US 2006O128794A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0128794 A1 Sandage, JR. et al. (43) Pub. Date: Jun. 15, 2006

(54) TREATMENT OF INTERSTITIAL CYSTITIS Publication Classification USING (6AR,10AR)- DELTA8-TETRAHYDROCANNABINOL-11 OCACDS (51) Int. Cl. A6II 3 L/353 (2006.01) (75) Inventors: Bobby W. Sandage JR. Acton, MA (US); Glenn L. Cooper, Wayland, MA (52) U.S. Cl...... 514/454 (US) Correspondence Address: KATTEN MUCHIN ROSENMAN LLP (57) ABSTRACT 525 WEST MONROE STREET CHICAGO, IL 60661-3693 (US) The present invention relates to non-psychoactive deriva tives of tetrahydrocannabinol, which are useful in treating (73) Assignee: Indevus Pharmaceuticals, Inc., Lexing interstitial cystitis and relieving symptoms thereof. The ton, MA invention uses (6aR,10aR)-A-tetrahydrocannabinol-11-oic Appl. No.: 11/299,688 acids (hereinafter referred to as (6aR.10aR)-A-THC-11-oic (21) acid), as well as pharmaceutical compositions containing the (22) Filed: Dec. 13, 2005 (6aR.10aR)-A-THC-11-oic acids, for treatment of intersti tial cystitis in a mammal. The invention further covers Related U.S. Application Data methods of formulating and administering the compounds and pharmaceutical compositions as therapeutic agents in (60) Provisional application No. 60/658,578, filed on Mar. the treatment of interstitial cystitis, with particularly pre 7, 2005. Provisional application No. 60/635,005, filed ferred administration routes being oral and via intravesicular on Dec. 13, 2004. instillation.

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PRELIMINARY DOSE-RESPONSE (VOLUME= 0.5 m) (24 HOURS POST TREATMENT) O 0.4 mg/ml Z 5 1.6 mg/ml Fig. 9A P n=2 O O 0.8 mg/ml SS

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TREATMENT OF INTERSTITIAL CYSTITIS b.dpyran-1-ol, hereinafter referred to as A-THC), which is USING (6AR,10AR)- depicted below in Formula II, has indicated that certain DELTA8-TETRAHYDROCANNABNOL-11-OC derivatives of this compound may prove clinically useful. ACDS

CROSS REFERENCE TO RELATED Formula II

APPLICATIONS 0001. This non-provisional application claims the benefit of U.S. Provisional Application Nos. 60/658,578, filed Mar. 7, 2005, and 60/635,005, filed Dec. 13, 2004, the entire disclosures of which are incorporated by reference herein. FIELD OF THE INVENTION 0002 The present invention relates to the treatment of interstitial cystitis using non-psychoactive derivatives of tetrahydrocannabinol, which exhibit anti-inflammatory and 0005) The 11-carboxy derivative of A-THC A-THC analgesic properties. In particular, the present invention 11-oic acid has been reported to be a non-psychoactive, further relates to the use of (6aR.10aR)-A-tetrahydrocan potent antagonist to endogenous platelet activating factor nabinol-11-oic acids, and pharmaceutical compositions and, thus, a useful treatment for PAF-induced disorders, comprising therapeutically effective amounts of the acids, Such as asthma, systemic anaphylaxis, and septic shock. for the treatment of interstitial cystitis. (See U.S. Pat. No. 4,973,603, incorporated herein by refer ence.) Another derivative, (3S4S) more accurately, 6aS, BACKGROUND OF THE INVENTION 10aS-11-hydroxy-A-THC-1'.1' dimethylheptyl, essentially THC Derivatives free of the (3R,4R) more accurately, 6aR, 10aR) form, has been reported to possess analgesic and anti-emetic activities. 0003) A-Tetrahydrocannabinol (THC), depicted below (See U.S. Pat. No. 4,876,276, also incorporated herein by as Formula I under alternate numbering systems, is the major psychoactive constituent of marijuana. reference.) Interstitial Cystitis 0006 Interstitial cystitis (IC) is a chronic pelvic pain disorder that results in recurring discomfort or pain in the bladder and the Surrounding pelvic region. The symptoms of IC vary from case to case and even in the same individual. Patients may experience mild discomfort, pressure, tender ness, or intense pain in the bladder and pelvic area. Symp toms may include an urgent need to urinate and/or frequent need to urinate. The pain may change in intensity as the O O 6 t 3" bladder fills with urine or as it empties. 0007. In IC, the bladder wall may be irritated and become Al-THC scarred or stiff. Glomerulations (pinpoint bleeding caused by recurrent irritation) may appear on the bladder wall. Some people with IC find that their bladders cannot hold much urine, which increases the frequency of urination. Also, people with IC often experience pain during sexual inter COUS. 0008 Because IC symptoms and severity vary greatly, most researchers believe that it encompasses not one, but several, diseases. In the past, cases were mainly categorized as ulcerative IC or nonulcerative IC, based on whether ulcers had formed on the bladder wall. Even today, it is easier to define IC by what it isn’t than by what it is, and to reach a diagnosis of IC, the physician must first rule out bacterial cystitis—the most common urinary tract infection—whose In addition to mood-altering effects, THC has been reported symptoms it most closely resembles. Bladder cancer, kidney to exhibit other activities, some of which may have thera stones, vaginitis, endometriosis, sexually transmitted dis peutic value. The potential therapeutic value of THC has led eases, tuberculosis, and radiation cystitis, as well as prostate to a search for related compounds which, while devoid of infections in men, are some other conditions that must be psychoactive effects, retain the activities of potential medici considered. Thus, IC is a diagnosis of exclusion. nal value. 0009. Although some of the symptoms of IC resemble 0004 Previous work with A-tetrahydrocannabinolóaR, those of a bacterial infection, medical tests reveal no organ 7,10,10aR-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo isms in the urine of patients with IC. Furthermore, patients US 2006/O128794 A1 Jun. 15, 2006

with IC do not respond to antibiotic therapy. Researchers are A measured amount of DMSO is passed through the catheter still working to understand the causes of IC and to find into the bladder, where it is retained for about 15 minutes effective treatments. Some have suggested it may be an before being expelled. Treatments are usually given every autoimmune disorder of the bladder's connective tissue, in week or two for 6 to 8 weeks and repeated as needed. which the body's defense mechanisms against invading Doctors think IVI administration of DMSO works in several bacteria turn Suddenly against healthy tissue. In some ways. Because it passes into the bladder wall, it may reach patients, special white blood cells called mast cells, which tissue more effectively to reduce inflammation and block are associated with inflammation, are found within the pain. It may also prevent muscle contractions that cause bladder's mucous lining. It has also been theorized that the pain, frequency, and urgency. disorder may be an allergic reaction, because many patients 00.15 Pentosan polysulfate sodium (Elmiron(R) was the have a history of allergies. Some scientists have Suggested first oral drug developed for IC to have been approved by the that certain Substances in urine may be irritating to people FDA. In clinical trials, the drug improved symptoms, but its with IC, but no substance unique to people with IC has as yet method of action is unknown. One theory is that it may been isolated. repair defects that might have developed in the lining of the 0010 Another theory is that a bacterium may be present bladder. The FDA-recommended oral dosage of Elmiron is in bladder cells but not detectable through routine urine 100 mg. three times a day. Patients may not feel relief from tests. Researchers are also beginning to explore the possi IC pain for the first 2 to 4 months. A decrease in urinary bility that heredity may play a part in some forms of IC, but frequency may take up to 6 months to achieve. no gene has yet been implicated. One theory holds that the inner lining of the bladder (the glycosaminoglycan or GAG 0016 Other oral medications such as aspirin and ibupro layer) that protects the bladder wall from toxic effects of fen may be used as a first line of defense against mild discomfort. Doctors may recommend other drugs to relieve urine may be “leaky, allowing Substances in the urine to pain. Some patients may experience improvement in their penetrate the bladder wall and trigger IC symptoms. A recent urinary symptoms by taking antidepressants or antihista study found that 70 percent of IC patients they examined had mines. Antidepressants help reduce pain and may also help a “leaky bladder lining. patients deal with the psychological stress that accompanies 0011. There is no cure for IC, and current therapies are living with chronic pain. In patients with severe pain, aimed at trying to relieve the symptoms, which vary from narcotic analgesics such as acetaminophen with codeine or person to person. People may have flare-ups and remissions, longer acting narcotics may be necessary. and different patients respond to different treatments. A particular type of therapy may work for a while and then lose 0017 Transcutaneous electrical nerve stimulation its effectiveness. Sometimes, stress or a change of diet (TENS) involves having mild electric pulses enter the body triggers symptoms. Occasionally, IC goes into remission for minutes to hours two or more times a day, either through spontaneously. Even when symptoms disappear, they may wires placed on the lower back or just above the pubic area, return after days, weeks, months, or years. between the navel and the pubic hair, or through special devices inserted into the vagina in women or into the rectum 0012 Factors that influence the treatment options avail in men. Although scientists do not know exactly how TENS able typically include whether bladder capacity under anes relieves IC pain, it has been suggested that the electrical thesia is great or Small, and whether mast cells are present pulses may increase blood flow to the bladder, strengthen in the tissue of the bladder wall, which may be a sign of an pelvic muscles that help control the bladder, or trigger the allergic or autoimmune reaction. In some cases, the Success release of Substances that block pain. or failure of a treatment helps characterize the type of IC. Some current treatments for IC include bladder distention, 0018 None of the currently used treatments for IC is administration of pharmaceutical compositions by bladder capable of fully relieving the symptoms of IC. Patients instillation (also known as intravesicular instillation (IVI)). frequently combine different treatments in an attempt to oral administration of pharmaceutical compositions, and address all of their IC symptoms. Further, patients usually transcutaneous electrical nerve stimulation. These treatment cannot achieve long term relief using any of these treat options will be described in greater detail below. ments, and once a particular treatment loses its effectiveness, the patient must introduce a new treatment in its place. 0013 Bladder distention is often performed to diagnose Clearly, although numerous treatments have been developed IC, but because many patients have noted an improvement in an attempt to control the symptoms of IC, there is still a in Symptoms after the procedure, it is often thought of as one great need in the art for effective treatments for IC. of the first treatment attempts. Researchers are not sure why distention helps, but some believe that it may increase Description of Related Art capacity and interfere with pain signals transmitted by nerves in the bladder. Symptoms may temporarily worsen 24 0.019 U.S. Pat. No. 5,338,753 discloses (3R,4R)-A- to 48 hours after distention, but should return to predisten THC-7-oic acids (which correspond to (6aR.10aR)-A- tion levels or improve after 2 to 4 weeks. THC-11-oic acids, but were named using an alternative numbering system) that are useful as anti-inflammatory 0014. During bladder instillation or intravesicular instil agents and analgesics, as well as methods of synthesizing lation (IVI), which may also be called a bladder wash or them, but does not disclose compositions or methods for bath, the bladder is filled with a solution that is held for treating patients Suffering from IC. varying periods of time, averaging 10 to 15 minutes, before being emptied. IVI is typically performed using dimethyl 0020 U.S. Pat. Nos. 6,162,829 and 6,355,650 disclose sulfoxide (DMSO, RIMSO-50). DMSO IVI treatment derivatives of (6aR.10aR)-A-THC-11-oic acids that are also involves guiding a catheter up the urethra into the bladder. useful as anti-inflammatory agents and analgesics, and US 2006/O128794 A1 Jun. 15, 2006 methods of synthesizing them. They do not disclose com 0028. According to a second aspect of the present inven positions or methods for treating patients Suffering from IC. tion, unique compositions and methods are provided for a 0021 U.S. Pat. No. 6,448,288 discloses the use of pharmaceutical composition for use in treating interstitial A-THC-11-oic acids to decrease cell proliferation, but fails cystitis in a mammal, particularly humans, including a to disclose compositions or methods for treating patients therapeutically effective amount of a compound having suffering from IC. Formula II 0022 U.S. Published application No. 2004/0054.007 dis closes methods for decreasing cell proliferation using (6aR, Formula II 10aR)-A-THC-11-oic acid, but it also fails to disclose compositions or methods for treating patients suffering from IC. 0023 U.S. Published application No. 2004/0225011 dis closes methods of using cannabinoid compounds that are derivatives of THC to decrease cell proliferation, and does not disclose compositions or methods for treating patients R2 suffering from IC. 2^ 4 0024. The disclosures of each of these patents and pub lished applications are incorporated herein by reference in their entirety. wherein R" is hydrogen, COCH or -COCHCH; and R is a branched C-C alkyl compound, which may option 0025. It is desired, however, to provide a method of ally have a terminal aromatic ring, or optionally a branched treating, alleviating, and/or relieving symptoms associated —OCHCH-(CH2) alkyl compound, which may have a with IC by use of the A-THC-11-oic acid derivatives, such terminal aromatic ring, wherein m is 0 to 7, or a pharma as those described above, as well as pharmaceutical com ceutically acceptable salt, ester or solvate thereof. The positions suitable for Such use. The present invention may pharmaceutical composition may optionally include a thera control the symptoms and improve the quality of life for peutically effective amount of one or more compounds patients suffering from IC and may also reduce the urgency selected from the group consisting of sodium pentosan and frequency associated with urination. polysulfate, antihistamines, antidepressants, imipramine, antispasmodics, urinary anesthetics, and capsaicin. The SUMMARY OF THE INVENTION pharmaceutical composition may also optionally include a 0026. It is an advantage of the present invention to therapeutically effective amount of an anticholinergic agent provide compositions and methods for treating a patient selected from the group consisting of anisotropine, suffering from interstitial cystitis, whereby the (6aR, 10aR)- aprophen, artane, atropine, belladonna, benactyzine, benz A8-THC-1 1-oic acids according to the present invention are tropine, clidinium, dicyclomine, glycopyrrolate, homatro advantageously administered to said patient. pine, hyoscyamine, isopropamide, mepenZolate, methanthe line, methScopolamine, oxybutynin, oxyphencyclimine, 0027 According to a first aspect of the present invention, propantheline, Scopolamine, terodiline, tridihexethyl, trihex unique methods are provided for the treatment of interstitial yphenidyl, and troSpium. cystitis in a mammal using a compound having Formula II 0029. According to a third aspect of the present inven tion, unique compositions and methods are provided for Formula II pharmaceutical composition for use in treating interstitial cystitis in a mammal, including an effective amount of a compound having Formula III

COOH

OH R2 Q 4 wherein R" is hydrogen, COCH or COCHCH; and R is a branched C-C alkyl compound which may option ally have a terminal aromatic ring, or optionally a branched —OCHCH (CH), alkyl compound which may have a terminal aromatic ring, wherein m is 0 to 7. The method or a pharmaceutically acceptable salt, ester or Solvate comprises the steps of identifying a mammal Suffering from thereof. or Suspected of Suffering from interstitial cystitis; and administering to the mammal an effective amount of the 0030. In another aspect of the invention, subjects suffer compound of formula II, or a pharmaceutically acceptable ing from or suspected of suffering from IC are treated by salt, ester, or solvate thereof. administering an effective amount of at least one compound US 2006/O128794 A1 Jun. 15, 2006

selected from the compound of Formula II or III, or a comprise A-THC-11-oic acids and derivatives and analogs pharmaceutically acceptable salt, ester, or Solvate thereof. thereof, as depicted below in Formula II: BRIEF DESCRIPTION OF THE DRAWINGS 0031 Exemplary embodiments of the presently preferred Formula II features of the present invention will now be described with COOH reference to the accompanying drawings. 0032 FIG. 1 is a synthetic scheme for the (6aR,10aR)- A-THC-11-oic acids of the present invention. 0033 FIG. 2 shows cystometrograms relating to Example i. R2 0034 FIG. 3 is a summary of results of Example i. Q 4 0035 FIG. 4 is a summary of results of Example i. expressed as a percent of control. wherein R' is hydrogen, COCH or -COCH2CH: R is 0.036 FIG. 5 is a summary of the numerical results of a branched C-C alkyl compound, which may optionally Example i. have a terminal aromatic ring, or optionally a branched 0037 FIG. 6 shows cystometrograms relating to OCHCH (CH), alkyl compound, which may have a Example j. terminal aromatic ring, wherein m is 0 to 7. 0044 Particularly preferred compounds are obtained 0038 FIG. 7 is a summary of results of Example j. when R' is hydrogen, and R is 1", 1'-dimethylheptyl (IP 0.039 FIG. 8 is a summary of the numerical results of 751). Thus, in this preferred form, the compounds have the Example j. formula shown in Formula III below: 0040 FIGS. 9A-9C show a preliminary dose-response curve, response to acetic acid 24 hours post drug treatment, and response to acetic acid 48 hours post drug treatment. COOH

DETAILED DESCRIPTION OF THE OH PRESENTLY PREFERRED EMBODIMENTS Introduction 0041) The present invention relates to (6aR,10aR)-A- THC-1 1-oic acids, pharmaceutical compositions comprising therapeutically effective amounts of these compounds, and methods of treating IC in a mammal by administering Such compounds or pharmaceutical compositions. The THC derivatives of the present invention have reduced or no 0045. The preferred compounds are also similarly pre psychoactivity and do not bind to the CB1 receptor. A ferred when used in pharmaceutical compositions and for particularly preferred A-THC-11-oic acid analog in accor methods of treating IC by administration of the compounds dance with the present invention is 1", 1'-dimethylheptyl-A- or pharmaceutical compositions according to the invention. THC-11-oic acid (also known as CT3 or ajulemic acid), shown below in Formula III, 0046) The phrase “therapeutically effective amount means that amount of the pharmaceutical composition that provides a therapeutic benefit in the treatment, prevention, COOH or management of interstitial cystitis. 0047 Dosage amounts for the (6aR,10aR)-A-THC-11 OH oic acids according to the present invention, when admin istered orally for the relief of symptoms of IC, are generally between about 1 mg and about 200 mg, preferably between about 10 mg and about 100 mg per day, and more preferably between about 20 mg and about 60 mg per day, administered about 2 to about 4 times daily. As would be understood by one skilled in the art, the dose, and dose frequency, will vary according to the patient’s age, body weight, and therapeutic response, as well as the severity of the condition. 0.042 although use of other THC derivatives in the treat ment of IC is specifically envisioned by the present inven 0048. The orally administered compounds and pharma tion. ceutical compositions according to the present invention may be optionally administered in conjunction with other The Compositions of the Preferred Embodiments existing oral treatments for IC, including, but not limited to, 0043. The present invention relates to compositions and sodium pentosanpolysulfate (Elmiron(R), preferably admin pharmaceuticals useful in relieving symptoms of IC, which istered as about 100 mg three times a day; antihistamines US 2006/O128794 A1 Jun. 15, 2006 such as hydroxizine (Atarax R. Vistaril(R); antidepressants be selected from anisotropine, aprophen, artane, atropine, (for their direct effect on bladder pain fibers) such as belladonna, benactyzine, benztropine, clidinium, dicyclom amitriptyline HCL (Elavil(R), Triavil(R), preferably adminis ine, glycopyrrolate, homatropine, hyoscyamine, isopropam tered as from about 25 mg to about 75 mg daily, or doxepin ide, mepenZolate, methantheline, methScopolamine, oxybu HCL (Sinequan R), preferably administered as about 75 mg tynin, oxyphencyclimine, propantheline, Scopolamine, at bedtime; imipramine (Trazodone(R), preferably adminis terodiline, tridihexethyl, trihexyphenidyl, and trospium. Use tered as about 25 mg three times a day; antispasmodics of other compounds including an anticholinergic action is (AnaspazR), Cystospaz(R), Ditropan R, Levsin(R), LevsineXOR, specifically envisioned by the present invention. Preferably, Urispas(R), UrisedR)); urinary anesthetics such as the anticholinergic agents are administered in a manner phenazopyridine (Pyridium(R), Uristat(R); and capsaicin. consistent with their present use in the treatment of IC. Preferably, they are administered in a manner consistent with their present use in the treatment of IC. 0055. The pharmaceutical compositions of the present invention may include the active ingredients described 0049. The orally administered compounds and pharma above, and may also contain pharmaceutically acceptable ceutical compositions according to the present invention carriers, excipients and the like, and optionally, other thera may be optionally administered in conjunction with existing peutic ingredients. In one embodiment, for example, the treatments for IC that are administered via IVI. drug may be suspended in a vegetable oil. Such as olive oil or peanut oil, and, optionally encapsulated in a gelatin 0050. The compounds and pharmaceutical compositions capsule. For human therapy, the compounds or pharmaceu according to the present invention may also be beneficially tical compositions are preferably administered orally, in the administered as formulations for use in bladder instillation form of a gelatin capsule, or by IVI in the form of a or intravesicular instillation (IVI). Suspension or solution. 0051 Dosage amounts for the (6aR,10aR)-A-THC-11 0056. The term “pharmaceutically acceptable salt” refers oic acids according to the present invention, when admin to a salt prepared from pharmaceutically acceptable non istered via IVI, are generally between about 12.5 and about toxic acids or bases including inorganic or organic acids. 3500 ng/ml exposure within the bladder per administration, Examples of Such inorganic acids are hydrochloric, hydro preferably between about 20 ng/ml exposure to about 2,000 bromic, hydroiodic, Sulfuric, and phosphoric. Appropriate ng/ml exposure within the bladder per administration. More organic acids may be selected, for example, from aliphatic, preferably, the amount of exposure of the patient to the aromatic, carboxylic and Sulfonic classes of organic acids, compounds of interest within the bladder per administration examples of which are formic, acetic, propionic, succinic, ranges from about 50 ng/ml to less than about 1,000 ng/ml. glycolic, glucuronic, maleic, furoic, glutamic, benzoic, Depending on the amount of urine in the bladder, and the anthranilic, Salicylic, phenylacetic, mandelic, embonic instilled volume (usually approximately 25 ml), the dose (pamoic), methanesulfonic, ethanesulfonic, pantothenic, would be less than about 1 mcg to about 100 mcg per benzenesulfonic, Stearic, Sulfanilic, algenic, and galactur administration, preferably less than about 10 mcg to about onic. Examples of Such inorganic bases, for potential salt 50 mcg, more preferably less than about 20 mcg to about 40 formation with sulfate or phosphate compounds of the mcg, administered twice, once or fewer times daily. As invention, include metallic salts made from aluminum, cal would be understood by one skilled in the art, the dose, and cium, lithium, magnesium, potassium, Sodium, and zinc. dose frequency, will vary according to the patient’s age, Appropriate organic bases may be selected, for example, body weight, and therapeutic response, as well as the from N,N-dibenzylethylenediamine, chloroprocaine, cho severity of the condition. line, diethanolamine, ethylenediamine, meglumaine (N-me 0.052 The compounds and pharmaceutical compositions thylglucamine), and procaine. The compounds and pharma according to the present invention may be administered via ceutical compositions of the present invention may be IVI, optionally in conjunction with other existing IVI treat administered in the form of Such pharmaceutically accept ments for the side effects of IC, including, but not limited to, able salts. The compounds of interest may also be admin dimethylsulfoxide (DMSO), heparin, hyaluronic acid, Cys istered in the form of esters, e.g., methyl, ethyl and the like. titat, silver nitrate, chlorpactin, and Bacillus Calmette Solvates of the compounds of interest may also be useful, Guerin (BCG). Other compositions suitable for administra including hydrates and the like. tion via IVI may also be combined with the compositions and pharmaceuticals of the present invention. Preferably, 0057 The compounds and pharmaceutical compositions of the present invention may also be included in formula they are administered in a manner consistent with their tions such as Suspensions, Solutions and elixirs; aerosols; or present use in the treatment of IC. carriers such as starches, Sugars, microcrystalline cellulose, 0053. The compounds and pharmaceutical compositions diluents, granulating agents, lubricants, binders, disintegrat according to the present invention may be administered via ing agents, and the like, in the case of oral Solid preparations IVI, optionally in conjunction with other existing orally (such as powders, capsules, and tablets), with oral Solid administered treatments for the side effects of IC. preparations being preferred over oral liquid preparations. 0054 According to a particularly preferred aspect of the The most preferred oral Solid preparations are capsules. present invention, the compounds and pharmaceutical com 0058 Because of their ease of administration, tablets and positions may optionally be administered in conjunction capsules represent the most advantageous oral dosage unit with an anticholinergic agent. The anticholinergic agent is form, in which case solid pharmaceutical carriers are preferably administered orally or via IVI, although other employed. If desired, tablets may be coated by standard routes of administration are contemplated in accordance aqueous or nonaqueous techniques. Because of the benefits with the present invention. Such anticholinergic agents may of IVI for relieving symptoms of IC, IVI formulations are US 2006/O128794 A1 Jun. 15, 2006 another particularly preferred dosage form, in which case the 0062 Generally, the oral administration methods and compounds and pharmaceutical compositions of the present formulations of the present invention provide between about invention are provided dissolved or Suspended in a pharma 1 mg and about 200 mg per day, preferably between about ceutically acceptable solvent or diluent. 10 mg and about 100 mg per day, and more preferably 0059. In addition to the dosage forms set out above, the between about 20 mg and about 60 mg per day, administered compounds and pharmaceuticals of the present invention about 2 to about 4 times daily, of the (6aR.10aR)-A-THC may also be administered by controlled release means and/or 11-oic acids (i.e., excluding excipients, carriers, and any of delivery devices such as those described in U.S. Pat. Nos. the optional additional active ingredients described herein). 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, If desired, the daily dose may include two or more unit the disclosures of which are hereby incorporated by refer doses, i.e., tablets, cachets or capsules, to be administered CCC. each day. The Methods of the Preferred Embodiments 0063 Dosage amounts for the IVI methods of adminis 0060. The compounds and pharmaceutical compositions tration and formulation of the present invention are gener of the present invention can be used in methods of treating ally between about 12.5 and about 3500 ng/ml exposure mammals suffering from IC, in both veterinary medicine and within the bladder per administration, preferably between human therapy contexts. The method of administering the about 20 ng/ml exposure to about 2,000 ng/ml exposure compounds and pharmaceutical compositions in the acute or within the bladder per administration. More preferably, the chronic management of IC will vary with the severity of the amount of exposure of the patient to the compounds of condition and the route of administration. The dose, and interest within the bladder per administration ranges from perhaps the dose frequency, will also vary according to the about 50 ng/ml to less than about 1,000 ng/ml. Depending on age, body weight, and response of the individual patient. The the amount of urine in the bladder, and the instilled volume actual preferred amounts of the active ingredients adminis (usually approximately 25 ml), the dose would be less than tered will vary with each case, according to the species of about 1 mcg to about 100 mcg per administration, preferably mammal, the nature and severity of affliction being treated, less than about 10 mcg to about 50 mcg, more preferably less and the method of administration. In general, the compounds than about 20 mcg to about 40 mcg, administered twice, and pharmaceutical compositions of the present invention once or fewer times daily. As would be understood by one are periodically administered to an individual patient as skilled in the art, the dose, and dose frequency, will vary necessary to improve symptoms associated with IC. The according to the patient’s age, body weight, and therapeutic length of time during which the compounds and pharma response, as well as the severity of the condition. ceutical compositions are administered and the total dosage 0064. It is further recommended that children, patients will necessarily vary with each case, according to the nature aged over 65 years, and those with impaired renal or hepatic and severity of the IC with which the patient is afflicted, and function initially receive low doses, and that they then be the physical condition of the subject. titrated based on individual response(s) or blood level(s). It 0061 The compounds and pharmaceutical compositions may be necessary to use dosages outside these ranges in may be administered via any appropriate route, e.g. intra Some cases, as will be apparent to those of ordinary skill in venously, intraarterially, topically, by injection, intraperito the art. Further, it is noted that the clinician or treating neally, intrapleurally, orally, Subcutaneously, intramuscu physician will know how and when to interrupt, adjust, or larly, Sublingually, intraepidermally, or rectally. The terminate therapy in conjunction with individual patient preferred methods of administration are orally and via IVI. response. The oral formulations may be solutions, Suspensions, Sup 0065. The methods of the present invention envision the positories, tablets, granules, powders, capsules, ointments, optional inclusion of existing treatments for IC in conjunc or creams. The IVI formulations may be solutions or sus tion with the methods of administration and formulation of pensions, including compositions comprising liposomes. In compounds and pharmaceutical compositions comprising the preparation of the pharmaceuticals, a solvent (e.g., water the (6aR, 10aR)-A-THC-11-oic acids of the present inven or physiological saline), Solubilizing agent (e.g., ethanol, tion. PolySorbates, or Cremophor EL7), agent for making isoto nicity, preservative, antioxidizing agent, excipient (e.g., lac 0066. Also envisioned are methods of administration and tose, starch, crystalline cellulose, mannitol, maltose, calcium formulation that provide for the optional inclusion of anti hydrogen phosphate, light silicic acid anhydride, or calcium cholinergic agents with the administration and formulation carbonate), binder (e.g., starch, polyvinylpyrrolidone, of compounds and pharmaceutical compositions comprising hydroxypropyl cellulose, ethyl cellulose, carboxy methyl the (6aR,10aR)-A-THC-11-oic acids of the present inven cellulose, or gum arabic), lubricant (e.g., magnesium Stear tion. ate, talc, or hardened oils), or stabilizer (e.g., lactose, man 0067. According to an additional embodiment of the nitol, maltose, polysorbates, macrogols, or polyoxyethylene present invention, the methods of administration and for hardened castor oils) can be added. If necessary, glycerin, mulation include the administration and formulation of dimethylacetarnide, 70% sodium lactate, a surfactant, or a compounds and pharmaceutical compositions comprising basic Substance Such as sodium hydroxide, ethylenediamine, the (6aR, 10aR)-A-THC-11-oic acids in accordance with the ethanolamine, Sodium bicarbonate, arginine, meglumine, or present invention, in conjunction with both anticholinergic trisaminomethane is added. Pharmaceutical preparations agents and existing treatments for IC. Such as Solutions, tablets granules or capsules can be formed with these components. Compositions for slow release of the 0068 These methods of administration and formulation compound can be formed as described in U.S. Pat. No. of the present invention are beneficially used to treat symp 4,880,830. toms caused by IC. Preferably, the existing IC treatments US 2006/O128794 A1 Jun. 15, 2006 and/or anticholinergic agents are formulated or co-adminis or tablets, or aerosol sprays, each containing a predeter tered with the (6aR,10aR)-A-THC-11-oic acids in accor mined amount of the active ingredient, as a powder or dance with the present invention in a manner that is con granules, as creams, pastes, gels, or ointments, or as a sistent with their present use in the treatment of IC. Solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid 0069. The optional addition of existing treatments for IC emulsion. Formulations that include micelles are also con to the methods of the present invention may include oral templated. Such compositions may be prepared by any of the administration of sodium pentosanpolysulfate (Elmiron(R), methods of pharmacy, but all methods include the step of preferably administered as about 100 mg three times a day; bringing into association the carrier with the active ingre antihistamines such as hydroxizine (Atarax(R) Vistaril (R): dient which constitutes one or more necessary ingredients. antidepressants (for their direct effect on bladder pain fibers) In general, the compositions are prepared by uniformly and such as amitriptyline HCL (Elavil(R), Triavil(R), preferably intimately admixing the active ingredient with liquid carriers administered as from about 25 mg to about 75 mg daily, or or finely divided solid carriers or both, and then, if neces doxepin HCL (Sinequan R), preferably administered as sary, shaping the product into the desired presentation. about 75 mg at bedtime; imipramine (Trazodone(R), prefer ably administered as about 25 mg three times a day; antis 0073 For example, a tablet may be prepared by com pasmodics (AnaspaZR), CystospaZR), Ditropan R. Levsin(R), pression or molding, optionally, with one or more accessory Levsinex(R), Urispas(R), Urised R); urinary anesthetics such as ingredients. Compressed tablets may be prepared by com phenazopyridine (Pyridium(R), Uristat(R); and capsaicin. pressing in a suitable machine the active ingredient in a Other IC treatments suitable for oral administration may also free-flowing form, Such as powder or granules, optionally be combined with the compounds and pharmaceutical com mixed with a binder (e.g., carboxymethylcellulose, gum positions of the present invention. Where appropriate, these arabic, gelatin), filler (e.g., lactose), adjuvant, flavoring oral IC treatments may be formulated as a single unit dose agent, coloring agent, lubricant, inert diluent, coating mate with the compounds and pharmaceutical compositions of the rial (e.g., wax or plasticizer), and a surface active or dis present invention. When such formulations are not possible persing agent. Molded tablets may be made by molding, in or desirable, these oral IC treatments may be beneficially a Suitable machine, a mixture of the powdered compound co-administered with the compounds and pharmaceutical moistened with an inert liquid diluent. Those skilled in the compositions of the present invention. art will know, or will be able to ascertain with no more than routine experimentation, appropriate pharmacological carri 0070 The optional addition of existing IVI treatments for ers for said pharmaceutical compositions. IC to the methods of the present invention may include administration of IVI formulations of dimethyl sulfoxide 0074. When the compositions and pharmaceuticals (DMSO), heparin, hyaluronic acid, Cystitat, silver nitrate, according to the present invention are administered using the chlorpactin, and Bacillus Calmefte Guerin (BCG). Other IC IVI method, it is preferred that they be provided as disper treatments suitable for administration via IVI may also be sions, Suspensions, or Solutions. combined with the compounds and pharmaceutical compo 0075. The methods of the present invention may com sitions of the present invention. Other IC treatments suitable prise administering to an afflicted individual a compound or for oral administration may also be combined with the pharmaceutical composition comprising an effective amount compounds and pharmaceutical compositions of the present of the (6aR.10aR)-A-THC-11-oic acids of the present invention. Where appropriate, these IVI formulated IC treat invention for use in treating IC, where the compositions are ments may be formulated as a single solution or Suspension provided in a pharmacologically acceptable carrier, for with the compounds and pharmaceutical compositions of the example, a gelatin capsule, or edible oil (e.g., a vegetable present invention. When such formulations are not possible oil) for oral administration; or a pharmaceutical composition or desirable, these IVI formulated IC treatments may be comprising an effective amount of the (6aR.10aR)-A-THC beneficially co-administered with the compounds and phar 11-oic acids of the present invention, which may be option maceutical compositions of the present invention. ally provided in liposomes and Suspended in a sterile Saline 0071 According to a particularly preferred aspect of the solution for IVI administration. present invention, the oral and IVI administration and for 0076. The methods of the present invention include the mulation methods of the present invention may optionally determination of optimum doses of the compounds and include providing an anticholinergic agent in the formula pharmaceutical compositions for treating IC Symptoms, tion, where feasible, or coadministering the anticholinergic which may be determined in consideration of the results of agent with the compounds and pharmaceutical compositions animal experiments. More specific doses obviously vary of the present invention. Such anticholinergic agents may be depending on the administration method, the condition of selected from anisotropine, aprophen, artane, atropine, bel the Subject such as age, body weight, sex, sensitivity, food ladonna, benactyzine, benztropine, clidinium, dicyclomine, eaten, dosage intervals, medicines administered in combi glycopyrrolate, homatropine, hyoscyamine, isopropamide, nation, and the seriousness and degree of the IC. The optimal mepenZolate, methantheline, methScopolamine, oxybutynin, dose and the administration frequency under a given con oxyphencyclimine, propantheline, Scopolamine, terodiline, dition must be determined by the appropriate dosage test of tridihexethyl, trihexyphenidyl, and trospium. Use of other a medical specialist based on the aforementioned guidelines, compounds including an anticholinergic action is specifi and does not constitute undue experimentation for one cally envisioned by the present invention. skilled in the art. 0072 Pharmaceutical compositions for use in the meth EXAMPLES ods of the present invention suitable for oral administration 0077. The invention is further defined by reference to the may be presented as discrete units such as capsules, cachets, following examples describing in detail the preparation of US 2006/O128794 A1 Jun. 15, 2006

the compound and the compositions used in the methods for 49:4735 (1984)), dry pyridine (2.3 mL) followed by chromic treating IC according to the present invention, as well as oxide (1.44 g. 14.4 mmol) was added to a solution of their utility. The examples are representative, and they methylene chloride-DMF (4:1) (36 mL). The mixture was should not be construed to limit the scope of the invention. stirred for fifteen (15) minutes. The primary allylic hydroxy 0078 a. Preparation of Derivatives compound 4a (1.8 g., 3.6 mmol) in methylene chloride-DMF (4:1) (7.2 mL) was added, and the reaction mixture was 0079 The compounds of the present invention may be stirred at room temperature for one (1) hour. Ethanol (1.8 prepared according to the synthetic scheme depicted in FIG. mL) was added, and the mixture was stirred for an additional 1. ten (10) minutes and was then diluted with ethyl acetate (180 0080. In general, melting points were taken in glass mL). The resulting mixture was filtered through a sintered capillary tubes with a Thomas-Hoover Uni-Melt apparatus. glass funnel, packed with silica (3 cm), with a layer of Infrared spectra were recorded on a JASCOA-200 spectro anhydrous sodium sulfate on top, and eluted with ethyl photometer. Rotations were determined on a Perkin-Elmer acetate (ca 600 mL). The ethyl acetate filtrate was washed Model 141 polarimeter in chloroform. Chromatographic with dilute hydrochloric acid (1 N) and then with sodium separations were performed on silica gel columns (Woelm bicarbonate solution and water. After evaporation of the TSC silica, for dry chromatography, activity III/30 mm, No. dried organic solvent, a semisolid compound (5b, 1.7 g. 04530). The high-resolution mass spectrometry (HRMS was 95%) was obtained. Crystallization from pentane gave the performed on a Varian 711 instrument. aldehyde 5b: mp 80-81° C.; W -268 (c 6.82 mg/mL, 0081 b. Synthesis of Compound 4a CHCI), IR 8, 1690 cm (neat); H NMR (CDC1) A 3.82 (1 H, brid, J-15 Hz, C-2 eqH), 6.38 and 6.42 (2 H, s, atom), 0082 In general, this esterification follows the procedure 6.80 (1 H, m, C-6 H), 9.50 (1 H, s, C-7 H). Anal. of Corey and Venkateswarlu (Corey E.J. and Venkateswarlu A. "Protection of Hydroxyl Groups as Tert-Butyldimethyl (CHsOSi) C. H. silyl Derivatives.” J. Am. Chem. Soc. 94:6190 (1972). 0.086 d. Synthesis of (6aR,10aR)-A-THC-DMH-11-oic Compound 1b (2.9 g, 6.17 mmol), W 1152.60 (c 17.2 Acid (3a) m/mL. CHCl), prepared according to Mechoulam et al. (Mechoulam R. et al. “Synthesis of the Individual, Pharma 0087. Following the procedure described by Pellegata et cologically Distinct, Enantiomers of a Tetrahydrocannabinol al. (Pellegata R et al. “An Improved Procedure for the Derivative.” Tetrahydron: Asymmetry 1:315 (1990)), was Synthesis of Oleuropeic Acid.” Synth. Commun. 15:165 dissolved in dry dimethylformamide (DMF) (6 mL). Dim (1985)), sodium chloride (488 mg) was added portionwise ethyl-tert-butylsilyl chloride (1.85g. 12.27 mmol) and imi with vigorous stirring to a mixture of the aldehyde 5b (498 dazole (1.67 g, 24.6 mmol) were added, and the resulting mg, 1 mmol), 2-methyl 2-butene (2.24 mL), Saturated aque mixture was stirred for 48 hours at 38°C. Water (30 mL) was ous potassium dihydrogen phosphate (1.34 mL), and tert added, and the mixture was extracted with ether. After butyl alcohol (22 mL). The reaction mixture was stirred at evaporation of the dried ether layer, an oil (4b, 3.6 g) was room temperature for five (5) hours. Water (20 mL) was obtained: W 153° (c. 24.45 mg/mL, CHCl); IR8 (neat) added, and the mixture was extracted several times with 1725 cm', no free hydroxyl groups were observed; H ethyl acetate, dried, and evaporated to give the crude acid NMR (CDC1) A 3.28 (1 H, brid, J=16 Hz, C-2 eq H), 4.46 which was purified on a silica gel column (10g, elution with (2 H, s, C-7 H), 5.70 (1 H, m, C-6 H), 6.38 (1 H, d. J=1.5 10% ether-petroleum ether) to give the acid 3b (460 mg. HZ, arom), 6.42 (1 H, d. J=1.5 Hz, atom). This oil (com 89%) as an oil: W -2.18° (c. 13.7 mg/mL, CHCl); IR8, pound 4b) was used in the next step with no further 1680 cm and a broad band in the 2800-3600 cm region, purification. "H NMR (CDC1) A 3.75 (1 H, brid, J-18 Hz, C-2 eq H), 0083. A solution of compound 4b (3.2g, 5.5 mmol) in dry 6.23 (1 H, d. J=1.5 Hz, arom), 6.27 (1 H, d, J=1.5 Hz, arom), ether (50 mL) was added under a nitrogen atmosphere to 7.00 (1 H, brd, C-6 H). lithium aluminum hydride (870 mg) in dry ether (60 mL). The resulting mixture was boiled under reflux for 1.5 hours. 0088 Tetrabutylammonium fluoride (0.6 mmol from a After the standard workup (ethyl acetate followed by slow 1.OM solution in THF, Aldrich.) was added by injection addition of a saturated Solution of magnesium Sulfate until a under a nitrogen atmosphere to a cold solution (ice bath) of clear Supernatant was formed), the ether layer was dried and the acid 3b (280 mg. 0.54 mmol) in tetrahydrofuran (THF) evaporated to give an oil (3.2 g). The oil was chromato (3 mL). The resulting solution was stirred at 0.degree. C. for graphed on a silica gel column (100 g), using ether-petro fifteen (15) minutes. Water was added, and the mixture was leum ether (6:4) as eluent, to give the alcohol 4a (8g 67%): extracted several times with ether. The ether layer was dried IV -175° (c. 7.6 mg/M1, CHCl); IR 8, (neat) 3320 and evaporated to give the crude product. The product was cm (OH band), no carbonyl bands; H NMR (CDC1) A further purified by silica gel column with ether-petroleum 3.38 (1 H, brd, J=16 Hz, C-2 eq H), 4.02 (2 H, s, C-7 H), ether (1:1) as eluent. The solid thus obtained (140 mg, 56%) 5.72 (1 H, brd, J=16 Hz, C-2 eq H), 4.02 (2 H, s, C-7 H), was crystallized from acetonitrile to give the acid 3a: mp 5.72 (1 H, brd, C-6 H), 6.36, 6.42 (2 H, s, atom). 112-114°C. (sintering); W -275.degree. (c 3.8 mg/mL, CHCl); IR 8 (Nujol) 1680 cm and a broadband in the 0084 c. Synthesis of Compound 5b 3100-3600 cm region; H NMR (CDC1,) A 3.82 (1 H, br 0085 Following the procedure of Corey and Samuelsson d, J=18 Hz, C-2 eq H), 6.22 (1 H, d. J=18 Hz, C-2 eq H), (Corey E. J. and Samuelsson B. “One Step Conversion of 6.22 (1 H, d. J=1.5 Hz, arom), 6.38 (1 H, d, J=1.5 Hz, arom), Primary Alcohols in the Carbohydrate Series to the Corre 7.16 (1 H, m, C-6, H); m/z 400(M); HRMS calculated for sponding Carboxylic-Tert-Butyl Esters. J. Org. Chem. CHO, 400.2613, found 400.2592. US 2006/O128794 A1 Jun. 15, 2006

0089 e. Synthesis of (6aR,10aR)-A-THC-DMH-11-oic sion (acute model) and administration of cyclophosphamide Acid Acetate (3.c) (subacute model) without affecting bladder contractility. 0090. A solution of acid 3a (100 mg, 0.25 mmol) in These results indicate that (6aR.10aR)-A-tetrahydrocan pyridine (2 mL) and acetic anhydride (1 mL) was stirred nabinol-11-oic acids (and their esters) can Suppress bladder overnight at room temperature. Water (5 mL) was added to nociceptive responses induced by bladder irritation, prob hydrolyze any mixed anhydride formed. The mixture was ably due to suppression of bladder sensory activity. Thus, stirred for two (2) hours and then partitioned between water these compounds can be effective for the treatment of pain and ether. The ether layer was washed with dilute HCl (to and urinary frequency symptoms in patients with painful remove the pyridine) and water. The organic layer was dried bladder syndrome/interstitial cystitis. and evaporated. Pure product was obtained by preparative 0099 i. Acute Bladder Irritation by Acetic Acid (AA) TLC (eluent ether-petroleum ether, 60:40) and crystalliza Infusion tion from pentane. The acetate 3c. 65 mg, melts at 120°-122 C.: W -265° (c 9.0 mg/mL, CHCl); IR8 (Nujol) 1760 0.100 Saline infusion was performed for 1 to 2 hours cm and a broad band in the 3100-3600 cm region; H prior to drug (or vehicle) administration and control CMGs NMR (CDC1,) A 2.30 (3 H, s, OCOCH), 3.38 (1 H, brid, were recorded. Compound 3a (aka CT-3 or IP-751, dissolved J=19 HZ, C-2 eq H), 6.56 (1 H, d. J=1.5 Hz, atom), 6.68 (1 in 30% Cremophor EL saline solution; three concentrations H, d. J=1.5 Hz, arom), 7.18 (1 H, m, C-6, H); HRMS of 1, 3, and 10 mg/kg) or vehicle was administrated intra calculated for CHO 442.2719, found 442.2691. venously when starting infusion of acetic acid solution 0091 f. Preparation of Capsules (0.25%) into the bladder. 0092. A large number of unit capsules are prepared by 0101 Changes in cystometric parameters such as inter filling standard two-piece hard gelatin capsules each with contraction intervals (ICIS), maximum voiding pressure the desired amount of the powdered active ingredient as (MVP), pressure threshold (PT) and baseline pressure (BP) described above, 150 milligrams of lactose, 50 milligrams of were evaluated before and after i.v. administration of Com cellulose, and 6 milligrams magnesium Stearate. The cap Sules may also be prepared to include existing compounds pound 3a or vehicle. useful in treating interstitial cystitis, and/or anticholinergic 0102) In the vehicle group, 0.25% acetic acid infusion agents. induced significant bladder overactivity, as evidenced by a 0093. g. Preparation of Soft Gelatin Capsules reduction in ICIs to 42.9% of the control value. This 0094. A mixture of active ingredient in a digestible oil reduction in ICIS was Suppressed by Compound 3a, prefer Such as Soybean oil, lecithin, cottonseed oil or olive oil is ably at a dose of 10 mg/kg, giving rise to an ICI that was prepared and injected by means of a positive displacement 112.4% of the control value (P<0.05, n=6). Lower doses of pump into gelatin to form soft gelatin capsules containing Compound 3a (1 mg/kg and 3 mg/kg giving rise to ICI the desired amount of the active ingredient. The capsules are values of 45.2% and 51.1% of the control value, respec washed and dried for packaging. The Soft gelatin capsules tively) were less effective. Compound 3a (or its acetate ester, may also be prepared to include existing compounds useful a prodrug of 3a) at a dose of 10 mg/kg is also expected to in treating interstitial cystitis, and/or anticholinergic agents. increase the pressure threshold to 127.2% of the control 0.095 h. Preparation of IVI Formulation value while vehicle, 1 mg/kg, or 3 mg/kg of Compound 3a did not have such increases (87.1%, 74.1%, 94.1% of the 0096] A formulation suitable for administration via intra control value, respectively). No significant changes in MVP vesicular instillation is prepared by dissolving the desired amount of the active ingredient as described above in a and BP were observed. Thus, Compound 3a, preferably at 10 suitable volume of saline. The formulation may also be mg/kg (i.v.), significantly suppressed acetic acid-induced prepared to include existing compounds useful in treating bladder overactivity without affecting bladder contractions interstitial cystitis, and/or anticholineric agents. Preferably, during voiding. The results are shown in FIGS. 2-5. because the active ingredient may be relatively insoluble in water, it may be advantageously incorporated into lipo 0.103 j. Subacute Bladder Irritation by Cyclophospha mide SOS. 0097. The Effects of (6aR,10aR)-A-Tetrahydrocannab 0.104 One day after intraperitoneal injection of cyclo inol-11-oic Acids (and their Esters) on Bladder Overactivity phosphamide (CYP 150 mg/kg), control CMGs were Induced by Acute and Subacute Bladder Irritation in Rats recorded for 1 to 2 hour prior to i.v. administration of 0.098 Cystometrograms (CMGs) were performed under Compound 3a or vehicle. See, example i, above. Following urethane anesthesia (1 g/kg, s.c.) using a catheter inserted administration of Compound 3a, changes in cystometric into the bladder through the bladder dome via a midline parameters such as ICIs, MVP, PT and BP were recorded to abdominal incision. Saline was infused at a rate of 0.04 evaluate the effects of Compound 3a on cyclophosphamide ml/min to elicit repetitive bladder contractions. Effects of induced bladder overactivity. intravenous (i.v.) injection of Compound 3a on bladder overactivity induced by either intravesical administration of 0105 Bladder overactivity indicated by significant ICI acetic acid solution or one day treatment with cyclophos reductions was observed one day after CYP injection. phamide were investigated. As discussed further, below, Administration of Compound 3a at a dose of 10 mg/kg (i.v.) Compound 3a at a preferred dose of 10 mg/kg significantly significantly suppressed CYP-induced bladder overactivity suppressed bladder overactivity induced by acetic acid infu as evidenced by the increment of ICIs to 5.14 min from US 2006/O128794 A1 Jun. 15, 2006

control value (3.65 min) while vehicle did not alter ICIs equivalents to the specific embodiments of the invention (3.89 vs. 3.94 min) in CYP-treated rats. No significant described herein. Such equivalents are intended to be changes were observed in MVP, PT and BP after IP-751 encompassed by the following claims. administration in CYP-treated rats. The results are shown in FIGS. 6-8. 0106 Intravesical Administration of Compound 3a Using What is claimed is: Liposomes as a Delivery Vehicle (Observation Of Biological 1. A method of treating mammals suffering from intersti Activity at 24 Hours and 48 Hours Post-Administration) tial cystitis using a compound having Formula II 0107 Cyclophosphamide (100 mg/kg) was injected intra peritoneally into test rats 12 hours before the start of Formula II transurethral open cystometry under urethane anesthesia. CMGs were recorded while saline was instilled intravesi cally (that is, intravesicularly) for 1 hour. Afterwards, a saline solution of Compound 3a (0.24 mg/ml) entrapped in liposomes was instilled similarly. Comparison of the result ing CMGs revealed a significant reduction in bladder con traction frequency after infusion of the Saline Solution of R2 Compound 3a/liposomal mixture compared with simple Q 4 saline (P<0.01, n=7). 0108 Similarly, instillation of liposomal-Compound 3a wherein R' is hydrogen, COCH or -COCHCHs; R is was first conducted. Then, 24 hours and 48 hours after a branched C-C alkyl compound, which may optionally instillation, under urethane anesthesia, bladder hyperactivity have a terminal aromatic ring, or optionally a branched was induced by infusing acetic acid at the concentration of OCHCH (CH), alkyl compound, which may have a 0.125% and 0.25%. Prior to acetic acid infusion, baseline terminal aromatic ring, wherein m is 0 to 7, or a pharma CMG was conducted by saline infusion (0.04 ml/min) to ceutically acceptable salt, ester, or solvate thereof, the measure intercontraction interval (ICI). A percentage reduc method comprising: tion in ICI was measured following acetic acid infusion as identifying a mammal Suffering from or Suspected of an indicator of bladder irritation. The results, described Suffering from interstitial cystitis; and further below...indicated that the percentage reduction in ICI administering to the mammal an effective amount of the is lower in animals instilled with liposomal-Compound 3a compound of Formula II. 24 hours and 48 hours prior to acetic acid infusion, com pared to the same protocol in the absence of drug (control 2. The method of claim 1, wherein R' is hydrogen. saline and control empty liposome). 3. The method of claim 2, wherein R is a C alkyl. 4. The method of claim 3, wherein the C alkyl is a 0109 ICI reductions in the treatment groups were branched alkyl. approximately 50% lower then those of the control groups 5. The method of claim 4, wherein the branched alkyl is (saline and empty liposome), Suggesting an effective 1,1-dimethylheptyl. response at both the 24-hour and 48-hour time points. See, 6. The method of claim 1, wherein R is a Co alkyl. FIGS. 9B and 9C, respectively. Each group consisted of a 7. The method of claim 6, wherein the C alkyl is a minimum of seven Subjects, except for those of a prelimi branched alkyl. nary dose response study, where two Subjects were used in 8. The method of claim 7, wherein the branched alkyl is each group. The preliminary dose response study indicated 1,1-dimethylheptyl. an optimal Compound 3a dose of 0.8 mg/ml. See, FIG.9A. 9. The method of claim 1, wherein the mammal is a In these experiments, 1.6 mg/ml was highest concentration human. of Compound 3a encapsulated into liposomes; higher con 10. The method of claim 1, wherein the compound is centrations apparently compromised formulation stability. administered orally. 0110 Comparable results are obtained using any of the 11. The method of claim 1, wherein the compound is compounds of the invention including, but not limited to, administered via intravesicular instillation. Compounds 3a, 3b, 3c, 3d, 3e, their prodrugs (e.g., esters) 12. The method of claim 1, wherein the compound is and pharmaceutically acceptable salts or Solvates thereof. administered via an implant. Comparable results are also obtained using other models of 13. The method of claim 12, wherein the implant provides bladder overactivity using irritants including, but not limited slow release of the compound. to, nerve growth factor and protamine Sulfate. 14. The method of claim 1, wherein the compound is administered intravenously. CONCLUSION 15. Use of a compound having Formula II or a pharma ceutically acceptable salt, ester, or solvate thereof for the 0111 Those skilled in the art will recognize, or be able to preparation of a pharmaceutical composition for treating ascertain using no more than routine experimentation, many interstitial cystitis in a mammal, US 2006/O128794 A1 Jun. 15, 2006 11

symptoms of interstitial cystitis selected from the group consisting of sodium pentosanpolysulfate, antihistamines, Formula II antidepressants, imipramine, antispasmodics, urinary anes thetics, capsaicin, DMSO, heparin, hyaluronic acid, Cystitat, silver nitrate, chlorpactin, and BCG. 18. The Use of claim 15 in which the pharmaceutical composition is formulated for oral administration. 19. The Use of claim 15 in which the pharmaceutical composition is formulated for administration via intrave Sicular instillation. 20. Use of a compound having Formula III or a pharma Q 4 ceutically acceptable salt, ester, or solvate thereof for the preparation of a pharmaceutical composition for wherein R' is hydrogen, COCH or -COCHCHs; R is a branched C-C alkyl compound, which may optionally have a terminal aromatic ring, or optionally a branched Formula III —OCHCH (CH), alkyl compound, which may have a COOH terminal aromatic ring, wherein m is 0 to 7. 16. The Use of claim 15 in which the pharmaceutical OH composition further comprises an anticholinergic agent selected from the group consisting of anisotropine, aprophen, artane, atropine, belladonna, benactyzine, benz tropine, clidinium, dicyclomine, glycopyrrolate, homatro pine, hyoscyamine, isopropamide, mepenZolate, methanthe line, methScopolamine, oxybutynin, oxyphencyclimine, propantheline, Scopolamine, terodiline, tridihexethyl, trihex yphenidyl, and trospium. treating interstitial cystitis in a mammal. 17. The Use of claim 15 in which the pharmaceutical composition further comprises an agent useful in relieving k k k k k