FI108792B - Process for the preparation of novel therapeutically useful furanone derivatives - Google Patents

Description

108792

A process for the preparation of novel therapeutically useful furanone derivatives

BACKGROUND OF THE INVENTION This invention relates to a process for the preparation of compounds for the treatment of cyclooxygenase-related disorders.

Non-steroidal anti-inflammatory drugs exert most of their anti-inflammatory, anal-10 genetic and antipyretic effects and inhibit hormone-induced uterine contractions and certain types of cancer growth by inhibiting prostaglandin G / H synthesis, also known as cyclooxygenase. To date, only one form of cyclooxygenase has been characterized and corresponds to cyclooxygenase-1, a constitutive enzyme as originally identified in bovine semen. Today, the gene for another derived form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chick, mu-20 rine (mouse) and human origin. This enzyme differs from cyclooxygenase-1, which is now: Y also cloned from a sheep, murine and human source. Second: Y: the cyclooxygenase form, cyclooxygenase-2, is readily and readily available by a number of factors including. . ·. 25 mitogens, endotoxin, hormones, cytokines and growth factors. When prostaglandins have both physiological and pathological functions, we have come to the conclusion,. that the constitutive enzyme, cyclooxygenase-1, largely accounts for the endogenous ··· 'production of prostaglandins and thus plays an important role in their physiological functions such as digestion and renal blood flow. On the other hand, we have come to the conclusion that the i · · · inducible form, cyclooxygenase-2, is primarily responsible for the pathological effects of prostaglandin, whereas the rapid induction of 35 enzymes takes care of factors 2 108792 such as inflammatory factors, hormones, growth factors and cytokines. Thus, the selective inhibitor of cyclooxygenase-2 has similar anti-inflammatory, anti-pyretic and analgesic effects to that of a conventional non-steroidal anti-inflammatory drug, but also inhibits hormone-induced uterine contractions and has potent anticancer effects, some mechanism-based side effects. In particular, such a compound would have reduced efficacy in inducing digestive poisoning, reduced efficacy in causing renal side effects, reduced activity in bleeding times, and possibly reduced ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.

Detailed Description of the Invention

The invention relates to a process for the preparation of new compounds of the formula XXXIII

! R1 j 20 "jf: 2 XXX, n: 25 night

.: I :. O

And can be used for cyclooxygenase-2-related. in the treatment of diseases wherein R 1 is -S (O) 2 CH 3 or -S (O) 2 NH 2 and ··· 'R 2 is phenyl or mono- or disubstituted phenyl wherein the substituents are selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, and CF 3, · · · *. with the exception of 3- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (5H) -furanone and 3- (4-fluoro-phenyl) - 4- [4- (aminosulfonyl) phenyl] -2- (5H) -furanone.

3, 108792

The features of the process according to the invention are set forth in claim 1.

In the present specification, the definition of alkyl includes straight chain, branched and cyclic structures, C 1-4 alkyl means methyl, ethyl, propyl, 2-propyl, s and t-butyl, butyl, 1,1-dimethylethyl, cyclopropyl and cyclobutyl. Similarly, C 1-4 -cloxy denotes alkoxy groups of 1 to 4 carbon atoms which are straight-chain, branched or cyclic.

Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and the like. Similarly, C 1-4 alkylthio means alkylthio groups having 1 to 4 carbon atoms having a straight chain, branched or cyclic configuration. Examples of lower alkylthio groups include, but are not limited to, methylthio, propylthio, isopropylthio, etc. For clarification, the propylthio group is -SCH 2 CH 2 CH 3.

Examples of the invention include: 3- (3-fluorophenyl) -4- (4-methylsulfonyl) phenyl) -2- (5H) -furanone, 3- (3,4-difluorophenyl) -4- (4-methylsulfonyl) ) - • · · Phenyl) -2- (5H) -furanone • · ·: 3- (3,4-dichlorophenyl) -4- (4-methylsulfonyl) phenyl) -2- (5H) - furanone and? ·? -? - 3-phenyl-4- (4-methylsulfonyl) phenyl) -2- (5H) -. 25 furanones.

Some of the compounds described herein contain one or more asymmetric centers and thus may increase the amount of diastereomers and optical isomers.

The present invention encompasses such diastereomers, as well as their racemic and resolved, enantiomerically pure forms and their pharmaceutically acceptable, * * *. salts.

35 4 108792 ί!

Some of the compounds described herein contain olefinic double bonds and unless otherwise specified, both geometric E and Z isomers are meant.

The invention enables the preparation of pharmaceutical compositions for the inhibition of cyclooxygenase and for the treatment of cyclooxygenase-related diseases, which contain a pharmaceutically acceptable carrier and a non-toxic and therapeutically effective amount of a compound of formula XXXIII described above.

Accordingly, the invention enables the preparation of pharmaceutical compositions for the inhibition of cyclooxygenase-2 and for the treatment of cyclooxygenase-2-related disorders as set forth herein, comprising a pharmaceutically acceptable carrier and a non-toxic and therapeutically effective amount. of Formula XXXIII as described above.

The invention provides a method of inhibiting cyclooxygenase and treating cyclooxygenase-related diseases, preferably comprising treating with an active agent that selectively inhibits COX-2 over COX-1 as disclosed herein, wherein , ···, a patient in need of such treatment is administered a non-toxic, therapeutically effective amount of Formula XXXIII! lane compound as disclosed herein.

* ('25) For purposes of this publication, a compound is said to selectively inhibit COX-2 over COX-1 · * 1, wherein the ratio of the IC50 concentration of COX-1 inhibition to the concentration of COX-2 is 100 or higher.

The pharmaceutical compositions contain as active ingredient a compound of formula XXXIII or a pharmaceutically acceptable salt thereof, and may contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, non-toxic bases, including inorganic bases and organic 1G8792

D

those bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron (II), iron (III), lithium, magnesium, manganese (II) salts, manganese (IV) - , potassium, sodium, zinc | 5 salts, etc. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts which are derivatives of pharmaceutically acceptable organic non-myristic bases include primary, secondary and tertiary amines, substituted amines, which include naturally occurring substituted amines. and, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N-dibenzyl-ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, diamine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, trimethylamine, trimethylamine, trimethylamine, trimethylamine, and the like.

It is understood that in the following discussion of treatment methods, references to compounds of Formula XXXIII are also meant to include pharmaceutically acceptable salts.

A compound of formula XXXIII may be used. 25 for the relief of pain, fever and inflammation in a variety of conditions such as rheumatic fever, symptoms associated with influenza or other viral infections, common colds, lower back and neck pain, menstrual disorders, headache, toothache, sprains and 30 inflammation, myalgia, arthritis, arthritis, including rheumatoid arthritis,

• I

associated with degenerative diseases (osteoarthritis), gout and rheumatoid arthritis, mucositis, burns, injuries due to surgical or

M I t I

35 dental measures. In addition, such compounds can inhibit cell growth changes and metastatic tumor growth and thus may also be used in the treatment of cancer. The compounds of Formula I may also be used in the treatment of dementia, including early and old age dementia, and in particular dementia associated with Alzheimer's disease (i.e., Alzheimer's dementia).

The compounds of Formula XXXIII may also inhibit prostanoid-related soft muscle contraction by inhibiting the synthesis of contractile prostanoids, and thus may be used in the treatment of menstrual disorders, premature labor and asthma.

Due to its high cyclooxygenase-2 (COX-2) activity and / or selectivity for cyclooxygenase-2 compared to cyclooxygenase-1 (COX-1), compounds of formula XXXIII can be demonstrated. useful as an alternative to non-steroidal anti-inflammatory drugs (NSAIDs), particularly if such non-steroidal anti-inflammatory drugs are contraindicated, such as in patients with gastro-duodenal ulcer, gastric ulcer, · "! inflammation, inflammation of the sac pouch (diverticulitis) or recurrent lesions of the gastrointestinal tract; genital bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems (including those associated with tt | !!! reduced or impaired platelet function) ); kidney disease (such as impaired kidney function); persons who must take anticoagulants prior to surgery; and individuals sensitive to 30 NSAID-induced asthma.

Compounds of formula XXXIII may likewise be ···. used to partially or completely replace traditional '·' NSAIDs in preparations where they are administered together with ···: other substances or ingredients. The invention thus also provides the preparation of pharmaceutical compositions for the treatment of cyclooxygenase-2-related disorders, as defined above, wherein a non-toxic therapeutically effective amount of a compound of formula XXXIII as defined above and one or more agents are administered. , such as other analgesic agents, including acetominophen or phenacetin; an enhancer including caffeine; H2 antagonist, aluminum or magnesium hydroxide, simerticone, antihypertensive agent which include phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, efinephrine, naphtha-10-soline, xylometazoline, propylhexedrine or levo; antitussive including codeine, hydrocodone, caramifene, carbetapentane or dextramethorphan; a diuretic; sedative or non-sedative antihistamine. The invention further provides a method of treating cyclooxygenase-related diseases, the method comprising: administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of formula XXXIII, optionally with one or more of the ingredients listed above.

The compounds of the present invention are * t * '' inhibitors of cyclooxygenase-2 and can therefore be used in the treatment of those associated with cyclooxygenase-2. the diseases listed above. This activity is illustrated by their ability to selectively inhibit cyclooxygenase-2 instead of cyclooxygenase-1. Its

s t I

in one experiment, the ability of the compounds of this invention to treat cyclooxygenase

MIM

| Diseases may be represented by measuring the amount of prostaglanin • 30 dinine E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2, and a compound of formula XXXIII. IC50-ar- t I i ·. The voters indicate the concentration of inhibitor required to restore the observed PGE 2 synthesis to 50% of that in the uninhibited control. To illustrate this side we have found that the compounds of Examples A 108 792 are 100 times more effective at inhibiting COX-2 than they are to inhibit COX-I's. In addition, they all have a COX-2-IC50 of 1 nM -1 μΜ. For comparison, ibuprofen can be reported to have an IC 50 for COX-2 of 1 µM and indome-5 to have a IC 50 for COX-2 of about 100 nM. For the treatment of any cyclooxygenase-related disease, the compounds of Formula XXXIII may be administered orally, topically, parenterally, by inhalation spray, or rectally in unit dosage forms containing: | These include conventional non-toxic pharmaceutically acceptable carriers, excipients and solvents. As used herein, the term parenteral refers to subcutaneous injections, intravenous, intramuscular, subcutaneous injection, or infusion techniques. In addition to treating warm-blooded animals such as mice, rats, horses, sheep, dogs, cats, etc., the compound of the invention is effective in treating humans.

As stated above, the pharmaceutical compositions for the treatment of cyclooxygenase-2-related diseases, as defined above, may optionally contain one or more of the ingredients listed above. Pharmaceutical formulations containing the active ingredient may be in a form suitable for oral use, for example, in the form of tablets, troches, lozenges, in the form of aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs, and for oral use may be made by any of the methods well known in the art. and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavorings, colorings, and preservatives to provide pharmaceutically finely-pleasing and non-toxic pharmaceutically acceptable excipients. with 9,108,792 suitable tablets These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents, for example, corn starch or alginic acid; binders, for example starch, gelatin or acacia, and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and, therefore, may have a sustained action over a long period. For example, glyceryl monostearate or glyceryl distearate may be recommended as the time delay material. They may also be coated by the methods described in U.S. Patent Nos. 15,425,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release of the active ingredient.

Formulations for oral use may also be in the form of hard gelatine capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules containing the active with.

Aqueous suspensions contain the active ingredient in admixture. '.' as fillers suitable for the preparation of aqueous suspensions. Such excipients include suspending agents, for example sodium carboxymethylcellulose, sodium alginate, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; disperse or water · 1 ·. the lubricants may be naturally occurring phosphatides, e.g. lecithin, or condensation products of alkylene oxide and fatty acids, e.g. condensation products of partial esters of hexitol, for example polyoxyethylene-5 sorbitol monooleate, or condensation products of ethylene oxide and partial esters of fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl 10, n-propyl or p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils. oil, such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The sweeteners described above and flavoring agents may be added to provide a pleasant oral preparation.

!!! These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of 25 aqueous suspensions, when added to water, containing: the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. dispersing or wetting agents include those mentioned above Other excipients such as sweetening, flavoring and coloring agents may also be present.

»· A

The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifiers may be naturally occurring phosphatides, for example soybean, lecithin and esters or partial esters of fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene oxide. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an irritant, a preservative, and a flavoring or coloring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated in a manner known in the art using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable excipients and solvents that may be used ;;; are water, Ringer's solution and isotonic sodium chloride '···' solution. In addition, sterile fatty oils are usually employed as a solvent or suspending medium. Any blended fatty oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have utility in the preparation of injectable solutions.

Compounds of formula XXXIII may be administered. ···, also as suppositories for rectal administration of the drug.

These compositions can be prepared by mixing the drug with a suitable non-irritating diluent which is solid at normal temperatures but liquid in rectal temperature and therefore melts in the rectum to release the drug. Such agents include cocoa butter and polyethylene glycols.

12108792

Ointments, creams, jellies, solutions, suspensions, etc. containing a compound of formula XXXIII are used for topical use. (For the purposes of this application, topical mouthwashes and mouthwashes.)

Dosage levels of the order of about 0.01 to 140 mg / kg of body weight per day may be used to treat the above conditions, or alternatively about 0.5 to 7 g per patient per day. For example, inflammation 10 can be effectively treated by administering about 0.01 to 50 mg of compound per kilogram of body weight per day, or alternatively about 0.5 mg to 3.5 g per patient per day. Vassa.

The amount of active ingredient that can be combined with the 15 carriers to provide a single dosage form will vary depending upon the subject being treated and the actual route of administration. For example, a formulation for oral administration to man may contain from 0.5 to 5 g of active ingredient in combination with a suitable and appropriate amount of a carrier, which amount may vary from about 5 to 95% of the total composition. The unit dosage form will usually contain from about 1 mg to about 500 mg of active ingredient, ... · typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 U, · · mg, 500 mg, 600 mg, 800 mg or 1000 mg.

: 25 However, it is clear that the actual dosage level; for each of these patients depends on various factors including age, body weight, general health, sex, diet, time of administration, route of administration, particulars >>>; time of treatment, combination of drugs, and severity of the condition being treated.

Synthetic Methods v_: The compounds described herein can be prepared according to the following procedures.

35 13 108792

Method I:

The appropriately substituted aryl bromomethyl ketone is reacted with an appropriately substituted aryl acetic acid in a solvent, for example acetonitrile, in the presence of 5 bases, for example triethylamine, and then treated with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), .

Method I

10

R1 (tS

^ CP

L I r2 ^ co2h T

R2-V7 15 sr \ A0 emas r'0

O

XXXI1 XXXIII

(R 2 is optionally mono- or disubstituted phenyl).

20

Representative compounds

Table I shows the compound points of formula XXXIII • · * ··· '.

* * • • * * • • • • • • • • • • • • • • • • • • • • • • • • • • • • ••••••••••••••• I

Table I

108792 e c γ * '| p Example Method # 0. 1 '^^ S02Me & £ j 1 ^^ S02Me o F «ö 4 1 S02Me OCL, o oCXp, 5'

F

c ^ iT ^ l 6 1:, / so2Me \ 15 108792

Table I (continued)

Example Method ^^ SO2Me18 8 ^ ^ SO2Me ^ -γΟΜβ 9 1

Lv ^ "S02Me 10 1 L's" ^ S02Me :, i; oXj * ° 'θΓΐ 11 1 ^^ S02Me t 1 08792 16

Table I (continued) ^ Example Method

0L / V

12 1 ^^ S02Me

o TI

I JJ-p 13 '

O TJ

o3pp 14 1! ^^ v'S02Me

• jX

O ^ XfS 15 1 V ·; ^^ S02Me

S% JX

oCv ^ i 16 1 ^ '• ^ SOgMe ♦, i * v

f * f I

17

Table I (continued) 108792

Example Method ° \ J ^ ditch 0¾ 18 1 tv "^ S02Me

f ^ VCI

ojkpy 19 I

Hi • ;;;: ojkp, 20 1: * v tvv5? ^ 'S02Me

ί! RRF

o λ, Λ * · *. ·

OJL ^ 21 I

'; * / ^ "^ SOaMa * *

> I I

f t> I * »ί j 18 1 08792 f

Table X (continued)

j OF

\ Example Method o oJ-fS 22 '^ OMe

vA

oCU 23 'A ^ S02Me OMe

Qy_XXi ° Jy ^ 24 ί A ^ S02Me ^ SyOMe I 25 1; ^ So2Me * 1 * 1 1

O

öj-f ^ 26 1 ·: ··· / 1 # 1 * 1 »1 · * * 1 * 1 · * · · I t I * · * ·! t »t S I · l» ti »» 108792

Table I (continued) 19 ί

r ^ -v ^ SMe Example Method O

kx ^ S02Me vA, ojys 28 1

Lxi ^ S02Me

CHQ

29 1 ^ v, Me = :::: V ^ Br ·: '; orJLn 30 1 · / ^ '^' SOaMe r: \ ΡΥΎΒΓ ° ^ ηΡί 31 '... · ^ S02Me »108792 20

Table I (continued)

Example Method ° v-r55 ^ Br i

32 I

^^ S02Me j ^ ycl ονΑΛρ θΛ-r ^ N 33 1 ^^ S02Me nrBr

Oyj ^ F

° 'θΓΐ 34 j ^^ S02Me | CIv ^ v ^ Br S 35 1

Table I (continued) 2i 1 08792

Example Method cf / 36 ^^ so2nh2

O.J0C

ojys,. 37 1

Lx ^ so2nh2 ^ τν, ΟΜε • * 38 '; ·;: ^^ S02NH2 ^ .OMe «uOc *:;!': Ojvs 39 1 l ^^ so2nh2 • ·« * · 22 1 08792

Experiments to determine biological activity

Compounds of formula XXXIII may be tested using the following assays to determine their cyclooxygenase-2 inhibitory activity.

5 Inhibition of cyclooxygenase activity

Compounds were tested as inhibitors of cyclooxygenase activity in whole cell assays and microsomal cyclooxygenase assays. Both of these experiments measured prostaglandin E2 (PGE2) synthesis against arachidonic acid by a ra-10 immunoassay. The cells used for the whole cell assay and those from which the microsomes were prepared for the microsomal assay were human bone sarcomas cells 143 (expressing in particular cyclooxygenase-2) and human U-937 cells (expressing in particular 15 cyclooxygenase- from). In these experiments, 100% activity is defined as the difference between prostaglandin E2 synthesis in the absence and addition of arachidonate. IC 50 values indicate the concentration of putative inhibition required to restore PGE 2 synthesis to 50% of that obtained for the uninhibited control sample. Illustrative results are shown in Table II.

Representative Rat Paw Swelling Assay - Experimental Design :: Male Sprague-Dawley rats (150-200 g) were fasted overnight and administered orally with 25 co-administered vehicle (5% Tween 80 or 1%). Metho-· · · cel) or the test compound at 9-10. An hour later, a dash was permanently marked above the ankle of one hind paw to define the area of the paw to be observed. The paw volume (V0h) was measured using a • t ··· '30 volume meter (plethysmometer) (Uga-Basile, Italy),: Y: operated by the principle of water substitution. The animals were then injected via the foot with 50 µl of a 1% solution of carrageenan in brine (FMC Corp., Maine) to the paw using an insulin syringe with a needle number of 25 35 (or 500 µg of carrageenan per paw). Three hours later, paw volume (V3h) was measured and 23 238792 paw volume increases (V3h - Voh) were calculated. Animals were sacrificed with CO2 and stomach lesions or lesions were noted. Gastric lesions were expressed as the sum of total lesions in millimeters. The paw swelling data was compared with the control group receiving the mediator and calculated as percent inhibition by taking the control group as a value! 100%. When a maximal inhibition of 60-70% (paw swelling) was obtained using standard NSAIDs, ED50 values were used for comparison. All treatment groups were marked with 10 codes to avoid the observer's preconceptions. Using this assay, the ED30 for indomethacin is 1.0 mg / kg. Illustrative results are shown in Table III.

* • t · • f • · · • t · • · »» • · · * »· · 24 1 08792

Table II *

Oxygenate Concentration COX-2 COX-1 I I Concentration I COX-2 COX-1 I

(nM) __ esto-4 esto-fe 1 j (nM) esto-% esto-% 2 20 39_ 2__80 76__ 2 __160 95 __ 3 20__41 __ 3__40__50 __ 3 __160 85 __ 4 __40 41 __ 4 160 77 __ 5 '40 24__ 5 __160 58 __ 6 __40 21 ___ 6 160 59 __ 7 __10 70 __ 7 __40 91 __ 8 __10 50 __ 8 __40__94 __ 9 __20__39 __ .y. 9 160 98 __ 10 __20__50 __ 10 160 88 ~ _'__ n 40 43 __: 11 160 78 __ 12 160__40 __ "·: 13 80 27 __; __ 13 160 39__ j .y 14 20__38 __ *:!? 14 I 160 I 97 I 11, 1 25 1 08 792

Example Concentration COX-2 COX-1 I Concentration COX-2 COX-1 ____ (nM) estd-% I inhibition-4 I | (nM) I esto-% esto- * ~ 15__20__48 ZZiniZZ__ is 160__69 ZZZZJjZZZZZ__ 16 20__78 __ 16 160 85__; 17 160 30__ 18__20__49 __ 18 160 87__ 19 5__43 __ 19 -10__73 ~~~ ~ __ 19 40__92 ~ __ 19 80__99 ~ __ 20 160__6 __ 21 10 30 _____ _ 21 40__80 ~ __ 21 160 102 __ 22 __20__32 ____ 22 40__57 __: Y: 22 160 83 ~ __ Ϊ '.' 23 10__11 ~ ____ • 23 40__50 ___:; j ;: 23 160 -89 __ 24__10__53 __ 24 40 82 ____ *: ·: 24 160 93 _: _ 25 10 25 __ 25 40__63 __ 25 160 88 __ 26 ~ 10 I 17 1 11 _ i 1 08792 26

EXAMPLE Concentration COX-2 COX-1 L Concentration COX-2 COX-1 1 __ (nM) Inhibition-41 Inhibitory (nM) Inhibitory% Inhibitory-1

26 160 84 _ 27 __10__43 _ 27__40__72 _ 27 160 96 _ 28 ___I I _ 28 ___I I _ 29 __20__10 _ 29 160 44 _ 30 10 78 _—— q I 30 40 101_ 31 20__14 ~ _ 31__40__55 _ 31 160 106_ 32 __10__16 _ 32 __40__61 _ 32 160 101 _ 33 __10__76 ZHHZj I 33__40 94 _ZZZZZj! : V: 33 160 97 ~ _ZZZZZZ]

34 10__61 ~ _ZZZZJ

. . ·. 34__4o__74 _ZZZZZj 34 160 101 _ 35 10__7 ~ _

35 160 47 1 11 _ I

27 108792

Example Concentration COX 2 COX-i l Concentration! COX-2 | COX 1 (tlM) esto-4 esto-4 (nM) esto-% esto-i 36 5 49 ___ 36 20 95______ 36 __40 102______ 37 __10 50 _____ j 37__40__82______ 37 160 102______ 38 10 54 10 ------- ----: - 38__40__96_______ 38 160 102 _____ 39 __10__81 ___.___ 39__80__91______ 39.160 99 15 - - * In the whole cell assay, the ibuprofen IC50 for COX-1 is 1000 nM and the IC50 for COX-2 is 3000 nM. Correspondingly, indomethacin-la has an IC50 of 100 nM and an IC50 of COX-2 of 10 nM.

• • k * · * * * t »28 1 08792

Table III

I 2,03 ^ \ ^ S02Me ^ xx

F F

] 1,49 - ^ S02Me f ^ * * · · • · · • ·: 0; 35 ^ r ^ SOgMe f! t l <I U · ^ j i ί 29 1 08792 O, 33 ^ \ / S02Me ^ Br ° »90 ^^ S02Me ° vK ^ \ ^ xx

Cl • · · • · »I · * * * __ _ ____ I · *:, i,: Or38 ^ N ^ .S02Me ....; 0Υ \ ^

\ j O T ^ J

»*« * T · t · »• il» t »I * · • · 30 1 08792 0.88 .- ^ S02Me οΠΓ ^

VQ

Br ci i I _______. ___ '0.47 ^ γ $ ΟζΜβ

Fx ^ / ^ ci «I · it« * I · t »t I * · t · tt * t * * _ * * _ ^^^ ™ * · - I * · *» · »· ° / 71 - ^ S02Me ....: 0νΧ / ΧΧ * ;;: · o | Q).: <:. Cl I · »#

MH

I »» i »» t __ · ___ 31 1 08792 ΐ I -1.00 ^^ S02Me ° CJL ^ a I · _ ___ - --- h 85 ^^ S02Me c, AvAc | «· · 0.22 ^ v. / S02Me:: ·: 0.23 Γ Ύ

Q

i ·: ·: ^ "Cl! · · 32 1 08792 0.43 ^ N ^ S02Me οΠΓ ^

^ F

! ! ! - - - "* *" "" "! 2,17 ^ \. S02Me ^ cf3

• »I

'· 7 0.81 S02Me

i! ° p (j ^ F

·: · * OMe I »33 1 08792 0.68„., SO2M θ oQl Υ \ ^ β \ ^ OMe ~ 1.0 ° ^ s ^ S02Me ° Ρθ \ ^ SMe * 1 · · 1 1 · • · ts 1 1 34 1 08792 0.33 ^ X / S02Me

! F

0.46 ^ S02Me tch3; ··: Br • · · 0, .76 - ^ S02Me οΠ {ΥγΎ *: Λ: ^ Br i 35 1 08792 ° '48 ^ r ^ S02NH2

F

° '46 · ^^ so2nh2 · ° 0 <^ i T ci | Cl • · · ° »26 ^^ sozMe: ·; ·: Cl

F

[36 1 08792 ^ SOoMe

0.55 rY

5 ° C

T Br F

I 10 I __________

The invention will now be illustrated by the following non-limiting Examples, in which, unless otherwise stated: | (i) all work steps were carried out at room temperature or ambient temperature, i.e. in the range of 18-25 ° C; evaporation of the solvent was performed using 20 rotary evaporators under reduced pressure (600-4000 Pa: ···, 4.5-30 mmHg) with a bath temperature of up to •60 ° C; at the end of the reaction, thin layer chromatography (TLC) was performed and reaction times are reported as observational • · · * * *! NPI; melting points are uncorrected and "d" • · · * · '· 25 denotes decomposition; given melting points are those obtained for substances prepared as described; ·, · '· Polymorphism may result from the isolation of substances with different melting points in some manufacturing processes; ·: ·: The structure and purity of all final products were confirmed by at least one of the following methods: TLC, • I * mass spectrometry, nuclear magnetic resonance (NMR) or microanalytical data; yields are given * ·; · 'for illustrative purposes only; if NMR data is provided, ·· they are expressed as delta values (δ) for the major diagnostic · · · 35 for protons with values in ppm as the internal standard for tetramethylsilane (TMS) 37 108792 and determined at 300 to 400 MHz using the solvent provided; the usual abbreviations for the signal form used are: p. singlet; d. dup-pigtail; t. triplet; m. multiplet; br. wide; etc .: for li-5, "Ar" represents an aromatic signal; Whereas chemical labels have their usual meanings; the following abbreviations are also used, v (volume), w (mass), kp. (boiling point), m.p. (melting point), 1 (liters), ml (milliliters), g (grams), mg (milligrams), mol (moles), mmol 10 (millimoles), eq (equivalents).

The following abbreviations have the following meanings:

Ac = acetyl Bn = benzyl DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene DIBAL = diisobutylaluminum hydride DMAP = 4- (dimethylamino) pyridine DMF = N, N-dimethylformamide Et3N = triethylamine and LDA = lithium diisopropylamide | 20 m-CPBA = methachloroperbenzoic acid MMPP = monoperoxyphthalic acid MPPM = magnesium salt of monoperoxyphthalic acid, 6 H2O Ms = methanesulfonyl = mesyl = SO2Me MsO = methanesulfonate = mesylate 25 NSAID = non-steroidal inflammatory drug: pyridine dichromate j Ph = phenyl ... 30 Phe = benzenediyl 'I' Pye = pyridinediyl rt = room temperature · rac. = racemic SAM = aminosulfonyl or sulfonamide or SO2NH2 35 TBAF = tetra-n-butylammonium fluoride

Th - 2- or 3-thienyl i! i i! 38 108792 TFAA = trifluoroacetic anhydride THF = tetrahydrofuran Thi = thiophenediyl TLC = thin layer chromatography 5 TMS-CN = trimethylsilyl cyanide C 3 H 5 = allyl j Abbreviations for alkyl groups j Me = methyl j Et = ethyl | 10 n-Pr = normal propyl i-Pr = isopropyl j n-Bu = normal butyl i-Bu = isobutyl i s-Bu = secondary butyl 15 t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl! c-Pen = cyclopentyl j c-Hex = cyclohexyl I 20 ···. The compound prepared according to Example 1 is excluded • ♦ !!! claims.

Example 1? -? -? - 3- (4-Fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -1'- (2H) -2- (5H) -furanone

Step 1: 2-Bromo-1- (4-methylsulfonyl) phenyl) - [*] ethanone

A solution of 197 g of 4- (methylthio) acetophenone ·: ··· (Ref: JACS 1952, 74, p. 5475) in 700 mL of MeOH and 30 · 3500 mL of CH 2 Cl 2 was added to 881 g of MMPP. one minute na. After 3 hours at room temperature, the reaction mixture was filtered and the filtrate washed with 2 L of saturated aqueous NaHCO 3 and 1 L of brine. The aqueous phase was further extracted with 2 L CH 2 Cl 2. The combined extracts were dried * * | · 35 with Na 2 SO 4 and concentrated to give 240 g of 4- (methylsulfonyl) acetophenone as a white solid.

39 108792 To a cooled (-5 ° C) solution of 174 g of 4- (methylsulfonyl) acetophenone in 2.5 L of CHCl 3 was added 20 mg of AlCl 3, followed by a solution of 40 mL of Br 2 in 300 mL of CHCl 3. The reaction mixture was then treated with 1.5 L of water and CHCl 3 was separated. The aqueous layer was extracted with 1 liter of EtOAc. The combined extracts were dried over Na 2 SO 4 and concentrated. The crude product was recrystallized from a 50/50 mixture of EtOAc-hexane to give 210 g of 2-bromo-1- (4-methylsulfonyl) phenyl) ethanone as a white solid.

Step 2:

To the product of Step 1 (216 mg) dissolved in acetonitrile (4 mL) was added Et 3 N (0.26 mL) followed by 4-fluorophenylacetic acid (102 mg). After 1.5 hours at room temperature, 0.23 mL of DBU was added. The reaction mixture was stirred for an additional 45 minutes and then treated with 5 ml of 1M (IN) HCl. The product was extracted with EtOAc, dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography (40% EtOAc in hexanes) to give 150 mg of the title compound as a solid.

1 H-NMR (CD 3 COCD 3): δ 3.15 (3H, s), 5.36 (3H, s),: ···: 7.18 (2H, J = 8.9 HZ, t), 7.46 (2H, m), 7.7 (2H, J = 8.65 *, .delta. Hz, d), 7.97 (2H, J = 8.68, d).

V ·: 25 Example 2: Γ: 3- (2,4-Difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis for C 17 H 12 F 2 O 2 S ____: Calculated C 58.28; H, 3.45; S 9.15-1.1, t 30 Found C 58.27; H, 3.50; S, 9.27

Example 3 v: 3- (3,4-Difluoro-phenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone

To a solution of 3,4-difluorophenylacetic acid 35 (Aldrich Chimical) (10 g) and 2-bromo-1- (4- (methyl

t I

sulfonyl) phenyl) ethanone (Example 1, Step 1) (17.3 40.08792 grams) in acetonitrile (200 mL) at room temperature, triethylamine (20.2 mL) was added slowly. After 1 hour at room temperature, the mixture was cooled in an ice bath and treated with 17.4 mL of DBU. After 2 hours at 0 ° C, the mixture was treated with 200 mL of 1M (1N) HCl and the product was extracted with EtOAc, dried over Na 2 SO 4 and concentrated. The residue was passed through a pad of silica gel (glass sinter) and eluted with 75% EtOAc / hexane to give 10 g of the title compound after evaporation of the solvent and stirring with ethyl acetate.

Analysis calculated for C 17 H 12 F 2 O 4 S requires C, 58.28; H, 3.45; S 9.15 Found C 58.02; H, 3.51; S 9.35 Example 4 3- (2,6-Difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 12 F 2 O 4 S requires C, 58.28; H, 3.45; S 9.15 20 Found C 58.18; H, 3.50; S, 9.44

Example 5 • «3- (2,5-Difluorophenyl) -4- (4- (methylsulfonyl) phenyl} -2- (5H) -furanone» · ·

Analysis for C 17 H 12 F 2 O 4 S

? 25 calculated for C 58.28; H, 3.45; S, 9.15:. Found C, 58.89; H, 3.51; Example 9 3- (3,5-Difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

· "*. 30 Analysis for C 17 H 12 F 2 O 4 S

Calc'd for C 58.28; H, 3.45; S, 9.15. Found C, 58.27; H, 3.62; S 9.32 «t ·» · I {41 1 08792

Example 7 3- (4-Bromo-phenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 13 BrO 4 S 5 C, 51.94; H, 3.33; S, 8.16 Found C, 51.76; H, 3.42; S 8.21 Example 8 3- (4-Chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 10 H-NMR (300 MHz, CDCl 3) δ 7.93 (2H, d ), 7.49 (2H, d), 7.35 (4H, m), 5.16 (2H, s), 3.06 (3H, s).

Example 9 3- (4-Methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

15 Analysis for C 18 H 16 O 5 S

Found: C, 62.78; H, 4.68; S 9.31 Found C 62.75; H, 4.72; S 9.39 Example 10 I 3- (Phenyl) -4- (4- (methylsulfonyl) phenyl) -2- (20H) -furanone

To a solution of phenylacetic acid (27.4 grams, 201 mmol) and 2-bromo-1- (4- (methylsulfonyl) phenyl ··· * *) ethanone (Example 1, Step 1) (60 g, 216 mmol, 1.075 eq.) In acetonitrile (630 mL) was added at room temperature. ··· 25 mL of triethylamine (30.8 mL, 1.1 eq.) Slowly.

The mixture was stirred for 20 minutes at room temperature and

then cooled in an ice bath. DBU was added slowly

; (60.1 mL, 3 eq). After stirring for 20 minutes in an ice bath, the reaction was complete and the mixture was made acidic to 30% with 1M (1N) HCl (color change from dark brown to yellow). Then, 2.4 L of ice water was added, stirred for a few minutes, then the precipitate was filtered and rinsed with water (64 g of crude wet product was obtained). The solid was dissolved in 750 mL of dichloromethane 35 (dried over MgSO 4, filtered) and 300 g of silica gel was added. The solvent was evaporated to near dryness (silica gel 42 108792 slightly tacky) and the residue was applied to a silica gel pad (glass sinter) and eluted with 10% EtOAc / CH 2 Cl 2 / to give 36.6 g (58%) of the title compound after evaporation of solvent and stirring with ethyl acetate.

Analysis calculated for C 17 H 14 O 4 S C, 64.95; H, 4.49; S, 10.20 Found: C, 64.63; H, 4.65; S, 10.44

Example 1I 10 3- (2-Chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C17 H13 ClO3 S, C, 58.54; H, 3.76; S 9.19 Found C 58.59; H, 3.80; S 9.37 Example 12 3- (2-Bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 12 BrF 4 O 4 C, 49.75; H, 2.93 Found: C, 49.75; H 3.01 ... Example 13 3- (2-Bromo-4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 4: v: 1 H NMR (300 MHz, acetone-d 6) δ 7.95 (2H, d), 7.85 (1H, d), 7.63 (2H, dd), 7.55 (1H, dd), δ , 45 (1H, d), 5.50; (2H, s), 3.15 (3H, s).

Example 14? - (4-Chloro-2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone? 30 H-NMR (300MHz, acetone-d6) δ 8.0 (2H, d), 7.70 (2H, d), 7.50-7.30 (3H, m), 5.35 (2h, s), 3.15 (3H, s).

V, 'Example 15

3- (3-Bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 35 Analysis for C 17 H 12 BrFO 4 S

Found: C, 49.75; H, 2.93; 4310, 8, 9, 9; Found C, 49.44; H 2.98 Example 16 3- (3-Chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

5 Analysis for C 17 H 13 ClO 4 S

Found: C, 58.54; H, 3.76 Found: C, 58.29; H, 3.76

Example 17 3- (2-Chloro-4-fluoro-phenyl) -4- (4- (methylsulfonyl-10-yl) -phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 12 ClFO 4 S: C, 55.67; H, 3.30 Found C, 55.67; H, 3.26

Example 18 3- (2,4-Dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 12 Cl 2 O 4 S requires C, 53.28; H, 3.16; S 8.37 Found C 52.89; H, 3.23; S 8.58 Example 19 3, 3 - (3,4-Dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone * ·

Analysis for C 17 H 12 Cl 2 O 4 S

* ♦ V: Calcd. C 53.28; H, 3.16; S 8.37 • '.' • f 25 Found C 53.07; H, 3.32; S 8.51: Example 20 * * *: 3- (2,6-Dichlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis for C 17 H 12 Cl 2 O 4 S

i * * 30 calculated C, 53.28; H, 3.16; S 8.37 Found C, 52.99; H, 3.22; S 8.54 * t »'♦ i J 1 I 1 · *> I t t« »» »' I» »1 I I I» * 44 1 08792

Example 21 3- (3-Chloro-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 1 H-NMR (300 MHz, acetone-d 6) δ 8.0 ( 2H, d), 7.70 δ (2H, d), 7.60 (1H, d), 7.25-7.40 (2H, m), 5.35 (2H, s), 3.15 (3H, S).

Example 22 3- (4-Trifluoromethylphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 1 H-NMR (CD 3 COCD 3) δ 8.10 (2H, d), 7.82 -7.93 (4H, m), 7.75 (2H, d), 5.55 (2H, s), 3.30 (3H, s).

Example 23 3- (3-Fluoro-4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis for C18H15F05S

Found: C, 59.66; H, 4.17 Found C, 59.92; H 4.37 Example 24 3- (3-Chloro-4-methoxyphenyl) -4- (4- (methylsulfonyl-20-yl) phenyl) -2- (5H) -furanone

Analysis for C 18 H 15 ClO 5 S

¹ I I C 57.07; H, 3.99 Found C, 57.29; H 4.15 • · ·

Example 25 3- (3-Bromo-4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

* · '' Analysis for C18H15BrO5S

Found: C, 51.08; H 3.57: Found C, 51.38; H 3.62 "· 30 Example 26 3- (2-Fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

T Analysis for C17H13F04S

Found: C, 61.44; H, 3.94; Found: C, 61.13; H 3.85 45 108792

Example 27 3- (4-Methylthiophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 1 H-NMR (300 MHz, acetone-d 6) d 8.0 (2H, d), 7.70 δ (2H, d), 7.25 (2H, d), 5.35 (2H, s), 3.15 (3H, s), 2.55 (3H, s).

Example 28 3- (3-Fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 10: 1 H-NMR (300 MHz, CDCl 3) δ 7.93 (2H, d), δ , 49 (2H, d), 7.35 (1H, m), 7.12 (3H, m), 5.18 (2H, s), 3.06 (3H, S).

Example 29 3- (2-Chloro-6-fluoro-phenyl) -4- (4- (methylsulfonyl-15-yl) -phenyl) -2- (5H) -furanone 1 H-NMR (300MHz, acetone-d 6) d 8, 0 (2H, d), 7.70 (2H, d), 7.55 - 7.65 (1H, m), 7.40 (1H, d), 7.30 (1H, m), 5.60 (2H, s), 3.15 (3H, s).

Example 30 3- (3-Bromo-4-methyl-phenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone

Analysis calculated for C 18 H 15 BrO 4 S requires C, 53.08; H, 3.71 Found C, 53.06; H 3.83 * *. * Example 31 3- (4-Bromo-2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 12 BrFO 4 S requires C, 49.65; H, 2.94. Found: C, 49.76; H, 3.00

Example 32 3- (3,4-Dibromophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone 1 H-NMR (300 MHz, acetone-d 6) δ 8.0 ( 2H, d), 7.80: ··· 35 (1H, d), 7.75 (3H, m), 7.25 (1H, d), 5.35 (2H, s), 3.15 ( SH, S).

461 08792

Example 33 3- (4-Chloro-3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

! Analysis for C 17 H 12 ClF 4 S

5 calculated C 55.67; H, 3.30 Found C, 55.45; H 3.30 Example 34 3- (4-Bromo-3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone

Analysis for C17H12BrFO4S

Found: C, 49.66; H, 2.94; S, 7.80 Found C, 49.79; H, 3.01; S, 7.51

Example 35 3- (4-Bromo-2-chloro-phenyl) -4- (4- (methylsulfonyl-15-yl) -phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 12 BrClO 4 S: C, 47.74; H, 2.83; S, 7.50 Found C, 47.92; H, 2.84; S, 7.42

Example 36 3- (3,4-Dichlorophenyl) -4- (4- (aminosulfonyl) phenyl) -2- (5H) -furanone 1H-NMR (400MHz, CD3COCD3) δ 7.92 (2H, dd), 7.64 .V. (3H, dm), 7.60 (1H, dd), 7.32 (1H, dd), 6.70 (1H, broad δ) / 5/38 (2H, s).

* 25 Example 37 3- (3,4-Difluorophenyl) -4- (4- (aminosulfonyl) phenyl) -2- (5H) -furanone 1 H-NMR (400MHz, CD3COCD3)? , 92 (2H, dd), 7.64 (2H, dm), 7.30-7.45 (2H, m), 7.22 (1H, m), 6.68 (2H, le ')]. 30 (s), 5.37 (2H, s).

»» »T» j 47 108792

Example 38 3- (3-Chloro-4-methoxyphenyl) -4- (4- (aminosulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 14 ClNO 5 S 5 requires C, 53.76; H, 3.72; N, 3.69 Found C, 53.32; H, 3.84; N 3.59 M.S. (DCI, CH4) calcd for ion M +, 379 Obtained for ion M + + 1, 380 Example 39 10 3- (3-Bromo-4-methoxyphenyl) -4- (4- (aminosulfonyl) phenyl) -2- (5H) -furanone

Analysis calculated for C 17 H 14 BrNO 5 S requires C, 48.13; H, 3.33; N, 3.30 Found C, 48.26; H, 3.40; N 3.28 15 M.S. (DCI, ch4) calcd for M +, 423

Obtained for ion M + +1, 424.

• · «• a • 4 4 • · t a a • * a • a a t a · • · · a • a *» *! a! * * * * ϊ a I I I • »a ί * a I * # a j .. ί * Σ

Claims (3)

A process for the preparation of novel therapeutically useful furanone derivatives of the formula XXXIII r1 Wherein R 1 is -S (O) 2 CH 3 or -S (O) 2 NH 2 and R 2 is phenyl or mono- or disubstituted phenyl, wherein * ♦ · /: *. the substituents are selected from the group formed by halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio and CF 3, with the exception. take of the compounds 3- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (5H) -furanone and 3- (4-fluorophenyl) -4- [4-aminosulfonyl] Phenyl] phenyl] -2- (5H) -furanone, characterized in that a: V: compound of formula XXXIII in R1 JL xxxii ..... ·. 0 52 1 08792 in which R 1 is the same as above is reacted in a non-aqueous polar solvent with a compound of formula R 2 Process according to claim 1, characterized in that 3- (phenyl) -4- [4- (methylsulfonyl) phenyl] -2- (5H) -furanone is prepared. A process according to claim 1, characterized in that a compound is selected from the group comprising: (a) 3- (2,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (b) 3- (3,4-difluorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (c) 3- (2, 6-difluorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (d) 3- (2,5-difluorophenyl) -4- (4- (methylsulfonyl) -phenyl) -phenyl nyl) -2- (5H) -furanone; (e) 3- (3,5-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone. : (f) 3- (4-bromophenyl) -4- (4- (methylsulfonyl) phenyl) -2-. , ·. (5H) -furanone, lit (g) 3- (4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (i) 3- (2-chlorophenyl) -4 - (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, t (30) 3- (2-bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) -: Y; phenyl) -2- (5H) -furanone. (k) 3- (2-bromo-4-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, ···· * (1) 3- (4-chloro) -2-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, m) 3- (3-bromo-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (n) 3- (3-chlorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, 5 ( o) 3- (2-chloro-4-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (p) 3- (2,4-dichlorophenyl) -4- ( 4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (q) 3- (3,4-dichlorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (r) 3- (2,6-dichlorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (s) 3- (3-chloro-4-fluorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (t) 3- (4-trifluoromethylphenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (u) 3- (3-fluoro-4-methoxyphenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (v) 3- (3-chloro-4-methoxyphenyl) ) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (1) (w) 3- (3-bromo-4-methoxyphenyl) -4- (4- (methylsulfonyl) - * phenyl) -2- (5H) -furanone, (*) (X) 3- (2-Fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone ,. (Z) 3- (3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (1H (5H) -furanone) * (aa) 3- (2-chloro-6- fluorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (bb) 3- (3-bromo-4-methylphenyl) -4- (4- (methylsulfonyl) - ... (Phenyl) -2- (5H) -furanone, (cc) 3- (4-bromo-2-fluorophenyl) -4- (4- (methylsulfonyl) - (phenyl) -2- (5H) - furanone, * t (dd) 3- (3,4-dibromophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, * (35) ee (3-) 4- chloro-3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone, (ff) 3- (4-bromo-3-fluorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (gg) 3- (4-bromo-2-chlorophenyl) -4- (4- (methylsulfonyl) -phenyl) -2- (5H) -furanone, (Jj) 3- (3,4-dichlorophenyl) -4- (4- (aminosulfonyl) phenyl) -2- (5H) -furanone, (kk) 3- (3,4-difluorophenyl) -4- (4- (aminosulfonyl) phenyl) -2- (5H) -furanone, (11) 3- (3-chloro-4-methoxyphenyl) -4- (4- (aminosulfonyl) phenyl) -2- ( 5H) -furanone, and j (mm) 3- (3-bromo-4-methoxyphenyl) -4- (4- (aminosulfonyl) -phenyl) -2- (5H) -furanone. • · · • t · I I I * «· <t I * *« * * · * · * · * * · • I · • · * * · * * · f! t t * ft t · ·> • * hi «» I I * • t I • I I * * »t * I I t I I I I * * ·> I I I I i I li» I |