USRE38103E1 - 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 - Google Patents

5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 Download PDF

Info

Publication number
USRE38103E1
USRE38103E1 US09/827,508 US82750801A USRE38103E US RE38103 E1 USRE38103 E1 US RE38103E1 US 82750801 A US82750801 A US 82750801A US RE38103 E USRE38103 E US RE38103E
Authority
US
United States
Prior art keywords
1h
2h
cyclooxygenase
compound
mg
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US09/827,508
Inventor
Daniel Guay
Chun-Sing Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Canada Inc
Original Assignee
Merck Canada Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US98928692A priority Critical
Priority to US3339793A priority
Priority to US08/147,804 priority patent/US5604260A/en
Application filed by Merck Canada Inc filed Critical Merck Canada Inc
Priority to US09/827,508 priority patent/USRE38103E1/en
Application granted granted Critical
Publication of USRE38103E1 publication Critical patent/USRE38103E1/en
Anticipated expiration legal-status Critical
Application status is Expired - Fee Related legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00Systems containing two condensed rings
    • C07C2602/02Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Abstract

The Compound of Formula I and pharmaceutically acceptable sales thereof in the treatment of cyclooxygenase-2 mediated diseases are disclosed.
Figure USRE038103-20030429-C00001

Description

This is a continuation-in-part of U.S. Ser. No. 07/989,286 filed Dec. 11, 1992, now abandoned, and U.S. Ser. No. 08/033,397, filed Mar. 19, 1993, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compounds and pharmaceutical compositions for the treatment of inflammation, particularly cyclooxygenase mediated diseases and methods of treating thereof.

Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for an inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, mu-rine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and characterized from sheep, murine and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have physiological and pathological roles, we have concluded that the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinflammatory, antipyretic and analgesic properties of a conventional non-steroidal antiinflammatory drug (NSAID), and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.

SUMMARY OF THE INVENTION

The invention encompasses compounds of Formula I useful in the treatment of inflammation such as cyclooxygenase mediated diseases, particularly cyclooxygenase-2 mediated diseases.

Figure USRE038103-20030429-C00002

The invention also encompasses methods of treating inflammation including cyclooxygenase mediated diseases, particularly cyclooxygenase-2 mediated diseases comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I.

Figure USRE038103-20030429-C00003

The invention also encompasses certain pharmaceutical compositions for treatment of inflammation including cyclooxygenase mediated diseases, particularly cyclooxygenase-2 mediated diseases comprising compounds of Formula I and a pharmaceutically acceptable carrier.

The invention also encompasses the compound 12

Figure USRE038103-20030429-C00004

and pharmaceutically acceptable salts thereof which are useful in the treatment of inflammation such as cyclooxygenase mediated diseases, in particular cyclooxygenase-2 mediated diseases.

The invention also encompasses anti-inflammatory pharmaceutical compositions such as those useful for inhibiting a cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of the compound of Formula I as described herein.

The pharmaceutical compositions of the present invention comprise a compound of Formulas I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also 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 s inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from o pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline,-N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylgncamine, morpholine, piperazine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

The invention also encompasses methods of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of compound of Formula I as disclosed herein.

It will be understood that in the discussion of methods of treatment which follows, references to the compound of Formula I are meant to also include the pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I useful in the treatment of inflammation such as cyclooxygenase mediated diseases, particularly cyclooxygenase-2 mediated diseases

Figure USRE038103-20030429-C00005

wherein Y is O, S, S(O), S(O)2, —CH2—, —NH—, CO or

Figure USRE038103-20030429-C00006

X is H, halo, including Cl and Br, or C1-6alkyl; and

Ar1 and Ar2 are as defined below in the following five embodiments.

In one embodiment the invention encompasses compounds of Formula I wherein Y is

Figure USRE038103-20030429-C00007

wherein

R1 and R2 are each independently selected from the group consisting of

(a) NHS(O)2C1-6alkyl,

(b) halo, including Fluoro,

(c) C1-6alkyl,

(d) S(O)2C1-6alkyl,

(e) OC1-6alkyl, and

(f) hydrogen,

with the proviso that R1 and R2 are not simultaneously the same.

In a second embodiment, the invention encompasses compounds of Formula I wherein

wherein Y is O, S, S(O), S(O)2, —CH2—, —NH— or CO, preferably S or O; Ar1 is

Figure USRE038103-20030429-C00008

Ar2 is a group selected from the group consisting of:

Figure USRE038103-20030429-C00009

wherein

R3 is NHS(O)2C1-6alkyl, NHS(O)2CF3, or N(CH3CO)S(O)2CH3;

R4 is selected from the group consisting of

(a) acyl such as CO—C1-3alkyl,

(b) cyano,

(c) carboxy;

(d) carboxy C1-6alkyl ester,

(e) carboxamide,

(f) C1-6alkyl sulfinyl,

(g) C1-6alkyl sulfonyl, and

(h) nitro;

R5 is H, C1-3alkyl, or R4 and R5 are joined together to form a saturated monocyclic ring of five (5) carbons, wherein one of the carbons is substituted with an oxo or oximino group, or one of the carbons may be replaced by S(O)2;

R6 and R7 are each independently selected from the group consisting of hydrogen, C1-3alkyl or halo, including fluoro;

n is 0, 1, or 2; and

Z is O or S.

In a third embodiment the invention encompasses compounds of formula I wherein

Y is O;

Ar1 is

Figure USRE038103-20030429-C00010

R7 is a group such as

(a) NHS(O)2C1-6alkyl,

(b) N(CH3CO)S(O)2CH3, or

(c) NHS(O)2CF3; and

Ra and Rb are jointly oxo or oximino;

Ar2 is

Figure USRE038103-20030429-C00011

wherein Rc and Rd are each independently selected from hydrogen or halo, such as fluoro, Cl, Br, or Iodo.

With regard to the third embodiment Ar2 may alteratively be tri substituted with substituents independently selected from:

(a) hydrogen,

(b) F, Cl, Br, or I,

(c) methyl or ethyl,

(d) —CF3,

(e) vinyl or —C≡CH,

(f) —OCH3 or —OCF3,

(g) SCH3 or SCF3,

(h) CN, or

(i) N3,

the substitutents residing at position 1, 3 and 5 of the phenyl.

Thus one alternative to this third embodiment is the compounds of Formula I

Figure USRE038103-20030429-C00012

wherein

Ar1 is

Figure USRE038103-20030429-C00013

Y is O or S; and

Ar2 is

Figure USRE038103-20030429-C00014

wherein A, B and C are each independently selected from

(a) hydrogen,

(b) F, CI, Br, or I,

(c) methyl or ethyl,

(d) —CF3,

(e) vinyl or —C≡CH,

(f) —OCH3 or —OCF3,

(g) SCH3 or SCF3,

(h) CN, or

(i) N3.

In a fourth embodiment the invention encompasses compounds of Formula I wherein

Y is O or S;

Ar1 is

Figure USRE038103-20030429-C00015

wherein

R9 is a group such as RxS(O)2NR, wherein

Rx is C1-3alkyl or CF3, and

R is hydrogen or a pharmaceutically acceptable cation;

R8 is nitro or acyl, such as CO—C1-3alkyl;

Ar2 is

Figure USRE038103-20030429-C00016

R6 and R7 are each independently selected from the group consisting of hydrogen, C1-3alkyl or halo, including fluoro;

In a fifth embodiment the invention encompasses compounds of Formula I wherein

Ar1 is

Figure USRE038103-20030429-C00017

Re is C1-3alkyl or trifluoromethyl;

Y is O, S, S(O), or S(O)2; and

Ar2 is

Figure USRE038103-20030429-C00018

wherein

R6 and R7 are each independently selected from the group consisting of hydrogen, Cl-3alkyl or halo, including fluoro; or

Ar2 is

Figure USRE038103-20030429-C00019

wherein n is 0, 1, or 2.

Exemplifying this aspect of the invention are the following compounds:

Figure USRE038103-20030429-C00020

as well as compound compound 12 mentioned above

Figure USRE038103-20030429-C00021

and pharmaceutically acceptable salts thereof.

A is appreciated by thoses of skill in the art, compounds A to D are known by the names Dup 697 (compound A), Flosulide (compound B), Nimesulide (compound C), and NS 398 (compound D).

Illustrative of the pharmaceutically acceptable salts is the formula

Figure USRE038103-20030429-C00022

wherein Z+ is a pharmaceutically acceptable counterion. As is well appreciated by those of skill in the an, the pharmaceutically acceptable counterions include, aluminum, calcium, lithium, magnesium, potassium, sodium, barium, zinc, ammonium, or an amino acid such as glycine, alinine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, lysine, hydroxylsine, histidine, arginine, phenylalanine, tyrosine, tryptophan, thyroxine, cystine, x s cysteine, methionine, proline, hydroxyproline, ornithine, b-alanine, a-amino butyric acid, sarcosine, betaine, homoserine, and citrulline, or mono, di, or triC1-6alkylamino.

The invention also encompasses anti-inflammatory pharmaceutical compositions such as for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.

Within this embodiment the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.

The invention also encompasses a method of inflammation such as inhibiting cyclooxygenase (e.g. cyclooxygenase-2) and treating cyclooxygenase (e.g. cycloxygenase-2) mediated diseases as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of compound of Formula I as described above.

Within this embodiment the invention encompasses a method of selectively inhibiting cyclooxygenase-2 and selectively treating cyclooxygenase-2 mediated diseases as disclosed herein comprising: administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of compound of Formula I as disclosed herein. For purpose of this specification a compound that is selective for the inhibition of cyclooxygenase-2 or for treatment of cyclooxygenase-2 mediated diseases is a compound that demonstrates an in vitro or in vivo IC50 ratio for COX-1 to COX-2 of approximately 1000 or greater.

As disclosed elsewhere in this specification in further detail, these diseases include pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries.

The compound of Formula I is useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursiris, bums, injuries, following surgical and dental procedures. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. The compounds of Formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma. Compounds of formula 1 may also be useful in the treatment of Alzheimers disease and menentia.

By virtue of their high cyclooxygenase-2 (COX-2) activity and/or their specificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), the compound of Formula I will prove useful as alternatives to conventional non-steroidal anti-inflammatory drugs (NSAID'S) particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; those prior to surgery or taking anticoagulants.

Similarly, the compound of Formula I, will be useful as a partial or complete substitute for conventional NSAID'S in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, s pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or nonsedating antihistamine. In addition the invention encompasses a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.

The compounds of the present invention is an inhibitor of cyclooxygenase-2 and is thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activity is illustrated by it's ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. The IC50 values represent the concentration of inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Illustrating this aspect, is the a comparison is provided hereinunder of the compound 12 with Flosulide:

Figure USRE038103-20030429-C00023

This compound and it's method of preparation is disclosed in U.S. Pat. No. 4,375,479, issued to Schroeder, et al., Mar. 1, 1983.

By way of comparison, Ibuprofen has an IC50 for COX-2 of 1 mM, and Indomethacin has an IC50 for COX-2 of approximately 100 nM.

For the treatment of any of these cyclooxygenase mediated diseases the compound of Formula I and pharmaceutically accetable salts thereof may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.

As indicated above, pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the an for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycertanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, 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 arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. s The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. 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 a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known an using those suitable dispersing or wetting agents and suspending agents which have been 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-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.

The compound of Formula (I) and pharmaceutically acceptable salts thereof may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula (I) are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)

Dosage levels of the order of from about 0.01 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g. per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 1.0 g per patient per day. A typical dosage range is 100 or 200 mg to about 1000 mg. An upper ranges of 500 or 2000 mg is also be regarded as typical.

The amount of active ingredient that may be combined with the carder materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 1000 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Compounds of the instant invention are conveniently prepared using the procedures described in the methods below. Additional relevant chemistry is described in U.S. Pat. No. 4,375,479, issued to Schroeder, et al., Mar. 1, 1983 which is hereby incorporated by reference.

METHOD A

5-Aminoindane II is acetylated, followed by bromination to give the 5-acetylamino-6-bromoindane III. Oxidation with chromium trioxide in aqueous acetic acid, followed by acidic hydrolysis gives the 5-amino-6-bromo-1-indanone IV. The amino group is converted to the nitro group by diazotization followed by treatment of the corresponding diazonium salt with sodium nitrite in the presence of copper powder. Subsequent protection of the carbonyl as a dioxolane provides 5-nitro-6-bromo-1-indanone ethylene ketal V. Coupling with an appropriate s nucleophile proceeds under basic conditions with or without the presence of a copper salt. Reduction of the nitro group with iron powder or tin(II) chloride in aqueous ethanol with concomitant hydrolysis of the ketal group leads to amino indanone VI. Sulfonylation with excess methanesulfonyl chloride in the presence of trimetylamine yields the corresponding bissulfonamide, which upon subsequent hydrolysis with sodium hydroxide yields the title compound I′.

Figure USRE038103-20030429-C00024

METHOD B

4-Chloro-3-nitrobenzaldehyde is coupled with an appropriate nucleophile under basic conditions to give VII. Reduction of the nitro groups with iron powder of tin/II chloride in aqueous ethanol gives the corresponding aniline, which is converted to the bissulfonamide with excess methanesulfonyl chloride in the presence of triethylamine. Basic hydrolysis of the bissulfonamide then yields IX. A two carbon elongation step with triethyl phosphonoacetate anion (prepared from treatment with sodium hydride) or (carbethoxymetylene)triphenylphosphorane provides an α, β-unsaturated ester. Reduction of the double bond with 10% palladium on charocoal under hydrogen atmosphere followed by ester hydrolysis affords acid X. The acid X is converted to the acid chloride and then treated with aluminum chloride or other standard Friedel-Crafts Lewis acid catalysts to give the title compound I′.

Figure USRE038103-20030429-C00025

ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY

The compound of Formula I were tested using the following assays to determine their cyclooxygenase-2 inhibiting activity.

INHIBITION OF CYCLOOXYGENASE ACTIVITY

Compounds were tested as inhibitors of cyclooxygenase activity in whole cell and microsomal cyclooxygenase assays. Both of these assays measured prostaglandin E2 synthesis in response to arachidonic acid, using a radioimmunoassay. Cells used for whole cell assays, and from which microsomes were prepared for microsomal assays, were human osteosarcoma 143 cells (which specifically express cyclooxygenase-2) and human U-937 cells (which specifically express cyclooxygenase-1). In these assays, 100% activity is defined as the difference between prostaglandin E2 synthesis in the absence and presence of arachidonate addition.

RAT PAW EDEMA ASSAY—PROTOCOL

Male Sprague-Dawley rats (150-200 g) were fasted overnight and were given po either vehicle (1% methocel) or a test compound. One hr later, a line was drawn using a permanent marker at the level above the ankle in one hind paw to define the area of the paw to be monitored. The paw volume (VO) was measured using a plethysmometer (Ugo-Basile, Italy) based on the principle of water displacement.

The animals were then injected subplantarly with 50 μl of 1% carrageenan solution in saline (FMC Corp, Maine) into the paw using an insulin syringe with a 25 -gauge needle (i.e. 500 μg carrageenan per paw). Three hr later, the paw volume (V3) was measured and the increases in paw volume (V3−V0) were calculated. The animals were sacrificed by CO2 aphyxiation and the absence or presence of stomach lesions scored. Data were compared with the vehicle-control values and percent inhibition calculated. Since a maximum of 60-70% inhibition (paw edema) was obtained with standard NSAIDs, ED30 values were used for comparison and at at least 3 different concentrations. At least 6 animals were used at each concentration All treatment groups were coded to eliminate observer bias.

REPRESENTATIVE BIOLOGICAL DATA

The compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of inflammation such cyclooxygenase-2 mediated diseases as enumerated above. The activities of the compound against cyclooxygenase may be seen in the representative results shown below. In the assay, inhibition is determined by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a putative inhibitor. The IC50 values represent the concentration of putative inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control.

The results for inhibition of PGE2 production may be seen in the following Table.

COMPARISON OF SELECTED COMPOUNDS WITH FLOSULIDE
Rat Paw Rat Plasma Monkey
CONC COX-2 COX-1 EDEMA Levels @ 1 hr Cmax Monkey (n = 2)
(nM) % INHB % INHB ED30 (mpk) (μg/ml) (μg/ml) (Estimated)
INDOMETHACIN IC50 50 nM 10 nM 1.1 ± .3
Figure USRE038103-20030429-C00026
IC50 50 nM Inactive at 50 μM 1.1 ± .4 48 @ 20 mpk 17 @ 10 mpk <4 hr
Figure USRE038103-20030429-C00027
 10  100 1000 43    87    91    Inactive at 10 μM 0.3 ± .1 70 @ 10 mpk 35 @ 5 mpk >9 hr
Figure USRE038103-20030429-C00028
IC50  8 nM Inactive at 100 μM 0.22
Figure USRE038103-20030429-C00029
IC50  7 nM 0.1 

BIOLOGICAL ACTIVITIES OF PREPARED EXAMPLES
Com- COX-2 COX-1
pound IC50 IC50
# (nM) (nM) Rat Paw Edema ED50 (mpk)
1 30 Schering U.S. Pat. No. 4,244,960
2 9
3 50  >50,000 0.62 Schering U.S. Pat. No. 4,375,479
(Flo-
sulide)
4  8 >100,000 0.22
5 100
6 50 >100,000 0.16
7 100
8 100
9 100
10 8  >10,000 3.0
11 10
12 50   >10,000 0.3
13 100
14 13
15 10
16 11
17 7
18 60 >100,000
19 100
20 50
21 100
22 50
23 300
24 100
25 1,000

NMR DATA FOR EXAMPLES
Com-
pound
# X A B C NMR δ (ppm)
1 O H H H See U.S. Pat. No. 4,244,960
2 O H Br H (CDCl3) 7.73(s, 1H), 7.53(d, 2H), 7.29(m, 1H), 7.14(s, 1H),
6.94(d, 2H), 3.16(s, 3H), 3.13(t, 2H), 2.70(t, 2H).
3 O F F H See U.S. Pat. No. 4,375,479
4 O Cl Cl H (CDCl3) 7.73(s, 1H), 7.50(s, 1H), 7.32(m, 2H), 7.08(d, 1H),
6.90(s, 1H), 3.14(s, 3H), 3.10(t, 2H), 2.68(t, 2H).
5 O H SMe H (Acetone-d6) 8.65(brs, 1H), 7.79(s, 1H), 7.38(d, 2H), 7.08(d, 2H),
7.01(s, 1H), 3.20(s, 3H), 3.14(t, 2H), 2.62(t, 2H), 2.50(s, 3H).
6 S H H H (CDCl3) 8.08(s, 1H), 7.85(s, 1H), 7.80(s, 1H), 7.32-7.10(m, 5H),
3.20(t, 2H), 2.78(s, 3H), 2.74(t, 2H).
7 S F H H (CDCl3) 8.02(s, 1H), 7.97(brs, 1H), 7.28(m, 1H) 7.15(t, 1H),
7.08(m, 2H), 3.13(t, 2H), 2.97(s, 3H), 2.70(t, 2H).
8 S H F H (CDCl3) 8.00(s, 1H), 7.80(s, 1H), 7.76(s, 1H) 7.16(t, 2H),
6.98(t, 2H), 3.16(t, 2H), 2.88(s, 3H), 2.72(t, 2H).
9 S H Cl H (CDCl3) 8.04(s, 1H), 7.82(brs, 2H), 7.25(d, 2H), 7.08(d, 2H),
3.20(t, 2H), 2.92(s, 3H), 2.75(t, 2H).
10 S H Br H (Acetone-d6) 9.15(brs, 1H), 7.75(s, 1H), 7.65(s, 1H), 7.54(d, 2H),
7.22(d, 2H), 3.18(t, 2H), 3.10(s, 3H), 2.65(t, 2H).
11 S H I H (CDCl3) 8.03(s, 1H), 7.78(brs, 2H), 7.56(d, 2H), 6.82(d, 2H),
3.18(t, 2H), 2.88(s, 3H), 2.71(t, 2H).
12 S F F H (CDCl3) 8.05(s, 1H), 7.98(s, 1H), 7.78(s, 1H), 7.30(m, 1H),
6.88(m, 2H), 3.16(t, 2H), 3.06(s, 3H), 2.70(t, 2H).
13 S F H F (CDCl3) 8.22(brs, 1H), 8.03(s, 1H), 7.72(s, 1H), 7.32(m, 1H),
6.96(m, 2H), 3.11(t, 2H), 3.05(s, 3H), 2.65(t, 2H).
14 S F Cl H (CDCl3) 7.97(s, 1H), 7.92(bs, 1H), 7.75(s, 1H) 7.08(m, 3H),
3.14(t, 2H), 3.30(s, 3H), 2.70(t, 2H).
15 S F Br H (CDCl3) 7.97(s, 1H), 7.91(brs, 1H), 7.77(s, 1H) 7.23(m, 2H),
7.00(t, 1H), 3.13(t, 2H), 3.03(s, 3H) 2.70(t, 2H).
16 S Cl F H (CDCl3) 7.97(s, 1H), 7.82(brs, 1H), 7.78(s, 1H), 7.19(m, 1H),
6.88(d, 2H), 3.18(t, 2H), 3.00(s, 3H), 2.71(t, 2H).
17 S Cl Cl H (CDCl3) 8.00(s, 1H), 7.82(s, 1H), 7.78(s, 1H), 7.46(d, 1H),
7.10(dd, 1H), 6.68(d, 1H), 3.20(t, 2H), 3.02(s, 3H), 2.78(t, 3H).
18 S F Br F (CDCl3) 8.18(brs, 1H), 8.03(s, 1H), 7.74(s, 1H), 7.16(d, 2H),
3.14(t, 2H), 3.11(s, 3H), 2.69(t, 2H).
19 S CH3 H H (CDCl3) 7.97(s, 1H), 7.82(s, 1H), 7.68(brs, 1H), 7.23(d, 1H), 7.15(t, 1H),
7.05(t, 1H), 6.76(d, 1H), 3.18(t, 2H), 2.82(s, 3H), 2.75(t, 2H).
20 S H CH3 H (CDCl3) 8.04(s, 1H), 7.82(s, 1H), 7.78(s, 1H), 7.10(s, 4H),
3.16(t, 2H), 2.78(s, 3H), 2.72(t, H), 2.30(s, 3H).
21 S CF3 H H (CDCl3) 8.05(s, 1H), 7.81(s, 1H), 7.74(s, 1H), 7.70(d, 1H),
7.30(m, 2H), 6.92(d, 1H), 3.18(t, 2H), 2.86(s, 3H), 2.73(t, 2H).
22 S H CF3 H (CDCl3) 8.06(s, 1H), 7.85(s, 1H), 7.80(brs, 1H), 7.52(d, 2H),
7.16(d, 2H), 3.23(t, 2H), 2.97(s, 3H), 2.78(t, 2H).
23 S H OCH3 H (CDCl3) 7.98(s, 1H), 7.80(brs, 1H), 7.72(s, 1H), 7.20(d, 2H),
6.72(d, 2H), 3.76(s, 3H), 3.13(t, 2H), 2.79(s, 3H), 2.69(t, 2H).
24 S H CH═CH2 H (CDCl3) 8.06(s, 1H), 7.84(s, 1H), 7.82(s, 1H), 7.31(m, 2H),
7.12(m, 2H), 6.65(q, 1H), 5.72(d, 1H), 5.28(d, 1H), 3.18(t, 2H),
2.80(s, 3H), 2.75(t, 2H).
25 S H Et H (CDCl3) 8.04(s, 1H), 7.80(brs, 1H), 7.77(s, 1H), 7.12(s, 4H),
3.18(t, 2H), 2.77(s, 3H), 2.73(t, 2H), 2.61(q, 2H), 1.19(t, 3H).

EXAMPLES

The invention is illustrated by the following non-limiting examples. Unless stated otherwide it is to be understood that (i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18°-25° C.; (ii) evaporation of solvent was carded out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5−30 mm. Hg) with a bath temperature of up to 60° C.; (iii) the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; (iv) melting points are uncorrected and ‘d’ indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; (v) the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; (vi) yields are given for illustration only; (vii) when given, NMR data is in the form of delta (d) values for major diagnostic protons, given in pans per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition “Ar” signifies an aromatic signal; and (viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).

PREPARATION EXAMPLE FOR METHOD A (COMPOUND 12)

5-Methanesulfonamido-6-(2,4-difluorophenylthio)- 1-indanone

Step 1: 5-Acethylamninoindane

To a solution of 5 -aminoindane (10.0 g, 7.5 mmol) in CH2Cl2 (100 mL) was added dropwise acetic anhydride (9.2 g, 9.0 mmol) over a period of 15 min. After further stirring for 30 min, the mixture was quenched with 1M aqueous NaOH (100 mL). The CH2Cl2 layer was separated, washed successively with 1M aqueous HCl, brine, and was then dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with ethyl acetate-:hexanes (1:1) afforded 12.2 g (85%) of the title compound as a light brown powder. 1H NMR (CDCl3): δ7.44 (1H, s), 7.12 (3H, three overlapping s), 2.88 (4H, m), 2.15 (3H, s), 2.06 (2H, m).

Step 2: 5-Acetylamino-6-bromoindane

To a solution of 5-acetylaminoindane (53.0 g, 0.30 mol) in glacial acetic acid (1 L) at 10° C. was added dropwise over a period of 1 h a solution of bromine (19.0 mL, 0.37 mol). The mixture was further stirred at 10° C. for 15 min, and was then diluted with water until no more precipitate formed. The precipitate was collected, washed with water and dried under vacuum to give 61 g (80%) of the title compound.

1H NMR (CDCl3): δ5 8.14 (1H, s), 7.50 (1H, s), 7.38 (1H, s), 7.38 (4H, m), 2.20 (3H, s), 2.08 (2H, m).

Step 3: 5-Acetylamino-6-bromo-1-indanone

To a solution of 5-acetylamino-6-bromoindane (43.0 g, 0.17 mol) in glacial acetic acid (400 mL) at 50°-55° C. was added dropwise a solution of chromium trioxide (70.0 g, 0,7 mol) in 50% aqueous acetic acid (400 mL) over a period of 30 min. After further stirring for 15 min, the mixture was cooled to 0° C. and quenched with 2-propanol (100 mL). Solvent was removed in vacuo. The residue was diluted with water (1 L) and extracted with ethyl acetate (2×500 mL). The combined ethyl acetate layer was washed with 0.5M aqueous NaOH (1 L), brine, dried over anhydrous MgSO4 and concentrated to give 36 g (80%) of the title compound as a light brown solid which was contaminated with about 10% of 5-bromo-6-acetylamino- 1-indanone. 1H NMR (CDCl3); δ8.60 (1H, s), 7.90 (1H, s), 7.90 (1H, s), 3.10 (2H, t), 2.70 (2H, t), 2.30 (3H, s).

Step 4: 5-Amino-6-bromo-1-indanone

A mixture of 5-acetylamino-6-bromo-1-indanone (36.0 g, 0.13 mol) and 6M aqueous hydrochloric acid (800 mL) was refluxed for 1 h. The homogenous solution was then cooled to 0° C. and adjusted to pH 8 with 10M aqueous NaOH (−480 mL). The precipitate formed was collected, washed with water and dried under vacuum to afford 30.0 g (quantitative) of the title compound as a light brown powder. 1H NMR (acetone-d6): δ7.65 (1H, s), 6.90 (1H, s), 5.80 (2H, br s), 2.95 (2H, t), 2.50 (2H, t).

Step 5: 5-Nitro-6-bromo-1-indanone

To a suspension of 5-amino-6-bromo-1-indanone (30.0 g, 0.13 mol) in 20% aqueous fluoroboric acid (120 mL) at 0° C. was added dropwise 4M aqueous NaNO2 (50 mL, 0.20 mol) over a period of 30 min. The mixture was stirred for 30 min after completion of addition. The resulting foamy suspension was added portionwise to a vigorously stirred mixture of copper powder (40 g, 0.62 mol) and sodium nitrite (120 g, 1.74 mol) in water (240 mL) at room temperature over a period of 15 min. During the addition, excessive foaming was broken up by the addition of small amounts of diethyl ether. After further stirring for 30 min, the mixture was filtered through celite, washed with ethyl acetate (5′300 mL). The ethyl acetate layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with CH2Cl2, yielded 17.5 g (51%) of the title compound as a pale yellow solid.

1H NMR (CDCl3); δ8.10 (1H, s), 7.85 (1H, s), 3.20 (2H, t), 2.85 (2H, t); mass spectrum (DCI, CH4) m/e 256 (M+ +H). Step 6: 5-Nitro-6-bromo-1-indanone ethylene ketal.

To a suspension of 5-nitro-6-bromo-1-indanone (11.0 g, 43 mmol) and bis(trhnethylsilyloxy)ethane (22.0 mL, 90 mmol) in CH2Cl2 (90 mL) at room temperature was added trimethylsilyl trifluoromethanesulfonate (100 μL). The mixture was stirred for 2 h and the homogeneous solution was quenched with saturated aqueous NaHCO3 (100 mL). The CH2Cl2 layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel, eluting with ethyl acetate:hexanes (2:5), furnished 10.2 g (79%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): δ7.70 (1H, s), 7.68 (1H, s), 4.15 (4H, m), 2.98 (2H, t), 2.38 (2H, t)

Step 7: 5-Nitro-6-(2,4-difluorophenylthio)-1-indanone ethylene ketal

To a mixture of 5-nitro-6-bromo-1-indanone ethylene ketal (600 mg, 2.0 mmol) and 2,4-difluorothiophenol (F. Klages and K. Bott Chem. Ber. 97,735 (1964)) (440 mg, 3.0 mmol) in pyridine (4.0 mL) was added a solution of 8M aqueous potassium hydroxide (375 μL, 3.0 mmol) at room temperature. The mixture was stirred for 2 h, diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed successively with 1M aqueous NaOH (2x),0.5M aqueous HCl (1x), brine, dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography over silica gel and eluted with toluene: ethyl acetate (10:1) afforded the title compound (590 mg, 81%) as a pale yellow solid.

1H NMR (CDCl3)δ8.12 (s,1H), 7.60 (m, 1H), 7.00 (m, 2H), 6.70 (s, 1H), 4.10−3.90 (m 4H), 2.95 (t, 2H), 2.30 (t, 2H).

Step 8: 5-Amino-6-(2,4-difluorophenylthio)-1-indanone

A mixture of 5-nitro-6-(2,4-difluorophenylthio)-1-indanone ethylene ketal (580 mg, 1.59 mmol), iron powder (500 mg, 8.9 mmol) and ammonium chloride (50 mg, 0.93 mmol) in 30 mL of ethanol:water (2:1) was refluxed for 1 h. The hot mixture was filtered through celite. The solvente was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous MgSO4 and concentrated to give the title compound (410 mg, 81%) as a light brown solid. 1H NMR (CDCl3) δ7.95 (s, 1H), 7.00 (m, 1H), 6.80 (m, 2H), 6.72 (s, 1H), 4.95 (br s, 2h), 3.05 (t, 2H), 2.65 (t, 2H).

Step 9: 5-Methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone

A mixture of 5-amino-6-(2,4-difluorophenylthio)-1-indanone (400 mg, 1.25 mmol), triethylamine (1.0 mL, 7.2 mmol) and methanesulfonyl chloride (300 μL, 3.9 mmol) in methylene chloride (10 mL) was stirred at room temperature for 1 h. After dilution with more methylene chloride (20 mL), the mixture was washed successively with saturated aqueous sodium bicarbonate, 1M aqueous HC1 and brine. The methylene chloride layer was separated, dried over anhydrous MgSO4 and concentrated to give a dark solid residue.

To a solution of the above residue in MeOH:THF (2:1, 24 mL) at room temperature was added 10M aqueous NaOH (375 μL, 3.75 mmol). The mixture was stirred at room temprature for 30 min and then acidified with 3M aqueous HCl (1.5 mL). The volatile solvents were evaporated in vacuo. The residue was diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with brine, dried over anhydrous MgSO4 and concentrated. Chromatography over silica gel and elution with hexanes: ethyl acetate (1:1) yielded the title compound (350 mg, 76%) as a light brown solid. 1H NMR (CDCl3) δ8.05 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.30 (m, 1H), 6.88 (m, 2H), 3.16 (t, 2H), 3.06 (s, 3H), 2.70 (t, 2H).

PREPARATION EXAMPLE FOR METHOD B (COMPOUND 17)

4-(2,4-dichlorophenoxy)-3-nitrobenzaldehyde

Figure USRE038103-20030429-C00030

To powdered potassium hydroxide (9.0 g, 0.12 mol) at 110° C. was added 2,4-dichlorophenol (19.0 g, 0.12 mol) in one portion. The mixture was stirred for 15 min. and a homogenous solution resulted. 4-Chloro-3-nitrobenzaldehyde (20.0 g, 0.11 mol) was added and the thick mixture was stirred at 110° C. for 1 h. After cooling to room temperature, the mixture was partitioned between 2M aqueous sodium hydroxide and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of solvent and recrystallization from ethanol afforded 27.0 g (80%) of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ9.80 (s, 1H), 8.48 (s, 1H), 7.90 (d, 1H), 7.53 (s, 1H), 7.35 (d, 1H), 7.16 (d, 1H), 6.88 (d, 1H). 3-Amino-4-(2,4-dichlorophenoxy)benzaldehyde

Figure USRE038103-20030429-C00031

A mixture of 4-(2,4-dichlorophenoxy)-3-nitrobenzaldehyde (19.0 g, 0.006 mol), iron powder (13.0 g, 0.23 mol) and ammonium chloride (saturated aqueous solution, 50 ml) in 600 mL of ethanol:water (2:1) was refluxed for 1.5 h. The hot mixture was filtered through celite. Solvent was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. Chromatography over silica gel and elution with hexanes:ethyl acetate (2:1) gave the title compound (10.0g, 60%) as a white solid. 1H NMR (CDCl3)δ9.83 (s, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 7.15 (d, 1H), 7.00 (d, 1H), 6.68 (d, 1H), 4.1 (brs, 2H).

4-(2,4-Dichlorophenoxy)-3-methanesulfonamido-benzaldehyde

Figure USRE038103-20030429-C00032

A mixture of 3-amino-4-(2,4-dichlorophenoxy)benzaldehyde (8.0 g, 0.028 mol), trietylamine (15.8 mL, 0.11 mol) and methanesulfonyl chloride (9.75 g, 0.085 mol) in dichloromethane (200 mL) was stirred at 0° C. for 1 h. The mixture was then washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated to give a dark solid residue.

To a solution of the above residue in MeOH:THF (2:1,150 mL) at 0° C. was added 2M aqueous sodium hydroxide (42 mL, 84 mmol). The mixture was stirred at room temperature for 1 h and then acidified with 1M aqueous hydrochloric acid. Most of the organic solvents-were evaporated in vacuo. The residue was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The solid residue was suspended in ethanol and filtered to give the title compound. The filtrate was concentrated and chromatographed over silica gel with hexanes-:ethyl acetate (2:1) to give the title compound (14.0 g, 92% combined yield) as a white solid. 1H NMR (CDCl3) δ9.90 (s, 1H), 8.13 (s, 1H), 7.58 (d, 1H), 7.53 (s, 1H), 7.35 (d,1H), 7.11 (d, 1H), 7.03 (brs, 1H), 6.68 (d, 1H), 3.12 (s, 3H).

Ethyl 4-(2,4-dichlorophenoxy)-3-methanesulfonamido-cinnamate

Figure USRE038103-20030429-C00033

To a suspension of sodium hydride (500 mg, 16.7 mmol) in tetrahydrofuran (15 mL) was added dropwise triethylphosphonoacetate (1.87 g, 8.3 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min. and a homogeneous solution resulted. A solution of 4-(2,4-dichlorophenoxy)-3-methanesulfonamido-benzaldehyde (2.5 g, 6.94 mmol) in tetrahydrofuran (20 mL) was added slowly. After stirring at room x s temperature for 2 h, the mixture was quenched with acetic acid (1mL). Solvent was evaporated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography over silica gel and elution with hexanes:ethyl acetate (3:1) yielded the title compound (2.57 g, 86%) as a solid. 1H NMR (CDCl3)δ7.82 (s, 1H), 7.60 (d, 1H), 7.50 (s, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.89 (s, 1H), 6.60 (d, 1H), 6.36 (d, 1H), 4.25 (q, 2H) 3.08 (s, 3H), 1.30 (t, 3H).

Ethyl 3-[4-(2,4-dichlorophenoxy)-3-methanesulfonamido] phenylpropionate

Figure USRE038103-20030429-C00034

A mixture of ethyl 4-(2,4-dichlorophenoxy)-3-methanesulfonamido-cinnamate (2.2 g, 5.1 mmol) and 10% palladium on Charcoal (850 mg) in ethyl acetate (75 mL) was hydrogenated at room temperature under 30 psi of hydrogen atmosphere for 2 h. The catalyst was filtered off and the tiltrate was concentrated to give the title compound (2.1 g, quantitative yield). 1H NMR (CDCl3) δ7.40 (s, 2H), 7.22 (d, 1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.82 (brs, 1H), 6.59 (d, 1H), 4.08 (q, 2H), 3.0 (s, 3H), 2.90 (t, 2H), 2.59 (t, 2H), 1.22 (t, 3H).

3-[4-(2,4-Dichlorophenoxy)-3-methanesulfonamido]phenylpropionic acid

Figure USRE038103-20030429-C00035

To a solution of ethyl 3-[4-(2,4-dichlorophenoxy-3methanesulfonamido]phenylpropionate (2.1 g, 5.0 mmol) in ethanol (70 mL) was added an aqueous solution of 2 M sodium hydroxide (6.0 mL, 12 mmol). The mixture was stirred at 45° C. for 2 h and acidified with acetic acid. Solvent was removed in vacuo. The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed successively with water, brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography over silica gel and elution with hexanes:ethyl acetate (3:1) with 2% acetic acid yielded the title compound (1.7 g, 84%) as a white solid. 1H NMR (CDCl3) δ7.51 (s, 1H), 7.48 (s, 1H), 7.24 (d, 1H), 6.96 (d, 1H), 6.92 (d, 1H), 6.78 (brs, 1H), 6.60 (d, 1H), 3.02 (s, 3H), 2.93 (t, 2H), 2.68 (t, 2H).

5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone

Figure USRE038103-20030429-C00036

To a mixture of 3-[4-(2,4-dichlorophenoxy)-3-methanesulfonamido]phenylpropionic acid (1.2 g, 3.0 mmol) and N,N-dimethylformamide (1 drop) in dichloromethane (12 mL) at 0° C. was added dropwise oxalyl chloride (785 mg, 6.2 mmol). The mixture was stirred for 30 min. and solvent was evaporated in vacuo to give a foam.

The above foam residue was dissolved in anhydrous 1,2-dichloroethane (10 mL). Aluminum trichloride anhydrous (1.2 g, 9.0 mmol) was added portionwise at 0° C. The mixture was stirred at room temperature for 30 min. and 1M aqueous hydrochloric acid was added. The whole mixture was extracted twice with dichloromethane. The combined organic extracts were washed successively with water, brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography over silica gel and elution with hexanes-:ethyl acetate (2:1) afforded a solid residue. Recrystallization from ethanol yielded the title compound (870 mg, 75%) as white needles. 1H NMR (CDCl3) δ7.73 (s, 1H), 7.50 (s, 1H), 7.32 (m, 2H), 7.08 (d, 1H), 6.90 (s, 1H), 3.14 (s, 3H), 3.10 (t, 2H), 2.68 (t, 2H).

Claims (7)

What is claimed is:
1. A compound of the formula I
Figure USRE038103-20030429-C00037
or a pharmaceutically acceptable salt thereof.
2. A method of selectively inhibiting cyclooxygenase-2 comprising administration to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound according to claim 1.
3. A method of treating a cyclooxygenase-2 mediated disease in patients having a history of a gastro-intestinal disorder comprising administration to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound according to claim 1.
4. A method of selectively inhibiting cyclooxygenase-2 comprising administration to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound according to claim 1.
5. A method for selectively inhibiting cyclooxygenase- 2 activity in a human host, comprising administering a non-steroidal compound that selectively inhibits activity of the cyclooxygenase- 2 gene product to a human host in need of such treatment, wherein said non-steroidal compound is a compound of the formula I
Figure USRE038103-20030429-C00038
or a pharmaceutically acceptable salt thereof.
6. The method of claim 5, wherein the compound of formula I is administered at a dosage of from about 0.01 mg to about 140 mg per kilogram of body weight per day.
7. The method of claim 5, wherein the compound of formula I is administered in an amount from about 1 mg to about 1000 mg.
US09/827,508 1992-12-11 2001-04-06 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 Expired - Fee Related USRE38103E1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US98928692A true 1992-12-11 1992-12-11
US3339793A true 1993-03-19 1993-03-19
US08/147,804 US5604260A (en) 1992-12-11 1993-11-04 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
US09/827,508 USRE38103E1 (en) 1992-12-11 2001-04-06 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US09/827,508 USRE38103E1 (en) 1992-12-11 2001-04-06 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/147,804 Reissue US5604260A (en) 1992-12-11 1993-11-04 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2

Publications (1)

Publication Number Publication Date
USRE38103E1 true USRE38103E1 (en) 2003-04-29

Family

ID=27364391

Family Applications (2)

Application Number Title Priority Date Filing Date
US08/147,804 Expired - Lifetime US5604260A (en) 1992-12-11 1993-11-04 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
US09/827,508 Expired - Fee Related USRE38103E1 (en) 1992-12-11 2001-04-06 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US08/147,804 Expired - Lifetime US5604260A (en) 1992-12-11 1993-11-04 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2

Country Status (7)

Country Link
US (2) US5604260A (en)
EP (1) EP0673366B1 (en)
JP (1) JPH08504408A (en)
AU (1) AU5621594A (en)
CA (1) CA2151235A1 (en)
DE (2) DE69321604D1 (en)
WO (1) WO1994013635A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040131615A1 (en) * 2002-10-08 2004-07-08 Shelton David L. Methods for treating pain by administering a nerve growth factor antagonist and an opioid analgesic and compositions containing the same
US20040237124A1 (en) * 2002-12-24 2004-11-25 Jaume Pons Anti-NGF antibodies and methods using same
US20040253244A1 (en) * 2003-02-19 2004-12-16 Shelton David L. Methods for treating pain by administering a nerve growth factor antagonist and an NSAID and compositions containing the same
US20050265994A1 (en) * 2004-04-07 2005-12-01 Shelton David L Methods for treating bone cancer pain by administering a nerve growth factor antagonist
US20070160605A1 (en) * 2002-10-08 2007-07-12 Shelton David L Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist antibody
US7252822B2 (en) 2002-10-08 2007-08-07 Rinat Neuroscience Corp. Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist
US20080182978A1 (en) * 2002-12-24 2008-07-31 Rinat Neuroscience Corp Anti-ngf antibodies and methods using same
US20100004253A1 (en) * 2006-09-19 2010-01-07 Novartis Ag Biomarkers of target modulation, efficacy, diagnosis and/or prognosis for raf inhibitors
US20100111858A1 (en) * 2007-01-19 2010-05-06 Howard Carol P Diangostic and Therapeutic Cyclooxygenase-2 Binding Ligands

Families Citing this family (172)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840746A (en) * 1993-06-24 1998-11-24 Merck Frosst Canada, Inc. Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases
AU715676B2 (en) * 1993-03-12 2000-02-10 Merck Frosst Canada & Co. Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases
GB9420616D0 (en) * 1994-10-12 1994-11-30 Merck Sharp & Dohme Method, compositions and use
GB2294879A (en) * 1994-10-19 1996-05-15 Merck & Co Inc Cylcooxygenase-2 Inhibitors
US5968958A (en) * 1995-01-31 1999-10-19 Merck Frosst Canada, Inc. 5-Methanesulfonamido-3H-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2
US5571825A (en) * 1995-03-31 1996-11-05 Warner-Lambert Company Method of selectively inhibiting prostaglandin G/H synthase-2
US5643933A (en) * 1995-06-02 1997-07-01 G. D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6515014B2 (en) 1995-06-02 2003-02-04 G. D. Searle & Co. Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
WO1996038418A1 (en) 1995-06-02 1996-12-05 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US5700816A (en) * 1995-06-12 1997-12-23 Isakson; Peter C. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
WO1996041626A1 (en) * 1995-06-12 1996-12-27 G.D. Searle & Co. Compositions comprising a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
CA2224563A1 (en) 1995-06-12 1996-12-27 G.D. Searle & Co. Combination of a cyclooxygenase-2 inhibitor and a leukotriene b4 receptor antagonist for the treatment of inflammations
US6593361B2 (en) 1995-07-19 2003-07-15 Merck & Co Inc Method of treating colonic adenomas
US5968974A (en) * 1995-07-19 1999-10-19 Merck & Co., Inc. Method of treating colonic adenomas
AT196629T (en) * 1995-07-21 2000-10-15 Nycomed Austria Gmbh Derivatives of benzosulfonamiden as inhibitors of the enzyme cyclooxygenase II
DE19533643A1 (en) * 1995-09-12 1997-03-13 Nycomed Arzneimittel Gmbh New N-hetero-aryl alkane-sulphonamide derivs.
JPH09176038A (en) * 1995-09-18 1997-07-08 Hisamitsu Pharmaceut Co Inc Antiinflammatory antisense medicine
AU716582B2 (en) * 1995-10-17 2000-03-02 G.D. Searle & Co. Method of detecting cyclooxygenase-2
AT223732T (en) 1996-02-13 2002-09-15 Searle & Co Pharmaceutical compositions containing combinations with immunosuppressive effects which cyclooxygenase-2 inhibitors and leukotriene LTA4 anhydrase inhibitors
DE69709069D1 (en) 1996-02-13 2002-01-24 Searle & Co contain compositions with immunosuppressive effects which are 5-lipoxygenase inhibitors and cyclooxygenase-2 inhibitors
AT296114T (en) 1996-02-13 2005-06-15 Searle & Co Preparations comprising antagonists a cyclooxygenase-2 inhibitor and a leukotriene B4 receptor
AP1009A (en) 1996-04-12 2001-09-21 Searle & Co Substituted benzenesulfonamide derivatives as products of COX-2 inhibitors.
US5939069A (en) * 1996-08-23 1999-08-17 University Of Florida Materials and methods for detection and treatment of immune system dysfunctions
IT1288123B1 (en) * 1996-09-04 1998-09-10 Nicox Sa Use of nitrates for urinary incontinence
ES2308068T3 (en) 1996-10-15 2008-12-01 G.D. Searle Llc Use of cyclooxygenase-2 in the treatment and prevention of neoplasia.
US5681842A (en) * 1996-11-08 1997-10-28 Abbott Laboratories Prostaglandin synthase-2 inhibitors
US5985930A (en) * 1996-11-21 1999-11-16 Pasinetti; Giulio M. Treatment of neurodegenerative conditions with nimesulide
ATA16597A (en) * 1997-02-03 1998-04-15 Nycomed Austria Gmbh New substituted p-sulfonic acid amides sulfonylaminobenzol-
WO1998051667A1 (en) * 1997-05-16 1998-11-19 Chugai Seiyaku Kabushiki Kaisha Indole derivatives and mono- and diazaindole derivatives
ES2138902B1 (en) * 1997-05-19 2000-09-16 Salvat Lab Sa "5-arylthio-6-sulfonamido-3 (2h) -benzofuranonas as cox-2".
US6004950A (en) * 1997-09-12 1999-12-21 Merck Frosst Canada, Inc. 2-aminopyridines as inhibitors of cyclooxygenase-2
DE69829861T2 (en) * 1997-09-12 2006-03-02 Merck Frosst Canada & Co, Kirkland 2-aminopyridine as inhibitors of cyclooxygenase-2
RS49982B (en) 1997-09-17 2008-09-29 Euro-Celtique S.A., Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
US7041694B1 (en) 1997-12-17 2006-05-09 Cornell Research Foundation, Inc. Cyclooxygenase-2 inhibition
DK2266564T3 (en) 1997-12-22 2013-06-03 Euro Celtique Sa A pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
CA2314896C (en) * 1997-12-22 2005-09-13 Euro-Celtique, S.A. A method of preventing abuse of opioid dosage forms
NZ333399A (en) 1997-12-24 2000-05-26 Sankyo Co Cyclooxygenase-2 inhibitors (COX-2) for the prevention and treatment of tumors, cachexia and tumor-metastasis
US6677364B2 (en) 1998-04-20 2004-01-13 G.D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
JP2002520276A (en) * 1998-07-09 2002-07-09 ワーナー−ランバート・カンパニー Compositions for Pain Relief sinus headache comprising Gaba analogs and decongestants
US6512121B2 (en) 1998-09-14 2003-01-28 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6649645B1 (en) 1998-12-23 2003-11-18 Pharmacia Corporation Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia
WO2001021163A2 (en) * 1999-09-21 2001-03-29 Emory University Methods and compositions for treating platelet-related disorders using mpl pathway inhibitory agents
MXPA01008058A (en) * 1999-12-08 2004-04-05 Pharmacia Corp Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect.
IL150368D0 (en) * 1999-12-23 2002-12-01 Nitromed Inc Nitrosated and nitrosylated cyclooxygenase-2-inhibitors, compositions and methods of use
CA2400578C (en) 2000-02-08 2007-01-02 Euro-Celtique, S.A. Controlled-release compositions containing opioid agonist and antagonist
SI2092936T1 (en) 2000-02-08 2013-07-31 Euro-Celtique S.A. Tamper-resistant oral opioid agonist formulations
TR200001872A3 (en) 2000-06-26 2002-01-21 Fako Ilaclari A.S 4- [5- (4-Methylphenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide's new crystalline form designated "Form II" and methods relating to the production of these products.
EP1299123A2 (en) * 2000-07-13 2003-04-09 Pharmacia Corporation Use of cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
PE01462002A1 (en) * 2000-07-13 2002-03-31 Upjohn Co ophthalmic formulation comprising a cyclooxygenase-2 (cox-2)
WO2002007721A2 (en) 2000-07-20 2002-01-31 Lauras As Use of cox-2 inhibitors for preventing immunodeficiency
US6716829B2 (en) 2000-07-27 2004-04-06 Pharmacia Corporation Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
WO2002017896A2 (en) * 2000-08-29 2002-03-07 Peter Van Patten Combination for the treatment of migraine comprising a cyclooxygenase-2 inhibitor and acetylsalicylic acid
IL145209D0 (en) 2000-09-06 2002-06-30 Pfizer Prod Inc Pharmaceutical combinations for the treatment of stroke and traumatic brain injury
US7115565B2 (en) * 2001-01-18 2006-10-03 Pharmacia & Upjohn Company Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
MY137736A (en) 2001-04-03 2009-03-31 Pharmacia Corp Reconstitutable parenteral composition
ITMI20010733A1 (en) 2001-04-05 2002-10-07 Recordati Chem Pharm Use of cox-2 inhibitors dell'isoenzina for the treatment of urinary incontinence
US20030105144A1 (en) 2001-04-17 2003-06-05 Ping Gao Stabilized oral pharmaceutical composition
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
KR20120028993A (en) 2001-05-02 2012-03-23 유로-셀티크 소시에떼 아노뉨 Once-a-day oxycodone formulations
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
WO2003007802A2 (en) * 2001-07-18 2003-01-30 Euro-Celtique, S.A. Pharmaceutical combinations of oxycodone and naloxone
US20030044458A1 (en) * 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
EP1414451B1 (en) 2001-08-06 2009-05-20 Euro-Celtique S.A. Opioid agonist formulations with releasable and sequestered antagonist
US20030157168A1 (en) * 2001-08-06 2003-08-21 Christopher Breder Sequestered antagonist formulations
US20030108575A1 (en) * 2001-08-06 2003-06-12 Lu Guang Wei Stabilized oral suspension formulation
AR038957A1 (en) 2001-08-15 2005-02-02 Pharmacia Corp Combination therapy for the treatment of cancer
TWI334779B (en) 2002-04-05 2010-12-21 Euro Celtique Sa Pharmaceutical preparation containing oxycodone and naloxone
EP1495132B1 (en) 2002-04-17 2013-08-28 The Cleveland Clinic Foundation Systemic marker for monitoring anti-inflammatory and antioxidant actions of therapeutic agents
GT200300083A (en) * 2002-04-22 2004-03-29 Pfizer Selective inhibitors of cyclooxygenase-2
AU2003234407B2 (en) 2002-05-09 2008-12-18 The Brigham And Women's Hospital, Inc. 1L1RL-1 as a cardiovascular disease marker and therapeutic target
AU2003229016A1 (en) * 2002-05-10 2003-11-11 The Trustees Of Columbia University In The City Of New York Genetically engineered cell lines and systems for propagatingvaricella zoster virus and methods of use thereof
ITMI20021391A1 (en) 2002-06-25 2003-12-29 Nicox Sa Nitro-derivatives of cyclooxygenase-2 inhibitors
EP1539679A4 (en) * 2002-06-28 2007-07-04 Nitromed Inc Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxigenase-2 selective inhibitors, compositions and methods of use
EP2422775A3 (en) * 2002-09-20 2012-04-18 Alpharma, Inc. Sequestering subunit and related compositions and methods
FR2849849B1 (en) * 2003-01-13 2006-08-04 Merck Sante Sas New carboxylic acids and derivatives for the treatment and prevention of diabetes and dyslipaemias
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
MY135852A (en) 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
CA2536173A1 (en) * 2003-08-20 2005-03-03 Nitromed, Inc. Nitrosated and nitrosylated cardiovascular compounds, compositions and methods of use
EP2384753B1 (en) 2003-08-29 2016-01-06 The Brigham and Women's Hospital, Inc. Hydantoin derivatives as inhibitors of cellular necrosis
SI1663229T1 (en) 2003-09-25 2010-08-31 Euro Celtique Sa Pharmaceutical combinations of hydrocodone and naltrexone
WO2005044227A1 (en) * 2003-11-05 2005-05-19 Glenmark Pharmaceuticals Limited Topical pharmaceutical compositions
US20050100594A1 (en) * 2003-11-12 2005-05-12 Nilendu Sen Pharmaceutical formulation containing muscle relaxant and COX-II inhibitor
US7067159B2 (en) 2003-12-05 2006-06-27 New Chapter, Inc. Methods for treating prostate cancer with herbal compositions
US7070816B2 (en) 2003-12-05 2006-07-04 New Chapter, Inc. Methods for treating prostatic intraepithelial neoplasia with herbal compositions
AT546734T (en) 2003-12-05 2012-03-15 Cleveland Clinic Foundation Risk markers for cardiovascular disease
WO2005070006A2 (en) * 2004-01-22 2005-08-04 Nitromed, Inc. Nitrosated and/or nitrosylated compounds, compositions and methods of use
US7763341B2 (en) 2004-01-23 2010-07-27 Century-Board Usa, Llc Filled polymer composite and synthetic building material compositions
CA2904275A1 (en) 2004-05-23 2005-12-08 Gerard M. Housey Theramutein modulators
US8431110B2 (en) 2005-05-23 2013-04-30 Hmi Medical Innovations, Llc. Compounds and method of identifying, synthesizing, optimizing and profiling protein modulators
EP1604666A1 (en) * 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
RU2007103816A (en) 2004-07-01 2008-08-10 Мерк энд Ко., Инк. (US) Inhibitors of the mitotic kinesin
US7622142B2 (en) 2004-09-14 2009-11-24 New Chapter Inc. Methods for treating glioblastoma with herbal compositions
WO2006041855A2 (en) 2004-10-04 2006-04-20 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US9164104B2 (en) 2004-10-06 2015-10-20 The Brigham And Women's Hospital, Inc. Relevance of achieved levels of markers of systemic inflammation following treatment
EP1814535A4 (en) * 2004-11-08 2008-06-04 Nitromed Inc Nitrosated and nitrosylated compounds, compositions and methods for the treatment of ophthalmic disorders
WO2006078995A1 (en) * 2005-01-21 2006-07-27 Nitromed, Inc. Cardiovascular compounds comprising heterocyclic nitric oxide donor group compositions and methods of use
US20090042819A1 (en) * 2005-02-16 2009-02-12 Nitromed, Inc. Organic nitric oxide donor salts of antimicrobial compounds, compositions and methods of use
WO2006093864A1 (en) * 2005-02-28 2006-09-08 Nitromed, Inc. Cardiovascular compounds comprising nitric oxide enhancing groups, compositions and methods of use
EP1702558A1 (en) * 2005-02-28 2006-09-20 Euro-Celtique S.A. Method and device for the assessment of bowel function
JP2008533031A (en) * 2005-03-09 2008-08-21 ニトロメッド インコーポレーティッド Organic nitric oxide enhancing salt of an angiotensin ii antagonists, compositions and use
US8362075B2 (en) 2005-05-17 2013-01-29 Merck Sharp & Dohme Corp. Cyclohexyl sulphones for treatment of cancer
EP1883614A4 (en) * 2005-05-23 2010-04-14 Nicox Sa Organic nitric oxide enhancing salts of nonsteroidal antiinflammatory compounds, compositions and methods of use
WO2007016677A2 (en) 2005-08-02 2007-02-08 Nitromed, Inc. Nitric oxide enhancing antimicrobial compounds, compositions and methods of use
TW200804345A (en) * 2005-08-30 2008-01-16 Novartis Ag Substituted benzimidazoles and methods of preparation
WO2007041681A2 (en) * 2005-10-04 2007-04-12 Nitromed, Inc. Methods for treating respiratory disorders
US8119358B2 (en) * 2005-10-11 2012-02-21 Tethys Bioscience, Inc. Diabetes-related biomarkers and methods of use thereof
WO2008131224A2 (en) 2007-04-18 2008-10-30 Tethys Bioscience, Inc. Diabetes-related biomarkers and methods of use thereof
WO2007059311A2 (en) * 2005-11-16 2007-05-24 Nitromed, Inc. Furoxan compounds, compositions and methods of use
US20090053328A1 (en) * 2005-12-20 2009-02-26 Nitromed, Inc. Nitric Oxide Enhancing Glutamic Acid Compounds, Compositions and Methods of Use
EP1971340A2 (en) * 2005-12-22 2008-09-24 Nitromed, Inc. Nitric oxide enhancing pyruvate compounds, compositions and methods of use
EP1978964A4 (en) 2006-01-24 2009-12-09 Merck & Co Inc Jak2 tyrosine kinase inhibition
GB0603041D0 (en) 2006-02-15 2006-03-29 Angeletti P Ist Richerche Bio Therapeutic compounds
WO2007109056A2 (en) 2006-03-15 2007-09-27 The Brigham And Women's Hospital, Inc. Use of gelsolin to diagnose and treat inflammatory diseases
WO2007126609A1 (en) * 2006-03-29 2007-11-08 Nitromed, Inc. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
SMP200800063B (en) 2006-04-19 2009-11-06 Novartis Ag benzazolici compounds and benzothiazole -6-0-substituted and inhibition methods of the cfs-1r signal
US20080057590A1 (en) 2006-06-07 2008-03-06 Mickey Urdea Markers associated with arteriovascular events and methods of use thereof
PL2484346T3 (en) * 2006-06-19 2017-07-31 Alpharma Pharmaceuticals Llc Pharmaceutical compositions
US8173629B2 (en) 2006-09-22 2012-05-08 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
EP2805945B1 (en) 2007-01-10 2019-04-03 MSD Italia S.r.l. Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors
JP5330274B2 (en) 2007-03-01 2013-10-30 ノバルティス アーゲー Pim kinase inhibitors and methods of use thereof
EP2152700B1 (en) 2007-05-21 2013-12-11 Novartis AG Csf-1r inhibitors, compositions, and methods of use
EP3103791B1 (en) 2007-06-27 2018-01-31 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2009035818A1 (en) 2007-09-10 2009-03-19 Calcimedica, Inc. Compounds that modulate intracellular calcium
EP2224808A4 (en) * 2007-12-17 2013-11-27 Alpharma Pharmaceuticals Llc Pharmaceutical composition
US8623418B2 (en) * 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
KR20100126467A (en) 2008-03-03 2010-12-01 타이거 파마테크 Tyrosine kinase inhibitors
GB2462022B (en) * 2008-06-16 2011-05-25 Biovascular Inc Controlled release compositions of agents that reduce circulating levels of platelets and methods thereof
PE04222011A1 (en) * 2008-07-07 2011-07-01 Euro Celtique Sa pharmaceutical composition comprising opioid antagonists
EP2321303A4 (en) 2008-08-27 2011-11-16 Calcimedica Inc Compounds that modulate intracellular calcium
US20100151014A1 (en) * 2008-12-16 2010-06-17 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
WO2010071865A1 (en) 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Pharmaceutical compositions and methods for treating hyperuricemia and related disorders
WO2011032175A1 (en) 2009-09-14 2011-03-17 Nuon Therapeutics, Inc. Combination formulations of tranilast and allopurinol and methods related thereto
US20100160351A1 (en) * 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Pharmaceutical compositions and methods for treating hyperuricemia and related disorders
WO2010103039A1 (en) 2009-03-10 2010-09-16 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
JP2013518618A (en) 2010-02-01 2013-05-23 ザ・ホスピタル・フォー・シック・チルドレンThe Hospital For Sick Children Remote ischemic conditioning for the treatment and prevention of restenosis
PT2563776T (en) 2010-04-27 2016-09-19 Calcimedica Inc Compounds that modulate intracellular calcium
US8518907B2 (en) 2010-08-02 2013-08-27 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (siNA)
RU2624045C2 (en) 2010-08-17 2017-06-30 Сирна Терапьютикс,Инк RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
AU2011291462A1 (en) 2010-08-19 2013-03-14 Zoetis Belgium S.A. Anti-NGF antibodies and their use
EP2608669B1 (en) 2010-08-23 2016-06-22 Merck Sharp & Dohme Corp. NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS
WO2012030685A2 (en) 2010-09-01 2012-03-08 Schering Corporation Indazole derivatives useful as erk inhibitors
US9242981B2 (en) 2010-09-16 2016-01-26 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel ERK inhibitors
EP3327125A1 (en) 2010-10-29 2018-05-30 Sirna Therapeutics, Inc. Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina)
EP2654748B1 (en) 2010-12-21 2016-07-27 Merck Sharp & Dohme Corp. Indazole derivatives useful as erk inhibitors
UA114887C2 (en) 2010-12-22 2017-08-28 Пюрдю Фарма Л.П. Encased tamper resistant controlled release dosage forms
NZ612996A (en) 2010-12-23 2015-05-29 Purdue Pharma Lp Tamper resistant solid oral dosage forms
WO2012145471A1 (en) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Insulin-like growth factor-1 receptor inhibitors
CA2836649A1 (en) 2011-05-20 2012-11-29 Alderbio Holdings Llc Anti-cgrp compositions and use thereof
EP2770987B1 (en) 2011-10-27 2018-04-04 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
WO2013066729A1 (en) 2011-10-31 2013-05-10 Merck Sharp & Dohme Corp. Aminopyrimidinones as interleukin receptor-associated kinase inhibitors
EP3453762A1 (en) 2012-05-02 2019-03-13 Sirna Therapeutics, Inc. Short interfering nucleic acid (sina) compositions
MX2014013760A (en) 2012-05-11 2015-08-05 Reset Therapeutics Inc Carbazole-containing sulfonamides as cryptochrome modulators.
US9617334B2 (en) 2012-06-06 2017-04-11 Zoetis Services Llc Caninized anti-NGF antibodies and methods thereof
WO2014052563A2 (en) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
KR20150088257A (en) 2012-11-28 2015-07-31 머크 샤프 앤드 돔 코포레이션 Compositions and methods for treating cancer
JP6387013B2 (en) 2012-12-20 2018-09-12 メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. Substituted imidazopyridines as HDM2 inhibitors
WO2014120748A1 (en) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as hdm2 inhibitors
JP6208261B2 (en) 2013-02-05 2017-10-04 パーデュー、ファーマ、リミテッド、パートナーシップPurdue Pharma L.P. Tampering resistant pharmaceutical preparations
US20140271896A1 (en) 2013-03-15 2014-09-18 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
WO2015006181A1 (en) 2013-07-11 2015-01-15 Merck Sharp & Dohme Corp. Substituted amidopyrazole inhibitors of interleukin receptor-associated kinases (irak-4)
JP2016525138A (en) 2013-07-23 2016-08-22 ユーロ−セルティーク エス.エイ. The combination of oxycodone and naloxone for use in the treatment of pain in patients suffering from diseases increase the risk for diseases and / or Enterobacteriaceae migration results in pain and intestinal Disconnect bio cis
WO2015034925A1 (en) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Circular polynucleotides
WO2015054283A1 (en) 2013-10-08 2015-04-16 Calcimedica, Inc. Compounds that modulate intracellular calcium
TW201605835A (en) 2014-04-07 2016-02-16 Reset Therapeutics Inc Carbazole-containing amides, carbamates, and ureas as cryptochrome modulators
JP2017523215A (en) 2014-08-06 2017-08-17 ノバルティス アーゲー Protein kinase c inhibitors and methods of use thereof
EP3292213A1 (en) 2015-05-04 2018-03-14 Academisch Medisch Centrum Biomarkers for the detection of aspirin insensitivity

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2646385A (en) * 1951-06-01 1953-07-21 Mozes J Lewenstein Pharmaceutical product for dysmenorrhea
US3010873A (en) * 1956-10-03 1961-11-28 Maggioni & C Spa alpha-[(p-chlorophenyl)-alpha-phenyl]-4-pyridyl carbinol as a potentiating agent
US3121044A (en) * 1960-10-06 1964-02-11 Beecham Res Lab Three-layer compressed penicillin tablet
US3128226A (en) * 1962-08-22 1964-04-07 Hoffmann La Roche Composition for relieving pain
US3439009A (en) * 1968-08-02 1969-04-15 Grace W R & Co Preparation of olefin metal complexes
US3840597A (en) * 1971-02-24 1974-10-08 Riker Laboratories Inc Substituted 2-phenoxy alkane-sulfonanilides
US4244960A (en) * 1978-07-27 1981-01-13 Schering, Aktiengesellschaft Indanyl derivatives and their use
US4375479A (en) * 1981-01-27 1983-03-01 Schering Aktiengesellschaft Indanyl derivatives and use
US4820827A (en) * 1982-03-03 1989-04-11 E. I. Du Pont De Nemours And Company 2,3-diaryl-5-bromothiophene compounds of use for the treatment of inflammaton and dysmenorrhea
US4866091A (en) * 1986-12-31 1989-09-12 Fujisawa Pharmaceutical Co., Ltd. Alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same
US4885367A (en) * 1987-11-19 1989-12-05 Taisho Pharmaceutical Co., Ltd. Sulfonanilide compounds
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3439094A (en) * 1967-07-20 1969-04-15 Warner Lambert Pharmaceutical Analgesic compositions containing namol xenyrate,caffeine and acetyl-rho-aminophenol
DE3442817A1 (en) * 1984-11-23 1986-05-28 Boehringer Mannheim Gmbh and reagent whole blood method for the quantitative determination of free thyroxine in plasma, serum or
JP2893903B2 (en) * 1990-09-12 1999-05-24 藤沢薬品工業株式会社 Ischemia - reperfusion injury prevention, treatment agents

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2646385A (en) * 1951-06-01 1953-07-21 Mozes J Lewenstein Pharmaceutical product for dysmenorrhea
US3010873A (en) * 1956-10-03 1961-11-28 Maggioni & C Spa alpha-[(p-chlorophenyl)-alpha-phenyl]-4-pyridyl carbinol as a potentiating agent
US3121044A (en) * 1960-10-06 1964-02-11 Beecham Res Lab Three-layer compressed penicillin tablet
US3128226A (en) * 1962-08-22 1964-04-07 Hoffmann La Roche Composition for relieving pain
US3439009A (en) * 1968-08-02 1969-04-15 Grace W R & Co Preparation of olefin metal complexes
US3840597A (en) * 1971-02-24 1974-10-08 Riker Laboratories Inc Substituted 2-phenoxy alkane-sulfonanilides
US4244960A (en) * 1978-07-27 1981-01-13 Schering, Aktiengesellschaft Indanyl derivatives and their use
US4375479A (en) * 1981-01-27 1983-03-01 Schering Aktiengesellschaft Indanyl derivatives and use
US4820827A (en) * 1982-03-03 1989-04-11 E. I. Du Pont De Nemours And Company 2,3-diaryl-5-bromothiophene compounds of use for the treatment of inflammaton and dysmenorrhea
US4866091A (en) * 1986-12-31 1989-09-12 Fujisawa Pharmaceutical Co., Ltd. Alkanesulfonanilide derivatives, processes for preparation thereof and pharmaceutical composition comprising the same
US4885367A (en) * 1987-11-19 1989-12-05 Taisho Pharmaceutical Co., Ltd. Sulfonanilide compounds
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Boyce et al. Nueropharmacology. 1994. vol. 33, No. 12, pp. 1609-1611.* *
Chem Abstracts. 1983. vol. 100, No. 1, AB #6113u.* *
Chem Abstracts. 1985. vol. 104, AB #107904r.* *
Chem Abstracts. 1987. vol. 106, AB #60922u.* *
Chem Abstracts. 1989. vol. 110, AB #128249v.* *
Chem Abstracts. 1990. vol. 113, AB #224303r.* *
D.P. Carr, et al., Agents and Actions, vol. 19, 5/6 (1986) pp. 374-375, "Comparison of the systemic inhibition of thromboxane synthesis, anti-inflammatory activity and gastro-intestinal toxicity . . .".* *
Gans et al. Journal of Pharm. and Experim. Ther., 1990. vol. 254, No. 1, pp. 180-187.* *
Hla et al. Proceedings of the National Academy of Sciences, USA. 1992. vol. 89, pp. 7384-7388.* *
Lombardino et al. Arzneim.-Forsch. (Drug Res.) 1975. vol. 25, No. 10, pp. 1629-1635.* *
Lombardino. Nonsteroidal Antiinflammatory Drugs. 1985. pp. 114-130.* *
National Meeting of the American Chemical Society, Washington, D.C., USA, Aug. 21-25, 1994. Abstracts of Papers American Chemical Society. 208 (1-2), 1994 MEDI 116, ISSN: 0065-7727.* *
National Meeting of the American Chemical Society, Washington, D.C., USA, Aug. 21-25, 1994. Abstracts of Papers American Chemical Society. 208 (1-2), 1994 MEDI 272, ISSN: 0065-7727.* *
Rufer et al. European Journal of Med. Chem. Chim. Ther. 1982. vol. 17, pp. 173-180. *
Wisenberg-Bottcher et al. Agents and Actions. 1989. vol. 26, pp. 240-242.* *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040131615A1 (en) * 2002-10-08 2004-07-08 Shelton David L. Methods for treating pain by administering a nerve growth factor antagonist and an opioid analgesic and compositions containing the same
US20070160605A1 (en) * 2002-10-08 2007-07-12 Shelton David L Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist antibody
US7252822B2 (en) 2002-10-08 2007-08-07 Rinat Neuroscience Corp. Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist
US7255860B2 (en) 2002-10-08 2007-08-14 Rinat Neuroscience Corp. Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist antibody
US20040237124A1 (en) * 2002-12-24 2004-11-25 Jaume Pons Anti-NGF antibodies and methods using same
US8088384B2 (en) 2002-12-24 2012-01-03 Rinat Neuroscience Corp. Anti-NGF antibodies and methods using same
US7655232B2 (en) 2002-12-24 2010-02-02 Pfizer Inc. Anti-NGF antibodies and methods using same
US20070212357A1 (en) * 2002-12-24 2007-09-13 Jaume Pons Anti-NGF antibodies and methods using same
US7569364B2 (en) 2002-12-24 2009-08-04 Pfizer Inc. Anti-NGF antibodies and methods using same
US20080182978A1 (en) * 2002-12-24 2008-07-31 Rinat Neuroscience Corp Anti-ngf antibodies and methods using same
US7449616B2 (en) 2002-12-24 2008-11-11 Pfizer Inc. Anti-NGF antibodies and methods using same
US8034346B2 (en) 2003-02-19 2011-10-11 Rinat Neuroscience Corp. Methods for treating pain by administering a nerve growth factor antagonist and an NSAID and compositions containing the same
US20040253244A1 (en) * 2003-02-19 2004-12-16 Shelton David L. Methods for treating pain by administering a nerve growth factor antagonist and an NSAID and compositions containing the same
US7655231B2 (en) 2003-02-19 2010-02-02 Pfizer Inc. Methods for treating pain by administering a nerve growth factor antagonist and an NSAID
US7425329B2 (en) 2004-04-07 2008-09-16 Rinat Neuroscience Corp. Methods for treating bone cancer pain by administering a nerve growth factor antagonist
US20080081040A1 (en) * 2004-04-07 2008-04-03 Shelton David L Methods for treating bone cancer pain by administering a nerve growth factor antagonist
US20050265994A1 (en) * 2004-04-07 2005-12-01 Shelton David L Methods for treating bone cancer pain by administering a nerve growth factor antagonist
US8007800B2 (en) 2004-04-07 2011-08-30 Pfizer Inc. Methods for treating bone cancer pain by administering a nerve growth factor antagonist antibody
US20090252744A1 (en) * 2004-04-07 2009-10-08 Pfizer Inc. Methods for Treating Bone Cancer Pain by Administering A Nerve Growth Factor Antagonist antibody
US8226951B2 (en) 2004-04-07 2012-07-24 Pfizer Inc. Methods for treating bone cancer by administering a nerve growth factor antagonist antibody
US20100004253A1 (en) * 2006-09-19 2010-01-07 Novartis Ag Biomarkers of target modulation, efficacy, diagnosis and/or prognosis for raf inhibitors
US20100111858A1 (en) * 2007-01-19 2010-05-06 Howard Carol P Diangostic and Therapeutic Cyclooxygenase-2 Binding Ligands

Also Published As

Publication number Publication date
JPH08504408A (en) 1996-05-14
DE69321604D1 (en) 1998-11-19
DE69321604T2 (en) 1999-05-20
CA2151235A1 (en) 1994-06-23
EP0673366B1 (en) 1998-10-14
AU5621594A (en) 1994-07-04
US5604260A (en) 1997-02-18
EP0673366A1 (en) 1995-09-27
WO1994013635A1 (en) 1994-06-23

Similar Documents

Publication Publication Date Title
US3385886A (en) Phenyl propionic acids
US6291523B1 (en) Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives
KR101025226B1 (en) Novel curcumin analogues and uses thereof
CN1181825C (en) Use of colchinol derivatives in preparation of vascular damaging agents drug
AU2005226359B2 (en) 9-substituted 8-oxoadenine compound
RU2288220C2 (en) Derivatives of tetralone as antitumor agents and pharmaceutical composition based on thereof
KR0148680B1 (en) Method for treatment of endotoxic shock in a mammal
US5639780A (en) N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors
ES2205242T3 (en) Pyridines as inhibitors of cyclooxygenase-SELECTIVE 2`.
JP3231042B2 (en) 2-nitrate esters derivatives of (2,6-di - - halo phenyl amino) phenylacetic acid and their preparation
KR100382619B1 (en) 2,3-Diaryl-Pyrazolo[1,5-B]Pyridazines Derivatives, Their Preparation and Their Use As Cyclooxygenase 2(COX-2) Inhibitors
US4568693A (en) N-Naphthoylglycine derivatives
US20030007958A1 (en) Paste formulations
ES2309451T3 (en) Derivatives nitric esters of COX2 inhibitors their use for treating inflammation and cardiovascular diseases.
US5612377A (en) Method of inhibiting leukotriene biosynthesis
US4755524A (en) Novel phenolic thioethers as inhibitors of 5-lipoxygenase
US4323581A (en) Method of treating carcinogenesis
KR100412971B1 (en) Substituted 4-biarylbutyric or 5-biarylpentanoic acids and derivatives as matrix metalloprotease inhibitors
FI108792B (en) Process for the preparation of novel, therapeutically useful furanonijohdannaisten
FI112222B (en) Process for the preparation of novel, therapeutically useful furanonijohdannaisten
JP2512751B2 (en) Pharmacologically active 1,5-diaryl --3-substituted - pyrazole - Le acids and methods of producing them
CN1103332C (en) Biphenyl-5-alkanoic acid derivative and is application
CN1100056C (en) Compound for inhibition of gastric acid secretion
CA2157107C (en) Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
EP1119542A1 (en) Prostaglandin receptor ligands

Legal Events

Date Code Title Description
REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees