WO2007129169A2 - Cox- ii inhibitors for improving reproductive success in a female animal - Google Patents

Abstract

Inhibitors of COX-II are useful for improving reproductive success in female animals.

Description

Veterinary Method and Composition

The present invention relates to a method for improving animal reproduction. In particular it relates to the use of cyclooxygenase-ll (COX-II) inhibitors for improving the success rate of insemination, and especially artificial insemination, in animals susceptible to sub-clinical endometritis.

Background

Dairy production has become a highly intensified and medicalised process in many countries (incl. US, Japan and EU). This trend has been accompanied by a constant decrease in fertility. In the US and Japan dairy cows have nowadays an average conception rate of only 35-40% as compared to 60% in the 1980's. This loss of overall fertility represents a high cost to the farmer [Ferguson ef ai, 1999].

The general concept of reproduction management is the induction of pregnancy in cows at a biologically optimal time and at an economically profitable interval after calving [Sheldon ef a/., 2006]. However, uterine disease is associated with lower conception rates, increased intervals from calving to first service or conception, and more cattle culled for failure to conceive [Sheldon et al., 2006].

Among the known uterine diseases, endometritis, or inflammation of the endometrium, is a potential cause of reduced fertility. Two distinct forms of endometritis have been described.

The clinically visible form of this disease - "clinical endometritis" - is usually described as an infection of the uterus occurring at parturition or mating, which results in more or less severe clinical signs such as purulent discharge and other classical symptoms of inflammation [Sheldon et ai., 2006]. This disease has been known for centuries and various treatment options such as antibiotics and prostaglandins are available.

In contrast, subclinical endometritis can be defined as an endometrial inflammation of the uterus usually determined by cytology, in the absence of purulent material in the vagina [first described Gilbert ef a/., 1998, definition by Sheldon ef a/., 2006]. This subclinical disease is diagnosed in animals without signs of clinical endometritis by measuring the number of neutrophils in a tissue sample collected by a non-invasive method (principally with a cytobrush). This diagnosis can eventually be completed by establishing the presence of fluid in the uterine lumen with an ultrasonographic examination [Kasimanickam et a/., 2004]. Currently no treatment is available to cure subclinical endometritis and restore endometrial health to a normal level.

Several independent research groups in North America and Europe have demonstrated subclinical endometritis to be highly prevalent in dairy cows. This condition is associated with impaired conception and increased culling rates [Gilbert et a/., 1998 and 2005, Kasimanickam et a/., 2005, Linke et a/., 2005].

There is a continuing interest in developing pharmaceutical methods .for improving reproductive efficiency in dairy cattle. The present invention relates to pharmaceutical intervention with inhibitors of cyclooxygenase (COX).

Cyclooxygenase is an enzyme that is involved in the biosynthesis of prostaglandins. Two subtypes have been identified: cyclooxygenase-l (COX-I) and cyclooxygenase-ll (COX-II). COX-I is widely expressed in healthy animals. COX-II is generally considered to be expressed only in animals with inflammatory conditions. Inhibitors of COX-I and COX-II are known, and are alternatively known as non-steroidal anti-inflammatory drugs (NSAIDs).

Published International Patent Application WO94/15613 describes the use of COX inhibitors for enhancing uterine blood flow resulting in better embryo implantation. The discussion focuses on the application of the method to human reproduction, and particularly to improving reproductive success in healthy humans. Aspirin is the only COX inhibitor used in the examples, and there is no discussion of the role of the different COX subtypes in bringing about the claimed effects. However, there are intrinsic differences between human and bovine uterine and ovarian physiology. The intensive and regular breeding of cattle also means that findings related- to human reproductive health cannot necessarily be extrapolated to bovine reproductive health. Moreover, aspirin has a particular mechanism of action among NSAIDs (irreversible binding to platelet COX-I), and is selective for COX-I.

A study where ibuprofen was administered at 5 mg/kg BW intramuscularly one hour before embryo transfer has shown a significant increase in pregnancy rate in the treated animals compared to the placebo [EIIi et a/., 2001]. However, all the cattle included in this study were naϊve cows (heifers) at their first service and were thus free of any adverse inflammatory condition of the endometrium. Furthermore, these animals were synchronised before a high quality fertilised egg was transferred into the lumen on day 7 of the oestrus cycle, hence creating experimental conditions completely different from natural or artificial insemination in pluripartum cows.

Flunixin, an NSAID with both COX-I and COX-II activity, has been intensively studied for its effect on ovarian cycle and embryo implantation in the cow. It was not shown to be effective in the treatment of certain endometrial diseases (retained placenta and post-partal endometritis) when administered at 2.2 mg/kg BW per os twice daily [Konigsson et al., 2001]. After Intramuscular administration of 2.2 mg/kg BW Flunixine 2 to 4 times a day for 10 days to cows subjected to an asynchronous embryo transfer, embryos survive initially when transferred to the advanced uterus (3 days later than the optimal transfer date), but are unable to implant despite the inhibition of luteolysis and prolongation of the oestrous cycle by flunixin [Odensvik et al., 1994]. In another study, intensive Intramuscular treatment with Flunixin did not modify the involution pattern of the uterus in post-partum cows [Odensvik et al., 1993].

The results of these studfes demonstrate that, in cows, intramuscularly or orally administered Flunixin impacts prostaglandin production and luteolysis without effecting embryo implantation or endometrial health.

This research with fiunixin in dairy cattle is also in the line with speculations of Thun et al. [1989], where carprofen is proposed as a candidate therapeutic agent for use in bovine endometrial disease and/or mastitis. This anticipated potential therapeutic benefice is clearly directed to the early postpartum cow and hence to the treatment of clinical endometritis (see definitions above and Sheldon et al., [2006])

Overall, the influence of cyclooxygenase inhibitors on fertility is controversial. Where a limited number of publications describe a potentially beneficial effect [EIIi et al., 2001], other publications suggest that intensive treatment with COX inhibitors has a negative impact on pre and post implantation losses in rodent models [Shafiq et al., 2004, Sookvanichsilp et al., 2002].

References

EIIi M, Gaffuri B, Frigerio A, Zanardelli M, Covini D, Candiani M, Vignali M.: Effect of a single dose of ibuprofen lysinate before embryo transfer on pregnancy rates in cows. Reproduction, 2001, 121(1):151-4. Ferguson JD, Galligan DT: Veterinary reproductive programs. Proceedings of the Thirty- Second Annual Conference American Association of Bovine Practitioners, Nashville Tennessee USA, 23-26 September 1999, p. 131-137.

Gilbert RO, Shin ST, Guard CL, Erb HN Incidence of endometritis and effects on reproductive performance of dairy cows. Theriogenology, 1998, 49(1): 251.

Gilbert RO, Shin ST, Guard CL, Erb HN, Frajblat M.: Prevalence of endometritis and its effects on reproductive performance of dairy cows. Theriogenology, 2005, 64: 1879-1888.

Kasimanickam, R.; Duffield, T. F.; Foster, R. A.; Gartley, C. J.; Leslie, K. E.; Walton, J. S.; Johnson, W. H.: Endometrial cytology and ultrasonography for the detection of subclinical endometritis in postpartum dairy cows. Theriogenology, 2004, 62(1/2)9-23.

Kasimanickam R, Comwell JM, Nebel RL: Effect of presence of clinical and subclinical endometritis at the initiation of Presynch-Ovsynch program on the first service pregnancy in dairy cows. Anim Reprod Sci, 2005 Nov 16; [Epub ahead of print].

Konigsson K, Gustafsson H, Gunnarsson A, Kindahl H: Clinical and bacteriological aspects on the use of oxytetracycline and flunixin in primiparous cows with induced retained placenta and post-partal endometritis. Reprod Domest Anim., 2001 , 36(5): 247-56.

Lincke A, Kersting S, Drillich M et al.: Treatment of subclinical endometritis in dairy cows with proteolytic enzymes or prostaglandin F2alpha and its effect on reproductive performance. 6th Middle European Buiatrics congress, Krakau/Polen, 2005

Odensvik K, Gustafsson H: Effect of flunixin during asynchronous embryo transfer in the heifer. Animal Reproduction Science, 1994, 36(1-2): 13-24.

Odensvik K. Fredriksson G: The effect of intensive flunixin treatment during the postpartum period in the bovine. Journal of Veterinary Medicine Serie A, 1993, 40(8):561-8.

Shafiq N, Malhotra S, Pandhi P: Comparison of nonselective cyclo-oxygenase (COX) inhibitor and selective COX-2 inhibitors on preimplantation loss, postimplantation loss and duration of gestation: an experimental study. Contraception, 2004, 69(1): 71-75.

Sheldon IM, Lewis GS, Leblanc S, Gilbert RO: Defining postpartum uterine disease in cattle. Theriogenology. 2006, 65(8): 1516-1530.

Sookvanichsilp N, Pulbutr P: Anti-implantation effects of indomethacin and celecoxib in rats. Contraception, 2002, 65(5):373-8. Thun R, Eggenberger E, Zerobin K₁ Rehm WF, Ludwig B.: Carprofen in veterinary medicine. II. Inhibitory effect on the release of PGF2 alpha in the early postpartum cow. SchweizArch Tierheilkd, 1989,131(4):205-12.

We have now found that COX-II inhibitors can be used to improve the fertility of animals with, or susceptible to, sub-clinical endometritis.

Summary of the Invention

In a first aspect, the present invention provides a method for improving reproductive success in a female animal comprising administering a COX-II inhibitor to the female animal.

In another aspect, the present invention provides for a method of prophylactic, palliative or curative treatment of sub-clinical endometritis in a cow in the second or higher lactation comprising the administration to the cow of an effective amount of a COX-II inhibitor.

In a further aspect, the present invention provides for the use of a COX-II inhibitor for the preparation of a medicament for improving reproductive success in a female animal.

Detailed Description of the Invention

The method of the present invention is applicable to mammals in general, including human and non-human mammals. In a preferred embodiment the method is applicable to non- human mammals, including domesticated and non-domesticated mammals. Domesticated mammals include livestock mammals, such as cattle, pigs and sheep, and companion mammals, such as cats, dogs and horses. Non-domesticated mammals include mammals in zoological and other collections, and particularly rare and endangered species in captive . breeding programs. The method is more preferably applicable to livestock mammals, especially cattle, and most preferably to dairy cows in the second or higher lactation.

The method of the present invention is not intended to be limited to any particular method of insemination. Accordingly, in the case of cattle, the success rate of impregnation by a bull may be improved by treatment with a COX-II inhibitor. Equally, the success rate of artificial insemination may also be improved by such treatment.

Any COX-II inhibitor may be suitable for use in the present invention. ^■ Many such compounds have been described, and the person skilled in the art will understand the test methods by which further suitable inhibitors may be identified. For example, published International Patent Application WO 2003/037874 describes assays for the determination of inhibitory activity against human and canine COX-II. The method may be adapted for use with the bovine enzyme.

It will be understood that, when the teaching of the present invention is applied to animals other than cattle, references to the bovine COX-II enzyme should be read as references to the enzyme as found in that other species.

Inhibitory activity is generally characterized by a parameter such as an IC₅₀ or a Kj. COX-Il inhibitors of particular value in the context of the present invention are those with an IC₅₀ of no more than 100μM against bovine COX-II. More preferred are those inhibitors with an IC₅O of no more than 50μM. Yet more preferred are those inhibitors with an IC₅₀ of no more than 25μM, particularly no more than 10μM, more particularly no more than 5μM, and most particularly no more than 1μM.

In one aspect, the COX-II inhibitor is a selective COX-II inhibitor. Selectivity in this context means selectivity for COX-II over COX-I. Selectivity can be characterized as the ratio of the IC₅₀ for COX-I to the IC₅₀ for COX-II. Thus a compound that has an IC₅₀ of 50μM for COX-I and 10μM for COX-II has a selectivity of 5:1 for COX-II over COX-I.

Preferred COX-II inhibitors have a selectivity for COX-II over COX-I of at least 1:1, more preferably at least 2:1 , yet more preferably at least 5:1 , and most preferably at least 10:1.

Published international patent application WO2005/084654 discusses a number of genera that are COX-II inhibitors. These genera are equally suitable as COX-II inhibitors for use in the present invention.

Examples of COX-II inhibitors for use for the invention are:

Aceclofenac ([({2-[(2,6-dichlorophenyl)amino]phenyl}acetyl)oxy]acetic acid) and other compounds and other compounds disclosed in EP-119932 and US-4548952; Ampiroxicam (ethyl 1-({2-methyl-1 ,1-dioxido-3-[(pyridin-2-ylamino)carbonyl]-2H-1 ,2- benzothiazin-4-yl}oxy)ethyl carbonate) and other compounds and other compounds disclosed in EP-147177 and US-4551452; Amtolmetin guacil (3-methoxyphenyl N-{[1-methyl-5-(4-methyIbenzoyl)-1H-pyrrol-2- yl]acetyl}glycinate) and other compounds and other compounds disclosed in GB-

2115417 and US-4578481 ; AU-8001 (4-(acetylamino)phenyl [5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetate) and other compounds and other compounds disclosed in Arzneimittel-Forschung (1983),

33(6), 831-3. ; Bermoprofen (2-(8-methyl-11-oxo-10,11-dihydrodibenzo[b,f]oxepin-2-yl)propanoic acid) and other compounds disclosed in EP-3893 and US-4238620; BF-389 ((4Z)-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-1 ,2-oxazinan-3-one) and other compounds disclosed in Agents and Actions (1992), 37(1-2), 90-8. ; Bromfenac ([2-amino-4-(4-bromobenzoyl)phenyl]acetic acid) and other compounds disclosed in Agents and actions (1988), 25(1-2), 77-85. ; Butibufen (2-(4-iso-butylphenyl)butanoic acid) and other compounds disclosed in GB-

1528956; Cinnoxicam (2-methyl-1 ,1-dioxido-3-[(pyridin-2-ylamino)carbonyl]-2H-1 ,2-benzothiazin-4-yl

(2E)-3-phenylacrylate) and other compounds disclosed in EP-79639 and US-

4461768; Dexketoprofen ((2S)-2-(3-benzoylphenyl)propanoic acid) and other compounds disclosed in

GB-1164585 and US-3641127; Diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid) and other compounds disclosed in US-3558690 and GB-1132318; Droxicam (5-methyl-3-pyridin-3-yl-2H,5H-[1 ,3]oxazino[5,6-c][1 ,2]benzothiazine-2,4(3H)-dione

6,6-dioxide) and other compounds disclosed in EP-99770 and US-4563452; DuP-697 (4-[5-bromo-2-(4-fluorophenyl)-3-thienyl]phenyl methyl sulfone) and other compounds disclosed in EP-87629 and US-4590205; E-5110 ((3E)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-1-methoxypyrrolidin-2-one) and other compounds disclosed in EP-204964 and US-4833160; Eltenac ({4-[(2,6-dichlorophenyl)amino]-3-thienyl}acetic acid) and other compounds disclosed in EP-5559 and US-4272507; Fenclozic acid ([2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]acetic acid) and other compounds disclosed in US-3538107; Flobufen (4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid) and other compounds disclosed in EP-180290 and US-4683331; Flurbiprofen (2-(2-fluorobiphenyl-4-yl)propanoic acid) and other compounds disclosed in NL-

6500865; FPL-62064 (N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine) and other compounds disclosed in EP-178035 and US-4810719; lndobufen (2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanoic acid) and other compounds disclosed in GB-1344663; Ketoprofen (2-(3-benzoylphenyl)propanoic acid) and other compounds disclosed in GB-

1164585 and US-3641127; Ketorolac (5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid) and other compounds disclosed in US-4089969; Licofelone ([6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) and other compounds disclosed in Drugs of the Future 1995, 20 (10), 1007-

1009; Lomoxicam (6-chloro-4-hydroxy-2-methyl-N-pyridin-2-yl-2H-thieno[3,2-e][1,2]thiazine-3- carboxamide 1,1-dioxide) and other compounds disclosed in EP-1113 and US- • 4180662; Mofezolac ([3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetic acid) and other compounds disclosed in EP-26928 and US-4327222; Nepafenac (2-(2-amino-3-benzoylphenyl)acetamide) and other compounds disclosed in GB-

2059963 and US-4313949; Orpanoxin (3-[5-(4-chlorophenyl)-2-furyl]-3-hydroxypropanoic acid) and other compounds disclosed in US-3962284; Oxindanac (5-benzoyl-6-hydroxyindane-1-carboxylic acid) and other compounds disclosed in

US-4057573; Pamicogrel (ethyl {2-[4,5-bis(4-methoxyphenyl)-1 ,3-thiazol-2-yl]-1H-pyrrol-1-yl}acetate) and other compounds disclosed in EP-159677 and US-4659726; Pelubiprofen (2-{4-[(E)-(2-oxocyclohexylidene)methyl]phenyl}propanoic acid) and other compounds disclosed in US-4254274; Pirazolac ([4-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-pyrazol-3-yl]acetic acid) and other compounds disclosed in EP-22906; Piroxicam (4-hydroxy-2-methyl-N-pyridin-2-yl-2H-1 ,2-benzothiazine-3-carboxamide 1,1- dioxide) and other compounds disclosed in US-4074048; Pranoprofen (2-(5H-chromeno[2,3-b]pyridin-7-yl)propanoic acid) and other compounds disclosed in DE-2337052; SKF-105809 (2-[3-(methylsulfinyl)phenyl]-3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[1 ,2- a]imidazole) and other compounds disclosed in EP-306300 and US-5145858; Sulindac ({(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)benzylidene]-1H-inden-3-yl}acetic acid) and other compounds disclosed in US-3692651; TA-60 (2-(4-allylphenyl)propanoic acid) and other compounds disclosed in DE-2920812; Talniflumate (3-oxo-1,3-dihydro-2-benzofuran-1-yl 2-{[3-

(trifluoromethyl)phenyl]amino}nicotinate) and other compounds disclosed in BE-

858864; Tebufelone (1-(3,5-di-tert-butyl-4-hydroxyphenyl)hex-5-yn-1-one) and other compounds disclosed in EP-251408 and US-4708966; Tenoxicam (4-hydroxy-2-methyl-N-pyridin-2-yl-2H-thieno[2,3-e][1,2]thiazine-3-carboxamide

1 ,1 -dioxide) and other compounds disclosed in US-4177193; Tepoxalin (3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N-hydroxy-N- methylpropanamide) and other compounds disclosed in EP-248594 and US-

4826868; Tilnoprofen (2-(dimethylamino)-2-oxoethyl 2-(2-methyl-5H-chromeno[2,3-b]pyridin-7- yl)propanoate) and other compounds disclosed in EP-284069 and US-4808593; Tinoridine (ethyl 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate) and other compounds disclosed in US-3563997; Ximoprofen (2-{4-[(3Z)-3-(hydroxyimino)cyclohexyl]phenyl}propanoic acid) and other compounds disclosed in US-3935255; Zaltoprofen (2-(10-oxo-10,11-dihydrodibenzo[b,f]thiepin-2-yl)propanoic acid) and other compounds disclosed in US-4247706; Diphenylthiophenes disclosed in US-5705525; Compounds disclosed in JP-2006076910; and Indolequinazolines disclosed in published international patent application WO-0623377.

Further examples of COX-II inhibitors for use for the invention are:

Carprofen (2-(6-chloro-9H-carbazol-2-yl)propanoic acid) disclosed in US-3896145 and GB- 1385620;

Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulphonamide); SC-59630 (4-(4-chloro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide) disclosed in EP-731795 and US-5466823;

Valdecoxib (4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulphonamide); SC-66791 (4-[5- (difluoromethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide); SC-66448 (4-(5-ethyl-3- phenylisoxazol-4-yl)benzenesulfonamide); SC-66956 (4-[5-(methoxymethyl)-3- phenylisoxazol-4-yl]benzenesulfonamide); SC-66775 (4-[3-(4-fluorophenyl)-5- methylisoxazol-4-yl]benzenesulfonamide); SC-68173 (4-(5-chloro-3-phenylisoxazol-4- yl)benzenesulfonamide) disclosed in EP-809636 and US-5833272; Parecoxib (N-^-Cδ-methyl-S-phenyW-isoxazolylOphenyllsulphonylJ-propanamide), SC-

75416 ((2S)-7-tert-butyl-6-chloro-2-(trif luoromethyl)-2H-chromene-3-carboxylic acid) disclosed in EP-977748 and US-6034256; 6,8-Dichloro-2-trifluoromethyl-2H-chromene-3-carboxylic acid, disclosed in EP-977748 and

US-6034256; (2S)-8-ethyi-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid; (2S)-6- chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid; [(2S)-6,8- dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, sodium salt, 6-ethyl-8- methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, disclosed in published international patent application WO-0487686; {6-chloro-2-[(4-ethylpyridin-2-yl)carbonyl]-1H-indol-3-yl}acetic acid, disclosed in EP-1045833 and US-6608070; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]benzenesulfonamide, disclosed in

EP-731795 and US-5466823; 4-[3-(3-fluorophenyl)-5-methylisoxazol-4-yl]benzenesulfonamide; 5-(difluoromethyl)-4-[4-

(methylsulfonyl)phenyl]-3-phenylisoxazole, disclosed in published international patent application WO-9625405; 2-fluoro-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonarriϊde, disclosed in published international patent application WO-0181332; 3-{1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2-yl}pyridine, disclosed in EP-

772600 and US-6613789; (2S)-6-iodo-2-(trifluoromethyl)-1 ^-dihydroquinoline-S-carboxylic acid, disclosed in WO-

9847890; δ-^ethylsulfonyO^-Cδ-pyridin-S-yl-S-^rifluoromethyO-IH-i ^^-triazol-i-yllpyridine, disclosed in published international patent application WO-0414878; and 2-[3-(difluoromethyl)-5-phenyl-1 H-pyrazol-1 -yl]-5-(methylsulfonyl)pyridine, disclosed in published international patent application WO-0140216.

Still further examples of COX-il inhibitors for use for the invention include:

Firocoxib (3-(cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one) disclosed in EP-863891; Vedaprofen (2-(4-cyclohexyl-1-naphthyl)propanoic acid) disclosed in GB-2006763 and US-

4218473;

Tolfenamic acid (2-[(3-chloro-2-methylphenyl)amino]benzoic acid) disclosed in DE-1543295; Suxibuzone (4-[(4-butyl-3,5rdioxo-1 ,2-diphenylpyrazolidin-4-yl)methoxy]-4-oxobutanoic acid) disclosed in DE-1936747; 4-(2-oxo-3-phenyl-2,3-dihydro-1 ,3-oxazol-4-yl)benzenesulfonamide disclosed in published international patent application WO-9914205; Rofecoxib (3-phenyl-4-[4-(methylsulphonyl)phenyl)-2(5H)-furanone) disclosed in EP-705254 and US-5474995.; Etodolac ((i.δ-diethyl-I .S^.Θ-tetrahydropyranotS^-blindol-i-yOacetic acid) disclosed in US-

3939178; Etoricoxib (5-chloro-6'-methyl-3-[4-(nnethylsulfonyl)phenyl]-2,3'-bipyridine) disclosed in EP-

912518 and US-6071936; Lumiracoxib ({2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl}acetic acid) disclosed in

EP-1007505 and US-6291523; Meloxicam (4-hydroxy-2-methyl-N-(5-methyl-1 ,3-thiazol-2-yl)-2H-1 ,2-benzothiazine-3- carboxamide 1,1-dioxide) disclosed in EP-2482 and US-4233299; Nimesulide (N-(4-nitro-2-phenoxyphenyl)methanesulfonamide) disclosed in US-3840597 and GB-1435755; CV-247 (3-isopropoxy-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one) disclosed in

EP-863891; GW 406381 (2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]pyrazolo[1 ,5-b]pyridazine) disclosed in EP-1032575 and US-6451794; Cimicoxib (4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide) disclosed in EP-1122243 and US-6838476; CS-502 Sankyo CAS Reg No 346670-87-9;

CS 706 (N-[4-(4-fluorophenoxy)-2-thienyl]methanesulfonamide) disclosed in US-5783597; ABT 963 (2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-

(methylsulfonyl)phenyl]pyridazin-3(2H)-one) disclosed in EP-1124804 and US-

6307047; Ajulemic acid ((6aR,10aR)-3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6a,7_l10,10a- tetrahydro-6H-benzo[c]chromene-9-carboxylic acid) disclosed in EP-650483 and US-

5338753; BMS 347070 ((SZJ-S-^S-chlorophenyO^methylsulfonyOphenyllmethyleneJdihydrofuran-

2(3H)-one) disclosed in EP-891345 and US-6180651; D-1367 Chiroscience CAS Reg No 215435-18-0; Darbufelone ((5Z)-2-amino-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-1,3-thiazol-4(5H)-one) disclosed in EP-449216 and US-5143928; E-6087 (4-[5-(2,4-dif luorophenyl)-3-(trif luoromethyl)-4,5-dihydro-1 H-pyrazol-1 ■ yljbenzenesulfonamide) disclosed in EP-1083171 and US-6353117; GR-253035 Glaxo Wellcome CAS Reg No 215522-99-9; DRF-4367 (2-(hydroxymethyl)-4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H-pyrazol-1 - yljbenzenesulfonamide) disclosed in published international patent application WO-

0066562; lguratimod (N-[3-(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide) disclosed in GB-2210879 and US-4954518; Imrecoxib (3-(4-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-1-propyl-1,5-dihydro-2H-pyrrol-2- one) disclosed in US-2004029951; LAS 34475 Almirall Profesfarma CAS Reg No 485397-26-0; Nabumetone (4-(6-methoxy-2-naphthyl)butan-2-one) disclosed in US-4061779; Nitroflurbiprofen (4-(nitrooxy)butyl 2-(2-fluorobiphenyl-4-yl)propanoate) disclosed in WO-

0313499; NS 398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide) disclosed in EP-317332 and US-4885367; PMI-001 (2,6-di-tert-butyl-4-(5-ethoxy-1,3,4-thiadiazol-2-yl)phenol) disclosed in Journal

Medicinal Chemistry, 199, 42, 7, 1161; S 2474 (2,6-di-tert-butyl-4-[(E)-(2-ethyl-1 ,1-dioxidoisothiazolidin-5-ylidene)methyl]phenol) disclosed in EP-595546 and US-5418230; SVT 2016 Salvat CAS Reg No 630395-06-1; Tazofelone (5-(3,5-di-tert-butyl-4-hydroxybenzyl)-1,3-thiazolidin-4-one) disclosed in EP-

211670 and US-5356917; Tilmacoxib (4-(4-cyclohexyl-2-methyl-1,3-oxazol-5-yl)-2-fiuorobenzenesulfonamide) disclosed in EP-745596 and US-5994381; Deracoxib (4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1 H-pyrazol-1 - yl]benzenesulfonamide) disclosed in EP-731795 and US-5466823; Flosulide (N-[6-(2,4-Difluoro-phenoxy)-1-oxo-indan-5-yl]-methanesulfonamide) disclosed in

EP-56956 and US-4375479; L-745337 (N-{6-[(2,4-difluorophenyl)thio]-1 -oxo-2,3-dihydro-1 H-inden-5- yl}methanesulfonamide) disclosed in published international patent application WO-

9413635; L-768277 (5-[4-(methylsulfonyl)phenyl]-6-phenyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazole) disclosed in published international patent application WO-9621667; L-776967 (2-(3,5-dif luorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1 -one) disclosed in EP-863134; L-783003 (5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-3-phenylfuran-2(5H)-one) disclosed in published international patent application WO-9619469; L-804600 (2-benzyl-4-isopropoxy-5-[4-(methylsulfonyl)phenyl]pyridazin-3(2H)-one) disclosed in published international patent application WO-9841511; 1-{3,3-dimethyl-5-[4-(methylsulfonyl)phenyl]cyclopenta-1,4-dien-1-yl}-4-fluorobenzene disclosed in published international patent application WO-9530656; 4,4-Dimethyl-2-phenyl-3-[4-(methylsulfonyl)phenyl]cyclobutenone disclosed in Bioorganic. &

Medicinal Chemistry Letters (1996), 6(22), 2677-2682; 1 -(7-t-butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-4-cyclopropylbutan-1 -one disclosed in published international patent application WO-9603396; RWJ-63556 (N-[5-(4-fluorophenoxy)-2-thienyl]methanesulfonamide) disclosed in US-

5783597; S-33516 (1,3-bis(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-4,7-ethanoisoindole) disclosed in

Journal of Medicinal Chemistry (2000), 43(24), 4582-4593 ; SC-299 (4-(2-methyl-4-phenyl-1 ,3-oxazol-5-yl)benzenesulfonamide) disclosed in published international patent application WO-9636617; and UR-8877 (4-[4-chloro-5-(4-ethoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide) disclosed in published international patent application WO-0023426.

Still further examples of COX-II inhibitors for use in the invention include: 3-(2-methoxytetrahydrofuran-2-yl)-1-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-1H- pyrazole disclosed in Bioorganic and Medicinal Chemistry Letters, 2004, 14, 24,

6049; nitrosated and nitrosylated cyclooxygenase-2 inhibitors disclosed in published international patent application WO-0145703;

1 ,4-benzodioxans disclosed in Journal of Medicinal Chemistry (1995), 38(1), 68-75.,; lndanyl derivatives disclosed in EP-56956;

Compounds described in published international patent application WO-9850033; (3,5-di-tertiary-butyl-4-hydroxyphenyl)thiadiazoles, -oxadiazoles, and -triazoles disclosed in

EP-371438;

2-Aryl-substituted isoxazolo[2,3-a]pyridinyl halides disclosed in US-3983237; 2-heterocyclic-5-hydroxy-1,3-pyrimidines disclosed in published international patent application WO-9403448; 3,5-di-tertiarybutyl-4-hydroxyphenylmethylene derivatives of 2-substituted thiazolidinones, oxazolidinones, and imidazolidinones disclosed in EP-449216 and US-5143928; thiadiazoles disclosed in Journal of Medicinal Chemistry (1999), 42(7), 1161-1169. ; Aryl phenylhydrazides disclosed in US-6077869; 2-aryloxy-5-alkanesulfonamido-thiophenes disclosed in US-5783597; diphenylthiophenes disclosed in EP-728755;

1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives disclosed in Journal of Medicinal

Chemistry (2000), 43(24), 4582-4593. ;

(phenylethyl)sulfonamides and (alkylsulfonyl)ethylbenzenes disclosed in ES-2158809; Dihydrobenzofurans disclosed in published international patent application WO-9603396; APHS and analogues disclosed in published international patent application WO-9829382; (Methylsulfonyl)phenyl-2-(5H)-furanones disclosed in published international patent application WO-9714691; 5-methanesulfonamido-1-indanone inhibitors disclosed in published international patent application WO-9413635; compounds described in "COX-II inhibitors - A new generation of safer NSAIDs? Donnelly

MT, Hawkey CJ Alimentary Pharmacology & Therapeutics 1997, 11:2 (227-236)"; Diaryl-2(5H)-furanones disclosed in published international patent application WO-9619469; 3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to cyclooxygenase-2 inhibitors disclosed in published international patent application WO-9716435; (Phenyl)heterocyclic compounds disclosed in published international patent application WO-

9500501; indoles disclosed in published international patent application US-5436265; 5-methanesulfonamido-3H-isobenzofuran-1-ones disclosed in published international patent application WO-9623786; N-Benzylindol-3-ylbutanoic acid derivatives disclosed in published international patent application WO-9637467; 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one disclosed in EP-

863134; aryl-substituted, 5,5-fused aromatic nitrogen compounds disclosed in published international patent application WO-9621667; 3-(thiazol-2-ylmethyl)indoles disclosed in published international patent application WO-

9839330; JTE-522 and other oxazoles disclosed in published international patent application WO-

9619463;

2,3'-Bipyridines disclosed in ES-2214130; 2-phenylpyran-4-ones disclosed in published international patent applications WO-0472058,

WO-0168633, WO-0018753;

4-phenylpyran-2-ones disclosed in published international patent application WO-0306451 ; 2(3H)-oxazolones disclosed in published international patent applications WO-9914205, WO-

9734882; diarylcycloalkylpyrazoles disclosed in published international patent application WO-

9822442;

2,3-diaryl-5-halothiophenes disclosed in EP-87629;

XU-745 and analogues disclosed in published international patent application WO-9610012; 1,2,4-triazoles disclosed in published international patent application WO-0446121; 1-(hetero)aryl-3-trifluoromethyl-1H-1 ,2,4-triazoles disclosed in published international patent application WO-0414878; pyrazol-3-ones disclosed in published international patent application WO-0400206; 2-thioxothiazoles disclosed in published international patent application WO-0400822; diaryl 1 ,2,4-triazoles disclosed in published international patent application WO-0355875; bipyridinyl derivatives disclosed in published international patent application WO-0355874; triterpenoids disclosed in published international patent application WO-0359339; pyrazoles disclosed in published international patent application WO-0066562; 3,4-diphenyl-2,5-dihydro-2-furanones disclosed in published international patent application

WO-0190097; phenylpyrazoles disclosed in published international patent applications WO-0018741, WO-

9925695, WO-9915505; imidazoline or oxazoline derivatives disclosed in JP-10291982; indol-2-ones disclosed in published international patent application WO-0389427; 1-[sulfonylphenyl(or pyridyl)] pyrazoles disclosed in published international patent application

WO-0337874; 5-heterocyclo-1-(5-methanesulfonylpyridin-2-yl)-1H-pyrazoles disclosed in published international patent application WO-0337351 ; 1-(5-sulfonyl-pyridin-2-yl)-5-(methylidene-cycloalkylmethoxy)-1H-pyrazole-4-carbonitriles disclosed in published international patent application WO-0337336; heteroaryl substituted pyrazoles disclosed in published international patent application WO-

0337335; 5-(alkylidene-cycloalkyl)- and 5-(alkylidene-heterocyclyl)-pyrazoles disclosed in EP-

1308446; heteroaryl substituted pyrazoles disclosed in EP1308445; 5-N-heterocyclyl-1-(4-sulfonylphenyl)-1H-pyrazoles disclosed in published international patent application WO-0337352; sulfonyl(hetero)arylpyrazoles disclosed in published international patent application WO-

0337330; heterocyclo-alkylsulfonyl pyrazoles disclosed in EP-1273582 and US-2003119836; sulfonyl heteroaryl triazoles disclosed in EP-1273580 and US-2003119835, ; sulphonyl aryl triazoles disclosed in EP-1273576; benzimidazoles disclosed in US-2003013886, EP-937782, EP-846689; pyrazole ethers, thioethers and amines disclosed in published international patent application

WO-0164669; heterocyclo-alkylsulfonyl pyrazoles disclosed in published international patent application

WO-0140216; sulfamoylheteroaryl pyrazoles disclosed in EP-1104760; heteroaryl phenyl pyrazoles disclosed in EP-1104759; 5-alkynylphenyl-1-sulfonylarylpyrazoles disclosed in EP-1104758; heterocyclyl sulfonylbenzenes disclosed in published international patent application WO-

9964415;

3-aminoindoles disclosed in published international patent application WO-9905104; azaoxindole-1-carboxamides disclosed in US-5811482; [(hetero)arylacyl]tetralones, -chromenones disclosed in EP-439265; triazolopyridines disclosed in published international patent application WO-0618727; 2H-chromene-3-carboxylates disclosed in published international patent applications WO-

0487687, WO-0487686; pyrazoles disclosed in published international patent application WO-03104223; fluoro-substituted benzenesulfonyl pyrazoles and isoxazoles disclosed in EP-1251126; heterocyclo substituted hydroxamic acid derivatives disclosed in US-6696477, US-6432999; dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines disclosed in published international patent application WO-0149675; pyrazolylbenzenesulfonamides disclosed in published international patent application WO-

9515316; benzopyrancarboxylates and quinolinecarboxylates disclosed in published international patent application WO-0023433; 3,4-substituted pyrazoles disclosed in published international patent application WO-

9603385;

2,3-diarylpyridines disclosed in published international patent application WO-9624584; benzopyrans disclosed in published international patent application WO-9847890; pyrroles disclosed in published international patent application WO-9825896; [(alkylsulfonyl)phenyl]oxazoles disclosed in published international patent application WO-

9427980;

Aryl- and pyridyl-substituted cyclopentenes disclosed in US-5663180; Heterocyclo-substituted imidazoles disclosed in published international patent application

WO-9727181; Pyrazolylbenzenesulfonamides disclosed in published international patent application WO-

9711704;

1 ,2-diarylimidazoles disclosed in published international patent application WO-9603388; sulfonylphenylheterocycles disclosed in published international patent application WO-

9638442; Heterocyclo substituted hydroxamic acid and derivatives disclosed in published international patent application WO-9638418;

Oxazoles disclosed in published international patent application WO-9636617; 2,3-substituted pyridines disclosed in published international patent application WO-

9624584; isoxazoles disclosed in published international patent application WO-9625405; 3,4-diarylpyridines disclosed in published international patent application WO-9624585; benz[g]indazole derivatives disclosed in published international patent application WO-

9609293; 4,5-Substituted imidazolyl compounds disclosed in published international patent application

WO-9603387; 1 ,2-Substituted imidazolyl compounds disclosed in published international patent application

WO-9603388;

Substituted thiazoles disclosed in published international patent application WO-9603392; phenylcyclopentadiene spiro derivatives disclosed in published international patent application WO-9530652; 1 ,3,5-trisubstituted pyrazoles disclosed in published international patent application WO-

9515318; Substituted spiro compounds disclosed in published international patent application WO-

9521817; arylcycloalkyl carboxyalkyl ethers disclosed in US-5420343; cyclopentadienylbenzene compounds disclosed in published international patent application

WO-9530656;

3,4-diaryl thiophenes disclosed in published international patent application WO-9415932; flavonoids disclosed in published international patent application WO-0534937; azulenes disclosed in JP-11302266; 3-diafylmethylidene-2-furanones disclosed in published international patent application WO-

9737984; diarylmethylidene furan derivatives disclosed in published international patent application

WO-0014082; Diarylpyrazoles disclosed in published international patent application WO-9962884; 5-(arylthio)-6-sulfonamido-3(2H)-benzofuranones disclosed in ES-2138902; 2-(4-(3-Methyl-2-thienyl)phenyl)propionic acid disclosed in US-4230719.

Still further examples of COX-II inhibitors for use for the invention include: lndoleacetic acid and indenacetic acid derivatives disclosed in published international patent application WO-05112921 ; dammarane analogues disclosed in JP-2005306785; acylindoles disclosed in US-2005234244, US-2005234030; Dimethylfuranone derivatives disclosed in published international patent application WO-

0594815; nitric oxide releasing prodrugs of diaryl-2(5H)-furanones disclosed in published international patent applications WO-0570883, WO-0570874; pyrazole/isoxazole derivatives disclosed in published international patent application WO-

0554204; heterocyclic thione derivatives disclosed in published international patent application WO-

0551941; prodrugs of diaryl-2-(5H)-furanones disclosed in published international patent application

WO-0542476; heteroaryl or heterocyclic derivatives disclosed in published international patent application

WO-0537227; 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid and pharmaceutically acceptable salts disclosed in published international patent application WO-0537266; benzene sulphonamides disclosed in published international patent application WO-

0525510;

7-azaindoles disclosed in published international patent application WO-0516924; straight-chain and branched-chain lipid amides disclosed in published international patent application WO-0514528; withanolide compounds disclosed in published international patent application WO-0443478; 4-aryl-5H-thiophen-2-one derivatives disclosed in published international patent application

WO-04106321; 1-(4-sulfamylaryl)-3-substituted-5-heteroaryl-2-pyrazolines disclosed in published international patent application WO-0493829; substituted pyrazoles disclosed in published international patent application WO-0487074; 4-(4-methylsulfinylphenyl)-3-phenylfuran-2-one disclosed in published international patent application WO-0472057; 2,3'-bipyridine derivatives disclosed in published international patent application WO-

0472037; arylpyridazinones disclosed in published international patent application WO-0024719; phosphoramide derivatives disclosed in published international patent application WO-

0458778; 4-Nitro-2-[(4'-methoxy)-phenoxy]-methanesulfonanilides disclosed in published international patent application WO-0458697;

1 ,2,4-triazoles disclosed in published international patent application WO-0448347; substituted amino phenylacetic acids and derivatives disclosed in published international patent application WO-0448314; pyrimidine derivatives disclosed in published international patent application WO-0448344; 1 ,2,4-triazole derivatives disclosed in published international patent application WO-

0448367; nitric oxide releasing prodrugs of diaryl-2-(5H)-furanones disclosed in published international patent application WO-0441803; celecoxib prodrug disclosed in US-2004092566; sulphonyl carbamate derivatives disclosed in published international patent application WO-

0437798; isothiazole derivatives disclosed in published international patent application WO-0435553; [(methylsulfonyl)phenyl]pyridines disclosed in published international patent application WO-

0424691;

2,3-diarylindoles disclosed in US-2004058977; pyrimidine derivatives disclosed in published international patent application WO-0418452; ortho-pyridinequinone derivatives disclosed in published international patent application WO-

0418427; nitric oxide releasing diaryi-2-(5H)-furanone prodrugs disclosed in published international patent application WO-0411421 ; Nitrosated and/or nitrosylated compounds disclosed in published international patent application WO-0410945; pyrimidine derivatives disclosed in published international patent application WO-0409560; peptides disclosed in JP-2004057114; nitrosated and/or nitrosylated oximes and/or hydrazones disclosed in published international patent application WO-0402420; trisubstituted pyrazoles disclosed in published international patent application WO-0402409; pyrimidones disclosed in published international patent application WO-0384938; nitrooxy derivatives disclosed in published international patent application WO-0400781 ; 4-hydroxy-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1 -dioxides disclosed in published international patent application WO-0413148; 4-(sulfoximinyl)phenyl substituted heterocyclic compounds disclosed in published international patent application WO-0387062; compounds disclosed in published international patent application WO-0389013; 1-Pyridino-5-phenyl-pyrazoles disclosed in KR-2003055777; Methane phosphonate derivatives disclosed in JP-2003238415; pyrimidinediones disclosed in published international patent applications WO-0384937, WO-

0384936, WO-0384935;

Imidazole derivatives disclosed in published international patent application WO-9314081; Pyridazinones disclosed in US-2003105101; basic amino acid derivatives disclosed in published international patent application WO-

0366673; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-acetic-4-(acetylamino)-phenylester disclosed in FR-2835433; (Z)-Styryl acetoxyphenyl sulfides disclosed in published international patent application WO-

0077169; 1-(4-Arylsulfonyl)-3-substituted-5-aryl-2-pyrazolines disclosed in published international patent application WO-0076983; 1-(4-Sulfamylaryl)~3-substituted-5-aryl-2-pyrazolines disclosed in published international patent application WO-0076503; heteroaryl substituted hydrazones disclosed in published international patent application

WO-0349698; azolylamidines disclosed in US-6555563; deuterated dihydrofuranones disclosed in published international patent application WO-

0350101; pyridazinones disclosed in US-6525053; sulfonylphenylpyrazoles disclosed in published international patent application WO-0116138; 3τ[2-(piperazin-1-yl)ethyl]-2-methylindoles disclosed in ZA-9802828; pyridazinones disclosed in published international patent application WO-9910332; arylpyridazinones disclosed in published international patent application WO-9910331; N-[2-(aryloxy)- or 2-(heteroaryloxy)phenyl] sulfonamides disclosed in US-5681842; diarylisoxazoles and 2-isoxazolines disclosed in published international patent application

WO-0331404; 3,4-dihydro-i H-naphthalene derivatives disclosed in published international patent application WO-0331418; ^-methanesulfonyl-biphenyl derivatives disclosed in published international patent application WO-0331398; fatty, acyl lipid compounds disclosed in published international patent application WO-

02102757;

1H-indoles disclosed in published international patent application WO-0331409; pyridinesulfonamides disclosed in published international patent application WO-0329217; Indole derivatives disclosed in published international patent application WO-0329212; benzofuran-2-carbonitriles and benzothiophene-2-carbonitriles disclosed in published international patent application WO-0246178; quinoline derivatives disclosed in published international patent application WO-0212192; N-substituted para-(sulfonyl)(hetero)arylamines disclosed in published international patent application WO-0183434; 5-aroylnaphthalene-2-sulfonamides disclosed in published international patent application

WO-9832732; pyrroles disclosed in published international patent application WO-9746524; inositol derivatives disclosed in JP-2003034690; arylfuranones and related compounds disclosed in US-2002183366; pyridines, pyrimidines, and pyrazolopyridazines disclosed in published international patent application WO-0548999; Pyrimidin-2-amines disclosed in published international patent applications WO-0314091,

WO-0296427, WO-0138311 ; methylsulfonylphenylpyrimidines disclosed in published international patent application WO-

0296886; pyrimidine derivatives disclosed in published international patent application WO-0296885; pyrazolo[1 ,5-b]pyridazines disclosed in published international patent application WO-

0232895; substituted pyrimidines disclosed in published international patent application WO-0218374; 2-pyrimidinamines disclosed in published international patent application WO-0158881 ; pyrazolopyridines disclosed in published international patent applications WO-0052008, WO-

0026216; 2,3-Diarylpyrazolo[1,5-b]pyridazines disclosed in published international patent application

WO-9912930; pyrimidinylimidazoles and analogues disclosed in published international patent application

WO-9725045; 2,3-diphenylimidazo[1,2-a]pyridines disclosed in published international patent application

WO-9631509; diaryl ureas disclosed in published international patent application WO-0292576; azolylphenylsulfonamide prodrugs of cyclooxygenase-2 inhibitors disclosed in published international patent application WO-0283655; diterpene triepoxide lactones and diterpene lactones or triterpenes zq US-2002068098; Substituted aryl compounds disclosed in published international patent application WO-

0260378; optionally nitrosated and/or nitrosylated oxime and/or hydrazones disclosed in published international patent application WO-0260378; Nitrosated and/or nitrosylated cyclooxygenase -2 selective inhibitors disclosed in published international patent application WO-03103602; Organic plant extracts and purified compositions disclosed in published international patent application WO-0247707; pyrones disclosed in published international patent application WO-0202547; 1 ,2,3-Thiadiazoles disclosed in published international patent application WO-0117996; diphenyl-1 ,2,3-thiadiazole 3-oxides disclosed in published international patent application

WO-0068215;

(methylsulfonyl)phenyl-2-(5H)-furanones disclosed in US-6169188; 4-aryl-(5H)-furan-2-ones disclosed in US-5981576; diaryl-5-alkyl-5-methyl-2(5H)-furanones disclosed in published international patent application WO-9923087; 2-amino-3-(4-methylsulfonylphenyl)pyridines disclosed in published international patent application WO-9914195;

2,3,5-trisubstituted pyridines disclosed in published international patent application WO- 9914194; diarylfuranones, and related compounds disclosed in published international patent application WO-474995;

5-methanesulphonamido-1-indanones disclosed in US-5604260; 2-aryl-3-aryl-5-halo pyridines disclosed in published international patent application WO-

9847871; alpha-methylene gamma lactones disclosed in published international patent application

WO-9843966; bis(aryl) cyclobutene derivatives disclosed in US-5817700; 4-[4-(methylsulfonyl)phenyl]-2-(5H)-furanones disclosed in published international patent application WO-9841516; pyridazinones disclosed in published international patent application WO-9841511; alkylated styrenes as prodrugs to cyclooxygenase -2 inhibitors disclosed in US-5789413; Diphenyl stilbenes as prodrugs to cyclooxygenase -2 inhibitors disclosed in US-5733909; substituted pyridines disclosed in published international patent application WO-9803484; 4-(4-methylsulfonylphenyl)-2-furanones disclosed in published international patent application WO-9745420; pyridinyl-2-cyclopenten-1-ones disclosed in published international patent application WO-

9740012;

Diphenyl-1 ,2-3-thiadiazoles disclosed in US-5677318; bisarylcyclobutene derivatives disclosed in published international patent application WO-

9736863; alkylated styrenes as prodrugs to cyclooxygenase -2 inhibitors.disclosed in published international patent application WO-9728121 ; stilbene derivatives as prodrugs to cyclooxygenase -2 inhibitors disclosed in published international patent application WO-9728120; N-benzylindole-3-propanoates disclosed in published international patent application WO-

9637469; diaryl-2(5H)-furanones and analogues disclosed in published international patent application

WO-9636623;

5-methanesulfonamido-6-(2-pyridylthio)-1-indanones disclosed in CA-2164559; 3-aryl-4-(4-methylsulfonylphenyl)-2-furanones and analogues disclosed in US-5663195; stilbene derivatives disclosed in published international patent application WO-9613483; 3-phenyl-4-(4-methylsulfonyl)-2-furanones disclosed in published international patent application WO-9608482; diary! bicyclic heterocycles disclosed in published international patent application WO-

9606840; N-Benzylindole-3-propionates and analogues disclosed in published international patent application WO-9637468; 2-substituted-3,4-di(aryl)thiophenes disclosed in published international patent application

WO-9426731 ; pyrazoles disclosed in EP-1142889 and US-2002115856; heterocyclo substituted hydroxamic acid derivatives disclosed in US-2001056189; 1-(benzothiazol-2-yl)pyrazole derivatives disclosed in published international patent application WO-0187880; imidazole sulfones and analogues disclosed in published international patent application

WO-0183475; 2-fluorobenzenesulfonyl-heterocycles disclosed in published international patent application

WO-0181332; tetrazole-biphenyl compounds disclosed in published international patent application WO-

0182858; Heterocyclic substituted 4-aminoglutarimides disclosed in published international patent application WO-0174362;

Imidazoles disclosed in published international patent application WO-0170704; 2-acetoxyphenyl alkyl(or alkenyl or alkynyl) sulfides disclosed in US-6284918; arylhydropyrrolizines disclosed in published international patent application WO-0151491; Pyrazolo[1 ,5-b]pyridines disclosed in JP-2001139575;

Pyrazolopyridazines disclosed in published international patent application WO-0146194; 5-aryl-1 H-1 ,2,4-triazoles disclosed in published international patent application WO-0134577; tricyclic imidazoles disclosed in published international patent application WO-0129038; Flavones disclosed in published international patent application WO-0130342; lndolealkanol esters and indolealkylamides disclosed in published international patent application WO-0115686; Indoles disclosed in EP-1065204; Tetrazolyl indoles disclosed in EP-1065206;

Indoloquinazolinones disclosed in published international patent application WO-0061159; 4,5-diaryl-3(2H)-furanones disclosed in published international patent application WO-

0061571;

1 ,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles disclosed in US-6083969; 3,4,5-trisubstituted aryl nitrones disclosed in published international patent application WO-

0032567; imidazoles disclosed in published international patent application WO-0023426; indoles disclosed in EP-985666 and US-6277878; diarylbenzopyrans disclosed in published international patent application WO-0010993; imidazo[1 ,2a]azines disclosed in published international patent application WO-0008024; α-(2-hydroxyphenyl)nitrones disclosed in published international patent application WO-

0003977; 2-phenylcarbamoyl-phenyl selenols and derivatives disclosed in published international patent application WO-OO01380; Multibinding inhibitors of cyclooxygenase-2 disclosed in published international patent application WO-9963939; indole derivatives disclosed in published international patent application WO-9961436; pyrroles disclosed in published international patent application WO-9961016; biarylacetic acid derivatives disclosed in published international patent application WO-

9941224; B2007/001082

- 25 - benzimidazoles disclosed in EP-937722;

2,3-Substituted indoles disclosed in published international patent application WO-9935130;

Diphenylpyrrole derivatives disclosed in JP-11180871; substituted pyridine and pyridazine compounds disclosed in published international patent application WO-9932448;

5-arylpyrroles disclosed in published international patent application WO-9933796; 2,4,5-triarylimidazoles disclosed in US-5916891; pyrroles disclosed ϊn EP-921119 and US-6114360; 5-alkyl-2-arylaminophenylacetic acids disclosed in published international patent application

WO-9911605; phenylacetic acid derivatives disclosed in published international patent application WO-

0123346; δ-alkyl^-arylaminophenylacetic acids disclosed in published international patent application

WO-9911605; indenyl tetronic acids disclosed in US-5869524; urea derivatives disclosed in published international patent application WO-9900357; indene derivatives disclosed in published international patent application WO-9857924; indole, monoazaindole, and diazaindole derivatives disclosed in published international patent application WO-9851667; pyrazoles disclosed in published international patent application WO-9846594; pyranoindoles and tetrahydrocarbazoles disclosed in US-5830911; pyranoindoles disclosed in US-5824699; pyranoindoles disclosed in US-5776967; Aryl and heteroaryl substituted fused pyrroles disclosed in published international patent application WO-9822457; azulenecarboxylates disclosed in GB-2320715; oxime derivatives of indole and indene compounds disclosed in US-5750558; oxime derivatives of fenamates disclosed in US-5840758; benzylideneindenylacetylhydroxyfuranones disclosed in published international patent application WO-9821195;

2-Phenylazulene derivatives disclosed in US-5843999; benzenesulfonamides disclosed in published international patent application WO-9833769; diarylmethylene derivatives disclosed in published international patent application WO-

9815528; 3,4-diaryloxazolone derivatives disclosed in published international patent application WO-

9811080; Imidazole compounds disclosed in published international patent application WO-9807425; pyranoindoles and carbazoles disclosed in published international patent application WO-

9804527;

1,2-diarylindoles disclosed in published international patent application WO-9805639; Substituted benzenesulfonamide derivatives as prodrugs of COX-2 inhibitors disclosed in published international patent application WO-9738986; 2-benzyl-4-sulfonyl-4H-isoquinoline-1 ,3-diones disclosed in published international patent application WO-9746532;

6-benzyl-2H-pyridazin-3-ones disclosed in EP-810218; diarylmethylenecyclopentanes disclosed in published international patent application WO-

9805643;

1 ,2-diphenylpyrroles disclosed in EP-799823 and US-5808858; indoles disclosed in published international patent application WO-9730030; cycloalkyl-substituted imidazoles disclosed in published international patent application WO-

9725048; i-cycloalkyM-phenyl-δ-pyrimidinylimidazoles disclosed in published international patent application WO-9725047; imidazoles disclosed in published international patent application WO-9725046, WO-

9725045; 1,2 diarylcyclopentenyl compounds disclosed in published international patent application

WO-9511883; heteroarylindole-1 -carboxamides disclosed in published international patent application WO-

9713767; 1 ,3,5-trisubstituted pyrazoles disclosed in published international patent application WO-

9713755; diphenyl-1 ,2,3-thiadiazoles disclosed in CA-2180624; 2-(2,6-dichloro-4-hydroxyanilino)phenylacetic acid disclosed in published international patent application WO-9709977; imidazoles disclosed in US-5593991 ;

4-sulfonamidobenzenesulfonamides disclosed in DE-19533644; sulfonylaminobenzisothiazoles disclosed in DE-19533643; Derivatives of benzenesulfonamides disclosed in published international patent application

WO-9703953;

Imidazoles disclosed in published international patent application WO-9640143; alkylsulfonylbiphenyl and aminosulfonylbiphenyl derivatives disclosed in published international patent application WO-9626921 ; 5-methanesulfonamido-6-(2-pyridylthio)-1-indanones disclosed in CA-2164559; 1-cycloalkylimidazoles disclosed in published international patent application WO-9621654; 1 ,4,5-substituted imidazoles disclosed in published international patent application WO-

9621452; phenoxybenzopyranone disclosed in JP-08157361; oxazoles disclosed in published international patent application WO-9619462; Substituted biphenyl compounds disclosed in published international patent application WO- 9616934;

Pyrroles disclosed in EP-714895 and US-5622948;

Benzopyranopyrazoles disclosed in published international patent application WO-9609304; Phenyl heterocycles disclosed in published international patent application WO-9518799; Indoles disclosed in GB-2283745 and US-5436265;

Imidazoles disclosed in published international patent application WO-9502591; Triazolopyridines disclosed in published international patent application WO-0618735, WO-

0618727;

Tylophora alkaloids disclosed in published international patent application WO-0603676; Amino acid phenoxy ethers disclosed in published international patent application WO-

0466964; propenone derivatives disclosed in published international patent application WO-05121129; triazolopyridines disclosed in published international patent application WO-0272576; isoquinolines, isochromanones and isothiochromanones disclosed in published international patent application WO-0230888; 3,4-diarylthiazolin-2-ones or -2-thiones disclosed in published international patent application

WO-9918093;

Astaxanthin and/or its esters disclosed in JP-2006008718;

Aryl compounds disclosed in published international patent application WO-0629436; Stilbenes disclosed in published international patent application WO-0516860; Sauchinone disclosed in KR-2003086819; Seco-steroidal indene derivatives disclosed in published international patent application WO-

0492100; nitric oxide releasing prodrugs of diaryl-2-(5H)-furanones disclosed in published international patent application WO-04103955; flavanoids disclosed in published international patent application WO-374065; indoles disclosed in CN-1127482B;

4-(heterocyclyl)benzenesulfonamides disclosed in US-2002107276; indoles and mono- or diazaindoles disclosed in JP-2000136182; B2007/001082

- 28 - carbazoles disclosed in US-3896145 and GB-1385620; benzopyrans disclosed in published international patent application WO-9847890;

4-Cyclohexylnaphthalen-i -acetic acid derivatives disclosed in US-4218473 and GB-

2006763;

N-Substituted anthranilic acids disclosed in DE-1543295; N-[[(heteroaryl)thio]oxoindanyl]methanesulfonamides disclosed in published international patent application WO-9420480; 4-(5~methyl-3-phenylisoxazol-4-yl)benzenesulfonamide disclosed in published international patent application WO-9806708; 1-(3-indolecarbonyl)piperazines disclosed in published international patent application WO-

9806715; indole-3-carbonyl piperidides and analogues disclosed in published international patent application WO-9828292; and compounds disclosed in published international patent application WO-0613873.

One preferred group of COX-II inhibitors for use in the invention includes: Aceclofenac;

Ampiroxicam; Amtolmetin guacil; Bermoprofen; Bromfenac; Butibufen; Cinnoxicam;

Dexketoprofen; Diclofenac; Droxicam ; Eltenac; Fenclozic acid; Flobufen; Flurbiprofen;

Indobufen; Ketoprofen; Ketorolac; Licofelone; Lomoxicam; Mofezolac; Nepafenac;

Orpanoxin; Oxindanac; Pamicogrel; Pelubiprofen; Pirazolac; Piroxicam; Pranoprofen; Sulindac; Talniflumate; Tebufelone; Tenoxicam; Tepoxalin; Tilnoprofen; Tinoridine; Ximoprofen; and Zaltoprofen.

Another preferred group of COX-II inhibitors for use in the invention includes: Carprofen; Celecoxib; Valdecoxib; Parecoxib; Firocoxib; Vedaprofen; Tolfenamic acid; Suxibuzone; Rofecoxib; Etodolac; Etoricoxib; Lumiracoxib; Meloxicam; Nimesulide; Cimicoxib; Ajulemic acid; Darbufelone; Iguratimod; Imrecoxib; Nabumetone; Nitroflurbiprofen; Tazofelone; Tilmacoxib; Deracoxib; and Flosulide.

A particularly preferred COX-II inhibitor is carprofen, which is also known as 2-(6-chloro-9H- carbazol-2-yl)propanoic acid, and which is disclosed in US-3896145 and GB-1385620.

Where the COX-II inhibitor may exist in more than one tautomeric form then all these forms, and mixtures thereof, are included within the scope of the present invention. Where the COX-II inhibitor may exist as more than one optical isomer then all these isomers, and mixtures thereof, are included within the scope of the present invention.

References to COX-II inhibitors in the context of the present disclosure include the inhibitors per se and, in the case of inhibitors that have acidic and/or basic properties, their pharmaceutically acceptable salts.

Inhibitors with basic functional groups may form acid addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Inhibitors with acidic functional groups may form salts with bases. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olaniine, potassium, sodium, tromethamine and zinc salts.

References to COX-II inhibitors in the context of the present disclosure also include pharmaceutically acceptable solvates of the inhibitors and their pharmaceutically acceptable salts.

Where the COX-II inhibitor, salt or solvate may exist in more than one solid form, including amorphous forms and different polymorphic crystalline forms, then all these solid forms are included within the scope of the present invention.

The COX-II inhibitors may be administered by any suitable route, including oral, parenteral, transdermal, transmucosal and topical administration. Parenteral administration includes intravenous, intraarterial, intraperitoneal, intramuscular and subcutaneous administration. Transmucosal administration includes buccal, sublingual, rectal and intravaginal ad ministration. Topical administration, in the context of the present disclosure, means intrauterine administration.

A preferred route of administration is subcutaneous administration.

The COX-II inhibitors may be administered alone or in combination with one or more other drugs (including as a combination of two or more different COX-II inhibitors). For example, the COX-II inhibitors may be used in combination with antibiotics, such as penicillins, and antiseptics, such as iodine. Combinations may be administered in a single dose unit or may be presented as separate dose units for simultaneous or sequential administration.

I

Generally, the COX-II inhibitors will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Suitable pharmaceutical compositions and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).

The formulation may be a solid, such as a tablet, suppository or powder, a semi-solid, such as a paste or cream, or a liquid, such as a solution, suspension or emulsion. Liquid formulations may be presented as a kit comprising a powder and a carrier liquid to be made up prior to administration. Liquid formulations for oral administration may be presented in capsules.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of - solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug- loaded poly(cf/-lactic-coglycolic)acid (PGLA) microspheres.

Intrauterine formulations may be solutions or suspensions of the COX-II inhibitor in a suitable liquid such as sterile water or a pharmaceutically acceptable oil. The solution or suspension may further comprise one or more excipients such as buffering agents, preservatives and the like. The intrauterine formulation may be adapted for immediate-release or modified-release in a manner analogous to that described above in respect of parenteral formulations.

For tablet dosage forms, depending on dose, the COX-II inhibitor may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the COX-II inhibitor, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, poiyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose 001082

- 32 -

(monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from^'0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% COX-II inhibitor, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weigΗt % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. '

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets. Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

The amount of COX-II inhibitor administered will depend on the potency of the particular inhibitor and on the size of the animal. For a particularly potent inhibitor the dose may be 0.05 mg/kg or less. For a less potent inhibitor the dose may be 40 mg/kg or more. Doses within this range are preferred. For carprofen, a preferred dose range is 0.1 mg/kg to 20 mg/kg, more preferably 0.5 mg/kg to 10 mg/kg, and most preferably 1 mg/kg to 5 mg/kg. 2

- 33 -

The COX-II inhibitor may be given in a single administration or the administration may be repeated. For example the COX-II inhibitor may be administered two or three times over a period of up to one week. It is generally more convenient to give a single dose of the COX-II inhibitor.

The COX-II inhibitor may be administered several weeks prior to insemination or impregnation. For example the COX-Il inhibitor may be administered up to 3 weeks prior to insemination or impregnation. Preferably the inhibitor is administered up to 2 weeks prior to insemination or impregnation. More preferably the inhibitor is administered no more than one week prior to insemination or impregnation.

Where the method of the invention is used in the context of artificial insemination, the dose (or, in the case of multiple dosing, the last dose) of COX-II inhibitor is generally administered not more than 5 days after artificial insemination. Preferably the COX-II inhibitor is administered in the period starting 2 days before artificial insemination and ending two days after artificial insemination. More preferably the COX-II inhibitor is administered in the period starting 24 hours before artificial insemination and ending 24 hours after artificial insemination. Yet more preferably, the COX-II inhibitor is administered at the time of artificial insemination or in the subsequent 24 hours. Most preferably the COX-II inhibitor is administered at the time of artificial insemination. In this context, "at the time of artificial insemination" means the period starting 1 hour before artificial insemination and ending 1 hour after artificial insemination.

Where the method of the invention is used in the context of impregnation by a male animal, it may be difficult to anticipate with precision the time of insemination and so plan the dosing schedule. Nevertheless, the aim should be to administer the COX-II inhibitor no more than 5 days after impregnation, preferably no more than 2 days after, and more preferably no more than 24 hours after impregnation.

Example 1

Dairy cows in their second or later lactation, clinically healthy and at the appropriate physiological stage for first Al - at least 40 days after calving - are randomised to one of three groups. Animals in Group 1 receive artificial, insemination in accordance with normal practice. Animals in Group 2 are treated with carprofen (Rimadyl™) at 1.4 mg/kg subcutaneously at the time of the artificial insemination. Animals in Group 3 are treated with carprofen (Rimadyl™) at 1.4 mg/kg into the uterus on the morning following artificial insemination (at least 12 hours post-AI). Pregnancy is assessed at 30-42 days post insemination by transrectal palpation or ultrasound performed by a skilled technician or the attending veterinarian. Repeat breeding is detected according to usual practice- by the farmer. The following parameters are recorded:

i.) First service conception rate (FSCR) ii.) All service conception rate (ASCR), iii.) Days to first service (DFS). iv.) % pregnant at d 150 or 200 in milk, v.) Days open (DOPN).

First service conception rate in the three treatment groups

Treatment Group Number of cows Pregnant from 1^st Al FSCR (%) bred

Control 208 87 41 ,8

Subcutaneous 220 98 44,5

Intrauterine 193 69 35,8

Total 621 254 40,9

All published patents and patent applications, and all other publications, mentioned in the foregoing specification are hereby incorporated by reference in their entirety.

Claims

Claims

1. A method for improving reproductive success in a female animal comprising administering a COX-II inhibitor to the female animal.

2. The method of claim 1 wherein the female animal has, or is susceptible to, sub-clinical endometritis.

3. The method of claim 1 or 2 wherein the COX-II inhibitor is administered subcutaneously.

4. The method of any one of claims 1 to 3 wherein the female animal is a dairy cow.

5. The method of claim 4 wherein the dairy cow is in at least the second lactation.

6. The method of any one of claims 1 to 5 wherein animal is artificially inseminated and the COX-II inhibitor is administered no more than 5 days after artificial insemination.

7. The method of claim 6 wherein the COX-II inhibitor is administered no more than 2 days before or after artificial insemination.

8. The method of claim 7 wherein the COX-II inhibitor is administered no more than 24 hours before or after artificial insemination.

9. The method of claim 8 wherein the COX-II inhibitor is administered at the time of artificial insemination.

10. The method of any one of claims 1 to 9 wherein the COX-II inhibitor has an IC₅₀ of no more than 100μM for bovine COX-II.

11. The method of claim 10 wherein the COX-II inhibitor has an IC₅₀ of no more than 50μM for bovine COX-II.

12. The method of claim 11 wherein the COX-II inhibitor has an IC₅₀ of no more than 10μM for bovine COX-II.

13. The method of claim 12 wherein the COX-II inhibitor has an IC₅₀ of no more than 5μM for bovine COX-II.

14. The method of claim 13 wherein the COX-II inhibitor has an IC₅₀ of no more than 1μM for bovine COX-II.

15. The method of any one of claims 1 to 14 wherein the COX-II inhibitor has a selectivity for bovine COX-II over bovine COX-I of at least 1:1.

16. The method of claim 15 wherein the COX-II inhibitor has a selectivity for bovine COX- Il over bovine COX-I of at least 2:1.

17. The method of claim 16 wherein the COX-II inhibitor has a selectivity for bovine COX- Il over bovine COX-I of at least 5:1.

18. The method of claim 17 wherein the COX-II inhibitor has a selectivity for bovine COX- Il over bovine COX-I of at least 10:1.

19. The method of any one of claims 1 to 9 wherein the COX-II inhibitor is selected from: Carprofen; Celecoxib; Valdecoxib; Parecoxib; Firocoxib; Vedaprofen; Tolfenamic acid; Suxibuzone; Rofecoxib; Etodolac; Etoricoxib; Lumiracoxib; Meloxicam; Nimesulide; Cimicoxib; Ajulemic acid; Darbufelone; Iguratimod; Imrecoxib; Nabumetone; Nitroflurbiprofen; Tazofelone; Tilmacoxib; Deracoxib; and Flosulide.

20. The method of claim 19 wherein the COX-II inhibitor is carprofen.

21. The method of any one of claims 1 to 9 wherein the COX-II inhibitor is selected from: Aceclofenac; Ampiroxicam; Amtolmetin guacil; Bermoprofen; Bromfenac; Butibufen; Cinnoxicam; Dexketoprofen; Diclofenac; Droxicam ; Eltenac; Fenclozic acid; Flobufen; Flurbiprofen; Indobufen; Ketoprofen; Ketorolac; Licofelone; Lomoxicam; Mofezolac; Nepafenac; Orpanoxin; Oxindanac; Pamicogrel; Pelubiprofen; Pirazolac; Piroxicam; Pranoprofen; Sulindac; Talniflumate; Tebufelone; Tenoxicam; Tepoxalin; Tilnoprofen; Tinoridine; Ximoprofen; and Zaltoprofen.

22. A method of prophylactic, palliative or curative treatment of sub-clinical endometritis in. a cow in the second or higher lactation comprising the administration to the cow of an effective amount of a COX-II inhibitor.

23. The method of claim 22 wherein the COX-II inhibitor is carprofen.

24. The use of a COX-II inhibitor for the preparation of a medicament for improving reproductive success in a female animal.

25. The use of claim 24 wherein the COX-II inhibitor is carprofen.