WO2011094589A1 - Nonsteroidal antiinflammatory derivatives with decreased toxicity and methods of use - Google Patents

Abstract

Novel compounds are disclosed with anti-inflammation, anti-pyretic and analgesic activities. Pharmaceutical compositions and methods of use are also described.

Description

NONSTEROIDAL ANTIINFLAMMATORY DERIVATIVES WITH

DECREASED TOXICITY AND METHODS OF USE

FIELD OF THE INVENTION

[0001] The invention is directed to compounds, pharmaceutical compositions comprising same, and method using the same to treat inflammation-related diseases, fever and pain. The invention is further directed to methods of synthesis of the compounds and compositions.

BACKGROUND OF THE INVENTION

[0002] Non-steroidal anti-inflammatory drugs (NSAIDs) are pharmaceuticals with analgesic, antipyretic and anti-inflammatory effects. They differ from steroids, which have similar anti-inflammatory action. Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX- 1) and cyclooxygenase-2 (COX-2) isozymes, which results in inhibition of the formation of prostaglandins. A variety of COX-independent effects of NSAIDs have also been described with an ability to inhibit the growth of cancer cells ( Hanif et al. Biochem Pharmacol, 52: 237-245., 1996.).

[0003] NSAIDs are broadly classified based on their chemical structure. NSAIDs within a group tend to have similar characteristics and tolerability. Different NSAIDs have very similar clinical efficacy when used at equivalent doses, but differ in their dosing regimens (due to the compound's elimination half-life), route of administration, and tolerability profile.

[0004] NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention and treatment of other conditions, such as cancer and cardiovascular disease (Rayyan et al, Cancer Invest, 20: 1002-1011., 2002). NSAIDs are also enjoying extensive use for the control of pain associated with veterinary procedures and in general for animal analgesia. Compounds employed in veterinary applications include ketoprofen and flunixin meglamine.

[0005] Although widely used, NSAIDs have significant toxicity, including gastrointestinal toxicity. Chronic ingestion of NSAIDs increases the risk for gastrointestinal complications, which range from dyspepsia to gastrointestinal bleeding, obstruction, and perforation (Wolfe et al, N Engl J Med, 340: 1888-1899, 1999). Among patients using NSAIDs, up to 4% per year suffer serious gastrointestinal complications ( Bjorkman Am J Med, 107: 3S-8S; discussion 8S- 10S., 1999.; and Bjarnason and Macpherson, Pharmacology & Therapeutics, 62: 145-157, 1994.). In 1998 the number of deaths in the US from NSAID-induced GI complications was 16,550, virtually identical to that from AIDS (16,685) ( Singh, G. and Triadafilopoulos, G. J Rheumatol, 26: 18-24., 1999). Within a six-month period of treatment, 5-15% of patients with rheumatoid arthritis discontinue NSAID therapy because of dyspepsia alone (Wolfe et al, N Engl J Med, 340: 1888-1899, 1999.).

[0006] NSAIDs also are associated with renal toxicity, including a wide range of tubular, interstitial, glomerular and vascular renal lesions; the risk of chronic renal failure is high (Elseviers and De Broe, Drugs Aging, 12: 391-400., 1998.).

[0007] Additional side effects of NSAIDs, some of them serious, include: hypersensitivity reactions; hepatotoxicity and prolongation of the bleeding time (summarized in Roberts and Morrow, In: Hardman and Limbird (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition, pp. 687-731. New York: McGraw-Hill, 2001.).

[0008] Taking the specific example of sulindac, it is of interest to note the rather wide range of its main side effects falling under four categories: 1) Gastrointestinal: seen in nearly 20% of the patients, they include abdominal pain and nausea; 2) CNS: seen in up to 10%, include dizziness, drowsiness, headache and nervousness; 3) Skin rash and pruritus: they occur in 5% of patients; and 4) Elevations of hepatic enzymes in plasma, which are less common and often transient. These side effects are taken from Goodman and Gilman's standard pharmacology textbook ( Roberts and Morrow,, In: Hardman and Limbird (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th edition, pp. 687-731. New York: McGraw-Hill, 2001.); the list of side effects in the Physician's Desk Reference (PDR) is much longer.

[0009] Efforts to reduce the side effects of NSAIDs include the concomitant intake of compounds such as proton pump inhibitors, as for example, omeprazole, that suppress gastric acid production or by administering misoprostol, a prostaglandin analogue (associated with diarrhea in about one third of the patients) or using enteric-coated preparations. These methods, however, have their own undesired side effects.

[0010] Thus, there is a need for novel, safe anti-inflammatory therapeutics, such as NSAIDs derivatives, that overcome the shortcomings of the currently available drugs.

SUMMARY OF THE INVENTION

[0011] As discussed above, NSAIDs in general manifest significant gastric and duodenal toxicity. While not willing to be bound by any theory, applicant believes that this is due to their interaction in the acidic environment of the upper gastrointestinal tract with the gastric and duodenal mucosa, causing shallow mucosal erosions which evolve into ulcers that can have catastrophic consequences in the form of bleeding and perforation (Rigas and Spiro, Clinical Gastroenterology, McGraw Hill, New York, NY, 1995; .

[0012] It has now been surprisingly discovered that modification of NSAIDs by covalently attaching thereto a suitable moiety, for example, binding a 6-carbon alkyl group to aspirin through an ester bond, precludes the interaction of the NSAID moiety with the gastric mucosa and prevent its gastric toxicity.

[0013] Such a modification of the NSAID molecule also has the surprising effect that the covalently modified NSAID will be absorbed intact in the moderately alkaline environment of the small bowel. Cleavage via e.g. hydrolysis of the bond linking the NSAID to the added moiety will release the original (unmodified) NSAID over a period of time. The result will be that, compared to the situation when the NSAID is administered unmodified, the pharmacologically active NSAID molecule will accumulate in blood and tissues at a slower rate. The lower peak levels of the active drug will reduce its toxicity to any tissues that it may reach via the circulation, including the stomach and duodenum.

[0014] For example, it is known that nitric oxide-donating aspirin (also known as nitroaspirin), a compound consisting of aspirin to which a nitrophenoxyl moiety is covalently bound through an ester bond, traverses the stomach intact and causes no mucosal damage (Carini et al., Life Sci. 2004; 74: 3291-305). Similarly, nitric oxide-donating indomethacin consists of indomethacin to which a nitroalkyl moiety is bound through a thioether bond (Ye et al, Biochem Pharmacol. 2004; 67:2197- 205

[0015] As further proof that cleavage of the covalently attached moiety to an NSAID is responsible for gastric toxicity, Rao et al. reported that, in contrast to nitric oxide-donating aspirin, nitric oxide-donating indomethacin does cause some gastric toxicity in rats, which is dose-dependent (Rao et al Mol Cancer Ther. 2006; 5:1530-8). The hydrolysis of the ester bond of nitric oxide-donating aspirin is much slower than that of the thioether of nitric oxide-donating indomethacin, especially in acidic pH. It is entirely possible that the differences in gastric toxicity between these two compounds are due to the following differences between the two compounds. In the case of nitric oxide-donating aspirin minimal, if any, aspirin is released in the stomach and hence no gastric damage is observed. In the case, however, of nitric oxide-donating indomethacin some of indomethacin is released in the stomach and this accounts for the gastric damage that it causes.

[0016] The present invention provides a new class of safe anti-inflammatory therapeutics. In a first aspect, the present invention provides compounds of general Formula I:

A-B-X¹-X²

Formula (I) or a tautomer thereof, or a prodrug, salt, hydrate or ester thereof, wherein A is any suitable NSAID which comprises a functional group preferably selected from the group consisting of -COOH, -OH, -SH and -NH2 group, to which group B is attached; wherein B is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, a heteroaromatic moiety; an acyl, or alkoxy moiety; preferably, B is an optionally substituted alkyl group, preferably a C2-10 straight or branched alkyl chain with or without substitutions, or a -(CH2)_X-Aryl- (CH2)- wherein in a preferred embodiment x+y=l to 6; wherein X¹ is selected from the group consisting of -H; -O-; -S-; -NR¹-; and -C(Ri) 2- wherein R¹ is H or alkyl; wherein X² does not exist if X¹ is H, otherwise X² is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, a heteroaromatic moiety; an acyl, or alkoxy moiety; preferably, X² is selected from the group consisting of -CO-(R, Ar) wherein R=alkyl and Ar= aryl or hetero-aryl; nicotinic acid; isonicotinic acid;

NHR(Ar) _wnerem R is alkyl and Ar is aryl or hetero-aryl;

wherein Rⁿ is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or a heteroaromatic moiety;— ^{co N} (alpha-picolinic -H; phosphite; phosphate; tosylate; halogen; or inorganic ester;

[0017] Certain nitrate compounds, such as the molecule shown below

are specifically excluded.

[0018] In preferred embodiments, A is salicylate, such as: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium Salicylate, and Salicyl salicylate (salsalate). Examples of modifed salicylate

include _{¾ com}p_0un(j

of the fol

lowing structure excluded

[0019] In a preferred embodiment, A is an arylalkanoic acid, such as Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumetone, Sulindac, and Tolmetin. For example, a modified arylalkanoic

[0020] In another preferred embodiments, A is a 2-Arylpropionic acid

(profen), such as Ibuprofen, Carprofen, Fenbufen, Fenoprofen, Flurbiprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, and Suprofen. Examples of modified arylalkanoic acid include

[0021] In a further embodiment, A is an N-Arylanthranilic acid (fenamic acid), such as Mefenamic acid and Meclofenamic acid:

[0022] In a further embodiment, A is a Pyrazolidine derivative, such as Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, and Sulfinpyrazone .

[0023] In a further embodiment, A is a COX-2 Inhibitor, such as Celecoxib, Etoricoxib, Rofecoxib. Examples thereof include

[0024] In a further embodiment, A is a sulphonanilide, such as a Nimesulide:

[0025] A according to the present invention A may also be a licofelone.

[0026] In a further aspect, the invention is directed to a pharmaceutical composition comprising a compound of Formula I, as described generally herein, and a pharmaceutically acceptable excipient. In a specific embodiment, the pharmaceutical composition comprising a compound of Formula I is useful in the treatment of human and animal diseases including but not limited to rheumatologic diseases such as rheumatoid arthritis and Sjogren;s syndrome; cardiovascular diseases, such as coronary artery disease, peripheral vascular disease and hypertension; neurodegenerative diseases, for example, Alzheimer's disease and its variants or cerebrovascular diseases; and autoimmune diseases such as lupus erythematosus; other conditions characterized by chronic inflammation of organs such as for example the lung, such as chronic bronchitis or the sinuses, such as chronic sinusitis; and various neoplastic and pre-neoplastic diseases, such as for example, benign prostatic hypertrophy, prostate cancer, colon adenomas and colon cancer, cancer of the lung, lymphomas and leukemias. Such compositions can comprise one or more other pharmaceutical agents in addition to one or more compounds of the invention.

[0027] In another embodiment, the invention is directed to a method for inhibiting inflammation, both acute and chronic, in a subject in need thereof by administering to the subject an amount of the compound or composition of the present invention effective to inhibit inflammation. The subject may be a human patient or animal.

[0028] In yet another aspect, the present invention provides methods for treating any disorder related to undesirable inflammation comprising administering to a subject (e.g., human patient or animal) in need thereof a therapeutically effective amount of a compound of Formula I or a compound of Formula I of the invention or a pharmaceutical composition comprising a compound of the invention. In a preferred embodiment, the disorder includes, but is not limited to rheumatologic diseases such as for example rheumatoid arthritis and Sjogren;s syndrome; cardiovascular diseases, such as, for example, coronary artery disease, peripheral vascular disease and hypertension; neurodegenerative diseases, such as, for example, Alzheimer's disease and its variants or cerebrovascular diseases; autoimmune diseases such as for example lupus erythematosus; and other conditions characterized by chronic inflammation of organs such as for example the lung, such as chronic bronchitis or the sinuses, such as chronic sinusitis.

[0029] The present invention further provides a method for treating pain in a mammal in need thereof, comprising administering to the mammal an effective amount a pharmaceutical composition of the present invention, optionally in combination with an effective amount of another analgesic.

[0030] A person of ordinary skills in the art will recognize that according to the invention, the term "treating" and "treatment" include prophylaxis or prevention of pain, amelioration or elimination of developed pain once it has been established, or alleviation of the characteristic symptoms of such pain.

[0031] The skilled artisan will also appreciate that pain is a heterogeneous disorder. In the method according to the invention, the term "pain" shall refer to all types of pain, including acute and persistent pain. Preferably, the term shall refer to persistent pains, such as, but not limited to, neuropathic pain, diabetic neuropathy, fibromyalgia, pain associated with somatoform disorders, arthritic pain, cancer pain, neck pain, shoulder pain, back pain, cluster headaches, tension- type headache, migraine, herpes neuralgia, phantom limb pain, central pain, dental pain, NSAID-resistant pain, visceral pain, surgical pain, post-operative pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, angina pain, and genitourinary tract-related pain including cystitis. The term persistent pain may also refer to nociceptive pain or nociception.

[0032] The present invention further provides a method for treating fever in a mammal in need thereof, comprising administering to the mammal an effective amount a pharmaceutical composition of the present invention, optionally in combination with an effective amount of another anti-fever agent. It is readily recognized that fever suitably treatable by the present invention may be caused by endogenous or exogenous pyrogens. The fever may be a low-grade, moderate or high-grade fever. The fever may be caused by inflammation and others conditions or diseases, such as by an infectious disease (e.g. influenza, common cold, HIV, malaria, infectious mononucleosis, or gastroenteritis); a skin inflammation (e.g. boils, pimples, acne, or abscess); an immunological disease (e.g. lupus erythematosus, sarcoidosis, inflammatory bowel diseases); a cancer; tissue destruction, which may be due to hemolysis, surgery, infarction, rhabdomyolysis, cerebral hemorrhage; or a drug fever, which may be directly caused by a drug, e.g. lamictal, progesterone, or chemotherapeutics causing tumor necrosis or as an adverse reaction to drugs, e.g. antibiotics or sulfa drugs; a metabolic disorder, e.g. gout or porphyria; or a thrombo-embolic process e.g. pulmonary embolism or deep venous thrombosis.

[0033] The compounds of the present invention may be used for the manufacture of a medicament for treatment of a disease listed above.

[0034] DEFINITIONS

[0035] The term "aliphatic", as used herein, includes both saturated and unsaturated, straight chain (i.e. , unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, and alkynyl moieties. Thus, as used herein, the term "alkyl" includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl" and the like. Furthermore, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like encompass both substituted and unsubstituted groups. In certain embodiments, as used herein, "lower alkyl" is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.

[0036] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl (propargyl), 1-propynyl and the like.

[0037] The term "alicyclic", as used herein, refers to compounds, which combine the properties of aliphatic and cyclic compounds and include but are not limited to monocyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, "alicyclic" is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups. Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH2-cyclopropyl, cyclobutyl, -CH2-cyclobutyl, cyclopentyl, -CH2- cyclopentyl, cyclohexyl, -ClH -cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.

[0038] The term "alkoxy" or "alkyloxy", as used herein refers to a saturated (i.e., O-alkyl) or unsaturated (i.e., O-alkenyl and O-alkynyl) group attached to the parent molecular moiety through an oxygen atom. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, ieri-butoxy, neopentoxy, n-hexoxy and the like. [0039] The term "alkylthio" or "thioalkyl" as used herein refers to a saturated (i.e., S-alkyl) or unsaturated (i.e., S-alkenyl and S-alkynyl) group attached to the parent molecular moiety through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of thioalkyl include, but are not limited to, methyl thio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0040] The term "alkylamino" refers to a group having the structure -NHR' wherein R' is alkyl, as defined herein. The term "aminoalkyl" refers to a group having the structure NH2R'-, wherein R' is alkyl, as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.

[0041] Some examples of substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryl oxy; alkylthio; aryl thio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -OH; -NO₂; -ONO₂; -CN; -CF₃; -CH₂CF₃; -CHCI2; - CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)R_x; -CO₂(Rx); -CON(R_x)₂; - OC(O)R_x; -OCO₂R_x; -OCON(R_x)₂; -N(R_X)₂; -S(O)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0042] In general, the term "aromatic moiety", as used herein, refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. In certain embodiments, the term "aromatic moiety" refers to a planar ring having p-orbitals perpendicular to the plane of the ring at each ring atom and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer. A mono- or polycyclic, unsaturated moiety that does not satisfy one or all of these criteria for aromaticity is defined herein as "non-aromatic", and is encompassed by the term "alicyclic."

[0043] In general, the term "heteroaromatic moiety", as used herein, refers to a stable mono- or polycyclic, unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted; and comprising at least one heteroatom selected from O, S and N within the ring (i.e., in place of a ring carbon atom). In certain embodiments, the term "heteroaromatic moiety" refers to a planar ring comprising at least one heteroatom, having p-orbitals perpendicular to the plane of the ring at each ring atom, and satisfying the Huckel rule where the number of pi electrons in the ring is (4n+2) wherein n is an integer.

[0044] It will also be appreciated that aromatic and heteroaromatic moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases "aromatic or heteroaromatic moieties" and "aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic, and

-(heteroalkyl)heteroaromatic" are interchangeable. Substituents include, but are not limited to, any of the previously mentioned substituents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.

[0045] The term "aryl", as used herein, does not differ significantly from the common meaning of the term in the art, and refers to an unsaturated cyclic moiety comprising at least one aromatic ring. In certain embodiments, "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

[0046] The term "heteroaryl", as used herein, does not differ significantly from the common meaning of the term in the art, and refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

[0047] It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryl oxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHC1₂; -CH₂OH; - CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(O)R_x; -CO₂(R_x); -CON(R_x)₂; -OC(O)R_x; - OCO₂R_x; -OCON(R_x)₂; -N(R_X)₂; -S(O)R_x; -S(O)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl substituents described above and herein may be substituted or unsubstituted. Additionally, it will be appreciated, that any two adjacent groups taken together may represent a 4, 5, 6, or 7-membered substituted or unsubstituted alicyclic or heterocyclic moiety. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0048] The term "cycloalkyl", as used herein, refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -OH; -NO₂; -CN; -CF₃; - CH₂CF₃; -CHC1₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(O)R_x; -CO₂(R_x); -CON(R_x)₂; -OC(O)R_x; -OCO₂R_x; -OCON(R_x)₂; -N(R_X)₂; -S(O)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0049] The term "heteroaliphatic", as used herein, refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom. Thus, a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be linear or branched, and saturated or unsaturated. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -OH; -NO₂; -CN; -CF₃; -CH₂CF₃; - CHC1₂; -CH2OH; -CH2CH2OH; -CH2NH2; -CH2SO2CH3; -C(O)R_x; -CO₂(Rx); - CON(Rx)₂; -OC(O)R_x; -OCO₂R_x; -OCON(R_x)₂; -N(R_X)₂; -S(O)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0050] The term "heterocycloalkyl", "heterocycle" or "heterocyclic", as used herein, refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include, but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring systems having 5-16 atoms wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), wherein the ring systems are optionally substituted with one or more functional groups, as defined herein. In certain embodiments, the term "heterocycloalkyl", "heterocycle" or "heterocyclic" refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S and N (wherein the nitrogen and sulfur heteroatoms may be optionally be oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl, and benzofused derivatives thereof. In certain embodiments, a "substituted heterocycle, or heterocycloalkyl or heterocyclic" group is utilized and as used herein, refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; - OH; -NO₂; -CN; -CF₃; -CH₂CF₃; -CHC1₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂SO₂CH₃; -C(O)R_x; -CO₂(R_x); -CON(R_x)₂; -OC(O)R_x; -OCO₂R_x; -OCON(R_x)₂; - N(R_X)₂; -S(O)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, saturated or unsaturated, and wherein any of the aromatic, heteroaromatic, aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples, which are described herein.

[0051] Additionally, it will be appreciated that any of the alicyclic or heterocyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0052] The terms "halo" "halide" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine. [0053] The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

[0054] The term "amino", as used herein, refers to a primary (-NH2), secondary (-NHR^X), tertiary (-NR^xR^y) or quaternary (-N⁺R^xR^yR^z) amine, where R^x, R^v and R^z are independently an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein. Examples of amino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.

[0055] The term "acyl", as used herein, refers to a group having the general formula -C(=0)R, where R is an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein.

[0056] The term "sulfonamido", as used herein, refers to a group of the general formula -S02NR^xR^y, where R^x and R^y are independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety, as defined herein.

[0057] The term "benzamido", as used herein, refers to a group of the general formula PhNR^x-, where R^x is hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety, as defined herein.

[0058] The term "Ci-6alkylidene", as used herein, refers to a substituted or unsubstituted, linear or branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, having a free valence "-" at both ends of the radical.

[0059] The term "C2-6alkenylidene," as used herein, refers to a substituted or unsubstituted, linear or branched unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence "-" at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.

[0060] As used herein, the terms "aliphatic", "heteroaliphatic", "alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms "alicyclic", "heterocyclic", "heterocycloalkyl", "heterocycle" and the like encompass substituted and unsubstituted, and saturated and unsaturated groups. Additionally, the terms "cycloalkyl", "cycloalkenyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl", "heteroaryl" and the like encompass both substituted and unsubstituted groups.

[0061] The phrase, "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains at least one additional moiety, which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester, which is cleaved in vivo to yield a compound of interest. Prodrugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Compounds of the invention may be considered prodrugs as both the ester or amide linkage adjacent to substituent A, and leaving group D, generate quinone intermediates that are anti-inflammatory. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.

DETAILED DESCRIPTION OF THE INVENTION

[0062] The present invention discloses compounds and pharmaceutical compositions thereof that possess anti-inflammatory, anti-pyretic, and analgesic activities.

[0063] The compounds of the invention include compounds of the general Formula (I) as defined above.

[0064] Thus, based on the selections of substituents described above, among the various non-limiting examples of compounds of the invention derived from indomethacin include but are not limited to:

Indomethacin-based compound

Indomethacin-based compound [0065] Compounds of the invention comprising ibuprofen include but are not limited to:

Ibuprofen-based compound (I)

Ibuprofen-based compound

[0066] Compounds of the invention comprising aspirin include but are not limited to:

Aspirin based compound (I)

Aspirin based compound (II)

Aspirin based compound but the following compound is excluded:

[0067] It will be appreciated that for each of the classes and subclasses described above and herein, any one or more occurrences of aliphatic or heteroaliphatic may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched and any one or more occurrences of aryl, heteroaryl, cycloaliphatic, cycloheteroaliphatic may be substituted or unsubstituted.

[0068] Some of the foregoing compounds can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., stereoisomers and/or diastereomers. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, mixtures of stereoisomers or diastereomers are provided. Moreover, when compounds of the invention exist in tautomeric forms, each tautomer is embraced herein. [0069] Furthermore, certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated. The invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g. , racemic mixtures of stereoisomers. In addition to the above- mentioned compounds per se, this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.

[0070] Compositions

[0071] As discussed above, this invention provides novel compounds that have biological properties useful for the treatment of any of a number of conditions or diseases generally characterized by inflammation, fever, or pain, or prophylaxis in instances wherein a risk of appearance of such conditions or diseases is present. Moreover, certain compounds known in the art have been newly identified as having activity likewise useful in the prophylaxis or treatment of abnormal inflammation, and the invention is also directed to anti- inflammation compositions comprising such compounds.

[0072] Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents. For example, additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved anti-inflammation agent, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder related to inflammation. Such additional therapeutic agents may also be provided to promote the targeting of the compounds of the invention to the desired site of treatment, or may increase its stability, increase its half-life, etc. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2 -hydroxy- ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0074] Additionally, as used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates. [0075] Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0076] As described above, the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0077] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut (peanut), corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0078] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0079] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0080] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0081] Compositions to deliver the agent directly to the colon - for example, pills from which the active agent is released into the colon by a pH-dependent or other mechanism ensuring exclusive or predominant colonic delivery of said compound, suppositories, enemas and other means for colonic delivery. [0082] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0083] Solid dosage forms for oral administration include but are not limited to capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0084] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0085] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include but are not limited to polymeric substances and waxes.

[0086] The present invention encompasses pharmaceutically acceptable topical formulations of inventive compounds. The term "pharmaceutically acceptable topical formulation", as used herein, means any formulation which is pharmaceutically acceptable for intradermal administration of a compound of the invention by application of the formulation to the epidermis. In certain embodiments of the invention, the topical formulation comprises a carrier system. Pharmaceutically effective carriers include, but are not limited to, solvents (e.g. , alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals. A more complete listing of art-known carriers is provided by reference texts that are standard in the art, for example, Remington's Pharmaceutical Sciences, 16^th Edition, 1980 and 17^th Edition, 1985, both published by Mack Publishing Company, Easton, Pa., the disclosures of which are incorporated herein by reference in their entireties. In certain other embodiments, the topical formulations of the invention may comprise excipients. Any pharmaceutically acceptable excipient known in the art may be used to prepare the inventive pharmaceutically acceptable topical formulations. Examples of excipients that can be included in the topical formulations of the invention include, but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or additional therapeutic agents used in combination to the inventive compound. Suitable preservatives include, but are not limited to, alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants that can be used in the topical formulations of the invention include, but are not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0087] In certain embodiments, the pharmaceutically acceptable topical formulations of the invention comprise at least a compound of the invention and a penetration enhancing agent. The choice of topical formulation will depend or several factors, including the condition to be treated, the physicochemical characteristics of the inventive compound and other excipients present, their stability in the formulation, available manufacturing equipment, and costs constraints. As used herein the term " penetration enhancing agent " means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al. , Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, 111. (1997). In certain exemplary embodiments, penetration agents for use with the invention include, but are not limited to, triglycerides (e.g. , soybean oil), aloe compositions (e.g. , aloe-vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g. , isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.

[0088] In certain embodiments, the compositions may be in the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. In certain exemplary embodiments, formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate. In certain embodiments, the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. As discussed above, penetration enhancing agents can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0089] It will also be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anti-inflammation agent), or they may achieve different effects (e.g., control of any adverse effects).

[0090] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., anti-inflammatory and/or palliative). For purposes of the invention, the term "Palliative" refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative. For example, palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs. [0091] In certain embodiments the compounds of the present invention can be covalently or non-covalently bound to for example polyethylene glycol or other similar molecules to make them suitable for administration to the patient either in one of the forms described above or using nanodevices. Alternatively, the compounds of the present invention can be formulated using the principles of nanoscience to optimize their therapeutic application.

[0092] Uses and Methods of Treatment

[0093] As discussed above, certain of the compounds as described herein exhibit activity generally as inhibitors of inflammation. Thus, in certain embodiments, compounds of the invention are useful for the treatment of any of a number of conditions or diseases in which inflammation, in particular chronic inflammation is the cause of or relates to the onset or continued occurrence of the disease or condition, such as but not limited to rheumatologic diseases such as rheumatoid arthritis and Sjogren's syndrome; cardiovascular diseases, for example, coronary artery disease, peripheral vascular disease and hypertension; neurodegenerative diseases, for example, Alzheimer's disease and its variants or cerebrovascular diseases; and autoimmune diseases such as lupus erythematosus; other conditions characterized by chronic inflammation of organs such as the lung, such as chronic bronchitis or the sinuses, such as chronic sinusitis.

[0094] Accordingly, in another aspect of the invention, methods for the treatment of inflammation-related disorders are provided comprising administering a therapeutically effective amount of a compound of Formula I or Formula Γ to a subject in need thereof. In certain embodiments, a method for the treatment of related disorders is provided comprising administering a therapeutically effective amount of an inventive compound, or a pharmaceutical composition comprising an inventive compound to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result. [0095] The invention is also directed to the use of any compound of Formula (I) for the preparation of a medicament for administration to a human or animal patient in need thereof, to inhibit or block inflammation. Such compounds preferably are administered once an inflammation-related disease or an inflammatory condition that may predispose to disease has been diagnosed in the patient, optionally in combination with other anti- inflammation agents or other agents such as those that maintain therapeutic levels of the compounds within the body. Compounds of the invention also may be administered after other therapies have been tried and failed, and may be administered prophylactically.

[0096] In certain embodiments, the uses and methods of the invention involve the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal, including livestock, domesticated or zoo animals) in need thereof.

[0097] It will be appreciated that the compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for the treatment of conditions or diseases in which anti-inflammation or related activities have a therapeutically useful role. Thus, the expression "effective amount" as used herein, refers to a sufficient amount of agent to inhibit inflammation and to exhibit a therapeutic effect. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular therapeutic agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0098] Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the location and extent of the disease being treated. In certain embodiments, the compounds of the invention may be parenterally administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. In other embodiments, compounds of the invention may be administered orally or rectally at dosage levels of about 0.01 mg/kg to about 100 mg/kg, from about 0.05 mg/kg to about 50 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally. [0099] Treatment Kit

[00100] In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Alternatively, placebo dosages, or calcium dietary supplements, either in a form similar to or distinct from the dosages of the pharmaceutical compositions, can be included to provide a kit in which a dosage is taken every day. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[00101] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. [00102] The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations falling within the scope of the appended claims and equivalents thereof. Furthermore, the teachings and disclosures of all references cited herein are expressly incorporated in their entireties by reference.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:

A-B-X^!-X²

Formula (I) or a tautomer thereof, or a prodrug, salt, hydrate or ester thereof, wherein A is an NSAID which preferably comprises a functional group preferably selected from the group consisting of -COOH, -OH, -SH and -N¾ group, to which group B is attached; wherein B is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, a heteroaromatic moiety; an acyl, or alkoxy moiety; wherein X¹ is selected from the group consisting of -H; -O-; -S-; -NR¹-; and -C(Ri) 2- wherein R¹ is H or alkyl; and wherein X² does not exist if X¹ is H, otherwise X² is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, a heteroaromatic moiety; an acyl, or alkoxy moiety;

provided that compounds of the formula are

excluded.

2. The compound of claim 1, wherein B is an optionally substituted alkyl group, preferably a C2-10 straight or branched alkyl chain with or without substitutions, or a -(CH2)x-Aryl-(CH2)- wherein in a preferred embodiment x+y=l to 6.

3. The compound of claim 1, wherein X² is selected from the group consisting of - CO-(R, Ar) wherein R=alkyl and Ar= aryl or hetero-aryl; nicotinic acid; isonicotinic acid; CONHR(Ar) _wnerem R is alkyl and Ar is aryl or hetero-aryl;

wherein Rⁿ is an optionally substituted aliphatic alicyclic, heteroaliphatic, heterocyclic, aromatic, or a heteroaromatic moiety;

(alpha-picolinic acid); -H; phosphite; phosphate; tosylate; halogen; or inorganic ester.

4. The compound of claim 1, wherein A is a salicylate.

5. The compound of claim 4, wherein A is selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium Salicylate, and Salicyl salicylate (salsalate).

6. The compound of claim 1, which is

7. The compound of claim 1, wherein A is an arylalkanoic acid.

8. The compound of claim 7, wherein is Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumetone, Sulindac, or Tolmetin.

9. The compound of claim 8, which is

10. The compound of claim 1, wherein A is a 2-Arylpropionic acid.

11. The compound of claim 10, wherein A is selected from the group consisting of Ibuprofen, Carprofen, Fenbufen, Fenoprofen, Flurbiprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, and Suprofen.

13. The compound of claim 1, wherein A is an N-Arylanthranilic acid.

14. The compound of claim 13, wherein A is Mefenamic acid or Meclofenamic acid.

15. The compound of claim 1, wherein A is a Pyrazolidine derivative.

16. The compound of claim 15, wherein A is selected from the group consisting of Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, and Sulfinpyrazone .

17. The compound of claim 1, wherein A is a COX-2 Inhibitor.

18. The compound of claim 17, wherein A is Celecoxib, Etoricoxib, or Rofecoxib.

19. The compound of claim 18, which is

The compound of claim 1, wherein A is a sulphonanilide. The compound of claim 20, which is

22. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable excipient.

23. A method for treating an inflammation related disease, or treating fever, or treating pain, comprising administering the pharmaceutical compositon of Claim 9 to a subject in need thereof.