WO2009022346A2

WO2009022346A2 - Phenyl carbamates for treating gastrointestinal inflammation

Info

Publication number: WO2009022346A2
Application number: PCT/IL2008/001127
Authority: WO
Inventors: Marta Weinstock-Rosin; Avraham Rubinstein; Tareq Taha Jubeh
Original assignee: Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority date: 2007-08-14
Filing date: 2008-08-14
Publication date: 2009-02-19
Also published as: WO2009022346A3

Abstract

The present invention is directed to pharmaceutical compositions comprising inhibitors of acetylcholine esterase useful in methods for treating inflammatory diseases and autoimmune diseases of the gastrointestinal tract. In particular, the present invention provides pharmaceutical compositions comprising phenyl carbamates including rivastigmine that are known acetylcholine esterase inhibitors, now disclosed to be useful for treating inflammatory bowel disease and other autoimmune and chronic inflammatory gastrointestinal diseases and conditions.

Description

PHENYL CARBAMATES FOR TREATING GASTROINTESTINAL

INFLAMMATION

FIELD OF THE INVENTION The invention relates to the use of phenyl carbamates, including rivastigmine, for treating gastrointestinal inflammatory diseases and conditions.

BACKGROUND OF THE INVENTION

Crohn's disease, ulcerative colitis, inflammatory bowel disease and other related conditions form a spectrum of chronic inflammatory diseases of the gastrointestinal tract having unclear etiology and pathogenesis. Inflammatory bowel disease (IBD), a form of chronic gastrointestinal inflammation, includes a group of chronic inflammatory disorders of generally unknown etiology, including ulcerative colitis (UC) and Crohn's disease (CD). These diseases appear to result from the unrestrained activation of an inflammatory response in the intestines. This inflammatory cascade is thought to be perpetuated through the actions of proinflammatory cytokines and selective activation of lymphocyte subsets. In patients with IBD, ulcers and inflammation of the inner lining of the intestines lead to symptoms of abdominal pain, diarrhea, and rectal bleeding. Ulcerative colitis occurs in the large intestine, while in Crohn's the disease can involve the entire GI tract, both small and large intestines. UC is a condition that primarily affects the superficial layer of the colon mucosa and histological analyses reveal ulceration of the mucosa, blunting and loss of crypts, and an inflammatory infiltrate.

Treatment of IBD commonly utilizes a variety of orally administered systemic antiinflammatory agents designed to reduce the inflammatory response. First line therapy commonly employs 5-aminosalicylate (Mesalamine), or 5 -aminosalicylate precursors, such as sulfasalazine, olsalazine, or balsalazide, immunosuppressive agents, such as cyclosporine, azathioprine, and 6-mercaptopurine, corticosteroids such as beclometasone or budesonide and biologies such as infliximab (chimeric monoclonal antibody to tumor necrosis factor α, TNFα), anti-leukocyte adhesions molecules, and daclizumab (a recombinant humanized immunoglobulin Gl monoclonal antibody to interleukin-2 receptor α, IL-2Rα). Due to the postulated role of bacterial infection in IBD, eradication of the gut bacterial flora is also attempted by means that include use of antibiotics and antimicrobial agents (see, e.g. U.S. Pat. Nos. 5,599,795, 5,443,826 and 5,674,858). About 20-25% of the patients with UC fail to respond to medical therapy and therefore are referred to surgery for total proctocolectomy. In general, patients with CD are less responsive to medical therapy and usually do not respond to surgical treatment.

Rivastigmine

US Patent 4,948,807 is directed to a novel group of phenyl carbamates of the general Formula (I):

wherein

Ri is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,

R₂ is hydrogen, methyl, ethyl or propyl, or

Ri and R2 together with the nitrogen to which they are attached form a morpholino or piperidino radical,

R₃ is hydrogen or lower alkyl,

R₄ and R₅ are the same or different and each is a lower alkyl, and the dialkylarninoalkyl group is in the meta, ortho or para position.

Included within the scope of Formula (I), and specifically claimed in US 4,948,807, is the compound N-ethyl-N-methyl-3-[l-(dimethylamino)ethyl] phenyl carbamate. Rivastigmine is the trivial chemical name of the isolated (S) enantiomer of this compound. US 4,948,807 further discloses and claims use of rivastigmine and related phenyl carbamates for alleviation of symptoms associated with decline in cholinergic function as is known to occur in certain neurodegenerative diseases and dementias. Rivastigmine is a cholinesterase inhibitor (ChEI) classified as an intermediate- acting or pseudo-irreversible agent and is primarily indicated for the treatment of Alzheimer's disease. The full chemical name of Rivastigmine is (S)-N-ethyl-N-methyl-3- [l-(dimethylamino)ethyl] -phenyl carbamate which is specifically disclosed and claimed in US 5,602,176. The tartrate salt of Rivastigmine (Rivastigmine Tartrate), chemically named (S)-N-ethyl-N-methyl-3-[l-(dimethylamino) ethyl]-phenyl carbamate hydrogen-(2R,3R)- tartrate, is currently marketed under the trade name EXELON^®. The chemical structure of Rivastigmine Tartrate is represented in Formula (II) below:

Thus, rivastigmine is a well known drug for preventing cognitive decline and loss of cholinergic function in certain types of dementia. Controlled release oral compositions comprising rivastigmine are described in US 6,565,883. US 6,335,031 discloses formulations of rivastigmine containing an antioxidant suitable for transdermal delivery.

U.S. Patent Application Publication No. 2003/0225031 is directed to pharmaceutical compositions for nasal administration comprising AChE inhibitors, including, inter alia, rivastigmine, and methods of using same for the treatment of Alzheimer's disease and other neurological conditions associated with cognitive impairment in a mammal.

Several recent studies indirectly suggest that cholinergic up-regulation may result in anti-inflammatory effects. It was shown, that immune system cells possess various subtypes of muscarinic and nicotinic cholinergic receptors. In addition, lymphocytes synthesize acetylcholine (ACh), which is degraded by acetylcholinesterase (AChE) (Kawashima et al., 2003a; Kawashima et al., 2003b).

Borovikova et al. (2000) demonstrated that administration of acetylcholine or its agonist nicotine to lipopolysaccharide-stimulated human macrophage cultures attenuates the release of the cytokines tumor necrosis factor (TNF), interleukin (IL)-I β, IL-6 and IL- 18, but not the anti-inflammatory cytokine IL-10. Direct electrical stimulation of the peripheral vagus nerve during lethal endotoxaemia in rats inhibited TNF synthesis and peak serum levels, and prevented the development of endotoxic shock. Wang et al. (2003) further showed that the nicotinic acetylcholine receptor α7 subunit is required for inhibition of macrophage TNF release by acetylcholine or nicotine. Saeed et al. (2004) reported that human microvascular endothelial cells express α7 nicotinic acetylcholine receptors (α7 nAChR), and that nicotine, a cholinergic agonist thereof, and vagus nerve stimulation inhibit endothelial cell activation, thereby inhibiting leukocyte recruitment in the carrageenan air pouch model of local inflammation. Other studies performed in animal models disclose that nicotine suppresses the progression of experimental ulcerative colitis (Sykes et al., 2000; Eliakim et al., 2003) and cutaneous inflammation (Sopori et al., 1998) and improves survival during endotoxemia and sepsis (Wang et al., 2004). Nicotine was also reported to impair antigen presentation, and oc7 nAChR has also been disclosed to be expressed on microglia and astrocytes. In addition, the use of nicotine patches for the treatment of human ulcerative colitis was examined in clinical trials (Sandborn et al., 1997). However, the use of nicotine as a therapeutic agent is limited by its toxicity.

Nizri et al. (2005) discloses bi-functional compounds consisting of the nonsteroidal anti-inflammatory drug ibuprofen and pyridostigmine, a cholinesterase inhibitor that acts as a cholinergic up-regulator. These bi-functional compounds exhibited improved efficiency in an EAE mouse model compared to ibuprofen alone. Although treatment of mice by pyridostigmine alone resulted in reduced lymphocyte proliferation, such treatment did not change disease severity. Another such bi-functional compound, namely IBU- Octyl-Cytisine, containing ibuprofen and Cytisine as the nicotinic agonist, has been described by Nizri et al. (2007), which further report that each moiety separately failed to reproduce the effect of this compound.

Nizri et al. (2006) reports suppressed lymphocyte proliferation and proinflammatory cytokine production induced by the ChE inhibitors pyridostigmine and edrophonium administered to the cells in vitro. The disclosure further reports that administration of an antisense oligodeoxynucleotide targeted to AChE mRNA, reduced the clinical severity and CNS inflammation intensity in an EAE model.

It has been suggested that inhibition of antibody-forming cell response by ChE inhibitors requires their presence in the CNS₃ based on experiments performed with physostigmine, physostigmine bromide and edrophonium (Langley et al., 2004).

U.S. Patent Application Publication No. 2005/0222123 is directed to a method of treating a subject with a cytokine-mediated inflammatory disorder comprising administering to the subject a cholinesterase inhibitor other than galantamine. The ' 123 application lists a wide range of structurally-unrelated compounds, including nicotinic and muscarinic AChE inhibitors and butyrylcholinesterase inhibitors, as potential inhibitors for treating a variety of disorders. The specification of '123 exemplifies the use of galantamine, tacrine, huperzine, neostigmine and physostigmine in acute inflammatory models of sepsis and endotoxemia in mice. Reale et al. (2004, 2006) disclose that donepezil treatment down-regulates IL-I,

IL-6 and TNF, and up-regulates the expression and production of IL-4 and MCP-I in PBMC in AD patients.

Pollak et al. (2005) report that peripheral administration of certain cholinesterase inhibitors including rivastigmine to mice attenuates the production of interleukin-lbeta in the hippocampus and blood, concomitantly with the reduction in acetylcholinesterase activity.

Tyagi et al. (2007) studied the effect of tacrine, rivastigmine and donepezil in mice that received intraperitoneal administration of LPS, and found that LPS-induced increased levels of IL-2 were attenuated, independently from a reduction of brain AChE activity. None of the prior art specifically discloses or demonstrates that rivastigmine or related phenyl carbamates may be useful as anti-inflammatory drugs particularly for the treatment of chronic inflammatory diseases afflicting the gastrointestinal tract. There remains an unmet medical need for safe and effective treatment of gastrointestinal inflammatory and autoimmune diseases. SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions comprising phenyl carbamates including rivastigmine useful for inhibition of gastrointestinal (GI) inflammation. These compounds were known for the treatment of Alzheimer's disease and other forms of dementia. The present invention provides novel uses of compositions comprising rivastigmine and certain other phenyl carbamates for treating and inhibiting the progression of inflammatory diseases, particularly colitis, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome and autoimmune and chronic inflammatory diseases of the GI tract. In other words, the present invention is directed to treatment of a subject not otherwise in need of treatment with rivastigmine or other phenyl carbamates.

The invention is based, in part, on the unexpected discovery that rivastigmine functions as an anti-inflammatory agent in animal models of GI inflammatory and autoimmune diseases. Administration of rivastigmine was surprisingly found to inhibit intestinal inflammation in experimental colitis, an animal model of inflammatory bowel disease.

According to a first aspect, there is provided a method of inhibiting inflammation of the GI tract in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I):

O

wherein

Ri is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl, R₂ is hydrogen, methyl, ethyl or propyl, or Ri and R₂ together with the nitrogen to which they are attached form a morpholino or piperidino radical, R₃ is hydrogen or lower alkyl,

R₄ and R₅ are the same or different and each is a lower alkyl, and the dialkylaminoalkyl group is in the meta, ortho or para position, or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

In one currently preferred embodiment, the active ingredient is N-ethyl-N-methyl- 3-[l-(dimemylamino)ethyl]-phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another preferred embodiment, the active ingredient is (S)-N- ethyl-N-methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. In yet another particularly preferred embodiment, the active ingredient is rivastigmine tartrate.

In another aspect, the invention provides a method of treating a GI inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, the GI inflammatory disease or condition is a chronic inflammatory disease or condition of the gastrointestinal tract.

In another embodiment, the GI inflammatory disease or condition is an autoimmune disease of the gastrointestinal tract.

In various embodiments, the compositions are particularly useful for treating chronic conditions associated with the gastrointestinal system including, but not limited to colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, celiac disease, and inflammatory bowel disease.

In another particular embodiment, said condition is inflammatory bowel disease. In another particular embodiment, said condition is colitis. In another particular embodiment, said condition is Crohn's disease. In another particular embodiment, said condition is irritable bowel syndrome. In another aspect, there is provided a method of inhibiting a clinical symptom associated with GI inflammation in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

In a preferable embodiment, the compound utilized in the methods of the invention is rivastigmine or a pharmaceutically acceptable salt, hydrate or solvate thereof, preferably rivastigmine tartrate.

In another embodiment, the subject is human. In other embodiments, the subject is a non-human mammal.

In other embodiments, the active ingredient may be administered enterally, parenterally or topically. According to currently preferable embodiments, the active ingredient is administered in a manner selected from the group consisting of: orally, subcutaneously, transdermally, rectally and intramuscularly. In another currently preferable embodiment, the active ingredient is administered in a manner selected from the group consisting of: orally, subcutaneously and intramuscularly.

In another embodiment, the active ingredient is formulated in the form of extended release, sustained release and controlled-release formulations. In certain particular embodiments, oral sustained release and controlled release formulations are contemplated. In other embodiments, the active ingredient is formulated in the form of a transdermal delivery device.

Other objects, features and advantages of the present invention will become clear from the following description and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Ratio (whole colon weight/whole body weight at time of measurement) of healthy (Healthy) rats, colitis-induced rats treated with saline (Colitis), or those treated with Rivastigmine (Rivastigmine). Mean results of 3-4 rats ± SEM. Figure 2. Myeloperoxidase (MPO) activity in the colon of healthy (Healthy) rats, colitis-induced rats treated with saline (Colitis), or treated with rivastigmine. Mean results of 3-4 rats ± SEM.

Figure 3. Tissue levels of thiobarbituric acid reactive substances (TBARS; absorbance units/ tissue protein) in the colon of healthy (Healthy), colitis-induced rats treated with saline (Colitis), or treated with Rivastigmine (Rivastigmine). Mean results of 3-4 rats ± SEM.

Figure 4. MPO activity in the colon of healthy (Healthy) rats, colitis-induced rats treated with saline (Colitis), or rats treated with budesonide (Sol-Bud). Mean results of 3-8 rats ± SEM.

Figure 5. Tissue levels of TBARS (absorbance units/ tissue protein) in the colon of healthy (Healthy) rats, colitis-induced rats treated with saline (Colitis), or treated with budesonide (Sol-Bud). Mean results of 3-8 rats ± SEM.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the use of rivastigmine, related phenyl carbamates and salts thereof for immunomodulation. The present invention provides compositions comprising these compounds and methods of using same for treating and ameliorating autoimmune and inflammatory diseases and conditions afflicting the GI system.

The present invention is directed to novel therapeutic uses for compositions comprising a compound of the general Formula (I):

wherein

R₄ and R₅ are the same or different and each is a lower alkyl, and the dialkylaminoalkyl group is in the meta, ortho or para position. In one preferable embodiment, the compound is N-ethyl-N-methyl-3-[l-

(dimethylammo)ethyl]-phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another preferable embodiment, the compound is (S)-N-ethyl-N-methyl- 3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. In yet another particularly preferable embodiment, the compound is rivastigmine tartrate.

The compounds of the invention, methods of preparation thereof, and uses thereof for preventing cognitive decline and loss of cholinergic function in certain types of dementia, were disclosed by U.S. Patent Nos. 4,948,807 and 5,602,176. The present invention unexpectedly discloses novel uses of these known compounds as anti- inflammatory drugs particularly useful for treating chronic and autoimmune GI inflammatory conditions.

According to one aspect of the present invention, there is provided a method of inhibiting an inflammatory response associated with a disease of the GI tract in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

According to another aspect of the present invention, there is provided a method of inhibiting an inflammatory response associated with a disease of the GI tract in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising rivastigmine or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent. The term "inhibiting" as used herein is intended to include diminishing, ameliorating, alleviating or otherwise lowering the extent of the response, including both prevention and reduction of symptoms and adverse effects of inflammation, in comparison to the response in the absence of the test drug. Preferably, the inhibition is statistically significant. In one embodiment, the compounds of Formula (I) as defined herein are particularly useful for the treatment of chronic (persistent) inflammatory responses.

Gastrointestinal inflammatory diseases

In another aspect, the invention provides a method of treating an inflammatory disease or condition of the GI tract in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the invention provides a method of treating an inflammatory disease or condition of the GI tract in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising rivastigmine or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

The term "treating" refers to administering a therapy in amount, manner, and/or mode effective to improve a condition, symptom, or parameter associated with a disorder or to prevent progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art. The terms "treating" and "treatment" also include reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage. With respect to inflammatory disorders, the term further includes slowing or preventing progression of deterioration due to inflammatory processes. An effective amount, manner, or mode can vary depending on the subject and may be tailored to the subject.

In one embodiment, the inflammatory disease or condition associated with the GI tract is a T-cell mediated pathology. The term "T-cell mediated pathology" refers to a condition in which an inappropriate T cell response is a component of the pathology. The term is intended to include both diseases directly mediated by T cells, and also diseases in which an inappropriate T cell response contributes to the production of abnormal antibodies.

In another preferable embodiment, the condition is a chronic inflammatory condition associated with pathological inflammation of the GI tract or a portion thereof in the individual that is persistent, whether continuous or intermittent.

In certain particular embodiments, the inflammatory gastrointestinal condition includes, but is not limited to, inflammatory bowel diseases (e.g. ulcerative colitis and

Crohn's disease) irritable bowel syndrome, ileitis, chronic inflammatory intestinal disease, and celiac disease. Each possibility represents a separate embodiment of the present invention.

Crohn's disease is characterized by ulcerations of the small and/or large intestines, but can affect the digestive system anywhere from the mouth to the anus. Various terms are used to describe Crohn's disease, and tend to reflect the portion of the gastrointestinal tract affected. For example, involvement of the large intestine (colon) only has been termed Crohn's colitis or granulomatous colitis, while involvement of the small intestine only has been termed Crohn's enteritis. Disease in the terminal portion of the small intestine i.e. the ileum, has been termed Crohn's ileitis. When both the small intestine and the large intestine are involved, the condition has been termed Crohn's enterocolitis or ileocolitis. Ulcerative colitis is a condition related to Crohn's disease that involves only the colon, and collectively these diseases are frequently referred to as inflammatory bowel disease (IBD), Irritable bowel syndrome (IBS) is a common disorder that has a pronounced effect on the quality of life and that accounts for a large proportion of healthcare costs. The disorder is characterized by lower abdominal pain, bloating, diarrhea, constipation, or constipation alternating with diarrhea. Altered bowel motility, visceral hyperalgesia, food allergy, bacterial overgrowth, psychosomatic factors, stress associated with the myenteric nervous system have all been proposed as playing a part in the pathogenesis of IBS.

Gastrointestinal inflammation may also be associated with irritable bowel syndrome, along with stress. Although the processes involved in the etiology and pathology of the disease are not fully elucidated, it has been reported that altered proinflammatory cytokine release may occur in some patients (Liebregts et ah, 2007).

It is to be understood, that the compounds of Formula (I) as defined herein are known as being useful for treating a subject suffering from senile dementia, Alzheimer's disease, Huntingdon's chorea, tardive dyskinesias, hyperkinesia, mania, acute confusion disorders, Friedrich's ataxia or Down's syndrome. The treatment of a subject afflicted with any of these diseases is excluded from the scope of the present invention.

Preferably, the subject treated by the methods of the present invention should not suffer simultaneously from MS, MS-related disorders, senile dementia, Alzheimer's disease, Huntingdon's chorea, tardive dyskinesias, hyperkinesia, mania, acute confusion disorders, Friedrich's ataxia or Down's syndrome. It is noted, that use of cholinergic stimulation may be contraindicative in certain conditions, e.g. asthma and peptic gastric ulcers. Myasthenia gravis, a disease characterized by episodic muscle weakness caused by loss or dysfunction of acetylcholine receptors, is known to be treatable with acetylcholinesterase inhibitors such as pyridostigmine.

Inflammatory diseases are associated with reactions of both the specific and non- specific defense systems. A specific defense system reaction is a specific immune system reaction response to an antigen (possibly including an autoantigen), e.g. reactions mediated by B cells and T cells. A non-specific defense system reaction is an inflammatory response mediated by leukocytes incapable of immunological memory. Such cells include granulocytes, macrophages, neutrophils and eosinophils. Inflammation is associated with activation of a large array of enzymes, increase in vascular permeability and extravasation of blood fluids, cell migration and release of chemical mediators. Numerous inflammatory mediators involved in such inflammatory reactions or inflammatory cascades are known, including, but not limited to, cytokines, chemokines and acute phase proteins. Assays for inflammation are well known in the art. Without wishing to be bound by any theory or mechanism of action, the immunomodulatory effect of the compounds of the invention may be determined by one or more such inflammatory parameters, including, but not limited to, leukocyte and lymphocyte (e.g. T cell) activation, proliferation, migration and infiltration into inflammatory sites.

Pharmaceutical compositions and therapeutic methods

In another aspect, the invention provides use of a compound of Formula (I) as defined herein for the preparation of an anti-inflammatory medicament for treating a GI- associated inflammatory disease or condition.

In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I) as defined herein for treating a gastrointestinal inflammatory disease or condition, for inhibiting inflammation of the gastrointestinal tract in a subject and/or for inhibiting a clinical symptom associated with gastrointestinal inflammation.

According to various embodiments of the present invention, the compounds of Formula (I) as defined herein may be used in the form of the free base or a pharmaceutically acceptable salt thereof. For rivastigmine formulations, preferably the hydrogen tartrate (hta) is used. Other pharmacologically acceptable salts of these compounds include, but are not limited to, the acetate, salicylate, fumarate, phosphate, sulphate, maleate, succinate, citrate, tartrate, propionate and butyrate salts thereof.

The compounds of Formula (I) as defined herein or physiologically acceptable salt(s) thereof may be compounded with one or more physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavors, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage is obtained.

By "pharmaceutically acceptable", or "physiologically acceptable", is meant herein a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. "Pharmacologically active" (or simply "active"), as in a "pharmacologically active" derivative or metabolite, refers to a derivative or metabolite having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. When the term "pharmaceutically acceptable" or "physiologically acceptable" is used to refer to a derivative (e.g., a salt) of an active agent, it is to be understood that the compound is pharmacologically active as well, i.e., therapeutically effective for reducing inflammation.

"Carriers" or "vehicles" as used herein refer to conventional pharmaceutically acceptable carrier materials suitable for drug administration, and include any such materials known in the art that are nontoxic and do not interact with other components of a pharmaceutical composition or drug delivery system in a deleterious manner.

As used herein, a "pharmaceutically acceptable carrier, excipient or diluent" may refer to a single auxiliary material or to various mixtures and combinations of such non- active ingredients.

Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppeπnint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Other examples of suitable pharmaceutical adjuvants as well as techniques for formulation and administration of drugs are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

By means of a non-limitative example, rivastigmine tartrate may be formulated as capsules for oral administration, containing as inactive ingredients hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, and silicon dioxide. Each hard-gelatin capsule may contain, for example, gelatin, titanium dioxide and dyes (e.g. red and/or yellow iron oxides; Exelon^® capsules). In another non-limitative example, rivastigmine tartrate may be formulated as an oral solution (comprising e.g. a rivastigmine tartrate concentration equivalent to 2 mg/mL of rivastigmine base), comprising as inactive ingredients citric acid, a dye (e.g. D&C yellow #10), purified water, sodium benzoate and sodium citrate (Exelon^® oral solution). Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection. Buffers, preservatives, antioxidants and the like can be incorporated as required.

Preferred antioxidants for use with the compounds of the present invention include sodium metabisulphite and ascorbic acid.

The pharmaceutical composition of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository bases such as cocoa butter or other glycerides.

In other embodiments, the invention is directed to the use of sustained-release or controlled release formulations of the compounds of Formula (I) as defined herein or salts thereof, including, but not limited to those disclosed by U.S. Patent No. 6,565,883 For example, the composition may comprise a core coated with two films, the first inner film being a semi-permeable to water or body fluids film applied directly on said core and comprising cellulose acetate, the second outer film being a permeable to water or body fluids film comprising ethylcellulose.

The term "controlled release" is intended to refer to any drug-containing formulation in which release of the drug is not immediate, i.e., with a "controlled release" formulation, oral administration does not result in immediate release of the drug into an absorption pool. The term is used interchangeably with "nonimrnediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). As discussed therein, immediate and nonimmediate release can be defined.

For a formulation of the drug administered at a particular absorption site, the drug level achieved is the outcome of rate constants for (1) release of the drug from the formulation, (2) absorption, and (3) elimination, respectively. For immediate release dosage forms, the rate constant for drug release is far greater than the absorption rate constant. For the controlled release formulations, the opposite is true, such that the rate of release of drug from the dosage form is the rate-limiting step in the delivery of the drug to the target area. The term "controlled release" as used herein is intended to include any nonimmediate release formulation, including but not limited to sustained release, delayed release and pulsatile release formulations.

The term "sustained release" is used in its conventional sense to refer to a drug formulation that provides for gradual release of drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of drug over an extended time period. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay provided between oral administration of a drug dosage form and the release of the drug therefrom. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and thus may or may not be "sustained release". A controlled release formulation may comprise, for example, controlled release beads comprising the drug. A common type of controlled release beads comprises an inert core, such as a sugar sphere, coated with an inner drug-containing layer and an outer membrane layer controlling drug release from the inner layer. An example of such controlled release beads is described in U.S. Pat. No. 5,783,215 where each bead comprises (i) a core unit of a soluble or insoluble inert material, (ii) a first layer on the core unit comprising an active ingredient dispersed in a hydrophilic polymer, (iii) an optional second layer of hydrophilic polymer covering the first layer, and (iv) an outermost membrane layer effective for controlled release of the active ingredient. In the above and similar controlled release beads it is not uncommon to apply a "sealcoat" in the form of a small amount (e.g. 1-3%) of a water-soluble polymer, such as hydroxypropylmethyl cellulose (HPMC) or polyvinylpyrrolidone (PVP), between the inert core and the layer containing the active ingredient. The purpose thereof is generally to isolate the drug from the core surface in the event that a drag-core chemical interaction is possible, and/or to smooth the surface of the inert core such that the surface area is more consistent from lot to lot to thereby improve the coating quality when the drug layer and the controlled release membrane layers are applied.

The cores are typically of a water-soluble or swellable material, and may be any such material that is conventionally used as cores or any other pharmaceutically acceptable water-soluble or water-swellable material made into beads or pellets. Especially, the beads are spheres of sucrose/starch (Sugar Spheres NF), sucrose crystals, or extruded and dried spheres typically comprised of excipients such as microcrystalline cellulose and lactose.

The substantially water-insoluble material in the first or sealcoat layer is generally a "GI insoluble" or "GI partially insoluble" film forming polymer (latex or dissolved in a solvent). As examples may be mentioned ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polymethacrylates such as ethyl acrylate/methyl methacrylate copolymer

(Eudragit NE-30-D) and ammonio methacrylate copolymer types A and B (Eudragit

RL30D and RS30D), and silicone elastomers. Usually, a plasticizer is used together with the polymer. Exemplary plasticizers include: dibutylsebacate, propylene glycol, triethylcitrate, tributylcitrate, castor oil, acetylated monoglycerides, acetyl triethylcitrate, acetyl butylcitrate, diethyl phthalate, dibutyl phthalate, triacetin, fractionated coconut oil

(medium-chain triglycerides).

The second layer containing the active ingredient may be comprised of the active ingredient (drug) with or without a polymer as a binder. The binder, when used, is usually hydrophilic but may be water-soluble or water-insoluble. Exemplary polymers to be used in the second layer containing the active drug are hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyalkylene glycol such as polyethylene glycol, gelatine, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, acrylic acid polymers, polymethacrylates, or any other pharmaceutically acceptable polymer.

In a particular embodiment, the composition is a controlled release formulation formulated for colonic delivery. For example, colonic delivery systems are disclosed in U.S. Pat. Nos. 5,525,634 and 5,866,619 to some of the inventors of the present invention.

In further alternate embodiments, transdermal pharmaceutical compositions comprising the compounds of Formula (I) as defined herein may be used in accordance with the methods of the present invention. These formulations may be administered using a transdermal device, e.g. a transdermal patch. Exemplary transdermal formulations comprising inter alia rivastigmine and transdermal devices thereof are disclosed in U.S. Patent No. 6,335,031. The compounds according to the invention may be administered by any conventional route, in particular enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions (e.g. for subcutaneous or intramuscular administration). In certain embodiments, such as for the treatment of inflammatory gastrointestinal diseases, topical (e.g. rectal or colonic) administration is advantageous.

The exact amounts of the compound of Formula (I) as defined herein to be administered may depend on a number of factors, e.g. the drug release characteristics of the compositions, the drug penetration rate observed in vitro and in vivo tests, the duration of action required, the form of the compound of Formula (I), and for transdermal compositions the dimensions of the skin contact area, and the part of the body to which the unit is fixed. The amount of and, e.g. area of the transdermal composition etc. may be determined by routine bioavailability tests comparing the blood levels of active agents after administration of the compound of Formula (I) as defined herein in a composition according to the invention to intact skin and blood levels of the compound of Formula (I) observed after oral administration of a therapeutically effective dose of the compound, or the amount of drug in the inflamed tissue.

Orally, rivastigmine is well tolerated in humans at an initial dose of 1.5 mg twice a day orally and the dose may be stepped up to 3 mg twice daily in week 2. Higher dosages are possible, for example 4.5 mg twice daily and even 6 mg twice daily. Tolerability is seen to be even better for a transdermal device, wherein, for example, 24 mg may be absorbed in 24 hours.

For example, oral formulations of rivastigmine tartrate as described above may be administered to a subject in need thereof so that a dose equivalent to 1.5 mg rivastigmine is administered twice daily, and this dose may be gradually increased to a maximal daily dose equivalent to between 9-12 mg rivastigmine. Intramuscular and subcutaneous rivastigmine administration can be e.g. from 0.75 mg twice daily to a maximal daily dose equivalent to 5-6 mg rivastigmine.

In another aspect, the invention provides a method of inhibiting inflammation of the gastrointestinal tract in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of the general Formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, said subject is not otherwise in need of treatment with rivastigmine or other phenyl carbamates.

In one embodiment, the compound is N-ethyl-N-methyl-3-[l- (dimethylamino)ethyl] -phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the compound is (S)-N-ethyl-N-methyl-3-[l- (dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the pharmaceutical composition comprises rivastigmine tartrate. In another embodiment, said compound is formulated in a form selected from the group consisting of extended release, sustained release and controlled-release formulations.

In another aspect, there is provided a method of treating a gastrointestinal inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

In another embodiment, the gastrointestinal inflammatory disease is a chronic inflammatory disease. In another embodiment, the gastrointestinal inflammatory disease is an autoimmune disease. In another embodiment, the condition is selected from the group consisting of: colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, celiac disease, and inflammatory bowel disease, wherein each possibility represents a separate embodiment of the present invention. In another embodiment, the condition is irritable bowel syndrome.

In another embodiment, the method is useful for inhibiting a clinical symptom associated with gastrointestinal inflammation in said subject. By "inhibiting a clinical symptom" it is meant reduction in severity and/or frequency of one or more symptoms, elimination of symptom(s) and prevention of the occurrence of symptom(s).

In another embodiment, the compound is N-ethyl-N-methyl-3-[l-

(dimethylamino)ethyl]-phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the compound is (S)-N-ethyl-N-methyl-3-[l-

(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the pharmaceutical composition comprises rivastigmine tartrate.

In another embodiment, the subject is selected from the group consisting of humans and non-human mammals. In another embodiment, the compound is administered in a manner selected from the group consisting of: enterally, parenterally and topically, wherein each possibility represents a separate embodiment of the present invention. In another embodiment, the compound is administered in a manner selected from the group consisting of: orally, subcutaneously, transdermally, rectally and intramuscularly, wherein each possibility represents a separate embodiment of the present invention.

In another embodiment said compound is formulated in a form selected from the group consisting of extended release, sustained release and controlled-release formulations, wherein each possibility represents a separate embodiment of the present invention. particular embodiment, said compound is formulated in the form of a transdermal delivery device.

In another aspect, the invention is directed to the use of a pharmaceutical composition comprising a compound of the general Formula (I) as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, for the preparation of a medicament for inhibiting inflammation of the gastrointestinal tract. In another aspect, the invention is directed to the use of a pharmaceutical composition comprising a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof for the preparation of a medicament for treating a gastrointestinal inflammatory disease or condition.

In another aspect, the invention is directed to a pharmaceutical composition comprising a compound of the general Formula (I) as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof, for inhibiting inflammation of the gastrointestinal tract.

In another aspect, the invention is directed to a pharmaceutical composition comprising a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof for treating a gastrointestinal inflammatory disease or condition. In another embodiment, the gastrointestinal inflammatory disease is a chronic inflammatory disease. In another embodiment, the gastrointestinal inflammatory disease is an autoimmune disease. In another embodiment, the condition is selected from the group consisting of: colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, celiac disease, and inflammatory bowel disease, wherein each possibility represents a separate embodiment of the present invention.

In another embodiment, the composition is useful for inhibiting a clinical symptom associated with gastrointestinal inflammation.

In another embodiment, the compound is N-ethyl-N-methyl-3-[l- (dimethylamino)ethyl]-phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the compound is (S)-N-ethyl-N-methyl-3-[l- (dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. In another embodiment, the pharmaceutical composition comprises rivastigmine tartrate. In another embodiment, the composition may be administered enterally, parenterally or topically, wherein each possibility represents a separate embodiment of the present invention. In another embodiment, the composition may be administered orally, subcutaneously, transdermally, rectally or intramuscularly, wherein each possibility represents a separate embodiment of the present invention. In another embodiment, said composition is formulated as an extended release, sustained release or controlled-release formulation, wherein each possibility represents a separate embodiment of the present invention, particular embodiment, said composition is formulated as transdermal delivery device.

The following examples are presented in order to more fully illustrate some embodiments of the invention. They should, however, in no way be construed as limiting the broad scope of the invention.

EXAMPLES

A. Topical treatment of Inflammatory Bowel Disease by rivastigmine tartrate

Materials: Rivastigmine hydrogen tartrate.

Induction of colitis in the rat and analysis of inflammation severity. Colitis was induced in male rats weighing 25Og by intra-colonic administration under light ether inhalation anesthesia of 1 ml of dinitrobenzensulfonic acid (DNBS) (20 mg/ml, in ethanol 30 % v/v). The solution was instilled slowly over 20 seconds via a flexible, perforated Foley catheter, which was then immediately removed. The rats were placed in an upside down position for another 40 seconds. The control group was treated with saline instead of rivastigmine using the same procedure. Treatment groups:

Rivastigmine

Group 1 (n=5) was given rivastigmine hydrogen tartrate (2 mg/kg, ImI; "rivastigmine") intra-rectally one hour prior to induction of colitis, and then 12, 24, 36, 48 and 60 hours later. Group 2 (n=3) was given saline (1 ml/rat) instead of rivastigmine. Group 3 (n= 3) was given saline instead of DNBS. Budesonide

In a separate study the steroid drug budesonide (aqueous solution) was give in a similar protocol of topical treatment, as follows: Group 4 (n=8) was given 200 μg of budesonide (in ImI of hydroalcoholic solution), intra- rectally one hour after the induction of colitis, and then 12, 24, 36, 48 and 60 hours later (altogether: 1.2 mg budesonide).

Group 5 (n=8) was given ImI saline instead of budesonide. Group 6 (n= 3) was given saline instead of DNBS. Tissue collection. The rats were anesthetized by ketamine (100 mg/kg body weight) given by intraperitoneal injection and the colon was exposed through a longitudinal abdominal incision. The distal 10 cm of the colon was removed, cut open and rinsed with ice-cold saline.

Euthanasia of the anesthetized rats was performed by puncturing of the chest wall.

Analysis of inflammation severity. The fresh tissues were scored for presence of (1) edema, (2) hyperemia and (3) number and areas of mucosal ulcers. If present, the total area of all ulcers was taken. They were then blotted dry, weighed and immediately frozen in liquid nitrogen. On the day of analysis the colon specimens were warmed to 4⁰C, homogenized (Polytron, Kinematica GmbH, Germany) in 10 volumes of 0.02M phosphate- buffer, pH 7.4, and stored at -74⁰C for biochemical analysis of inflammatory markers.

Example 1. Evaluation of Rivastigmine in Reducing Inflammation Severity in the Experimental Colitis Model.

Based on the macroscopic assessment of inflammation severity, rivastigmine was herein found to be effective in the topical treatment of induced colitis in rats.

As can be seen in Figure 1, the whole colon weight/whole body weight ratio of colitis-induced rats treated with rivastigmine was lower than that of colitis-induced rats treated with saline, and resembled the ratio measured in healthy rats.

Table 1 demonstrates that rivastigmine treatment was associated with reduced edema and hyperemia, as well as lower incidence and severity of ulcers:

Table 1: Macroscopic score of healthy (Healthy), colitis-induced rats treated with saline (Diseased), or treated with Rivastigmine hydrogen tartrate (Rivastigmine). Mean results of 3-4 rats are presented.

These findings were then verified by biochemical measures, as detailed below. Tissue myeloperoxidase (MPO) activity is a marker of inflammation severity, as MPO mediates reactive oxygen metabolites of activated polymorphonuclear cells (PMN)₅ e.g. the production of hypochlorous acid by PMN. Tissue MPO activity was assayed as follows: one ml of the homogenized specimens was centrifuged at 25,00Og for 5 min. The pellet was re-suspended in 0.5 ml ice-cold 50 mM phosphate buffer pH 6, containing 1 ml hexadecyltrimethyl ammonium bromide (HTAB). The suspension was freeze-thawed twice, sonicated for 15 seconds and centrifuged at 500Og for 5 min. 0.1 ml of the supernatant was added to 2.9 ml of phosphate-buffer pH 6, containing 0.167 mg/ml o- dianisidine hydrochloride and 5x10^'4 % v/v of hydrogen peroxide. The kinetics of the change in absorbance was determined at 460 nm over 30 seconds and slopes were calculated (Grisham et al., 1990) using an 8 points calibration curve and expressed as enzyme activity per tissue protein (mg).

Tissue malondialdehyde (MDA, an end product of the oxidation and decomposition of polyunsaturated fatty acids containing three or more double bonds) was monitored by assessing the MDA-thiobarbituric acid (TBA) adduct, TBARS (thiobarbituric acid reactive substances) (Levine et al., 1990. Determination of carbonyl content in oxidatively modified proteins. Methods EnzymoL, 186: 464-478). One ml of the homogenized specimen was centrifuged at 25,000 g for 5 min. The supernatant was separated and added to a 2 ml mixture of 15% trichloroacetic acid, 0.375% thiobarbituric acid and 0.25N HCl. The mixture was heated in boiling water bath for 15 min. It was then centrifuged and the absorbance of the supernatant was recorded at 535 nm (Levine et al., 1990) and normalized to tissue protein. Tissue protein was measured by the Bradford method using standard procedure.

As can be seen in Figures 2 and 3, both markers were lower in the rivastigmine treated animals compared with the non-treated controls. Rivastigmine was 1.8- to 2,5-fold more effective than budesonide in inhibiting inflammation (compare Figure 2 with Figure 4, and Figure 3 with Figure 5).

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Claims

1. A method of inhibiting inflammation of the gastrointestinal tract in a subject in need thereof, comprising administering to the subject a therapeutically- effective amount of a pharmaceutical composition comprising a compound of the general Formula (I): O

wherein

Ri is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,

R₂ is hydrogen, methyl, ethyl or propyl, or

Ri and R₂ together with the nitrogen to which they are attached form a morpholino or piperidino radical,

R₃ is hydrogen or lower alkyl,

R₄ and R₅ are the same or different and each is a lower alkyl, and the dialkylaminoalkyl group is in the meta, ortho or para position, and pharmaceutically acceptable salts, hydrates or solvates thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

2. The method of claims 1, wherein the compound is N-ethyl-N-methyl-3-[l~ (dimethylamino)ethyl] -phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The method of claim 2, wherein the compound is (S)-N-ethyl-N-methyl-3-[l- (dimethylamino)ethyl] -phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The method of claim 3, wherein the pharmaceutical composition comprises rivastigmine tartrate.

5. The method of claim 1, wherein said compound is formulated in a form selected from the group consisting of extended release, sustained release and controlled-release formulations.

6. A method of treating a gastrointestinal inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically-effective amount of a pharmaceutical composition comprising a compound of Formula (I) as defined in claim 1, or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier, excipient or diluent.

7. The method of claim 6, wherein the gastrointestinal inflammatory disease is a chronic inflammatory disease.

8. The method of claim 6, wherein the gastrointestinal inflammatory disease is an autoimmune disease.

9. The method of claim 6, wherein the condition is selected from the group consisting of: colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, celiac disease, and inflammatory bowel disease.

10. The method of claim 9, wherein the condition is inflammatory bowel disease.

11. The method of claim 9, wherein the condition is colitis.

12. The method of claim 9, wherein the condition is Crohn's disease.

13. The method of claim 6, wherein the condition is irritable bowel syndrome.

14. The method of claim 6 for inhibiting a clinical symptom associated with gastrointestinal inflammation in said subject.

15. The method of claim 6, wherein the compound is N-ethyl-N-methyl-3-[l-

(dimethylamino)ethyl]-phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof.

16. The method of claim 6, wherein the compound is (S)-N-ethyl-N-methyl-3-[l- (dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

17. The method of claim 6, wherein the compound is rivastigmine tartrate.

18. The method of claim 6, wherein the subject is selected from the group consisting of humans and non-human mammals.

19. The method of claim 6, wherein the compound is administered in a manner selected from the group consisting of: enterally, parenterally and topically.

20. The method of claim 6, wherein the compound is administered in a manner selected from the group consisting of: orally, subcutaneously, transdermally, rectally and intramuscularly.

21. The method of claim 6, wherein the compound is administered in a manner selected from the group consisting of: orally, subcutaneously and intramuscularly.

22. The method of claim 6, wherein said compound is formulated in a form selected from the group consisting of extended release, sustained release and controlled-release formulations.

23. The method of claim 6, wherein said compound is formulated in the form of a transdermal delivery device.

24. Use of a pharmaceutical composition comprising a compound of the general Formula (I):

O

wherein

Ri is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,

R₂ is hydrogen, methyl, ethyl or propyl, or

R3 is hydrogen or lower alkyl,

Ri and R₅ are the same or different and each is a lower alkyl, and the dialkylaminoalkyl group is in the meta, ortho or para position, and pharmaceutically acceptable salts, hydrates or solvates thereof, for the preparation of a medicament for inhibiting inflammation of the gastrointestinal tract.

25. Use of a pharmaceutical composition comprising a compound of Formula (I) as defined in claim 24, or a pharmaceutically acceptable salt, hydrate or solvate thereof for the preparation of a medicament for treating a gastrointestinal inflammatory disease or condition.

26. The use of claim 25, wherein the gastrointestinal inflammatory disease is a chronic inflammatory disease.

27. The use of claim 25, wherein the gastrointestinal inflammatory disease is an autoimmune disease.

28. The use of claim 25, wherein the condition is selected from the group consisting of: colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, celiac disease, and inflammatory bowel disease.

29. The method of claim 25, wherein the condition is irritable bowel syndrome.

30. The use of claim 25 for inhibiting a clinical symptom associated with gastrointestinal inflammation.

31. The use of any one of claims 24-30, wherein the compound is N-ethyl-N- methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate or a pharmaceutically acceptable salt, hydrate or solvate thereof.

32. The use of any one of claims 24-30, wherein the compound is (S)-N-ethyl-N- methyl-3-[l-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

33. The use of any one of claims 24-30, wherein the compound is rivastigmine tartrate.

34. The use of any one of claims 24-30, wherein the medicament is administered enterally, parenterally or topically.

35. The use of any one of claims 24-30, wherein the medicament is administered orally, subcutaneously, transdermally, rectally or intramuscularly.

36. The use of any one of claims 24-30, wherein said medicament is formulated as an extended release, sustained release or controlled-release formulation.

37. The use of any one of claims 24-30, wherein said medicament is formulated as transdermal delivery device.