Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

• the present invention relates to methods of treatment for irritable bowel syndrome and for nonulcer dyspepsia.
• Tofisopam has been shown in humans to have an activity profile that is significantly different from that of widely used 1,4-benzodiazepine (BZ) anxiolytics such as diazepam (Valium®) and chlordiazepepoxide (Librium®).
• BZ 1,4-benzodiazepine
• the 1,4-benzodiazepines in addition to having sedative-hypnotic activity, also possess muscle relaxant and anticonvulsant properties which, though therapeutically useful in some disease states, are nonetheless potentially untoward side effects.
• the 1,4-benzodiazepines though safe when administered alone, may be dangerous in combination with other CNS drugs, including alcohol.
• Tofisopam in contrast, is a non-sedative anxiolytic that has no appreciable sedative, muscle relaxant or anticonvulsant properties
• Tofisopam improved rather than impaired psychomotor performance and showed no interaction with ethanol (Id.).
• GYKI-52466 and GYKI-53655 act as noncompetitive glutamate antagonists at the AMPA ( ⁇ -amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid) site, and have demonstrated neuroprotective, muscle relaxant and anticonvulsant activity (Id.).
• AMPA ⁇ -amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid
• Another group of 2,3- benzodiazepines that have been investigated are represented by the compound GYKI-52895, and show activity as selective dopamine uptake inhibitors with potential use in antidepressant and anti-Parkinsonism therapy.
• Tofisopam is a racemic mixture of (R)- and (S)- enantiomers. This is due to the asymmetric carbon, i.e., a carbon with four different groups attached, at the 5-position of the benzodiazepine ring.
• the structure and conformational properties of tofisopam have been determined by NMR, CD and x-ray crystallography See Nisy et al, Chirality 1:271-275 (1989), the entire disclosure of which is incorporated herein by reference.
• the 2,3-diazepine ring exists as two different conformers. The major conformers, (+)R and (-)S have the 5-ethyl group in a quasi-equatorial position.
• racemic tofisopam may exist as four molecular species, i.e., two enantiomers, each of which exists in two conformations.
• the sign of the optical rotation is reversed upon inversion of the diazepine ring from one conformer to the other.
• tofisopam exists only as the major conformations, with dextrorotatory tofisopam being of the (R) absolute configuration. See Toth et al., J.
• Tofisopam is metabolized in human, rat, dog, monkey and rabbit to one or more of six major metabolites, depending on the host species: Compound # Compound Name
• IBS Irritable bowel syndrome
• A the presence for at least 12 weeks (not necessarily consecutive) in the preceding 12 months of abdominal discomfort or pain that cannot be explained by structural or biochemical abnormalities, and (B) at least two of the following three (1) pain relieved with defecation; (2) pain, when the onset thereof is associated with a change in the frequency of bowel movements (diarrhea or constipation); and pain, when the onset thereof is associated with a change in the form of the stool (lose, watery, or pellet-like).
• IBS may be divided into four subcategories according to whether the predominant symptom is abdominal pain, diarrhea, constipation, or constipation alternating with diarrhea. Approximately 15 percent of U.S. adults report symptoms that are consistent with the diagnosis of the IBS; the disease affects three times as many women as men. Whether this difference reflects a true predominance of the disorder among women or merely the fact women are more likely to seek medical care has not been determined. IBS is the most common diagnosis made by gastroenterologists in the United States and accounts for 12 percent of visits to primary care providers. It is estimated that only 25 percent of persons with this condition seek medical care for it, and studies suggest that those who seek care are more likely to have behavioral and psychiatric problems than are those who do not seek care.
• IBS in addition, patients with a diagnosis of IBS are at increased risk for other, non-gastrointestinal functional disorders such as fibromyalgia and interstitial cystitis.
• the irritable bowel syndrome accounts for an estimate $8 billion in direct medical costs and $25 billion in indirect costs annually in the United States.
• Nonulcer dyspepsia has been defined as chronic or recurrent upper abdominal pain or discomfort for a period of more than three months' duration, with symptoms present for more than 25 percent of the time, in the absence of another organic cause. See Fisher RS, Parkman HP, “Management of nonulcer dyspepsia,” New Engl J Med 1998; 339: 1376-1381, the entire disclosure of which is incorporated herein by reference.
• Locke "persistent or recurrent upper abdominal pain or discomfort with no structural or biochemical explanation for the patient's symptoms.” See Locke GR, "Nonulcer dyspepsia: what it is and what it is not," Mayo Clin Proc 1999;74:1011-15, the entire disclosure of which is incorporated herein by reference
• NUD may include bloating, nausea, early satiety, eructation and heartburn. It is a symptom complex rather than a specific condition. An organic cause is found in only 40 percent of patients with dyspepsia. The most common causes are gastroduodenal ulcer, GERD, gastroparesis, and gastric cancer. Other causes include cholelithiasis or choledocolithiasis, pancreatitis, carbohydrate malabsorption, intestinal parasites, NSAID or other medication injury, diabetes, thyroid disorders or connective tissue disorders, ischemic bowel, and abdominal cancer.
• the 60 percent of patients without an organic cause are considered to have "nonulcer dyspepsia,” and fall into a continuum of functional gastrointestinal disorders, including irritable bowel syndrome, functional heartburn, and noncardiac chest pain. See Freidman LS., "Helicobacter pylori and Nonulcer Dyspepsia,” New Engl J Med 1998; 339: 1928-30, the entire disclosure of which is incorporated herein by reference.
• NUD has many similarities to IBS. NUD and IBS are usually differentiated by whether the abdominal pain is associated with abnormal bowel habits. If the association is present, the condition is considered to be IBS rather than NUD. Like IBS, the cause of NUD is not well understood. NUD is most likely caused by an alteration in the perception of sensations arising from the gut. Other possible causes of NUD have been investigated, including Helicobacter pylori infection (a bacterial infection in the stomach that is associated with ulcer disease), and an alteration in the function of the stomach, resulting in a delayed emptying of the stomach contents. About 25-50% of patients with NUD have slowed emptying from the stomach which may, in part, explain the increased symptoms after meals.
• New agents are needed which are useful in the treatment of IBS and NUD.
• agents are needed that are appropriate for chronic long-term use in treatment and prevention these chronic disorders.
• a method of treating or preventing IBS or NUD comprising administering to an individual in need of such treatment an effective amount of at least one compound according to formula I:
• R 1 is -(C ⁇ -C 7 )hydrocarbyl or -(C 2 -C 6 )heteroalkyl;
• R 2 is -H or -(C ⁇ -C )hydrocarbyl; wherein R 1 and R 2 may combine to form a carbocyclic or heterocyclic 5- or 6-membered ring; and one of R 3 , R 4 , R 5 or R 6 (hereinafter, collectively "phenyl ring substituents”) is -OH, and the remaining phenyl ring substituents are independently selected from the group consisting of -(C ⁇ -C )hydrocarbyl, -CF 3 , -O(C 1 -C 7 )hydrocarbyl, -O-acyl, -NH 2 , -NH(C ⁇ -C 6 )alkyl, -N((C ⁇ -C 6 )alkyl) 2 , - NH-acyl and halogen, wherein R 5 and R 6 may combine to form a 5, 6- or 7- membered heterocyclic ring; and wherein the carbon-carbon single bond designated by rLn -
• At least one compound according to formula I is used in the preparation of a medicament for treating or preventing IBS or NUD.
• one of R 3 or R 4 is -OH, and the other phenyl ring substituents are independently selected from the group consisting of -(C ⁇ -C )hydrocarbyl, -CF 3 , -O(C ⁇ -
• one of R 3 or R 4 is -OH
• one or two of the other phenyl ring substituents is -OCH 3
• the other phenyl ring substituent(s) are independently selected from the group consisting of -(C ⁇ -C )hydrocarbyl, -CF 3 , -O(C ⁇ -C 7 )hydrocarbyl, -O-acyl,
• one phenyl ring substituent is -OH, and the other phenyl ring substituents are independently selected from -O(C ⁇ -C 7 )hydrocarbyl.
• one phenyl ring substituent is -OH, and the other phenyl ring substituents are independently selected from -O(C ⁇ -C 7 )alkyl.
• one phenyl ring substituent is -OH, and the other phenyl ring substituents are -OCH 3
• the phenyl ring substituent which is -OH in the third, fourth and fifth sub-embodiments is R 3 or R 4 .
• R 1 and R 2 are independently selected from -(C ⁇ -C )alkyl, preferably, -(C ⁇ -C 3 )alkyl. In a preferred sub-
• R is -CH 2 CH 3 and R is -CH .
• Preferred compounds for use in the practice of the invention are selected from the group consisting of: l-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H- 2,3-benzodiazepine; l-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-
• More preferred compounds for use in the practice of the invention are selected from the group consisting of: l-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H- 2,3-benzodiazepine; l-(3-methoxy-4-hydroxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H- 2,3-benzodiazepine; or pharmaceutically-acceptable salts thereof.
• irritable bowel syndrome refers to a disorder, often recurrent, characterized by abnormally increased motility of the small and large intestines, producing abdominal pain, constipation, or diarrhea.
• nucle dyspepsia refers to a disorder manifesting chronic or recurrent upper abdominal pain or discomfort for a period of more than three months' duration, with symptoms present for more than 25 percent of the time, in the absence of another organic cause.
• the alkyl portion is preferably (C ⁇ -C 6 )alkyl, more preferably (C ⁇ -C )alkyl.
• the R is hydrocarbyl, it is preferably (C ⁇ -C )hydrocarbyl.
• R is hydrocarbyl, it is preferably alkyl, more preferably (C ⁇ -C 6 )alkyl.
• alkyl by itself or as part of another substituent means, unless otherwise stated, a straight, branched or cyclic chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. C ⁇ -C 6 means one to six carbons).
• Alkyl groups include straight chain, branched chain or cyclic groups, with straight being preferred. Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclohexyl and cyclopropylmethyl. (C ⁇ -C 6 ) Alkyl is preferred.
• (C ⁇ -C 3 )alkyl particularly ethyl, methyl and isopropyl.
• alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• Preferred is (C ⁇ -C 6 )alkoxy. More preferred is (C ⁇ -C 3 )alkoxy, particularly ethoxy and methoxy.
• amine refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical, or wherein R and R' combined form a heterocycle.
• amino groups include: -NH 2 , methyl amino, diethyl amino, anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl.
• Preferred hydrocarbyl radicals are (C ⁇ -C 7 )hydrocarbyl radicals.
• hydrocarbyl radicals that are alkyl radicals. More preferred is (C ⁇ -C 6 )alkyl.
• aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (4n + 2) delocalized ⁇ (pi) electrons).
• aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl; anthracyl; and naphthyl.
• hydrocarbyl refers to any moiety comprising only hydrogen and carbon atoms. This definition includes for example alkyl, alkenyl, alkynyl, aryl and benzyl groups. Preferred are (C ⁇ -C 7 )hydrocarbyl.
• heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S. Nitrogen and sulfur atoms may be optionally oxidized to the N-oxide and sulfoxide or sulfone, respectively. In addition, a nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
• heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or -CH 2 -CH 2 -S-S-CH 3 . More preferred are heteroalkyl groups containing one or two oxygen atoms.
• a carbocyclic ring is preferably saturated.
• Preferred heterocyclic rings are saturated rings containing one or two heteroatoms selected from N, O and S.
• Heterocyclic rings annulated to the benzodiazepine seven- membered ring in this way include, for example, furan, dihydrofuran, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran, thiophene, dihydrothiophene, tetrahydrothiophene, pyrrole, dihydropyrrole, pyrrolidine, pyridine, dihydropyridine, tetrahydropyridine and piperidine.
• heterocyclic rings are 5- or 6-membered rings containing one or two heteroatoms selected from N, O and S. More preferred are heterocyclic rings containing one heteroatom selected from N, O and S.
• Heterocyclic rings annulated to the benzodiazepine phenyl ring in this way include, for example, furan, dihydrofuran, dioxane, dioxolane, pyran, dihydropyran, tetrahydropyran, thiophene, dihydrothiophene, pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyrrole, dihydropyrrole, imidazole, dihydroimidazole, thiazole, dihydrothiazole, oxazole, and dihydrooxazole.
• substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
• substituted refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
• the substituents are independently selected, and substitution may be at any chemically accessible position.
• optically active refers to a property whereby a material rotates the plane of plane-polarized light.
• a compound that is optically active is nonsuperimposable on its mirror image.
• the property of nonsuperimposablity of an object on its mirror image is called chirality.
• the property of "chirality" in a molecule may arise from any structural feature that makes the molecule nonsuperimposable on its mirror image.
• the most common structural feature producing chirality is an asymmetric carbon atom, i.e., a carbon atom having four nonequivalent groups attached thereto.
• enantiomer refers to each of the two nonsuperimposable isomers of a pure compound that is optically active. Single enantiomers are designated according to the Cahn-Ingold-Prelog system, a set of priority rules that rank the four groups attached to an asymmetric carbon. See March,
• the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S).
• R the descending rank order of the other groups
• S the descending rank of the other groups proceeds counterclockwise
• the molecule is designated (S).
• racemate or the phrase “racemic mixture” refers to a 50-50 mixture of two enantiomers such that the mixture does not rotate plane- polarized light.
• (R)-enantiomer substantially free of the (S)-enantiomer is meant a compound of formula I that comprises 80% or more by weight of the (R)- enantiomer and likewise contains 20% or less of the (S)-enantiomer as a contaminant, by weight.
• (S)-enantiomer substantially free of the (R)-enantiomer is meant a compound of formula I that comprises 80% or more by weight of the (S)-enantiomer and likewise contains 20% or less of the (R)- enantiomer as a contaminant, by weight.
• an effective amount when used to describe the amount of drug administered to a patient suffering from irritable bowel syndrome, refers to the amount of a compound that prevents or alleviates the symptoms of IBS, when administered to a patient suffering from a disorder which manifests chronic or acute symptoms of IBS.
• an "effective amount" of the compound when used to describe the amount of drug administered to a patient suffering from nonulcer dyspepsia refers to the amount of a compound that prevents or alleviates the symptoms of
• NUD when administered to a patient suffering from a disorder which manifests chronic or acute symptoms of NUD.
• the term "individual” or “subject” includes human beings and non- human animals. With respect to the disclosed methods of treating IBS and NUD, these terms refer, unless the context indicates otherwise, to an organism that is afflicted with or diagnosed with such a disorder. With respect to disclosed methods of "preventing” or “delaying the onset” of IBS or NUD, these terms refer unless the context indicates otherwise, to an organism that has a medical history of IBS or NUD that manifests as a recurrent disorder.
• compounds of formula I, and pharmaceutically acceptable salts thereof are useful in methods of treatment or prevention of irritable bowel syndrome or nonulcer dyspepsia.
• Compounds used in the methods of the present invention that comprise substantially isolated enantiomers preferably have a composition that is 85% by weight or greater of the desired enantiomer, and 15% by weight, or less, of the other enantiomer. More preferably, compounds used in methods of the present invention have a composition that is 90% by weight or greater of the desired enantiomer and 10% by weight, or less, of the other enantiomer. More preferably, compounds used in the methods of the present invention have a composition that is 95% by weight or greater of the desired enantiomer and 5% by weight, or less, of the other enantiomer. Most preferably, compounds used in the methods of the present invention have a composition that is 99% by weight or greater of the desired enantiomer and 1% by weight, or less, of the other enantiomer.
• the compounds of formula I useful in the methods of the present invention may be prepared by one of several methods. These methods generally follow the synthetic strategies and procedures used in the synthesis of 2,3- benzodiazepines such as tofisopam and tofisopam analogs. See U.S. Patent Nos. 3,736,315 and 4,423,044 (tofisopam syntheses) and Horvath et al, Progress in Neurobiology 60(2000) p.309-342 and references cited therein (preparation of tofisopam and analogs thereof), the disclosures of which are incorporated herein by reference. In the synthesis methods that follow, the products of the chemical synthesis are racemic compounds of formula I.
• the racemic mixture may be subsequently separated using known methods of resolution to produce the (R)- enantiomer substantially free of the corresponding (S)-enantiomer, and the (S)- enantiomer substantially free of the corresponding (R)-enantiomer.
• 2,3-Benzodiazepines of formula I may be synthesized from the corresponding 2-benzopyrilium salt H by reaction with hydrazine hydrate, wherein X " is a counterion such as, for example perchlorate:
• hydrazine hydrate (98%, approximately 3 equivalents based on the 2-benzopyrylium salt) is added dropwise to a stirred solution of the 2-benzopyrylium salt H in glacial acetic acid (approximately lmL/3rnmol of 2- benzopyrylium salt).
• the solution is maintained at an elevated temperature, preferably, 80-100°C.
• the solution is then maintained a higher elevated temperature, preferably 95-100°C, for about one hour.
• the reaction mixture is diluted with 2% aqueous sodium hydroxide solution (approximately 3 equivalents based on the 2-benzopyrylium salt) and cooled.
• the product 2,3 -benzodiazepine separates as a solid and is removed by filtration, washed with water and dried.
• the crude product may be purified by taking it up in a polar aprotic solvent such as dimethylformamide (DMF) at an elevated temperature, preferably 100-130°C, and decolorizing the solution with activated carbon. The carbon is removed by filtration and the filtered solution is diluted with water. The purified product precipitates out of the solution and is collected by filtration.
• a polar aprotic solvent such as dimethylformamide (DMF)
• intermediate benzopyrilium salt, H may be prepared from one of several starting materials. According to one such method, illustrated in Scheme 1, intermediate H is prepared from the corresponding aryl ethanol derivative D via the isochroman intermediate F; wherein X " is a counterion such as, for example, perchlorate:
• the ⁇ -substituted benzyl alcohol, B is taken up in a high boiling solvent such as toluene and a catalytic amount of para-toluene sulfonic acid (p-TsOH).
• p-TsOH para-toluene sulfonic acid
• the mixture is warmed to reflux and may be monitored for disappearance of starting materials.
• the volatiles are removed in vacuo and the crude product C is purified by column chromatography.
• the substituted styrene, C is hydroxylated under anti-Markovnikov conditions to give intermediate phenylethyl alcohol D.
• a solution of D, and of a substituted benzaldehyde, E (1.2 eq) are dissolved in anhydrous dioxane.
• the resulting solution is then saturated with gaseous HC1 and warmed, preferably to reflux temperature for about one hour.
• the mixture is then cooled to room temperature, poured into water, basified, preferably with aqueous sodium hydroxide and extracted with an organic solvent, preferably ethyl acetate.
• the extract is dried, filtered and concentrated under vacuum.
• the resulting residue is purified, preferably by crystallization to yield F.
• the aqueous alkaline fraction is then acidified, preferably with dilute aqueous hydrochloric acid and extracted with an organic solvent, preferably, chloroform.
• the chloroform extract is dried, filtered and concentrated under vacuum to give G.
• the crude residue may further be purified by column chromatography.
• the 2- ⁇ -acyl hydrocarbylbenzophenone, G (5g) is dissolved in glacial acetic acid (15mL). To this mixture is added 60% perchloric acid (7.5mL). The resulting mixture is warmed to 100°C (steam bath) for three minutes. The mixture is allowed to cool to room temperature. Crystallization of the crude product may begin spontaneously at this point or may be induced by addition to the reaction mixture of ether or ethyl acetate. The product 2-benzopyrylium salt H is removed by filtration and purified by recrystallization, preferably from ethanol or glacial acetic acid/ethyl acetate. A synthetic sequence, similar to that outlined above, for preparation of
• 2,3-benzodiazepines is disclosed in US Patent 3,736,315, the entire disclosure of which is incorporated herein by reference. Synthetic strategies for preparation of 2,3-benzodiazepines are also disclosed in Horvath et al, Progress in Neurobiology 60(2000) p309-342 and references cited therein; the entire disclosures of which are incorporated herein by reference.
• Racemic compounds of formula I may be converted to the (S)- dibenzoyltartaric acid salt, which is a diastereomeric mixture of SS and RS configurations.
• the pair of diastereomers (R,S) and (S,S) possess different properties, e.g., differential solubilities, that allow for the use of conventional separation methods. Fractional crystallization of diastereomeric salts from a suitable solvent is one such separation method. This resolution has been successfully applied to the resolution of racemic tofisopam. See Hungarian Patent 178516 and also Toth et al, J. Heterocyclic Chem., 20:09-713 (1983), the entire disclosures of which are incorporated herein by reference.
• racemic compounds of formula I may be derivatized via, for example, acylation of the aromatic hydroxy moiety with a chiral acylating reagent such as, for example, (S)-mandelic acid.
• a chiral acylating reagent such as, for example, (S)-mandelic acid.
• the resulting ester has a second chiral center, and thus exists as a diastereomeric pair separable using conventional methods such as crystallization or chromatography.
• the chiral moiety with which the compound was derivatized may be removed.
• Racemic compounds of formula I may be separated without diastereomer formation by differential absorption on a chiral stationary phase of a chromatography column, particularly a preparative HPLC column.
• Chiral HPLC columns are commercially available with a variety of packing materials to suit a broad range of separation applications.
• Exemplary stationary phases suitable for resolving the racemic 2,3-benzodiazepines include:
• macrocyclic glycopeptides such as silica-bonded vancomycin which contains 18 chiral centers surrounding three pockets or cavities;
• Chiral ⁇ i-acid glycoprotein is a highly stable protein immobilized onto spherical silica particles that tolerates high concentrations of organic solvents, high and low pH, and high temperatures.
• Human serum albumin though especially suited for the resolution of weak and strong acids, zwitterionic and nonprotolytic compounds, has been used to resolve basic compounds.
• CBH is a very stable enzyme that has been immobilized onto spherical silica particles and is preferentially used for the separation of enantiomers of basic drugs from many compound classes.
• the Chirobiotic NTM column is available in a semi-preparative size as employed for the above separation 500mm x 10mm).
• the stationary phase of the Chirobiotic NTM column is commercially available in bulk for packing of preparative chromatography columns with larger sample capacity.
• 2,3-benzodiazepines of formula I also exist in two stable conformations that may be assumed by the benzodiazepine ring as generally depicted below.
• the compound used in the compositions and methods of the present invention may take the form of a pharmaceutically-acceptable salt.
• salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
• pharmaceutically-acceptable salt refers to salts that possess toxicity profiles within a range so as to have utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in a synthetic process or in the process of resolving enantiomers from a racemic mixture.
• Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
• organic acids examples include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
• Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,
• Suitable pharmaceutically acceptable base addition salts of compounds of formula I include for example, metallic salts made from calcium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethylenediamine, chloroprocaine, choline. diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of formula I by reacting, for example, the appropriate acid or base with the compound of formula I.
• the compounds useful in the methods of the invention may be administered to individuals (mammals, including animals and humans) afflicted with IBS or NUD.
• the specific dose of a compound of formula I, or a substantially isolated enantiomer thereof to obtain therapeutic benefit will, of course, be determined by the particular circumstances of the individual patient including, the size, weight, age and sex of the patient. Also determinative will be the nature and stage of the disease and the route of administration. For example, a daily dosage of from about 100 to 1500 mg/kg/day may be utilized. Preferably, a daily dosage of from about 100 to 1000 mg/kg/day may be utilized. More preferably, a daily dosage of from about 100 to 500 mg/kg/day may be utilized. Higher or lower doses are also contemplated.
• the compound For prophylactic administration, the compound should be administered far enough in advance of a recurrence of symptoms such that the compound is able to reach the site of action in sufficient concentration to exert a therapeutic effect.
• the pharmacokinetics of specific compounds may be determined by means known in the art and tissue levels of a compound in a particular individual may be determined by conventional analyses.
• the compound may be administered in the form of a pharmaceutical composition comprising at least one compound of formula I in combination with a pharmaceutically acceptable carrier.
• the active ingredient in such formulations may comprise from 0.1 to 99.99 weight percent.
• pharmaceutically acceptable carrier is meant any carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient.
• the compound may be administered for therapeutic effect by any route, for example enteral (e.g., oral, rectal, intranasal, etc.) and parenteral administration.
• Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intravaginal, intravesical (e.g., into the bladder), intradermal, topical or subcutaneous administration.
• Also contemplated within the scope of the invention is the instillation of drug in the body of the patient in a controlled formulation, with systemic or local release of the drug to occur at a later time.
• the compound may optionally be localized in a depot for controlled or sustained release to the circulation, or controlled or sustained release to a local site such as for example the gastrointestinal tract or a portion thereof.
• the pharmaceutically acceptable carrier is selected on the basis of the selected route of administration and standard pharmaceutical practice.
• the active agent may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington 's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, PA. Suitable dosage forms may comprise, for example, tablets, capsules, solutions, parenteral solutions, troches, suppositories, or suspensions.
• the active agent may be mixed with a suitable carrier or diluent such as water, an oil (particularly a vegetable oil), ethanol, saline solution, aqueous dextrose (glucose) and related sugar solutions, glycerol, or a glycol such as propylene glycol or polyethylene glycol.
• a suitable carrier or diluent such as water, an oil (particularly a vegetable oil), ethanol, saline solution, aqueous dextrose (glucose) and related sugar solutions, glycerol, or a glycol such as propylene glycol or polyethylene glycol.
• Solutions for parenteral administration preferably contain a water-soluble salt of the active agent.
• Stabilizing agents, antioxidizing agents and preservatives may also be added. Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA.
• Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
• the composition for parenteral administration may take the form of an aqueous or nonaqueous solution, dispersion, suspension or emulsion.
• the active agent may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules or other suitable oral dosage forms.
• the active agent may be combined with at least one excipient such as fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents absorbents or lubricating agents.
• the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods.
• the compositions useful in the methods of the present invention may also be formulated so as to provide slow or controUed-release of the active ingredient therein.
• a controlled-release preparation is a composition capable of releasing the active ingredient at the required rate to maintain constant pharmacological activity for a desirable period of time.
• dosage forms may provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than other non-controlled formulations .
• U.S. Patent No. 5,674,533 discloses controlled-release compositions in liquid dosage forms for the administration of moguisteine, a potent peripheral antitussive.
• U.S. Patent No. 5,059,595 describes the controlled-release of active agents by the use of a gastro-resistant tablet for the therapy of organic mental disturbances.
• U.S. Patent No. 5, 591,767 discloses a liquid reservoir transdermal patch for the controlled administration of ketorolac, a non-steroidal anti-inflammatory agent with potent analgesic properties.
• U.S. Patent No. 5,120,548 discloses a controlled-release drug delivery device comprised of swellable polymers.
• U.S. Patent No. 5,639,476 discloses a stable solid controlled-release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer. The patents cited above are incorporated herein by reference.
• Biodegradable microparticles may be used in the controlled-release formulations of this invention.
• U.S. Patent No. 5,354,566 discloses a controlled-release powder that contains the active ingredient.
• U.S. Patent No. 5,733,566 describes the use of polymeric microparticles that release antiparasitic compositions. These patents are incorporated herein by reference.
• controlled-release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. Narious mechanisms of drug release exist.
• the controlled-release component can swell and form porous openings large enough to release the active ingredient after administration to a patient.
• controlled-release component in the context of the present invention is defined herein as a compound or compounds, such as polymers, polymer matrices, gels, permeable membranes, liposomes and/or microspheres, that facilitate the controlled-release of the compound of formula I in the pharmaceutical composition.
• the controlled-release component may be biodegradable, induced by exposure to the aqueous environment, pH, temperature, or enzymes in the body.
• sol-gels may be used, wherein the active ingredient is incorporated into a sol-gel matrix that is a solid at room temperature. This matrix is implanted into a patient, preferably a mammal, having a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing the active ingredient into the patient.
• Racemic-l-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H- 2,3-benzodiazepine was synthesized according to the route of Scheme 2.
• Elemental analysis (calculated/analysis): %C - 68.09/68.08; %H - 6.61/6.57; N - 7.53/7.35. Calculated values include 0.02 equivalents of ethyl acetate and 0.09 equivalents of residual water.
• DSC Differential scanning calorimetry
• Racemic-l-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8- dimethoxy-5H-2,3 -benzodiazepine is loaded onto a semipreparative (500mm x 10mm) Chirobiotic V column (ASTEC, Whippany, NJ). Elution of the enantiomeric mixture with methyl-tert-butyl ether/ acetonitrile (90/10 N/N), at a flow rate of 40mL/min, is monitored at 310nm. Fraction size is 10-20 mL and fractions are subjected to analytical chromatography using the same solvent composition on an analytical (150 x 4.6mm) Chirobiotic N column. The fractions containing each isolated enantiomer are processed by removing the elution solvent in vacuo.
• Example 4 Colonic Propulsion Study in the Mouse This model is predictive of agents that may be used to treat the alterations in propulsion of intestinal contents that occur in individuals diagnosed with IBS.
• the model is very sensitive to test compounds producing inhibitory effects on propulsive motor activity, but is not sensitive to test articles increasing colonic propulsive motility.
• the model provides a direct measure of colonic propulsion.
• a test compound that slows the rate at which a glass bead is expelled is predicted to have utility in the treatment of IBS.
• This test is also used to evaluate test articles with potential to produce constipation, antidiarrheal activity, or have selective visceral anti-nociceptive activity in addition to being used as an animal model for irritable bowel syndrome.
• test animals female, 6 week old Swiss Webster mice, 18-30g
• 7 groups of 10 animals each for administration of six test compounds and vehicle alone as a control.
• IP IP-dosed
• a 3mm glass bead was inserted through the anus to a depth of 2cm into the distal colon using a glass rod.
• the test animals were observed for expulsion of the bead and the time was noted. Any test animal that had not expelled the bead within a cut-off time of 30 minutes was sacrificed and the position of the bead in the lumen of the colon was verified.
• test animals were observed for signs of gross toxicity and/or behavioral changes during the 60-90 minute interval after dosing. Such observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behavioral patterns. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, sleep and coma. No signs of gross toxicity were observed. Mean and standard error of the mean were calculated for the expulsion times for each group. The data are summarized in Table 1 below.

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