FIELD OF THE INVENTION
The present invention relates to novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid represented hereinafter as Formula-I or its derivatives, process for preparation of such salts, compositions comprising the novel salts as pharmacologically active agent(s) and methods of using such compositions for the management such as prophylaxis, amelioration and/or treatment of inflammation and/or pain, or other associated disorders. The novel salts of the present invention are obtained in highly pure form, possess appreciable aqueous solubility and/or permeability and can easily be formulated into desired pharmaceutical compositions which can be administered to a subject in need thereof orally, parenterally, or by any other route of administration.
Formula-1
(Formula Removed)BACKGROUND OF THE INVENTION
Non-steroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid or diclofenac are regularly used for the treatment of mild to moderate pain and fever. The analgesic actions of this class of compounds result from their inhibition of the enzymatic production of prostaglandins. Prostaglandins are known to play an important role in the inflammation. Since prostaglandins (PG) are produced from arachidonic acid by cyclooxygenases, inhibition of prostaglandin synthesis by cyclooxygenases, especially synthesis of PGE2, PGG2, and PGH2, leads to the treatment of inflammation. There are at least two kinds of cyclooxygenases, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively present in the gastrointestinal tract and the kidney, and is implicated to be responsible for the maintenance of the physiological homeostasis, such as gastrointestinal integrity and renal function. Interruption of COX-1 activity can lead to life-threatening toxicities to the gastrointestinal tract, such as ulceration and bleeding. Another enzyme, COX-2, also produces these chemical messenger molecules, but the COX-2 enzyme is located specifically in areas of the body that are responsible for inflammation and not in the stomach. COX-2 is induced upon inflammatory stimuli and known to be responsible for
progression of inflammation. Thus, selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders without incurring gastrointestinal toxicities. COX-2 inhibitors are thus useful in relieving of pain and swelling of arthritis inflammation and are implicated to possess a broad therapeutic spectrum besides anti-inflammatory, analgesic, and antipyretic activity. For example, inhibition of COX-2 can prevent growth of certain types of cancer, especially colon cancer (J. Clin. Invest. 99, 2254 (1997)). Another application of a COX-2 inhibitor can be found in the treatment of degenerative chronic neurological disorders, such as Alzheimer's disease (Neurology 48, 626 (1997)). COX-2 inhibition would be useful in reducing the infarct volume accompanying the stroke (J. Neuroscience 17, 2746 (1997)).
Both the conventional NSAIDs and the selective COX-2 inhibitors primarily exert their activity by reducing the production of PCs induced in the inflammatory process. In recent years, it has been clarified that PG synthesis is only one part of the arachidonic acid pathway, this precursor being a substrate that gives rise to many other lipid mediators, such as the LTs (leukotriene) and the LXs (lipoxin). Leukotriene themselves have a major role in the development and persistence of the inflammatory process, and it is now clear that PGs and LTs have complementary effects, whereas the production of LXs can counteract the inflammatory actions of LTs. In view of these concepts, it has been suggested that blocking both LT and PG production might have synergistic effects and achieve optimal anti-inflammatory activity. In addition, taking into account the roles of particularly LTB4 and cysteinyl LTs (against which neither selective nor non-selective NSAIDs are effective) in the inflammatory process, dual inhibition of the COX and specifically 5-LOX (lipoxygenase) pathways could produce a wider spectrum of anti-inflammatory effects.
It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform). Arachidonic acid can also be converted to leukotrienes (LTs) by the action of 5-lipoxygenase (5-LOX). LTC4 LTD4 and LTE4 are potent bronchoconstrictors, whereas LTB4 is chemotactic for leukocytes and plays an important role in the development of gastrointestinal ulcers by contributing to the inflammatory process. Thus, developing dual inhibitor compounds that will simultaneously inhibit COX and 5-LOX could enhance their individual anti-inflammatory effects and reduce the undesirable side effects associated with NSAIDs, especially of the gastrointestinal tract. Dual inhibition of COX and 5-LOX may limit the vascular changes seen during inflammation and leukocyte induced gastrointestinal (GI)
damage. The most promising COX/5-LOX inhibitor is ML3000 ((2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-lH-pyrrolizine-5-yl)-acetic acid) also known as licofelone.
Licofelone (ML-3000) is a pyrrolizine derivative, orally active dual COX-1 and COX-2 and 5-LOX inhibitor (dual acting anti-inflammatory drug), under development as an anti-inflammatory and analgesic by the EuroAlliance consortium (Alfa Wassermann/Lacer/Merckle). Licofelone is undergoing evaluation in clinical trials for the indication of osteoarthritis (Laufer S., Expert Opin Investig Drugs 12(7): 1239-41, 2003; Reginster J. et al., Annual European Congress of Rheumatology, EULAR 2002, p.abstr. THU0189, 12 Jun. 2002), rheumatoid arthritis (Gay R. E., et al., J Rheumatol 28(9): 2060-5, 2001) and pain. In animal experiments the compound has antiphlogistic, analgesic, antipyretic, antiasthmatic and antiaggregative activity at a dosage that causes no gastrointestinal damage (Laufer S. et al, Arzneimittelforschung 44(5): 629-36, 1994). Results of a phase III trial showed that licofelone was at least as effective as naproxen in the long-term treatment of osteoarthritis of the knee (n=704). At dosages of licofelone 200 and 400 mg/day bid and naproxen 1000 mg/day bid, the greatest improvement in efficacy parameters was achieved with licofelone 400 mg/day bid (Blanco F. J. Et al, Ann Rheum Dis., 62(1): 262, 2003). In accordance with the prior art, licofelone doses of 200 and 400 mg/day, administered as divided doses have been found effective for many patients. Following a 200 mg licofelone dose administered twice daily, peak plasma licofelone concentrations of about 1650-1750 ng/ml were reached at 0.74-4 hr post-dose. Licofelone exhibited an elimination half-life (T [sub] l/2[small beta, Greek]) of about 8.7-11.1 hours (Albrecht W. et al., Annual European Congress of Rheumatology, EULAR 2002, p.abstr. AB0293, 12 Jun., 2002). A single dose of licofelone 800-3,200 mg (4-fold the therapeutic dose) was generally well tolerated in volunteers (Bias P. Et al., Ann Rheum Dis., 62 (1): 479 2003).
However, licofelone has the disadvantage of being very poorly soluble drug, and hence provides difficulty for formulating it into most of the dosage forms particularly oral and parenteral preparations. Furthermore, it is known that licofelone salts which are known so far, particularly the sodium and potassium salts, impose a relatively alkaline pH and create problems during formulation particularly as an injectable dosage form. Moreover, the sodium salt or potassium salt of licofelone has the disadvantages of releasing sodium ions or potassium ions therewith, which are often contraindicated.
Hence, there exists a need to develop suitable form of licofelone to overcome these problems associated with the prior art and to provide a water soluble form of the said compound, which is
non hazardous in nature and can be used especially for the preparation of suitable dosage form compositions while preserving the pharmacological prophylactic and/or therapeutic anti-inflammatory applications of licofelone.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid or derivatives thereof, wherein 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid has the following formula (Formula-I):
Formula-I (Formula Removed)
It is an objective of the present invention to provide novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or derivatives thereof with an organic basic amino acid or a neutral amino acid ester.
It is another objective of the present invention to provide novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or derivatives thereof with an organic basic amino acid preferably selected from a group comprising racemic arginine, racemic lysine and racemic ornithine, or their stereoselective enantiomers or mixtures thereof.
It is another objective of the present invention to provide novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or derivatives thereof with a neutral amino acid ester preferably selected from a group comprising glycine, leucine and serine in racemic or enantiomeric form or mixtures thereof.
It is another objective of the present invention to provide process of preparation of novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or derivatives thereof.
It is further objective to provide a process for the preparation of novel salts of the present
invention, wherein the said process comprises treating 6-(4-chlorophenyI)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid with amino acid to produce the amino acid salt.
It is still further objective to provide a process for the preparation of novel salts of the present invention, wherein the process comprises of the following steps:
i) Dissolving the compound of Formula-I in suitable solvent(s),
ii) Dissolving the amino acid in suitable solvent(s),
iii) Mixing together the solution of step (i) and (ii) with stirring, and
iv) Separating the salt of compound of Formula-I thus formed and drying.
It is another objective of the present invention to provide pharmaceutical compositions comprising novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or derivatives thereof.
It is further objective to provide pharmaceutical compositions comprising the novel salts of the present invention as pharmacologically active agent in an amount of from 0.01% w/w to 99.99% w/w of the composition, alongwith one or more pharmaceutically acceptable carrier(s)/excipient(s) in an amount of from 0.01% w/w to 99.99% w/w of the composition, optionally with other pharmacologically active agent(s).
It is yet another objective to provide a process for the preparation of pharmaceutical composition comprising the novel salts of the present invention alongwith pharmaceutically acceptable carrier(s)/excipient(s), optionally with other pharmacologically active agent(s) which comprises treating the novel salts and optionally other pharmacologically active ingredient(s) alongwith pharmaceutically acceptable carrier(s)/excipient(s) and formulating into a suitable dosage form.
It is a further objective of the present invention to provide a method of using such novel amino acid salts or pharmaceutical compositions comprising such novel amino acid salts which comprises administering to a subject in need thereof an effective amount of such novel amino acid salts or compositions thereof.
The novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid or derivatives thereof are obtained in highly pure form, possess appreciable aqueous solubility and good bioavailability.
The novel compounds of the present invention can be easily formulated into desired
pharmaceutical compositions particularly as oral solid or drinkable preparations, or injectable solutions, or into any other compositions that can be administered by different routes to a subject in need thereof.
The novel compounds of the present invention and compositions comprising them are highly effective in the management including prophylaxis, amelioration and/or treatment of inflammation and/or pain, or other associated diseases/disorders associated with inflammation and/or pain such as rheumatoid arthritis, osteoarthritis, asthma, fever or the like, or combination of such diseases/disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid of Formula-I or its derivatives thereof. The novel amino acid salts are useful as pharmacologically active agents(s).
(Formula Removed)Formula-I
In an embodiment of the present invention, the novel amino acid salts of the compound of Formula-I as stated herein are formed with an amino acid, preferably with an organic basic amino acid or a neutral amino acid ester.
In an embodiment, the organic basic amino acid is selected from but not limited to a group comprising racemic arginine, racemic lysine and racemic ornithine or their stereoselective enantiomers such as L and/or R-Lysine, L and/or R-arginine and L and/or R-ornithine and the like, or mixtures thereof. Preferably the organic basic amino acid is L-lysine, L-arginine, L-ornithine or the like, or mixtures thereof.
In an embodiment, the present invention provides novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid, or derivatives thereof with a neutral amino acid ester preferably selected from a group comprising glycine, leucine and serine,

or their stereoselective enantiomers or mixtures thereof.
In an embodiment of the present invention, the novel salts of the compound of Formula-1 as stated herein are highly pure and can be formulated into pharmaceutical compositions without substantial loss of chiral and/or chemical purity.
In a further embodiment of the present invention, the novel salts of Formula-I as stated herein have solid state properties which permit easy handling and allow preparation of pharmaceutical compositions along with pharmaceutically acceptable excipient(s) preferably by using conventional methods and equipments.
In an embodiment, the present invention provides novel salts of the compound of Formula I with organic basic amino acids selected from a group comprising L-arginte, L-lysine and ornithine as shown by Formula-11, III and IV respectively. The novel salts formed using amino acids of Formula-II, Formula-Ill and Formula-I are represented by Formula-V, Formula-VI and Formula-VII respectively. In an embodiment, the salt advantageously contains approximately 1 mole of organic basic cations of the amino acid per mole of the compound of Formula-I.


Formula-II Formula-III Formula-IV Formula-V Formula-VI formula-VII Formula Removed)
In an embodiment, the present invention provides novel amino acid salts of compound of Formula-1 as stated herein prepared with a compound selected from a group of esters of neutral cations, preferably selected from a group of esters of neutral amino acids such as glycine, leucine, serine shown by Formula-VIIl, Formula-lX and Formula-X respectively, or the like. The novel salts formed using the amino acids of Formula-VIII, Formula-IX and Formula-X are represented by the Formula-XI, Formula-XII and Formula-XIII respectively(Formula VIII to XIIIRemoved)
Where R is an alkyl group Formula-XIII
According to the further embodiment of the present invention is provided a method of preparation of novel amino acid salts of the compound of Formula-I. The process for the preparation of novel amino acid salts of the present invention comprises treating 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid (compound of Formula-I) with amino acid to produce the amino acid salt.
In an embodiment, the process of preparation of novel amino acid salt of the compound of Formula-I comprises the following steps: i) Dissolving the compound of Formula-1 in suitable solvent(s), ii) Dissolving the amino acid in suitable solvent(s), iii) Mixing together the solution of step (i) and (ii) with stirring, and
iv) Separating the salt of compound of Formula-I thus formed and drying to obtain the desired amino acid salt.
In an embodiment of the present invention, the solvents useful in the process of preparation of the novel amino acid salts of the compound of Formula-I are selected from but not limited to a group comprising water, hexane, heptane, petroleum ether, methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone, ethyl methyl ketone, and the like, or mixtures thereof.
In an embodiment, the salts are recovered by standard methods such as filtration and the like if they are insoluble in the solvent medium; or if they are soluble in the solvent medium, the salt is precipitated by evaporation of the solvent or by addition of a non-solvent for the salt.
In a further embodiment, the process for the preparation of novel amino acid salts of the present
invention comprises of the following steps:
(i) Dissolving 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-l H-pyrrolizin-5-yl-
acetic ac id (compound of Formula-I) in ethyl acetate, (ii) Dissolving L-arginine in water-acetone mixture, (iii) Mixing together the solution of step (i) and (ii) with stirring, and (iv) Separating the solid from the mixture of step (iii), filtering and then drying to obtain the L-
arginine salt of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-
acetic acid.
In an embodiment of the present invention, the novel amino acid salts of the compound of Formula-1 possess surprisingly an improved solubility and stability in aqueous solution. In a

further embodiment of the present invention the salts of compound corresponding to the Formula-1 are useful as potent cyclooxygenase and 5-lipooxygenase inhibitors.
In an embodiment of the present invention, the novel amino acid salts of the compound of Formula-I possess an improved solubility in aqueous medium in comparison to the compound of Formula-1 itself. In an embodiment, the solubility of the L-lysine salt of the compound of Formula-I was found to be significantly higher (about 1.337 mg/ml) in comparison to the compound of Formula-I which was insoluble in water based on a study done by using the following process:
a) Equal quantity of compound of Formula-1 and L-lysine salt of compound of Formula-I
was taken separately in a suitable container and sufficient quantity of water was added.
b) Both containers were kept on Shaker bath at 25°C for 24 hours.
c) The saturated solution was centrifuged and the supernatant was filtered.
d) After appropriate dilutions, samples were analyzed by absorption spectroscopy and the
solubility was calculated.
In another embodiment of the present invention, the novel amino acid salts possess good permeability in comparison to the compound of Formula-I. The novel amino acid salt formation preferably leads to charge neutralization of the compound of Formula-I thus decreasing the acidic nature of the compound and formation of a complex which has a better lipophilicity compared to the compound of Formula-I. The salts permeate better since the novel salts preferably remain unionized or have a substantially low degree of ionization in the composition and when exposed to in vivo environment. This, in turn, improves the absorption and thus the bioavailability of the compound of Formula-I when formulated as novel salts according to the present invention.
In another embodiment, the present invention provides pharmaceutical compositions comprising the novel amino acid salts. In a further embodiment, the pharmaceutical composition comprises novel amino acid salts of the compound of Formula-1 as pharmacologically active agent in an amount of from about 0.01% w/w to about 99.99% w/w of the composition, alongwith one or more pharmaceutical ly acceptable carrier(s)/excipient(s) in an amount of from about 0.01% w/w to about 99.99% w/w of the composition, optionally with other pharmacologically active agent(s).
The pharmaceutical compositions of the present invention can be manufactured by techniques that are well-known to the art and comprise operations such as sifting, mixing, granulating, compressing, dissolving, sterilizing, filtering, and the like or combinations thereof. According to an embodiment of the present invention, the pharmaceutical composition can be prepared by
-
mixing the novel amino acid salts of Formula-1 according to the present invention with one or more other pharmacologically active agent(s) along with pharmaceutically acceptable carrier(s)/excipient(s).
According to an aspect of the present invention, the mixture of novel salts of the present invention can be in the form of an associate or a complex or inclusion compounds with the pharmaceutically acceptable excipient(s). For example, a mixture of the novel salts and povidone can be in the form of an associate of the novel salts with povidone, a mixture of novels salts and phospholipid can be in the form of a complex, and a mixture of the salts with cyclodextrin can be in the form of an inclusion of the novel salts in cyclodextrin.
In an embodiment of the present invention, the novel salts of the present invention or pharmaceutical compositions comprising them can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intranasal, intraventricular injection or infusion techniques.
Topical administrations are particularly intended for the treatment of infectious areas or organs readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skins including the surface skin and the underneath dermal structures, or other lower intestinal tract. It also includes transdermal delivery to generate a systemic effect. The rectal administration includes the form of suppositories. The transmucosal administration includes nasal aerosol or inhalation applications. The preferred routes of administration are oral, parenteral or topical.
Pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulation, emulsifying, encapsulating, entrapping, lyophilizing processes, spray drying or the like. Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. The amount of the novel amino acid salts of the present invention to be incorporated into the pharmaceutical composition of the present invention can vary over a wide range depending upon known factors such as, for example, the disorder to be treated, the severity of the disorder, the subject's body weight, the dosage form, the

chosen route of administration and the number of administration per day. However, selection of optimum amount is simple and routine for a person skilled in the art. The selection of the formulation is dependent upon the route of administration chosen. For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. A carrier can be at least one substance, which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and/or encapsulating agent. Examples of such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols and other pharmaceutical acceptable materials. Tablets may be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. The compositions may also be coated with a functional coating. By the term 'functional coating' it is herein implied that the coating composition comprises a part of the active agent(s) and/or the composition comprises excipients which aid in controlling the rate of release of the active agent(s) and/or the composition comprises additionally another active agent which is different from the active agent present in the core composition. The composition may be formulated as layered tablets comprising at least two layers wherein the same active agent is present in all the layers exhibiting different release profiles or one or more additional active agent(s) is present in the layers exhibiting different release profiles. The coating composition employed in the present invention may be an aqueous, non-aqueous or a hydro-alcoholic system. The solvents used to prepare a non-aqueous coating composition is selected from but not limited to a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride, acetone or any other solvent known to the art for such use, or mixtures thereof.
Pharmaceutical compositions, which can be used orally, in an embodiment of the present invention, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active

compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides. Stabilizers may be added in these formulations also. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
The compound may also be formulated for parenteral administration, e.g., by injections, bolus injection or continuous infusion. Formulations for parenteral administration may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents. For injection, the compounds of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or physiological saline buffer. Suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+)-lysine and L (+)-arginine. Parenteral administrations also include aqueous solutions of a water soluble form. Additionally, suspensions of the compound may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For suppository administration, the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and other glycerides.
For administration by inhalation, compounds of the present invention can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or suspensions. The aerosol may use a pressurized pack or a nebulizer and a suitable propellant. In the case of a pressurized aerosol, the dosage unit may be controlled by providing a valve to deliver a metered amount of the novel salt of the present invention. Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch.

For topical applications, the pharmaceutical composition may be formulated in a suitable cream or ointment containing the active agent suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60 cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic and otitis uses, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as a benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be in the form of implants. A compound of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials etc. In a further embodiment, the compounds may be delivered using a sustained-release system. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours or for up to several days.
In an embodiment, typically the amount of the novel compounds of Formula-V, Formula-VI, Formula-VII, Formula-XI, Formula-XII, or Formula-XIII in the pharmaceutical composition of the present invention shall range from approximately 5 mg to approximately 1000 mg, preferably from about 10 mg to about 500 mg.
In another embodiment of the present invention, the novel amino acid salts of the compound of Formula-1 can be administered in combination with other pharmacologically active agent(s), selected from but not limited to a group comprising antipyretics such as acetaminophen; aldosterone receptor antagonists; antibiotics; various enzymes; antimuscarinic agents; anti-viral agents; protein kinase inhibitors; a2-adrenergic agonist; ACE inhibitors; opioid analgesics; steroids; leukotriene B4(LTB4) receptor antagonists; leukotriene A4 (LTA4) hydrolase inhibitors;

5-HT agonists; HMG CoA inhibitors; H2 antagonists; antineoplastic agents; antiplatelet agents; thrombin inhibitors; decongestants; diuretics; sedating or non-sedating anti-histamines; inducible nitric oxide synthase inhibitors; opioids; analgesics; Helicobacter pylori inhibitors; bronchodilators; spasmolytics such as scopolamine or glucagon, muscle relaxants; proton pump inhibitors; isoprostane inhibitors; PDE4-inhibitors; NSAIDs; selective or preferential COX-2 inhibitors; COX-1 inhibitors; expectorants such as bromohexine and pseudoephedrine; analgesics such as codeine, chlorzoxazone, mefenamic acid or tramadol; antiemetics; urinary acidifiers such as racemethionine; chondroitin; glucosamine; methyl sulfonyl methane (MSM); aspirin; antidepressants; antipsychotics; antimigraine agents, and the like or mixtures thereof.
In accordance with the present invention, it has been found that acidic hydrogen atom of the carboxylic group of compound of formula-I can be interacted with the amino group of basic or neutral amino acids and the product and/or ionic complex or the salt thus obtained is stable in solidified form. It has further been found that the salts thus obtained are water soluble even at the pH range between 4 and 8 so that they are well tolerated at the gastrointestinal level. Furthermore, they do not possess unpleasant taste and/or odour and are thus patient compliant.
In an embodiment, the present invention provides method of using such novel amino acid salts or pharmaceutical compositions comprising such novel amino acid salts which comprises administering to a subject in need thereof an effective amount of such novel salt or composition thereof. The pharmaceutically acceptable amino acid salts of the compound of Formula-I are suitable for use as cyclooxygenase and 5-lipooxygenase inhibitors. In a preferred embodiment, the novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid or derivatives thereof are obtained in highly pure form; possess good solubility in the desired solvent, particularly appreciable aqueous solubility; and good bioavailability.
In yet another embodiment, the present invention provides amino acid salts of compound of Formula-I and pharmaceutical compositions comprising the pharmaceutically acceptable salts of compound of Formula-I which are useful in the management of one or more diseases or disorders such as inflammation and/or pain; and/or other associated disease(s)/disorder(s) such as arthritis, asthma, angina, inflammatory bowel disease, Crohn's disease, migraine headaches, Alzheimer's disease, stroke, ischemia and trauma, gastric ulcer, intermittent or episodic pain, angiogenesis, viral infections, cardiovascular diseases, neoplasia, cancer, bacterial infections, and the like.

In a further embodiment, the present invention provides a method of using the novel compounds of the present invention and compositions comprising them for the management including prophylaxis, amelioration and/or treatment of inflammation and/or pain, or other associated diseases/disorders such as rheumatoid arthritis, osteoarthritis, asthma, fever or the like, or combination of such diseases/disorders.
In a still further embodiment, the present invention provides use of the novel amino acid salts for the preparation of a medicament for the treatment and/or prophylaxis and/or amelioration of cardiovascular diseases/disorders and/or for the promotion of blood circulation in the mesenteric vascular system and/or for the treatment and/or prophylaxis of gastrointestinal disorders which are associated with reduced gastrointestinal blood circulation and/or for the treatment/prophylaxis of abdominal angina.
The following examples are only intended to further illustrate the invention and therefore these examples are not deemed to restrict the scope of the invention in any manner whatsoever.
Example 1: Preparation of the L-arginine salt of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid. (Formula-V)
To a solution of the free acid of licofelone lO.Og (26.35 mmol) in 600 ml ethyl acetate, the free base of L-arginine 4.59 g (26.35 mmol) in 1:1 water-acetone (50 ml, 50 ml) was added with vigorous stirring at room temperature. The solid was separated out. The mixture was stirred for 30 minutes and then filtered to obtain the L-arginine salt. The L-arginine salt of 6-(4-chlorophenyl|-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid was dried to obtain 13.0 g as white free-flowing powder (yield: 89.10%)
H NMR (DMSO-d6): 87.27-7.3 (m, 2H), 7.15-7.2 (m, 4H), 6.97-7.05 (m, 3H), 3.73 (s, 2H), 3.49 (m, 1H), 3.19 (s, 2H), 2.76 (s, 2H), 2.65 (m, 2H), 1.78 (m, 2H), 1.55 (m, 2H), 1.22 (s, 6H)
Example 2: Preparation of the L-lysine salt of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid. (Formula-VI)
To a solution of the free acid of licofelone 10.0 g (26.35 mmol) in 600 ml of ethyl acetate, the free base of L-lysine 3.85 g (26.35 mmol) in 1:1 water-acetone (50 ml, 50 ml) was added with vigorous stirring at room temperature. The solid was separated out. The mixture was stirred for 30 minutes and then filtered to obtain the L-lysine salt. The L-lysine salt of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid was then finally dried to

obtain 12.0 g as white free-flowing powder (yield: 86.64%).
H NMR (DMSO-d6): 67.27-7.3 (m, 2H), 7.15-7.2 (m, 4H), 6.97-7.05 (m, 3H), 3.73 (s, 2H), 3.19 (s, 2H), 3.16 (m, 1H), 2.76 (s, 2H), 2.69-2.72 (m, 2H), 1.51-1.86 (m, 2H), 1.47-1.50 (m, 2H), 1.38-1.41 (m, 2H), 1.22 (s, 6H)
The examples provided hereinafter serves to illustrate various formulations comprising the novel salts of the present invention, and do not limit the scope of the invention in any manner. It might be noted that the quantity of active agent that is the novel salts of the compound of Formula-1 disclosed per unit dose or otherwise in the examples hereinafter represent the quantity equivalent of the compound of Formula-1.
Example-3: Table composition
S. No. Ingredient Quantity/tablet (mg)
1. Compound of Formula-V 100.0
2. Mannitol 310.0
3. Lactose 100.0
4. Sodium starch glycollate 20.0
5. Isopropyl alcohol q.s. (lost in processing)
6. Hydrogenated castor oil 7.5
7. Purified talc 7.5
8. Colloidal silicon dioxide 7.5
Procedure:
i) Compound of Formula-V, Lactose, Mannitol and Sodium starch glycollate were sifted
through #40 sieve and were mixed together, ii) The blend of step (i) was granulated by using Isopropyl alcohol.
iii) The wet mass of step (ii) was sifted through #24 sieve and the granules obtained were dried, iv) Hydrogenated castor oil, Purified talc and Colloidal silicon dioxide were sifted through #40
sieve and were mixed together.
v) Granules of step (iii) were mixed with the mixture of step (iv). vi) The material of step (v) was compressed into tablets.
Example-4: Capsule composition
S. No. Ingredient Quantity/capsule (mg)
1. Compound of Formula-VII 75.00
2. Magnesium carbonate 150.00

3. Dicalcium phosphate 131.25
4. Crospovidone 30.00
5. Magnesium stearate 10.00
Procedure:
i) Compound of Formula-VII, Magnesium carbonate, Dicalcium phosphate, Crospovidone, and Magnesium stearate were sifted through #40 sieve and were mixed together.
ii) The blend of step (i) was compacted and the compacts were passed through #30 sieve to obtain granules.
Hi) The granules of step (ii) were lubricated with #60 sieve passed Magnesium stearate.
iv) The material of step (iii) was filled into hard gelatin capsule.
Example-S: Injection composition
S. No. Ingredient Quantity/100 ml
1. Polyethylene glycol (PEG-400) 30.0ml
2. Propylene glycol 20.0 ml
3. Glycine buffer pH 11.3 35.0 ml
4. Compound of Formula-XI 2.5 g
5. Sodium hydroxide (NaOH) solution 4.0% w/v 10.0ml
Procedure:
i) Specified quantity (30.0 ml) of PEG-400 was taken into a vessel.
ii) Propylene glycol (20.0 ml) was added to step (i) with continuous stirring using
mechanical stirrer. iii) About 30.0 ml of the Glycine buffer pH 11.3 was added to the step (ii) with continuous
stirring to form a homogeneous mixture, iv) Weighed amount of Compound of Formula-XI (2.5 g) was passed through #60 sieve and
was added to the step (iii) with continuous stirring. v) Specified quantity (10.0 ml) of Sodium hydroxide (NaOH) 4.0% w/v solution was added
to the step (iv) with continuous stirring to form a homogeneous solution, vi) The solution of step (v) was mixed for about 30 minutes by continuous stirring, vii) Remaining quantity of Glycine Buffer pH 11.3 was added to make up volume to 100 ml. viii) The solution of step (vii) was mixed for about 10 minutes by continuous stirring, ix) Final pH was adjusted to 10.0 by adding Sodium hydroxide (NaOH) 4.0% w/v solution, x) The solution of step (ix) was mixed for about 10 minutes by continuous stirring.

Example-6: Modified release Tablet composition
S. No. Ingredient Quantity (rag)
1. Compound of Formula-Xll 200.00
2. Cetirizine hydrochloride 5.00
3. Mannitol 120.00
4. Croscarmellose sodium 30.00
5. Hydroxypropyl cellulose 67.00
6. Isopropyl alcohol q.s. (lost in processing)
7. Colloidal silicon dioxide 2.00
8. Stearic acid 2.00
Procedure:
i) Compound of Formula-XII, Cetirizine, Mannitol and Croscarmellose sodium were sifted
through #30 sieve and were mixed together, ii) Hydroxypropyl cellulose was dissolved in Isopropyl alcohol to obtain a homogeneous
dispersion,
iii) The blend of step (i) was granulated with the dispersion of step (ii). iv) The granules of step (iii) were dried and were sifted through #24 sieve. v) Colloidal silicon dioxide and Stearic acid were sifted through #40 sieve, vi) The material of step (v) was mixed with the material of step (iv) and compressed into tablets.
Example-7: Oral Liquid composition
S. No. Ingredient Quantity (mg/100 ml)
1. Compound of Formula-Vl 500.0
2. Trisodium phosphate 1.5
3. Hydroxyethyl cellulose 20.0
4. Xylitol solution (70% w/v) 50.0
5. Aspartame 0.5
6. Benzoic acid 1.0
7. Strawberry flavor q.s.
8. Purified water q.s. to 100ml
Procedure:
i) Compound of Formula-VI and Hydroxyethyl cellulose were sifted through #40 sieve and
were blended together, ii) Trisodium phosphate, Aspartame, Benzoic acid, Strawberry flavor and Xylitol solution were

dispersed together in Purified water.
iii) The material of step (i) was added with continuous stirring to the material of step (ii) and a homogeneous suspension was obtained.
Example 8: Topical Gel composition
S. No. Ingredient Quantity (g)
1. Formula-Xlll 1.0
2. Dimethylformamide 20.0
3. Ethyl Alcohol 40.0
4. Acetone 11.5
5. Cremophor® EL 4.0
6. Propylene glycol 35.0
7. Polyethylene glycol 400 48.8
8. Veegum® 4.0
9. Purified water 30.0
10. Triethylamine 1.2
Procedure:
i) Dimethylformamide is mixed with Ethyl alcohol and acetone at 30° C with stirring.
ii) Propylene glycol, Polyethylene glycol 400, Cremophor® EL, Formula-XIII and water were
mixed in homogenizer. iii) To the homogenized mixture obtained in step (ii), 1.5% w/w of Veegum® was added slowly
under stirring, iv) The mixture obtained in step (i) was added to the mixture obtained in step (iii) under stirring
without vortex formation to avoid aeration preferably under vacuum (25 mm of Hg). v) The mixture obtained was neutralized by slow addition of Triethylamine with slow stirring at
a temperature of 25-30° C and under vacuum (25 mm of Hg) to affect gel formation.

We Claim:
1. Novel amino acid salts of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid or its derivatives, wherein 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-yl-acetic acid has the following formula (Formula-I):
(Formula Removed)Formula-I

2. The salts as claimed in claim 1, wherein the salts are formed with amino acid selected from
a group comprising organic basic amino acids and neutral amino acid esters.

2. The salts as claimed in claim 2, wherein the organic basic amino acid is selected from a
group comprising racemic arginine, racemic lysine and racemic ornithine or their
stereoselective enantiomers or mixtures thereof.

2. The salts as claimed in claim 2, wherein the neutral amino acid ester is selected from a
group comprising glycine, leucine and serine in racemic or enantiomeric form or mixtures
thereof.

2. A process for the preparation of novel salts according to claim 1, wherein the said process
comprises treating 6-(4-chlorophenyI)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-
yl-acetic acid with amino acid to produce the amino acid salt.

2. A process for the preparation of novel salts according to claim 1, wherein the process
comprises of the following steps:
i) Dissolving the compound of Formula-I in suitable solvent(s),
ii) Dissolving the amino acid in suitable solvent(s),
iii) Mixing together the solution of step (i) and (ii) with stirring, and
iv) Separating the salt of compound of Formula-I thus formed and drying.
7. A process for the preparation according to claim 6, wherein the process comprises of the
following steps:
i) Dissolving 6-(4-chlorophenyI)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-pyrrolizin-5-
yl-acetic acid in ethyl acetate,
ii) Dissolving L-arginine in water-acetone mixture, iii) Mixing together the solution of step (i) and (ii) with stirring, and iv) Separating the solid from the mixture of step (iii), filtering and then drying to obtain
the L-arginine salt of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-lH-
pyrrolizin-5-yl-acetic acid.
8. A pharmaceutical composition comprising the novel salt according to claim 1 as
pharmacologically active agent in an amount of from 0.01% w/w to 99.99% w/w of the
composition, alongwith one or more pharmaceutically acceptable carrier(s)/excipient(s) in
an amount of from 0.01% w/w to 99.99% w/w of the composition, optionally with other
pharmacologically active agent(s).
9. A process for the preparation of pharmaceutical composition according to claim 8
comprising the novel salts according to claim 1 as pharmacologically active agent alongwith
one or more pharmaceutical ly acceptable carrier(s)/excipient(s), optionally with other
pharmacologically active agent(s) which comprises treating the novel salts according to
claim 1 in an amount of from 0.01% w/w to 99.99% w/w and optionally other
pharmacologically active agent(s) alongwith one or more pharmaceutically acceptable
carrier(s)/excipient(s) in an amount of from 0.01% w/w to 99.99% w/w of the composition
and formulating into a suitable dosage form.
10. The novel salts, pharmaceutical compositions comprising the novel salts and processes
thereof substantially as herein described and illustrated by the examples.