CA1330442C - Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxygenase inhibitors, pharmaceutical compositions and methods of use therefor - Google Patents

Abstract

ABSTRACT
The present invention is 3,5-substituted, isoxazoles, pyrazoles, isothiazoles, and analogs thereof having 5-lipoxygenase or cyclooxygenase inhibiting activity or as a sunscreen. The compounds have the general formula:
wherein

Description

~ ~ ` ` 2 ; l33a~
i ~3ACKGROU~D OF THE INVENTION

The present invention is novel styryl pyrazoles and analogs thereof as well as pharmaceutical compositions and methods of use therefor.
Styryl isoxazole derivatives having cardiovascular activity are known. For example, European Patent Applications No. 34754 and NO. 5192 and German Application No. 2943-405fi~ ving Derwent Abstract Nos. 66318 D/37, 84501 B/47 and 34567 D/20, respectively, disclose a compound of the general formula , , . .. ~. ~

,A' , '' ' " ;~

However, the present compounds differ from such references by a completely different side chain from ` that shown above linked to the phenyl at the 2-position through an ether group in each reference.
Further, European Patent Application No. 5186 reviewed by Derwent Abstract No. 844908/47 discloses ~ an intermediate isoxazole of the formula @ i.~ ~
~ 0~

133~4~2 ` `

I I alkyl ~o,t ':' for which no pharmaceutical utility is disclosed.
I Pyrazole derivatives having biological,~ specifically antiinflammatory, activity are found in i 5 Belgian Patent Nos. 819,890 and 844,972 abstracted in Derwent Abstract Nos. 20948W/13 and 09405Y/06, respectively. A similar derivative is disclosed in German Patent No. 2920941 of Derwent Abstract No.
86535C/49. However, each of these disclosed pyrazole derivatives requires substituents on adjacent carbons of the pyrazole ring.
Specifically excluded from the compounds of the present invention are the compounds of French Patent No. 2104932 of Derwent Abstract No. 46150T-B useful ~ -as hypocholesterolemics, antiinflammatories, analgesics, sedatives, antipyretics, and in some in~tances diuretics. The compounds of the French Patent generally have the formula ,~

~ ,O~/C~12C02~
~ fu~ylo~

-~; B, (~haloge~/alkyl/alkoxy~NO2)0_3 -~; lower alkyl, aryl, aralkyl, or ~itroaryl ~ 3 3 ~ 2 Finally, of lesser interest numerous imidazoles are known having various pharmaceutical activity.
For example, U.S. Patent No. 3812111 and British 1,046,248 disclose compoundx of general formula cli ~c ~

or Cl phenyl, isop~opyl, or hydroxyethyl ~ and ,~

~C~C~C-C`- ~
~ I I
~ N~C,N-- ' ~
' I :'' ~`

~ ! ~
respectively wherein the - represents various ,1~ substituents. However, the imidazoles are compounds differing from the present invention in that the ~ compoun!ds have ,a diffe.rent ring system from the ``.~ pyrazoles. ,, Thus, the novel compounds that are the present invention provide activity for use in the treatment of diseases in which 5-lipoxygenase enzyme activity contributes to the pathological condition. For ~--example, the use for the present novel compounds, compositions and methods of use is for allergy, ' :
asthma, arthrLtis, skin disorder~, such as psorlasis --s--i33~2 :
or acne, inflammation, for example, inflammatory bowel disease or pain, and further, also cardiovascular disorders including infarction, angina, arrhythmias, stroke, migraine, atherosclerosis, ulcers and other conditions particularly benefited by cytoprotective activity.
i An additional property of the present novel compounds 4. now found to provide usefulness, for example, as sun screens, is absorption of ultraviolet light.

~j 10SUMMARY OF THE INVENTION
~' The present invention is a novel compound of the formula (I) ~33 , R ~ Q ~ ~ I

, ;
and pharmaceu~ically acceptable salts thereof;
wherein (1) - - is a single or double bond;
i . (2) R, R1, and R2 may be the same or different :~
and are selected ~rom the group consisting of : hydrogen, lower alkyl, hydroxy, OR3 wherein R3 is lower alkyl, C(O)OR4 wherein R4 is hydrogen or lower alkyl, OC(O)R3 wherein R3 is independently as defined above, C(O)R3 wherein R3 is independently as defined above, NR6R7, wherein R6 and R7 may be the same or different and are hydrogen or lower alkyl, NHC~O)R3 ~; j: wherein R3 is independently as defined above, NHCHO, NHSO2R3 wherein R3 is independently as defined above, ., 1, . . .
5 I ~
:,: 1~

~33~2 NHCONHR4 wherein ~4 is independently as defined above, hydroxymethyl, halogen, trifluoromethyl, SR4 wherein R4 is independently as defined above, or nitro;

(3) Q is (CH2)n wherein n is an integer of zero to four, CH=CH or CH=C

wherein R4 is independently as defined above;

(4) X and Y are (i) N, (ii) NR5 wherein R5 is hydrogen, lower alkyl, -CHCO2R2 wherein Rl and R2 may R' be the same or different and are hydrogen or lower alkyl, C(O)R3 wherein R3 is independently as defined above, cycloalkyl of from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, or (iv) S; with the proviso that X
and Y cannot both be N, NR5, O or S at once and with : the proviso that one of X and Y cannot be O at the same time thè other of X and Y is S or NR5 and that one of X and Y cannot be S at the same time the other . of X and Y is NR5;

(5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R3, ~Q3 wherein R3 is independently as defined above, C(O)OR4 wherein R4 is independently as defined above, C(O)R3 ~: wherein R3 is indèpendently as defined above, CH~Rl)CO2R2 wherein Rl and R2 are independently as defined above, halogen, trifluoromethyl, CH=CH
. , . . . 'R2 wherein R, Rl and R2 are independently as defined `~ ;; above, heteroaryl, or heteroaralkyl; with the overall proviso that when one of R, Rl, and R2 is 2-hydroxy, X is O, Y is N and Q is CH=CH, then Z cannot be H or alkyl; and also with the overall proviso that when R, Rl, and R2 are hydroxy or lower alky~, Y and X axe N
~; ~ or NH, and n is zero then Z cannot be furyl or pnenyl .. .:~

:! ., L.. .~ ,, , ,, ",.. ..

` 133~2 unsubstituted or substituted with halogen, trifluoro-methyl, alkyl, alkoxy or NO2.
The present invention is also a pharmaceutical composition for treating a disease such as allergy, ~ s asthma, arthritis, psoriasis, acne, inflammation, : pain, or cardiovascular disorders comprising an antiallergic, antiinflammatory, analgesic; or beneficial cardiovascular effective amount of the compound of formula (I) X--Y

t R~
. :
, . and pharmaceutically acceptable salts thereof;
wherein (1) - - - is a single or double bond;
(2) R, Rl, and R2 may be the same or different and are selected from the group oonsisting of 15 hydrogen, lower alkyl, hydroxy, OR3 wherein R3 is lower alkyl, C~O)OR4 wherein R4 is hydrogen or lower : . alkyl, 4C(O)R3 wherein R3 is independently as defined e above, C(O)R3 wherein R3 is independently as defined ~b above, NR6R7 wherein R6 and R7 may be the same or . 20 different and are hydrogen or lower alkyl, NHC(O)R3 ~ ~ wherein R3 is independently as defined above, NHCHO, ; NHS02R3 wherein R3 is independently as defined above, NHCONHR4 wherein R4 is independently as defined above, hydroxymethyl, haloqen, trifluoromethyl, SR4 25 wherein R4 is independently as defined above, or b ~ nitro;
~ ~ ' p ~

'.?~.

~330~2 (3) Q is (CH2)n wherein n is an integer of zero to four, CH=C~ or CH=C
Co R
wherein R4 is independently as defined above;
(4) X and Y are (i~ N, (ii) NR5 wherein R5 is hydrogen, lower alkyl, -CHC02R2 wherein Ri and R2 may Ri be the same or different and are hydrogen or lower alkyl, C(O)R3 wherein R3 is independently as defined above, cycloalkyl of from three to twenty carbons , having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, (iv) S; with the proviso that X and Y cannot both be N, NR5, O or S àt once and with the proviso that one of X and Y cannot be O at the same time the other of X and Y is S or NR5 and that one of X and Y cannot be S at the same time the other of X
-: 15 and Y is NR5;
(5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R
wherein R3 is independently as defined above, C(O)OR4 wherein R4 is independently as defined above, C~O)R3 wherein R3 is independently as defined above, CH(R1)CO2R2 wherein R1 and R2 are independently as defined above, halogen, trifluoromethyl, CH=C~

wherein R, R1, and R2 are independently as defined above, heteroaryl, or heteroaralkyl; with the overall ` proviso that when R, Rl, and R2 are hydroxy or lower alkyl, n is zero, Y and X are N or NH, then Z cannot be furyl or phenyl unsubstituted or substituted with halogen, trifluoromethyl, alkyl, alkoxy or NO2 and a pharmaceutically acceptable carrier.
. ~ The present invention is also a composition of the compound of formula I not including the overall provisos and a carrier from among the carriers known to be for use in combination with a sunscreen.

,~ '-', ~t ~ ~
~ 1~

133~2 Further, the invention is a method for treating mammals having at least one of the diseases noted above by administering an amount effective to treat one of the diseases to such mammals a unit dosage form of t~he pharmaceutical composition as defined above.
Also, the invention is a method of using a compound of formula I; again as defined above but not including the overall provisos, as a sunscreen, for example, in a coating on humans, in paint and the like.
Finally, the present invention is a process of preparing a compound of formula I as defined above.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of formula I the term lower alkyl is of one to four carbons, inclusive, and includes methyl, ethyl, propyl, or butyl and isomers thereof.
Halogen includes particularly fluorine, chlorine hromine or iodine.
Aryl is phenyl unsubstituted or substituted by one, two or three substituents of one or more of each of alkyl of one to four carbons, inclusive, OR4 wherein R4 iS independently as defined above, SR4 R
wherein R4 is independently as defined above, R4~0 wherein R4 is independently as defined above, C(o) OR4 wherein R4 is independently as defined above, ~ydroxymethyl, NR6R7 wherein R6 and R7 are each independently as defined above, or nitro, or halogen.
Aralkyl is an aryl as defined above and attached through an alkylenyl such as methylenyl, ethylenyl, propylenyl, butylenyl and isomers thereof.
Heteroaryl means 2-, or 3-pyrrolyl; 2- or 3-furyl; 2- or 3-thiophenyl; 2-, 4-, or 5-oxazolyl;
~, ~ f}~

. , , -10-: 1330~l~2 .~ 2-, 4- or S-thiazolyl, 1-, 2- or 4-imidazolyl, 2-, j 3- or 4-isothiazolyl, 2-, 3- or 4-isoxazolyl, 1-, .. 2-, or 3-pyrazolyl, and 2-, 3-, 4-pyridyl .
Heteroaralkyl iS a heteroaryl as defined above -~ 5 and attaclled through a lower alkyl.
The compounds of the present invention contemplate compounds having the following ring systems .' ~' : :
., :', ~ . ~ .

::
,., ~ , ;

,~- .
;i ~, ~.

133~ l b A. ~o--- R5 ~ Z ~

R ~
. 1, , ' .,~'~
: IN O
- B.
!.

:~ ~
~Z

. and ~

', ' ' .;

~; ~ 8 L~'l L ¦ 5 wherein - - -, R5 and Z are as defined above.
'~ ;~ .

~, ~

~ L -` . ; ';, ~ -12-1330~

When R5 is hydrogen it is understood the ring system may be represented by the following equilibrium:
: ,.

~S ~ ~
, ' .
The compounds of formula I are useful bcth in the free base form, in the form of base salts where possible, and in the form of acid addition salts.
The three forms are within the scope of the invention. In practice, use of the salt form amounts to use of the base form. Appropriate ; pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfamate, methanesulfonate, benzenesulfonate, - p-toluenesulfonate, and the like, respectively or those derived from bases such as suitable organic and inorganic bases. Examples of suitable inorganic bases for the formation of salts of compounds of this invention include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, j! ' calcium, magnesium, aluminum, zinc, and the like.
~ ,.

d :
:

, . ~33~2 , Salts may also be formed with suitable organic bases. Bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include or~anic bases which are nontoxic and strong enough to form such salts. These organic bases form a class whose limits are readily understood by those skilled in the art. Merely for purposes of illustration, the class may be said to include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and triethylamine; mono-, di- or trihydroxyalkylamines such as mono-, di- and triethanolamine; amino acids such as arginine, and lysine; quanidine; N-methylglucosamine;
N-methylglucamine; L-glutamine; N-methylpiperazine;
morpholine; ethylenediamine; N-benzylphenethylamine;
tris(hydroxymethyl)aminomethane; and the like. (See for example, "Pharmaceutical Salts," J. Pharm. Sci.
66(1):1-19 (1977~.) The acid addition salts of said basic compounds are prepared either by dissolving the free base of compound I, I' or II in aqueous or agueous alcohol solution or other suitable solvents containing the appropria~e acid or base and isolating the salt by evaporating the solution, or by reacting the free base of compound I, I' or II with an acid as well as reacting compound I, I' or II having an acid group thereon with a base such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds of the invention may contain an asymmetric carbon atom. Thus, the invention includes the individual stereoisomers, and the mixtures thereof. The individual isomers may be prepared or isolated by methods known in the art.
.

~ .
:
., ,v ... ,. ~, .. .: ,. :: .~: ,: ,.,. . , : , -,, . ~ .

` -~ -14-~30~2 Compounds of the present invention that are preferred are of formula I wherein Y is N and X is NH
or Y is N and X is o.
The most preferred compounds of the present invention are 5-[~-(4'-hydroxy-3',5'-bis(1,1-dLmethylethyl)phenyl)ethenyl]-3-methylisoxazole, 3-~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methyl-pyrazole, and 5-[~-(4'-hydroxy-3',5'-dimethoxy-phenyl)ethenyl]-3-methylisoxazole.
A physician or veterinarian of ordinary skill readily determines a subject who is exhibiting symptoms of any one or more of the diseases described above. Regardless of the route of administration selected, the compounds of the present invention of the formula I as described in pharmaceutical compositions above are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art.
The compounds can be administered in such oral unit dosage forms as tablets, capsules, pills, powders, or granules. They also may be administered rectally or vaginally in such forms as suppositories or bougies; they may also be introduced parenterally (e.g. subcutaneously, intravenously, or intramuscularly), using forms known to the pharmaceutical art. They are also introduced directly to an affected area (e.g., in the form of eye drops or by inhalation). For the treatment of asthma or allergies, particularly dermatological disorders; such as erythema, psoriasis and acne, the compounds may also be administered topically in the form of ointments, gels, or the like. However, in general, the preferred route of administration is orally.
; 35 An effect ve but nontoxic quantity of the compound is employed in treatment. The ordinarily skilled physician or veterinarian will readily . ' .

~ -15-1 3 3 ~ 2 determine and prescribe the effective amount of the compound to prevent or arrest the progress of the condition for which treatment is administered. In so proceeding, the physician or veterinarian could employ relatively low dosages at first, subsequently increasing the dose until a maximum response is obtained.
Initial dosages of the compounds of formula I of the invention in pharmaceutical compositions are ordinarily in the area of 10 mg up to 2 grams per day orally, preferably 10 mg to 500 mg per dose orally given one to four times daily or as needed. When other forms of administration are employed equivalent doses are administered.
Additionally, the present invention is compositions comprising the compounds of formula I, for use as sunscreens, having a suitable carrier therefor.
The ultraviolet absorbing properties of the compounds of the present invention is generally shown by a comparison with p-aminobenzoic acid which is the ~; active ingredient in most commercial sunscreens.
Such properties are within the ultraviolet absorbing ranges of 260 to 300 nM range critical to effectiveness. A representative compound of the invention is compared to p-aminobenzoic acid in the following Table.

~TABLE

Com~ound W max a 80 p-aminobenzoic acid 285 nM 132.2 .
3-~-(4'-hydroxy-3'-methoxy- 292 nM 111.1 ~; phenyl)ethenyl]-5-methylpyrazole ,, ~' .

~ - -16-~33~
. The methods of preparation for the compounds of the present invention may, genexally, be accomplished in a manner according to the definition of X and Y.
For example, generally compounds of formula I
S wherein X and Y are each N or NRS are prepared in a . manner shown by Scheme I as follows:
. ~''.
. ~.
.

~;
~

~ . ' ~;
~:

~ 17-~33~2 SCHEME I

O
~1~
R2 III./~II3 IStep 1 R tT ~

: ~ :
R2 ~R5 wherein R5is other than hydrogen .~ optionally Step 2 R ~ z ~` and1 R2 nerein ~5 is oeher than hydrogen 1~ Z
~ R2 herein R5 is o~her than hydrogen f;~
~:
:`
. wherein - - -, R, Rl, R2, R5 and Z are as defined above.

~ -18-t33~
:
In Step 1 of Scheme I equimolar parts of hydrazine hydrate and a compound of the formula III
wherein R, R1, R2 and Z are as defined above are .`
combined in a solvent such as 1 part ethanol and 1 part butanol, or 2-propanol, and the like. A small amount of about 0.1 ml to 10 ml preferably 0.5 ml of acetic acid is added with the hydrazine hydrate.
Optionally, the step 1 product of formula I1 is further reacted as shown in step II with a compound MR5 wherein M is an electrofuge such as halogen, sulfonate, or the like and R5 is as defined above but other than hydrogen to obtain a mixture of the compound of formula Ii and I1 wherein - - -, R, R1, -R2, R5 when not hydrogen and Z are as defined above.
The compounds Ii and I1 may be separated by conventional means.
Similarly compounds of formula I wherein X and Y :;
are each N or NR5 wherein Q is CH2 and n is 1 can be prepared according to the following Scheme Ia using analogous conditions as provided above for Scheme I.

SCHEME Ia :
:

Rl~o R I~N--Nll Rl~ N--NR5 R2 acetic acid r ~: ~ 1~ .

~, ,~
~ , .
~' ~:

-lY-- -133~2 Further, the compounds of formula I2 are prepared as shown in the following Scheme II and IIa.

; ':
::~

' (¢~

.,~

-~ --20--~ 33~2 SCHEME II

Cl ~J~2 Z R2 IlIz ~ O--N
C ~ ~

~ ~ N S
~ Cl- ~Z

~ SN ::

, II2 ~ l~ N2 1~
i j R2 . I i R2 I i ; wherein X and Y are O or N and s or N.

--21-- .

.. .
133~
~ SCHEME IIa Rl~ ~ 1 II2a N--S

'~ OHC z . ~ , R~Z or , J -: I 'a : :
Triphenylphosphonium halide; preferably -chloride, of the formula II2 or II2a are contacted by an excess of a compound of the formula III2 or III2a ~: in a solvent such as dimethylsulfoxide, toluene, or the like to which an equivalent amount of potassium t-butoxide is added. The mixture is stirred at about :
room temperature for from 10 minutes to 2 hours or more under an inert atmosphere. A compound of formula I2 or I2a is obtained wherein R, R1, R2 and Z
are as defined above and Y and X are each either N or o and N or S, respectively.
~ ~ild hydrogenation by conventional methods by an j~ 15 ordinarily skilled artisan may be carried out to 1~ provide a compound of formula I'2 wherein R, Rl, R2 ~ ' . ~''.
~ 1;~

. -22-~33~2 and Z are as defined and Y and X are O or N and s or ` -N, respectively.
~ Additionally, for compounds wherein Z is defined such that the two substituents on the heterocyclic - 5 ring of formula ~, ' ` ; .
~ or ~ ~

. ~' :

:~are the same, the compounds may be prepared according - 10 to the following Scheme III.
~ .:
SCHEME III

1 ~ ~ g~ R~

'~ 1' Y `` R

wherein Z is Q ~ R1 ~ and wherein R, R1, ^~R2, and Q are as defined above and Y and X are either 0 and N or N and 0.

~ , ,, ':

~3~2 The conditions of the reaction in Scheme III
are, generally, carried out with equimolar parts of the compound of formula III3 and hydroxylamine hydrochloride in a solvent such as methanol, ethanol and the like in the presence of a buffer such as sodium acetate at reflux temperature until completion as determined by TLC.
~, .

. , .

,~

~:
~ `~ .

~ -24-~33~
SCHEME IV

1 1 ~ 2 R ' R2 Li HC l/MeOH
~ /

R
~ , R ~

~1:X,Y = any combination ~,,-' (-H20)(-C02) ~o~ N,O/O,N/N,NH ~ / For R4=H
,~ ~ X_Y
~-H20) ~ R

~ ~ C~=C ~ 2 2 b~ ~ wherein R, Rl, R2, and Z are as defined above.

,.~

.
~ 3 ~ 2 The conditions of the synthesis in Scheme IV
step 1 are, generally, carried out in a manner analogous to those described by C. Kashima et al, Bull. Chem. Soc. Japan, 46, 310 (1973) and C. Kashima et al, Heterocycles, 6, 805 (1977). Unexpectedly the step 2 dehydration when R4 is H or alkyl and also further decarboxylation when R4 is H are carried out in a one pot reaction together with step 1.
Condi~ions for step 2 are analogous to those known in the art and, thus, within the ordinary artisan's skill.

SCHEME V

Rl ~ Z~ ~zN N~z l , ..
~ :' The conditions of the above Scheme V are analogous to those described by M. Nitta, J. Chem. Soc. Chem. Commun., 877, 1982.
Finally, conditions analogous to those described in copending Canadian application serial Number 532,053, filed March 13, 1987 are useful in step 1 of Scheme VI below. Step 2 of Scheme VI is ~' carried out using anhydrous conditions in an inert solvent at about the temperature of 0 to 50C for from 90 min to 18 hours.
-~ .
,~
~,-13~4~

SC~EME VI

C~O ~ Step 2 X~
Step ~ Rl~ ~
2 R2 or R2 ~ .
' ~2C'C-Z

~ ' , ~:
....

.,~
, .~ .
:

, ! ~ :
"~ ,.
ii'~
'`~' ' :
'',;
~ .
'' ~ ' ' ''' .
. .
` ~ : ~
~ ~ .

~33~2 .

c80 o O -~
R~ z ,: RL~Z

III; / III3 i ~ 2 "

R~

'2 IIli / III 3 :
~:

-`~ The compounds in Scheme VII are compounds wherein R, R1, R2 and Z are as defined above for compounds of formula III3 and III3 but IIIi and III1 are ~ sym~etrical. .
,~
." ~ ~ .
i' (~

~ -28-~33~
An alternate preparation for the compounds of formula III3 is as found in Scheme VIII as follows: ;

SCHEME VIII

R .O
Rl ~ C~O

R2 . ~ l ) Z
,~ , 112)C~Z ~,' , Rl ~ ~ `Z

. 2 ISI3 '~ ¦optionally R O OB

~ ~ ~`Z

~ .III3 ,^;~;

~ -29-~33~2 Finally, the compound of formula II2 as shown in Scheme II above can be prepared by the following method.

SCHEME IX

~O ~ ~ Cl .' O---N ~_ Z Cl Ph3P
_ ~I2 N _ S Cl ~ 2 ~ ~ J l c~

Under certain circ~mstances it is necessary to protect either the N or O of intermediates in the above noted process with suitable protecting groups which are known. Introduction and removal of such suitable oxygen and nitrogen protecting groups are well-known in the art of organic chemistry; see for example "Protective Groups in Organic Chemistry," J.
F. W. McOmie, ed., (New York, 1973), pages 43ff, 95ff, J. F. W. McOmie, Advances in Or~anic ChemistrY, ~-Vol. 3, 191-281 (1963); R. A. Borssonas, Advances in Oraanic Chemistry, Vol. 3, 159-190 ( 1963); and J. F.
W. McOmie, Chem. & Ind., 603 (1379).

~ -30-~ 3 ~ 2 Examples of suitable oxygen protecting groups are benzyl, t-butyldimethylsily, ethoxyethyl, and the like. Protection of an N-H containing moiety is necessary for so~e of the processes described herein for the preparation of compounds of this invention.
Suitable nitrogen protecting groups are benzyl, triphenylmethyl, trialkylsilyl, trichloroethylcarbamate, trichloroethoxycarbonyl, vinyloxycarbamate, and the like.
Under certain circumstances it is necessary to protect two different oxygens with dissimilar protecting groups such that one can be selectively removed while leaving the other in place. The benzyl and t-butyldimethylsilyl groups are used in this way;
either is removable in the presence of the other, benzyl being removed by catalytic hydrogenolysis, and t-butyldimethylsilyl being removed by reaction with, for example, tetra-n-butylammonium fluoride.
In the process described herein for the preparation of compounds of this invention the requirements for protective groups are generally well recognized by one skilled in the art of organic chemistry, and accordingly the use of appropriate protecting groups is necessarily implied by the processes of the charts herein, although not expressly illustrated.
The products of the reactions described herein are isolated by conventional means such as extraction, distillation, chromatography, and the like.
Starting materials not described herein are available commercially, are known, or can be prepared - by methods known in the art.
The salts of the compounds of formula I
described above are prepared by reacting the appropriate base or acid with a stoichiometric eguivalent of the compounds of formula I, :~ ' ::
~: .

~33~2 respectively, to obtain pharmaceutically acceptable salts thereof.

DESCRIPTION OF THE PREFERRED EM~ODIMENTS

The invention is further elaborated by the representative examples as follows. Such examples are not meant to be limiting.

Exam~le 1 1/

3,5-Bis~-(4'-hydroxY-3'-methoxvPhen~l)ethen~l]-EYrazole Curcumin (5.93 ~, 16.1 mmoles) (Sigma Co., St.
Louis) is dissolved in 100 ml of 50% ethanol in butanol. Hydrazine hydrate (O.81 g, 16.1 mmoles) and 0.5 ml of acetic acid are added. The reaction is warmed in an oil bath at 6QC for 24 hours. The solvents are removed under vacuum, and the residue is chromatographed on silica gel in ethyl acetate to give a red solid. Recrystallization of the product from methanol/water gives 0.3 g of the product as a hydrate. Analysis for C21H20N2O4 0.1 2 requires C-68.87, H-5.52, N-7.65. Found; C-68.77, H-5.50, N-7.44. mp=211-214C.
-1' Exam~le 2 - ~
, ~.
3,5-BisL3-(4'-hydroxv-3'-methoxY~henvl)ethyl]-pyrazole According to the procedure of Example 1, ~ 1,7-bis(4'-hydroxy-3'-methoxyphenyl)-3,5-heptadione `~ ull. AcadO Polon. Sci. 6, 481-486, 1958) is reacted ;~ with hydrazine hydrate to afford 3,5-bis[~-(4'- `
~; hydroxy-3'-methoxyphenyl)ethyl]pyrazole in 65% yield, mp-125-128C.
, ~ . :
, ;~ .
::
`~:
~ .
, ~ 3 3 ~

Example 3 3,5-Bis[~-(4'-hYdroxYPhenyl)ethvl]pyrazole According to the procedure of Example 1, 1,7-bis(4'-hydroxyphenyl)-3,5-heptadione is reacted with hydrazine hydrate to afford 3,5-bis[~-(4'-hydroxyphenyl)ethyl]pyrazole in 45% yield, mp=193-195C.

ExamPle 4 3-~3-(4'-Hvdroxv-3'-methoxYphenYl)ethenYll-5-phenyl-1 0 vrazole According to the procedure of Example 1, 1-(4'-hydroxy-3'-methoxyphenyl)-5-phenyl-1-pentene-3,5-dione is reacted with hydrazine hydrate to afford 3-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-phenyl-pyrazole in 9% yield, mp-132-134C.

Exam~le 5 3-[3-(4'-Hvdroxv-3'-methoxv~henYl)ethenvl]-5-methYl-yrazole According to the procedure of Example 1, 1-(4'-hydroxy-3'-methoxyphenyl)-1-hexene-3,5-dione is reacted w~th hydrazine hydrate to afford 3-t~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methyl-pyrazole in 53% yield, mp=144-146C.

Example 6 .~ , 3-[3-(4'-H~droxv-3'-methoxYphenyl)ethyl]-5-methYl-pYrazole Accordin~ to the procedure of Example 1, ~ 1-(4'-hydroxy-3'-methoxyphenyl)-3,5-hexanedione is ?~
'', ,~
~ .
,~
,-,,,~

s~h ~
. . ."~., ,.,, ~ , ," ~, " ` ~ --- ,,-, ,, ,,` ,- ,,, ~,;

~1 33~42 reacted with hydrazine hydrate to afford 3-~-(4l-hydroxy-3'-methoxyphenyl~ethyl]-5-methyl-pyrazole in 68% yield, mp=84-86c.

. Exam~le 7 3-[~-(4'-HYdroxv-3'-chloro~heny~ethenYl]-5-methYl-pYrazole According to the procedure of Example 1, 1-~4'-hydroxy-3'-chlorophenyl)-1-hexene-3,5-dione is reacted with hydrazine hydrate to afford 3-[~-(4'-hydroxy-3'-chlorophenyl)ethenyl]-5-methyl-pyrazole in 61% yield, mp=183-184C.

Exam~le 8 : 3-~3-(4'-MethoxY-3'-hvdroxv~henyl)ethenyl L- 5 -methYl -~yrazole According to the procedure of Example 1, 1-(4'-methoxy-3'-hydroxyphenyl)-1-hexene-3,5-dione is reacted with hydrazine hydrate to afford 3-~-(4'-methoxy-3'-hydroxyphenyl)ethenyl]-5-methyl-pyrazole in 72% yield, mp=221-222C.

~ 20 Exam~le 9 ~ 3-[3-(4'-Hydroxv-3'-metho~yphenYl)ethenvllzS-ethYl-Yrazole According~to.the proçedure of Example 1, 1-(4'-hydroxy-3'-methoxyphenyl)-1-heptene-3,5-dione 25 is reacted with hydrazine hydrate to afford 3-~ 4'- ~
hydroxy-3'-methoxyphenyl)ethenyl~-5-ethyl-pyrazole in ~ ::
26% yield, mp=61-64C.

.~::
~'~

~;~

~ . -34-l 3 3 ~

Exam~le_10 Ethyl-3-[~-~3-methoxv-4-hvdroxv~henyl)ethenvl]-lH-EYrazole-5-carboxylate According to the procedure of Example 1, ethyl s 6-(3-methoxy-4-hydroxyphenyl)-2,4-dioxo-5-hexenoate is reacted with hydrazine hydrate to afford ethyl-3-~-(3-methoxy-4-hydrox~phenyl)ethenyl]-lH-pyrazole-5-carboxylate in 51% yield, mp-99-101C.
.~
ExamPle lOA

1o 3-~-(4'-Hvdroxv-3'-methoxvphenvl)ethenvl]-5-trifluoromethYl~vrazole According to the procedure of Example 1, 1-.(4'-hydroxy-3'-methoxyphenyl)-6,6,6-trifluoro-l-hexene-3,5-dione is reacted with hydrazine hydrate 15 to afford 3-~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]- :
5-trifluoromethylpyrazole in 71% yield, mp -145-147C~
I
Exam~le lOB

3-~3-(4'-t-Butyldimethvlsilvloxv-3'-methoxy~henvl) ethenvl]-5-methyl~vrazole ~ According to the procedure of Example 1, -! . 1 (4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-1-hexene-3,5-dione is reacted with hydrazine hydrate to ~: afford 3-~-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole in 52% yield, sufficiently pure for further use.
~, , ~' '~ . ' `~
,~
.
:

:~
, ~ 35-1 3 ~
Exam~le lOc 3-[~-(4'-t-ButyldLmethvlsilvloxv-3,5-dimethox~æhenYl) ethenvl]-5-methvl~vrazole According to the procedure of Example 1, 1-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxyphenyl~-1-hexene-3,5-dione is reacted with hydrazine hydrate to afford 3-[~-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxyphenyl)ethenyl]-5-methylpyrazole in 32%
yield, mp = 133-136C.

lo Exam~le lOD

(E)-5-[~-~4'-~ydroxv-3' 5'-dimethoxv~henvl~ethenvl]-3-methyl-lH-~vrazole-1-acetic acid, ethvl ester A solution of 1-(4'-hydroxy-3',5'-dimethoxy-phenyl)-l-hexene-3,5-dione (1.0 g, 3.8 mmol) in absolute ethanol (100 mL) is added to a solution.of ethyl hydrazinoacetate in absolute ethanol ~100 mL) according to the procedure found in A. Carmi et al, J. ora. Chem., 25, 44 (1960). The reaction mixture is acidified with acetic acid (2 mL) and is stirred for 30 minutes at room temperature. The solvent is evaporated, and the residue is suspended in water (50 mL). The solid which is collected is then puri~ied by flash chromatography (silica gel, 1:1 . methylenechloride/ethyl acetate) and subsequent recrystallization (methylenechloride/ethyl acetate l:l) to;afford 0.45 g (34%) of (E)-5-[~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methyl-lH-pyrazole--1-acetic acid, ethyl ester, mp = 159-160C. Analysis ~` for C18H22N2O5. Calculated C-62.42, H-6.40, N-8.09.
F~und C-62.08r H-6.39, N-8.26.

": ~:

.:;~ .

~ -36-1330~2 ExamP1e lOE

5-[~-(4'-t-Butyldimethylsilyloxv-3'-methoxv~henvl) ethenvl]-3-methyl-lH-Pvrazole-1-acetic acid, methvl ester: and 3-[3-(4'-t-butvldimethvlsilvloxv-3'-methoxY~henvl)ethenYll-5-methvl-lH-pYrazole-l-acetic acid, methYl ester 3-~ 4'-t-butyldLmethylsilyloxy-3'-methoxy-phenyl)ethenyl]-5-methylpyrazole (2.57 g, 7.5 mmol) is dissolved in DMF (20 mL). Potassium carbonate lo (10.30 g, 75 mmol) is ground into a fine powder and added to the-reaction. The reaction is stirred at room temperature for 10 minutes under argon atmosphere. Methyl bromoacetate is added and the reaction is stirred for 2 hours. The mixture is then poured into water (200 mL) and neutralized with aqueous HCl. The layers are separated, and the aqueous layer is washed with methylenechloride. The combined organic layers are washed with water and brine. Drying over MgSO4 followed by evaporation of solvents affords a brown oil. Flash chromatography (10% ethyl ether in methylenechloride) separates two ll products: 3-[~-(4'-t-butyldimethylsilyloxy-3'-¦ methoxyphenyl)ethenyl]-5-methyl-lH-pyrazole-1-acetic ~ acid, methyl ester (Rf = 0.31); 1.5 g; and ¦ 25 5-~-(4~-t-butyldimethylsilyloxy-3~-methoxyphenyl) ethenyl]-3-methyl-lH-pyrazole-1-acetic acid, methyl ester (Rf = 0.14), 0.55 g.
.~
;~ ' ~ , .
~ .
.
.~ ....
, `

~330~
Example lOF

3-[~-(4'-t-butyldimethylsilvloxv-3',5'-dimethoxv E~henyl)ethenvl]-5-methYl-lH-py~azole-l-acetic acid, methvl ester and 5-[~-(4'-t-butyldimethYlsil~oxY-s 3',5'-dimethoxye@~y~L_henyl]-3-methvl-lH-~vra201e-l-acetic acid, methyl ester According to the procedure of Example lOE, 3-~-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxy-phenyl)ethenyl]-5-methylpyrazole (3.5 g, 9.35 mmol) is reacted with methyl bromoacetate to afford 3-[~-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxy-phenyl)ethenyl]-5-methyl-lH-pyrazole-l-acetic acid, methyl ester, 2.3 g (55%), mp = 139-141C; and 5-t~-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxy-phenyl)ethenyl]-3-methyl-lH-pyrazole-l-acetic acid, methyl ester, 0.9 g (21%), mp = 150-151C.

Exam~le lOG

3-[~-(4'-HYdroxy-3l~sl-di-t-butyl~henyl)etkenyl]-5 methYl-lH-~yrazole-l-acetic acid, methvl ester and 5-[3-(4~-hYdroxY-3~,5~-di-t-butYl~henvl)ethenYl~-3 methYl-lH-~vrazole-l-acetic acid, methvl ester According to the procedure of Ex2mple lOE, 3-~-(4'-hydroxy-3',5'-di-t-butylphenyl~ethenyl]-5-methylpyrazole (3.0 g, 9.6 mmol) is reacted with methyl bromoacetate in DMF, with the exception that sodium acetate is used in place of potassium carbonate. Flash chromatography separates ~- 3-[~-(4'-hydroxy-3'j5'-di-t-butylphenyl)ethenyl]-5-methyl-lH-pyrazole-l-acetic acid, methyl ester, 0.65 g (18%~, mp = 170-174C; and 5-[~-(4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-3-methyl-lH-pyrazole-l-acetic acid, methyl ester, (as HCl salt) 0.72 g (17%), mp = 179-180C. Analysis for C23H33ClN203.
'.
.,~ .

~ -38-1 330~
Calculated C-65.62, H-7.90, N-6.65, Cl-8.42. Found C-65.53, H-7.99, N-6.46, Cl-8.31.

Example lOG

3-t~-(4'-Hydroxv-3',5'-di-t-but~lphenYl)ethenvl]-1,5-dimethvl~vrazole and 5-[~-(4'-hvdroxy-3',5'-di-t-butYlPhenyl?ethenvl]-1,3-dimethvl~Yrazole.
According to the procedure of Example lOG, 3-tt3-(4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-5-methylpyrazole is reacted with methyl iodide and lO sodium acetate to afford two regioisomeric products '~
separated by flash chromatography (chloroform):
3-[~-(4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-1,5-dimethylpyrazole ( %), mp = 155-157C;
5-[~-(4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]- ;' 1,3-dimethylpyrazole ( %), mp = 120-122C.
~ , Exam~le lOH

3-[3-(4'-HYdroxv-3'.5'-dimethoxY~henYl)ethenyl]-5-: methyl-lH-pYrazole-l-acetic acid, methvl ester To a solution of 3-[~-(4'-t-butyldimethyl--~ 20 silyloxy-3',5'-dimethoxyphenyl)ethenyl]-S-methyl-lH-pyrazole-l-acetic acid, methyl ester (2.25 g, 5.0 '~ mmol) in dr~ THF (150 mL) is added tetra-n-butyl-ammonium fluoride (7.5 mL, lM solution in THF) at 0C. The reaction mixture is stirred at 0C for one ~- 25 hour and then quenched'by the dropwise addition of brine (100 mL) at 0C. The layers are separated and :~ the agueous layer extractet with ethyl acetate. The combined organic layers are evaporated and the residue purified by flash chromatography ~ethyl a~etate/methylene chloride l:l) to afford 1.35 g (80%) of 3-t~-(4'-hydroxy-3',5'-dimethoxyphenyl) ethenyl]-5-methyl-lH-pyrazole-l-acetic acid methyl ; ' ester, mp = 112-114C. Analysis for C17H20N2O5.
- ,~;

:

~ -39-~33~
Calculated C-61.44, H-6.07, N-8.43. Found C-61.23, H-6.08, N-8.44.

ExamPle lOI

5-[~-(4'-HvdroxY-3'-methoxy~he~yl1ethenyl~-3-methyl-lH-pvrazole-l-acetic acid methyl ester According to the procedure of Example lOH, 5-[~-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl) ethenyl]-3-methyl-lH-pyrazole-l-acetic acid methyl ester is reacted with tetra-n-butyl ammonium fluoride to afford 5-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-lH-pyrazole-l-acetic acid methyl ester, in ¦ 46% yield, mp = 159-160C. Analysis for C16H18N204.
I Calculated C-63.55, H-6.01, N-9.27. Found C-63.68, ! H-6.05, N-9.20.
"
Exam~le lOJ ~
. : ,.
3-[3-(4'-HYdroxY-3'-methoxY~henvl)ethenYll-5-meth lH-Pvrazole-l-acetic acid,_methYl ester According to the procedure of Example lOH, 3-~-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl) -ethenyl]-5-methyl-lH-pyrazole-l-acetic acid methyl ester is reacted with tetra-n-butyl ammonium fluoride to afford 3~ (4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methyl~lH-pyrazole-l-acetic acid methyl ester, in 78% yield, mp = 141-143C. Analysis for C16H18N204.
Calculated C-63.55, H-6.01, N-9.27. Found C-63.53, H-6.02, N-8.89.
'.
~ ExamPle lOK
.
3-~-(4' HYdroxY-3'-methoxYPhenyl)ethenyl]-5-meth lH-~Yrazole-l-acetic acid ~ 30 A solution of 3-~3-(4'-hydroxy-3'-methoxyphenyl) :~ ethenyl]-5-methyl-lH-pyrazole-l-acetic acid methyl ,- :
~ .

,,:

~ 3 ~
ester (1.1 g, 3~6 mmol) in aqueous sodium hydroxide (200 mL, lN solution) with the minimum amount of hot ethanol needed for dissolution, is heated on a steam bath for 2 hours. The reaction mixture is cooled and neutralized with 4 N HCl. The resulting precipitate is collected by filtration and recrystallized from 2-propanol/water to afford 3-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methyl-lH-pyrazole-1-acetic acid, 0.64 g (62%), mp = 225-232C. Analysis for C15H16N2O4. Calculated C-62.49, H-5.59, N-9.72.
Found C-62.35, H-5.64, N-9.69.

ExamPle lOL

5-[~-~4'-Hydroxy-3'-methoxvphenYl)ethenYl]-3-methYl-lH-~vrazole-1-acetic acid According to the procedure of Example lOK, 5-~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-lH-pyrazole-1-acetic acid methyl ester is saponified to afford 5-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-lH-pyrazole-1-acetic acid, in il% yield.
Mp = 265-268C. Analysis for C15H16N2O4- Calculated ~ C-62.49, H-5.59, N-9.72. Found C-62.26, H-5.58, ¦~ N-9.56.

Exam~le lOM

5-~3-~4'-Hvdroxv-3',5'-dimethoxvPhenvl)ethenYl]-3-methyl-lH-~Yrazole-l-acetic acid According to the procedure of Example lOK, 5-[~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methyl-lH-pyrazole-1-acetic acid methyl ester is saponified to afford 5-[~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methyl-lH-pyrazole-1-acetic acid, in 90% yield. Mp = 240-243C. Analysis for C16H18N2O5-0.1 H2O. Calculated C-60.03, H-5.73, N-8.75. Found C-59.90, H-5.50, N-8.66.

~ ~ !
, .
' :

~ 3 3 ~
ExamPle lON

3-L~-(4~-Hvdroxy-3~5~-dimethoxyphenyl)ethenyl]-5 methvl-lH-Pyrazole-l-acetic acid According to the procedure of Example lOK, 3-[~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-5-methyl-lH-pyrazole-l-acetic acid methyl ester is saponified to afford 3-[~-t4'-hydroxY-3',5'-dimethoxyphenyl)ethenyl]-S-methyl-lH-pyrazole-l-acetic acid, in 65% yield. Mp = 232-234C. Analysis for C16H18N2O5. Calculated C-60.37, H-5.70, N-8.80.
Found C-60.20, H-5.88, N-8.53.

ExamPle lOP

5-[3-(4'-HvdroxY-3~5~-di-t-butvl~henYl)ethenyl]-3-meth~l-iH-~Yrazole-l-acetic acid -~
According to the procedure of Example lOK, 5-[~-(4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-3-methyl-lH-pyrazole-l-acetic acid methyl ester is saponified to afford 5-~ 4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-3-methyl-lH-pyrazole-l-acetic acid, in 50% yield. Mp = 220-224C. Analysis for C22~30N2O3. Calculated C-71.32, H-8.16, N-7.56.
Found C-71.14, H-8~16, N-7.46.

ExamPle 100 3-[~-(4'-Hydroxv-3',5'-di-t-butvl~henvl)ethenylL-S-methvl-lH-~y~azole-l-acetic acid According to the procedure of Example lOK, 3-~-(4'-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-5-methy}-lH-pyrazole-l-acetic acid methyl ester is saponified to afford 3-[~-(4'-hydroxy-3',5'-di-t butylphenyl)ethenyl]-5-methyl-lH-pyrazole-l-acPtic acid, in 50% yield. Mp = 227-229C. Analysis for ,'.~
'~ -:
.,~

.

~3~
C22H30N2O3. Calculated C-71.32, H-8.16, N-7.56.
Found C-71.22, H-8.18, No7.53.

Example 11 3-[~-(3-MethoxY-4-hYdroxy~henvl)ethenYl]-lH-S pYrazole-5-carboxylic acid Ethyl-3-[~-(3-methoxy-4-hydroxyphenyl)ethenyl]-lH-pyrazole-5-carboxylate (0.49 g, 1.7 mmoles) is added to a solution of KOH (0.38 g, 6.8 mmoles) in 50 ml EtOH. The reaction is warmed to reflux overnight. After cooling to room temperature, the reaction is diluted to 200 ml with H2O, and acidified ~ -to pH~4 with HCl. A white precipitate forms, and it is collected by filtration. Drying in vacuum in the presence of P2O5 gives 0.3 g (68~) of the desired product, mp=270-271C (dec).
, ; ExamDle 12 I
3,5-Bis[3-(4'-h~drox~-3'-methox~henyl)ethYl]-isoxazole 1,7-Bis(4'-hydroxy-3'-methoxyphenyl)-3,5-heptadione (1.00 g, 2.7 mmoles) (Bull. Acad. Polon.
Sci. 6, 481-486, 1958), hydroxylaminehydrochloride ; (0.19 g, 2.7 mmoles), and sodium acetate (0.44 g, 5.4 mmoles) are dissolved in 50 ml of 95% ethanol. The reaction is stirred at reflux overnight. The solvent is removed, and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed with water and dried over magnesium sulfate. A
precipitate forms on standing at room temperature for ~~ 2 days, and it is collected by filtration to give a k~ 30 white solid. The solid is taken up in 20 ml of ethanol containing 0.5 ml of 2~ hydrochloric acid.
The solution is heated to reflux for one hour. After neutralization with sodium bicarbonate, the ethanol .
:~;

, , is evaporated, and the residue is partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate and passed through a silica gel plug which is washed with 1:1 ethyl acetate/hexane. Evaporation of the solvent gives 0.2 g of the product obtained as a hydrate.
mp=106-107C. AnalysiS for C2lH25No6-o-4 mole ~2 Calculated C-66.97, ~-6.38, N-3.72. Found C-67.13, H-6.41, N-3.47.
ExamPle 13 S-[~-(4'-Acetoxv-3'-methoxY~ l)ethenyl~-3-trifluoromethvlisoxazole To a solution of isoxazole-3-trifluoromethyl-5-methyltriphenylphosphonium chloride (350 mg, 0.78 mmol) in dimethylsulfoxide (S ml) is added potassium t-butoxide (120 mg, 1.10 mmol). The mixture is stirred at room temperature for 45 minutes under an inert atmosphere. Acetylvanillin (170 mg, 0.89 mmol) is then added and the reaction stirred an additional one hour. The mixture is poured into saturated aqueous ammonium chloride and extracted into ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. Concentration and flash chromatography (hexane/ethyl acetate 3:1) afforded 150 mg of 5-[~-(4'-acetoxy-3'-methoxy-p~enyl)ethenyl]-3-trifluoromethylisoxazole, of sufficient purity for subseguent reaction~

., ~
, , :
.

~, :
~' -.
~3~4~2 ExamPle 13A

(E)-5-[~-(4'-Hydroxy-3',5'-bis(1,1-dimethylethyl) ~henvl)ethenvl]-3-trifluoromethYlisoxazole According to the procedure of Example 13, potassium t-butoxide (264 mg), isoxazole-3-trifluoro-methyl-5-methyl triphenylphosphonium chloride (1.054 g), and 3,5-di-t-butyl-4-hydroxybenzaldehyde (250 mg) are reacted in DMSO for 24 hr at room temperature to afford a cis-/trans-mixture of two olefinic products. Refluxing a mixture of this isomeric mixture in HCl/methanol (12 hrs) affords pure (E)-5-[!3-(4'-hydroxy-3',5l-bis(1,1-dimethyl-ethyl~phenyl)ethenyl]-3-trifluoromethylisoxazole (350 mg); mp = 132-134C- Analysis for C20H24NO2F3.
Calculated C-65.38, H-6.58, N-3O81. Found C-65.58, H-6.68, N-3.92.

Example 14 . . . '~
5-[3-(4'-HYdroxy-3'-methoxv~henvl)ethenYl]-3-trifluoromethYlisoxazole A solution of 5-[~-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-3-trifluoromethylisoxazole (120 mg, 0.34 mmol) in methanol (3 ml~ is cooled to 0C. Sodium methoxide (40 mg, 0.68 mmol) is added and the mixture stirred for 30 minutes. The mixture is diluted with ethyl acetate and washed with water.
The organic layer is dried (magnesium sulfate) and concentrated. Recrystallization from hexane/ethyl acetate affords 80 mg of pure 5-[~-(4'-hydroxy-3'-~; methoxyphenyl)ethenyl]-3-trifluoromethylisoxazole;
;~ 30 yield 82%; mp=83-87C.
.

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,~

S" ~

. ~- ~45~

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ExamPle 15 1 7-Bis-(4'-hvdroxyp_enYl)-3,5-he~tadione A solution of 1,7-bis-t4'-hydroxyphenyl)-1,6-heptadiene-3,5-dione (1.99 g, 6.5 mmoles) in S tetrahydrofuran (100 ml) is hydrogenated over Raney-nickel (O.2 g) under 30.4 psi of H2. The THF
is evaporated, and the residue chromatographed in 5%
MeOH/CHC13 to give 1.6 g (79%) of the desired product, mp=108-110C.

1o Example 16 1-(3'-Methoxy-4'-hYdroxY~hen~l)hexane-3,5-dione According to the procedure of Example 15, 1-(3'-methoxy-4'-hydroxyphenyl)-1-hexene-3,5-dione is - hydrogenated to afford in 90% yield 1-~3'-methoxy-4'-hydroxyphenyl)hexane-3,5-dione as an oil.

ExamPle 17 :~
~; 1-(4'-HvdroxY-3'-methoxY~henYl)-l-hexene-3,5-dione Boric anhydride (16.32 g, 237.2 mmoles) and acetylacetone are stirred at room temperature under ;~ 20 nitrogen for 12 hours. 4-Hydroxy-3-methoxybenzal-dehyde (18.06 g, 118.8 mmoles) and tributyl borate (364 g, 3.16 moles) are combined with the acetyl acetone/boric anhydride complex in 100 ml of ethyl acetate. The reaction is stirred at room temperature for one hour, at which time n-butylamine (4.34 g, 59.4 mmoles) is added in 4 egual portions over 8 hours. The reaction is allowed to stir for 12 hours. -300 ml of water containing 20 ml of concentrated hydrochloric acid is added to the reaction and stirred for 2 hours. The solid which forms is removed ffl filtration through celite, and the layers of filtrate are separated. The ethyl acetate layer .
,. . . .
.~ .

!; i '.' ' ~ S ` ~

,.
i 3 3 ~

is washed with 2 x 100 ml of saturated sodium bicarbonate, followed by 100 ml of brine. Drying over magnesium sulfate followed by evaporation of the solvent gives a red solid. Chromatography in 5%
ethyl acetate/chloroform gives 11.06 g (40%) of a yellow solid. mp=146-147C. Analysis for C13H140 reguires C-66.65, H-6.04. Found C-66.88, H-6.18.

The following compourlds were made by the above procedure:

R
~1 ~ , ;~ Ex. R Rl Z Meltina Point Yield 18 HO Cl Me 155-157C 14%

19 MeO HO Me 160-162C 13%

: 20 HO MeO ~ 1 155-157C 75%

21 HO MeOEt2 101-102C 21%

, lFrom ~
, ~ o O
2From JVL
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. -47-~3~0~2 ExamPle 22 Ethvl 6-(3'-methoxy-4'-hYdroxvPhenyl)-2,4-dioxo-5-hexenoate Sodium metal (1.8 g, 0.078 mole) is dissolved in absolute ethanol (50 ml) under an inert atmosphere.
An ethanolic solution of 1-(3'-methoxy-4'-hydroxy-phenyl)-l-butene-3-one (5.00 g, 0.026 mole) is then added slowly to the sodium ethoxide solution. The mixture is stirred for 10 minutes, after which diethyl oxalate (3.80 g, 0.026 mole) is added. The reaction is stirred at room temperaturé for 5 hours and then acidified with concentrated HCl. The mixture is then stirred at 0C for 1 hour. The precipitate is collected and dried to afford 4.8 g of ethyl 6-(3'-methoxy-4'-hydroxyphenyl)-2,4-dioxo-5-` hexenoate; 63% yield; mp=97-98C.
:: :
Exam~le 22A
-1-(4'-t-ButYldimethylsilYloxY-3'-methoxY~henYl) hexene-3,5-dione A solution of 1-(4'-t-butyldimethylsilyloxy-3'-methoxyphenyl)-l-butene-3-one (12.8 g, 41.8 mmol) in -hr (50 mL) is cooled to -78C under an argon atmosphere. Lithium di-isopropyl amide (83.5 mmol, in 50 mL THF) is slowly added to the reaction mixture. The reaction is stirred at -78C for 30 minutes. Acetyl chloride (16.4 g, 209 mmol) dissolved in THF (20 mL) is then added to the reaction over a 30 minute period. The reaction is quenched with aqueous HCl. The layers are separated, and the aqueous layer is washed with ethyl acetate.
The combined organic layers are washed with saturated aqueous sodium bicarbonate, dried over MgS04, and evaporated to give a red oil. Flash chromatography (ethyl ether/hexane 2:8) afford 5.0 g (34%) of :
;~
` O " `
`:~

~ 3 ~

1-(4'-t-butyldimethylsilyloxy-3'-methoxy-phenyl)-l-hexene-3,5-dione, mp = 81-85C.

Example 22B

1-(4'-Hvdroxy-3'-methoxYphenyl)-6,6,6-trifluoro-1-5 hexene-3,5-dione -According to the procedure of Example 22A, 1-(4'-hydroxy-3'-methoxyphenyl)-1-butene-3-one is reacted with lithium di-isopropylamide (3.0 equiv) and trifluoroacetic anhydride (2.0 equiv) to afford 1-(4'-hydroxy-3'-methoxyphenyl)-6,6,6-trifluoro-1-hexene-3,5-dione in 10% yield, mp =97-100C.

Exam~le 22C

1-(4'-t-But~ldimethvlsilyloxv-3'-methoxv~henvl)-1-butene-3-one 15To a methylene chloride (100 mL) solution of 1-(4'-hydroxy-3'-methoxyphenyl)-1-butene-3-one (10.0 g, 52 mmol) is added triethyl amine (5.8 g, 57.2 mmol) and t-butylchlorodimethyl silane (15.7 g, 104 mmol~. The reaction is stirred at room temperature for 12 hours under an argon atmosphere. The mixture is washed with water (3 X 100 mL) and brine (100 mL).
; The organic layer is dried over MgSO4 and evaporated.
Flash chromatography (ethyl ether/hexane 1:1) affords 12.8 g (80%) of the desired 1-(4'-t-butyldimethyl-silyloxy-3'-methoxyphenyl)-1-butene-3-one, mp =
65-68~C.

':

.

~33~2 Example 22D

1-(4'-t-But~ldimethYlsilylaxY-3',5'-dimethoxY~henyl)-1-hexene-3,5-dione According to the procedure of Example 22C, s 1-~4'-hydroxy-3',5'-dimethoxyphenyl)-1-hexene-3,5- - -dione is reacted with t-butylchlorodimethyl silane to afford 1-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxY-phenyl)-1-hexene-3,5-dione suitably pure for further use.

ExamPle 23 5-Chloromethvl-3-trifluoromethvlisoxazole A solution of 3-trifluoromethyl-5-hydroxy-methylisoxazole [(700 mg, 4.2 mmol) See K. Tanaka et al, Bull. Chem. Soc. J~n., 57, 2184 (1984)] and triphenylphosphine (1.43 g, 5.4 mmol) in carbon-tetrachloride (50 ml) and dichloromethane (20 ml) is heated at reflux for 6 hours. The reaction mixture is then cooled to room temperature and passed through a silica gel plug. Concentration affords in 82%
yield the desired 5-chloromethyl-3-trifluoromethyl-isoxazcle of sufficient purity for the following step (Example 24).

; Exam~le 24 Isoxazole, 3-trifluoromethvl-5-methYltriPhenYl-phosPhonium chloride Triphenylphosphine (1.016 g, 3.9 mmol) and 5-chloromethyl-3-trifluoromethylisoxazole (0.72 g, 3.9 mmol) are dissolved in toluene (40 ml) and heated at reflux for 24 hours. Upon cooling, a white ~ 30 precipitate formed and was filtered to aford in 60%
`~ yield the desired isoxazole, 3-trifluoromethyl-5-methyltriphenylphosphonium chloride, mp=245-250C.
,',::

.

_ 50-~ 3 ~ t~ 2 ExamPle 25 5-Isoxazoleethanol, a-[3,5-bis~l,l-dimethylethyl)-4-hvdroxY~henvl]-3-methyl-3,5-Dimethylisoxazole (26 g, 2.7xlO M) is dissolved in dry TH~ (100 ml) and cooled to -78C
with an acetone dry ice bath. n-Butyllithium (2.7xlO 1 M) is added dropwise via a syringe. The 3,5-dimethylisoxazole, n-butyllithium mixture is stirred at -78C for two hours under an argon atmosphere. 3,5-Di-tert-butyl-4-hydroxybenzaldehyde (18 g, 17.68xlO 2 M) is dissolved in dry THF (200 ml) and added dropwise via cannula under an argon atmosphere to the 3,5-dimethylisoxazole and _-butyllithium mixture. The reaction mixture is 1 15 allowed to warm to room temperature and is stirred ¦ for an additional eight hours. The reaction mixture ¦ is evaporated to near dryness, redissolved in ethyl acetate ~500 ml), washed with distilled water, then brine. The organic phase is dried over sodium sulfate, filtered, evaporated to dryness, and chromatographed on 1ash silica using hexane:ethyl acetate 3:2 to give 16.8 g (70% yield) of the desired 5-isoxazoleethanol, a-[3,5-bis(l,l-dimethylethyl)-4-hydroxyphenyl~-3-methyl-; mp=145-147C. Analysis for C20H29O3N (331.46). Calculated C-72.47, H-8.81, -N-4.22. Found C-72.31, H-8.84, N-4.24.

Exam~_e 25A

5-Isoxazoleethanol, a-~4-hvdroxY~henvl]-3-methvl-According to the procedure of Example 25, :~ .
3,5-dimethylisoxazole is reacted with 4-hydroxybenzaldehyde to afford 5-isoxazoleethanol, a-~4-hydroxyphenyl]-3-methyl-, pure enough for subsequent use.
~ .
, ~::

~ -51-133~2 Exam~le 25s 5-Isoxazoleethanol, a-~3,5-dimethYl-4-h drox~E~enyl]-3-methvl- -According to the procedure of Example 25, 3,5-dimethylisoxazole is reacted with 3,5-dimethyl-4-hydroxybenzaldehyde to afford 5-isoxazoleethanol, a-[3,5-dimethyl-4-hydroxyphenyll-3-methyl-, in 31%
yield.

Example 25C

lo 5-Isoæazoleethanol, a-[3,5-bis~l 21-dimethylethvl3-4-hvdroxYphenYl]-3-~henyl-According to the procedure of Example 25, 3-phenyl-5-methylisoxazole is reacted with 3,5-bis(l,l-dimethylethyl)-4-hydroxybenzaldehyde to afford 5-isoxazoleethanol, a-[3,5-bis(l,l-dimethyl-ethyl)-4-hydroxyphenyl]-3-phenyl-, in 33% yield. `

Exam~le 25D

5-Isoxa~doleethanol, a-[3,5-dimethoxY-~ vdroxY
~henvll-3-~henYl-According to the procedure of Example 25, 3-phenyl-5-methylisoxazole is reacted with 3,5-dimethoxy-4-hydroxybenzaldehyde to afford 5-isoxazoleethanol, a-t3,5-dimethoxy-4-hydroxy-; phenyl]-3-phenyl-,lin 30% yield.

Exam~le 25E

5-Isoxazoleethanol, a-[3-methoxy-4-hYdroxY~henY1]-3-,phenY~
According to the procedure of Example 25, 3-phenyl-5-methylisoxazole is reacted with vanillin `:

, . ~

.

~ 3 3 ~

to afford 5-isoxazoleethanol, a-[3-methoxy-4-hydroxy-phenyl]-3-phenyl-, in 41~ yield.

ExamF~le 25F

5-Isoxazoleethanol, a-~3,5-dibromo-4-hYdroxy~ enyll-s 3-methy~
According to the procedure of Example 25, 3,5-dimethylisoxazole is reacted with 3,5-dibromo-4-hydroxybenzaldehyde to afford 5-isoxazoleethanol, a-[3,5-dibromo-4-hydroxyphenyl]-3-methyl-, in 53%
yield. Mp = 139-143C.

ExamPle 25G

5-Isoxazoleethanol, a-[3,5-dichloro-4-hYdroxYphenyl~-3-methYl-~
According to the procedure of Example 25, 3,5-dimethylisoxazole is reacted with 3,5-`dichloro-4-hydroxybenzaldehyde to afford 5-isoxazoleethanol, a-~3,5-dichloro-4-hydroxyphenyl]-3-methyl-, in 61%
yield. Mp = 129-131C.
I ~
l Exam~le 25H
I ~
5-Isoxazoleethanol, a-t2-hvdroxy-3-methoxvPhenYl]-3-methvl-According to the procedure of Example 25,3,5-dimethylisoxazole is reacted with 2-hydroxy-3-methoxybenzaldehyde to afford 5-isoxazoleethanol, a-t2-hydroxy-3-methoxyphenyl]-3-methyl-, as an oil in 63% yield.

.

:~
: ' ' ,~

~ 3 ~ 2 ExamPle 25J

5-Isoxazoleethanol, a-[2 hydrs~;,3__ibromoPhen~l]- -3-methvl-According to the procedure of Example 25, 5 3,5-dimethylisoxazole is reacted with 3,5-dibromosalicylaldehyde to afford 5-isoxazoleethanol, a-[2-hydroxy-3,5-dibromophenyl]-3-methyl-, in 47% yield.
..
ExamPle 25K

5-Isoxazoleethanol, a-~2-hydroxy-3~ L~
3-methYl-According to the procedure of Example 25, - 3,5-dimethylisoxazole is reacted with 3,5-dichlorosalicylaldehyde to afford lS 5-isoxazoleethanol, a-[2-hydroxy-3,5-dichlorophenyl]-3-methyl- in 74% yield, mp = 151-153C.
~ . , .
ExamPle 26 5-Isoxazoleethanol, a-(4-hvdroxv-3-methoxYphenYl)-3-m~ethvl-According to the procedure of Example 25, 3,5-dimethylisoxazole (10 g, 0.103 mole, is reacted with n-butyllithium (0.103 mole) and vanillin (7.8 g, 0.0515 mole) to afford 5-isoxazoleethanolr a-(4-h-~droxy-3-methoxyphenyl)-3-methyl- ~10 g, 78%);
mp=128-135C.
~, ..
~ Exam~le 27 .,~ ~.
S-Isoxazoleethanol, a-(4-hvdroxY-3,5-bis(l-methYl-ethvl)~henYl)-3-methyl-According to the procedure o~ Example 25, 3,5-dimethylisoxazole (11.5 g, 0.049 mole) is reacted ,, .,~ ~ . . . .

~ ~4 ~33~

with n-butyllithium (O.049 mole) and "
3,5-bis~1-methylethyl)-4-hydroxybenzaldehyde (5 g, 0.0243 mole) to afford 5-isoxazoleethanol, a-(4-hydroxy-3,5-bis~1-methylethyl)phenyl)-3-methyl-(4.0 g, 56%); mp=79C.

Example 28 S-Isoxazoleethanol, a-(4-hYdrox~-3,5-dimetho ~-phenvl)-3-methYl-According to the procedure of Example 25, 3,5-dimethylisoxazole (4.26 g, 0.044 mole) is reacted with n-butyllithium (0.044 mole) and 4-hydroxy-3,5-dimethoxybenzaldehyde (4.00 g, 0.022 mole) to afford 5-isoxazoleethanol, a-(4-hydroxy-3,5-dimethcxyphenyl)-3-methyl- ~3.82 g, 63%); mp=142C.

ExamPle 29 5-~-(4'-Hydroxy_3',5'-bis(1,1-dimethvleth~l)~henyl) ethenvl]-3-methYlisoxazole A solution of 5-isoxazoleethanol, a-~3,5-bis(1,l-dimethylethyl)-4-hydroxyphenyl]-3-methyl- l16.8 g, 0.0507 mole) in HCl-saturated methanol (300 mL) is refluxed for 24 hr. The reaction mixture is evaporated to dryness, redissolved in ethyl acetate (400 mL), neutralized with 15% aqueous sodium bicarbonate and washed with brine. The residual organics are then dried (sodium sulfate) and concentrated to give a residue. Flash chromatography (hexane~ethyl acetate 3:1) affords ~ 11.0 g of 5-~-(4'-hydroxy-3',5'-bis(1,1-dimethyl-`~ ethyl)phenyl)ethenyl]-3-methylisoxazole;
;~ 30 - mp=174-175C. Calculated C-76.64, H, 8.68, N, 4.47.
~ ~ound C-76.60; H, 8.62; N, 4.33.
~ , .

. -55-.

~33 ~
ExamPle 30 5-[~-(4'-HYdroxv-3'-methoxvPhenvl)ethenvl]-3-methyl-isoxazole According to the procedure of Example 29, 5 5-isoxazoleethanol, a-(4-hydroxy-3-metho henyl)-3-methyl- (10 g, 0.04 mole) is reacted with HCl-methanol to afford 5-~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methylisoxazole (7.5 g, 80%); mp=123-127C. Calculated C-67.52, H-5.67, N-6.06. Found C-67.14, H-5.68, N-5.96.

ExamPle 31 5-~-(4'-Hvdroxy-3',5'-bis(l-methYleth~l)phenyl) ethenyl3-3-meth~lisoxazole I According to the procedure of Example 29, 5-isoxazoleethanol, a-(4-hydroxy-3,5-bis(l-methyl-ethyl)phenyl)-3-methyl- (4.0 g, 0.013 mole) is reacted with HCl-methanol to afford 5-~-(4-hydroxy-3',5'-bis(l-methylethyl)phenyl)ethenyl]-3-methyl-isoxazole (3.9 g, 98~); mp=119-120C. Calculated C-75.76, H-8.12, N-4.91. Found C-75.68, H-8.16, N-4.96.

Exam~le 32 .
5-~-(4'-Hvdroxy-3',5'-dimethoxvphenvl)ethenvl]-3-methvlisoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-(4-hydroxy-3,5-dimethoxy phen~l)-3-methyl- (3.00 g, 10.7 mmole) is reacted with HCl-methanol to afford 5-~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole (1.92 g, 69%); mp=152-157C. Calculated C-64.36, H-5.79, N-5.36. Found C-64.30, H-5.74, N-5.34.
.
''~:~
.
.."

1 3 3 ~

ExamPle 32A

5-~-(4'-Hvdroxy~henyl)ethenyl]-3-methvlisoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-~4-hydroxyphenyl]-3-methyl- is reacted with HCl-methanol to afford 5-~-(4'-hydroxy-phenyl)ethenyl]-3-methylisoxazole ~6.74 g, 14~); mp =
117-119C.

Exam~le 32B

5-[~-(4'-HydroxY-3'.5'-d_meth~lPhenvl)etheny~-3-methy~isoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-~3,5-dimethyl-4~hydroxyphenyl]-3-methyl- is reacted with HCl-methanol to afford 5-~-(4'-hydroxy-3',5'-dimethylphenyl)ethenyl]-3-mPthylisoxazole (0.62 g, 85~); mp = 158-161C.
Anaiysis for C14H15NO2- Calculated C-73.34, H-6.59, N-6.10. Found C-73.35, H-6.44, N-6.05.

Exam~le 32C

5-~3-(4'-Hvdroxv-3',5'-bis(l~l-dimethYlethyl)Phenvl) ethen~l] 3-~envlisoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-~3,5-bis(l,l-dimethylethyl)-4- ;~
hydroxyphenyl~-3-phenyl- is reacted with HCl-methanol to afford 5-[~-l4'-hYdroxY-3',5'-bis(l,l-dimethyl-ethyl)phe~yl) ethenyl]-3-phenylisoxazole (0.35 g, ~ 90%); mp = 157-161C. Analysis for C25H29NO2.
;~ Calculated C-79.96, H-7.78, N-3.73. Found C-79.78, H-7.74, N-3.71.

' ' ,.

, ~
'~:
.,~ .

~330'~2 ExamPle_32D

5-~-(4'-Hvdroxv-3',5'-dimethoxvPh-eny~ethe~yl]-3 phenvlisoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-[3,5-dimethoxy-4-hydroxy-phenyl]-3-phenyl- is reacted with HCl-methanol to afford 5-[~-(4'-hydroxy-3',5'-dimethoxyphenyl) ethenyl]-3-phenylisoxazole (1.1-g, 95%); mp = `
135-140C. Analysis for ClgH17N04~ Calculated C-70.58, H-5.30, N-4.33. Found C~70.70, H-5.17, N-4.25.

ExamPle 32E

5-~3-(4'-Hvdroxv-3'-methoxv~henyl)ethenvl]-3-~henvl isoxazole According to the procedure of ~xample 29, 5-isoxazoleethanol, a-[3-methoxy-4-hydroxyphenyl]-3-phenyl- is reacted with HCl-methanol to afford 5-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl~-3-phenyl-isoxazole ~1.0 g, 95~) mp = 148-152C. Analysis for ; 20 C18H15NO3. Calculated C-73.71, H-5.15, N-4.77.
Found C-73.33, H-5.13, N-4.69.

Exam~le 32F

5-[~-(2'-Hvdroxv-3'-methoxy~henvl)ethenvl]-3-methvl-isoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-~2-hydroxy-3-methoxyphenyl]-3-methyl- is reacted with HCl-methanol to afford ` ~ 5-~-(2'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-isoxazole (31%); mp = 129-131C. Analysis for ~ 30 C13H13NO3. Calculated C-67.51, H-5.68, N-6.06.
,~ Found C-67.51, H-5.70, N-5.95.
I
'.'~ `

: . -58-~ 3 3 ~ 2 Example 32G

5-~-(4'-H~droxy-3' 5'-dibromoPhenyl)ethen 1]-3-methvlisoxazole According to the procedure of Example 29, 5-isoxazoleethanol, a-[3,5-dibromo-4-hydroxyphenyl]-3-methyl- is reacted with HCl-methanol to afford 5~ (4'-hydroxy-3',5'-dibromophenyl)ethenyl]-3-methylisoxazole (15%), mp = 167-169C. Analysis for C12HgBr2NO2. Calculated C-40.12, H-2.53, N-3.90, Br-44.49. Found C-40.18, H-2.48, N-3.64, Br-44.88.

ExamPle 32H

5-~-(4'-Hvdroxv-3',5'-dichloroPhenYl~ethenvl]-3-I methYlisoxazole A toluene (100 mL) solution of 5-isoxazole-ethanol, a-~3,5-dichloro-4-hydroxyphenyl]-3-methyl-(5.5 g, 19.1 mmol) containing a catalytic amount of p-toluenesulfonic acid is warmed to reflux for 3 hours, with azeotropic removal of water. The solvent is evaporated, and the residue is chromatographed (ethyl acetate/chloroform, 1:9) to afford 5-~-(4'-hydroxy-3',5'-dichlorophenyl)ethenyl]-3-methylisoxazole (2.3 g, 45%); mp = 184-186C.
. Analysis for C12HgC12NO2. Calculated C-53.35, H-3.37, N-5.19. Found C-52.98, H-3.22, N-5.28.

ExamE~e 32I

5-t~-(2'-Hvdroxv-3',5'-dibromoPhenyl)ethenYl]-3-methylisoxazole According to the procedure of Example 32~, 5-isoxazoleethanol, a-~2-hydroxy-3,5-dibromophenyl]-3-methyl- is reacted with p-toluenesulfonic acid/toluene to afford 5-~-(2'-hydroxy-3',5'-~ : dibromophenyl)ethenyl]-3-methylisoxazole in 70%
.-.~

~ -59-~ 3 ~

yield, mp = 150-157C. Analysis for C12HgNO2Br2.
Calculated C-40.15, H-2.53, N-3.90. Found C-39.85, H-2.47, N-3.75.

ExamPle 32J

5-[~-~2'-HYdroxY-3'.5'-dichlorophenvl)ethenYl]-3-methylisoxazole According to the procedure of Example 32H, 5-isoxazoleethanol, a-[2-hydroxy-3,5-dichlorophenyl]-3-methyl- is reacted with p-toluenesulfonic acid/toluene to afford 5-~-(2'-hydroxy-3',5'-dichlorophenyl)ethenyl]-3-methylisoxazole in 80%
yield, mp = 143-145C. Analysis for C12HgNO2Cl2.
Calculated C-53.36, H-3.36, N-5.19, Cl-26.25. Found C-53.12, H-3.05, N-5.11, Cl-26.26.

Example 33 4-Acetoxy-3-methoxvcinnamaldehYde Acetoxy vanillin (5.0 g, 2.6x10-2 M) is dissolved in dry THF ~300 ml) with formyl methylenetriphenylphosphorane (78 g, 2.6xlO 2 M) and 2~ refluxed under an atmosphere of argon for 80 hours.
The reaction mixture is concentrated to dryness and chromatographed on flash silica to afford 4-acetoxy-3-methoxycinnamaldehyde (3 g, 54~ yield);
mp=83-86C.

Exam~le 34 4-Acetoxy-3-methox~cinnamaldehYde oxime 4-Acetoxy-3-methoxycinnamaldehyde (2.0 g, 9.1xlO 3 M) is dissolved in methanol (100 ml) and ., ~
cooled to 0C with an ice/water bath. Hydroxylamine hydrochloride (0.8 g, 1.2xlO 2 M) is added with sodium acetate (0.97 g, 1.2xlO 2 M) an~ stirred for , .

133~

one hour. The reaction mixture is concentrate~ ~o near dryness, and redissolved in ethyl acetate (150 ml). The residual organics are washed twice with water dried over sodium sulfate, filtered, evaporated to dryness, and chromatographed on flash s~ lLca ~s~ng h~xane:ethyl acet~te 3: 1 t~ aff~rd 1.45 g of 4-acetoxy-3-methoxycinnamaldehyde oxLme in 68% yield; mp=72-74C.

Exam~le 35 3-~3-~4~-Acetoxv-3'-methaxY~henvl)ethenY11~5-PhenYl- ---isoxazole 4-Acetoxy-3-methoxycinnamaldehyde oxime (O.6, 2.5xlO 3 M) is dissolved in dry DMF (15 ml) at 0C
under an atmosphere of argon. N-chlorosuccinLmide (0.4 g, 3.0xlO 3 M) is dissolved in dry DMF (10 ml) and transferred to the 4-acetoxycinnamaldehyde/DMF
solution via cannula under an atmosphere of argon.
- The reaction is stirred at 0C for nearly two hours.
Phenylacetylene ~1.3 g, 1.3xlO M) is mixed with triethylamine (0.38 g, 3.8xlO 3M) and dry DMF (5 ml).
This mixture is then added via syringe to the cinnamaldehyde/NCS mixture. The entire mixture is allowed to reach room temperature and is stirred overnight. The reaction mixture is redissolved in ethyl acetate (150 ml), washed first with water, then with brine. The organics are dried over sodium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on flash silica using ~- hexane:ethyl acetate 3:2 to afford 0.45 g of 3~ 3-~-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-phenyl-isoxazole in 54% yield; mp=139-144C.
, ~,:

''~

, ~61-~3~ 2 Exam~le 35A

~ 3-[~-~4'-Acetoxv-3'-methoxy~henYl)ethenyl]-5-(2'-¦ hydroxvethyl)isoxazole According to the procedure of Example 35, 4-acetoxy-3-methoxycinnamaldehyde oxime is reacted with N-chlorosuccinimide and 3-butyn-1-ol to afford 3-t~-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-(2'-hydroxyethyl)isoxazole (2.0 g, 50%); mp =
62-64C.

Exam~le 35B
. .
3-~-(4'-Acetoxv-3'-methoxvPhenyl)ethenYl]-5-h~droxv-methylisoxazole According to the procedure of Example 35, 4-acetoxy-8-methoxycinnamaldehyde oxime is reacted with N-chlorosuccinimide and propargyl alcohol to afford 3-~-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-hydroxymethylisoxazole (2.5 g, 67%); sufficiently pure for further use.

Exam~le 35C

3-Phenvl-5-methYlisoxazole Benzaldehyde oxime (20.0 g, 0.165 mole) is dissolved in DMF (250 mL) and cooled to 4C in an ice bath. N-chlorosuccinimide (33.1 g, 0.248 mole) is ; added to the reactionimlxture, and the mixture is 25 stirred for one hour. Isopropenyl acetate (41.3 g, -~ 0.41 mole) and triethyl amine (-24.8 g, 0.247 mole) I are added via an equal-pressure addition funnel to the solution of benzaldehyde hydroxamic chloride. -The ice bath is removed and the mixture is stirred for 24 hours. The mixture is then taken up into ethyl acetate (1 L) and washed with water (2 X 1 L).
Ihe organic layer is dried over sodium sul~ate and ~}~

:`y '' ~L33~4~2 ~ evaporated to give a residue. Flash chromatography j (hexane/ethyl acetate 9:1) affords 12.0 g of ~ 3-phenyl-5-methylisoxazole as a yellow oil. --~ :
~; Exam~le 36 3-[~-(4'-Hydroxv-3'-methoxyPhenYl)ethen~l]-5-phen ¦- isoxazole ; 3-~-(4'-Acetoxy-3'-methoxyphenyl)ethenyl]-5-phenylisoxazole (0.3 g, 8.9x10 4 M) is dissolved in - MeOH (20 ml) and stirred with sodium methoxide -(0.1 g, 1.8x10 3 M) for one hour. The reaction mixture is concentrated to dryness, redissolved in ethyl acetate (75 ml), and washed twice with water.
!i The organics are dried over sodium sulfate, filtered, evaporated to dryness, and chromatographed on flash , 15 silica using hexane:ethyl acetate to afford 0.25 g of ~
-~ 3-t~-(4'-hydroxy-3'-methoxyphe~yl)ethenyl]-5-phenyl- --;~ isoxazole in 97% yield; mp=135 138C. Calculated C-73;71, H-5.15, N-4.77. Found C-73.35, H-5.35, ~ N- .
,~
Exam~le 36A
.
3-[3-(4'-Hvdroxy-3'-methoxv~henvl)ethenYl]-5-~2'-h~droxvethvl)isoxazole According to the procedure of Example 36, 3-[~-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-(2'-hydroxyethyl)isoxazole is reacted with sodium methoxide/methanol to afford 3-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-~2'-hydroxyethyl)isoxazole (0.24 g, 93%); mp ~ 127-131C. Analysis for C14H15NO4. Calculated C-64.35, H-5.99, N-5.36.
Found C-64.40, H-5.79, N-5.15.

1 3 ~ 2 Exa~ 36B

3-[~-(4'-Hy~droxy-3'-methoxv~henYl)ethenYl]-5-hvdroxv-methvlisoxazole According to the procedure of Example 36, 3-[~-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-hydroxy-methylisoxazole is reacted with sodium methoxide/
methanol to afford 3-t~-(4'-hydroxy-3'-methoxyphenyl) ethenyl]-5-hydroxymethylisoxazole (0.6 g, 79%); mp =
39 143 C- ~nalysis for C13H13N~ o 4 H2o j lO Calculated C-63.36, H-5.46, N-5.50. Found C-63.34, H-5.53, N-5.30.

~xam~le_37 3-~Q-(4'-Acetoxv-3'-methoxY~hen~l)ethenvl]-5-meth~l-Pyrazole To a solution of 3-[~ (4'-hydroxy-3'-methoxy-phenyl)ethenyl]-5-methylpyra701e (2.50 g, 10.9 mmoles) in pyridine (30 mL) is added acetic anhydride ~5.54 g, 54.3 mmoles). The reaction is stirred at room temperature for 12 hr. A~ter this ~ime, the reaction mixture is added dropwise to vigorously stirred ice-water (500 mL). The resulting suspension .-is allowed to stand for 90 minutes and the crude diacetyl product (3.2 g) is collected by filtration.
; The crude diacetyl product is dissolved in acetone (300 mL), water (30 mL) and methanol (30 mL). Basic alumina tlO0 g, Woelm basic, tlc grade) is added and the reaction mixtùre refluxed for 4.5 hr. The alumina is filtered and rinsed with acetone (100 mL).
The combined filtrate is evaporated a~d the residue partitioned between water and ethyl acetate. The organic layer is dried (MgS04) and concentrated to afford, after flash chromatography [chloroform:ethyl acetate 3:1], 1.71 g of pure 3-r~-(4'-acetoxy-3'-,~ ` l !~

~, methoxyphenyl)ethenyl]-5-methylpyrazole; "
' 131-136C. Analysis for C15H16N2 3 I C-66.16, H-5.92, N-10.29. Found C-66.49, H-5.92, N-10.29.

Example 38 3-~-(4'-HYdroxY-3',5'-bis(1,1-dimethvlethYl)phenyl) ~ ethen~ll 5-methy~l~vrazole ¦ A solution of 5-~-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole ~ 10 (2.00 g, 6.4 mmoles), water (0.115 g, 6.4 mmoles) and ;~ molybdenum hexacarbonyl (1.27 g, 48 mmoles) in acetonitrile (75 mL) is refluxed for 12 hr under a nitrogen atmosphere. The reaction mixture is cooled and evaporated to dryness. The residue is dissolved in mathanol (250 mL) and acidified to pH ~ 1 with 4 N
~;: HCl. After stirring for 4 hr at room temperature, the methanol is evaporated. The resulting aqueous solution is neutralized with 1 N NaOH and the or~anic ;~ material is extracted into ethyl acetate. The organic solution is passed through a pad of silica gel (150 g) and further eluted with chlorofcrm (400 mL). The combined filtrate is evaporated to --dryness, taken up in a minimal amount of ethyl acetate, and passed through a silica gel pad again.
The resulting crude diketone (I.25 g) is then suspended in a mixture of acetic acid (100 mL) and 97% hydrazine (1.0 mL).~ The reaction mixture is stirred for 12 hr at room temperature. Evaporation ; affords a gummy residue which solidifies upon stirring in water (100 mL) for 30 minutes. The solid is purified by flash chromatography [methylenechloride/ethyl acetate 1:1] to afford ;~ 1.10 g of 3-[~-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-5-methylpyrazole;
~A '`~ 35 mp=218-223C- Analysis for C20H28N2 " ~ .

i~3~2 C-76.88, H-9.03, N-8.96. Found C-76.63, H-8.84, N-9.02.

Example 38A

3-[~-t4'-HYdroxY-3'~5~-bis(l-meth~lethYl)phenyl) S ethenvl]-5-methvlEyrazole According to the procedure of Example 38, 5~ -(4'-hydroxy-3',5'-bis(l-methylethyl)phenyl) ethenyl]-3-methylisoxazole is reacted with molybdenum hexacarbonyl to afford 3-[~-~4'-hydroxy-3',5'-bis(1,l-dimethylmethyl)phenyl)ethenyl]-5-methyl-pyrazole in 53% yield, mp = 183-184C. Analysis for C18H24N2O 0.1 H2O. Calculated C-75.54, H-8.52, N-9.79. Found C-7S.33, H-8.72, N-9.46.

Exam~le 38B

3-[3-(4'-HYdroxv-3l~5~-dimethox~henvl)ethenyl]-5 methYlpyrazole According to the procedure of Example 38, 5-~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole is reacted with molybdenum hexacarbonyl to afford 3-[~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-5-methylpyrazole in 56%
yield, mp = 153-158C. Analysis for C14~16N203.
Calculated C-64.60, H-6.19, ~-10.76. Found C-64.36, H-6.24, N-10.61.
;` ' ` ' ' . ~.
2s Exam~

3-~-(4'-HvdroxY-3'-methoxY~henYl~ethenYl]-5-meth razole According to the procedure of Example 38, 5-~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-~ 30 isoxazole is reacted with molybdenum hexacarbonyl to ,'~ ~

o~: ~ . . . ` ' ' ~ ' , ' ' , , ` ' ' afford 3-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole in 65% yield, mp = 145-147C.
Analysis for C13H14N202. Calculated c-67.81, H-6-13 N-12.17. Found C-67.62, H-6.18, N-11.93.

ExamEle 38D

3-[~-(2'-Hvdroxy-3',5'-dibromophenyl~ethenyl]-5-methYlPvrazole According to the procedure of Example 38, 5-[~-~2'-hydroxy-3',5'-dibromophenyl)ethenyl]-3-methylisoxazole is reacted with molybdenum hexacarbonyl to afford 3-[~-(2'-hydroxy-3',5'-dibromophenyl)ethenyl]-5-methylpyrazole in 30% yield, mp =191-200C. Analysis for cl2HloN2osr2-Calculated C-40.Z6, H-2.8Z, N-7.82, 8r-44.64. Found C-40.02, H-2.82, N-7.71, Br-44.35.

ExamPle 39 , .
~: 5-[13-~4~-Hvdroxy-3~5~-dimethoxvphenvl)ethenvl]-3 methvlisoxazole A solution of 3-methyl-5-isoxazoleacetic acid (10.0 g, 71 mmol) tsee reference R. G. Micetich, Canadian J. Chem., 48, 2006 (1970)], syringaldehyde (12.9 g, 71 mmol), piperidine (0.6 g, 7 mmol), and acetic acid (O.42 g, 7 mmol) in toluene (500 mL) is refluxed with azeotropic removal of water for 3 hours. The mixture is cooled, and the solid is collected by filtration. The solid is dissolved in pyridine (100 mL) and refluxed for 4 hours. The solvent is evaporated, and the residue purified by flash chromatography (methanol/chloroform 1:9) and recrystallization (ethyl acetate) to afford 5-[~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole (7.73 g, 42%); mp = 152-155C.

:~
: . .
. ,, ~ -67-~3~

Analysis for Cl4H15NO4. Calculated C-64.36, H-5.79, N-5.36. Found C-64.16, H-5.69, N-5.28.

Example 39A

5-~-(3'-Methoxy~-hvdroxv-5'-bromo~henvl)ethenvl]-3-methvlisoxazole ~, According to the procedure of Example 39, j 5-bromovanillin is reacted with 3-methyl-5-isoxazole-acetic acid to afford 5- r ~- ~3'-methoxy-4'-hydroxy-5'-bromophenyl)ethenyl-3-methylisoxazole in 55% yield, mp = 178-180C. Analysis ~or C13H12NO3Br.
Calculated C-50.33, H-3.90, N-4.54. Found C-50.35, H-3.88, N-4.44.
:"
Exam~le 40 5-~a-Carbomethoxv-~-l4'-hydroxY-3',5'-dimethoxy phenvl)ethenvl]-3-methYlisoxazole A solution of 3-methyl-5-isoxazoleacetic acid methyl ester (7.75 g, 50 mmol), syringaldehyde (9.1 g, 50 mmol), piperidine (0.42 g, 5 mmol), and acetic acid ~0.3 g, 5 mmol) in toluene (250 mL) is refluxed for 12 hours with azeotropic removal of water. Concentration affords a residue which is taken up in ethyl acetate and adsorbed onto dry silica gel pad. The pad is washed with ethyl ~;
acetate, and the filtrate is then evaporated.
Recrystallization $romiethyl acetate/hexane gives 5-[a-carbomethoxy-~-(4'-hydroxy-3',5'-dLmethoxy-phenyl)ethenyl]-3-methylisoxazole (7.9 g, 50%), mp =
130-132C. Analysis for C16H17NO6. Calculated ;~ C-60.17, H~5.38, N-4.39. Found C-60.17; H-5.53, N-4.34.
,~
, .

L ~:. ~

~ 3 ~ 2 Example 41 5-~a-Carbomethoxy-~-~4'-hvdroxy-3,5-dichloro~henvl) ethenvl]-3-methYlisoxazole ¦ According to the procedure of Example 40, ! 5 3-methyl-S-isoxazoleacetic acid methyl ester is reacted with 3,5-dichloro-4-hydroxybenzaldehyde to -af f ord 5-[a-carbomethoxy-~-(4'-hydroxy-3',5'-dichlorophenyl)ethenyl]-3-methylisoxazole (37%), mp =
198-200 C. Analysis for C14H11 2 4 C-51.24, H-3.39, N-4.27, Cl-21.61. Found C-S0.99, H-3.28, N-4.37, Cl-20.88. -~
: ~.
Exam~le 42 .j 5-ta-Carbamethoxv-3-(4'-hvdroxv-3',5'-bis(l-methyl- ~
ethvl)PhenYl)ethenvl]-3-methvlisoxazole ~. -According to the procedure of Example 40, 3-methyl-5-isoxazoleacetic acid methyl ester is reacted with 4-hydroxy-3,5-bis(l-methylethyl) benzaldehyde to afford 5-[a-carbomethoxy-~-(4'-hydroxy-3',5'-bis(l,l-dimethylmethyl)phenyl)ethenyl]-3-methylisoxazole (41%), mp = 126-128C. Analysis or C20H25NO4~ Calculated C-69.94, H-7.35, N-4.08.
Found C-69.88, H-7.29, N-3.72.
' ~ :
Exam~le 43 , 5-[a-Carbomethoxv-~-l4'-hvdroxv-3',5'-dimethYl-phenyl)ethenvl~-3-methvlisoxazole According to the procedure of Example 40, . ~: 3-methyl-5-isoxazoleacetic acid methyl ester is reacted with-4-hydroxy-3,5-dimethylbenzaldehyde to :: afford 5-[a-carbomethoxy-~-(4'-hydroxy-3',5'-" 30 dimethylphenyl)ethenyl~-3-methylisoxazole (45%), mp =
~, 176-178C. Analysis for C16H17N04- Calculated ~,r , 'D~ i '~

- ~y -1330~4~

C-66 . 88, H-5 . 98, N-4 . 38 . Found C-66 . 46, H-6 . 01, N-4 . 85 .

Exam~le 44 5-[a-Carbomethoxv-~-(4'-hYdroxv-3',5'-dibromoe~enYl) , 5 ethenvl]-3-methy_isoxazole ! According to the procedure of Example 40, 3-methyl-5-isoxazoleacetic acid methyl ester is :~
reacted with 4-hydroxy-3,5-dibromobenzaldehyde to afford 5-~a-carbomethoxy-~-(4'-hydroxy-3',5'-dibromophenyl)ethenyl]-3-methylisoxazole (48%), mp =
. 164-166C- Analysis for C14HllBr2N4- CalCUlated j C-40. 32, H-2. 66, N-3. 36, Br-38. 32. Found C-40.34, . H-2 . 61, N-3.30, 8r-38.38.
. ..
ExamPle 45 . , 15 5-~a-Carbomethoxv-~-(4'-hvdroxY-3'-methoXV~henyl) ~:
ethenvl]-3-methvlisoxazole According to the procedure of Example 40, 3-methyl-5-isoxazoleacetic acid methyl ester is reacted with vanillin to afford 5-[a-carbomethoxy-~-2 0 ( 4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl- :
isoxazole (51%), mp = 117~ C. Analysis for C15~15NO5. Calculated C-60.17, H-5.38, N-4.39.
: Found C-60.17, H-5.53, N-4.34.
, . Exam~le 46 . ' :~
5-[a-Carbomethoxv-~-(4l-hvdroxv-3l~5~-bis~
dimethvlethvl)~henvl)ethenyl]-3-methylisoxazole According to the procedure of Example 40, `~: 3-methyl-5-isoxazoleacetic acid methyl ester is reacted with 4-hydroxy-3,5-bis(l,l-dimethylethyl) ~: 30 benzaldeh~de (with the exception of a longer reaction time of 6 days) to afford S-[a-carbomethoxy-~-., ,,~
:

, 1 3 ~

(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl) ethenyl]-3-methylisoxazole (25%), mp = 131-136C.
C20H29NO4. Calculated C-71 13 H 7 87 N-3.77. Found C-71.41, H-7.99, N-3.75.

~ 5 Exam~le 46A

il 5-~a-CarbomethoxY-~ metho~y~-4'-hvdroxy-5'-bromo-phenvl)ethenY1~-3-methvlisoxazole According to the procedure of Example 40, f 3-methyl-5-isoxazoleacetic acid methyl ester is reacted with 5-bromovanillin to afford 5-[a-carbomethoxy-~-(3'-methoxy-4'-hydroxy-5'-bromo-phenyllethenyl]-3-methylisoxazole in 38% yield, mp =
138-140C. Analysis for C15H14N05Br. Calculated C-48.93, H-3.84, N-3.80, Br-21.70. Found C-49.10, H-3.88, N-3.96, 3r-21.35.

Example 47 ...
5-[a-Carboxy-~-(4'-_ydroxv-3'.5'-dimethoxY~henYl) ethenyl]-3-methYlisoxazole A solution of 5-~a-carbomethoxy-~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole (3.0 g, 9.4 mmol) in 1 N agueous KOH (100 mL) is stirred at room temperature for 18 hours. The solution is acidified with agueous HCl and the precipitate formed is collected by ~iltration. Recrystallization from 2s methanol/water 1:9 affords 5-[a-carboxy-~-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methyl-isoxazole (2.17 g, 76%); mp = 217-219C. Analysis for C15H15NO6. Calculated C-59.01, H-4.96, N-4.59.
~ Found C-58.36, H-4.90, N-4.51.
.~ .
.~
'-' .~ '~

~''''' , .
': ~' :. r' `~

, ~3~

Example 48 5-[a-Carboxy~ 4'-hvdroxv-3',5'-dichloro~henyl) ~-ethenvl]-3-meth~L soxazole According to the procedure of Example 47, 5-[a-carbomethoxy-~-(4'-hydroxy-3',5'-dichlorophenyl) ethenyl]-3-methylisoxazole is saponified to afford 5-~a-carboxy-~-(4'-hydroxy-3',5'-dichlorophenyl) e~henyl]-3-methylisoxazole (64%), mp = 229-230C.
Analysis for C13HgCl2NO4. Calculated C-49.70, j lO H-2.89, N-4.46, C1-22.57. Found C-49.46, H-2.65, i N-4.17, C1-22.54.

Exam~le 49 5-~a-Carboxy-3-(4'-~ydroxv-3',5'-bisll-methvl-ethyl)~henYl)ethenvl]-3-methylisoxazole According to the procedure of Example 47, 5-[a-carbomethoxy-~-~4'-hydroxy-3',5'-bis(1-methyl ethyl)phenyl)ethenyl]-3-methylisoxazole is saponified to afford 5-[a-carboxy-~-~4'-hydroxy-3',5'-bis(1,1-dimethylmethyl)phenyl)ethenyl]-3-methylisoxazole (R3%), mp = 192-194C. Analysis for C1gH23NO4. -Calculated C-69.27, H-7.05, N-4.25. Found C-69.51, H-7.06, N-4.16.
.
ExamPle 50 5-[a-Carboxy-3-(4'-hydrox~-3'-methoxvphenyl)ethenYl]-25 3-methYlisoxazole According to the procedure of Example 47, 5-[a-carbomethoxy-~-(4'-hydroxy-3'-methoxyphenyl) ethenyl]-3-methylisoxazole is saponified to afford 5-~a-carboxy-~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methylisoxazole (73%), mp = 198-199C. Analysis ~ for C14H13NO5. Calculated C-61.08, H-4.77, N-5.09.
} Found C-60.74, H-4.72, N-4.65.
~5, ~ .

~ .

133~

Example 5 1 5-[a-Carboxy-@~(4'-hvdroxY-3~,5'-bis(l,l-dimethvl-ethvl)PhenYl)ethenYl]-3-methvlisoxazole According to the procedure of Example 47, S-[a-carbomethoxy-~-(4'-hydroxy-3',5'-bis(l,l-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole is saponified to afford 5-[a-carboxy-~-t4'-hydroxy-3',5'-bis(l,l-dimethylethyl)phenyl)ethenyl]-3-methyl-isoxazole (85%)j mp = 219-221C. Analysis for C21H27NO4. Calculated C-70.55, H-7.63, N-3.92.
Found C-70.48, H-7.64, N-3.84.
.''~ ' .
~ ExamPle 52 :~, 5-[a-CarboxY-3-~4~-hvdroxy-3~5~-dimethvlPhenYl) ethenvl]-3-methYlisoxazole 15According to the procedure of Example 47, 5-[a-car~omethoxy-~-(4'-hydroxy-3',5'-dimethyl-phenyl)ethenyl]-3-methylisoxazole is saponified to afford 5-[a-carboxy-~-(4'-hydroxy-3',5'-dimethyl-phenyl)ethenyl]-3-methylisoxazole ~90%), mp 228-229C. Analysis for C15H15NO4. Calculated C-65.91, H-5.54, N-5.13. Found C-66.30, H-5.62, N-5.06.
~ (~
~ ExamPle 53 ~
`C' ~ :
, 5-[a-Carboxv ~-~4'-hvdroxv-3',5'-dibromoPhenvl) ethenvll-3-methylisoxazole According to the procedure of Example 47, 5~[a-carbomethoxy-~-(4'-hydroxy 3',5'-dibromophenyl) !j ;~ ethenyl]-3-methylisoxazole is saponified to afford 5-ta-carboxy~ 4'-hydroxy-3',5'-dibromophenyl) ethenyl]-3-methylisoxazole (77%), mp = 229-230C.
Analysis for C13HgBr2N04. Calculated C-38.74, ~: :

133~4~2 H-2.02, N-3.48, Br-39.65. Found C-38.75, H-2.20, N-3.45, Br-39.93.

Exam~le 53A

5-~a-Carboxv-~-(3'-methoxv-4'-hvdroxY-5'-bromo-phenYl)ethen21l-3-methvlisoxazole According to the procedure of Example 47, 5-~a-carbomethoxy-~-(3'-methoxy-4'-hydroxy-5'-bromo-phenyl)ethenyl]-3-methylisoxazole is saponified to afford 5-[a-carboxy-~-(3'-methoxy-4'-hydroxy-5'-bromophenyl)ethenyl]-3-methylisoxazole (98%), mp =
, 225-227C. Analysis for C14H12N05Br. Calculated ¦ C-47.47, H-3.42, N-3.96, Br-22.56. Found C-47.4S, H-3.42, N-4.14, Br-22.84.

ExamPle S4 3-~3-(4'-HvdroxY-3',5'-bis(1 l-dimethylethyl)~henyl) ~-: ethenvl]-5-methvlisoxazole According to the procedure of Example 39, 5-methyl-3-isoxazoleacetic acid is react~d with 4-hydroxy-3,5-bis~l,l-dimethylethyl)benzaldehyde to afford 3-~-(4'-hydroxy-3',5'-bis(l,l-dimethylethyl) phenyl)ethenyl]-5-methylisoxazole in 44% yield. ~p =
172-174C. Analysis for C20H27N02. Calculated C-76.64, H-8.68, N-4.47. Found C-76.44, ~-8.58, ~; N-4.59.
Exam~le 54A

~i 3-~3-(4'-Hydroxv-3' 5'-dibromo~henvl)ethenvl]-5-,~ methvlisoxazole Accordinq to the procedure of Example 39, ~` 5-methyl-3~isoxazoleacetic acid is reacted with 4-hydroxY-3,5-dibromobenzaldehyde to afford 3-tS-~4'-hydroxy-3~5~-dibromophenyl)ethenyl]-~330~2 5-methylisoxazole in 86% yield, mp = 178-182C.
Analysis for C12HgNO2Br2. Calculated C-40.14, H-2.53, N-3.90. Found C-40.09, H-2.54, N-3.99.

Example 55 3-[~-(4'-Hvdroxv-3',5'-bis(l,l-dimethvlethYl)~henYl) ethenvl]-5-carboxvmethylisoxazole A solution of 3-[~-(4'-hydroxY-3',5'-bis(l,l-dimethylethyl)phenyl)ethenyl]-5-methylisoxazole (O.S
g, 1.6 mmol) in T~F (15 mL) is cooled to -78C.
N-butyllithium (2 mL, 3.2 mmol) is added dropwise, and the solution is stirred for an additional 20 minutes. The reaction mixture is then poured onto dry ice and allowed to come to room temperature under a flow of argon gas. Water (100 mL) is added and the mixture is extracted with ethyl acetate (200 mL).
The organic layer is washed with saturated agueous NH4Cl (lX) and water (2X), then dried over sodium sulfate. Chromatography of the resid~e on silica (chloroform/methanol 95:5 containing 0.1% acetic acid) affords 3-[~-(4'-hydroxy-3',5'-bis(l,l-dimethylethyl)phenyl)ethenyl]-5-carboxymethyl-isoxazole (0.4 g, 70%), mp = 205-210C. i~nalysis for C21H27NO4. Calculated C-70.56, H-7.61, N-3.92.
Found C-70.19, H-7.86, N-3.80.

Exam~le 56 3-~3-(4'-HYdroxY-3',5'-bis(l,l-dimethvlethYl)phenyl) ethenYl]-5-methvlpYrazole A solution of 3-methyl-5-pyrazoleacetic acid (20.0 g, 0.14 mol), 4-hydroxy-3,5-bis(l,l-dimethyl-30 ethyl)benzaldehyde (33.4 g, 0.14 mol), piperidine (1.2 g, 0.014 mol), and acetic acid (0.85 g, 0.014 mol) in toluene (1 L) is refluxed for 24 hours with ~ ~ azeotropic removal of water. The mixture is cooled .~

~ :;
5 e ~

~33~

and evaporated to afford a residue, which is dissolved in methanol/ethyl acetate (1:9) and ' extracted with water (300 mL). The organic layer isevaporated and recrystallized from hexane/ethyl acetate (5:1) to afford 3-[~-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-5-methyl-~ pyrazole (27.4 g, 61%). Mp = 220-224C. Analysis ¦ for C20H28N2O. Calculated C-76.88, H-9.03, N-8.96.
Found C-77.15, H-9.14, N-9.09.

~ lO ExamPle 57 ,~ .
' 3-[~-(4'-Hydroxy-3',5'-dimethYl~henvl)ethenvl]-S-`! methvl~razole According to the procedure of Example 56, 3-methyl-5-pyrazoleacetic acid is reacted with 4-hydroxy-3,5-dimethylbenzaldehyde to afford 3-t~-(4'-hYdroxy-3~5~-dimethylphenyl)ethenyl]
methylpyrazole in 50% yield. Mp = 185-i88C.
Analysis for C14H16N2O. Calculated C-73.66, H-7.06, N-12.27. Found C-73.68, H-7.13, N-12.26.

Exam~le 58 :
3-t3-(4'-Hvdroxv-3',5'-dibromo~henYl)ethenvl]-5-methvl~vrazole According to the procedure of Example 56, `
3-methyl-5-pyrazoleacetic acid is reacted with 4-hydroxy-3,5-dibromobenzaldehyde to afford 3-t~-(4~-hydroxy-3~5~-dibromophenyl)ethenyl]-5 methylpyrazole in 51% yield. Mp = 101-10~C.
Analysis for C12HlOBr2N2O- Calculated C-40.26, H-2.82, N-7.82. Found C-39.92, H-2.83, N-7.70.

~:

:-~ ~".,; ~
~ i~

~,}, ~ "-~; ` !` ,,, ` `. .... ,, ~ ".

~33~
ExamPle 58A

3-[~-(3'-MethoxY-4'-hydroxY-5'-bromophenYl~ethen~l]-5-methylPvrazole According to the procedure of Example 56, 3-methyl-5-pyrazoleacetic acid is reacted with 3-methoxy-4-hydroxy-5-bromobenzaldehyde to afford 3-~-(3'-methoxy-4'-hydroxy-5'-bromophenyl)ethenyl]-I S-methylpyrazole in 20% yield; mp = 158-160C.
Analysis for C13H13N2O2Br. Calculated C-50.50, , lO H-4.24, N-9.06. Found C-50.84, H-4.37, N-8.88.
i Example 59 3-[a-Carbomethoxv-~-~4'-hydroxY-3',5'-dibromoPhenYl) ethenYl]-5-methyl~yrazole According to the procedure of Example 40, 3-methyl-5-pyrazoleace~ic acid methyl ester is reacted with 4-hydroxy-3,5-dibromobenzaldehyde to afford 3-[a-carbomethoxy-~-(4'-hydroxy-3',5'-dibromo-phenyl)ethenyl]-5-methylpyrazole in 40% yield, mp =
182-184~C.
~ . .
ExamPle 59A

3-[a-CarbomethoxY-3-(4'-hYdroxY-3',5'-dichloroPhe~
. ethenYl-5-methYl~Yrazole According to the procedure of Example 40, 3-methyl-5-isoxazoleacetic acid methyl ester is 25 reacted with 4-hydroxy-3,5-dichlorobenzaldehyde to ;
afford 3-[a-carbomethoxy-~-~4'-hydroxy-3',5'-dichlorophenyl)ethenyl]-5-methylpyrazole in 16~
~; yield, mp = 210-212C. Analysis for C14H12N203C12.
Calculated C-51.39, H-3.70, N-8.56. Found C-51.77, ` 30 H-3.80, N-8.43.

~33~2 Example 59B

3-[a-Carbomethoxv-~-(3'-methoxy-4'-hvdroxy-5'-bromo-~henYl)etheny~l]-5-methvlPvrazole According to the procedure of Example 40, 3-methyl-5-pyrazoleacetic acid methyl ester is reacted with 5-bromovanillin to afford 3-~a-carbomethoxy-~-(3'-methoxy-4'-hydroxy-5'-bromo-phenyl)ethenyl]-5-methylpyrazole in 17% yield, mp =
200-201C. Analysis for ClsHlsN2o4Br- Calculated C-49.06, H-4.13, N-7.63. Found C-49.29, H-4.11, - N-7.66.

Exam~le 60 3-Methvl-5-~yrazoleacetic acid methvl ester A solution of 3-methyl-5-pyrazoleacetic acid (5.0 g, 35.7 mmol) [see C. Ainsworth, J. Amer. Chem.
Soc., 76, 3172 (1954)] in methanol (50 mL) is saturated with HCl gas. The mixture is warmed to -reflux for 5 hours, after which the solution is concentrated. The solid residue is taken up in chloroform and washed with 0.5 N aqueous sodium bicarbonate, dried over MgSO4, and evaporated to ` afford 3-methyl-5-pyrazoleacetic acid methyl ester (3.9 g, 70%) sufficiently pure for further use.

Exam~le 61 , . ,;
3-~a-carboxv-~-(4~-hvdroxv-3~5~-dibromo~hen~
:. ethenyl]-5-methylPvrazole ~ According to the procedure of Example 47, -~ 3-~a-carbomethoxy-~-(4'-hydroxy-3',5'-dibromophenyl) ` ~` ethenyl]-5-methylpyrazole is saponified to afford ~ 30 3-~a-carboxy-~-(4'-hydroxy-3',5'-dibromophenyl) - ethenyl]-5-methylpyrazole in 88% yield, mp =
!: ,~ 194-l97C. AnalYSis for Cl3HloN2o3Br2-~ : ':

-78- ~3~a~2 C-38.83, ~-2.51, N-6.97. Found C-38.80, H-2.51, N-6.98.

Exam~le 62 3-[a-Carboxv-~-~4'-hvdroxY-3',5'-dichloro~henvl) 5 ethenyl]-5-methvlpYrazole l Accordin~ to the procedure of Example 47, ¦ 3-[a-carbomethoxy-~-~4'-hydroxy-3',5'-dichlorophenyl) i ethenyl]-5-methylpyrazole is saponified to afford 3-ta-carboxy-~-(4'-hydroxy-3',5'-dichlorophenyl) j lO ethenyl]-5-methylpyrazole in 71% yield, mp =
223_225oc. Analysis for C13HloN23Cl2-C-49.87, H-3.23, N-8.95, Cl-Z2.64. Found C-49.66, H-3.13, N-8.82, Cl-22.72.

Example 63 . .
3-~a-Carboxv-~-(3'-methoxv-4'-hydroxv-5'-bromophenyl) ethenvl]-5-meth~l~Yrazole According to the procedure of Example 47, 3-ta-carbomethoxy-~-(3'-methoxy-4~-hydroxy-5~-bromophenyl)ethenyl]-5-methylpyrazole is saponified to afford 3-~a-carboxy-~-(3'-methoxy-4'-hydroxy-5'-bromophenyI)ethenyl]-5-methylpyr~zole in 65% yield, mp = 145-148C. Analysis for C14H13N2O4Br 0.5 H2O.
~; Calculated C-46.42, H-3.62, N-7.74, Br-22.06. Found C-46.64, H-3.82, N-7.82, Br-22.01.

ExamPle 64 .,~ . :
5-~-(4'-Hvdroxy-3'-methoxY~henvl)ethenvl]-3-methvl-isothiazole To a suspension of 4-acetoxy-3-methoxybenzyl triphenyl phosphonium chloride tL. Lonsky et al., Manatshefte fur chemie, 107, 685-695 (1976)] (2.24 g, 4.7 mmol) in dry THF (100 mL) and DMSO (4 mL) at 0C

~ -79-~ 3 3 ~

under an argon atmosphere is added sodium hydride, 60% suspension in oil (0.18 g, 4.7 mmol). The reaction mixture is stirred at room temperature for one hour and then 3-methylisothiazole-5-carbox-aldehyde (D. Buttimore et al., JCS, 2063, (1963)](0.6 g, 4.7 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into a saturated solution of ammonium chloride (250 mL) and the product is extracted into ethyl acetate (2x200 mL). The crude intermediate 5-[~-(4'-acetoxy-3'-methoxyphenyl) ethenyl]-3-methylisothiazole (mixture of cis and trans isomers) is purified by flash chromatography (silica, 25% EtOAc/CH2C12). The intermediate acetoxy compound (0.72 g) is dissolved in methanol (20 mL) and treated with sodium methoxide (0.26 g) and the reaction mixture is stirred at room temperature for one hour. The reaction mixture is diluted with ethyl - -acetate (50 mL) and washed with water (50 mL). The organic layer is dried (NgSO4) and evaporated to give 5-[~-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-isothiazole (0.54 g). Flash chromatography (silica, 5% EtOAc/CHC13) gave separation of the trans and cis isomers, High Rf isomer (0.35 g, 30%), Rf = 0.53 (silica, 8:1/CH2C12:EtOAc); mp = 187-189C, Low Rf isomer (0.10 g, 9%), Rf = 0.43 (silica, 8:1/CH2C12:EtOAc); mp = 120-124C.
.; . : , :
The usefulness of the compounds of the present invention as inhibitors of lipoxygenase enzyme or other related biochemical actions is demonstrated by their effectiveness in various standard test procedures. A description of each procedure follows.

~i~ ~ ; 3 - ; ~

133~2 - 5-LipoxYaenase Assav Usinq Isolated Human Leukoc~tes (5LOA2) The formation of 5-HETE in human leukocytes is considered a measure of 5-lipoxygenase activity. The protocol is described in the following.
Fresh heparinized or EDTA treated human blood is mixed with 6% dextran-3% dextrose in isotonic saline in the ratio 0.25 ml dextran solution per 1.0 ml blood. After mixing the blood is allowed to sit at room temperature for about 90 minutes while the RBC's settle. During this period, the plasma is removed with a plastic pipette to nalgens tubes.
The plasma is centrifuged at 800 rpm ~125 kg) on !': the Beckman Td-b refrigerated centrifuge to remove the platelets (which remain in the supernatant). The pellet, consisting of leukocytes and erythrocytes, is ~reated ~ith 10 ml 0.87% ammonium chloride at room temperature for four minutes, lysing the red cells.
At the end of four minutes the cells are diluted with a 2x volume of phosphate buffered saline, pH 7.4, and centrifuged for ten minutes. The cells are washed ` three times with the phosphate buffered saline. Any of the pelleted cell matter which is not easily resuspended is discarded during the washings--the 25 material contains platelets (12-lipoxygenase -~
- activity).
After washing, the cells are resuspended in phosphate bufferedisaline containing 1.0 mM calcium ;~- and 0.5 mM magnesium. After counting, the cells are ~ 30 diluted to 1.5-2.0 x 107 leukocytes per milliliter.
-~s ~ To each polypropylene reaction tube is added 0.48 ml leukocytes in Ca-Mg phosphate buffered saline, pH 7.4; 1-5 ~l test compound dissolved in DMSO and buffer; or DMSO for control tubes.
The tubes preincubate at 37C for five minutes.

~ii ~'~ .,.,. , ,", " .. ,, . , .; . ,,;., ~,, . ,. "" ,, ~ -81-~3~a~

The reaction is started by adding 20 ~1 of the following, 0.5 ~1, 20 mM arachidonic acid--final concentration = 20 ~M; 1 ~l, 5 mM calcium ionophore A23187--final concentration = 10 ~M; and 18.5 ~l buffer.
The reaction proceeds for five minutes, then is stopped by adding 0.5 ml, 0.5 mM ice-cold Tris buffer, pH 8Ø The tubes are chilled on ice for ten minutes and then extracted three times with a total 1 10 of 3.5 ml ethyl acetate ~3.0 ml removed).
! The tubes can be stored at this point. For I extended storage, the tubes should be filled with i, nitrogen.
The ethyl acetate is evaporated with a Sorvall Speed-Vac. The residue is dissolved in ethanol. The tubes can also be stored at this point at -20C under nitrogen.
A portion of the ethanol solution is injected into the HPLC system for 5-HETE quantitation.
The HPLC system consists of Hewlett-Packard 1040A W spectrophotometry system with an HP85 computer. Injections are made automatically with a Waters WISP 710B. The pump is a Spectra Physics SP8700. Peaks are measured with a Hewlett-packard 3390A integrator. An RP C-18 column is used. The solvent system is isocratic; the solvent is 70%
methanol and 30% O.OlM sodium acetate, pH 5.7, pumped at 1.0 ml/min. The flow is monitored at 235 nm for 5-HETE quantitation. Using a 15 cm Alltech Nucleosil C-18 5 ~M column provides for a sample turnaround time of about 16 minutes.
IC50 is calculated as the amount of test agent that causes 50% inhibition of the formation of 5-HETE
relative to the control.

~ , : R ~

~330~L2 Cvclooxv~enase Enzvme Assay - Additionally, inhibition of cyclooxygenase is considered a measure of relevance to the pathophysiology of the above noted diseases. For example, see "Inhibition of Immunoglobulin - E-Mediated, Antigen-Induced Monkey Asthma and Skin Reactions by 5,8,11,14-Eicosatetraynoic Acid," by Roy Patterson, M.D. and Kathleen E. Harris, B.S. in J. Allerq~ Clin. Immunol., Vol. 67, No. 2, pp.
, 10 146-152.
The assay consists of incubating 2 mg bovine - seminal vesicle powder with 2 mM epinephrine, 2.5 mM
reduced glutathione, 100 ~M arachidonic acid, and the test agent for 20 minutes. The reaction mixture is acidified and extracted with ethyl acetate (3 x 1.0 ml) and the pooled extract is evaporated to dryness using a Speed Vac Concentrator or under a stream of nitrogen. The residue was dissolved in ethanol. An aliquot is applied on 20 x 20 cm silica gel plate and developed using water:ethyl acetate:hexane-:acetic acid (60:54:2S:12.5, upper phase) to separate PGE2 from arachidonic acid.
; 14C-PGE2 formed is identified by co-chromatography with authentic 3H-PGE2 and the amount of radioactivity is quantitated using an automatic TLC
~; linear scanner (Berthold, Pittsburgh, Pennsylvania) :~
linked to an Apple II-e computer and an IC50 is calculated as thç amount of test compound causing 50%
~; inhibition of cyclooxygenase enzyme relative to the control.
The above defined value for each of tested ~; compounds of the present invention having the noted Example numbers are as found in the following Table 2.

l ~
, ~, ~ , -.
2 :, . ' , ~ ,'`'~ ~

. ~

~ . 0,~

- 13~
.

ExamPle # 5-LO(IC50_ n ~M) BSV(IC50 in ~M) 1 1.0 66.0 2 53.0 67.0 3 15.0 44.0 4 4.3 40.0 7.1 33.0 3 6 >20 7 5.5 34.0 8 >20 9 7.5 56.0 18.0 :~ 12 29.0 31.0 29 7.8 10.0 15 30 6.8 32 1.8 ~ ARBL/ARBC Whole Cell 5-Li~oxy~enase - and CYclooxyqenase Assavs Materials The rat basophilic leukemia cell line (RBL-l) ~
;~;~ was obtained from the American Type Culture .~:
! Collection (Rockville, MD).
;~ Radioimmuno assay (RIA) kits of LTB4 and PGF2a were obtained from Amersham (Arlington Heights, IL) and Seragen (Boston,.MA) respectively.
All tissue culture media were obtained from GI3CO (Grand Island, NY).
.~ ' ~

RBL-l cells were grown in culture (suspension) in Eagle's minimum essential medium supplemented with ~, .~`~ 12% fetal bovine serum and 1:100 antibiotic-; antimycotic mi~ture at 37C in an incubator supplied ,`'~
~, .

r~ -84-~1 33~2 with air-5% carbon dioxide. Cells were harvested by centrifugation. They were washed with cold phosphate buffered saline pH 7.4 (PBS; NaCl, 7.1 g; Na2HPO4, 1.15 g; KH2PO~, 0.2 g; and KCl, 0.2 g/L). Cells were finally suspended in P~S containing 0.88 ~M, calcium at a density of 2.4x106 cells/ml. Cells were incubated with and without test agent (in DMSO) (1%
DMSO was without effect on ara~hidonic acid metabolism) for ten minutes at room temperature.
Calcium ionophore A23187 (5 ~M,) was added and cells were incubated for seven minutes at 37C. The reaction was stopped by chilling the tubes in ice for ten minutes. Cells were separated by centrifugation and the supernatant was stored at -20. Aliquots (100 ~1) were analyzed for LT94 and PGF2a using radioimmuno assay kits as provided by the supplier.
Table 3 contains biochemical data obtained from this R9L-l whole cell assay.
:

:

1 ' ' :
.

. . .
. ~.
, .
' , ':
:
~i, :, ~ ;~
~ .~ .
~' ~ . ' . .

, -85-1 330~2 Example #ARBL (IC50, ~)~3C (IC50, ~M?

I 1.6 2.5 0.8 13.0 7 9.5 6.8 5.2 11.0 lOA 3.8 4.5 lOD 0.3 >30 lOG-14.5 ~30 lOG 24.1 >30 lOH 9.5 >30 lOI >10 >25 lOJ >10 30.0 lOK >20 - -lOL >20 ~; lOM >30 >30 lON >20 >30 lOP12.0 >30 lOQ >30 >30 29 2.4 1.5 5.5 12.0 31 1.0 10.0 32 1.4 22.0 `~
32B 4.5 1.2 32D<1.0 5.4 32E 4.5 2.8 32F~12.0 30.0 32G11.0 16.0 32H21.0 13.8 32J 4.7 >30 36A21.5 N
37 3.5 38 3.0 o.g :
' ~3Ic ~

,~ -86-~33~2 TABLE 3 (Continued) Exam~le #ARBL (IC50, ~M)ARBC (IC50. uM) 38A 3.6 14.0 38B 2.6 >30 39A 4.0 9.3 >10 >25 41 >30 5.0 43 17.0 2.2 44 12.0 5.2 46 10.0 2.0 ~, 46A >30 12.0 51 20.0 2.5 52 >20 >20 54 2.7 ~0.3 54B 3.3 4.2 17.0 >30 57 0.82 4.6 58 5.7 14.5 .
a~3L-1 intact cell 5-lipoxygenase IC50 values ~M) RBL-1 intact cell cyclooxygenase IC50 values (~M) Accordingly, the present invention also includes a pharmaceutical composition for treating one of the above diseases or conditions comprising an antidisease or anticondition effective amount of a compound of the formula I as defined above together with a pharmaceutically acceptable carrier.
The present invention further includes a method for treating one of the above named diseases or conditions in mammals, including man, suffering therefrom comprising administering to such mammals either orally or parenterally, preferably oral, a ~ corresponding pharmaceutical composition containing a O ~
,~ . :
'~ ,.

''=s ~

87- 13~ 2 dOSage forrl. d above in aPpropriate ~' 5~

"~ ~erlt ~lit~llle 5~ Ot ~t the ~ tragac Xtrin~ starch gelat. ~ Sugar~
anth~ methylcellulose di 30~ ~

dil3Persed ~

~ ~ - ~' ~.
, ~

~ 88-~330~2 molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylione glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable 1 colorants, flavors, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and ;~ other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liguid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions. These particular solid form preparations are most conveniently provided in unit dose form and as such ; are used to provide a single liguid dosage unit. Alternatelyt sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetermined volumes of the liquid form preparation as with a syringe, teaspoon, or other volumetric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature ~i.e., under refrigeration) in order to retard possible decomposition. The solid form preparations ;~`- intended to be converted to liquid form may contain, ~, .'~
,.

~0 ~330~2 in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The liquid S utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol, and the like as well as mixtures thereof. Naturally, the liquid utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage ~ form can be a packaged preparation, the package : containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appro~riate number of any of these in packaged form.
The quantity of active compound in a unit dose ~ of preparation may be varied or adjusted from 1 mg to ; 25 500 mg preferably to 1 to 50 mg according to the particular application and the potency of the active . ingredient. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as described above, the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.
Determination of the proper dosage for a particular sitùation is within the skill of the art. Generally, ; 35 treatment is initiated with the smaller dosages which are less than the optimum dose of the compoound.
~ Thereafter the dosage is increased by small :i., ":

~ :~:
~ `"~

- - - 9o -1 3 ~ 2 increments until the op~imum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
As used herein cardiovascular diseases or conditions particularly include 1) reductions of the extent of infarct damage in a myocardial infarction, 2) prevention of recurrent myocardial infarction, 3) stroke, 4) anaphylactic shock, and 5) vasospastic disease.
An additional advantageous benefit of the cytoprotective property of the compounds of formula I
are for use, for example to protect against damage from various GI tract conditions.
Various assays that are generally accepted can I be used to measure cytoprotective ability.
The magnitude of a prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature of the severity of the condition to -~`
be treated and with the particular compound of formula I and its route of administration. In general, the daily dose range for anti-asthmatic, ~
anti-allergic or anti-inflammatory use and, generally `
uses other than cytoprotection, lies within the range ;;~ 25 of from about 10 ~g to about 20 mg per kg body weight of a mammal, preferably from about 50 ~g to about 20 mg per kg of body weight of a mammal, and most preferably from about 100 ~g to about 10 mg per kg of body weight of a mammal. ~ ~
The exact amount of a compound of the formula I
to be used as a cytoprotective agent will depend on, -~ inter alia, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e.g., gastro-intestinal ulcerations vs. nephrotic necrosis), and on the nature of the causative agent. An example of the use ~; of a compound of the formula I in avoiding future ~33~2 damage would be co-administration of a compound of the formula I with a non-steroidal anti-inflammatory drug (for example, indomethacin) that might otherwise cause such damage. For such use, the compound of , 5 formula I is administered from 30 minutes prior up to l 30 minutes after administration of the NSAID.
¦ Preferably, it is administered prior to or simultaneously with the NSAID (e.g. as a combination 'l dosage form).
The effective daily dosage level for compounds of formula I inducing cytoprotection in mammals, especially humans, will generally range from about ~ 0.002 mg~kg to about 100 mg/kg, preferably from about i 0.02 mg/kg to about 30 mg/kg. The dosage may be administered in single or divided individual doses.
Thus, in addition to the compounds of formula I, the pharmaceutical compositions can also contain other active ingredients, such as cyclooxygenase inhibitors non-steroidal anti-inflam~atory drugs (NSAIDs), peripheral analgesic agents such as zomepirac, diflunisal and the like. The weight ratio of the compound of the formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the formula I is combined with an NSAID, the weight ratio of the compound of the formula I to the NSAID will generally range from about 1000:1 to~about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
Combin~tions of a compound of the formula I and other active ingredients will generally be in the aforementioned ratios.

~ ~ .

~ 3 3 ~

NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives;
t3) the fenamic acid derivatives;
(4) the biphenylcarboxylic acid derivatives;
and (5) the oxicams or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be used comprise: ibuprofen, ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, pirprofen, carprofen, ' oxaprozin, pranoprofen, miroprofen, tioxaprofen, ¦ suprofen, alminoprofen, tiaprofen, fluprofen and 15 bucloxic acid. Structurally related propionic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be included in this group. -~
Thus, "propionic acid derivatives" as defined 20 herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH(CH3)COOH or -CH2C~2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO Na or -CH2CH2COO Na+), typically - 25 attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
The acetic acid derivatives which may be used comprise: indomethacin, which is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac, 30 fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozic acid.
Structurally related acetic acid derivatives having similar analgesic and antiinflammatory properties are 35 also inte~ded to be encompassed by this group. -~
.~ , ~
; Thus, "acetic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal . ~
~: , ~ ;~

1330~4~

anti-inflammatory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acc~ptable salt group, e.g.
-CH2COO Na~), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise: mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid.
Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "fenamic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:

NH

COOH
i.
:
: ::

which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO Na~.
The biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and flufenisal.
Structurally related biphenylcarboxylic acid derivatives h-ving similar analgesic and 1 3 ~ 2 :.

` anti-inflammatory properties are also intended to be j encompassed by this group.
Thus, "biphenylcarboxylic acid derivatives" as ~ defined herein are non-narcotic analgesics/
i 5 non-steroidal anti-inflammatory drugs which contain ~ the basic structure:

/1 .
`I . -/=\ /~\
~ Coo~ , ..

which can bear a variety of substituents and in which the free -COO~ group can be in the form of a lo pharmaceutically acceptable salt group, e.g., -COO-Na~.
The oxicams which can be used in the present invention comprise: piroxicam, sudoxicam, isoxicam and 4-hydroxyl-1,2-benzothiazine 1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by bhis group.i Thus, "oxicams" as defined herein are non- ~-narcotic analgesics/non-steroidal anti-inflammatory ~ drugs which have the general formula:
;' ~' ' , ~ ~

~ - - 9s -~L 3 ~ 2 oa o C-~H-R

~ ~ ~ C~3 wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used:
acemetacin, alminoprofen, amfenac sodium, s aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen, cinmetacin, ~, ciproquazone, clidanac, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac, fenclorac, fendosal, fenflumizole, ;; fentiazac, ~eprazone, floctafenine, flunixin, flunoxaprofen, fluproguazone, fopirtoline, fosfosal, furcloprcfen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxepac, isoxic*m, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium, lotiazole, loxoprofen, lysin, clonixinate, meclofenamate sodium, meseclazone, microprofen, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proguazone, pyridoxiprofen, sudoxicam, suprofen, talmetacin, t~lniflumat~, tenoxicam, !~

~33~42 thiazolinobutazone, thielavin B, tiapro~enic acid, tiaramide HC1, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol, tryptamid, ufenamate, and zidometacin.
Finally, NSAIDs which may also be used include the salicylates, specifically aspirin, and the ~ phenylbutazones, and pharmaceutically acceptable .! salts thereof.
t Pharmaceutical compositions comprising the formula I compounds may also contain as the second . active ingredient, antihistaminic agents such as benadryl, dramamine, histadyl, phenergan and the like. Alternatively, they may include prostaglandin antagonists such as those disclosed in European Pa~ent Application 11,067 or thromboxane antagonists such as those disclosed in U.S. 4,237,160. They may also contain histidine decarboxylase inhibitors such as a-fluoromethylhistidine, described in U.S.
4,325,961. The compounds of the formula I may also be advantageously combined with an H1 or H2-receptor antagonist, such as for instance cimetidine, ranitidine, terfenadine, ~amotidine, temelastine, acrivastine, loratadine, cetrizine, tazifylline, azelastine, aminothiadiazoles disclosed in EP 81102976.8 and like compounds, such as those IS disclosed in U.S. Patent Nos. 4,283,408; 4,362,736;
J. 4,394,508 and European Patent Application No. 40,696.
The pharmaceutical compositions may also contain a K /H+ ATPase inhibitor such as omeprazole, disclosed i 30 in U.S. Pat. 4,255,431, and the like.

`.' ~
~ .','~ , ~ .`

~ .~ ~

Claims (96)

1. A compound of the formula (I) and pharmaceutically acceptable salts thereof;
wherein (1) is a single or double bond;
(2) R, R1, and R2 may be the same or different and are selected from the group consisting of hydrogen, lower alkyl, hydroxy, OR3 wherein R3 is lower alkyl, C(O)OR4 wherein R4 is hydrogen or lower alkyl, OC(O)R3 wherein R3 is independently as defined above, C(O)R3 wherein R3 is independently as defined above, NR6R7, wherein R6 and R7 may be the same or different and are hydrogen or lower alkyl, NHC(O)R3 wherein R3 is independently as defined above, NHCHO, NHSO2R3 wherein R3 is independently as defined above, NHCONHR4 wherein R4 is as defined above, hydroxymethyl, halogen, trifluoromethyl, SR4 wherein R4 is independently as defined above, or nitro;
(3) Q is CH=CH or wherein R4 is independently as defined above;
(4) X and Y are (i) N, (ii) NR5 wherein R5 is hydrogen, lower alkyl, wherein R?

and R2 may be the same or different and are hydrogen or lower alkyl, C(O)R4 wherein R4 is independently as defined above, cycloalkyl of from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, (iv) S; with the proviso that X and Y
cannot both be N, NR5, O and S at once and with the proviso that one of X and Y cannot be O at the same time the other of X and Y is S or NR5 and that one of X and Y cannot be S at the same time the other of X and Y is NR5;
(5) Z is H, lower alkyl, aryl, aralkyl, R3OH, OC(O)R3 wherein R3 is independently as defined above, C(O)OR4 wherein R4 is independently as defined above, C(O)R3 wherein R3 is independently as defined above, CH(R?)CO2R?
wherein R? and R? are independently as defined above, halogen, trifluoromethyl, wherein R, R1 and R2 are independently as defined above, heteroaryl, or heteroaralkyl;
with the overall proviso that when one of R, R1, and R2 is 2-hydroxy, X is O, Y is N and Q is CH=CH, then Z cannot be H, alkyl;
wherein each:
aryl is phenyl unsubstituted or substituted by one, two or three substituents of one or more of each of alkyl of one to four carbons, inclusive, OR4 wherein R4 is independently as defined above, wherein R4 is independently as defined above, C(O)OR4 wherein R4 is independently as defined above, wherein R4 is independently as defined above, hydroxymethyl, NR6R7 wherein R6 and R7 are each independently as defined above, or nitro, or halogen;
aralkyl is an aryl as defined above and attached through a lower alkylenyl;

-98a-heteroaryl is 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2-, 4- or 5-oxazolyl,

2-, 4- or 5-thiazolyl, 1-, 2- or 4-imidazolyl, 2-

3- or 4-isothiazolyl, 2-, 3- or 4-isoxazolyl, 1-, 2- or 3-pyrazolyl, or 2-, 3-, 4-pyridyl; and heteroaralkyl is a heteroaryl as defined above and attached through a lower alkyl.

2. A compound of Claim 1 wherein Q is CH=CH.

3. A compound of Claim 1 wherein Q is wherein R4 is as defined in claim 1.

4. A compound according to Claim 2 wherein X and Y
are N and NR5, NR5 and N, O and N or N and O.

5. A compound according to Claim 4 wherein X and Y
are N and NR5 wherein R5 is hydrogen.

6. A compound according to Claim 4 wherein X and Y
are O and N or N and O.

7. A compound according to Claim 6 wherein X is O
and Y is N.

8. A compound according to Claim 4 wherein X is N
and Y is NR5 wherein R5 is not hydrogen.

9. A compound according to Claim 4 wherein X is NR5 and Y is N wherein R5 is not hydrogen.

10. A compound according to Claim 6 wherein X=N and Y=O.

11. A compound according to Claim 5 and being 3,5-Bis[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-pyrazole.

12. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-phenylpyrazole.

13. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole.

14. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3'-chlorophenyl)ethenyl]-5-methylpyrazole.

15. A compound according to Claim 5 and being 3-[.beta.-(4'-methoxy-3'-hydroxyphenyl)ethenyl]-5-methylpyrazole.

16. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-ethylpyrazole.

17. A compound according to Claim 5 and being ethyl-3-[.beta.-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate.

18. A compound according to Claim 5 and being 3-[.beta.-[3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylic acid.

19. A compound according to Claim 7 and being 5-[.beta.-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-3-trifluoromethylisoxazole.

20. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-trifluoromethylisoxazole.

21. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl) phenyl)ethenyl]-3-methylisoxazole.

22. A compound according to Claim 7 and being 5-[.beta.-[4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methylisoxazole.

23. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-bis(1-methylethyl)phenyl) ethenyl]-3-methylisoxazole.

24. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole.

25. A compound according to Claim 10 and being 3-[.beta.-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-phenylisoxazole.

26. A compound according to Claim 10 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-phenylisoxazole.

27. A compound according to Claim 5 and being 3-[.beta.-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole.

28. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl) phenyl)ethenyl]-5-methylpyrazole.

29. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-trifluoromethylpyrazole.

30. A compound according to Claim 9 and being (E)-5-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl) ethenyl]-3-methyl-1H-pyrazole-1-acetic acid, ethyl ester.

31. A compound according to Claim 8 and being 3-[.beta.-(4-hydroxy-3',5'-di-t-butylphenyl)ethenyl]-5-methyl-lH-pyrazole-1-acetic acid, methyl ester.

32. A compound according to Claim 9 and being 5-[.beta.-(4'-hydroxy-3',5'-di-t-butylphenyl) ethenyl]-3-methyl-1H-pyrazole-1-acetic acid, methyl ester.

33. A compound according to Claim 8 and being 3-[.beta.-(4-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-5-methyl-1H-pyrazole-1-acetic acid, methyl ester.

34. A compound according to Claim 9 and being 5-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-1H-pyrazole-1-acetic acid methyl ester.

35. A compound according to Claim 8 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methyl-1H-pyrazole-1-acetic acid, methyl ester.

36. A compound according to Claim 8 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methyl-1H-pyrazole-1-acetic acid.

37. A compound according to Claim 9 and being 5-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methyl-1H-pyrazole-1-acetic acid.

38. A compound according to Claim 9 and being 5-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl) ethenyl]-3-methyl-1H-pyrazole-1-acetic acid.

39. A compound according to Claim 8 and being 3-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl) ethenyl]-5-methyl-1H-pyrazole-1-acetic acid.

40. A compound according to Claim 9 and being 5-[.beta.-(4'-hydroxy-3',5'-di-t-butylphenyl) ethenyl]-3-methyl-1H-pyrazole-1-acetic acid.

41. A compound according to Claim 8 and being 3-[.beta.-(4'-hydroxy-3',5'-di-t-butylphenyl) ethenyl]-5-methyl-1H-pyrazole-1-acetic acid.

42. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxyphenyl)ethenyl]-3-methyl-isoxazole.

43. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-dimethylphenyl)ethenyl]-3-methylisoxazole.

44. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl) phenyl)ethenyl]-3-phenylisoxazole.

45. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-phenylisoxazole.

46. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-phenylisoxazole.

47. A compound according to Claim 7 and being 5-[.beta.-(2'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methylisoxazole.

48. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-dibromophenyl)ethenyl]-3-methylisoxazole.

49. A compound according to Claim 7 and being 5-[.beta.-(4'-hydroxy-3',5'-dichlorophenyl)ethenyl]-3-methylisoxazole.

50. A compound according to Claim 10 and being 3-[.beta.-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-(2'-hydroxyethyl)isoxazole.

51. A compound according to Claim 10 and being 3-[.beta.-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-hydroxymethylisoxazole.

52. A compound according to Claim 10 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-(2'-hydroxyethyl)isoxazole.

53. A compound according to Claim 10 and being 3-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-hydroxymethylisoxazole.

54. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3',5'-bis(1-methylethyl) phenyl)ethenyl]-5-methylpyrazole.

55. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-5-methylpyrazole.

56. A compound according to Claim 3 and being 5-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3',5'-dimethoxy-phenyl)ethenyl]-3-methylisoxazole.

57. A compound according to Claim 3 and being 5-[a-carbomethoxy-.beta.-(4'-hydroxy-3,5-dichloro-phenyl)ethenyl]-3-methylisoxazole.

58. A compound according to Claim 3 and being 5-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3',5'-bis(1-methylethyl)phenyl)ethenyl]-3-methyl-isoxazole.

59. A compound according to Claim 3 and being 5-[.alpha. carbomethoxy-.beta.-(4'-hydroxy-3',5'-dimethyl-phenyl)ethenyl]-3-methylisoxazole.

60. A compound according to Claim 3 and being 5-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3',5'-dibromo-phenyl)ethenyl]-3-methylisoxazole.

61. A compound according to Claim 3 and being 5-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3'-methoxy-phenyl)ethenyl]-3-methylisoxazole.

62. A compound according to Claim 3 and being 5-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole.

63. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-dimethoxy-phenyl)ethenyl]-3-methylisoxazole.

64. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-dichlorophenyl) ethenyl]-3-methylisoxazole.

65. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-bis(1-methyl-ethyl)phenyl)ethenyl]-3-methylisoxazole.

66. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3'-methoxyphenyl) ethenyl]-3-methylisoxazole.

67. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole.

68. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-dimethylphenyl) ethenyl]-3-methylisoxazole.

69. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-dibromophenyl) ethenyl]-3-methylisoxazole.

70. A compound according to Claim 10 and being 3-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl) phenyl)ethenyl]-5-methylisoxazole.

71. A compound according to Claim 10 and being 3-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl) phenyl)ethenyl]-5-carboxymethylisoxazole.

72. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3',5'-dimethylphenyl)ethenyl]-5-methylpyrazole.

73. A compound according to Claim 5 and being 3-[.beta.-(4'-hydroxy-3',5'-dibromophenyl)ethenyl]-5-methylpyrazole.

74. A compound according to Claim 3 and being 3-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3',5'-dibromo-phenyl)ethenyl]-5-methylpyrazole.

75. A compound according to Claim 7 and being 5-[.beta.-(2'-hydroxy-3',5'-dichlorophenyl)ethenyl]-3-methylisoxazole.

76. A compound according to Claim 7 and being 5-[.beta.-(2'-hydroxy-3',5'-dibromophenyl)ethenyl]-3-methylisoxazole.

77. A compound according to Claim 5 and being 3-[.beta.-(2'-hydroxy-3',5'-dibromophenyl)ethenyl]-5-methylpyrazole.

78. A compound according to Claim 7 and being 5-[.beta.-(3'-methoxy-4'-hydroxy-5'-bromophenyl) ethenyl]-3-methylisoxazole.

79. A compound according to Claim 3 and being 5-[.alpha.-carbomethoxy-.beta.-(3'-methoxy-4'-hydroxy-5'-bromophenyl)ethenyl]-3-methylisoxazole.

80. A compound according to Claim 3 and being 5-[.alpha.-carboxy-.beta.-(3'-methoxy-4'-hydroxy-5'-bromo-phenyl)ethenyl]-3-methylisoxazole.

81. A compound according to Claim 10 and being 3-[.beta.-(4'-hydroxy-3',5'-dibromophenyl)ethenyl]-5-methylisoxazole.

82. A compound according to Claim 7 and being (E)-5-[.beta.-(4'-hydroxy-3',5'-bis(1,1-dimethyl-ethyl)phenyl)ethenyl]-3-trifluoromethyl-isoxazole.

83. A compound according to Claim 5 and being 3-[.beta.-(3'-methoxy-4'-hydroxy-5'-bromophenyl) ethenyl]-5-methylpyrazole.

84. A compound according to Claim 3 and being 3-[.alpha.-carbomethoxy-.beta.-(4'-hydroxy-3',5'-dichloro-phenyl)ethenyl]-5-methylpyrazole.

85. A compound according to Claim 3 and being 3-[.alpha.-carbomethoxy-.beta.-(3'-methoxy-4'-hydroxy-5'-bromophenyl)ethenyl]-5-methylpyrazole.

86. A compound according to Claim 3 and being 3-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-dibromophenyl) ethenyl]-5-methylpyrazole.

87. A compound according to Claim 3 and being 3-[.alpha.-carboxy-.beta.-(4'-hydroxy-3',5'-dichlorophenyl) ethenyl]-5-methylpyrazole.

88. A compound according to Claim 3 and being 3-[.alpha.-carboxy-.beta.-(3'-methoxy-4'-hydroxy-5'-bromo-phenyl)ethenyl]-5-methylpyrazole.

89. A compound according to Claim 3 wherein X is S
and Y is N.

90. A compound according to Claim 89 and being 5-[.beta.-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-3-methylisothiazole.

91. A pharmaceutical composition for use as inhibitors of 5-lipoxygenase or cyclooxygenase comprising a 5-lipoxygenase or cyclooxygenase inhibiting amount of a compound of formula (I) I

and pharmaceutically acceptable salts thereof;
wherein (1) is a single or double bond;
(2) R, R1, and R2 may be the same or different and are selected from the group consisting of hydrogen, lower alkyl, hydroxy, OR3 wherein R3 is lower alkyl, C(O)OR4 wherein R4 is hydrogen or lower alkyl, OC(O)R3 wherein R3 is independently as defined above, C(O)R3 Claim 91 continued...
wherein R3 is independently as defined above, NR6R7, wherein R6 and R7 may be the same or different and are hydrogen or lower alkyl, NHC(O)R3 wherein R3 is independently as defined above, NHCHO, NHSO2R3 wherein R3 is independently as defined above, NHCONHR4 wherein R4 is independently as defined above, hydroxymethyl, halogen, trifluoromethyl, SR4 wherein R4 is as defined above, or nitro;
(3) Q is CH=CH or wherein R4 is independently as defined above;
(4) X and Y are (i) N, (ii) NR5 wherein R5 is hydrogen, lower alkyl, wherein R?

and R? may be the same or different and are hydrogen or lower alkyl, C(O)R3 wherein R3 is independently as defined above, cycloalkyl of from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) O, (iv) S; with the proviso that X and Y
cannot both be N, NR5, O and S at once and with the proviso that one of X and Y cannot be O at the same time the other of X and Y is S or NR5 and one of X and Y cannot be S at the same time the other of X and Y is NR5;
(5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R3 wherein R3 is independently as defined above, C(O)OR4 wherein R4 is independently as defined above, C(O)R3 wherein R3 is independently as defined above, CH(R?)CO2R?
wherein R? and R? are independently as defined above, halogen, trifluoromethyl, wherein R, R1, and R2 are independently as defined above, heteroaryl, or heteroaralkyl;
wherein each:
aryl is phenyl unsubstituted or substituted by one, two or three substituents of one or more of each of alkyl of one to four carbons, inclusive, OR4 wherein R4 is independently as defined above, SR4 wherein R4 is independently as defined above, wherein R4 is independently as defined above, C(O)OR4 wherein R4 is independently as defined above, hydroxymethyl, NR6R7 wherein R6 and R7 are each independently as defined above, or nitro, or halogen;

aralkyl is an aryl as defined above and attached through a lower alkylenyl;

heteroaryl is 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 2- or 4-imidazolyl, 2-, 3- or 4-isothiazolyl, 2-, 3- or 4-isoxazolyl, 1-, 2- or 3 pyrazolyl, or 2-, 3-, 4-pyridyl;
and heteroaralkyl is a heteroaryl as defined above and attached through a lower alkyl; and a pharmaceutically acceptable carrier.

92. A composition of Claim 91 of the compound of formula I wherein Q is CH=CH.

93. A composition of Claim 91 wherein Q of the compound of formula I is wherein R4 is as defined in Claim 91.

94. A sunscreen composition for use as a sunscreen comprising an ultraviolet absorbing amount of a compound of Claim 1 and a suitable carrier therefor.

95. A pharmaceutical composition as claimed in Claim 91 additionally comprising an effective amount of a second active ingredient that is a non-steroidal anti-inflammatory drug; a peripheral analgesic agent; a cyclooxygenase inhibitor; a leukotriene antagonist; an antihistaminic agent; a prostaglandin antagonist or a thromboxane antagonist.

96. Use of a compound of Claim 1 for protection from ultraviolet light.