
wherein R4 is independently as defined above, C(O- The compounds of this invention may also exist in
DOR4 wherein R4 is independently as defined above, hydrated or solvated forms.
hydroxymethyl, NR6R7 wherein R6 and R7 are each 50
The usefulness of the compounds of the present in
independently as defined above, or nitro, or halogen. vention as inhibitors of one of the 5-lipoxygenase en
Aralkyl is an aryl as defined above and attached zyme or cyclooxygenase enzyme or both, or in treating
through an alkylenyl such as methylenyl, ethylenyl, related diseases or conditions may be demonstrated by
propylenyl, butylenyl and isomers thereof. their effectiveness in various standard test procedures.
Me is methyl. 55
A description of each procedure follows.
The compounds of the invention may contain geo
metric isomers. Thus, the invention includes the indi ARBL/ARBC Whole Cell 5-Lipoxygenase and
vidual isomers and mixtures thereof. The individual Cyclooxygenase Assays
isomers may be prepared or isolated by methods known Materials
in the art.
A tautomeric form of selected compounds of formula The rat basophilic leukemia cell line (RBL-1) was
I or II would be recognized by an ordinarily skilled obtained from the American Type Culture Collection
artisan to be within the present invention. (Rockville, Md.).
The compounds of formula I or II are useful both in Radioimmunoassay (RIA) kits of LTB4 and PGF2,
the free base and where possible the free acid form or in 65 were obtained from Amersham (Arlington Heights, Ill.)
the form of base salts thereof, as well as in the form of and Seragen (Boston, Mass.), respectively.
acid addition salts. All forms are within the scope of the All tissue culture media were obtained from GIBCO
invention. In practice, use of the salt form amounts to (Grand Island, N.Y.).
 5,143,928
5 6
Method geenan. The difference between the 5-hour and the
initial paw volume is expressed as delta edema. The
RBL-1 cells are grown in suspension culture in Ea delta edema for each test group of animals is used to
gle's minimum essential medium supplemented with calculate the percent inhibition of edema achieved by
12% fetal bovine serum at 37° C. in an incubator sup the compound at the test dose compared with the vehi
plied with air-5% carbon dioxide. Cells are harvested cle control group. The data in Table I (the dose at
by centrifugation. They are washed with cold phos which swelling is inhibited by the noted percent) is
phate buffered saline pH 7.4 (PBS; NaCl, 7.1 g Na2H calculated by probit analysis for the dose at which per
PO4, 1.15 g; KH2PO4, 0.2 g; and KCl, 0.2 g/L). Cells cent inhibition occurs.
are finally suspended in PBS containing 1.0 mM cal 10
Mycobacterium-Induced Rat Footpad Edena Assay
cium at a density of 2x 106 cells/mL. Cells are incu (MFE): Protocol
bated with and without test agent (in DMSO) (1%
DMSO is without effect on arachidonic acid metabo Mycobacterium butyricum (5 mg/mL) is suspended in
lism) for 10 minutes at room temperature. Calcium iono paraffin oil by sonication for 10 minutes in an ice bath.
phore A23187 (5 uM) is added and cells are incubated 15 Footpad edema is induced on Day 0 by injecting 0.1 mL
for 7 minutes at 37 C. The reaction is stopped by chill of the Mycobacterium mixture into the left hindpaw of
ing the tubes on ice for 10 minutes. Cells are separated lightly anesthetized rats. Swelling in the injected hind
by centrifugation and the supernatant is stored at -20. paw is determined by mercury plethysmography 72
Aliquots (100 uIL) are analyzed for LTB4 and PGF2. hours after injection. Groups of rats are treated with
using radioimmunoassay kits as provided by the sup 20 test compounds (suspended in 0.5% hydroxypropyl
plier. methylcellulose with 0.2% Tween-80) or vehicle 1 hour
Table I contains biochemical data obtained from this before Mycobacterium injection and on Days 1 and 2.
whole cell assay as IC50s which are calculated as the Inhibition of swelling is determined by comparing the
amount of test compound causing 50% inhibition or % change in hindpaw volume in compound- and vehicle
of inhibition at the named micromoles (LM) of LTB4 or 25 treated rats. An ID40 (the dose at which swelling is
PGF2 formation. inhibited by 40%) is calculated by probit analysis or
Carrageenan-Induced Rat Foot Paw Edema-2 (CFE-2) shown as the % inhibition at the dose expressed as LM,
Assay Protocol i.e., 9% at M.
Carageenan solution (1% w/v) is prepared by dis 30 Gastric Ulcerogenicity (UD): Protocol
solving 100 mg carrageenan (Marine Colloidal Div., Male outbred Wistar rats (100-250 g) are fasted for 24
Springfield, N.J.) in 10 mL of sterile saline (0.9%) solu hours. After fasting, test compounds are administered
tion (Travenol). The solution is vortexed for 30 to 45 orally (in 2 mL/kg of 0.5% hydroxypropyl methylcel
minutes. Animals are dosed with compound 1 hour lulose) and the rats are denied access to food and water
before carrageenan challenge. Foot paw edema is in 35 for 6 more hours. The rats are then sacrificed with CO2
duced by injecting 0.10 mL of the 1% carrageenan so that the stomachs can be removed, opened along the
subcutaneously into the plantar portion of the right hind greater curvature, and evaluated for the presence of
paw of each rat under light anesthesia. Initial foot paw gastric ulcers. Results are expressed as the percent of
volume is measured immediately following carrageenan rats with gastric ulcers at a given dose or as the UD50
challenge using mercury plethysmography (Buxco 40 (the dose which causes ulcers in 50% of the rats).
Electronics). Edema is measured 5 hours after carra
TABLE I

CMe3
% at M/ % at M/ Gastric
Example ICSO (M) D40 (mg/kg) Ulcerogenicity
Number Y ARBL ARBC CFE MFE UD50
1B NH2 100% G 10 80% G 10d CO NG 200?
3 CH 1.7a 0.33 41% G 10 3.2
/
N
N
OCH3
4. NHOH 100% G 10 81% G 10d 32% G 10
17% G 30
5 SCH3 0.5/0.8 <0.6 47% G 30 27% (a 2
36% G 10 23% G 50
12 CH3
NH-e-CHCOOH
 5,143,928
TABLE I-continued

CMe3
% at uM/ % at uM/ Gastric
Example ICSQ (M) ID40 (mg/kg) Ulcerogenicity
Number Y ARBL ARBC CFE MFE UD50
7 i O,390 4.55
NH-NH-C-NH2
9 NHCN 0.63 0.16 49%. G. 30
32% G 3
16 H 100% G 10b 87% G iod

Cso for LTB inhibition

% inhibition of LT by G 10 uM
Cso for PGF2a.
% inhibition of PGFa
N is not active at the dose tested

first, subsequently increasing the dose until a maximum

Accordingly, the present invention also includes a response is obtained.
pharmaceutical composition for treating one of the In determining when a lipoxygenase, cyclooxyge
above diseases or conditions comprising an antidisease nase, or dual lipoxygenase/cyclooxygenase inhibitor is
or anticondition effective amount of a compound of the 30 indicated, of course inter alia, the particular condition in
formula I or II or salt thereof as defined above together question and its severity, as well as the age, sex, weight,
with a pharmaceutically acceptable carrier. and the like of the subject to be treated, must be taken
The present invention further includes a method for into consideration and this determination is within the
treating one of the above named diseases or conditions skill of the attendant physician.
in mammals, including man, suffering therefrom com 35 For medical use, the amount required of a compound
prising administering to such mannals either orally or of formula I or II or pharmacologically acceptable salt
parenterally, preferably oral, a corresponding pharma thereof to achieve a therapeutic effect will, of course,
ceutical composition containing a compounds of the vary both with the particular compound, the route of
formula I or II or salt thereof. administration, the mammal under treatment, and the
A physician or veterinarian of ordinary skill readily 40 particular disorder or disease concerned. A suitable
determines a subject who is exhibiting symptoms of any dose of a compound of formula I or II or pharmacologi
one or more of the diseases described above. Regardless cally acceptable salt thereof for a mammal suffering
of the route of administration selected, the compounds from, or likely to suffer from any condition as described
of the present invention of the formula I as described in hereinbefore is 0.1 g to 500 mg of the compound per
pharmaceutical compositions above are formulated into 45 kilogram body weight. In the case of systemic adminis
pharmaceutically acceptable dosage forms by conven tration, the dose may be in the range of 0.5 to 500 mg of
tional methods known to the pharmaceutical art. the compound per kilogram body weight, the most
The compounds can be administered in such oral unit preferred dosage being 0.5 to 50 mg/kg of mammal
dosage forms as tablets, capsules, pills, powders, or body weight administered two to three times daily. In
granules. They also may be administered rectally or 50 the case of topical administration, e.g., to the skin or
vaginally in such forms as suppositories or bougies; they eye, a suitable dose may be in the range 0.1 ng to 100 g
may also be introduced parenterally (e.g., subcutane of the compound per kilogram, typically about 0.1
ously, intravenously, or intramuscularly) using forms ug/kg.
known to the pharmaceutical art. They are also intro In the case of oral dosing for the treatment or prophy
duced directly to an affected area (e.g., in the form of 55 laxis of arthritis or inflammation in general, due to any
eye drops or by inhalation). For the treatment of asthma course, a suitable dose of a compound of formula I or II
or allergies, particularly dermatological disorders such or physiologically acceptable salt thereof, may be as
as erythema, psoriasis, and acne, the compounds may specified in the preceding paragraph, but most prefera
also be administered topically in the form of ointments, bly is from 1 mg to 10 mg of the compound per kilo
gels, or the like. However, in general, the preferred gram, the most preferred dosage being from 1 mg to 5
route of administration is orally. mg/kg of mammal body weight, for example from 1 to
An effective but nontoxic quantity of the compound 2 mg/kg.
is employed in treatment. The ordinarily skilled physi It is understood that the ordinarily skilled physician
cian or veterinarian will readily determine and pre or veterinarian will readily determine and prescribe the
scribe the effective amount of the compound to prevent 65 effective amount of the compound to prevent or arrest
or arrest the progress of the condition for which treat the progress of the condition for which treatment is
ment is administered. In so proceeding, the physician or administered. In so proceeding, the physician or veteri
veterinarian could employ relatively low dosages at narian could employ relatively low doses at first, subse
 9
5,143,928 O
quently increasing the dose until a maximum response is salt group, e.g. -CH2COO-Na+), typically attached
obtained. directly to a ring system, preferably to an aromatic or
While it is possible for an active ingredient to be heteroaromatic ring system.
administered alone, it is preferable to present it as a The fenamic acid derivatives which may be used
pharmaceutical formulation comprising a compound of 5 comprise: nefanamic acid, meclofenamic acid, flufe
formula I or II or a pharmacologically acceptable acid namic acid, niflumic acid, and tolfenamic acid. Structur
addition or base salt thereof and a pharmacologically ally related fenamic acid derivatives having similar
acceptable carrier therefor. Such formulations consti analgesic and antiinflammatory properties are also in
tute a further feature of the present invention. tended to be encompassed by this group.
In addition to the compounds of formula I, the phar 10 Thus, "fenamic acid derivatives' as defined herein
maceutical compositions can also contain other active are nonnarcotic analgesics/nonsteroidal antiinflamma
ingredients, such as cyclooxygenase inhibitors, nonste tory drugs which contain the basic structure:
roidal antiinflammatory drugs (NSAIDs), peripheral
analgesic agents such as zonepirac, diflunisal, and the
like. The weight ratio of the compound of the formula 15
I to the second active ingredient may be varied and will
depend upon the effective dose of each ingredient. Gen
erally, an effective dose of each will be used. Thus, for
example, when a compound of the formula I or II is COOH
-C)
combined with an NSAID, the weight ratio of the com 20
pound of the formula I to the NSAID will generally which can bear a variety of substituents and in which
range from about 1000:1 to about 1:1000, preferably the free -COOH group can be in the form of a pharma
about 200:1 to about 1:200. Combinations of a com ceutically acceptable salt group, e.g., -COONa.
pound of the formula I and other active ingredients will The biphenylcarboxylic acid derivatives which can
generally also be within the aforementioned range, but 25 be used comprise: diflunisal and flufenisal. Structurally
in each case, an effective dose of each active ingredient related biphenylcarboxylic acid derivatives having simi
should be used. lar analgesic and antiinflammatory properties are also
Combinations of a compound of the formula I and intended to be encompassed by this group. .
other active ingredients will generally be in the afore Thus, "biphenylcarboxylic acid derivatives' as de
mentioned ratios. 30 fined herein are nonnarcotic analgesics/nonsteroidal
NSAIDs can be characterized into five groups: antiinflammatory drugs which contain the basic struc
(i) the propionic acid derivatives; ture:
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;
(4) the biphenylcarboxylic acid derivatives; and 35
(5) the oxicans
or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be used COOH
comprise: ibuprofen, ibuprufen aluminum, indoprofen,
ketoprofen, naproxen, benoxaprofen, flurbiprofen, feno which can bear a variety of substituents and in which
profen, fenbufen, pirprofen, carprofen, oxaprozin, the free -COOH group can be in the form of a pharma
pranoprofen, miroprofen, tioxaprofen, suprofen, al ceutically acceptable salt group, e.g., -COONa.
minoprofen, tiaprofen, fluprofen, and bucloxic acid. The oxicans which can be used in the present inven
Structurally related propionic acid derivatives having tion comprise: piroxican, sudoxican, isoxicam, and
similar analgesic and antiinflammatory properties are 45 4-hydroxyl-1,2-benzothiazine 1,1-dioxide 4-(N-phenyl)-
also intended to be included in this group. carboxamide. Structurally related oxicans having simi
Thus, "propionic acid derivatives' as defined herein lar analgesic and antiinflammatory properties are also
are nonnarcotic analgesics/nonsteroidal antiinflamma intended to be encompassed by this group.
tory drugs having a free -CH(CH3)COOH or Thus, "oxicams' as defined herein are nonnarcotic
-CH2CH2COOH group (which optionally can be in SO analgesics/nonsteroidal antiinflammatory drugs which
the form of a pharmaceutically acceptable salt group, have the general formula:
e.g., -CH(CH3)COO-NA+ or -CH2CH
2COONa), typically attached directly or via a car
bonyl function to a ring system, preferably to an aro
matic ring system. 55
The acetic acid derivatives which may be used com
prise: indomethacin, which is a preferred NSAID, sulin
dac, tolmetin, zomepirac, diclofenac, fenclofenac, al
clofenac, ibufenac, isoxepac, furofenac, tiopinac,
zidonetacin, acemetacin, fentiazac, clidanac, oxpinac,
and fenclozic acid. Structurally related acetic acid de wherein R is an aryl or heteroaryl ring system.
rivatives having similar analgesic and antiinflammatory The following NSAIDs may also be used: acemeta
properties are also intended to be encompassed by this cin, alminoprofen, amfenac sodium, aminoprofen, ani
group. trazafen, antrafenine, auranofin, bendazac lysinate, ben
Thus, "acetic acid derivatives' as defined herein are 65 zydamine, beprozin, broperamole, bufezolac, carprofen,
nonnarcotic analgesics/nonsteroidal antiinflammatory cinmetacin, ciproguaZone, clidanac, cloximate, dazida
drugs having a free-CH2COOH group (which option mine, deboxanet, delmetacin, detomidine, dexindo
ally can be in the form of a pharmaceutically acceptable profen, diacerein, di-fisalamine, difenpyramide, emorfa
 5,143,928
11 12
zone, enfenamic acid, enolican, epirizole, etersalate, 30, 1989 and published in EP application 89121896.8.
etodolac, etofenamate, fanetizole mesylate, fenclofenac, which, therefore, is incorporated by reference.
fenclorac, fendosal, fenflumizole, fentiazac, feprazone, An alternate procedure for the preparation of the
floctafenine, flunixin, flunoxaprofen, fluproguazone, above compound 2 is the condensation of methylmer
fopiirtoline, fosfosal, furcloprofen, furofenac, capto compound 3 with amines such as N-isopropylhy
glucametacin, guainesal, ibuproxam, isofezolac, iso droxylamine, N-cyclohexylhydroxylamine, methoxyla
mixin, isoprofen, isoxepac, isoxicam, lefetamine HCl, mine, aqueous methylamine, aqueous dimethylamine,
leflunomide, lofemizole, lonazolac calcium, lotifazole, guanidine, -thiosemicarbazide in alcoholic solvents at
loxoprofen, lysin, clonixinate, meclofenamate sodium, temperature 24'-100° C. with the evolution of methyl
meseclazone, microprofen, nabumetone, nictindole, O marcaptan.
ninesulide, orpanoxin, oxanetacin, oxapadol, oxapro Another procedure for the preparation of the above
zin, perisoxal citrate, pimeprofen, pimetacin, piproxen, compound 2 is the condensation of methylmercapto
pirazolac, pirfenidone, pirprofen, pranoprofen, pro compound 3 with cyanamide, glycine, dl-alanine, 2
glumetacin maleate, proquaZone, pyridoxiprofen, cyanoacetamide in hydroxylic solvents such as metha
sudoxican, suprofen, talmetacin, talniflunate, tenox 15 nol, ethanol, isopropanol at temperature 40'-100' C. in
icam, thiazolinobutazone, thielavin B, tiaprofenic acid, the presence of potassium t-butoxide.
tiaramide HCl, tiflamizole, timegadine, tioxaprofen, 3,5-di-tert-butyl-4-hydroxy-2-methylmarcapto com
tolfenamic acid, tolpadol, tryptamid, ufenamate, and pound 3, is used as a starting material for a variety of
zidometacin. transformations. The compound 3 is synthesized from 1
Finally, NSAIDs which may also be used include the 20 by reacting with methyliodide in dioxane in the pres
salicylates, specifically aspirin, and the phenylbuta ence of triethylamine at 0-50° C.
zones, and pharmaceutically acceptable salts thereof. Similar treatment of 1 with isopropyl iodide or bromo
Pharmaceutical compositions comprising the formula acetic acid gives the desired compound 4, where
I compounds may also contain as the second active R-CH(CH3)2, CH2CO2H
25
ingredient, antihistaminic agents such as benadryl,
dramamine, histadyl, phenergan, and the like. Alterna l
tively, they may include prostaglandin antagonists such Me3C N NH
as those disclosed in European Patent application
11,067 or thromboxane antagonists such as those dis x-
closed in U.S. Pat. No. 4,237,160. They may also con HO \,
tain histidine decarboxylase inhibitors such as a CMes
fluoromethylhistidine, described in U.S. Pat. No.
4,325,961. The compounds of the formula I or II may 2
also be advantageously combined with an H1 or H2 35 Me3C
receptor antagonist, such as for instance cimetidine,
ranitidine, terfenadine, famotidine, temelastine, acrivas
tine, loratadine, cetrizine, tazifylline, azelastine, amino HO
thiadiazoles disclosed in EP 81 102976.8 and like com
CMe3 R
pounds, such as those disclosed in U.S. Pat. Nos.
4,283,408; 4,362,736; 4,394,508, and European Patent O 3
Application No. 40,696. The pharmaceutical composi
tions may also contain a Kit/H+ ATPase inhibitor such Me3C N N
as omeprazole, disclosed in U.S. Pat. No. 4,255,431, and A.
the like. Each of the references referred to in this para 45 HO X
graph is hereby incorporated herein by reference. SCH3
The compounds of the formula I or II are prepared CMe3
generally by the following processes and constitute a 4
further aspect of the present invention.
Generally, the compounds of formula I or II are SO
prepared by one of the following methods.
General Procedure for the Preparation of
3,5-Di-tertbutyl-4-hydroxyphenylmethylene CMe3
Derivatives of 2-Substituted Thiazolidinones, 55
Oxazolidinones and Immidazolidinones as One of skill in the art would recognize variations in
Antiinflammatory Agents the sequence and would recognize variations in the
A general method for the preparation of benzylidene appropriate reaction conditions from the analogous
compound 2 is the condensation of the thione 1 (Iso reactions shown or otherwise known which may be
Katsumi et al Chem. Pharm. Bull, 34(4); 1619-1627 appropriately used in the processes above to make the
(1986) with amines such as hydroxylamine, N-methyl compounds of the formula I or II herein.
hydroxylamine, and N,N-dimethylethylamine in hy Introduction and removal of such suitable oxygen
droxylic solvents such as methanol, ethanol, isopropa protecting groups are well known in the art of organic
nol at temperature 24-100° C. with the evolution of chemistry; see for example, "Protective Groups in Or
hydrogen sulfide. Variations in the definition of Y as 65 ganic Chemistry,” J. F. W. McOmie, ed., (New York,
found in the compound of formula I of the present in 1973), pages 43ff, 95ff, J. F. W. McOmie, Advances in
vention are prepared by processes analogous to those Organic Chemistry, Vol. 3, 159-190 (1963); J. F. W.
described in U.S. application Ser. No. 426,814 filed Oct. McOmie, Chem. & Ind., 603 (1979), and T. W. Greene,
 5,143,928
13 14
"Protective Groups in Organic Synthesis”, Wiley (New Anal. for C18H24N2O2S.CH3SO3H.O. 13H2O: Calcd:
York), 1981, Chapters 2, 3, and 7. C, 52.96; H, 6.61; N, 6.50; S, 14.88. Found: C, 52.58; H,
Examples of suitable oxygen protecting groups are 6.57; N, 6.38; S, 14.94.
benzyl, trialkylsilyl, ethoxyethyl, methoxyethox EXAMPLE 2
ymethyl, methoxymethyl, trialkylsilylethyl, and the
like. 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme
In the process described herein for the preparation of thylene-2-(hydroxymethylamino)-4-(5H)-thiazolone,
compounds of this invention the requirements for pro (Z)-
tective groups are generally well recognized by one O A mixture of N-methylhydroxylamine hydrochloride
skilled in the art of organic chemistry, and accordingly (12.52 g, 0.15 mole), barium carbonate (14.8 g., 0.075
the use of appropriate protecting groups is necessarily mole), ethanol (50 mL), and water (50 mL) is stirred at
implied by the processes of the charts herein, although room temperature for ten minutes. 5-(3,5-bis (1,1-dime
such groups may not be expressly illustrated. thylethyl)-4-hydroxyphenyl)methylene-2-thioxo-4-
The products of the reactions described herein are is thiazolidinone (see Ikuo Katsumi et al Chem. Pharm.
isolated by conventional means such as extraction, dis Bull, 34(4), 1619-1627 (1986)) (17.5 g, 0.05 mole) and
tillation, chromatography, and the like. ethanol (600 mL) are added to it and the resulting mix
Starting materials not described herein are available ture is stirred and refluxed for 8 hours. The reaction
commercially, are known, or can be prepared by meth mixture is then cooled, filtered, and the solvent is re
ods known in the art. moved at 45° C. under reduced pressure. The residue is
20
The salts of the compounds of formula I or II de treated with ice-water and the resulting solid is sepa
scribed above are prepared by reacting the appropriate rated by filtration, washed with water and extracted
base or acid with a stoichiometric equivalent of the with methylene chloride. The organic layer is dried and
compounds of formula I or II. concentrated to give 19 g of a residue. The residue is
The invention is further elaborated by the representa- 25 flash chromatographed over silica gel (214 g), eluting
tive examples as follows. Such examples are not meant first with methylene chloride and then with methylene
to be limiting. chloride-methanol (9:1) to give 11.5g of the pure prod
uct. It is recrystallized from methanol-ethyl acetate, to
EXAMPLE 1. give 8.6 g (48%) of 5-2,6-Bis(1,1-dimethylethyl)-4-
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me- 30 hydroxyphenyl)methylene-2-(hydroxymethylamino)-
thylene-2-imino-4-thiazolidinone, (Z)- 4(5H)-thiazolone, (Z)-, mp 199-200 C. (dec).
A mixture of 3,5-di-tert-butyl-4-hydroxybenzalde Anal. for C19H26N2O3S: Calcd: C, 62.96; H, 7.23; N,
hyde (9.4 g, 0.04 mole), pseudothiohydantoin (4.7 g, 7.73; S, 8.84. Found: C, 62.72; H, 7.23; N, 7.43; S, 8.59.
0.04.05 mole), sodium acetate (8.3 g, 0.1 mole), and gla 35 EXAMPLE 3
cial acetic acid (200 mL) is stirred and heated at reflux 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
for 21 hours. The cooled mixture is added to ice-water thylene-2-(methoxymethylamino)-4-(5H)-thiazolone,
and the precipitated solid is filtered and washed with monohydrochloride, (Z)-
water. The solid residue is dissolved in ether and
washed successively with water, aqueous sodium bicar A solution of 5-(3,5-bis(1,1-dimethylethyl)-4-hydrox
bonate solution, and water. The extract is dried and the yphenyl)methylene-2-(methoxymethylamino)-4-(5H)-
solvent is removed to give 9.4 g of a residue. The crude thiazolone (8.3g, 0.022 mole) in 50 mL methylene chlo
product is recrystallized from methanol-ethyl acetate to ride is treated with ethereal hydrogen chloride to give
give 3.8 g (38%) of 5-3,5-Bis(1,1-dimethylethyl)-4- 9.1 g (quantitative yield) of pure product, mp 177-179
hydroxyphenyl)methylene)-2-imino-4-thiazolidinone, 45 C. It is recrystallized from methylene chloride
(Z)-, mp 277-279 C. methanol-ether to give 6.0 g (66%) of analytically pure
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
Anal. for C18H24N2O2S: Calcd: C, 65.03; H, 7.28; N, thylene-2-(methoxymethylamino)-4(5H)-thiazolone,
8.43; S, 9.64. Found: C, 64.90; H, 7.30; N, 8.21; S, 9.50. monohydrochloride, (Z)-, mp 177-179 C.
EXAMPLE 1B 50 Anal. for C20H28N2O3S.HCl: Calcd: C, 58.17; H,
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme 7.08; N, 6.78; S, 7.76; Cl, 8.58. Found: C, 58.60; H, 7.20;
thylene-2-imino-4-thiazolidinone, (Z)-, N, 6.81; S, 7.85; Cl, 8.31.
methanesulfonate (1:1) salt EXAMPLE 4
A solution of methanesulfonic acid (0.75 g, 0.0078 55
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
mole) in tetrahydrofuran (4 mL) is added to a stirred thylenel-2,4-thiazolidinedione, 2-oxime (Z)-
solution of 5-(3,5-bis(1,1-dimethylethyl)-4-hydroxy A mixture of hydroxylamine hydrochloride (40.75 g,
phenyl)methylene-2-imino-4-thiazolidinone (2.32 g, 0.59 mole), potassium-t-butoxide (60.6 g., 0.54 mole),
0.007 mole) in tetrahydrofuran (189 mL) at room tem and methanol (500 mL) is stirred at room temperature
perature. The mixture is stirred for 25 minutes and the so for 25 minutes. A solution of 5-(3,5-bis (1,1-dimethyle
solvent is removed <30 C. under reduced pressure. thyl)-4-hydroxyphenyl)methylene-2-thioxo-4-
The residue is triturated with ether and the resulting thiazolidinone (49.64g, 0.14 mole) in methanol (2.5L) is
solid is collected, washed with ether to give 2.99g of a then added and the mixture is stirred and refluxed for 23
solid mp 252 C. (dec). The residue is recrystallized hours. The reaction mixture is then cooled, filtered, and
from methanol-ether to give 2.67 g (89.3%) of 5-3,5- 65 the solvent evaporated at 45 C. under reduced pres
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- sure. The residue is treated with ice-water and the re
imino-4-thiazolidinone, (Z)-, methanesulfonate (1:1) sulting solid is separated, washed with water, and then
salt, mp. 252 C. (dec). dissolved in ether. The organic layer is dried to give 15
 5,143,928
15 16
g of a solid. The solid is recrystallized from ether-tol 3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
uene to give 14.6 g (30%) of pure 5-3,5-bis(1,1-dime thylene-4-oxo-2-thiazolidinylidenehydrazinecarbo
thylethyl)-4-hydroxyphenyl)methylene-2,4-thiazoli thiamide, (Z)-, mp 200-202 C.
dinedione, 2-oxime (Z)-, mp. 241 C. (dec). Anal. for C19H26N4O2S2.H2O: Calcd: C, 53.75; H,
The compound of Example 4 is also made via BaCO3 6.65; N, 13.20. Found: C, 53.76; H, 6.48; N, 13.24.
method as described in Example 2 using appropriate
corresponding starting materials. EXAMPLE 8
EXAMPLE 5 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
thylene-2-hydroxy(1-methylethyl)amino-4(5H)-
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me O thiazolone, (Z)-
thylene)-2-(methylthio)-4(5H)-thiazolone, (Z)-
A solution of 5-(3,5-bis(1,1-dimethylethyl)-4-hydrox A mixture of N-isopropylhydroxylamine hydrochlo
yphenyl)methylene-2-thioxo-4-thiazolidinone (69.9 g, ride (5.5 g, 0.049 mole), potassium-t-butoxide (4.83 g,
0.2 mole) and triethylamine (20.24g, 0.2 mole) in diox 0.043 mole), and ethanol (500 mL) is stirred at room
ane (1.1 L) is stirred at room temperature for 1 hour. 15 temperature for 15 minutes. 5-(3,5-Bis(1,1-dimethyle
Methyl iodide (141.9 g, l mole) is added and the reac thyl)-4-hydroxyphenyl)methylene-2-(methylthio)-
tion mixture is stirred for additional 20 hours. The mix 4(5H)-thiazolone (7.27 g, 0.02 mole) is then added and
ture is filtered and the excess solvent is removed <40 the mixture is refluxed with stirring for six hours. After
C. under reduced pressure. The cooled mixture is added removal of the solvent under reduced pressure, the
to ice-water and extracted with chloroform. The solu cooled reaction mixture is poured into a mixture of
tion is washed with water and concentrated to leave a ice-water containing 1N hydrochloric acid and ex
residue. This residue is recrystallized first from toluene tracted with ether. The organic layer is washed with
and then from methanol to give 19.2 g (26%) of pure water, dried, and the solvent is evaporated to give 7.7g
product, mp 159-160° C. The combined filtrates are of a residue. The residue is flash chromatographed on
evaporated and the residue is recrystallized from metha 25 silica gel (202 g), eluting first with methylene chloride
nol to give additional amount of 20.7 g (29%) of the and then with methylene chloride-methanol (9:1) to
product which is 5-3,5-Bis(1,1-dimethylethyl)-4- give 7.0 g purified product. It is recrystallized from
hydroxyphenyl)-methylene)-2-(methylthio)-4(5H)- methylene chloride-ethyl acetate-ether to give 4.2 g
thiazolone, (Z)-, mp 159-160 C. (54%) of pure 5-3,5-Bis-(1,1-dimethylethyl)-4-hydrox
Anal for C19H25NO2S2: Calcd: C, 62.77; H, 6.93; N, 30 yphenyl)methylene-2-hydroxy(1-methylethyl)amino
3.85; S, 17.64. Found: C, 62.80; H, 6.54; N, 3.47; S, 4(5H)-thiazolidinone, (Z)-, mp. 208 C. (dec).
17.72. Anal. for C21H3ON2O3S: Calcd: C, 64.58; H, 7.74; N,
EXAMPLE 6 7.17. Found: C, 64.52; H, 7.67; N, 6.92.
N-(5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me 35
EXAMPLE 9
thylene-4-oxo-2-thiazolidinylidenelglycine, (Z)- 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
A mixture of glycine (2.25 g, 0.03 mole), potassium-t- thylenel-4,5-dihydro-4-oxo-2-thiazolylcyanamide
butoxide (2.81 g, 0.025 mole), and ethanol (700 mL) is A solution of cyanamide (5.04 g, 0.12 mole) and
stirred at room temperature for 15 minutes. 5-(3,5- potassium-t-butoxide (12.28 g, 0.11 mole) in ethanol (1
Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- 40
L) is stirred at room temperature for 15 minutes. 5-C3,5-
(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene)-2-
added to it and the mixture is refluxed with stirring for (methylthio)-4(5H)-thiazolone (36.36 g, 0.1 mole) is
20 hours. The mixture is then filtered and the solvent then added to the solution and the mixture is refluxed
removed at 40 C. under reduced pressure. The residue 45
with stirring for 23 hours. After removal of the solvent
is treated with ice-water, acidified with 1N aqueous (-650 mL), the cooled reaction mixture is poured into
hydrochloric acid and extracted with ether. The or a mixture of ice-water containing 1N hydrochloric acid.
ganic layer is washed with water, dried, and the solvent The solid is filtered, washed with water and then dis
removed to give 7.75 g of a solid. The crude solid is solved in ether-ethyl acetate. The organic layer is
recrystallized from tetrahydrofuran-ether to give 2,95g washed with water, dried and the solvent removed to
(38%) of pure N-(5-3,5-bis(1,1-dimethylethyl)-4- SO
give 35.7 g of a solid. The solid is recrystallized from
hydroxyphenyl)methylene-4-oxo-2- methanol to give 25.1 g (70%) of pure (5-3,5-Bis(1,1-
thiazolidinylidenelglycine, (Z)-, mp. 260' C. (dec). dimethylethyl)-4-hydroxyphenyl-methylene-4,5-dihy
Anal. for C20H26N2O4S.0.25C4H8O: Calcd: C, 61.74; dro-4-oxo-2-thiazolylcyanamide, mp. 240-242 C.
H, 6.91; N, 6.86; S, 7.85. Found: C, 61.82; H, 7.08; N, Anal. for C19H23NO2S.0.2CH3OH: Calcd: C, 63.38;
6.50; S, 7.55. 55
H, 6.59; N, 11.55; S, 8.81. Found: C, 63.18; H, 6.70: N,
EXAMPLE 7 11.55: S, 8.75.
2-5-3,5Bis(1,1-dimethylethyl)-4-hydroxyphenyl EXAMPLE 9B
methylene)-4-oxo-2-thiazolidinylidenehydrazinecarbo 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
thiamide, (Z)- thylenel-4,5-dihydro-4-oxo-2-thiazolyl)cyanamide,
A mixture of 5-(3,5-bis(1,1-dimethylethyl)-4-hydrox choline salt
yphenyl)methylene-2-(methylthio)-4-(5H)-thiazolone
(6.13 g, 0.0169 mole) and thiosemicarbazide (1.53 g, To a solution of 5-(3,5-bis(1,1-dimethylethyl)-4-
0.0169 mole) in ethanol (300 mL) is refluxed with stir hydroxyphenyl)methylenel-4,5-dihydro-4-oxo-2-
ring for 7 hours. After standing overnight at room tem 65 thiazolylcyanamide (12.7 g, 0.035 mole) is added cho
perature, the product is separated by filtration, washed line bicarbonate (12.1 g, 0.034 mole, 46.6% aqueous).
with ethanol to give 5.78g of a solid. It is recrystallized The mixture is refluxed for two hours. After removal of
from DMF-methanol to give 3.4 g (47%) of pure 2-5- the solvent, the residue is digested with ethyl acetate,
 5,143,928
17 18
then cooled and the precipitate is separated by filtration, EXAMPLE 10
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxylphenyl)me
washed with ethyl acetate to give 15 g of pure product, thylene)-2-[2-(dimethylamino)ethylamino-4(5H)-
thiazolone, (Z)-
mp 189-190° C. It is recrystallized from methanol A mixture of 5-((3,5-bis(1,1-dimethylethyl)-4-hydrox
yphenyl)methylene)-2-thioxo-4-thiazolidinone (6.99 g,
ethyl acetate to give 14.02 g (89.3%) of a white crystal 0.02 mole), N,N-dimethylaminoethylamine (5.29 g, 0.06
10 mole), and ethanol (250 mL) is refluxed with stirring for
line analytically pure (5-3,5-Bis(1,1-dimethylethyl)-4- 7.5 hours. The solvent is distilled off under reduced
pressure and the residue is recrystallized from toluene,
hydroxyphenyl)methylenel-4,5-dihydro-4-oxo-2- to give 5.7 g of a solid. The solid is recrystallized from
methanol-ethyl acetate-toluene to give 3.4 g (42%) of
thiazolylcyanamide, choline salt, mp 189-190° C. 15
pure 5-(2,6-Bis(1,1-dimethylethyl)-4-hydroxylphenyl
methylene-2-[2-(dimethylamino)ethylamino-4(5H)-
thiazolone, (Z)-, mp. 209-21 C.
Anal. for C19H23N3O2S.C5H4NO: Calcd: C, 62.58; Anal. for C22H33N3O2S: Calcd: C, 65.48; H, 8.24; N,
10.41. Found C, 65.38; N, 8.34; S, 10.19.
H, 7.88; N, 12.16; S, 6.96. Found: C, 62.53; H, 7.86; N, 20
Following the procedure of Examples 1-10, the fol
lowing examples were prepared using appropriate cor
12.21; S, 7.14. responding starting materials.

25

30

35

45

50

55

65
 5,143,928
25 26
EXAMPLE 2.0 EXAMPLE 22
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me (5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
thylene-2-thioxo-4-oxazolidinone thylenel-4,5-dihydro-4-oxo-2-oxazolylcyanamide
A mixture of 14.1 g (0.060 mole) of 3,5-di-tertbutyl-4- A suspension of 0.38 g (0.0090 mole) of cyanamide in
hydroxybenzaldehyde, 7.0 g (0.060 mole) of 2-thioxo-4- 50 mL of ethanol is cooled in ice and treated in small
oxazolidinone, 17.4 g (0.21 mole) of sodium acetate, and portions with 0.93 g (0.0083 mole) of potassium tert
75 mL of acetic acid is stirred and heated at reflux under butoxide. After stirring for 15 minutes, 2.6 g (0.0075
mole) of 5-3,5-bis(1,1-dimethylethyl)-4-hydroxy
a nitrogen atmosphere for 20 hours. The cooled reac O
phenylmethylene-2-(methylthio)-4-(5H)-oxazolone is
tion mixture is added to 900 g of ice/water and the added, followed by an additional 25 mL of ethanol. The
precipitated product filtered and washed with water. mixture is stirred at reflux for 3 hours, then cooled to
There is obtained 16.2 g (81% yield) of the oxazole allow precipitation of the potassium salt of the product.
product, suitable for further reaction. 15 The salt is filtered, washed several times with ether,
A sample of the above crude product is chromato suspended in 100 mL of cold water, and acidified with
graphed over silica gel, using elution with 2.5% ethyl 1.0 mL of acetic acid. The mixture is stirred for 30
acetate in dichloromethane followed by 25% ethyl ace minutes and extracted with ethyl acetate (4X75 mL).
tate. The chromatography product is recrystallized The combined organic layers are washed with brine
from aqueous acetonitrile to yield the purified oxazoli 20 (2X 150 mL), dried (anhydrous sodium sulfate), and
dinone, 5-3,5-bis(1,1-dimethylethyl)-4-hydroxy evaporated to yield 1.0 g (38%) of the nitrile product,
phenyl)methylene-2-thioxo-4-oxazolidinone, mp. 240 (5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenylme
C. dec.
thylene-4,5-dihydro-4-oxo-2-oxazolylcyanamide. A
sample recrystallized from hexane:ethyl acetate had mp
Anal. for C18H23NO3S: Calcd: C, 64.B3; H, 6.95; N, 25 220 C. dec.
4.20. Found: C, 65.00: H, 6.95: N, 4.17. Anal. for C19H23N3O3: Calcd: C, 66.84; H, 6.79; N,
EXAMPLE 20A 12.31. Found: C, 66.81; H, 6.83; N, 11.92.
An alternate procedure for the preparation of the EXAMPLE 23
above compound is as follows: 30 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
A mixture of 18.8 g (0.080 mole) of 3,5-di-tertbutyl-4- thylenel-4,5-dihydro-4-oxo-2-oxazolylcyanamide
hydroxybenzaldehyde, 10.0 g (0.085 mole) of 2-thioxo choline salt
4-oxazolidinone, 28 mL of acetic acid, and 1.6 g (0.018 A solution of 0.95 g (0.0028 mole) of the parent cyan
mole) of 6-alanine in 80 mL of toluene is stirred and amide of the title compound in 10 mL of methanol is
heated at reflux (with the inclusion of a Dean-Stark 35 treated with a solution of 1.0 g (0.0028 mole) of 46%
trap) for 4 hours. The precipitated crude product is aqueous choline bicarbonate in 5 mL of methanol. The
filtered from the cooled reaction mixture and washed mixture is digested for a few minutes on the steam bath,
with hexane. Recrystallization from aqueous acetoni filtered, cooled, and the filtrate is evaporated. The resi
trile yields 11.1 g (41%) of the oxazolidinone product, due is redissolved in methanol and reevaporated three
identical with that prepared previously, i.e., 5-3,5- times. The final glassy residue is stirred in 40 mL of
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- hexane. Filtration yields 0.64 g (53%) of the choline
thioxo-4-oxazolidinone. salt, 5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-
methylenel-4,5-dihydro-4-oxo-2-oxazolyl)cyanamide
EXAMPLE 21
45
choline salt, mp. 85 C. dec.
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me Anal. for C24H36N4O4.0.5H2O: Calcd: C, 63.55; H,
thylene-2-(methylthio)-4(5H)-oxazolone 8.22; N, 12.35. Found: C, 63.92; H, 8.38; N, 12.31.
EXAMPLE 24
A solution of 5.0 g (0.015 mole) of 5-3,5-bis(1,1- 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme
dimethylethyl)-4-hydroxyphenyl)methylene-2-thioxo 50 thylene-2-thioxo-4-imidazolidinone
4-oxazolidinone in 75 mL of tetrahydrofuran is cooled
in ice and treated with 2.4 mL (1.7 g, 0.017 mole) of A mixture of 3,5-di-tert-butyl-4-hydroxybenzalde
triethylamine. The mixture is stirred with ice cooling hyde (300 g, 128 mmols), 2-thiohydantoin (14.8 g., 128
for 1 hour, then treated with 4.5 mL (10.3 g, 0.072 mole) mnols), and sodium acetate (36 g) in acetic acid (200
of iodomethane. The ice bath is removed, and the mix 55 ml) is stirred under nitrogen and heated to reflux. After
ture is stirred for an additional 24 hours. The reaction 24 hours the mixture is allowed to cool, and is stirred
mixture is filtered, and the filter cake is washed several into water (2 L). After an hour the product is filtered
times with fresh tetrahydrofuran. The combined fil off, washed three times with water, and dried. Recrys
trates are evaporated, and the residue is chromato
tallization from acetonitrile gave the 5-3,5-bis(1,1-
dimethylethyl)-4-hydroxyphenyl)methylene-2-thioxo
graphed (silica gel, 2.5-5% ethyl acetate in dichloro 4-imidazolidinone (24.6 g), mp 278-279 C. (dec).
methane elution) to yield 4.3 g (83%) of the purified EXAMPLE 25
thio ether, 5-3,5-bis(1,1-dimethylethyl)-4-hydroxy
phenyl)methylene-2-(methylthio)-4-(5H)-oxazolone. A 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme
sample recrystallized from ethyl acetate:hexane had mp 65 thylene-1,5-dihydro-2-(methylthio)-4H-imidazol-4-one
164-166 C. Iodomethane (0.5 mL, 8 mmols) is added to a stirred
Anal. for C19H25NO3S: Calcd: C, 65.67; H, 7.25; N, suspension of 5-3,5-bis(1,1-dimethylethyl)-4-hydroxy
4.03. Found: C, 65.72; H, 7.20; N, 3.81. phenyl)methylene)-2-thioxo-4-imidazolidinone (2.5 g,
 5, 143,928 28
27
7.5 mmols) and diisopropylethylamine (1.35 mL, 7.7 Starting Materials
mnols) in ethanol (25 mL), and the mixture is stirred 1-Methyl-2-thioxo-4-imidazolidinone is prepared by
under an inert atmosphere at room temperature. After 5 the procedure of Kenyon, J. Am. Chem. Soc. 93 (1971)
hours the resultant solution is stirred into water (150 5 5542.
ml). After a hour the precipitate is filtered off, rinsed All other reagents were obtained from commercial
three times with water and dried to afford the 5-3,5- SOCCS.
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene)-
1,5-dihydro-2-(methylthio)-4H-imidazol-4-one (2.6 g), EXAMPLE 29
mp 248-249 C. 10 (5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
EXAMPLE 26 thylene)-4,5-dihydro-4-oxo-2-oxazolyl)guanidine
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me A solution of 2.0 g (0.02l mole) of guanidine hydro
thylene-1-methyl-2-thioxo-4-imidazolidinone chloride in 75 mL of ethanol is cooled in ice and treated
15 in portions with 2.2 g (0.020 mole) of potassium tert
A mixture of 3,5-di-tert-butyl-4-hydroxybenzalde butoxide. The mixture is stirred for 15 minutes, and then
hyde (19.0 g, 81 mmols), 1-methyl-2-thioxo-4- rapidly filtered into a suspension of 4.6 g (0.013 mole) of
inidazolidinone (10.6 g., 81 mmols) and beta-alanine (4.7 5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
g, 53 mmols) in acetic acid (150 ml) is stirred under an thylene-2-(methylthio)-4-(5H)-oxazolone in 75 mL of
inert atmosphere and heated to reflux. After 5 hours the 20 ethanol. The new reaction mixture is stirred at reflex for
mixture is allowed to cool, and is stirred into water (1.5 3 hours, then cooled and filtered. The filtrate is evapo
L). After an hour the product is filtered off, washed rated 50% and added to 500 g of ice and water. The
three times with water, and dried. Recrystallization precipitated solid is filtered, washed with water, and
from acetonitrile gave the 5-3,5-Bis(1,1-dimethyle dissolved in 200 mL of ethyl acetate. The solution is
thyl)-4-hydroxyphenyl)methylene)-1-methyl-2-thioxo 25 washed with brine (3x200 mL), dried (anhydrous so
4-imidazolidinone (17.5 g), mp 242-244 C. dium sulfate), and evaporated. The residue is chromato
graphed over silica gel, using elution with 10% acetoni
EXAMPLE 27 trile in ethyl acetate. The purified product, (5-3,5-
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene)-
30 4,5-dihydro-4-oxo-2-oxazolyl)guanidine, is 2.6 g (55%
thylene-1,5-dihydro-1-methyl-2-(methylthio)-4H yield). A sample recrystallized from aqueous acetoni
imidazol-4-one trile has mp 258'-dec.
Iodomethane (1.2 mL, 19 mmols) is added to a stirred Calcd. for C19H26N4O3: Calcd: C, 63.66; H, 7.31; N,
suspension of 5-3,5-bis(1,1-dimethylethyl)-4-hydroxy 15.63. Found: 63.93; H, 7.25; N, 15.57. w
phenyl)methylene-1-methyl-2-thioxo-4-inidazolidi 35
EXAMPLE 30
none (4.0 g, 12 mmols) and diisopropylethylamine (2.4 (5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
mL, 14 mmols) in ethanol (50 ml) and the mixture is thylene)-4,5-dihydro-4-oxo-2-oxazolylguanidine
stirred under an inert atmosphere at room temperature. methanesulfonate
After 18 hours the mixture is stirred in water (300 mL) A solution of 1.80 g (0.0050 mole) of the parent guani
for an hour and the product is filtered off, washed three dine derivative of the title compound in 80 mL of warm
times with water, and dried. Recrystallization from 2-propanol is treated with a solution of 0.50 g (0.0052
ethyl acetate gave the pure 5-3,5-Bis(1,1-dimethyle mole) of methanesulfonic acid in 50 mL of 2-propanol.
thyl)-4-hydroxyphenyl)methylene-1,5-dihydro-1-meth The precipitate that forms is redissolved by the addition
yl-2-(methylthio)-4H-imidazol-4-one (3.0 g), mp 45 of a small amount of 2-propanol and hot water. The
177-179 C., retaining 0.25 equivalents of solvent of solution is filtered hot and allowed to slowly cool to
crystallization. room temperature to precipitate 0.76 g (33% yield) of
EXAMPLE 28 the methanesulfonate salt, mp 278'-dec.
Calcd. for C19H26N4O3. CH4O3S: Calcd: C, 52.84; H,
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me 50
6.65; N, 12.33. Found: C, 52.70; H, 6.75; N, 12.19.
thylenel-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl EXAMPLE 31
cyanamide
Cyanamide (0.2g, 4.8 mmols) is added to a solution of 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme
5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methy 55
thylene)-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl
guanidine
lene-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol
4-one (1.5 g, 3.9 mmols) and potassium tert-butoxide Guanidine hydrochloride (1.7g, 18 mmoles) is added
(0.5g, 4.3 mmols) in ethanol (25 mL) and the mixture is to a mixture of 5-3,5-bis(1,1-dimethylethyl)-4-hydrox
stirred under an inert atmosphere and heated to reflux. yphenyl)methylene)-1,5-dihydro-1-methyl-2-(methyl
After 2.5 hours the mixture is allowed to cool, and is
60 thio)-4-H-imidazole-4-one (3.0 g, 8 mmoles) and potas
then poured into water (200 mL), acidified with phos sium tert-butoxide (1.5 g, 13 mmoles) in ethanol (50
mL). and stirred and heated to reflux under an inert
phoric acid, and stirred. After half an hour the product atmosphere. After 24 hours the mixture is allowed to
is filtered off, washed three times with water, and dried. cool, and is poured into water (300 mL) and stirred.
Recrystallization from acetonitrile gave the 5-3,5- 65 After half an hour the product is filtered off, rinsed
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene)- three times with water and dried. Recrystallization
4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-cyana from ethanol/DMF gave pure 5-3,5-bis(1,1-dimethyle
mide (0.7g), mp 257-259 C. (dec). thyl)-4-hydroxyphenyl)methylene)-4,5-dihydro-1-
 5,143,928 30
29
methyl-4-oxo-1H-imidazol-2-yl-guanidine (0.6 g), mp. ran added to effect solution is stirred overnight under
288-290° C. (dec). N2 at room temperature, then stirred into 250 mL of ice
Preparation of Intermediate: Methyl water. The precipitate is filtered off, rinsed with water,
(4-oxo-2-thiazolidinylidene) Acetate (A mixture of E:Z dried, and recrystallized from ethyl acetate to afford the
isomers)
5 product (1.6 g) 5-3,5-bis(1,1-dimethylethyl)-4-hydrox
yphenyl)methylene-1,5-dihydro-1-methyl-2-(methyl
A mixture of potassium-tert-butoxide (112.2 g, thio)-4H-imidazol-4-one, mp. 177-178 C., retaining
mole) and methanol (400 mL) is kept at -10 to -6' C. 0.25 equivalent of solvent of recrystallization.
and a mixture of methyl thioglycolate (106.14 g, 1 mole) EXAMPLE 35
and methylcyanoacetate (99.09 g, 1 mole) is added over O
a period of 20 minutes. When the addition is completed 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
stirring is continued at ~ -6° C. for 20 minutes, then at thylenel-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-
room temperature for 1.5 hours. The mixture is diluted yl)cyanamide
with ether (-1.5 l) and the precipitate is removed by A solution of 5-3,5-bis(1,1-dimethylethyl)-4-hydrox
filtration, washed with ether, and air dried. The precipi 15 yphenyl)methylene-1,5-dihydro-1-methyl-2-(methyl
tate is then dissolved in ice water and carefully acidified
with 4N hydrochloric acid. The product is separated by thio)-4H-imidazol-4-one (1.5 g, 3.9 mmoles), potassium
t-butoxide (0.5g, 4.3 mmoles) and 25 mL of ethanol is
filtration, washed with water, and dried to give 119 g of treated with cyanamide (0.2g, 4.8 mmoles) and heated
a white solid. It is recrystallized from tetrahydrofuran
ethyl acetate to give 80.95 g (47%) of analytically pure 20 under reflux for 2.5 hours. The mixture is stirred into
product, mp 171-172 C. 200 mL of water, acidified with phosphoric acid, and
Anal. Calcd. for C6HNO3S: C, 41.61; H, 4.07; N, the precipitate filtered off, rinsed with water, dried, and
8.09. Found: C, 41.56: H, 4.11: N, 8.05. recrystallized from acetonitrile to afford the pure prod
uct (0.7 g), which is 5-3,5-Bis(1,1-dimethylethyl)-4-
EXAMPLE 32
25 hydroxyphenyl)methylenel-4,5-dihydro-1-methyl-4-
Methyl oxo-1H-imidazol-2-yl)cyanamide, mp 257-259 C.
5-(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me (dec.).
thylene-4-oxo-2-thiazolidinylidenelacetate (Double EXAMPLE 36
bond in position 5 is Z, double bond in 2 position is a
mixture of E:Z isoners) 30 N-5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme
A mixture of 3,5-di-tert-butyl-4-hydroxybenzalde thylene-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-
hyde (23.4g, 0.1 mole), methyl 4-oxo-2-thiazolidinyli yiguanidine
dene)acetate (17.52 g, 0.101 mole), piperidine (3 mL) A mixture of 5-3,5-bis(1,1-dimethylethyl)-4-hydrox
and ethanol (1 L) is refluxed with stirring for 21 hours. yphenyl)methylene-1,5-dihydro-1-methyl-2-(methyl
The reaction mixture is then cooled and the precipitate 35 thio)-4H-imidazol-4-one (3.0 g, 8 mmoles), guanidine
is separated by filtration to give 31.4 g of a solid, mp hydrochloride (1.7g, 18 mmoles) and 50 mL of ethanol
256°-258 C. It is recrystallized from tetrahydrofuran is treated with potassium t-butoxide (1.5 g, 13 mmoles)
ethyl acetate to give 19.4 g (50%) of analytically pure and heated under reflux for 20 hours, then stirred into
product which is methyl 5-3,5-bis(1,1-dimethylethyl)- 400 mL of water. The precipitate is filtered off, rinsed
4-hydroxyphenyl)methylene-4-oxo-2-thiazolidinyli with water, dried, and recrystallized from acetone to
deneacetate, mp 257-259 C. afford the product (1.4 g), mp 286-287 C. (dec). A
Anal. Calcd. for C2H27NO4S: C, 64.75; H, 6.99; N, sample recrystallized from DMF/EtOH was analyti
3.60; S, 8.23. Found C, 64.59; H, 6.89; N, 3.65; S, 8.03. cally pure which is N-(5-3,5-bis(1,1-dimethylethyl)-4-
EXAMPLE 33
hydroxyphenyl)methylenel-4,5-dihydro-1-methyl-4-
45 oxo-iH-imidazol-2-yl)guanidine, mp. 288-290 C.
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)me (dec).
thylene-1,5-dihydro-2-(methylthio)-4H-imidazol-4-one EXAMPLE 37
A mixture of iodomethane (0.5 mL, 8 mmoles), 5 5-1-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)e-
3,5-bis(1,1-dimethylethyl)-4-hydroxyphenylme 50 thylidene-2,4-thiazolidinedione
thylene-2-thioxo-4-imidazolidinone (2.5g, 7.5 mmoles)
and diisopropylethylamine (1.35 mL, 7.7 mmoles) in 25 A mixture of 3,5-bis(1,1-dimethylethyl)-4-hydrox
mL of ethanol is stirred at room temperature under N2 yacetophenone (Tet Lett. 1981, 5293) (4.0 g, 16
for 18 hours, then stirred into 150 mL of water. The mmoles), 2,4-thiazolidinedione (3.0 g, 26 mmoles) and
precipitate is filtered off, rinsed with water, and dried to 55 ammonium acetate (1.9 g, 25 mmoles) in 12 mL of tolu
afford the pure product (2.5 g) which is 5-3,5-bis(1,1- ene is stirred under N2 and heated to reflux for 48 hours,
dimethylethyl)-4-hydroxyphenyl)methylene-1,5-dihy then stripped of solvent by rotary evaporator. The resi
dro-2-(methylthio)-4H-imidazol-4-one, mp. 248-249 C. due is boiled briefly in 20 mL of methanol, cooled, and
EXAMPLE 34 the precipitate filtered off, rinsed with methanol, and
dried to afford the pure product of 5-1-3,5-bis(1,1-
5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenylme dimethylethyl)-4-hydroxyphenyl-ethylene-2,4-thiazoli
thylene-1,5-dihydro-1-methyl-2-(methylthio)-4H dinedione (3.7 g), mp 253-254 C.
imidazol-4-one
EXAMPLE 38
A mixture of iodomethane (0.7 mL, 11 mmoles), 5 5-1-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyle
(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenylme 65
thylidene-2-thioxo-4-thiazolidinone
thylene-1-methyl-2-thioxo-4-imidazolidinone (2.5 g, 7
mmoles) and diisopropylethylamine (1.5 mL, 8.5 A mixture of 3,5-bis(1,1-dimethylethyl)-4-hydrox
immoles) in 25 mL of ethanol with enough tetrahydrofu yacetophenone (20.2g, 81 mmoles), rhodanine (11.8g,
 5,143,928
31 32
86 mmoles), and ammonium acetate (6.6 g., 86 mmoles)
in 110 mL of toluene under N2 is heated under reflux R8 I
using a Dean and Stark trap for 3 days, additional am Me3C
monium acetate (3.0 g, 37 mmoles) is added, and heating N N
continued for a total of 96 hours. The mixture is cooled A.
in an ice bath and the precipitated product is filtered off,
rinsed with toluene then ethanol and dried to afford
HO x -( Y
CMe3
gold-brown
crystals (22.2 g), mp 244-246 C. A sample recrystal O and a pharmaceutically acceptable base or acid addition
lized from acetonitrile was analytically pure, which is salt thereof: wherein
5-(1-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)e- Me is methyl;
thylidene-2-thioxo-4-thiazolidinone, mp unchanged. X is S;
EXAMPLE 39 R8 is hydrogen or methyl;
5-(1-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyle
15 Y is SCH3, SOCH3, SOCH, NRR2, NHCN
thylidene-2-(methylthio)-4-(5H)-thiazolone
A mixture of 5-1-3,5-bis(1,1-dimethylethyl)-4-hy f NH
NHCNHR3, NHNHCNH2, NHNHCNH2, NOR6)R, CHCOR4,
Hs
droxyphenyl)ethylidene-2-thioxo-4-thiazolone (1.6 g., 4
mnoles), iodomethane (0.45 mL, 7 mmoles), and diiso (CH2)CO2R4, N(OH)CORs, NRW,
propylethylamine (1.1 mL, 6 mmoles) in 20 mL of etha S(CH2)CO2R6, or NR7COR6;
nol is stirred under N2 at room temperature for 16 n is 1, 2 or 3;
hours, then stirred into 200 mL of water. The precipi m is 1 to 5;
tate is filtered off, rinsed with water, and dried to afford 25 R1 and R2 are independently H, lower alkyl, phenyl
the product (1.4 g) of 5-1-3,5-bis(1,1-dimethylethyl)-4- alkyl, in which phenyl is unsubstituted or substi
hydroxyphenyl-ethylidene-2-(methylthio)-4(5H)- tuted as defined below, or (CH2)NR6R7;
thiazolone, mp 206-209 C. A sample recrystallized R3 is H, lower alkyl, phenyl or phenyl substituted by
from acetonitrile was analytically pure, mp 224-226 one, two or three substituents of one or more of
C. each of alkyl of one to four carbons, OR4, SR4,
EXAMPLE 40
O
5-(1-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyle
thylidenel-4,5-dihydro-4-oxo-2-thiazolylcyanamide
35
Potassium t-butoxide (0.9 g, 8 mmoles) is added to a C(O)CR4, hydroxymethyl, NR6R7, nitro or halo
stirred suspension of 5-1-3,5-bis(1,1-dimethylethyl)-4- gen;
hydroxyphenyl)ethylidene-2-(methylthio)thiazolone R4 is H or lower alkyl;
(2.5 g, 7 mmoles) in 30 mL of ethanol under N2, fol R5 lower alkyl, phenyl or phenyl substituted as de
lowed by cyanamide (0.4g, 10 mmoles), and the mix 40 fined above, or CF3;
ture is heated under reflux. After 2 hours the mixture is R6 is H or lower alkyl;
cooled, stirred in 200 mL of water, and acidified with R7 is lower alkyl;
H3PO4. The precipitate is filtered off, rinsed with wa Z is O, S, NH, NCN; and
ter, and dried to afford the product (2.3 g). Recrystalli W is CO2R7 wherein R7 is as defined above,
zation of a sample from acetonitrile gave the analyti 45 (CH2)COOH,
cally pure material, which is 5-1-3,5-bis(1,1-dime
thylethyl)-4-hydroxyphenyl-ethylidenel-4,5-dihydro CH3
4-oxo-2-thiazolylcyanamide, mp 229-230° C.
CHCOOH,
EXAMPLE 41 50
N-(5-1-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyle (CH2)OH, or C(CH2OH)3.
thylidenel-4,5-dihydro-4-oxo-2-thiazolyl)guanidine 2. A compound of claim 1 wherein Y is SCH3.
3. A compound of claim 1 wherein Y is SOCH3.
Potassium t-butoxide (1.2g, 10 mmole) is added to a 4. A compound of claim 1 wherein Y is NOR6)R.
stirred suspension of 5-1-3,5-bis(1,1-dimethylethyl)-4- 55 5. A compound of claim 1 which is (Z)-5-3,5-bis(1,1-
hydroxyphenyl)ethylidene-2-(methylthio)thiazolone dimethylethyl)-4-hydroxyphenyl)methylene-2-innino
(2.5 g, 7 mmoles) in 30 mL of ethanol under N2, fol 4-thiazolidinone.
lowed by guanidine hydrochloride (1.4g, 15 mmoles), 6. A compound of claim 1 which is (Z)-5-[3,5bis(1,1-
and the mixture is heated under reflux. After 2 hours, dimethylethyl)-4-hydroxyphenyl)methylene-2-imino
the mixture is cooled, stirred into 200 mL of water, and 60 4-thiazolidinone methanesulfonate.
the precipitate filtered off, rinsed with water, and dried 7. A compound of claim 1 which is 5-3,5-bis(1,1-
to give the product (2.5 g). A sample recrystallized dimethylethyl)-4-hydroxyphenyl)methylene-2-amino
from ethanol/acetonitrile was analytically pure, which 4-(5H)-thiazolone.
is N-(5-1-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl 8. The maleic acid salt of the compound of claim 5.
ethylidenel-4,5-dihydro-4-oxo-2-thiazolyl)guanidine, 65 9. The hydrochloride salt of the compound of claim
mp 277 C. (dec). 5.
We claim: 10. The 4-methylbenzenesulfonate salt of the com
1. A compound of the formula I pound of claim 5.
 5,143,928
33 34
11. The 2-hydroxyethanesulfonate salt of the com 29. A compound of claim 1 which is (E)-N-(5-3,5-
pound of claim 5. bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-4-
12. A compound of claim 1 which is (Z)-5-3,5- oxo-2-thiazolidinylidene-DL-alanine.
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- 30. A compound of claim 1 which is (Z)-5-
(hydroxymethylamino)-4-(5H)-thiazolone. 5 3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
13. A compound of claim which is (Z)-5-3,5- thylene-2-(cyclohexylhydroxyamino)-4-(5H)-thiazo
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- lone.
(methoxymethylamino)-4-(5H)-thiazolone. 31. A compound of claim 1 which is (Z)-5-3,5-
14. The monohydrochloride salt of the compound of O bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene
claim 13. 2(1-methylethyl)thio)-4-(5H)-thiazolone.
15. A compound of claim 1 which is (Z)-5-3,5- 32. A compound of claim 1 which is (Z)-N-15
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene (3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
2,4-thiazolidinedione, 2-oxime.
thylene-4,5-dihydro-4-oxo-2-thiazolylguanidine.
16. A compound of claim 1 which is 4-5-3,5- 33. A compound of claim 1 which is (Z)-N-5-
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene 5 3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl)me
4,5-dihydro-4-oxo-2-thiazolyl)aminobutanoic acid. thylenel-4,5-dihydro-4-oxo-2-thiazolyl)guanidine,
monohydrochloride.
17. A compound of claim 1 which is 5-3,5-bis(1,1- 34. A compound of claim 1 which is (Z)-5-3,5-
dimethylethyl)-4-hydroxyphenylmethylene-2-(dime bis(1,1-dimethyl-4-hydroxyphenylmethylidene-a-
thylamino)(imino)methyl)amino-4(5H)-thiazolone. 20 cyano-4,5-dihydro-4-oxo-2-thiazoleacetamide.
18. A compound of claim 1 which is 5-3,5-bis(1,1- 35. A compound of claim 1 which is 5-3,5-bis(1,1-
dimethylethyl)-4-hydroxyphenyl)methylene-2(2- dimethylethyl)-4-hydroxyphenyl)methylene)-2-me
hydroxyethyl)imino-4-thiazolidinone. thoxyamino-4(5H)-thiazolone.
19. A compound of claim 1 which is 53,5-bis(1,1- 36. A compound of claim 1 which is 5-3,5-bis(1,1-
dimethylethyl)-4-hydroxyphenyl)methylene-2-2- 25 dimethylethyl)-4-hydroxyphenyl)methylene-2-me
hydroxy-1,1-bis(hydroxymethyl)ethylamino-4(5H)- thylamino-4(5H)-thiazolone.
thiazolone. 37. A hydrochloride salt of the compound of claim
20. A compound of claim 1 which is (Z)-5-3,5- 36.
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene 38. A compound of claim 1 which is 5-3,5-bis(1,1-
2,4-thiazolidinedione, 2-oxime, ion(1-), 2-hydroxy 30 dimethylethyl)-4-hydroxyphenyl)methylene-2-dime
N,N,N-trimethylethanaminium. thylamino-4(5H)-thiazolone.
21. A compound of claim 1 which is (Z)-5-3,5- 39. A hydrochloride salt of the compound of claim
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- 38.
(methylthio)-4-(5H)-thiazolone. 40. A compound of claim 1 which is 5-3,5-bis(1,1-
22. A compound of claim 1 which is (Z)-N-(5-3,5- 35 dimethylethyl)-4-hydroxyphenyl)methylene)-4-oxo-2-
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylenel-4- thiazolidinylidenelacetic acid, ethyl ester.
oxo-2-thiazolidinylidenelglycine. 41. A compound of claim 1 which is methyl, 5-3,5-
23. A compound of claim 1 which is (Z)-2-5- bis(1,1-dimethylethyl)-4-hydroxy-phenyl)methylenel-4-
3,5bis(1,1-dimethylethyl)-4-hydroxyphenyl)me oxo-2-thiazolidinylidenelacetate.
thylene-4-oxo-2-thiazolidinylidenel-hydrazinecarbo 42. A compound of claim 1 which is 5-1-3,5-bis(1,1-
thiamide.
dimethylethyl)-4-hydroxyphenyl-ethylidene-2-(me
thylthio)-4(5H)-thiazolone.
24. A compound of claim 1 which is (Z)-5-3,5- 43. A compound of claim which is 5-1-3,5-bis(1,1-
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- dimethylethyl)-4-hydroxyphenyl-ethylidene4,5-dihy
hydroxy(1-methylethyl)amino-4(5H)-thiazolone. 45 dro-4-oxo-2-thiazolylcyanamide.
25. A compound of claim 1 which is 5-3,5-bis(1,1- 44. A compound of claim 1 which is N-5-1-
dimethylethyl)-4-hydroxyphenylmethylene)-4,5-dihy 3,5bis(1,1-dimethylethyl)-4-hydroxyphenyle
dro-4-oxo-2-thiazolylcyanamide. thylidenel-4,5-dihydro-4-oxo-2-thiazolyl)guanidine.
26. A compound of claim 1 which is 5-3,5-bis(1,1- 45. A pharmaceutical composition for use as an inhib
dimethylethyl)-4-hydroxyphenyl)methylenel-4,5-dihy SO itor of 5-lipoxygenase, cyclooxygenase, or both com
dro-4-oxo-2-thiazolyl)-cyanamide, 2-hydroxy-N,N,N- prising a 5-lipoxygenase, cyclooxygenase, or both inhib
trimethylethylethanaminium. iting amount of a compound of claim 1 and a pharma
27. A compound of claim 1 which is (Z)-5-3,5- ceutically acceptable carrier.
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene-2- 46. A method for treating an inflammatory disease or
2-(dimethylamino)ethylamino-4-(5H)-thiazolone. condition in a human suffering therefrom which com
28. A compound of claim 1 which is (Z)-5-3,5- prises administering a compound of claim 1 in unit dos
bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene age form.
4,5-dihydro-4-oxo-2-thiazolylthiolacetic acid.

65