EA003696B1 - Cox-2 selective carprofen for treating pain and inflammation in dogs - Google Patents

Abstract

1. A method of treating or preventing pain and inflammatory processes and diseases associated with the activity of inducible cyclo-oxygenase-2 (COX-2) in a member of the species Canis familiaris in need of such treatment, while at the same time reducing or eliminating undesirable side effects associated with simultaneous inhibition of the activity of constitutive cyclo-oxygenase-1 (COX-1) by selectively inhibiting COX-2 activity with reference to COX-1 activity, wherein the selectivity ratio of COX-2 : COX-1 activity inhibition is at least 3 : 1 based on ex vivo inhibition levels in whole blood measured at a dose giving >= 80% COX-2 inhibition, comprising administering to said member of the species Canis familiaris an amount therapeutically effective for treating pain and inflammation in accordance with the above recited limitations, of an anti-inflammatory selective COX-2 inhibitory compound comprising a compound of the formula: Formula (I) wherein: R<2> is where A is hydroxy, (C1-C4)alkoxy, amino, hydroxyamino, mono-(C1-C2)alkylamino di-(C1-C2)alkylamino; X and Y are independently H or (C1-C2)alkyl; and n is 1 or 2; R<6> is halogen, (C1-C3)alkyl, trifluoromethyl, or nitro; R<9> is H; (C1-C2)alkyl; phenyl or phenyl-(C1-C2)alkyl, where phenyl is optionally mono-substituted by fluoro or chloro; -C(=O)-R, where R is (C1-C2)alkyl or phenyl, optionally mono-substituted by fluoro or chloro; or -C(=O)-O-R<1>, where R<1> is (C1-C2)alkyl; where X and Y are different, the (-)(R) and (+)(S) enantiomers thereof; and all pharmaceutically acceptable salt forms, prod rugs and metabolites thereof which are therapeutically active for treating or preventing pain and inflammation. 2. A method of treating or preventing pain and inflammatory processes and diseases according to Claim 1 wherein said anti-inflammatory selective COX-2 inhibitory compound is carprofen, 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid. 3. A method of treating or preventing pain and inflammatory processes and diseases according to Claim 1 wherein said anti-inflammatory selective COX-2 inhibitory compound is comprised entirely of (S)-enantiomer of carprofen, 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid. 4. A method of treating or preventing inflammatory processes and diseases as in Claims 1, 2, or 3 further comprising wherein said inhibitory compound is used in combination with one or more other therapeutically active agents under the following conditions: A) where a joint has become seriously inflamed as well as Infected at the same time by bacteria, fungi, protozoa, and/or virus, said inhibitory compound is administered in combination with one or more antibiotic. antifungal, antiprotozoal, and/or antiviral therapeutic agents; B) where a multi-fold treatment of pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other mediators of inflammation, comprising one or more members independently selected from the group consisting essentially of: 1. NSAlDs; 2. H1 -receptor antagonists; 3. kinin-B1- and B2 -receptor antagonists; 4. prostaglandin inhibitors selected from the group consisting of PGD-, PGF, PGI2-, and PGE-receptor antagonists; 5. thromboxane A2 (TXA2-) inhibitors; 6. 5- and 12-lipoxygenase inhibitors; 7. leukotriene LTC4-, LTD4/LTE4-, and LTB4-inhibitors; 8. PAF-receptor antagonists; 9. gold in the form of an aurothio group together with one or more hydrophilic groups; 10. immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine, and methotrexate; 11. anti-inflammatory glucocorticoids; 12. penicillamine; 13. hydroxychloroquine; 14. anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone, and benzbromarone; C) where older dogs are being treated for disease conditions, syndromes and symptoms found in geriatric dogs, said inhibitory compound is administered in combination with one or more members independently selected from the group consisting essentially of: 1. cognitive therapeutics to counteract memory loss and impairment; 2. anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure, and myocardial infarction, selected from the group consisting of: a) diuretics; b) vasodilators; c) beta-adrenergic receptor antagonists; d) angiotensin-II converting enzyme inhibitors (ACE-inhibitors), alone or optionally together with neutral endopeptidase inhibitors; e) angiotensin II receptor antagonists; f) renin inhibitors; g) calcium channel blockers; h) sympatholytic agents; i) alpha2-adrenergic agonists; j) alpha-adrenergic receptor antagonists; and k) HMG-CoA-reductase inhibitors (anti-hypercholester-olemics); 3. antineoplastic agents selected from: a) antimitotic drugs selected from: i) vinca alkaloids selected from: [1] vinblastine, and [2] vincristine; 4) growth hormone secretagogues; 5) strong analgesics; 6) local and systemic anesthetics; and 7) H2 -receptor antagonists, proton pump inhibitors, and other gastroprotective agents. 5. A pharmaceutical composition for treating or preventing pain and inflammatory processes and diseases associated with the activity of inducible cyclo-oxygenase-2 (COX-2) in a member of the species Canis familiaris in need of such treatment, while at the same time reducing or eliminating undesirable side effects associated with simultaneous inhibition of the activity of constitutive cyclo-oxygenase-1 (COX-1), comprising: A) a therapeutically effective amount for treating pain and inflammation, of an anti-inflammatory selective COX-2 inhibitory compound which selectively inhibits COX-2 activity with reference to COX-1 activity, wherein the selectivity ratio of COX-2 COX-1 activity inhibition is at least 3 : 1 based on ex vivo inhibition levels in whole blood measured at a dose giving >=80% COX-2 inhibition, comprising an anti-inflammatory selective COX-2 inhibitory compound comprising a compound of the formula: Formula (I): wherein: R<2> is where A is hydroxy, (C1-C4)alkoxy, amino, hydroxyamino, mono-(C1-C2)alkylamino, di-(C1-C2)alkylamino; X and Y are independently H or (C1-C2)alkyl; and n is 1 or 2; R<6> is halogen, (C1-C3)alkyl, trifluoromethyl, or nitro; R<9> is H; (C1-C2)alkyl; phenyl or phenyl-(C1-C2)alkyl, where phenyl is optionally mono-substituted by fluoro or chloro; -C(=O)-R, where R is (C1-C2)alkyl or phenyl, optionally mono-substituted by fluoro or chloro; or -C(=O)-O-R<1>, where R<1> is (C1-C2)alkyl; where X and Y are different, the (-)(R) and (+)(S) enantiomers thereof; and all pharmaceutically acceptable salt farms, prodrugs and metabolites thereof which are therapeutically active for treating or preventing pain and inflammation; and B) a pharmaceutically acceptable carrier therefor. 6. A pharmaceutical composition according to Claim 5 wherein said anti-inflammatory selective COX-2 inhibitory compound is carprofen, 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid. 7. A pharmaceutical composition according to Claim 5 wherein said anti-inflammatory selective COX-2 inhibitory compound is comprised entirely of (S)-enantiomer of carprofen, 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid. 8. A pharmaceutical composition as in Claims 5, 6, or 7 further comprising wherein said anti-inflammatory selective COX-2 inhibitory compound is provided in a dosage form suitable for systemic administration by: A) injection or infusion in suitable liquid form which is intraarterial, intra- or transdermal, subcutaneous, intramuscular, intraspinal, intrathecal, or intravenous, wherein said inhibitory compound: 1) is contained in solution as a solute; 2) is contained in the discontinuous phase of an emulsion, or the discontinuous phase of an inverse emulsion which inverts upon injection or infusion, said emulsions containing suitable emulsifying agents; or 3) is contained in a suspension as a suspended solid in colloidal or microparticulate form, said suspension containing suitable suspending agents; B) injection or infusion into suitable body tissues or cavities as a depot, wherein said composition provides storage of said inhibitor and thereafter delayed-, sustained-, and/or controlled-release of said inhibitory compound for systemic distribution; C) instillation, inhalation or insufflation into suitable body tissues or cavities in suitable solid form, where said inhibitory compound: 1) is contained in a solid implant composition providing delayed-, sustained-, and/or controlled-release of said inhibitory compound; 2) is contained in a particulate composition to be inhaled into the lungs; or 3) is contained in a particulate composition to be blown into said suitable body tissues or cavities, wherein said composition optionally provides delayed-, sustained-, and/or controlled-release of said inhibitory compound; or D) ingestion in suitable solid or liquid form for peroral delivery of said inhibitory compound, where said inhibitory compound: 1) is contained in a solid dosage form; or 2) is contained in a liquid dosage form. 9. A pharmaceutical composition according to Claim 8 wherein said dosage forms comprise one or more members selected independently from the group consisting essentially of suppositories; solid peroral dosage forms selected from the group consisting of delayed release tablets, capsules, caplets, lozenges, troches, and multiparticulates; enteric-coated tablets and capsules which prevent release and absorption in the stomach of said member being treated to facilitate delivery distal to the stomach of said member; sustained-release oral tablets, capsules and microparticulates which provide systemic delivery of said inhibitor in a controlled manner over at least a 10-hour period; a chewable or ingestible oral tablet; a unit dose packet sachet, a suspension made from said unit dose packet sachet, a powder for oral suspe

Description

The present invention relates to the treatment of pain and inflammation in dogs with anti-inflammatory agents that are non-steroidal anti-inflammatory drugs (NSAIDs) and, in particular, such agents that are characterized by a reduced incidence of adverse gastrointestinal side effects, since such side effects are common and potentially severe problem in dogs.

BACKGROUND OF THE INVENTION

As well-known to ordinary specialists in this field, for example veterinarians, representatives of the canine family, for example dogs, especially old dogs, are very prone to chronic inflammatory processes, such as degenerative joint damage. Due to the very large number of dogs that are kept as pets or for utilitarian purposes, such as guard dogs and guide dogs, efforts have been made and are being made to find pharmaceutical agents that will impede or completely hinder development such inflammatory processes in dogs, or at least alleviate the symptoms of inflammation, such as pain and swelling. One of the classes of such pharmaceutical agents, which has been widely studied with respect to anti-inflammatory and analgesic use in humans, and most recently in dogs, is the class of non-steroidal anti-inflammatory drugs (NSAIDs). This type of anti-inflammatory drug has been well studied, and over the decades, new, improved agents of this type have been discovered and developed for use in humans.

However, the use of NSAIDs in dogs was more limited. For example, only two such NSAIDs, namely AROIEEK (meclofenamic acid) and SHMABU® (carprofen), were approved by the Veterinary Medicine Committee of the Food, Drug and Cosmetic Quality Control Department (EBA / SUM) for use in dogs in the USA . Therefore, in veterinary medicine there is less experience and knowledge on safety and efficacy in the use of NSAIDs in dogs. For example, in veterinary medicine, the most common indication for the use of NSAIDs is the treatment of degenerative joint damage (DPS), which in dogs is often the result of various evolutionary diseases, such as hip dysplasia and osteochondrosis, as well as traumatic joint injuries. In addition to treating chronic pain and inflammation, NSAIDs are also suitable in dogs for the treatment of acute postoperative pain, as well as for the treatment of clinical signs associated with osteoarthritis.

This need for treating dogs with NSAIDs, combined with the lack of any approved NSAIDs for this purpose, has led to significant inappropriate, sometimes detrimental, application in dogs of NSAIDs that are approved for humans. Veterinary literature is full of reports of gastrointestinal hemorrhage, perforation, and peritonitis in dogs that are associated with people-approved NSAIDs such as indomethacin, naproxen, aspirin, ibuprofen, and phenylbutazone. Despite the fact that such adverse gastrointestinal reactions also affect human patients, due to a lack of information on the correct dosage and because of their naturally high degree of exposure to such undesirable gastrointestinal reactions, dogs often receive disproportionately high doses. Accordingly, there is an urgent need for safe and also effective NSAIDs for the treatment of pain and inflammation in dogs.

While searching for effective and safe NSAID class agents for treating dogs has to deal with the possibility of serious adverse gastrointestinal reactions, other adverse reactions include toxicity to the kidneys and liver. However, the most serious of these are gastrointestinal effects, such as single and multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum, or small and large intestine. These adverse reactions usually deplete, but can often be severe, and sometimes even life threatening. In fact, the therapeutic index for the use of NSAIDs in dogs can be so low that they are contraindicated for such treatment.

The expression therapeutic index is sometimes generally defined as the ratio of LD ₅₀ to ED, drug and is considered an indicator of how selective the drug is in producing the desired effect. However, the expression therapeutic index, as used herein, is more consistent with the definition used in the field of animal health, namely: the ratio of the maximum tolerated dose for an animal to the minimum effective dose for an animal. In the present invention, the term animal refers, of course, to dogs. The maximum tolerated dose for a canine subject is usually determined by a number of different assays and techniques. For example, gastrointestinal hemorrhage can be determined by analysis methods commonly used to detect occult blood in stool samples, while endoscopy can be used to detect ulceration or perforation. In cases where the animal is killed during the study, valuable information can also be obtained by autopsy.

Until now, it has been expected in this area that any candidate for NSAIDs, especially for treating dogs, will have a low therapeutic index. At the same time, there was always the hope that the therapeutic index would not be so low as to render the candidate unacceptable for use in dogs. Thus, an important aspect of the present invention is the surprising discovery that the anti-inflammatory compositions described herein have an exceptionally high therapeutic index when used to treat pain and inflammation in dogs. In addition, these anti-inflammatory compositions, having this unexpected property, are unique, almost right up to the exclusion of all other NSAIDs.

In recent years, a considerable body of knowledge has been accumulated regarding the mechanisms of action by which NSAIDs achieve their anti-inflammatory therapeutic results, and at the same time produce serious adverse gastrointestinal reactions. Despite the fact that most of this mass of knowledge has been accumulated regarding the mechanisms of action of NSAIDs in humans, it is largely applicable to the same mechanisms of action on dogs, although there is, in all probability, some species specificity, as will be discussed in more detail below. Regarding the therapeutic efficacy of NSAIDs, it has long been known that the mechanism of action by which NSAIDs reduce inflammation is their ability to interrupt the cascade of arachidonic acid transformations that lead to endogenous production of prostaglandins, thromboxanes and leukotrienes. These lipid compounds are collectively called eicosanoids, since they are usually derivatives of C ₂ O polyunsaturated fatty acids, eicosenoic acids, of which the most common is arachidonic acid. Arachidonic acid, which is cis-Δ ⁵ , cis-Δ ⁸ , cis-Δ ¹¹ , cis-Δ ¹⁴ eicosatetraenoic acid, is the dominant precursor for many prostaglandins and leukotrienes, which are mediators of inflammation.

In the first stage of the arachidonic acid conversion cascade, arachidonic acid is released as a result of tissue-specific stimuli induced by hormones or proteases or membrane disturbances, and includes the action of specific phospholipase A ₂ . The result of this is free arachidonate, which at the second stage of this conversion cascade is affected by the bifunctional enzyme synthase of prostaglandin endoperoxide, also called prostaglandin H synthase (hereinafter referred to as PCH synthase), the first activity of which is similar to that of cyclooxygenase, while the second activity involves two-electron reduction. Most NSAIDs act as inhibitors of the cyclooxygenase activity of PCH synthase and thereby block the production of various prostaglandins, which are local hormones that perform their functions by binding to specific cellular receptors. Prostaglandins are potent, but also catabolize rapidly. Some of these prostaglandins are mediators of the inflammatory process, however, some of these prostaglandins also have a gastrointestinal protective function. Blocking the production of these beneficial prostaglandins is one of the main factors contributing to the adverse gastrointestinal reactions that occur when NSAIDs are used. Accordingly, there is a constant search for pharmaceutical agents that, acting as cyclooxygenase inhibitors, as well as by any additional principle of action, produce significantly reduced adverse gastrointestinal reactions and resulting side effects.

More recently, it was discovered that in humans and almost all other studied mammalian species, cyclooxygenase (COX) includes two isoenzymes, a constitutive enzyme (COX-1) and an inducible enzyme (COX-2), which have different activities in different systems. The identification of COX-2 led to the hunch that COX-2 may be responsible for the production of prostaglandins solely or mainly in areas of inflammation. Since it has now been shown that this is so, selective inhibition of the COX-2 isoenzyme should reduce inflammation without the side effects of gastrointestinal toxicity. COX-1 and COX-2 are homologous to 60%, have similar K _m values, and the same arachidonic acid binding sites, but COX-2 has a wider range of substrates than COX-1.

Another metabolic pathway leads from the aforementioned arachidonate to the production of leukotrienes through the action of lipoxygenase. Some of these leukotrienes are also mediators of inflammation.

Accordingly, a lot of effort has been expended in the search for pharmaceutical agents that are dual inhibitors of both cyclooxygenase and lipoxygenase.

A specific NSAID that is used to treat inflammatory diseases in dogs, and the only one of the two currently existing that has been approved by the Veterinary Medicine Committee of the U.S. Food and Drug Administration for this purpose, is the aforementioned carprofen . Carprofen, racemic 6-chloro-a-methylcarbazole-2-acetic acid, belongs to the class of NSAIDs, which is arylpropionic acid. Other members of this class are, for example, benoxaprofen, cycloprofen, phenoprofen, flurbiprofen, furaprofen, indoprofen, ketoprofen, pirprofen and suprofen. Although these compounds are similar in structure, they can nevertheless have various anti-inflammatory and other biological properties. For example, it has been shown that carprofen is a relatively weak cyclooxygenase inhibitor, but it has also been shown that in humans and in various animal models it significantly reduces pain and swelling, and other inflammation syndromes. These carprofen ratings are presented in the technical literature, some of which are cited and discussed below. It has also been shown that carprofen is inactive against lipoxygenase in rats and, presumably, does not block the production of leukotrienes. Although the principle of action of carprofen is still unclear, it has been shown that it has some activity against phospholipase A2.

Description of the prior art

The current state of knowledge in this area, as the descriptions of the literature discussed below show, turned out to be largely confused when trying to explain the mechanisms of action in dogs by which carprofen can have good anti-inflammatory activity and at the same time exhibit minimized adverse gastrointestinal and other reactions. In the prior art, carprofen is characterized as having a weak activity of a cyclooxygenase inhibitor, and it is concluded that for this reason it must act by some completely different mechanism of action.

As noted above, there has recently been a report on the existence of constitutive COX-1 and inducible COX-2 isoenzymes, and their different roles in protecting the gastrointestinal mucosa and in mediating inflammation, respectively. Naturally, this led to research and the search for compounds that, when used in dogs, as well as in other animals and humans, could inhibit only the inducible COX-2 isoenzyme, that is, to be selective COX-2 inhibitors. These studies included, in particular, an assessment of the inhibitory activity of enantiomers of various NSAIDs, including especially ketoprofen, ketorolac, and fluurbiprofen. These specific NSAIDs were tested for differences in the strength of the inhibitory effect of one enantiomer compared to another, as well as for the strength of the inhibitory effect in the case of each enantiomer individually against the COX-1 enzyme compared to the strength of the inhibitory effect against the COX-2 enzyme. The results of these studies showed that for all three NSAIDs, their enantiomers were equally effective against both enzymes, COX-1 and COX-2. Thus, neither the B- nor the δ-enantiomer of any of these NSAIDs showed any selectivity for COX-1 or COX-2. Despite the fact that there were indeed differences in the strength of action between the enantiomers, and in each case the δ enantiomer was more potent, but with regard to the inhibition of COX-1 compared to COX-2, each enantiomer showed an equal inhibitory strength, t. e. neither one nor the other enantiomer was able to distinguish between these two isoenzymes.

Accordingly, as a result of these previous studies, it has not yet been established in the state of the art that carprofen or any of the other classic NSAIDs having a carboxylic acid moiety are selective COX-2 inhibitors in dogs or any other species. These conclusions were supported by the description in the prior art of the conformation of sequenced structures of the COX-1 isoenzyme, as well as the COX-2 isoenzyme, in complexes with various inhibitors, at the level of their main functional molecular configurations. As a result, according to the state of the art, inhibitors containing a carboxylic acid group, such as carprofen, are inherently incapable of being selective COX-2 inhibitors. To date, it is only known that compounds containing a sulfonyl group and nabumetone, a naphthalenyl-2-butanone compound, are selective inhibitors of the COX-2 isoenzyme.

In addition, recently in this area, in connection with the aforementioned discovery of the existence of constitutive COX-1 and inducible COX-2 isoenzymes, studies have been conducted using various animal species in order to verify the existence of any stereoselective inhibition specific for one or more than one of these species. These studies of the individual activity of the B- and δ-enantiomers of specific NSAIDs in the inhibition of COX-1 compared to COX-2 in different animal species showed that there is a steady difference in the strength between the B- and 8-enantiomers of all the studied chiral NSAIDs. However, these studies also showed that neither the B- nor the 8 enantiomers of any investigated chiral NSAIDs have species-specific selectivity for COX-1 compared to COX-2. For example, it was shown that although in this animal species the 8-enantiomer, for example, is three times stronger than the B-enantiomer, inhibits both COX-1 and COX-2 isoenzymes, but with regard to each of these of the same isoenzymes, the 8-enantiomer shows the same potency in inhibiting both COX-1 and COX-2, that is, the 8-enantiomer does not show selective inhibition of COX-2 in these species.

From the point of view of the state of the art described above, especially if the species being examined are dogs, it was completely unexpected that in accordance with the present invention it was found that carprofen is an unexpectedly strong inhibitor of the COX-2 isoenzyme in dogs, and that it is also selective in dogs COX-2 inhibitor. Moreover, the selectivity of carprofen for COX-2 is two times higher than the selectivity of almost all other NSAIDs, including NSAIDs containing a carboxylic acid group, and, presumably, selective for COX-2 NSAIDs containing a sulfonyl group. The choice of carprofen from among all other NSAIDs as a selective COX-2 inhibitor in dogs, superior to all others, not only contradicts modern concepts in this field, but also is a completely unexpected discovery in the sense of the amazing results achieved. The fact that all other NSAIDs evaluated in this document have been approved in the United States for introduction to people, including those currently on sale, confirms these findings. Carprofen stands out from all the other NSAIDs evaluated here, including those that have been approved for human use or for clinical trials.

From the point of view of the state of the art described above, especially if the species being examined are dogs, it was also completely unexpected that in accordance with the present invention it was found that the 8 enantiomer of carprofen is a highly selective inhibitor of the COX-2 isoenzyme in dogs compared to the COX-1 isoenzyme, and to a much greater extent than all other NSAIDs or their 8-enantiomers, including NSAIDs containing a carboxylic acid moiety, and, presumably, COX-2 selective NSAIDs containing sulfone battening group. The choice of the 8-enantiomer of carprofen from among all other NSAIDs as such an outstanding selective inhibitor of the COX-2 isoenzyme in dogs, which at the same time exhibits slight or does not exhibit adverse gastrointestinal or other reactions in dogs, not only contradicts modern concepts in this field, but it is also a completely unexpected discovery in the sense of the amazing results achieved. The fact that all other representatives of NSAIDs reviewed here, including even those currently on sale, have been approved in the United States for introduction to people, confirms the validity of these findings.

From the point of view of the state of the art described above, especially if the species being examined are dogs, it was also completely unexpected that in accordance with the present invention it was found that the 8 enantiomer of carprofen, due to the fact that it is a highly selective inhibitor of the COX-2 isoenzyme, has an unexpectedly increased the level of anti-inflammatory, analgesic and antipyretic activity compared to all other NSAIDs, including those that have a carboxylic acid group, or their enantiomers mi, as well as an unexpectedly reduced level of adverse gastrointestinal and other reactions compared to all other NSAIDs, including those that have a carboxylic acid group, or their enantiomers.

As already mentioned, carprofen belongs to the class of NSAIDs, which are arylpropionic acids, and is also a representative of a subclass of such compounds, which are substituted carbazoleacetic acids. These compounds and their use as anti-inflammatory, analgesic and anti-rheumatic agents are described in US Pat. No. 3,896,145. The anti-inflammatory activity of carprofen in dogs was examined with McKe11ag c! A1., which was reported in RB Bagtasokteysk, Uliegapse apy kegit (kgotokhape ίηΗίόίΙίοη оГ sagrgoGep ίη 1ke iodine, 1oit1 oG 8t11 Ashta1 Prgase, 31, 443-448, 1990. Subsequently, MsKe11ag e biological activity! (B) - and (+) (8) -enantiomers of carprofen, as well as racemic carprofen in dogs, as was reported in 81 Geocres cryopteasocupius apyroptocoxysc. 1994. Reporting on the results of this study, these authors concluded that the principle of action of KPF [carprofen] remains I am unclear ... CPP, administered as a racemic mixture or as either (+) (8) - or (-) (B) -enantiomer, did not substantially inhibit the formation of thromboxane B ₂ (TxB ₂ ) from the blood or prostaglandin E ₂ (RFE ₂ ) and 12 hydroxyeycososetetraenate (12-NO) in inflammatory exudate, which implies that it does not act as a traditional NSAID.

It is known that the main principle of action of most NSAIDs is the inhibition of the cyclooxygenase enzyme in the generation of inflammatory prostaglandins from arachidonic acid.

... A large number of mediators, which are now known to be involved in inflammation, provide many possible targets for anti-inflammatory drugs, and it is likely that KPF has its main activity, which consists in acting on a number of mediators that are not yet identified.

Thus, these researchers working in this field have come to the conclusion that carprofen has a principle of action that is not primarily related to the inhibition of cyclooxygenase; and that in fact, the weak activity of carprofen against cyclooxygenase, lipoxygenase, and phospholipase confirms that its basic principle of action can be realized by mechanisms other than inhibition of eicosanoids. Such observations and conclusions have directed other researchers working in this field away from the unexpected discovery of the present invention that dogs given carprofen show almost complete inhibition of PCE ₂ synthesis, as shown in the working example below.

Another study of carprofen in dogs was reported by No1! a1. in Thieu Tiegareijs EGPsasu ok Sagrgokep (R1tabu-U ™) 1992; 5: 140-144. These authors, based on research by ίη ugo, put forward the theory that carprofen can and does have its anti-inflammatory effect, at least in part, by inhibiting neutrophil migration, and this may explain how carprofen can be equivalent to indomethacin as an anti-inflammatory agent and while having 16 times lower ulcer formation potential. However, these authors, making their conclusion, expressed many reservations and therefore were unable to identify the direction to the discovery on which the present invention is based.

A study of the use of carprofen for the treatment of osteoarthritis in dogs was reported by Wackeig e! a1. in Rapbopiheb, sop1go11eb k1ib ok 1st yyeksasu ok sagrgokep, and popk! his1ba1 apyshPapppaYugu bgid, sh 1ye 1gea1tep1 ok oCheoPypyk sh bodk, 1 At Ye! Meb Akkos, 206 (6): 807-811, 1995. These researchers also could not explain the activity of carprofen. On the one hand, they concluded that prostaglandins protect the gastrointestinal mucosa and that carprofen, like other NSAIDs, inhibits prostaglandinsynthetase, blocking the biosynthesis of prostaglandins. However, this conclusion was not consistent with the results of their study, which showed that in dogs carprofen has minimal harmful effects on the gastrointestinal mucosa or does not have them.

A study on the use of carprofen for the treatment of acute postoperative pain in dogs has been reported by LAX11EK e! a1. In Rock! .. in therapeutic doses, it appears to be a weak inhibitor of prostaglandin synthetase (or cyclooxygenase), an enzyme responsible for the synthesis of inflammatory mediators caused by tissue damage, while at the same time recognizing, on the other hand, that studies have shown that this is a good pain relief Detergent for both acute and chronic pain.

A much earlier study, which was a comparison of the biological activity of indomethacin with the biological activity of stereoisomers and carprofen racemate in humans, was carried out by Sai! e! A1, which was reported in 8! egeo1koteps Re1a! yupkyrk Atopd Apy-shk1atta! ogu Asyuyu, 1py1b1yop ok Р1а! е1е! Addgyediop, apb 1nLyyup ok Prgok! Ad1apbt 8up! Ee! Ake, RRO8TASYA] \ 1BW8, Wo1. 10, N0.1, 1i1u 1975. This study led to the conclusion that, unlike indomethacin, carprofen racemate does not affect platelet aggregation and, therefore, does not cause an increase in bleeding time at doses with anti-inflammatory activity. From the data of this study, it also follows that carprofen racemate and [8] isomer have greater specificity in favor of anti-arthritic activity and, to a lesser extent than indomethacin, leads to ulceration.

Some of the advances in prostaglandin research that were presented at the 9th International Conference on Prostaglandins and Related Compounds in 1994 focused on selectivity for COX-2. The message presented there is Wa! Yk! 1sh e! A1., entitled COX-1 apb COX2: That \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\:: T Nelsky and published in ΌΝ & Ε, 7 (8), Oct. 1994, contained comparative data obtained on a wide variety of cell types, including human, mouse and rat types, using various stimuli, as described in the sources of information referenced by YOURS! a1. Data were presented that demonstrated 1C ₅₀ values against COX-1 and COX-2 for numerous anti-inflammatory compounds, including carprofen, and the ratio of COX-1 / COX-2 was used to determine selectivity for COX-2. By reversing the ratios reported by Ba! Ϊ́ίδΐίηί e! A1. so that they, for ease of comparison, correspond to the ratios used here, the compounds most selective for COX-2 have ratios from 1428.57 to 50,000.00. It was shown that the values of 1C ₅₀ (μM) of carprofen for both COX-1 and COX-2 are exactly the same (10.96) with a ratio of 1.00, which clearly demonstrates that carprofen does not have selectivity against COX-2. About the meanings that led you! A1., originally reported Akagakegeepop! e! a1. at Ke1abue Ro! epsu £ Ы к его! 1 1 1 п Ап 11 аш Э Э Э Э Э Э ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ! 1. Rnagtasoe. Rgoseebshdk 8irr. BO 183P, 5-7 1st year 1994, and Mysie 11 e! a1. ! Same group 8e1esbuyu about £ ETRP ego1ba1 apYpPattaYugu bgtsdk ak 1pYyogk about £ sopkShiOue APB tbiaYe sus1oohudepake, Proc Na 1 Asab 8s1 I8A, 90: 11693-7, 1993. 1C ₅₀ values (mcg / ml) (n = 9 ) inhibition of COX-1 by carprofen (from bovine aortic endothelial cells) and COX-2 (from lipopolysaccharide-stimulated macrophages 1774.2) were 3 ± 0.41 and 3 ± 1.72, respectively, which gives a ratio of 1.00. This is in complete contradiction with the data for several compounds, with respect to which it was shown that they have 1000-4000 times greater selectivity for COX-2. This report noted that none of the described selective COX-2 inhibitors is a carboxylic acid, like the vast majority of available NSAIDs, including carprofen. In fact, all selective COX-2 inhibitors have a sulfonyl group in the molecule, which, in the case of meloxicam, is included in its ring structure of 1,2-benzothiazine-1,1 dioxide. This post suggests that if this correlation is valid, then the Arg-150 residue in the COX protein should not be an indispensable binding site for selective COX-2 inhibitors. Arginine is necessary for COX activity because it binds the terminal carboxyl group of arachidonic acid and, thus, is most likely the binding site for the carboxylic acid functional group of most existing NSAIDs. Accordingly, it can be expected that an inhibitor that is selective for COX-2 will be associated with a trait that is unique to the structure of the COX-2 isoenzyme protein, and not with a trait that is common to both COX-1 and COX protein structures -2.

An even more specific interpretation of the molecular interactions of classical NSAIDs and selective COX-2 inhibitors with the protein structure of synthase enzyme

RON, more commonly known as the cyclooxygenase enzyme, was reported by Kigitai e! but!. in 81gisliga1 Vak1k £ og 8e1esOue 1nByyu o £ Ss1oohudepake-2 LU Ap! 1-1nDatta! og Adep! k, ΝΛTIКЕ 384, 644-649, hereby 1996. This interpretation is based on non-mouse structures presented in this message 2 with ligands, and its complexes with flurbiprofen, indomethacin and 8C-558, a selective COX-2 inhibitor having a phenylsulfonamide group but not having a carboxylic acid group, which are defined with a resolution of 3.0 to 2.5 A.

The message under consideration indicates that the human and mouse COX-2 enzymes are considered very similar due to 87% identity and strict sequence preservation in the active center of cyclooxygenase.

Flurbiprofen, a slowly binding competitive inhibitor of both COX-1 and COX-2, binds in a long hydrophobic channel and displaces the substrate from the cyclooxygenase active center. 8C-558 is a diaryl heterocyclic inhibitor with a central pyrazole ring and a sulfonamide group attached to one of the aryl rings. In COX-2, the channel that leads from the membrane to the cyclooxygenase active center branches out at the 8C-558 binding site, with one branch forming a cavity that receives the 8C-558 bromophenyl ring, while the other branch forms a pocket, which in the COX structure -1 is practically unavailable, but in COX-2 it contains the entire phenylsulfonamide moiety. This pocket is more accessible in COX-2, because at position 523 valine replaces isoleucine, which has a larger side chain. The access of the phenylsulfonamide group to a new pocket in COX-2 is facilitated by another replacement of isoleucine with valine at position 434, which forms a molecular passage extending through the new hydrophobic pocket. Finally, at position 513, the histidine in COX-1 is replaced by arginine in COX-2, and the combination of these two enzymes suggests that the imidazole ring of the histidine in the COX-1 enzyme should not extend enough for direct interaction with the sulfonamide group 8C-558, as it has place with arginine in the COX-2 enzyme. In the considered message, it was noted that in each of the three cases described above, the inhibition profile of COX-2 changes dramatically by a mutation of a single amino acid.

Further, this message under consideration comes to the conclusion that it seems possible that the phenylsulfonamide group is the primary determinant of COX-2 selectivity in the diarylheterocyclic class of inhibitors, to which 8C-558 belongs. However, the absence of a carboxylate group is also significant. Arginine at position 120 with its guanidinium group is one of the few charged residues in the hydrophobic channel of cyclooxygenase, and it stabilizes the carboxylate of classical NSAIDs, such as flurbiprofen, by the interaction of charges. It is possible that the absence of such a carboxylate group in 8C-558 is also an important component of its selectivity for COX-2. This conclusion is confirmed by the results of attempts to improve its effectiveness against COX-2 by introducing an acid group on the pyrazole diaryl heterocyclic structure, which invariably led to poor selectivity. This message under consideration contains the first example of a membrane protein that has been successfully studied as a target in the structural design of drugs and brings the current state of the art closer to the relationship between the structure and activity of NSAIDs with respect to cyclooxygenase isoenzymes and their resulting anti-inflammatory activity as opposed to their unfavorable gastrointestinal reactions. It is in the context of this state of the art that the present invention appears to be a completely unexpected achievement, which, surprisingly, provides an optimal efficacy / safety profile for treating inflammation in dogs.

The possibility of enantioselective inhibition of COX-2 was investigated by CagLax c1 a1. and reported it in 81geekesesue еηΗίόίΙίοη about! The First Sustainable Dyuyu Shyga1 Yoik1eg1ya1 ApnPattaYugu Igidk, 1 S1sh Ragshaso1 1996; 36: 505-512. The stereoselective inhibition of COX-2 by ketoprofen, flurbiprofen and ketorolac was studied in three different ίη ugo systems, and the results were compared with the inhibition of COX-1 in three parallel ίη ugo models. It was found that both isoenzymes were inhibited by the 8-enantiomers of all three NSAIDs to the same degree, but the B-enantiomers of all three NSAIDs inhibited both isoenzymes with significantly and correspondingly lower efficiency. In other words, all three B-enantiomers showed equal efficacy in inhibiting both COX-1 and COX-2, but all levels of their effectiveness were much lower than the levels of the corresponding 8-enantiomers in all cases. The significant degree of enantioselectivity referred to in this post refers only to B- compared to 8- and does not apply to COX-2 selectivity, which, according to the present invention, the 8-enantiomer of carprofen uniquely exhibits.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method for the treatment or prevention of pain and inflammatory processes and diseases associated with the activity of inducible cyclooxygenase-2 (COX-2) in an individual of the species Sash GashShayk, which needs such treatment, while reducing or eliminating unwanted side effects, associated with the simultaneous inhibition of the activity of constitutive cyclooxygenase-1 (COX-1), by selective inhibition of the activity of COX-2 relative to the activity of COX-1, and the selectivity ratio inhibitory activity of COX-2: COX-1 is at least 3: 1 based on the levels of inhibition of ex U1yo in whole blood, measured at a dose giving> 80% inhibition of COX-2, preferably> 90% inhibition of COX-2 in which said specimen of the Sash GashI1ag1k species is administered a therapeutically effective amount for the treatment of pain and inflammation, in accordance with the above limitations, the amount of an anti-inflammatory COX-2 selective inhibitor compound independently selected from the group of anti-inflammatory compounds consisting essentially of salicylic acid derivatives paminofenola, indole and indenuksunyh acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids, enolic acids, and alkanones.

It is also within the scope of the present invention to implement the above method of treating or preventing pain and inflammatory diseases and processes by administering more than one compound selected from the above group of anti-inflammatory compounds. The desirability of any such combination of anti-inflammatory active agents will likely be based on obtaining a favorable balance of pharmacokinetic properties of the intended individual agents. For example, the onset of onset of action may be balanced with extended therapeutic half-life, or the tendency to form large cell reservoirs in certain tissues may be balanced with higher levels of plasma protein binding.

All such combinations are intended to be included within the scope of the present invention.

The present invention provides an anti-inflammatory selective COX-2 inhibitor that satisfies the limitations described above. Among such selective inhibitory compounds, there is a preferred subclass of carprofen compounds suitable in the treatment or prevention of pain and inflammatory processes and diseases in an individual of the Sash GashIlag1k species, of the formula:

i am ⁹

Formula (I) in which

I ² represents

where A represents hydroxy, (C ₁ -C ₄ ) alkoxy, amino, hydroxyamino, mono (C ₁ -C ₂ ) alkylamino, di- (C ₁ -C ₂ ) alkylamino; X and Υ independently represent H or (C ₁ -C ₂ ) alkyl; and η is 1 or 2;

I ⁶ represents halogen, (C ₁ -C ₃ ) alkyl, trifluoromethyl or nitro;

I ⁹ represents H, (C1-C2) alkyl; phenyl or phenyl- (C1-C2) alkyl wherein phenyl is optionally monosubstituted with fluorine or chlorine; —C (= O) —I, where I is (C1-C2) alkyl or phenyl, optionally monosubstituted with fluorine or chlorine; or -C (= O) -O-I ¹ where I ¹ is _(C1-C2) alkyl;

where X and Υ are different, its (-) (I) - and (+) (8) enantiomers and all their pharmaceutically acceptable salt forms, prodrugs and metabolites that are therapeutically active to treat or prevent pain and inflammation. If an inhibitor of formula (I) exists in the form of (-) (I) - and (+) (8) enantiomers, then according to the present invention, one (+) (8) enantiomer is provided, or if both enantiomers are present together, it is contemplated their racemic or non-racemic mixture.

Further, the present invention provides a preferred aspect of the above method of treating or preventing pain and inflammatory processes and diseases in an individual of the Sash GatShapk species in need of such treatment in which said individual is administered a therapeutically effective amount of COX-2 anti-inflammatory selective in the treatment of pain and inflammation inhibitory compound for which efficacy ίη νίΐτο 1C ₅₀ in said individual by at least 30 times, preferably at least 40 times, more redpochtitelno at least 50 times, even more preferably at least 60 times, even more preferably at least 80 times, most preferably at least 100 times greater than its effectiveness ίη νίΐτο 1C ₅₀ against COX 1 in the indicated individual, wherein said inhibitor is selected from the group of anti-inflammatory compounds consisting mainly of derivatives of salicylic acid and derivatives of p-aminophenol, indole and indenoacetic acids, heteroaryl acetic acids, arylpropionic acids, anthrinilic acids, and eno ovyh acids, and alkanones.

According to the present invention, another preferred aspect of the above method of treating or preventing pain and inflammatory processes and diseases in an individual of the Sash GatShike species in need of such treatment is provided in which said individual is administered a therapeutically effective amount of COX-2 anti-inflammatory selective in the treatment of pain and inflammation an inhibitory compound that inhibits essentially only inducible COX-2, essentially in the absence of inhibition of the corresponding constitutive oh COX-1.

In addition, the above methods are provided in which said therapeutically effective amount of an anti-inflammatory compound of formula (I), as defined, and in particular said (+) (8) - enantiomer 6-chloro-a-methyl-9H-carbazole-2- acetic acid, systemically enter the specified individual Sash GatShayk, and the specified systemic introduction includes:

(1) injection or infusion into appropriate tissues or cavities of the body of a pharmaceutical composition containing said inhibitor in a suitable liquid form for delivery of said inhibitor by systemic administration, which is intra-arterial, intra- or transdermal, subcutaneous, intramuscular, intravertebral, intrathecal or intravenous, where said inhibitor is contained (a) in solution as a solute;

(b) in the dispersed phase of the emulsion or the dispersed phase of the inverse emulsion, which is drawn upon injection or infusion, said emulsion containing suitable emulsifying agents; or (c) in suspension in the form of a suspended solid in colloidal or microdispersed form, said suspension containing suitable suspending agents;

(2) injection or infusion into the appropriate tissue or body cavity of a pharmaceutical composition containing said inhibitor in a suitable liquid form to serve as a depot for delivering said inhibitor by systemic administration, said composition providing storage of said inhibitor and subsequently delayed, prolonged and / or controlled release of said inhibitor for systemic distribution;

(3) instillation, inhalation or insufflation of a pharmaceutical composition containing said inhibitor in a suitable solid form into the appropriate tissues or cavities of the body to deliver said inhibitor, wherein said inhibitor is contained in (a) a solid implant composition that is placed in the corresponding tissues or cavities of the body, wherein said composition provides sustained, sustained and / or controlled release of said inhibitor;

(b) in a dispersed composition that is inhaled into the lungs; or (c) in a dispersed composition that is blown into the appropriate tissues or cavities of the body, wherein said composition possibly provides sustained, prolonged and / or controlled release of said inhibitor; or (4) swallowing a pharmaceutical composition containing said inhibitor in suitable solid or liquid form for oral delivery of said inhibitor, wherein said inhibitor is contained (a) in solid dosage form or (b) in liquid dosage form. Suppositories can be considered as a special type of implant, because they contain bases that are solid at room temperature but melt at body temperature, slowly releasing the active ingredient with which they are impregnated into the surrounding body tissue, where this active ingredient is absorbed and transported. by systemic administration. Dosage forms are also contemplated for administration through the skin or mucous membrane to achieve systemic delivery, in particular a transdermal patch.

Further, the above-described method of treating or preventing pain or inflammation is provided, comprising swallowing or administering a solid oral dosage form selected from the group consisting of an oral tablet, capsule, droplet, lozenges, troches, and a combination of delayed release particles; enteric-coated tablets and capsules that prevent release and absorption in the stomach to facilitate delivery distally to the dog’s stomach;

sustained release oral tablets, capsules and microparticles that provide systemic delivery of the active ingredient in a controlled manner for at least a 10-hour period; instant tablets, encapsulated solutions, oral paste, granular form introduced in or intended for administration to a dog’s food that is being treated, and a chewable form in which said active ingredient is eaten along with flavoring gum, or may be delivered by leaching from the mass of gum that is not eaten when chewed by a dog being treated. Along with the dosage forms described above, microencapsulated active ingredient formulations are also included in the dosage forms, which can then be included in a tablet, capsule, or other finished preparation. Further, the said method is proposed, including swallowing a liquid oral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture and concentrate, possibly for adding to the dog that is being treated in drinking water. Any of these liquid dosage forms, when prepared in accordance with methods well known in the art, can either be administered directly to the dog being treated or added to the drinking water of the dog being treated. On the other hand, a liquid form of the concentrate is prepared to be added first to a predetermined amount of water, from which an aliquot can be taken for direct administration to a dog or for addition to a dog’s drinking water.

In addition, the above methods are provided in which said therapeutically effective amount of an anti-inflammatory compound of formula (I), as defined, is administered locally to the site of inflammation of said Sash GashShapk specimen. Another proposed method of local administration, wherein said local administration includes: (1) injection or infusion into a local site of inflammation of a pharmaceutical composition containing said inhibitor in a suitable liquid form for delivery of said inhibitor by local administration, which is intra-arterial, intra-articular , intracranial, intracostal, intracystic, intracranial and percutaneous, intrafascial, intraciliary, intramuscular, intramuscular, intralural ostnoe, intrapelvic, vnutriperikardnoe, intravertebral, intrasternal, intrasynovial, or intrathecal administration intrapredplyusnoe; including components that provide sustained release, controlled release, and / or sustained release of said inhibitor to said local site of inflammation, said inhibitor being contained in (a) in solution as a solute; (b) in the dispersed phase of the emulsion or the dispersed phase of the inverse emulsion, which is drawn upon injection or infusion, said emulsion containing suitable emulsifying agents; or (c) in suspension in the form of a suspended solid in colloidal or microdispersed form, said suspension containing suitable suspending agents; (2) injection or infusion of a pharmaceutical composition containing said inhibitor in a suitable liquid form to serve as a depot for delivering said inhibitor to said inflammation site, said composition providing storage of said inhibitor and subsequently delayed, prolonged and / or controlled release said inhibitor for systemic distribution; or (3) instillation, inhalation or insufflation of a pharmaceutical composition containing said inhibitor in a suitable solid form for delivering said inhibitor to said inflammation site, where said inhibitor is contained in (a) a solid implant composition that is inserted into said local site of inflammation, said composition provides sustained, sustained and / or controlled release of said inhibitor; (b) in a dispersed composition that is inhaled to a local site of pneumonia; or (c) in a dispersed composition that is blown into a local site of inflammation, where said composition possibly provides sustained, prolonged and / or controlled release of said inhibitor to said local site of inflammation. Other specific dosage forms for topical administration are also within the scope of the present invention. For example, compositions for application to the skin, preferably with improved absorption by mechanical rubbing of the composition into the skin, can be used to deliver the active ingredient of the inhibitor to a local area, such as the area of the inflamed joint in need of such treatment. Such compositions may be in the form of gels, lotions, balms, ointments and other preparations intended for topical application.

The methods described above are also provided in which a therapeutically effective amount of an anti-inflammatory inhibitor is administered to said specimen of the Sash GatShapk species in an amount expressed in mg per kg of body weight of said specimen per day, ranging from about 0.01 mg / kg to about 20.0 mg / kg / day, preferably from about 0.1 mg / kg to about 12.0 mg / kg / day, more preferably from about 0.5 mg / kg to about 8.0 mg / kg / day. Administration of 6-chloro-a-methyl-9H-carbazole-2-acetic acid is typically provided with a dosage of about 4.0 mg / kg / day.

Additionally, the present invention provides a pharmaceutical composition for treating or preventing pain and inflammatory processes and diseases in an individual of the Sash GatShapk species. which needs such treatment, comprising a pharmaceutically acceptable carrier together with a therapeutically effective amount for the treatment of pain and inflammation of an anti-inflammatory selective cyclooxygenase-2 inhibitor (COX 2), the ratio of selectivity for COX-2 and selectivity for COX-1 being at least 3: 1 based on the levels of inhibition of ex νίνο in whole blood, measured at a dose giving> 80% inhibition of COX-2 and preferably> 90% inhibition of COX-2. In a preferred aspect of said pharmaceutical composition for treating and preventing pain and inflammatory processes and diseases, said therapeutically effective anti-inflammatory selective COX-2 inhibitor has an efficacy of 1C ₅₀ ίη νίίτο at least 30 times, preferably at least 40 times, more preferably at least 50 times, even more preferably at least 60 times, even more preferably at least 80 times and most preferably 100 times more than the efficiency against cyclooxygenase-1 (COX-1) at ₅₀ 1C ίη νίίτο, wherein said inhibitor is selected from the group of antiinflammatory compounds consisting essentially of salicylic acid derivatives and para-aminophenol derivatives, indole and indenuksusnyh acids geteroarilukususnyh acids, arylpropionic acids, Anthranilic acids, enolic acids and alkanones.

In addition, the above-described pharmaceutical composition is provided in which said inhibitor is selected from the group consisting of arylpropionic acids, and, moreover, said inhibitor is a compound of formula (I) as defined above. Further, the above-described pharmaceutical composition is proposed, wherein the effectiveness of the inhibitory compound of formula (I) with respect to cyclooxygenase-2 (COX-2) at 1C ₅₀ ίη νίίτο is at least 100 times greater than its effectiveness with respect to 1C ₅₀ ίη νίίτο with respect to cyclooxygenase- 1 (COX1), where one of X and Υ is H and the other is methyl, and where, when both enantiomers are present, the (+) (8) -enantiomer is present in an amount of at least 75%. In particular, the pharmaceutical composition described above is provided wherein, for formula (I), for B ² , η = 1, one of X or Υ is H and the other is methyl, A is hydroxy, (C1-C2) alkoxy, or amino, B ⁶ represents chloro or trifluoromethyl, and B ⁹ represents H, methyl, acetyl, benzoyl or acetyloxy; and where, when both obtained enantiomers are present together, the (+) (8) enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99%.

In addition, the pharmaceutical compositions described above are provided in which said inhibitor consists of 6-chloro-a-methyl

9H-carbazole-2-acetic acid, wherein when both obtained enantiomers are present together, the (+) (B) -enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99%. In particular, the pharmaceutical composition described above and below is provided in which said inhibitor consists entirely of the ^^ - enantiomer of 6-chloro-a-methyl-9H-carbazole-2-acetic acid.

The pharmaceutical compositions described above are also provided in which a therapeutically effective amount of an anti-inflammatory inhibitor present is sufficient, in the context of the dosage and administration parameters used, to provide the individual to be treated with the amount of said inhibitor, expressed in mg per kg body weight of said individual day in the range of from about 0.01 mg / kg to about 20.0 mg / kg per day, preferably from about 0.1 mg / kg to about 12.0 mg / kg / day, more preferably from approximately 0.5 mg / kg to about 8.0 mg / kg / day. Administration of 6-chloro-a-methyl9H-carbazole-2-acetic acid is typically provided with a dosage of about 4.0 mg / kg / day.

In yet another preferred aspect of the pharmaceutical compositions of the present invention, there is provided an anti-inflammatory selective COX-2 inhibitor that selectively inhibits essentially only inducible COX-2, essentially without inhibiting the corresponding constitutive COX-1. In particular, in its preferred embodiment, it comprises a pharmaceutically acceptable carrier, together with a therapeutically effective amount for the treatment of pain and inflammation, of an anti-inflammatory selective COX-2 inhibitor, which is a compound of formula (I), wherein for B ² p = 1, one of X or Υ represents H and the other represents methyl; A is hydroxy, _(C1-C2) alkoxy or amino; B ⁶ represents chloro or trifluoromethyl, and B ⁹ represents H, methyl, acetyl, benzoyl or methoxycarbonyl; and (+) ^) - enantiomer is present in an amount of at least 99%. In particular, said inhibitor consists entirely of the (+) ^) - enantiomer of 6-chloro-a-methyl-9Hcarbazole-2-acetic acid. Preferably, in said pharmaceutical composition, said therapeutically effective amount of said inhibitor is sufficient, in the context of the dosage and administration parameters used, to provide the individual to be treated with an amount of said inhibitor expressed in mg per kg body weight of said individual per day within from about 0.5 mg / kg to about 8.0 mg / kg / day.

Also proposed is the pharmaceutical composition described above in dosage form, which can provide the desired therapeutically effective amount for the treatment of pain and inflammation of the anti-inflammatory selective COX-2 inhibitor in a convenient manner. However, it is assumed that a number of the pharmaceutical compositions described above and below are long-acting compositions, that is, they provide inhibitory activity for longer than just hours or one day, namely: they provide such activity for several days up to a week or more. In particular, implants and depots are examples of such long-acting pharmaceutical compositions, and it is believed that some of them provide inhibitory activity for up to a month or more. The required therapeutically effective amount of the inhibitor needed to treat and prevent pain and inflammation, expressed in mg per kg of body weight of the specimen of the species Sash GashShapk per day, ranges from about 0.01 mg / kg to about 20.0 mg / kg / day, preferably from about 0.1 mg / kg to about 0.01 mg / kg / day, more preferably from about 0.5 mg / kg to about 10.0 mg / kg / day, and most preferably from about 0.5 mg / kg to about 8.0 mg / kg / day. Administration of 6-chloro-amethyl-9H-carbazole-2-acetic acid is typically provided with a dosage level of about 4.0 mg / kg / day.

In particular, the pharmaceutical compositions described above are further provided wherein said therapeutically effective amount of an anti-inflammatory inhibitor for treating pain and inflammation is provided in a dosage form suitable for systemically administering said Sash 1ash Shapk specimen, said pharmaceutical composition containing said inhibitor in a suitable liquid form for delivery of said inhibitor : (1) an injection or infusion that is intra-arterial, intra- and percutaneous, subcutaneous, intramuscular nasal, intravertebral, intrathecal or intravenous, the indicated inhibitor being contained: (a) in solution as a dissolved substance, (b) in the dispersed phase of the emulsion or the dispersed phase of the reverse emulsion, which is treated by injection or infusion, the emulsion containing suitable emulsifying agents or (c) in suspension in the form of a suspended solid in colloidal or microdispersed form, said suspension containing suitable suspending agents; (2) by injection or infusion into the appropriate tissues or cavities of the body in the form of a depot, wherein said composition provides storage of said inhibitor and, subsequently, delayed, prolonged and / or controlled release of said inhibitor for systemic distribution; (3) by instillation, inhalation or insufflation of the pharmaceutical composition in suitable solid form into the appropriate tissues or cavities of the body, wherein said inhibitor is contained in (a) a solid implant composition that provides sustained, prolonged and / or controlled release of said inhibitor, (b) c a dispersed composition for inhalation into the lungs, or (c) in a dispersed composition for injection into the corresponding tissues or cavities of the body, said composition possibly providing a delayed, prolonged and / or controlled release of said inhibitor; or (4) swallowing said pharmaceutical composition in a suitable solid or liquid form for oral delivery of said inhibitor, said inhibitor being contained (a) in solid dosage form or (b) in liquid dosage form.

In a particularly preferred aspect, the above pharmaceutical compositions that provide sustained, prolonged and / or controlled release of said anti-inflammatory COX-2 inhibitor contain all such dosage forms that produce COX 2 inhibition of> 80% and result in a plasma concentration of said inhibitor at least 10 μg / ml for at least 4 hours, preferably at least 8 hours, more preferably at least 12 hours, even more preferably at least at least 16 hours, even more preferably at least 20 hours and most preferably at least 24 hours. Preferably, the dosage forms described above produce COX-2 inhibition of> 80% and result in a plasma concentration of said inhibitor of at least 15 μg / ml for at least 4 hours, preferably at least 8 hours, more preferably at least 12 hours, even more preferably at least 16 hours and most preferably at least 24 hours. More preferably, the above drugs These forms produce COX-2 inhibition of> 90% and, as a result, give a concentration of the indicated inhibitor in plasma of at least 20 μg / ml for at least 4 hours, preferably at least 8 hours, more preferably at least 12 hours even more preferably at least 20 hours and most preferably at least 24 hours

Specific dosage forms of the above pharmaceutical compositions include suppositories as a special type of implant containing bases that are solid at room temperature but melt at body temperature, slowly releasing the active ingredient with which they are impregnated into the surrounding body tissue, where this active the ingredient is absorbed and transported by systemic administration; solid oral dosage forms selected from the group consisting of an oral tablet, capsule, droplet, lozenges, troches, and a combination of sustained release particles; enteric-coated tablets and capsules that prevent release and absorption in the stomach to facilitate delivery distally to the dog’s stomach; sustained release oral tablets, capsules and microparticles that provide systemic delivery of the active ingredient in a controlled manner for up to 24 hours; instant tablets, encapsulated solutions, oral paste, granular form introduced into or for administration to a dog’s food that is being treated; and a chewable form in which said active ingredient is eaten along with flavoring chewing gum, or it can be delivered by leaching from the mass of chewing gum, which, when chewed, is not eaten by the dog being treated; liquid oral dosage forms selected from the group consisting of solutions, suspensions, emulsions, inverse emulsions, elixirs, extracts, tinctures and concentrates, it is possible to add the dog that is being treated to drinking water. Any of these liquid dosage forms, when prepared according to methods well known in the art, can either be administered directly to the dog being treated or added to the drinking water of the dog being treated. On the other hand, a liquid form of the concentrate is prepared to be added first to a predetermined amount of water, from which an aliquot can be taken for administration to a dog or for addition to a dog’s drinking water.

Further, the above-described pharmaceutical compositions are provided in which said therapeutically effective amount of said anti-inflammatory inhibitor for the treatment of pain and inflammation is provided in a dosage form suitable for topical administration to the site of inflammation of said Sai15 GashShapk specimen, said pharmaceutical composition containing said inhibitor in a suitable liquid form for delivery of the indicated inhibitor (1) by injection or infusion into the local site of inflammation by intra-arterial, int articular, intracartilaginous, vnutrirebernym, vnutrikistoznym, intra- and transdermal, vnutrifastsi25 cial, intraligamentary, intramedullary, intramuscular, intranasal, vnutrinevralnym, intraocular, i.e., ophthalmologic, intraosseous, intrathoracic, intrapericardial, intravertebral, intrathoracic, intrasinovial, intrapreparal or intrathecal;

including components that provide sustained release, controlled release, and / or sustained release of said inhibitor to said local site of inflammation; wherein said inhibitor is contained (a) in solution as a solute; (b) in the dispersed phase of the emulsion or the dispersed phase of the inverse emulsion, which is drawn upon injection or infusion, said emulsion containing suitable emulsifying agents; or (c) in suspension in the form of a suspended solid in colloidal or microdispersed form, said suspension containing suitable suspending agents; (2) injection or infusion in the form of a depot for delivery of the indicated inhibitor to the specified local site of inflammation; moreover, the specified composition provides storage of the specified inhibitor and, subsequently, the delayed, prolonged and / or controlled release of the specified inhibitor in the specified local area of inflammation; or wherein said pharmaceutical composition comprises said inhibitor in suitable solid form for delivering said inhibitor (3) by instillation, inhalation or insufflation to said local site of inflammation, where said inhibitor is contained in (a) a solid implant composition that is inserted into said local site of inflammation, wherein said composition provides sustained, sustained and / or controlled release of said inhibitor to said local site of inflammation; (b) in a dispersed composition that is inhaled to a local site of pneumonia; or (c) in a dispersed composition that is blown into a local area of inflammation, where said composition contains components that will ensure that said inhibitor has predominantly local activity, with little transient systemic activity, and possibly provides delayed, prolonged and / or controlled the release of the specified inhibitor in the specified local area of inflammation.

The present invention provides combinations of one or more other therapeutically active agents together with the active ingredients for the treatment of pain and inflammation, which comprise the above described pharmaceutical compositions of the present invention. In cases where the joint is severely inflamed and simultaneously infected with microorganisms, for example bacteria, fungi, protozoa, virus and the like, it is desirable to administer the active ingredient of the present invention in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agent. Further, the active ingredient of the present invention can be administered not only in combination with other NSAIDs, but also in combination with inhibitors of other inflammatory mediators, including one or more than one representative selected from the group consisting mainly of such inhibitors and examples thereof, which include H1 receptor antagonists, kinin receptor antagonists B ₁ and B ₂ , prostaglandin inhibitors such as RSE-antagonists. PCE, PC1 ₂ - and PCE receptors. thromboxane A2 inhibitors (TXA2), inhibitors of 5- and 12-lipoxygenases, inhibitors of leukotrienes LTC ₄ , LTC ₄ / LTE ₄ and LB ₄ , antagonists of PAE receptors (platelet activating factor), gold in the form of an aurothio group with different hydrophilic groups, agents, for example cyclosporine, azathioprine and methotrexate, anti-inflammatory glucocorticoids, penicillamine, hydroxychloroquine; anti-gout agents, for example colchicine, xanthine oxidase inhibitors, for example allopurinol, and uricosuric agents, such as probenecid, sulfinpyrazole and benzbromarone. In addition, it is proposed to administer the anti-inflammatory agents of the present invention in combination with therapeutic agents intended for the treatment of disease states, syndromes and symptoms found in old dogs, including one or more of them selected from the group consisting mainly of therapeutic agents and conditions that are treated, which include cognitive therapeutic agents to counteract memory loss and impaired, antihypertensive and other cardiovascular drugs means intended to compensate for the consequences of atherosclerosis, including hypertension, myocardial ischemia, including angina pectoris, persistent heart failure, and myocardial infarction selected from diuretics, vasodilators, such as hydralazine, β-adrenergic receptor antagonists such as propranolol, 11 angiotenin inhibitors a converting enzyme (ACE inhibitors), such as enalapril, used to treat geriatric dogs with mitral regurgitation, and enalapril alone or in combination with an inhibitor mi neutral endopeptidases, angiotensin-торов receptor antagonists such as losartan, renin inhibitors, calcium channel blockers such as nifedipine, sympatholytic agents such as methyl-DOPA, α ₂ adrenergic agonists such as clonidine, α-adrenergic receptor antagonists such like prazosin, and GMGCoA reductase inhibitors (anti-hypercholesterolemia drugs) such as lovastatin or atorvastatin, antineoplastic agents, especially antimitotic drugs, including barb alkaloids NCA, such as vinblastine and vincristine, sekretagogov growth hormone, strong painkillers, local and systemic anesthetics and H ₂ receptor antagonists and other agents that protect the stomach. It is also proposed to use the above combinations of therapeutic agents for the treatment of acute conditions in dogs, including bacterial infections accompanying degenerative joint disease; and for treating chronic conditions in dogs, the regimen used for this purpose includes administering the anti-inflammatory agents of the present invention in combination with other drugs used regularly to treat chronic conditions, including osteoarthritis; it is also proposed to formulate anti-inflammatory agents of the present invention with one or more than one other therapeutic agent, which should form the intended combination, in a convenient dosage form containing all the drugs that make up this combination, including if these different drugs have different half-lives , by creating forms with controlled release of these drugs with different release times, which is achieved relative to uniform dosage; a dosage form of a drug-impregnated feed in which said drugs used in this combination are present together in a mixture in said feed composition. The present invention further provides co-administration in which a combination of drugs is created by simultaneously administering said drugs to give them in combination; including co-administration through various dosage forms and routes of administration; the use of combinations in accordance with various, but regular and continuous dosage regimens, by which the desired levels of the participating indicated drugs are maintained in the plasma of the dog being treated, even if the individual drugs constituting the specified combination are not administered to the specified dog at the same time.

The present invention also provides a packaging suitable for use in trade, for the therapeutic treatment or prevention of pain and inflammation processes and diseases in an individual of the Sashish GashShagi species in need of such treatment, including a suitable container that may be in the form of an external packaging and is removable the internal container placed in it; a suitable dosage form of the active ingredient contained in the indicated container containing a selective COX-2 inhibitor, the ratio of selectivity for COX-2 and COX-1 being at least 3: 1 based on the levels of inhibition of ex νίνο in whole blood, measured at a dose giving> 80% inhibition of COX-2, preferably> 90% inhibition of COX-2, as described here and elsewhere; and printed instructional and informational material connected to said container, which may be attached to said container, embedded in said container or displayed as an integral part of said container, said instructional and informational material containing a statement in words that inform its reader that said active ingredient when administered to the dog to be treated, it effectively inhibits COX-2 induced in the existing or suspected area of pain and inflammation in the indicated dogs, and the ratio of selectivity for COX-2 and COX-1 is at least 3: 1 based on the levels of inhibition of ex νίνο in whole blood, measured at a dose giving> 80% inhibition of COX-2, thus realizing treatment or prevention of the indicated pain and inflammation, which, otherwise, may occur as a result of this. In a preferred aspect of said packaging suitable for use in trade, said instructional and informational material contains a statement in words that convey to the reader that said active ingredient, when administered to the dog to be treated, effectively provides complete inhibition of the COX-2 induced in said dog, whereby treating or preventing pain and inflammation in her, and also that if the specified ingredient is thus administered to the specified dog, then it is essentially not will cause inhibition of constitutive COX1 in said dog, whereby undesirable gastrointestinal and other undesirable effects resulting from a significant inhibition of said COX1 will be excluded in the vast majority of dogs.

The present invention also provides a package such as that described immediately above, including a suitable container as described; an oral dosage form of a compound of formula (I) embedded in said container, which may be in the form of a chewable or swallowed oral tablet, a unit dose packet, called a sachet, a suspension made from the contents of a unit dose packet, an oral suspension powder or an oral suspension per se, which does not cause the effect of disgust; and printed instructional and informational material, as described, coupled to said container, in which there are no express or implied restrictions as to whether said oral dosage form can be taken with or without food.

DETAILED DESCRIPTION OF THE INVENTION

The aim of the present invention is to solve a serious problem regarding the need for an effective but safe anti-inflammatory treatment for dogs that has been facing veterinary medicine for decades. The seriousness and resilience of this problem stems from the fact that almost all anti-inflammatory agents, especially NSAIDs that were tested for use in dogs, had completely unacceptable and sometimes dangerous adverse reactions in dogs that greatly limited the use of these agents. Of course, the most widespread and dangerous of these adverse reactions is an upset and irritation of the gastrointestinal mucosa, leading to ulceration, hemorrhage and, finally, perforation and peritonitis. These unwanted adverse effects are mediated by the inhibition of various prostaglandins by NSAID inhibitors, which leads to a limited blood flow to the protective gastrointestinal mucosa, which in turn dangerously decreases both in the total mass and in the performance of protective functions.

Damage to the stomach NSAIDs is carried out by at least two different mechanisms. Local irritation with orally administered NSAIDs makes it possible to reverse diffuse the acid into the gastric mucosa, causing tissue damage. On the other hand, parenteral administration can also cause damage and bleeding, which are associated with inhibition of the biosynthesis of gastric prostaglandins, which perform a cytoprotective function in the gastric mucosa. These prostaglandins, especially PC1 ₂ and PCE ₂ , inhibit the secretion of acid by the stomach, increase the blood flow of the mucosa, and contribute to the secretion of cytotensive mucus in the intestines. Other undesirable side effects of NSAIDs include platelet dysfunction, prolonged pregnancy or spontaneous delivery, renal function changes, and hypersensitivity reactions.

All the above undesirable side effects of NSAIDs are likely to depend on the blockade of the synthesis of endogenous prostaglandins. Accordingly, there is considerable interest in the discovery of NSAIDs that do not lead to systemic production of such undesirable side effects. Dogs are not only particularly vulnerable to inflammatory processes and diseases, such as degenerative joint disease, but are also particularly prone to complications from the onset of adverse gastrointestinal reactions.

The term dog (s), as used in this document, means any individual of the Sash GatShapk species, in which there are a large number of different breeds. Although laboratory determination of biological activity could be carried out using a particular breed, it is believed that the inhibitory compounds of the present invention are useful for treating pain and inflammation in any of these many breeds.

In its broadest aspects, the essence of the present invention lies in the unexpected discovery that a small class of anti-inflammatory agents, of which carprofen, 6-chloro-a-methyl-9H-carbazole-2-acetic acid, is the best example, has a high degree of selectivity in in relation to canine cyclooxygenase-2 (COX2) and that this selectivity is unique among a large class of carboxyl and carboxy (C1-C4) alkylaryl and / or heteroaryl anti-inflammatory agents, to which carprofen compounds belong. This unique and unexpected selectivity in dogs has far-reaching consequences for the safe and effective treatment of dogs suffering from any of a variety of inflammatory processes and diseases.

Now in the field of treatment of inflammatory processes and diseases, especially in dogs, it is generally accepted that a cascade of endogenous reactions that starts with arachidonic acid, which produces various prostaglandin compounds in the body, is promoted with the help of a special enzyme called cyclooxygenase. It has been established that this enzyme exists in two isoenzyme forms that are independent and act independently - the isoenzyme constitutive cyclooxygenase-1 (COX-1) and the isoenzyme inducible cyclooxygenase-2 (COX-2). COX-1 in dogs is responsible for the production of prostaglandins, which perform important functions in the stomach, intestines, kidneys and blood platelets, some of which are protective in nature, especially in relation to the gastrointestinal mucosa. COX-2 in dogs is responsible for the production of prostaglandins, such as RFE ₂ , which in neutrophils, macrophages, endothelial cells and fibroblasts, where the COX-2 gene is expressed, mediate acute and chronic inflammation. COX-2 can induce endotoxin, lipopolysaccharide (LPS), various cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), growth factors, such as epidermal growth factor (EGF) and platelet growth factor (PSF) , and many other agents. For example, COX-2 can be detected by immunoblotting in mononuclear cells of lung exudate after carrageenan-induced pleurisy in a rat model.

Ultimately, the challenge in this area was to discover compounds that are able to inhibit COX-2 activity in dogs with an efficiency of 100%, while inhibiting COX-1 activity with an efficiency of 0%. In practice, this resulted in a search for compounds that selectively inhibit COX-2, that is, compounds that provide optimal anti-inflammatory therapy by means of relatively high levels of COX-2 inhibition at a dose that also causes minimal undesirable effects through relatively low levels of COX-1 inhibition. . Prior to the discovery of the present invention described herein, it was shown that compounds that exhibit COX-2 selectivity were only those compounds that have a sulfonyl group or sulfonamido group and not a carboxyl group characteristic of the vast majority of classical NSAIDs. These observations suggested that the Arg-150 residue of COX-1 is not an essential binding site for selective COX-2 inhibitors, while Arg-150 is essential for COX-1 activity, since it binds the terminal carboxyl group of arachidonic acid and , similarly, the carboxylic acid functional group of the aforementioned classic NSAIDs. It should be expected that selective COX-2 inhibitors will bind to some unique feature of the canine COX-2 isoenzyme, and not to a trait that is common to the canine COX-1 and COX-2 isoenzymes.

Accordingly, the present invention provides a method for selectively inhibiting inducible cyclooxygenase-2 (COX-2) with respect to inhibiting the corresponding constitutive cyclooxygenase (COX-1), and thereby treating and preventing pain and inflammatory processes and diseases associated with it in an individual Sash GashShapk species in need of such treatment, and the ratio of selectivity for COX-2 and selectivity for COX-1 is at least 3: 1 based on the levels of inhibition ίη νίνο and ex νίνο in whole blood, measured at a dose or dose range giving> 90% inhibition of COX-2, in which the indicated individual is administered an anti-inflammatory compound in an amount therapeutically effective for the treatment of pain and inflammation in accordance with the above limitations.

Further, according to the present invention, there is provided a method for treating or preventing pain and inflammatory processes and diseases in an individual of the Sash GatShapk species, wherein said anti-inflammatory selective COX-2 inhibitor consists of a compound of the formula

Formula (I) where

I ² represents

wherein A is hydroxy, (C1-C4) alkoxy, amino, hydroxyamino, mono- (C ₁ -C ₂₎ alkylamino, di- _(C1-C2) alkylamino; X and Υ independently represent H or (C1-C2) alkyl; and η is 1 or 2;

I ⁶ represents halogen, (C ₁ -C ₃ ) alkyl, trifluoromethyl or nitro;

I ⁹ is H, _(C1-C2) alkyl; phenyl or phenyl- (C1-C2) alkyl wherein phenyl is optionally monosubstituted with fluorine or chlorine; —C (= O) —I, where I is (C ₁ -C ₂ ) alkyl or phenyl, optionally monosubstituted with fluorine or chlorine; or -C (= O) -O-I ^! where I ¹ represents (C1-C2) alkyl;

where X and Υ are different, its (-) (I) - and (+) (8) enantiomers and all their pharmaceutically acceptable salt forms, prodrugs and metabolites that are therapeutically active to treat or prevent pain and inflammation. In cases where the inhibitor of formula (I) exists in the form of (-) (I) - and (+) (8) enantiomers, then according to the present invention one (+) (8) enantiomer is provided, or when both enantiomers present together, provides for their racemic or non-racemic mixture.

It is very unexpected that the preferred carprofen compounds characterized by the functional group of α-methylacetic acid have many times more selectivity for COX-2 than any of the carboxyl-containing classic NSAIDs, and also many times more selectivity for canine COX-2 than some of sulfonyl- and sulfonylamide-containing NSAIDs, which in this area are mistaken for compounds with high selectivity for COX-2. This aspect of the present invention is embodied in a method of treating and preventing inflammatory processes and diseases in a dog, in which an anti-inflammatory therapeutically effective amount of a dog cyclooxygenase-2 inhibitor (COX-2) is administered, for which the dog has at least 1C ₅₀ ίη νίίτο of said dog 50 times greater than the efficacy of 1C ₅₀ ίη νίίτο with respect to cyclooxygenase-1 (COX-1) in said dog, said inhibitor being an inhibitor selected from the group of anti-inflammatory compounds th, consisting mainly of derivatives of salicylic acid, derivatives of p-aminophenol, indole and indenoacetic acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids, enolic acids and alkanones, and especially selected from the group consisting of carboxyl and carboxy (C ₁ -C ₄ ) alkylaryl and / or heteroaryl anti-inflammatory agents. In particular, said inhibitor is an inhibitor selected from the group consisting of non-steroidal anti-inflammatory drugs of the arylpropionic acid class.

Carprofen and derivatives of carprofen, preferably used in the methods and compositions of the present invention, can be obtained in accordance with synthesis methods well known to the organic chemist of ordinary skill. For example, compounds of formula (I), wherein B ⁶ is halogen, (C ₁ -C ₃ ) alkyl, trifluoromethyl or nitro and where B ⁹ is H or methyl, can be prepared by reacting (1) phenylhydrazine in which phenyl the part has the required B ⁶ substituent, and the hydrazine α-nitrogen has the required B ⁹ substituent, with (2) cyclohexanone having the required B ² substituent. The resulting 1,2,3,4-tetrahydrocarbazole is then aromatized to give the desired carbazole of formula (I). Aromatization can be carried out using (1) a flavoring agent, for example, p-chloranil, o-chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone (DDX), sulfur, palladium on carbon or lead oxide in the presence of (2) a solvent such as xylene, benzene, toluene, quinoline, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) (3) at a temperature of the reaction mixture in the range from room temperature to the reflux temperature of the reaction mixture, preferably with the latter.

Compounds of formula (I), which are acids, that is, where A is hydroxy, and salts of such acids with bases, can be converted into amides of formula (I), where A is amino, hydroxylamino, mono (C ₁ -C ₂ ) alkylamino and di- (C ₁ C2) alkylamino, by (1) forming the corresponding acid chloride by treatment with phosphorus pentachloride (PC1 ₅ ) followed by (2) reacting with the corresponding amine reagent to form the desired amine, which is carried out in the presence of an equivalent amount of pyridine or trie ylamine, which serve as the base for the proton transfer step and thereby remove the formed H C1 ^{+ -.} The same acid chlorides that are formed in step (1) can be reacted with the corresponding alkanol to give esters of formula (I), wherein A is (C ₁ C ₄ ) alkoxy. This reaction is also desirably carried out in the presence of a base such as pyridine which can neutralize the H ⁺ produced C1 ^- so that it does not interfere to any acid reacts rapidly with the alkanol reactant.

The above synthetic approaches to the preparation of preferred carprofen compounds used in the methods and compositions of the present invention are described in detail in US Pat. No. 3,896,145, which is incorporated herein by reference in its entirety.

If X and Υ in the definition of substituent B ² are different, then there is a chiral (asymmetric) carbon atom. A racemic mixture of (B) - and (8) enantiomers is formed when there is a mixture of enantiomers in a ratio of 50:50. According to the present invention, it was discovered that the (8) enantiomer of the preferred carprofen compounds of formula (I) having a chiral carbon is an enantiomer that has an amazing degree of unexpected selectivity for canine COX-2, a unique biological activity that practically no classical NSAIDs having a carboxylic acid moiety, and in particular, their 8-enantiomers do not possess. Consequently, the (8) enantiomer of the preferred carprofen compounds of formula (I) having chiral carbon has an unexpectedly reduced level of adverse gastrointestinal and other effects in dogs compared to those of essentially all other NSAIDs having a carboxylic acid moiety, especially in compared to their 8-enantiomers. Thus, it is also completely unexpected that the 8-enantiomer of carprofen has, due to the fact that it is a highly selective inhibitor of canine COX-2 isoenzyme, a remarkably improved level of anti-inflammatory, analgesic and antipyretic activity in dogs compared with that of essentially all other NSAIDs characterized by a carboxylic acid moiety.

One particularly preferred embodiment of the present invention is the use of only the (8) -enantiomer of carprofen, 6-chloro-a-methyl-9H-carbazole-2-acetic acid, as an active ingredient in the methods and compositions of the present invention. However, it is contemplated that other embodiments are also included within the scope of this preferred class of the present invention. For example, non-racemic mixtures of (I) and (8) enantiomers can be used, in which case the (8) enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99%. Since (I) - and (8) enantiomers are identical in molecular weight, density, etc., there is no need to indicate from which calculation the above percentages are given. In other words, it can be percentages by weight, by volume, by chemical equivalence, etc. The reason for including the above amounts (I) of the enantiomer can be as simple as the practicality of not having to remove absolutely all the last traces (I) of the enantiomer from the racemic mixture. There may also be reasons to do so that are associated with total beneficial biological properties.

It will also be apparent to those skilled in the art that, in the case of a chiral compound, dose ranges of carprofen compounds indicated elsewhere herein are presented for a racemic mixture of enantiomers in a ratio of 50:50. This is done mainly for convenience. In cases where the active ingredient used as a therapeutic agent consists of a mixture of enantiomers other than a 50:50 mixture, or this therapeutic agent consists essentially of 100% of one (+) (8) - or (-) (I) -enantiomer , an ordinary person will be able to calculate the actual amount of the required dosage in the simplest way, simply by multiplying the indicated dosage amounts by a factor that reflects the ratio of the applied amount of enantiomer to the amount present for the indicated dosage based on the enatiom mixture a moat in the ratio 50:50. Accordingly, when a dose of 4 mg / kg / day is indicated for the 50:50 racemic mixture, the corresponding dosage amount, when essentially 100% (+) (8) eniomers are used, will be half the indicated amount, i.e., 2 mg / kg /day.

Since the racemic compositions of the present invention containing a representative of preferred carprofen compounds allow the use of racemic mixtures containing 50% of the (8) enantiomer, as well as non-racemic mixtures containing about 99% or less of the (8) enantiomer together with less than 50% (I ) enantiomer, racemates of the carprofen compounds of the formula (I) should be separated.

This can easily be done using procedures and techniques known in the art. For example, some racemic mixtures can be precipitated as eutectics, after which they can be separated. However, it is usually preferable to use chemical separation methods, according to which diastereoisomers are formed from the racemic mixture using an optically active resolving agent. For example, an optically active base, for example, Ό-α-methylbenzylamine, which can interact with a carboxyl group. Then, the diastereoisomers thus formed are separated by selective crystallization and converted into the corresponding optical isomer.

All anti-inflammatory therapeutically active and pharmaceutically acceptable salt forms, prodrugs and metabolites of the preferred carprofen compounds used in the present invention are included within the scope of the present invention. This particularly applies to their acid addition salts, where A is defined as everything except hydroxy, formed by treating compounds of formula (I) with pharmaceutically acceptable organic and inorganic acids, for example, hydrogen halides such as hydrogen chloride, hydrogen bromide, hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc., and alkyl and monoaryl sulfonates, such as ethanesulfonate, toluenesulfonate, benzenesulfonate, and other organic acids and their corresponding conductive salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, etc.

In cases where A in the preferred carprofen compounds used in the present invention is defined as hydroxy, their salts can be formed by treatment with pharmaceutically acceptable bases. Examples of such bases are alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide, alkaline earth metal hydroxides, including barium hydroxide and calcium hydroxide, alkali metal alkylates, for example, potassium ethanolate and sodium propanolate, and various organic bases such as piperidine, diethanolamine, and Ν-methylglutamine. Also included are aluminum salts of the compounds of formula (I).

In addition to using the various salt forms of the compounds of formula (I) described above, it is within the scope of the present invention to use all painkillers and anti-inflammatory therapeutically active and pharmaceutically acceptable prodrugs and metabolites of the above compounds as active ingredients. In particular, they include those derivatives where I ^{9 is} defined as (C1-C2) alkyl, especially methyl; phenyl or phenyl- (C1-C2) alkyl, especially benzyl, where phenyl is optionally mono-substituted with fluorine or chlorine, in particular 4-fluorophenyl; —C (= O) I, where I is (C1-C2) alkyl or phenyl, in particular acetyl or benzoyl, where phenyl is optionally mono-substituted with fluorine or chlorine; or —C (═O) —O — I ¹ , where I ¹ is (C1-C ₂ ) alkyl, in particular acetyloxy. These рупп groups are readily cleaved during the metabolism of the compound of formula (I), which makes these particular derivatives desirable prodrugs.

The present invention is described in the paragraphs immediately above specifically in connection with the preferred carprofen compounds of formula (I). However, the present invention provides a wider scope in terms of providing anti-inflammatory selective COX-2 inhibitors. As already indicated, such selective COX-2 inhibitors include inhibitors where the ratio of selectivity for COX-2 and selectivity for COX-1 is at least 3: 1 based on the levels of inhibition of ίη νίνο and ex νίνο in whole blood measured at a dose or dose range giving> 80% inhibition of COX-2. According to the pharmacokinetic (FC) data described below, it has been shown that in dogs there is a relationship between the pharmacological or toxic reactions to the anti-inflammatory selective COX-2 inhibitors of the present invention and the achievable concentration of these inhibitors, for example, in the blood or plasma of these dogs. For purposes of demonstrating the present invention by way of example, the indicated pharmacological reaction in dogs is considered here as an anti-inflammatory reaction resulting from inhibition of COX-2, while the indicated toxic reaction in dogs is considered here as an undesirable side effect, for example, a gastrointestinal reaction resulting from inhibition COX-1. Thus, the concentration of the inhibitory drug in the systemic circulation of the specified dog will be associated with the concentration of the inhibitory drug at the sites of its action.

It is well known that the most important pharmacokinetic parameters are bioavailability, the proportion of this drug that enters the circulatory system; the volume of distribution related to the quantitative measure of the space in the body that is available to contain the specified drug; and clearance related to the body’s ability to eliminate a specific drug. According to the present invention, the ratio of selectivity for COX-2 and selectivity for COX-1, which should be at least 3: 1, is determined on the basis of measuring ex νίνο percent (%) inhibition of each of these isoenzymes in whole blood of dogs. The procedure for performing these measurements ex νίνο can be briefly summarized as consisting, firstly, of administering the test selective inhibitory compound at a predetermined total dose level, for example 2 mg / lb (4.409 mg / kg), to pre-selected dogs. This dose is administered in accordance with a predetermined dosage regimen, for example, once a day (s.r.d.), twice a day (s.r.d.), etc., after which samples are taken from each test animal. whole blood. Assays for COX-1 and COX-2 activity are based on stimulation of this blood with either a calcium ionophore for thromboxane B2 (COX-1 activity) or lipopolysaccharide (LPS) for prostaglandin E ₂ (COX 2 activity), respectively. These procedures are described in more detail in the following illustrative descriptions.

Selectivity for COX-2 is an essential feature of the anti-inflammatory inhibitors useful in the present invention, and is required to have a ratio of at least 3: 1 compared to inhibition of COX1 activity. For this compound, it is not enough to simply have a selectivity ratio of 3: 1, since this compound may have the desired selectivity ratio at any point in the entire dose range, but still not be able to provide adequate total inhibition of COX-2 activity. Accordingly, in order for an anti-inflammatory inhibitor to be within the scope of the present invention, it is further required that it also provides> 80% inhibition of COX-2 activity and, preferably,> 90% inhibition of COX-2 activity. It is believed that this is the minimum level of inhibition, adequate in order to provide a satisfactory pharmacological activity in the sense of treatment and prevention of pain and inflammation.

Further, for this compound, it is not enough to have a selectivity ratio of 3: 1 at a given dose and provide> 80% inhibition of COX-2 activity, preferably> 90% inhibition of COX-2 activity at any other dose. But it is preferable if compliance with both criteria should be at a certain level of exposure and at the same time after the drug is given. Accordingly, it is also required that a selectivity ratio of 3: 1 takes place at a dose concentration or a range of dose concentrations that also provide> 80% inhibition of COX-2 activity.

In order to demonstrate how the above limitations should be applied to potential selective COX-2 inhibitors, the following example should be considered. This candidate is evaluated in accordance with the above procedures to measure the inhibition of COX1 and COX-2 activity in whole blood samples at a total dose of 2 mg / lb (4.409 mg / kg) administered in a r.d.d. determined 2, 4 and 12 hours after administration. When plotting the points corresponding to the data for COX-1 and COX-2 on the graph of the% inhibition versus time, it turns out that the curve for COX-1 decreases very steeply from 1015% inhibition after 2 hours to the absence of the observed inhibition after 12 hours. on the other hand, it turns out that the curve for COX-2 decreases over the same period of time only slightly, from 95% inhibition after 2 hours to about 90% inhibition after 12 hours.

Accordingly, it should be noted that at a dose of 2 mg / lb (4.409 mg / kg), administered in a r.d.d. regime, this potential inhibitor met the restrictions required for it to be an anti-inflammatory selective COX-2 inhibitor falling within within the scope of the present invention, which consists in (1) a selectivity ratio of at least 3: 1 and (2) COX-2 inhibition of> 80%. Since the data of both graphs were compared at a single dose of 2 mg / lb (4.409 mg / kg) and in one period of time (12 h), there is a compliance with the third restriction, namely, compliance with the first two restrictions in a single dose or dose range.

You can make the same definitions and build the same graphs of the data obtained for many different dose quantities of the specified candidate compounds. However, the cumulative results are shown in a graph in which% inhibition of COX-2 and COX-1 is plotted against dose or plasma concentration, and not against time. The curve representing the data for COX-2 starts first and rises steeply, starting from the first dose concentration, which causes a defined% inhibition, reaching inhibition at levels> 80% as the dose approaches higher concentrations and becomes further asymptotic. The curve representing the data for COX-1 starts after and rises less steeply than the data curve for COX-2, and also becomes asymptotic with a significantly lower level of% inhibition. A candidate compound falls within the scope of the present invention if a line parallel to the оси axis and intersecting both curves at a certain dose concentration gives as a result such data points that meet both restrictions: in a ratio of 3: 1 and inhibition of > 80%.

The scope of the present invention in that it relates to those anti-inflammatory selective COX-2 inhibitors that are included in it can be considered or described in different terms, although in essence equivalent to those used above. For example, it can be considered that the present invention specifically provides a method of treating or preventing pain and inflammatory processes and diseases in an individual of the Sash GashShayk species in need of such treatment in which said individual is administered a therapeutically effective amount of an anti-inflammatory cyclooxygenase inhibitor to treat and prevent pain and inflammation. 2 (COX-2), moreover, the effectiveness of 1C ₅₀ ίη νίΙΐΌ in the specified individual at least 30 times, preferably at least 40 times, more preferably at least at least 50 times, even more preferably at least 60 times, even more preferably at least 80 times and most preferably at least 100 times greater than the efficiency of 1C ₅₀ ίη ν 11th in relation to cyclooxygenase-1 (COX-1) in the indicated individual, wherein said inhibitor is selected from the group of anti-inflammatory compounds consisting mainly of derivatives of salicylic acid and derivatives of p-aminophenol, indole and indenoacetic acid, heteroaryl acetic acids, arylpropionic acids, anthranilic acids, enols acids and alkanones.

In accordance with the above methods of the present invention, a more specifically proposed method for the treatment and prevention of pain and inflammatory processes and diseases, in which the indicated efficacy of 1C ₅₀ ίη ν 11th in relation to cyclooxygenase-2 (COX-2) in the inhibitory compound of the formula ( I) at least 100 times greater than the indicated 1C ₅₀ Сη ν 11th efficacy with respect to cyclooxygenase-1 (COX-1) in the inhibitor compound of formula (I), where one of X and Υ represents H, and the other is methyl, and when both enantiomers obtained are present together, (+) (8) the enantiomer is present in an amount of at least 75%. In particular, the above-described method is proposed in which, for formula (I), for B ² , η = 1, one of X and Υ represents H, and the other represents methyl, and A represents hydroxy, (C1-C2) alkoxy or amino; ⁶ represents halogen, in particular chloro, or trifluoromethyl; and B ⁹ is H, methyl, acetyl, benzoyl or methoxycarbonyl, wherein when both obtained enantiomers are present together, the (+) (8) enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99%.

In addition, the above-described methods are proposed in which said inhibitor consists of 6-chloro-a-methyl-9H-carbazole-2-acetic acid, wherein when both obtained enantiomers are present together, the (+) (8) enantiomer is present in an amount of at least at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99%. In particular, the method described above is provided in which said inhibitor consists entirely of the (+) (8) enantiomer of 6-chloro-a-methyl-9H-carbazole-2-acetic acid.

The present invention can also be described as providing a method of selectively inhibiting essentially only inducible cyclooxygenase-2 (COX-2), essentially without inhibiting the corresponding constitutive cyclooxygenase-1 (COX-1), and thus treating or preventing pain and inflammatory processes and related diseases in an individual of the Sash GatShapk species in need of such treatment in which said individual is administered a therapeutically effective amount of an anti-inflammatory compound for the treatment of pain and inflammation the above formula (I), where B ² , X, Υ, η, B ⁶ and B ⁹ are as defined; including (-) B and (+) 8-enantiomers and all anti-inflammatory therapeutically effective and pharmaceutically acceptable salt forms, prodrugs and metabolites of the above compounds. Here again, when an inhibitor of formula (I) exists in the form of (-) B and (+) 8-enantiomers, the present invention provides for one (+) 8-enantiomer or, when both enantiomers are present together, provides for their racemic or non-racemic mixture .

In essence, similarly to the previous descriptions, the present invention can be further described as comprising the above method of selectively inhibiting essentially only inducible cyclooxygenase-2 (COX-2), wherein said inhibitor consists of 6-chloro-a-methyl-9H- carbazole-2-acetic acid, and when both enantiomers obtained are present, the (+) (8) -enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least

99% In particular, the method described above is proposed in which said inhibitor consists entirely of the (+) (8) -enantiomer of 6-chloro-methyl-9H-carbazole-2-acetic acid.

When the compounds of formula (I) or their enantiomers or salts are used as active ingredients in the methods and compositions of the present invention, they can be incorporated into standard pharmaceutical dosage forms. For example, they are suitable for administration in systemic or local, oral or parenteral forms of administration, and for this purpose they are combined with conventional pharmaceutical excipients, diluents and adjuvants, for example, organic and inorganic inert carrier materials such as water, gelatin, lactose, starch , magnesium stearate, talc, vegetable oils, resins, polyalkylene glycols, etc. These pharmaceutical preparations can be used in solid form, for example in the form of tablets, pills, suppositories, capsules, and especially in Combinations or in admixture with a flavoring a food product, suitable for dogs; or they can be administered in liquid form, for example, in the form of solutions, suspensions, standard or inverse emulsions and elixirs. Pharmaceutical excipients and adjuvants that may be added include preservatives, antioxidants, antimicrobial agents, and other stabilizers; humectants, emulsifiers and suspending agents and anti-caking agents; coloring and flavoring additives; compositions to improve compressibility or to create a sustained, prolonged or controlled release of the active ingredient; and various salts to alter the osmotic pressure of the pharmaceutical preparation or to act as a buffer. Specific dosage forms that have been used successfully include a 5% mixedprofile carprofen solution for intravenous injection, 3% flavoring paste or oral tablets in dosages of 25 mg, 75 mg and 100 mg.

In the methods and compositions of the present invention, especially those where the inhibitor consists of 6-chloro-a-methyl-9H-carbazole-2-acetic acid and the two enantiomers obtained are present together, a preferred embodiment is to use a non-racemic mixture. In particular, in such preferred non-racemic mixtures, it is desirable that the (+) (8) enantiomer is present in an amount of at least 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99% . Thus, in such non-racemic mixtures (+) (8), the enantiomer will be the predominant component43 not only because it is significantly more effective than the (-) (B) -enantiomer in inhibiting cyclooxygenase-2 (COX-2), but also because it is highly selective in inhibiting cyclooxygenase-2 (COX-2) compared to cyclooxygenase-1 (COX-1). In cases where it is believed that a balance of the inhibitory properties of the cyclooxygenase or other enzyme is considered desirable, it is possible to include in the composition accordingly smaller amounts of (-) (B) enantiomer, i.e., less than 15%, less than 10% and less than 5%, respectively. In cases where the amount of (-) (B) enantiomer present is less than 5% and less than 1%, the reason for this inclusion usually reflects the practical side of the process used to separate the enantiomers. If this method takes a lot of time or requires a lot of resources, it is often desirable, from a practical point of view, to simply allow this small fraction of the (-) (B) enantiomer to be transferred to the finished product, which is the final non-racemic mixture.

The anti-inflammatory inhibitors of formula (I) of the present invention can be administered systemically to the dog to be treated as a pharmaceutical composition in a suitable liquid form by injection or infusion. In the dog’s body, there are many sites and organ systems that allow a properly composed composition, when it is injected or infused, to spread throughout the dog’s body system and organs, which are treated. An injection is a single dose of a pharmaceutical composition, administered by force, usually with a syringe, into a predetermined tissue. The most traditional types of injections are intramuscular, intravenous and subcutaneous. In contrast, infusion is the gradual introduction of a pharmaceutical composition into a given tissue. The most traditional type of infusion is intravenous. Other types of injections or infusions include intra-arterial, intradermal and percutaneous (including subcutaneous) or intravertebral, especially intrathecal. In these liquid pharmaceutical compositions, the anti-inflammatory inhibitor may be present in solution as a solute. This is the most common and most preferred type of such composition, but it requires that the inhibitor be in salt form, which has a fairly good solubility in water. By far, the most preferred solvent for such compositions is water (or saline). It is sometimes possible to use supersaturated solutions, but they create stability problems that make their daily use impractical.

If, as this sometimes happens, it is impossible to obtain the form of any compound of formula (I) that has the required degree of solubility in water, then the preparation of an emulsion, which is a dispersion of small spheres of one liquid, a dispersed or internal phase, is within the skill of a specialist , in a continuous or external phase with which it does not mix. These two liquids are maintained in an emulsion state using emulsifiers that are pharmaceutically acceptable. So, if the anti-inflammatory inhibitor is a water-insoluble oil, then it can be administered as part of an emulsion in which it is a dispersed phase. An emulsion can also be used if this inhibitor is insoluble in water, but can be dissolved in a solvent not miscible with water. Despite the fact that the inhibitor should most often be used in the form of a dispersed or internal phase of what is called a direct emulsion, it can also be used in the form of a dispersed or internal phase of an inverse emulsion, which is usually called an emulsion of water in oil. In this case, such an anti-inflammatory inhibitor is soluble in water and can be administered as a simple aqueous solution. However, when injected or infused into an aqueous medium, such as blood, inverse emulsions circulate and create the advantage of dispersing the inhibitor more quickly and efficiently in this aqueous medium than can be achieved using an aqueous solution. Reverse emulsions are prepared using suitable pharmaceutically acceptable emulsifiers well known in the art. In cases where the anti-inflammatory inhibitor has limited solubility in water, it can be administered as a suspended solid in colloidal or microdispersed form in a suspension prepared using suitable pharmaceutically acceptable suspending agents. Suspended solids containing this inhibitor can also be formulated as sustained, sustained or controlled release compositions.

Although systemic administration is most often accomplished by injection or fluid infusion, there are many situations in which it is better or even necessary to deliver an anti-inflammatory inhibitor in the form of a solid. Systemic administration of solids is carried out by instillation, inhalation or insufflation of the pharmaceutical composition in a suitable solid form containing this inhibitor. The instillation of an inhibitor may entail the establishment of a solid implant composition in the appropriate tissues or cavities of the body. This implant may include a matrix of biocompatible and biodegradable materials in which particles of a solid inhibitor are dispersed or in which globules or individual cells of a liquid inhibitor are possibly contained. It is desirable that this matrix is destroyed and completely absorbed by the body. The composition of the matrix is preferably chosen so as to provide controlled, continuous and / or delayed release of the inhibitor over long periods of time, even up to months.

Significant amounts of the dosage forms described herein may be formulated so as to provide for a controlled, sustained and / or delayed release of the active ingredient from said dosage forms. A particularly preferred aspect of the pharmaceutical compositions of the present invention, which provide sustained, prolonged and / or controlled release of an active ingredient that is an anti-inflammatory selective COX-2 inhibitor, includes all such orally administered dosage forms that produce> 80% inhibition of COX-activity 2 and lead to a plasma concentration of the indicated inhibitor of at least 12 μg / ml for at least 4 hours; preferably at least 8 hours, more preferably at least 12 hours, even more preferably at least 16 hours, even more preferably at least 20 hours and most preferably at least 24 hours. Preferred dosage forms described above produce> 80% inhibiting the activity of COX-2 and lead to a concentration of the indicated inhibitor in plasma of at least 15 μg / ml for at least 4 hours, preferably at least 8 hours, more preferably at least 12 hours, even more preferably at least 20 hours and most preferably at least 24 hours. The dosage forms described above that produce> 90% inhibition of COX-2 activity and result in a plasma concentration of the indicated inhibitor of at least 20 μg / ml for at least 4 are more preferred. hours, preferably at least 8 hours, more preferably at least 12 hours, even more preferably at least 20 hours and most preferably at least 24 hours

Accordingly, a suitable dosage form of carprofen of the present invention for controlled release is one which maintains a plasma level of carprofen above 2 μg / ml for most of the day after a single oral dose of 2 mg / lb (4.409 mg / kg). Preferred oral dosage forms of carprofen for controlled release of the present invention are those that maintain a plasma concentration of carprofen above 10 μg / ml for a period of time greater than that for which immediate release carprofen dosage form maintains a comparable plasma level when said immediate release dosage form and controlled release dosage form are administered in the same dose, for example 2 g / lb (4,409 mg / kg); 1.8 mg / lb (3.968 mg / kg); 1.6 mg / lb (3.527 mg / kg) or 1.4 mg / lb (3.086 mg / kg). For example, the preferred oral dosage forms for the controlled release of the present invention at 2 mg / lb (4.409 mg / kg) maintain a plasma concentration of carprofen in excess of 10 μg / ml for more than 10.5 hours.

Dosage forms of immediate release carprofen containing doses of 1.8,

1.6 and 1.4 mg / lb (3.968; 3.527 and 3.086 mg / kg), maintain plasma concentrations of carprofen in excess of 10 μg / mg for 9.5 hours, 8.5 hours and

7.5 hours, respectively. Preferred oral dosage forms of controlled-release carprofen at 2 mg / lb (4.409 mg / kg) maintain a plasma concentration of carprofen in excess of 10 μg / ml for more than 9.5 hours. Similarly, the threshold duration for dosage forms per

1.6 and 1.4 mg / lb (3.527 and 3.086 mg / kg) are 8.5 and 7.5 hours, respectively. By assuming linear pharmacokinetics, performance characteristics for preferred oral dosage forms of carprofen of not more than 2 mg / lb (4.409 mg / kg) and less than 1.4 mg / lb (3.086 mg / kg) can be similarly calculated. More preferred sustained release oral carprofen dosage forms are those that maintain a plasma concentration of carprofen in excess of 10 μg / ml for a period of time greater than or equal to that observed when the immediate-release carprofen dosage form is given at any higher dose. Thus, these controlled release dosage forms support at least 80% inhibition of COX-2 in the blood of dogs for a period longer than that achieved by the immediate release dosage form at a higher dose.

The most preferred controlled-release carprofen dosage forms are those that are able to maintain plasma carprofen levels above about 10 μg / ml for a period of time greater than or equal to the time observed with the immediate-release carprofen dosage form at 2 mg / lb (4.409 mg / kg) (10.5 h) when said oral controlled-release carprofen dosage forms are administered at a dose of less than 2 mg / lb (4.409 mg / kg). The performance of the 2 mg / lb (4.409 mg / kg) immediate-release oral drug dosage of carprofen was taken as the base standard for such a comparison because 2 mg / lb / day (4.409 mg / kg / day) is currently recommended and the accepted effective dose according to the present invention, as described herein.

The term implant always refers to a solid pharmaceutical composition containing an anti-inflammatory inhibitor, while the term depot usually refers to a liquid pharmaceutical composition containing an anti-inflammatory inhibitor that is placed in any suitable tissues and cavities of the body to form a reservoir or pool that slowly migrates to surrounding tissues and organs and eventually becomes distributed systemically. However, in this area these differences are not always strictly adhered to and, therefore, it is assumed that the scope of the present invention includes liquid implants and solid depots, and even mixed solid and liquid forms of each. Suppositories can be considered as a type of implant because they include bases that are solid at room temperature but melt at body temperature, slowly releasing the active ingredient that they are impregnated into the surrounding body tissue, where this active ingredient is absorbed and transported to systemic administration.

Systemic administration can also be accomplished by inhalation or insufflation of a powder, i.e., an inhibitor-containing particle composition. For example, an inhibitor in the form of a powder can be inhaled into the lungs using conventional devices for spraying powder dosage forms. The inhibitor in the form of a powder can also be driven by insufflation, that is, injected or otherwise dispersed into suitable tissues and cavities of the body by simply sprinkling it or using traditional devices for dispersing dispersed preparations. These dispersed compositions can also be formulated to provide sustained, sustained and / or controlled release of an anti-inflammatory inhibitor in accordance with well-understood principles and known materials.

Other systemic administration agents in which the inhibitors of the present invention can be used in both liquid and solid form include transdermal, intranasal and ophthalmic routes. In particular, transdermal patches can be prepared in accordance with well-known drug delivery technologies and glued onto the skin of the dog to be treated, after which the active ingredient migrates through the epidermis and dermal layers of the skin due to its solubility characteristics, where it is captured as part of the general circulation dogs, which ultimately provides a systemic distribution of the active ingredient over the required long period of time. This also includes implants that are placed under the epidermal layer of the dog, that is, between the epidermis and the dermis of the skin of the dog that is being treated. Such an implant can be prepared in accordance with the well-known principles and materials commonly used in this delivery technology, and can be prepared in such a way as to provide a controlled, prolonged and / or delayed release of the active ingredient into the systemic circulation of this dog. Such subepidermal (subcuticular) implants provide the same installation ability and delivery efficiency as transdermal delivery patches, without limitation on the subject of destruction, damage or accidental removal due to being on the top layer of the dog’s skin.

Special type pharmaceutical compositions for oral administration to dogs may also be developed. Pharmaceutical compositions for oral administration, i.e., ingestion by mouth or administration by mouth, can be solid and liquid. Preferred oral dosage forms for systemic administration are solids, for example, flavoring oral compositions, such as instant taste wafers, tablets, capsules, droplets, lozenges, lozenges, etc., and liquids, such as solutions, suspensions, emulsions, elixirs, tinctures, etc .. You can use a special type of pharmaceutical composition suitable for oral administration to dogs, which includes, but is not limited to, things like oral paste for delivery to the rear the language of the dog that is being treated, a granular form for delivery through administration to the dog’s food, a chewable form in which the active ingredient is eaten along with flavoring gum, or a chewable form that can deliver the active ingredient by isolating from the mass of the chewing gum that does not eat, chewing the dog that is being treated. As is known in the art, the preparation of such edible compositions takes into account the behavior of dogs with regard to the degree of chewing of the dosage form and the resulting dosage level.

As for the other routes of administration described here and the corresponding dosage forms, dosage forms intended for oral administration are also prepared in such a way as to provide a controlled, continuous and / or delayed release of the active ingredient. Typically, they should include oral tablets, capsules, and sustained release particle aggregates, as well as enteric-coated tablets and capsules that prevent absorption of the active ingredient in the dog’s stomach and facilitate intestinal delivery distally to the stomach, i.e., into the dog’s intestines. Other typical oral dosage forms include oral tablets, capsules, and sustained release particle combinations that provide systemic delivery of the active ingredient in a controlled manner over an extended period of time, such as a 24-hour period. In cases where fast delivery of the active ingredient is required or desirable, the sustained release oral dosage form can be prepared in the form of a fast-dissolving tablet, which preferably should also include well-soluble salt forms of the active ingredient.

This description of dosage forms, which are intended to be within the scope of the present invention, provided a classification of the forms, mainly for convenience, into forms for local and systemic administration, as well as solid and liquid forms. However, these differences are completely arbitrary and should in no way be deemed to limit the scope of the present invention as regards the route of administration of dosage forms. For example, the description given here has already made it clear that some routes of administration, being seemingly local, may have systemic effects or consequences. The distinction made here between liquid and solid dosage forms can also be blurred in actual practice. For example, a suitable oral dosage form for use in the present invention includes encapsulated solutions, a mixed solid and liquid preparation. Microemulsion preparations, also within the scope of the present invention, can also be characterized as mixed solid and liquid dosage forms.

The anti-inflammatory inhibitor can be administered locally to the site of inflammation in the dog to be treated. Local administration compared with systemic administration entails a more targeted delivery of a composition containing an anti-inflammatory inhibitor than generalized delivery to a dog suffering from pain and inflammation. However, the use of depot and implants, as well as drugs for slow, prolonged and controlled release tends to blur these differences. Accordingly, the above liquid and solid pharmaceutical compositions containing an anti-inflammatory inhibitor, in most cases, can also be used for local administration with increased attention to the selection of such components for these compositions, which tend to promote absorption of this inhibitor in the tissue in the local area of inflammation, as well as tend to inhibit what occurs as a result of systemic transfer of infiltration and migration of the inhibitor to more external and distant tissues.

Topical administration targets the appropriate tissues and cavities in the body into which an anti-inflammatory inhibitor can be injected, infused, implanted, placed, inserted, inserted or inflated. Such administration may include intra-arterial, intra-articular, intra-cartilaginous, intracostal, intra-cystic, intra- and percutaneous, intrafascial, intracranial, intramedullary, intramuscular, intranasal, intra-neural administration, intraocular, intraocular, intracranial, intracranial , intrasynovial, intra-pretreatal, intrathecal or intravenous administration. Pharmaceutical compositions in liquid form containing this inhibitor have the advantage of injecting liquid into or in the immediate vicinity of the inflammation site. This is a special case associated with inflamed joints and degenerative joint disease. By injecting the inhibitor directly into the joint, it is possible to achieve a higher concentration of the inhibitor in a short period of time and therefore not only significantly increase the flow of the inhibitor to the site of inflammation and thus the therapeutic activity of this inhibitor, but at the same time minimize the occurrence of inappropriate adverse reactions that could happen otherwise. The result is a high local concentration of the inhibitor at a correspondingly low systemic concentration caused by transfer.

Inhibitor-containing pharmaceutical compositions may also be injected in which the pharmaceutical composition is in the form for sustained release, controlled release or sustained release. These formulations of known compositions may be combinations of solids, semi-solids, gels, or other combinations of liquid and solid in which a degradable matrix or series of shells is used to provide continuous release of this inhibitor at a predetermined rate or at varying rates, as desired. To describe these drugs, the terms extended release or long-term are used. All of them use various combinations of biodegradable polymers, for example various cellulosic polymers, and natural materials, for example corn starch, and magnesium stearate, to obtain a slow and / or uniform distribution of the inhibitor contained in this matrix. These pharmaceutical compositions can be injected into the area if they are suitably liquid or suspended, or if they are naturally harder, can be delivered by other means.

A therapeutically effective amount for the treatment of pain and inflammation, the amount of inhibitory compounds of formula (I) is administered to a dog that is being treated in an amount expressed in milligrams per kilogram of body weight of said dog per day mg / kg / day. The expression of the day when used here should not be interpreted as mandatory, requiring that any particular dosage form is administered daily to the dog that is being treated. The expression per day is simply an indication of the least convenient but arbitrary length of time that is used as part of the entire unit to measure the dose of the anti-inflammatory inhibitor that is administered. The dose, i.e. the amount of inhibitor therapeutically effective for the treatment of pain and inflammation, is usually in the range of from about 0.01 mg / kg / day to about 20.0 mg / kg / day, preferably from about 0.1 mg / kg / day up to about 12.0 mg / kg / day, more preferably from about 0.5 mg / kg / day to about 10.0 mg / kg / day, and most preferably from about 0.5 mg / kg / day to about 8, 0 mg / kg / day. For example, a 50-pound dog has a weight of 23 kg (1 kg = 2.2 pounds) and, therefore, it is most preferable to treat it with a dose of from about 10 mg to about 180 mg of therapeutic agent per day. Fractional amounts are not significant, and the doses should be properly rounded to the number that corresponds to the standard doses that are available in a way that is convenient. In cases where the dosage form is, for example, an injectable liquid, preferred dosage amounts can be achieved with greater accuracy. On the other hand, if the dosage form is, for example, an oral tablet, it will be necessary to make a less accurate approximation to the preferred dose. Thus, a dose of 10 mg can be approximated by dividing the tablet into 25 mg in half, and a dose of 180 mg can be approximated by using a 100 mg tablet with a 75 mg tablet or three 25 mg tablets, as these are typical dose amounts for oral tablets . As it should be clear to specialists, in cases where the most commonly used dosage form is an oral tablet, and a large number of dogs are treated daily, additional convenience will be obtained by using a dispenser containing all available dose amounts for these tablets, for example 25 tablets. 75 and 100 mg. In this way, almost any preferred dosage amount can be approximated using some combination of these tablets and / or their halves.

For a qualified specialist, such as a veterinarian, it is necessary not only to determine the preferred route of administration and the appropriate dosage form, but also the dosage amount. The specified specialist should also determine the dosage, that is, the frequency of dosing. In general, it is most likely that the choice will be between dosing once a day (r.d.) and twice a day (d.d.), and that the first choice will provide a faster and stronger treatment, whereas the latter option will provide a less powerful but more continuous treatment. However, this generalization does not take into account such important variables as the specific type of pain or inflammation, the particular therapeutic agent involved and its pharmacokinetics, and the particular patient (dog). In the case of a commercially available authorized product, much of this information is already known from the results of clinical trials conducted to obtain such permission. In other cases, such information can be obtained directly from the manual and instructions contained in the present description, considered in the light of the knowledge and qualifications of this specialist. The results obtained can also be compared with the data of the corresponding estimates obtained in the same analyzes of any permitted product.

The above dose range ranges, which are also indicated elsewhere herein, relate to racemic mixtures of compounds of formula (I) having a chiral carbon, or to individual compounds of formula (I) where a chiral carbon atom is not present. For a person skilled in the art, that is, a practicing veterinarian or possessing a high degree and experience in animal health, it is obvious that in cases where a mixture of the compounds of formula (I) other than the racemic is involved, the anti-inflammatory therapeutically effective amount will vary. For example, if 85% of the mixture is in the (8) -enantiomer, they tend to lower the required dose. These considerations are based on the supposed equal efficacy and the fact that the (8) -enantiomer is significantly more active than the (I) -enantiomer. However, when determining the correct dose, the degree of difference between the activities of these two enantiomers should also include other differences, especially the differences between the two enantiomers in pharmacokinetics. For example, it was shown that between the (+) (8) - and (-) (I) -enantiomers there is a significant difference in clearance rates. This, in turn, has a calculated effect on the amount of active compound to be administered. Typically, such definitions for each individual case should be made by a specialist, however, they are completely within the usual skills in this field, as it is established by the methods by which it is possible to obtain the data necessary for confirming calculations.

Typical dosage forms and dosage amounts should include (1) intravenous administration of carprofen at a dose of 4.0 mg / kg / day by body weight by injection into the right head vein, (2) oral administration of carprofen at a dosage of 4.0 mg / kg / day by weight in the form of an oral paste, applied by syringe to the back of the tongue, which is produced one hour before feeding, and (3) oral administration at a dosage of 4.0 mg / kg / day by body weight in the form of preparations that are 25, 75 and 100 mg tablets placed on the back of the tongue The dog is being treated, produced for an hour before feeding.

The active ingredients of the present invention can also be combined with other therapeutically active ingredients, which should be immediately apparent to a person skilled in the art and which are usually determined by the circumstances in which the therapeutic agent of the present invention is administered. For example, in cases where a large joint is severely inflamed and at the same time infected with microorganisms, for example bacteria, fungi, protozoa, virus and the like, it is desirable to administer the active ingredient of the present invention in combination with one or more antibiotic, antiprotozoal , an antiviral or similar therapeutic agent. The active ingredient of the present invention can be administered not only in combination with other NSAIDs of the type described in more detail here, but also in combination with inhibitors of other inflammatory mediators to achieve a combined inhibitory effect against inflammation. Additional classes of such inhibitors and their examples include, for example, H ₁ receptor antagonists, kinin receptor antagonists B! and B _2, prostaglandin inhibitors such as RSB- antagonists RSE-, PC1 ₂ - and PGE-receptor, inhibitors of thromboxane A2 (TXA2), inhibitors of 5- and 12-lipoxygenase inhibitors, leukotriene TS _4, TS _4/4 and TE LTB ₄ , antagonists of receptors for PAE (platelet activating factor), gold in the form of an aurothio group together with various hydrophilic groups, immunosuppressive agents, for example cyclosporine, azathioprine and methotrexate, anti-inflammatory glucocorticoids, penicillamine, hydroxychloroquin; anti-gout agents, for example colchicine, xanthine oxidase inhibitors, for example allopurinol; and uricosuric agents, for example, probenecid, sulfinpyrazole and benzbromarone.

Since inflammation is most common in geriatric dogs, those skilled in the art will recognize that the anti-inflammatory agents of the present invention can also be administered in combination with therapeutic agents for treating painful conditions, syndromes and symptoms that are also found in a large number in older dogs. Such therapeutic agents and conditions for the treatment of which they are used include, for example, cognitive therapeutic agents to counteract memory loss and impairment. Another large class of such therapeutic agents include antihypertensive and other cardiovascular drugs designed to compensate for hypertension, myocardial ischemia, including angina pectoris, persistent heart failure, and myocardial infarction, such as diuretics, cardiovascular agents such as hydralazine β-adrenergic receptor antagonists, such as propranolol, angiotensin-11-converting enzyme inhibitors (ACE inhibitors), such as enalapril, used to treat geriatric dogs with mitral regurgitation, and enalapril alone or in combination with neutral endopeptidase inhibitors, angiotensin-11 receptor antagonists such as losartan, renin inhibitors, calcium channel blockers such as nifedipine, sympatholytic agents such as methyl-DOPA, and ₂ β-adrenergic agonists, such as clonidine, α-adrenergic receptor antagonists, such as prazosin, and HMG-CoA reductase inhibitors (anti-hypercholesteronemia drugs), such as lovastatin.

Still other classes of such therapeutic agents include antineoplastic agents, especially antimitotic drugs, including vinca alkaloids such as vinblastine and vincristine, for treating various forms of cancer; therapeutic agents for the treatment of renal failure; anti-obesity drugs for treating overweight problems in dogs; antiparasitic drugs against both endo- and ectoparasites, which usually concern dogs, and anti-scab drugs for treating various types of scabies in dogs.

Other types of drugs that can be used in combination with the anti-inflammatory agents of the present invention include growth hormone secretagogues, strong painkillers, local and systemic anesthetics, and H ₂ receptor antagonists and other stomach protecting agents. Specialists will understand that some of the above combinations of therapeutic agents will most often be used to treat various acute conditions in dogs, such as bacterial infections that occur simultaneously with degenerative joint disease. However, there should be the same, if not more, interest from such specialists in the treatment of chronic conditions in dogs.

According to the regimen to be used for this purpose, it is contemplated that the anti-inflammatory agents of the present invention should be administered in combination with other medicines used in accordance with regular regimens for treating chronic conditions such as osteoarthritis. It can also be foreseen that the administration in combination may take many different forms and yet be within the scope of the present invention. For example, the anti-inflammatory agents of the present invention can simply be formulated with therapeutic agents, one or more than one to form the desired combination, in a convenient dosage form, such as an oral tablet containing all the drugs that make up this combination. A specialist in the preparation of drugs can take into account the varying half-lives of different drugs by creating forms of these drugs having different release times in order to achieve a relatively uniform dosage. Also, in accordance with well-known recipe principles, it is possible to prepare a medicinal product used as a dosage form, in which these drugs used in combination are simply present, mixed together, in a food composition.

The present invention also contemplates co-administration in which a combination of drugs is obtained by simultaneously administering drugs to be given in combination.

Such co-administration can even be carried out through different dosage forms and routes of administration. The present invention further contemplates the use of such combinations in accordance with different, but regular and continuous dosing regimens, by which the dog being treated maintains the desired levels of medication involved, even though the individual drugs constituting this combination are not administered to the indicated dog at the same time. All such combinations should be completely within the existing skills in this area regarding development and introduction.

The methods and compositions of the present invention are suitable for the treatment or prevention of pain and / or inflammation in dogs. Pain, which is a more or less localized sensation of discomfort, suffering or pain, resulting from the stimulation of specialized nerve endings, can occur or be considered as a separate and special form of inflammation. For example, chronic pain and pain caused by or associated with a surgical operation, such as surgical or postoperative pain, may initially have little to do with inflammation. Opioid painkillers are effective in the treatment of postoperative pain, but do not affect inflammation. However, NSAIDs may be superior to such opioid painkillers in the treatment of certain forms of postoperative pain, and they are especially effective in conditions where inflammation has caused sensitization of pain receptors to usually painless mechanical or chemical stimuli. While NSAIDs inhibit the biosynthesis and release of prostaglandins, which are inflammatory mediators, it also follows from these data that the analgesic effect of NSAIDs can be achieved through or through mechanisms that differ from inhibition of prostaglandin synthesis.

Accordingly, the present invention has been described in terms of suitability for the treatment and prevention of pain and inflammation, since tissue damage and disease processes and conditions that are mediated by COX-2 are very common. However, there is no intention to inextricably link pain and inflammation with regard to the usefulness of the present invention in their treatment and prevention, and thus, in the context of the current description of the invention, they, individually and individually, or in combination, are to be considered as an object of the methods, compositions and other aspects of the present invention.

The inflammatory process itself can have many causes that cause it, which include infectious agents, ischemia, the interaction between antigens and antibodies57, and thermal and other physical damage. The response to each of these causes is characteristically different, but they all have significant commonality. Clinical symptoms include erythema, edema, weakness, and pain. Three distinct phases can be distinguished, and each of them is mediated by different mechanisms from the others. The first, acute transient phase is accompanied by local vasodilation and increased capillary permeability; the second, prolonged subacute phase is accompanied by leukocyte and phagocytic cell infiltration, and the third, chronic proliferative phase, is accompanied by tissue degeneration and fibrosis. NSAIDs as a therapeutic class of anti-inflammatory agents appear to act by inhibiting the enzymatic production and release of prostaglandins, which are involved in the pathogenesis of inflammation and heat. However, NSAIDs do not inhibit the formation of eicosanoids such as leukotrienes, which are also involved in inflammation, and they also do not interfere with the formation of numerous other inflammatory mediators.

According to the present invention, it was found that among NSAIDs having a carboxylic acid moiety, only carprofen compounds of the formula (Ι), and especially carprofen itself, and in particular the (8) enantiomer of carprofen, have a surprisingly and unexpectedly high degree of specificity for COX-2. Despite the fact that this particular isoenzyme is an important mediator of inflammation, there are many other important mediators of inflammation that either do not interact with NSAIDs or do not have a clear understanding of the effect of NSAIDs. Such mediators include several classes of white blood cells; cell adhesion molecules; soluble mediators such as C5a, PAP (platelet activating factor) and leukotriene B4; cytokines such as IL-1 (interleukin-1) and TNF (tumor necrosis factor), growth factors such as 6M-C8P (factor that stimulates the formation of granulocyte monocyte colonies) and TOP-βι (transforming growth factor β ₁ ); histamine, bradykinin and 5-HT (5-hydroxytryptamine). Although it is shown here that the compounds of formula (Ι) are unique COX-2 inhibitors, there is no intention to bind to any specific mechanism of action by which the compounds of formula (Ι) could exert their anti-inflammatory effect.

In fact, it was noted even higher that the principle of anti-inflammatory action of carprofen and other compounds of formula (Ι) is poorly understood, and there are still assumptions that the actual principle of action may involve neutrophils, also known as polymorphonuclear leukocytes. PAP stimulates such cells to aggregate, release leukotrienes and lysosomal enzymes, and generate peroxide, which all contribute to inflammation.

In general terms, the uniqueness of carprofen and other compounds of formula (I) among NSAIDs has already been addressed. Despite the fact that the compounds of formula (I) are clearly NSAIDs, they do not fit easily into any recognized classification of NSAIDs:

Salicylic acid..................

p-Aminophenols ...........................

Indole / Indenoacetic Acids ...

Heteroaryl acetic acids .....

Arylpropionic acids ......

Anthranilic acids ...............

Enol acids .......................

Pyrazolidinediones .....................

Alkanones .....................................

Aspirin;

Acetaminophen;

Indomethacin, sulindac, etodolac;

Tolmetin, diclofenac, ketorolac;

Ibuprofen, naproxen, flurbiprofen, ketoprofen;

Mefenamic acid, meclofenamic acid; Oksikama, for example piroxicam, tenoksimkim;

Phenylbutazone;

Nabumeton.

Carprofen and the compounds of formula (I), although they are propionic acids, do not belong to the subclass of arylpropionic acids, since the carbazole group of carprofenes is heteroaryl and not aryl. Carprofenes do not belong to the subclass of heteroaryl acetic acids, since carprofenes are propionic acids and not acetic acids. Carprofen can not be placed in any of the other subclasses, without violating to any extent the basis of classification. In the above list, the only NSAID approved for the treatment of people with respect to which it is recognized that it is selective for human COX-2 activity is nabumetone, which is not an acid at all, but is 2-butanone. Although its active form is an acid metabolite, this metabolite has only a small fraction of the selectivity of carprofen for canine COX-2.

Examples of the many classic NSAIDs in this broad class are the compounds shown in the table below, which for each compound contains its common name and the name according to the nomenclature of the International Union of Theoretical and Applied Chemistry (UR AS) and its structure. All of the above compounds appear in I8R Ikbopagu £ I8AY apb 1n! Ehpa! Yupa Egid Yatek, 1995, S. A. P1eedeg, eb. Ipbeb 81a1ek RRagtasore1a1 Sopuepbop, 1ps. KoskuShe, ΜΌ. The I8AY Program (US-Accepted Names) generates simple but useful names without ownership of them for medicines, and the selection process begins when the drug is in the clinical trial phase. The name and structure of carprofen are given at the beginning of the table to facilitate comparison.

Table 1

COMMONLY ACCEPTED

TITLE

TITLE 111RAC

STRUCTURE

Carprofen

Alclofenac

2- (acetyloxy) benzoic acid

Diflunisal

Diclofenac

Etodolac acetic acid

3-chloro-4- (2-propenyloxy) benzoacetic acid

2 ’, 4'-difluoro-4-hydroxy-3biphenylcarboxylic acid

2 - {(2,6-dichlorophenyl) amino] benzeneacetic acid

6-chloro-a-methyl-9H-carbazole 2-acetic acid

Ropirano [3,4-6] indole-1-1,8-diethyl-1,3,4,9-tetrahydride -

Indomethacin 1 - <4-chlorobenzoyl) -5-methoxy- 2-methyl-7H-indole-3-acetic acid IT Indoprofen 4- (1,3-dihydro-1-OXO-2H- IZOINDOL-2-IL) benzeneacetic acid Isoxepack 6,11-dihydro-11oxodibene [P, e] oxepine-2-acetic acid Ketoprofen (KeYuGep®) ¹ 3-beneoyl-amethylbenzeneacetic acid About i Meclofenamic Acid (Agiae1®) 2 - [(2,6-dichloro-3-methylphenyl) amino] benzoic acid Oh ^ ^he C1 Mefenamova acidification 2 - [(2,3-dimethylphenyl) amino] benzoic acid / Y Meloxicam (Me1asat®) 4-hydroxy-2-methyl-H- (5methyl-2-thiazonyl) -2H-1,2benzothiazine-3-carboxamide o'o

Felbinak [1,1 ’-biphenyl] -4-acetic acid ABOUT Flufenamic acid 2 - {[3- (trifluoromethyl) phenyl] amino} beneneoic acid Oh he Flunixin Meglumin (Wapagnpe®) ¹ 2 - {[2-methyl-3- (trifluoromethyl) phenyl] amino} -3-pyrid incarboxylic acid mixed with 1-deoxy-1 - (methylamino) -Glucitol (1: 1) ¢¢ / he Flurbilrofen 2-fluoro-a-methyl- [1,1 biphenyl] acetic acid g Ibuprofen a-methyl-4- (2-methylpropyl) beneolacetic acid Ilonidap 6-chloro-5-fluoro-2, 3-d igidro (hydroxy-2-thienylmethylene) 2-oxo-7H-indole-1carboxamide □ γΝΗ,

Nabumetone and 6- 4- (6-methoxy-2-naphthalenyl) NMU 2-butanone, a prodrug metabolized by ίη νίνο to the active 6-methoxy-2naphthylacetic acid (6NMU) shown on the right

Naproxen

Niflumic acid

Nimesulide (ZiPREpe®) ¹

N8-398

Phenylbutazone ¹ Registered Trademark; approved for use in dogs outside the USA

6-methoxy-a-methyl-2naphthaleneacetic acid

2- [3- (trifluoromethyl) anilino] nicotinic acid

4’-nitro-2’ phenoxymethanesulfonanilide

Y- [2- (cyclohexyloxy) -4nitrophenyl] methanesulfonamide

4-butyl-1,2-diphenyl-3,5pyrazolidinedione

Description of preferred embodiments

Carprofen compounds characterized by the functionality of α-methylacetic acid have many times greater selectivity for COX-2 in dogs than any of the NSAID-containing sulfonyl or sulfonylamides shown in the above table. In order to demonstrate this unexpected property, a comparison was made between the selectivity for COX-2 of carprofen, a compound of the present invention, and the selectivity for COX-2 of some selected compounds from the above table. The results are illustrated by the following working examples.

As described above, selectivity for COX-2 is usually defined as the ratio of inhibition of COX-1 to inhibition of COX-2 or vice versa. In the present description, the ratio of COX-1 inhibition to COX-2 inhibition is used essentially for simplicity. Both inhibition values are TC ₅₀ values, which means that the more active the test compound, the lower the TC ₅₀ value. This, by its result, reverses the ratio under consideration in such a way that in cases where it is the COX-1: COX-2 ratio, and the test compound is very selective in relation to the dog COX-2, this ratio will be the ratio of a larger number to a much smaller number. Thus, most compounds that are selective for canine COX-2 will be those with the highest numbers for this ratio.

Example 1. Comparative evaluation of the inhibition of canine cyclooxygenases-1 and -2 by carprofen and other NSAIDs.

Canine COX-1 Activity Assessment Protocol

The day before the analysis, the drug compounds were dissolved and diluted with a mixture of 0.1 ml DMSO / 9.9 ml Hank's balanced saline (HB88) and stored overnight at 4 ° C. On the day of the analysis, citrate-stabilized blood was taken from the donor dog, centrifuged at 190 d for 25 min at room temperature, and the resulting platelet-rich plasma was transferred to a new tube for further procedures. Platelets were washed by centrifugation at 1500 d for 10 min at room temperature. Platelet washing was performed with platelet buffer, which includes Hank's buffer (without calcium) with 0.2% bovine serum albumin (B8A) and 20 mM HEPE8. Then the platelet samples were adjusted to 1.5 × 10 ⁷ / ml, after which 50 μl of calcium ionophore (A23187) with calcium chloride solution was added to 50 μl of diluted test drug compound in tablets so as to obtain A23187 concentrations of 1.7 μM and Ca 1.26 mm. Then, 100 μl of washed dog platelets were added and the samples were incubated at 37 ° C for 15 min, after which the reaction was stopped by adding 20 μl of 77 mM EDTA. The plates were then centrifuged at 2000 ° C for 10 min at 4 ° C, after which 50 μl of the supernatant for thromboxane B2 (TXB2) was analyzed by enzyme-linked immunosorbent assay (ELISA). The PO / ml of TXB2 was calculated from the standard curve for each plate, from which it was possible to calculate the percent inhibition of COX-1 and Κ. ' ₅₀ for test drugs.

Protocol for assessing the activity of canine COX-2

In compiling the protocol, the dog histocytoma cell line (macrophage-like) from the American Type Culture Collection, designated as OH82, was used to evaluate the activity of various test drug compounds against COX-2 inhibition. 10 μg / ml LPS was added to vials with these cells, after which cultures were incubated in vials overnight. For analysis on COX-2, the same dilutions of the tested drug compounds were used as in the above protocol for COX-1, and they were prepared the day before the analysis. Cells were collected from culture bottles by scraping, and then washed with a minimum amount of Eagle's medium (MEM) in combination with 1% fetal calf serum, centrifuged at 1500 rpm for 2 min and adjusted to a concentration of 3.2x10 ⁵ cells / ml. To 50 μl of the diluted test drug compound, 50 μl of arachidonic acid in MEM was added to give a final concentration of 10 μl, and 100 μl of a cell suspension was added to give a final concentration of 1.6 x 10 ⁵ cells / ml. Samples of the test suspensions were incubated for 1 h, and then centrifuged at 1000 rpm for 10 min at 4 ° С; after an aliquot of 50 μl of each test drug substance, it was transferred to ELISA plates. ELISA was performed on prostaglandin E ₂ (PCE ₂ ) and PCE2 concentrations in PC / ml were calculated from the standard curve for each plate. From these data, it was possible to calculate the percent inhibition of COX-2 and the value of 1C ₅₀ for the tested drugs. Repeated studies of the inhibition of COX-1 and COX-2 were carried out over several months. The results were averaged and one ratio of COX-1: COX-2 was calculated. The data obtained, together with an indication of the number of tests performed for each test sample, are shown in the following table of values.

table 2

NSAIDs Number of tests 1С50 (MKM) for TsOG-1 1C ₅ 0 (μM) for COX-2 Rel COX-1 / COX-2 Carprofen (racemate) nine 13,2 0.102 129 Carprofen (8-) 3 6.71 0,0371 181 Karprofen (P-) 4 > 25.0 5.97 > 4.19 Flufenamic acid 6 2,31 0.0475 48.6 Nimesulide 6 2.15 0,0565 38,0 Niflumic acid 6 1,03 0.0464 22.2 Meclofenamic acid 5 0.737 0,0478 15.4 Tolfenamic Acid 4 0.206 0.0137 15.0 Naproxen 3 7.08 0.626 11.3 Mefenamic acid 4 0.403 0,0362 11.1 Felbinak 3 2.54 0.362 7.01 6-NMU 6 28.3 4.21 6.72 N8-389 7 0.587 0.137 4.28 Flurbiprofen 4 0.505 0.123 4.10 Diclofenac 3 0.246 0,0778 3.16 Meloxicam 5 0.891 0,307 2.90 Phenylbutazone 5 > 10.0 3.79 > 2.46 Ibuprofen 4 1,03 0.391 2.63 Tenidap 12 0.469 0.228 2.06 Aklofenak 3 13,2 7.41 1.78 Ilonidap sixteen 0.472 0.270 1.75 Flunixin 5 0.00768 0.0121 0.635 Etodolac 3 1.33 2,57 0.517 Piroxicam 6 0.223 0.585 0.381 Ketoprofen 5 0,0286 0.123 0.232 Indomethacin 6 0,0558 0.366 0.152 Aspirin 3 34.3 > 100 <0.343 Vedaprofen

Example 2. Determination of inhibition by carprofen of the activity of COX-1 and COX-2 in canine whole blood ex u1uo.

The aim of this study was to evaluate the effectiveness of carprofen in inhibiting the activity of COX-1 and COX-2 using the ex v1y0 procedure on dog blood. Three dogs were dosed with a dose of 10 mg / kg of racemic 6-chloro-a-methylcarbazole-2-acetic acid (carprofen) orally in capsule dosage form. Three dogs were given the same dose of 2 mg / kg carprofen in the same way, and three dogs were not affected. Before dosing, all dogs took a blood sample at time zero, followed by blood sampling 1, 3, and 6 hours after dosing. Tubes were prepared containing 2 μl of either (A) calcium ionophore A23187 to obtain a final concentration of 10 μg / ml, which stimulates the production of thromboxane B ₂ (TBX ₂ ) to determine the activity of COX-2, or (B) lipopolysaccharide (LPS) to obtain final concentration of 10 μg / ml, which stimulates the production of prostaglandin E ₂ (RFE ₂ ) to determine the activity of COX-2. The tubes used for control contained a diluent, and they were not stimulated by the addition of any agent. A 500 μl blood sample was added to each of the tubes described above, after which they were incubated at 37 ° C for 1 hour in the case of tubes containing calcium ionophore and overnight in the case of tubes containing LPS. After incubation, 10 μl of EDTA was added to a final concentration of 0.03% to prevent clotting of the plasma, which sometimes occurs after thawing of frozen plasma samples. Incubated samples were centrifuged at 4 ° C, and the resulting plasma sample with a volume of approximately 200 μl was collected and stored at -20 ° C in 96-well polypropylene plates. To determine the final results of this study, Southap enzyme-linked immunosorbent assay kits were used to measure the production of TXB2 and PCE2 based on the principle of competitive label binding with antibody and determining the final result using colorimetry. Plasma samples were diluted to approximate the ranges of standard amounts that are attached to the diagnostic and research kits, namely, 1/500 in the case of TXB ₂ and 1/750 in the case of PCE2.

The data below in the table. 3 show the percent inhibition of the activity of COX-1 and COX-2 based on the corresponding values at time 0. These data are expressed as the average of the exposed groups in PC / ml produced by TXB2 and PCE2. Plasma dilution in the indicated values for the obtained data was not taken into account.

The data in the table. 3 show that at a dose of 2 mg / kg at all time points there was significant inhibition of COX-2. 3 and 6 hours after the dose, a slight decrease in COX-2 inhibition was observed when compared with the data obtained for a dose of 10 mg / kg. The data in the table. 3 also show that at a dose of 2 mg / kg, there was no significant inhibition of COX-1 activity at any of the time points. This result was consistent with the excellent tolerance of carprofen observed by the dogs selected for the study. The data for a dose of 10 mg / kg show that there was a complete inhibition of the activity of COX-2 at each time point and a very strong inhibition of the activity of COX-1, starting from the 1st hour with reaching a plateau over a period from the 3rd to the 6th of the hour. Accordingly, the data in table. 3 clearly show that at a dose concentration of 2 mg / kg, carprofen has good selectivity for COX-2. As the dose increases from 2 to 10 mg / kg, an increase in the inhibition of COX-1 activity becomes noticeable.

Table 3

Inhibition of COX-1 activity (group average) TXB ₂ , PO / ml / well % inhibition 0th hour 1st hour 3rd hour 6th hour 1st hour 3rd hour 6th hour No impact 102 134 77 65 0% 25% 36% 2 mg / kg 72 75 66 46 0% 8% 36% 10 mg / kg 51 31 6 7 39% 88% 86% Inhibition of COX-2 activity (group average) TXB ₂ , RS / ml / well % inhibition 0th hour 1st hour 3rd hour 6th hour 1st hour 3rd hour 6th hour No impact 393 900 349 406 0% eleven% 0% 2 mg / kg 511 33 98 190 94% 81% 63% 10 mg / kg 336 nineteen 12 12 94% 96% 96%

COX inhibition is observed when the measured percentage of inhibition is higher than the percentage of inhibition in the untreated control. The percent inhibition in the above table was calculated directly in accordance with the equation below: (PCE ₂ at (= 0) - (PCE ₂ at 1 = 1)% inhibition (1st hour) = ------------ ----------------- x 100 (RFE ₂ at 1 = 0)

Example 3. Determination of inhibition of COX-2 activity by carprofen in whole blood of dogs ex νίνο.

This study was carried out in accordance with the procedure described in example 2, but with some modifications described in detail below.

Three dogs were given a dose of 2 mg / kg of racemic 6-chloro-a-methylcarbazole-2-acetic acid (carprofen) orally in tablet form at time 0, three dogs were given a dose of 4 mg / kg carprofen in the same way at time 0 but did not affect three dogs. Before the dose was administered, all blood samples taken for the study were taken at a zero time blood sample, followed by blood sampling 2 and 4 hours after the dose was administered. Tubes containing 2 μl of lipopolysaccharide (LPS) were prepared to give a final concentration of 10 μg / ml. For control used tubes that were not processed. A 500 μl blood sample was added to each of the tubes described above, after which they were incubated at 37 ° C overnight. After incubation, 10 μl of EDTA was added to a final concentration of 0.03%. Incubated samples were centrifuged at 4 ° C, and the resulting plasma sample with a volume of approximately 200 μl was collected and stored at

20 ° C in 96-well polypropylene plates. To measure the production of RFE ₂ , we used Southap kits for enzyme-linked immunosorbent assay with the determination of the final result using colorimetry. Plasma samples for POE ₂ were diluted in the ratio 1/750.

Plasma samples were also analyzed for the total concentration of carprofen, for which HPLC was used with a chiral LOR column of 100x4.5 mm in size from Cfotlc, a mobile phase consisting of a mixture of 2-propanol and a phosphate buffer with a pH of 6.0 at a ratio of 10:90 (volume / volume), and with fluorescence detection (excitation at 285 nm, emission at 345 nm). Plasma samples (0.2 ml) were buffered with 0.05 M citric acid with a pH of 5.1, followed by the addition of (8) -naproxen as an internal standard, and then extracted with a mixture of diethyl ether and dichloromethane in a ratio of 4: 1 (v / v) . The ether layer was separated, subjected to back extraction in 0.005 M Na ₂ CO ₃ , after which the organic phase was removed by suction. The aqueous phase was buffered with 0.05 M citric acid with a pH of 5.1 and again extracted with a mixture of diethyl ether and dichloromethane. Then the ether was transferred to clean tubes, evaporated in a stream of nitrogen, and the residue was dissolved in a mobile phase HPLC for analysis.

The data below in the table. 4 show the production of POE ₂ , (PO / ml / well), the percent inhibition of COX-2 activity based on zero values for each dog, and the plasma action level for individual dogs.

The data in the table. 4 show that 2 and 4 hours after the dose was introduced, a slight difference was observed between the doses, with a dose of 4 mg / kg giving a slightly greater inhibition of COX2. Inhibition of COX-2 ex νίνο correlates well with plasma concentrations of carprofen.

Table 4

Inhibition of COX-2 activity and plasma concentration of carprofen Dog number Dose (mg / kg) POE2 (PO / ml / well) Percent inhibition Concentration in plasma (cg / ml) 0th hour 2nd hour 4th hour 2nd hour 4th hour 2nd hour 4th hour 35769 0 426 340 439 twenty% 0% - - 05690 0 130 239 219 0% 0% - - 06044 0 860 660 632 23% 27% - - 35773 2 293 35 69 88% 77% 21.9 13,4 35742 2 541 113 223 79% 59% 8.6 5.7 36184 2 409 46 90 89% 78% 17,2 10.6 05717 4 471 25 twenty 95% 96% 37.6 29.1 05704 4 393 21 25 96% 94% 29.9 21.1 36185 4 622 14 14 98% 98% 29.0 27.0

The percent inhibition in the above table was calculated directly in accordance with the equation below:

(RFE; at 1 = 0) - (P6E ₂ at 1 = 2)% inhibition (2nd hour) = ------------------------ ---- χ 100 (RFE ₂ at 1 = 0)

Example 4. Determination of ίη νίνο inhibition of COX-2 activity by carprofen in a model representing carrageenan-induced inflammation in dogs.

The aim of this study was to track ίη νίνο the activity of COX-2 in a chamber implanted under the skin during induced inflammation. The COX-2 enzyme can be detected by Western blot analysis 5 hours after treatment with carrageenan (T. Ktgaypet c1 a1., I. Ryattaso. Exp. Thyet. (1972) 282, 10941101). In addition, it is possible to simultaneously determine the activity of COX-1 by ex νίνο methods, as described in Example 2. Six hound dogs were surgically implanted under the skin immediately behind the shoulder blades of blown polyethylene golf balls with an outer diameter of about 4.2 cm. The dogs were given for 1 month recover after surgery before distributing them among the experimental groups.

The experiments were carried out in two parallels. On the day of the experiment, three dogs were orally given 2 mg / kg of carprofen 30 minutes before the onset of inflammation, and the other three dogs served as controls. The wool around the balls was shaved and this area was probed to determine the location of the hole in the ball. Then this area was labeled and sterilized with 2% iodine tincture. A needle was inserted into the hole and 1.5 ml of liquid was taken, which will hereinafter be called exudate liquid (EF). After collecting 1.5 ml of EJ, 0.33% solution of carrageenan in H ₂ O was injected into the ball to cause inflammation. EC samples were taken at 0 and 5 hours and 24 hours after administration of carrageenan. In addition to this, blood samples were taken so that COX-2 determination in whole blood ex νίνο could be carried out as described in Example 2.

EC samples before analysis had to be cleaned because of the small amount of RFE ₂ found in the ίη νίνο samples. This was carried out using ₂ columns affinity for RFE (Southap SPEPPSA). The column was first washed with 10 ml of 0.1 M phosphate buffer, and then with 10 ml of water. Then the EH was diluted 1: 5 with 0.1 M phosphate buffer and introduced into the column. The column was washed with 10 ml of phosphate buffer and then with 10 ml of water. Finally, RFE ₂ was removed from the column using 2.5 ml of 95% ethanol. The sample was evaporated in a stream of nitrogen, and then diluted for analysis on RFE ₂ using the ELISA kit on RFE ₂ (COX-2) from Southup, as described in examples 2 and 3.

Tab. 5 shows that carrageenan causes an almost 4-fold increase in the synthesis of RFE ₂ in balls over background levels. This increase was visible after 5 hours and persisted for at least 24 hours. Animals with a dose of carprofen of 2 mg / kg showed almost complete inhibition of PCE ₂ synthesis, which was statistically significant after 5 and 24 hours at values of 0.013 and 0.015, respectively. Data on COX-1 ex νίνο showed the absence of TXB2 inhibition at any of the studied time instants. This indicates that ίη νίνο carprofen showed inhibition of COX-2 in the absence at the same time of the influence of COX-1 ex νίνο on the activity.

Table 5

Inhibition of COX-2 activity ίη νίνο: group averages Dose (mg / kg) RFE ₂ (RS / ml / well) % inhibition 0 hour 5th hour 24th hour 5th hour 24th hour 0 3.4 17.1 13.0 0% 0% 2 6.5 1.9 3.2 71% 51%

Example 5. Calculation of the rates of administration and doses for oral delivery of controlled-release carprofen dosage forms that give COX-2 inhibition of 80% in dogs over a time longer than in the case of immediate-release carprofen dosage forms.

A study was conducted to obtain data to determine suitable, preferred, more preferred and most preferred oral dosage forms of extended release carprofen for use in the present invention. Plasma samples taken from dogs in Example 3 above were also analyzed for total plasma carprofen concentration by HPLC with a chiral ACP column of 100x4.5 mm in size from C11got1es11. the mobile phase, consisting of a mixture of 2-propanol and phosphate buffer with a pH of 6.0 at a ratio of 10:90 (volume / volume), and with fluorescence detection (excitation at 285 nm, emission at 345 nm). Plasma samples (0.2 ml) were buffered with 0.05 M citric acid with a pH of 5.1, followed by the addition of (8) naproxen as an internal standard, and then extracted with a mixture of diethyl ether and dichloromethane in a ratio of 4: 1 (v / v). The ether layer was separated, subjected to back extraction in 0.005 M Na ₂ CO ₃ , after which the organic phase was removed by a vacuum pump. The aqueous phase was buffered with 0.05 M citric acid with a pH of 5.1 and again extracted with a mixture of diethyl ether and dichloromethane. Then the ether was transferred to clean tubes, evaporated in a stream of nitrogen, and the residue was dissolved in a mobile phase HPLC for analysis.

Plasma carprofen levels were plotted against% inhibition of COX-2 (from Example 3). A check of this graph showed that COX-2 inhibition of 80% occurred at a plasma concentration of carprofen of approximately 10 μg / ml, COX-2 inhibition of 50% occurred at a plasma concentration of carprofen of approximately 2 μg / ml, and inhibition of COX-2 by 90% occurred with a concentration of carprofen in plasma of approximately 20 μg / ml.

Following oral administration to dogs of immediate-release carprofen at a dose of 2 mg / lb (4.409 mg / kg), plasma concentrations of carprofen were above 10 μg / ml for approximately 10.5 hours. According to the present invention, 2 mg / lb / day (4.409 mg / kg / day) is within the preferred doses of carprofen.

A suitable extended release carprofen dosage form of the present invention is a dosage form that maintains a plasma level of carprofen greater than 2 μg / ml for most of the day after a single oral dose of 2 mg / lb (4.409 mg / kg).

The preferred controlled-release carprofen dosage forms of the present invention are dosage forms that maintain a plasma concentration of carprofen greater than 10 μg / ml for a time longer than the time during which the immediate-release carprofen dosage form maintains a comparable plasma level when said drug the immediate release form and the controlled release dosage form are administered at the same dose, for example 2, 1.8, 1.6 or 1.4 g / lb (4,409; 3,968; 3,527, or 3,086 mg / kg). For example, the preferred dosage forms of a sustained release of 2 mg / lb (4.409 mg / kg) of the present invention maintain a plasma concentration of carprofen greater than 10 μg / ml for longer than 10.5 hours.

Dosage forms of immediate-release carprofen containing doses of 1.8, 1.6, and 1.4 mg / lb (3.968; 3.527 or 3.086 mg / kg) maintain a concentration of greater than 10 μg / ml for 9.5, 8.5, and 7.5 hours, respectively.

Preferred dosage forms of controlled release of 1.8 mg / lb (3.968 mg / kg) maintain a plasma concentration of carprofen in excess of 10 μg / ml for more than 9.5 hours. Likewise, the threshold duration for doses of 1.6 mg / lb and 1.4 mg / lb (3.527 and 3.086 mg / kg) is 8.5 hours and 7.5 hours, respectively. Assuming linear pharmacokinetics, similarly, performance can be calculated for preferred oral dosage forms of carprofen at doses higher than 2 mg / lb (4.409 mg / kg) or less than 1.4 mg / lb (3.086 mg / kg).

More preferred oral controlled-release carprofen dosage forms are those that maintain a plasma concentration of carprofen above 10 μg / ml for a period of time greater than or equal to that observed when immediate-release carprofen is given at any higher dose. Thus, these controlled release dosage forms support at least 80% inhibition of COX-2 in the blood of dogs for a period longer than that achieved by the immediate release dosage form at a higher dose.

The most preferred controlled-release carprofen dosage forms are those that are able to maintain plasma carprofen levels above about 10 μg / ml for a period of time greater than or equal to that observed with a 2 mg / lb immediate-release carprofen dosage form (4.409 mg / kg) (10.5 h) when the indicated oral dosage forms of controlled-release carprofen are administered at a dose of less than 2 mg / lb (4.409 mg / kg). The performance of the 2 mg / lb (4.409 mg / kg) immediate-release oral drug dosage of carprofen was taken as a reference standard for such a comparison, since 2 mg / lb / day (4.409 mg / kg / day) is currently recommended and taken effective dose of the present invention as described herein.

As described below, the controlled release rates of carprofen were calculated for oral dosage forms of carprofen, which resulted in plasma concentrations of carprofen greater than 10 μg / ml. For each calculation, these calculated speeds were zero-order speeds, and thus, these speeds were calculated for sustained release devices that release carprofen at a constant (i.e., zero order) speed. Those skilled in the art will understand that in practice, dosage forms are released at zero order only for some of the time they release the drug, after which they are released at a first order or mixed order speed. In order to make the determination of the rates of delivery of carprofen (or the release of carprofen) even clearer for the person skilled in the art, the following release rates were determined according to the time at which 80% of carprofen is released from the dosage form, regardless of the release mechanism Carprofen is involved.

Zero-order release rates leading to simulated plasma concentrations of carprofen higher than 10 μg / ml were determined by the known method CHNoy, M. any N. Ve, Ménuodu Gogiktdogo yoke rIag71 tasokete gibnos οί 1 е б теб ю и и д д 6 6 6 6 ί ί В В..... The average data resulting from the oral administration of 2 mg / lb (4.409 mg / kg) of carprofen in the form of immediate release preparations to the canine family obeyed the equation

C = C, (e ' ⁵² ' -e ⁵ · ') where C ₁ , 8 ₂ and 81 are parameters, and ί represents time. During the release of the zeroth order, plasma concentrations of carprofen were modeled according to the following equation:

С = (Л ₀ С, / О _{ге /} ) [(е- ⁵ · '-1) / 5, - (^ -1) / 52] where k0 is the zero-order release rate, and OhG is the standard dose. After completion of the release, the following equation is applicable: c = (k0C, /) [[(1-e ~ ^{5, m} ) / 5,] e ~ ^ - [(1-e) / 82] e ~ ^] where T = 0 _SV / k ₀ and O _SV represents the rate of controlled release. Preferred Oral Dosage Forms of Carprofen Controlled Release

The table below 6 shows that controlled-release carprofen dosage forms (2 mg / lb dose (4.409 mg / kg)), which release 80% of their carprofen in 1.6 to 19.2 hours, can produce plasma levels of more than one carprofen 10 μg / ml for more than 10.5 hours. Accordingly, they are the preferred dosage forms at 2 mg / lb (4.409 mg / kg).

The table below 7 shows that dosage forms of controlled-release carprofen (dose of 1.8 mg / lb (3.968 mg / kg)), which release 80% of their carprofen in a period of 1.6 to 19.2 hours, are capable of producing levels of carprofen in plasma more than 10 μg / ml for more than 9.5 hours. Accordingly, they are the preferred dosage forms of 1.8 mg / lb (3.968 mg / kg).

Tab. Figure 8 shows that controlled-release carprofen dosage forms (1.6 mg / lb dose (3.527 mg / kg)), which release 80% of their carprofen in 1.6 to 19.2 hours, are capable of producing carprofen levels in plasma more than 10 μg / ml for more than 8.5 hours. Accordingly, they are the preferred dosage forms of 1.6 mg / lb (3, 527 mg / kg).

Tab. Figure 9 shows that controlled-release carprofen dosage forms (1.4 mg / lb (3.086 mg / kg) dose) that release 80% of their carprofen in 1.6 to 19.2 hours can produce levels of carprofen in plasma more than 10 μg / ml for more than 7.5 hours. Accordingly, they are the preferred dosage forms at 1.4 mg / lb (3.086 mg / kg). More Preferred Oral Dosage Forms of Carprofen Controlled Release

The oral controlled-release carprofen dosage forms of the present invention are particularly useful because they are able to maintain plasma levels of carprofen above 10 μg / ml for more than 10.5 hours, even when they are administered at doses lower than the preferred effective dose of 2 mg / pound (4.409 mg / kg). Tab. 7 shows that oral dosage forms of controlled-release carprofen (dose of 1.8 mg / lb (3.968 mg / kg)), which release 80% of their carprofen in 1.6 to 19.2 hours, can produce levels of carprofen in plasma more than 10 μg / ml for more than 10.5 hours. They are more preferred dosage forms at a dose level of 1.8 mg / lb (3.968 mg / kg).

Tab. Figure 8 shows that oral controlled-release carprofen dosage forms (1.6 mg / lb dose (3.527 mg / kg)), which release 80% of their carprofen in 1.6 to 19.2 hours, can produce levels of carprofen in plasma more than 10 μg / ml for more than 9.5 hours, that is, longer than the immediate release dosage form of 1.8 mg / lb (3.968 mg / kg) can be achieved. Therefore, they are more preferred dosage forms at a dose level of 1.6 mg / lb (3.527 mg / kg).

Tab. 9 shows that oral dosage forms of controlled-release carprofen (dose of 1.4 mg / lb (3.086 mg / kg)), which release 80% of their carprofen in 1.6 to 19.2 hours, can produce levels of carprofen in plasma more than 10 μg / ml for 8.5 hours or more, that is, longer than the immediate release dosage form of 1.6 mg / lb (3.527 mg / kg) can be achieved. Therefore, they are more preferred dosage forms at a dose level of 1.4 mg / lb (3.086 mg / ml).

Most Preferred Oral Dosage Forms of Carprofen Controlled Release

The most preferred controlled-release oral dosage forms of carprofen are those that are able to maintain plasma levels of carprofen above about 10 μg / ml for a period of time greater than or equal to that observed with 2 mg / lb immediate-release carprofen dosage form ( 4.409 mg / kg) (10.5 h) when the indicated controlled-release oral dosage forms of carprofen73 are administered at a dose of less than 2 mg / lb (4.409 mg / kg). The performance of the indicated oral dosage form of carprofen 2 mg / lb (4.409 mg / kg) immediate release is taken as a reference standard for comparison since 2 mg / lb / day (4.409 mg / kg / day) is currently the recommended effective dose according to the present invention. The data in the table. 6-9 are used to characterize the most preferred oral controlled release forms of the present invention.

At a dose of 1.6 mg / lb (3.527 mg / kg), the most preferred oral dosage forms of controlled-release carprofen are those that release 80% of their carprofen in a period of 1.6 to 19.2 hours. At a dose of 1 4 mg / lb (3.086 mg / kg) The most preferred oral dosage forms of controlled-release carprofen are those that release 80% of their carprofen in about 12.8 hours (10-14 hours).

Table 6. The number of hours during which the concentration of carprofen in plasma exceeds 10 μg / ml after administration of dosage forms of carprofen controlled release at different speeds (calculated): dose = 2 mg / lb (4.409 mg / kg)

Zero-order release rate (mg / lb / h (mg / kg / h)) Release time of 80% carprofen from the dosage form (h) The length of time (h) during which the concentration of carprofen in plasma exceeds 10 μg / ml 0.084 (0.185) 19,2 17.50 0,100 (0,220) sixteen 16.5 0.125 (0.275) 12.8 15,5 0.165 (0.363) 9.6 13.5 0.250 (0.551) 6.4 12.5 0.330 (0.727) 4.8 12 1.0 (2.204) 1,6 eleven

Table 7. The number of hours during which the concentration of carprofen in plasma exceeds 10 μg / ml after administration of dosage forms of carprofen controlled release at different speeds (calculated): dose = 1.8 mg / lb (3.968 mg / kg)

Zero order release rate (mg / lb / h ((mg / kg / h)) Release time of 80% carprofen from the dosage form (h) The length of time (h) during which the concentration of carprofen in plasma exceeds 10 μg / ml 0.075 (0.165) 19,2 14 0.090 (0.198) sixteen 14.5 0.113 (0.249) 12.8 14.5 0.150 (0.330) 9.6 thirteen 0.225 (0.496) 6.4 11.5 0.3 (0.661) 4.8 eleven 0.9 (1.984) 1,6 10

Table 8. The number of hours during which the concentration of carprofen in plasma exceeds 10 μg / ml after administration of dosage forms of carprofen controlled release at different speeds (calculated): dose = 1.6 mg / lb (3.527 mg / kg)

Zero-order release rate mg / lb / h ((mg / kg / h)) The release time of 80% of carprofen from the dosage form (h) The length of time (h) during which the concentration of carprofen in plasma exceeds 10 μg / ml 0.067 (0.147) 19,2 eleven 0.080 (0.176) sixteen thirteen 0,100 (0,220) 12.8 12.5 0.135 (0.297) 9.6 11.5 0.2 (0.440) 6.4 eleven 0.27 (0.595) 4.8 10 0.8 (1.763) 1,6 nine

Table 9. The number of hours during which the concentration of carprofen in plasma exceeds 10 μg / ml after administration of dosage forms of carprofen controlled release at different speeds (calculated): dose = 1.4 mg / lb (3.086 mg / kg)

Zero-order release rate mg / lb / h ((mg / kg / h)) The release time of 80% of carprofen from the dosage form (h) The length of time (h) during which the concentration of carprofen in plasma exceeds 10 μg / ml 0.059 (0.130) 19,2 0 0.07 (0.154) sixteen nine 0.088 (0.194) 12.8 10.5 0.115 (0.253) 9.6 10 0.175 (0.385) 6.4 9.5 0.23 (0.507) 4.8 8.5 0.7 (1,543) 1,6 8

Example 6. Carprofen implants for dogs.

Carprofen implants are useful for delivering carprofen over long periods of time, for example 3 days, 7 days, 30 days, etc. The detailed example below describes the suitable and preferred release rates of carprofen from carprofen containing implants, and also determines the dose associated therewith.

The rate of entry of carprofen into the dog’s body, which should provide a stable plasma concentration of carprofen of 10 μg / ml, was calculated using the following equation from S1a1bG M and S. Regpeg Rbagtasokshebsk, 2pb eb. Igidk apb 1Ie Rbagtaseibsa1 8s1epsek, eb. 1.8. 15, 1982, Iete Wogk: Magse1 Iekkeg, 1ps .:

- c / where C _kk represents a stable plasma concentration of carprofen, K ₀ represents the rate of entry, and C1 represents the systemic clearance. Systemic clearance was determined based on the pharmacokinetics observed after oral administration to dogs of 2 mg / lb (4.409 mg / kg) carprofen, and using the following equation:

go a = - fox

Ί5

Ί6 where P is the bioavailability (which is assumed to be 1 for the implant), Ό is the oral dose, and AIS is the average area under the extrapolated to infinity curve of plasma concentration of carprofen in time.

The obtained C1 clearance was 11.02 per hour per kg of body weight. Using this clearance value and the target C _cc value of 10 μg / ml, it was calculated that the release rate of carprofen B ₀ is 2.64 mg / kg / day. For treatment lasting 3, 7, or 30 days, a total dose of 3.6 mg / lb (7.963 mg / kg), 8.4 mg / lb (18.52 mg / kg), or 36 mg / lb (79.39 mg) should be required / kg), respectively. In total, an implant containing 18.52 carprofen per kg body weight and releasing carprofen at a rate of 110.23 μg per kg body weight per hour, maintains a plasma concentration of carprofen of 10 μg / ml for 7 days. This will maintain 80% inhibition of COX-2 for 7 days.

To obtain the implant dose and the release rate of carprofen required to maintain the concentration of carprofen at 2 μg / ml (50% inhibition of COX-2), the dose and release rate for the target value of 10 μg / ml was adjusted linearly by multiplying by 0.2. Thus, for a target plasma concentration of carprofen of 0.2 μg / ml, a release rate of 10 mg / lb / hr (22 μg / kg / hr) or 0.24 mg / lb / day (0.529 mg / kg / day) is needed. ) For treatment, a duration of 3, 7, or 30 days should require a total total dose of 0.72 mg / lb (0.159 mg / kg), 1.68 mg / lb (0.370 mg / kg) or 7.2 mg / lb (1.588 mg / kg), respectively.

To obtain the implant dose and the release rate of carprofen required to maintain the concentration of carprofen at a level of 20 μg / ml (90% inhibition of COX-2), the dose and release rate for the target value of 10 μg / ml was adjusted linearly by multiplying by 2. Thus, for the target plasma concentration of carprofen is 20 μg / ml; the release rate of carprofen is 100 μg / lb / h (220 μg / kg / h) or 0.24 mg / lb / day (5.28 mg / kg / day). For treatment lasting 3, 7 or 30 days, a total dose of 7.2 mg / lb (1.592 mg / kg), 16.8 mg / lb (3.704 mg / kg) or 72 mg / lb (15.878 mg / kg) should be required. respectively.

Suitable implants of the present invention release carprofen into dogs at a rate of 0.24 mg / lb / day (0.529 mg / kg / day) or more.

Preferred implants of the present invention release carprofen into the dog’s body at a rate of 0.24 to

1.2 mg / lb / day (0.529 mg / kg / day to 2.645 mg / kg / day).

More preferred implants of the present invention release carprofen into dogs at a rate of 1.2 to 2.4 mg / lb / day (2.645 mg / kg per day to 5.29 mg / kg per day).

Suitable carprofen implants have a total dose of carprofen up to 2 g, limited by the size of the implant, which can reasonably be administered to the dog. Of course, more than one implant can be driven at the same time.

Example 7. The separation of (8) -6-chloro-amethylcarbazole-2-acetic acid.

A solution of 4.3 g of (B) -a-methylbenzylamine in 20 ml of acetone was added to a solution of 9.7 g of partially separated 6-chloro-a-methylcarbazole-2-acetic acid (isolated by filtration in the previous separation of the racemate). After standing at room temperature for 24 hours, the mixture was filtered and the filter cake was washed with cold acetone to obtain 7.3 g after drying. After two additional recrystallizations from acetone, 1.9 g of (B) -a-methylbenzylamine salt were obtained (8) - 6-chloro-a-methylcarbazole-2-acetic acid, [α] _η ²² = - 13.6 °. Further recrystallization from acetone did not change the angle of rotation. This salt was dissolved in 50 ml of warm acetone, and this solution, after filtration, was poured into 500 ml of diluted hydrochloric acid. After filtration and drying, 1.4 g were obtained, which, after crystallization from chloroform, gave 0.9 g of (8) -6-chloro-a-methylcarbazole-2-acetic acid, so pl. 198 ° -201 °, [α] η ²² = + 53.2 °, (c 1.33; CH3OH).

Example 8. Species specificity of selectivity for COX-2: activity in individuals of the Sash GatShapk species (dogs) compared with activity in individuals of the species Vayik pogueduyik (white rats) and Noto car1epk (humans).

The very high degree of selectivity for COX-2 exhibited by carprofen in dogs was already quite fully demonstrated in Example 1. Equally unexpected was the discovery that this selective inhibition of the COX-2 enzyme is an activity that is specific for Sash GatShapk and does not apply to other species. This discovery was based on an assessment of the inhibitory activity of racemic carprofen in individuals of the species Vayik pogueduyik (white rats) and individuals of the species Noto karepepk (humans).

The selectivity for cyclooxygenase W1U0 was evaluated in rats by the method that CrgHyyk e! a1. described in Aden! & Asyopk, 32, (1991), 313-320. Inhibitory activity against COX-2 was evaluated in accordance with the effect of racemic carprofen on prostaglandin E2 production in rats, measured in rat synovial fluid. The synovial fluid is secreted by the synovial membrane and is contained in the joint cavities.

During joint inflammation, COX-2 is induced in the joint tissue, and prostaglandin products accumulate in the synovial fluid. The inhibitory activity against COX-1 was evaluated in accordance with the effect of racemic carprofen on the production of POE ₂ when measured in the mucous membrane of the rat’s stomach, which contains significant amounts of constitutive COX-1. Inhibition of this gastric isoenzyme leads to adverse gastrointestinal side effects. ΕΌ ₅₀ for COX-1 was 6.4 mg / kg, while ΕΌ ₅₀ for COX-2 was 0.63 mg / kg. These results show that in rats there is only 10-fold selectivity of racemic carprofen for COX-2.

In humans, COX-2 inhibitory activity was evaluated according to the effect of racemic carprofen on COX-2 levels in human umbilical cord vein endothelial cells (UHEC) stimulated by interleukin-1 (IL-1) and phorbol myristate acetate (PMA) in accordance with in a way that nabl e! a1. described in I. Vu1. Sies., 268, 23448-23454, 1993. These endothelial cells, when stimulated by IL-1 or PMA, are likely to contain large amounts of COX-2 induced. Inhibitory activity against COX-1 was evaluated in accordance with the effect of racemic carprofen on COX-1 levels when measured by biochemical analysis of TXB2 in washed human platelets (PTC) in accordance with the procedure that Ogozshap e! a1. described in 1pyasht. Kegh., 44, 253-257, 1995. These platelets are likely to contain significant amounts of constitutive COX1. 1S50 for HUVEC (COX-2) was 1.20 M, whereas ₅₀ 1C for TXB ₂ in the SCL (COX-1) was 0.77 .mu.M. These results indicate that humans do not have racemic carprofen selectivity for COX-2.

Example 9. The preparation of tablets (8) -6-chloro-amethylcarbazole-2-acetic acid.

Tablet composition

Ingredients Weight per tablet (8) -6-Chloro-a-methylcarbazole-2-acetic acid 25.00 mg Lactose, United States Pharmacopeia 64.50 mg Corn starch 10.00 mg Magnesium stearate 0.50 mg

Example 10. The preparation of the capsule (8) -6-chloro-methylcarbazole-2-acetic acid.

Capsule composition

Ingredients Weight per capsule (8) -6-Chloro-a-methylcarbazole-2-acetic acid 50mg Lactose, United States Pharmacopeia 124 mg Corn starch 30mg Talc, United States Pharmacopeia 5 mg Total weight: 210 mg

Example 11. Parenteral drug (8) 6-chloro-a-methylcarbazole-2-acetic acid Composition of the parenteral preparation

Ingredients Weight per ampoule (8) -6-Chloro-a-methylcarbazole-2-acetic acid 10.2 mg Methylparaben, United States Pharmacopeia 1.8 mg Propylparaben, United States Pharmacopeia 0.2 mg Sodium hydroxide, United States Pharmacopeia, as required for pH 9.0 mg Water for Injection, United States Pharmacopeia, as required 1,0ml

CLAIM

Claims (36)

1) cognitive therapeutic agents to counteract memory loss and impairment; 1) non-steroidal anti-inflammatory drugs (NSAIDs); 1) contained in solid dosage form or 1) is contained in the composition of the solid implant, providing a sustained, prolonged and / or controlled release of the indicated inhibitory compound; 1) contained in solution in the form of a dissolved substance; 1) cognitive therapeutic agents to counteract memory loss and impairment; 1) non-steroidal anti-inflammatory drugs (NSAIDs); 1. A method for the treatment or prevention of pain and inflammatory processes and diseases associated with the activity of inducible cyclooxygenase-2 (COX-2) in an individual of the SapE GatShageE species that needs such treatment, while reducing or eliminating undesirable side effects associated with simultaneous inhibition activity of constitutive cyclooxygenase-1 (COX-1), by selective inhibition of COX-2 activity relative to COX-1 activity, and the ratio of selectivity inhibition of COX-2: COX-1 activity is at least 3: 1 based on the levels of inhibition of ex νίνο in whole blood, measured at a dose giving> 80% inhibition of COX-2, in which said specimen of the SapE GatShage species is administered therapeutically effective for the treatment of pain and inflammation, in accordance with the above limitations , the amount of an anti-inflammatory COX-2 selective inhibitory compound comprising a compound of formula I * formula (I) in which K ² is χΊ ° C — gC-A where A is hydroxy, (C1-C4) alkoxy, amino , hydroxyamino, m HO- (C1-C2) alkylamino, di- _(C1-C2) alkylamino; X and Υ independently represent H or (C1-C2) alkyl and n is 1 or 2; K ⁶ represents halogen, (C ₁ -C ₃ ) alkyl, trifluoromethyl or nitro; K ⁹ represents H, (C1-C2) alkyl; phenyl or phenyl- (C1-C2) alkyl wherein phenyl is optionally monosubstituted with fluorine or chlorine; -C (= O) -K, where K is (C1-C2) alkyl or phenyl, optionally monosubstituted with fluorine or chlorine; or -C (= O) -O-K ^1, where K ¹ represents a _(C1-C2) alkyl; where X and Υ are different; its (-) (B) - and (+) ^) enantiomers and all their pharmaceutically acceptable salt forms, prodrugs, and metabolites that are therapeutically active to treat or prevent pain and inflammation. 2) antihypertensive and other cardiovascular drugs designed to compensate for the effects of atherosclerosis, hypertension, myocardial ischemia, angina pectoris, congestive heart failure and myocardial infarction selected from the group consisting of a) diuretics; b) vasodilator; c) β-adrenergic receptor antagonists; d) angiotensin-11-converting enzyme inhibitors (ACE inhibitors) individually or possibly together with neutral endopeptidase inhibitors; e) angiotensin II receptor antagonists; e) renin inhibitors; g) calcium channel blockers; 2) antagonists of H1 receptors; 2) contained in liquid dosage form. 2) contained in a dispersed composition for inhalation into the lungs or 2) is contained in the dispersed phase of the emulsion or the dispersed phase of the inverse emulsion, which is drawn upon injection or infusion, the emulsions containing suitable emulsifying agents or 2) antihypertensive and other cardiovascular drugs designed to compensate for the effects of atherosclerosis, hypertension, myocardial ischemia, angina pectoris, congestive heart failure and myocardial infarction selected from the group consisting of a) diuretics; b) vasodilator; c) β-adrenergic receptor antagonists; d) angiotensin-11-converting enzyme inhibitors (ACE inhibitors) individually or possibly together with neutral endopeptidase inhibitors; e) angiotensin II receptor antagonists; e) renin inhibitors; g) calcium channel blockers; 2) antagonists of H1 receptors; 2. The method of treating or preventing pain and inflammatory processes and diseases according to claim 1, wherein said anti-inflammatory COX-2 selective inhibitor compound is carprofen, 6-chloro-a-methyl-9H-carbazole-2-acetic acid. 3) antineoplastic agents selected from a) antimitotic drugs selected from ί) vinca alkaloids selected from [1] vinblastine and [2] vincristine; 3) sympatholytic agents; i) a ₂ -adrenergic agonists; k) antagonists of α-adrenergic receptors and l) inhibitors of HMG-CoA reductase (anticholesterolemic drugs); 3) kinin B1 and B2 receptor antagonists; 3) is contained in a dispersed composition for injection into said appropriate tissues and body cavities, where said composition possibly provides sustained, prolonged and / or controlled release of said inhibitory compound; D) swallowing said inhibitory compound in a suitable solid or liquid form for oral delivery, wherein said inhibitory compound 3) is contained in the suspension in the form of a suspended solid in colloidal or microdispersed form, said suspension containing suitable suspending agents; B) injection or infusion into the appropriate tissues or cavities of the body as a depot, where the specified composition provides storage of the indicated inhibitor and subsequently delayed, prolonged and / or controlled release of the indicated inhibitory compounds for systemic distribution; B) instillation, inhalation or insufflation into the appropriate tissues or cavities of the body in a suitable solid form, where the specified inhibitory compound 3) sympatholytic agents; i) a ₂ -adrenergic agonists; k) antagonists of α-adrenergic receptors and l) inhibitors of HMG-CoA reductase (anticholesterolemic drugs); h) antineoplastic agents selected from a) antimitotic drugs selected from ί) vinca alkaloids selected from [1] vinblastine and [2] vincristine; 3) kinin B1 and B2 receptor antagonists; 3. The method of treating or preventing pain and inflammatory processes and diseases according to claim 1, wherein said anti-inflammatory COX-2 selective inhibitor compound consists entirely of the (b) -enantiomer of carprofen, 6-chloro-a-methyl9H-carbazole-2 acetic acid. 4) secretagogues of growth hormone; 4) prostaglandin inhibitors selected from the group consisting of antagonists for RSB, PCE, PC1 ₂ - and PCE receptors; 4) secretagogues of growth hormone; 4) prostaglandin inhibitors selected from the group consisting of antagonists of Ρ6Ό-, P6E-, P61 ₂ - and PCE receptors; 4. A method of treating or preventing inflammatory processes and diseases according to claims 1, 2 or 3, wherein in addition the indicated inhibitory compound is used in combination with one or more other therapeutically active agents, under the following conditions: A) if the joint is seriously inflamed, and also simultaneously infected with bacteria, fungi, protozoa and / or the virus, then the indicated inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal and / or antiviral therapeutic agents; B) if a versatile treatment of pain and inflammation is required, then the indicated inhibitory compound is administered in combination with inhibitors of other inflammatory mediators, including one or more than one representative, independently selected from the group consisting of 5) strong painkillers; 5) thromboxane A ₂ inhibitors (TXA2); 5. A pharmaceutical composition for the treatment and prevention of pain and inflammatory processes and diseases associated with the activity of inducible cyclooxygenase-2 (COX-2), in an individual of the species Sashkashashapk requiring such treatment, while reducing or eliminating undesirable side effects associated with while inhibiting the activity of constitutive cyclooxygenase-1 (COX-1), containing A) a therapeutically effective amount for the treatment of pain and inflammation of an anti-inflammatory COX-2 selective inhibitor compound that selectively inhibits COX-2 activity relative to COX-1 activity, wherein the ratio of selectivity inhibition of COX-2: COX-1 activity is at least 3: 1 based on the levels of inhibition of ex νίνο in whole blood, measured at a dose giving> 80% inhibition of COX-2, including an anti-inflammatory COX-2 selective inhibitor compound of the formula H ⁹ formula (I) in which I ² represents where A represents hydroxy, (C ₁ -C ₄ ) alkoxy, amino, hydroxyamino, mono (C ₁ -C ₂ ) alkylamino, di- (C1-C2) alkylamino ; X and Υ independently represent H or (C1-C2) alkyl and η is 1 or 2; I ⁶ represents halogen, (C1-C3) alkyl, trifluoromethyl or nitro; I ⁹ represents H, (C1-C2) alkyl; phenyl or phenyl- (C1-C2) alkyl wherein phenyl is optionally monosubstituted with fluorine or chlorine; —C (= O) —I, where I is (C1-C2) alkyl or phenyl, optionally monosubstituted with fluorine or chlorine; or -C (= O) -O-I ¹ where I ¹ is _(C1-C2) alkyl; where X and Υ are different; its (-) (I) - and (+) (8) enantiomers and all their pharmaceutically acceptable salt forms, prodrugs and metabolites that are therapeutically active to treat or prevent pain and inflammation; and B) a pharmaceutically acceptable carrier for it. 5) strong painkillers; b) local and systemic anesthetics and 5) thromboxane A ₂ inhibitors (TXA2); 6) local and systemic anesthetics and 6) inhibitors of 5- and 12-lipoxygenases; 6. The pharmaceutical composition according to claim 5, wherein said COX-2 anti-inflammatory inhibitory compound is carprofen, 6-chloro-amethyl-9H-carbazole-2-acetic acid. 6) inhibitors of 5- and 12-lipoxygenases; 7) antagonists of H ₂ receptors, proton pump inhibitors and other gastroprotective agents. 7) leukotriene inhibitors LTC ₄ , LTP ₄ / LTP ₄ and LTP ₄ ; 7. The pharmaceutical composition according to claim 5, wherein said COX-2 anti-inflammatory selective inhibitor compound consists entirely of the (8) enantiomer of carprofen, 6-chloro-a-methyl-9H-carbazole-2-acetic acid. 7) antagonists of H ₂ receptors, proton pump inhibitors and other gastroprotective agents. 7) leukotriene inhibitors LTC ₄ , LTP ₄ / LTP ₄ and LTP ₄ ; 8) platelet activation factor receptor antagonists (PAE); 8. The pharmaceutical composition according to claims 5, 6 or 7, where, in addition, the indicated anti-inflammatory COX-2 selective inhibitor compound is in a dosage form suitable for systemic administration A) by injection or infusion in a suitable liquid form, which is intra-arterial, intra- or transdermal, subcutaneous, intramuscular, intravertebral, intrathecal or intravenous, where the indicated inhibitory compound 8) platelet activation factor receptor antagonists (PAE); 9) gold in the form of an aurothio group together with one or more than one hydrophilic group; 9. The pharmaceutical composition of claim 8, where these dosage forms include one or more than one representative, independently selected from the group consisting of suppositories, solid oral dosage forms83 selected from the group consisting of tablets, capsules, droplets, cakes, lozenges and a combination of particles of slow release; enteric-coated tablets and capsules that prevent the release and absorption of said anti-inflammatory COX-2 inhibitory compound selective in the stomach of said individual, which is treated to facilitate delivery of said anti-inflammatory COX-2 selective inhibitor compound distally to the stomach of said individual ; sustained release oral tablets, capsules and microparticles that provide systemic delivery of the inhibitor in a controlled manner for at least a 10-hour period; a chewable or swallowed oral tablet; a sachet of a standard dose sachet, a suspension made from the contents of a sachet of a standard dose, powder for oral suspension or oral suspension; instant tablets, encapsulated solutions; oral paste; granular form, introduced into the composition or for introduction into the feed composition of the specified individual; and a tasty chewable form in which said inhibitor is eaten together with said tasty chewable form or delivered by leaching from said chewing gum that is not eaten when chewing said specimen being treated; liquid oral dosage forms selected from the group consisting of solutions, suspensions, emulsions, inverse emulsions, elixirs, extracts, tinctures and concentrates; and the above solid dosage forms containing microencapsulated dosage forms of the active ingredient, which are included in the composition of the solid dosage form. 9) gold in the form of an aurothio group together with one or more than one hydrophilic group; 10) immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine and methotrexate; 10. The pharmaceutical composition according to claim 9, containing an oral controlled release dosage form capable of maintaining plasma levels of said pharmaceutical composition above about 10 μg / ml over a period of time of more than 10.5 hours when administered at a dose of about 2 mg / lb (4.409 mg / kg) or less. 10) immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine and methotrexate; 11) anti-inflammatory glucocorticoids; 11. The pharmaceutical composition according to claims 5, 6 or 7, further comprising said anti-inflammatory COX-2 selective inhibitory compound in combination with one or more other therapeutically active agents independently selected from the group consisting of A) anti-infective agents, including one or more than one antibiotic, antifungal, antiprotozoal or antiviral therapeutic agent; B) inhibitors of other inflammatory mediators, including one or more than one representative, independently selected from the group consisting of 11) anti-inflammatory glucocorticoids; 12. Packaging suitable for use in trade, for the therapeutic treatment or prevention of pain and inflammatory processes and diseases in an individual of the species Sash GashShapk in need of such treatment, including A) a suitable container, possibly in the form of an outer packaging and an inner container removably inserted into it; B) the corresponding dosage form of an anti-inflammatory COX-2 selective inhibitor compound of the formula I ′ formula (I) in which B ² represents xL O --C - C-A -Ϋπ where A is hydroxy, (C1-C4) alkoxy, amino, hydroxyamino, mono (C1-C2) alkylamino, di- (C1-C2) alkylamino; one of X and Υ represents H, and the other represents (C1-C2) alkyl and η is 1 or 2; B ⁶ represents halogen, (C1-C3) alkyl, trifluoromethyl or nitro; B ⁹ is H; (C1-C2) alkyl; phenyl or phenyl- (C1-C2) alkyl wherein phenyl is optionally monosubstituted with fluorine or chlorine; -C (= O) -B, wherein B represents (C _£ -C ₂₎ alkyl or phenyl optionally monosubstituted by fluorine or chlorine; or —C (═O) —O — B \ wherein B ¹ is (C1-C2) alkyl; where the (+) (8) enantiomer is present in an amount of at least 75%; and all its pharmaceutically acceptable salt forms, prodrugs and metabolites that are therapeutically active for the treatment and prevention of pain and inflammation; and C) a printed instructional and informational material connected to the indicated container, which is attached to the indicated container, is enclosed in the indicated container or reflected as an integral part of the indicated container, the indicated instructional and informational material containing the statement that said active compound of the formula (I) constituting the therapeutic agent contained in the indicated package, upon administration of the indicated specimen of the Sash GannNapk species to be treated, effectively inhibits cyclooxygenase-2 (COX- 2) induced in an existing or suspected area of pain and inflammation in said dog, thereby treating or preventing said pain and inflammation that would otherwise have occurred as a result of this, while reducing or eliminating undesirable side effects associated with the simultaneous inhibition of the activity of constitutive cyclooxygenase-1 (COX-1), by selective inhibition of the activity of COX-2 relative to the activity of COX-1, and the ratio of selectivity to inhibition COX-2: COX-1 is at least 3: 1 based on ex νίνο inhibition levels in whole blood measured at a dose giving> 80% COX-2 inhibition. 12) penicillamine; 12) penicillamine; 13. The package according to item 12, where the specified anti-inflammatory selective for COX-2 inhibitory compound of the formula (I) consists of carprofen, 6-chloro-a-methyl-9Ncarbazole-2-acetic acid. 13) hydroxychloroquine; 13) hydroxychloroquine; 14. The package of claim 12, wherein said COX-2 anti-inflammatory selective inhibitor compound consists entirely of the (8) enantiomer of carprofen, 6-chloro-methyl-9H-carbazole-2-acetic acid. 14) gout agents, including colchicine; xanthine oxidase inhibitors, including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazole and benzbromarone; C) therapeutic agents for the treatment of geriatric dogs, including one or more than one representative, independently selected from the group consisting of 14) gout agents, including colchicine; xanthine oxidase inhibitors, including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazole and benzbromarone; C) if older dogs are treated for painful conditions, syndromes and symptoms found in geriatric dogs, then said inhibitory compound is administered in combination with one or more than one representative independently selected from the group consisting of 15. A method of treating or preventing pain and inflammatory processes and diseases associated with the activity of inducible cyclooxygenase-2 (COX-2) in an individual of the Sash GatShapk species. which needs such treatment, while reducing or eliminating undesirable side effects associated with the simultaneous inhibition of the activity of constitutive cyclooxygenase-1 (COX-1), by selective inhibition of the activity of COX-2 relative to the activity of COX-1, and the assessment was made and it was found that this individual (1) needs treatment in order to alleviate or prevent pain and inflammatory processes and diseases with reduced or absent unwanted gastrointestinal side effects, both clearly associated with the administration of non-steroidal anti-inflammatory drugs of the indicated individual, and (2) when using such treatment, the indicated individual should benefit from the selective inhibition of inducible COX-2 to prevent or alleviate these pains and inflammatory processes with weak or reduced inhibition of constitutive cyclooxygenase-1 (COX-1) to reduce or avoid these side effects, and the ratio of selectivity inhibition of COX-2: COX-1 activity is at least m re 3: 1 based on the levels of inhibition of ex v1y0 in whole blood, measured at a dose giving> 80% inhibition of COX-2, at which the indicated specimen of the species Sashka katShapk is administered therapeutically effective for the treatment of pain and inflammation, in accordance with the above restrictions, the amount of a COX-2 selective anti-inflammatory inhibitor compound comprising a compound of formula (Ι) in which P ² is wherein A is hydroxy, (C1-C4) alkoxy, amino, hydroxyamino, mono (C1-C2) alkylamino di _(C1-C2) alkylamino; X and Υ are independently H or _(C1-C2) alkyl and n is 1 or 2; R ⁶ is halogen, _(C1-C3) alkyl, trifluoromethyl or nitro; P ⁹ represents H, (C1-C2) alkyl; phenyl or phenyl- (C1-C2) alkyl wherein phenyl is optionally monosubstituted with fluorine or chlorine; —C (═O) —P wherein P is (C1-C2) alkyl or phenyl, optionally monosubstituted with fluorine or chlorine; or -C (= O) -O-R ¹ where R ¹ represents a _(C1-C2) alkyl; where X and Υ are different; its (-) (P) - and (+) (8) -enantiomers and all their pharmaceutically acceptable salt forms, prodrugs and metabolites that are therapeutically active to treat or prevent pain and inflammation. 16. The method according to claim 1 or 15, in which an individual, in respect of which an assessment has been made and it is established that she needs the specified treatment, is administered a drug that selectively inhibits the inducible COX-2 to prevent or alleviate these pain and inflammatory processes entities without inhibition of constitutive COX-1 to reduce or avoid these side effects. 17. The method according to claim 1 or 15, in which, for pain and inflammation caused by osteoarthritis, the drug administered is carprofen, and according to which a tablet, chewable tablet or suspension containing from 25 to 100 mg is orally administered once or twice a day. carprofen. 18. The method according to claim 1 or 15, in which, for pain and inflammation caused by osteoarthritis, the drug administered is carprofen and according to which an injection preparation containing 25-100 mg of carprofen is administered once or twice daily. 19. A method of treating or preventing pain and inflammatory diseases in a dog in which a therapeutically effective amount of a non-racemic mixture of carprofen is administered to a dog in need of such treatment. 20. The method according to claim 19, where the specified non-racemic mixture contains at least 75% of the (+) (8) -enantiomer of the specified carprofen. 21. The method according to claim 20, where the specified non-racemic mixture contains at least 85% of the (+) (8) -enantiomer of the specified carprofen. 22. The method according to item 21, where the specified non-racemic mixture contains at least 90% of the (+) (8) -enantiomer of the specified carprofen. 23. The method of claim 22, wherein said non-racemic mixture comprises at least 95% of the (+) (8) enantiomer of said carprofen. 24. The method according to item 23, where the specified non-racemic mixture contains at least 99% of the (+) (8) -enantiomer of the specified carprofen. 25. The method according to paragraph 24, where the specified non-racemic mixture almost entirely consists of (+) (8) -enantiomer of the specified carprofen. 26. A method for identifying a compound as an anti-inflammatory COX-2 selective inhibitor for dogs with a reduction in undesirable side effects associated with simultaneous inhibition of COX-1, in which the ratio of selectivity of inhibition of COX-2: COX-1 activity of said compound is estimated based on levels of inhibition of ex v1yo in whole blood, measured at a dose giving> 80% inhibition of COX-2; and identify the specified compound as an anti-inflammatory inhibitor of COX-2 with a specified ratio of selectivity of inhibition of COX-2: COX-1 of at least 3: 1. 27. The method according to p, where the specified ratio of selectivity of inhibition of COX2: COX-1 is evaluated at a dose giving> 90% inhibition of COX-2. 28. The method according to item 27, wherein, in addition, the compound is prescribed to dogs for use as an anti-inflammatory agent. 29. A method for the long-term treatment of chronic inflammation and pain in a dog in which a therapeutically effective amount of carprofen is administered to a dog in need of such treatment, the treatment lasting up to a month or more. 30. The method according to clause 29, where the specified dog is an old dog. 31. The method of claim 30, wherein said dog is a geriatric dog. 32. The method according to clause 29, wherein said chronic inflammation and pain is caused by a degenerative joint disease. 33. The method of claim 32, wherein said degenerative joint disease comprises ostearthritis. 34. The method according to clause 29, where the specified carprofen is administered in oral dosage form. 35. A method of treating degenerative joint disease in old dogs, in which a pill, chewable tablet or suspension containing from 25 mg to 100 mg of carprofen is orally administered on a regular basis according to the planned schedule, and the indicated planned schedule is maintained on a regular basis for up to a month or more . 36. The method according to clause 35, where the specified old dog is a geriatric dog and the specified planned schedule on a regular basis provides for the introduction of one or two times a day.