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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/82—Carbazoles; Hydrogenated carbazoles
  • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

• This invention is in the fields of antiinflammator and anticancer pharmaceutical agents and specifically relates to compounds, compositions and methods for treating infl.ammation and inflammation-associated disorders, such as arthritis and for treating colorectal cancer.
• Prostaglandins have been shown to be involved in the pathophysiology of .several chronic human diseases. They are involved as mediators of pain, edema and vascular permeability in arthritic diseases such as rheumatoid arthritis and osteoarthritis (Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)). In .addition, prostaglandins have been postulated to be involved in the pathophysiology of colorectal cancer (Marcus, New Eng. J. Med. , 333, 656-657 (1995)). Thus an agent that inhibits prostaglandin synthesis may be useful in treating these disorders.
• prostaglandins were previously thought to be due to the action of a single cyclooxygenase enzyme on arachidonic acid to afford prostaglandin H 2 (Vane et al, Postgrad. Med. J. , 66 (Suppl 4), S2-S 17 (1990), Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)).
• This intermediate is subsequently transformed into the various members of the prostaglandin family by more distal enzymes.
• cyclooxygenase inhibitors (often called NSAIDs: nonsteroidal antiinflammatory drugs) is well established in arthritic disorders (Brooks et al, New Eng. J. Med.
• COX-2 enzyme has been shown to be upregulated in colorectal cancer and a selective COX-2 inhibitor may also be of use in this disease (Sano et. al., Cancer Res., 55, 3785-3789 (1995)).
• indomethacin a relatively non-selective inhibitor of COX -2 with adverse G.I. side effects, has been shown to be useful in the treatment of Alzheimer's disease (Rogers et. al., Neurology, 43, 1609-1611 (1993)) which suggests that a COX-2 selective inhibitor would be not only useful for the treatment of Alzheimer's disease but also a safer therapy with fewer G.I. side effects.
• Humber et al have described the 10 step synthesis of the 4-oxo analog of the l,3,4,9-tetrahydro ⁇ yrano[3,4-b]indole, etodolac ⁇ JMed. Chem. 31 , 1712-1719 (1988); U.S. Pat. No. 4,686,213).
• the 4-oxo metabolite was active in blocking prostaglandin synthesis and had oral in vivo antiinflammatory activity.
• COX-2 inhibitors which are useful as antiarthritic, anticancer and antiAlzheimers agents of formula I:
• Rl, R2, R3 and R4 are, each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, aralkoxy of 7 to 12 carbon atoms, trifluoroalkoxy, alkanoyloxy of 2-6 carbon atoms, hydroxy, halo, trifluoromethyl, cyano, amino, mono- or di-alkylamino in which each alkyl group has 1-6 carbon atoms, alkylmido of 2-6 carbon atoms, or alkyl sulfonamido of 1-6 carbon atoms;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkoxyalkyl in which each alkyl moiety has 1-6 carbon atoms or alkylcycloalkyl in which the alkyl moiety has 1-6 carbon atoms and
• A is oxygen or NZ
• Z is hydroxyl, alkoxy, aryloxy, carboxyalkyloxy of 2-7 carbon atoms, arylamino, or alkylsulfonyamino of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
• This invention provides both the R and S stereoisomers of the C-1 .alkanoic acid, as well as to mixtures of the R and S stereoisomers.
• the n.ame of the product of this invention where the absolute configuration of the C-1 alkanoic acid is not indicated, is intended to embrace both R and S enantiomers as well as mixtures of the two.
• alkyl, alkenyl, and alkynyl include both straight chain as well as branched moieties.
• halo includes fluorine, chlorine, bromine, and iodine.
• the aryl moiety is a phenyl group which may be optionally mono-, di-, or tri-substituted with a substituent or substituents such as alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halogen, nitro, carboidkoxy of 2-7 carbon atoms, -CF 3 , -OCF 3 , -OCH 2 CF 3 , amino, dialkylamino of 1-6 carbons per alkyl group, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, SO3H, PO3H, and CO H.
• a substituent or substituents such as alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halogen, nitro, carboidkoxy of 2-7 carbon
• Preferred compounds of this invention include those in which R5 is hydrogen; those in which Rg is hydrogen and R5 is alkyl of 1-6 carbon atoms, alkenyl of 1-6 carbon atoms, or alkoxyalkyl in which each alkyl moiety has 1-6 carbon atoms; those in which Rg is hydrogen, R5 is .alkyl of 1-6 carbon atoms, alkenyl of 1-6 carbon atoms, or alkoxyalkyl in which each alkyl moiety has 1-6 carbon atoms, and A is oxygen: and those in which R6 is hydrogen, R5 is alkyl of 1-6 carbon atoms, alkenyl of 1-6 carbon atoms, or alkoxyalkyl in which each alkyl moiety has 1-6 carbon atoms, X is CH 2 or oxygen .and A is NZ where Z is OH or NHSO 2 alkyl in which each alkyl moiety has 1-6 carbon atoms .
• the pharmaceutically acceptable salts include those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids.
• Carboxylate salts preferably alkali metal salts, for example, sodium or lithium, may also be prepared as salts of carboxylic acids where R ⁇ is hydrogen.
• R,, R 2 , R 3 , R 4 , R s , R 6 and X are as defined above or a salt thereof so as to prepare a compound having the formula I as illustrated above in which A is oxygen and R,, R j , R 3 , R 4 , R 5 , R 6 and X are as defined above or a salt thereof; or
• R,, R 2 , R 3 , R 4 , R 5 and X are as defined above and R 6 is alkyl of 1-6 carbon atoms or alkenyl of 2-7 carbon atoms so as to form a compound having formula I as illustrated above where A, R,, R 2 , R 3 , R 4 , R 5 , R 6 and X are as defined above and R 6 is hydrogen or a salt thereof.
• a compound of the invention may be convened into a salt thereof (or such a salt may be converted into a compound of the invention). Such a conversion may be carried out by addition of an acid or a base as appropriate.
• the 4-oxo-l,2,3,4-tetrahydro-4H-c.arbazole-l -alkanoic acids of this invention can be conveniently prepared by oxidation of the corresponding carbazole (prepared via Fischer indolization of the appropriate cyclohexanone with the appropriately substituted phenylhydrazine) with either 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) or 2,2,6,6-tetramethyl-piperidine-l-oxonium tetrafluoroborate (TEMPO BF 4 ); the related 4-imino compounds can be preferably prepared by reaction of the 4-oxo esters with appropriately substituted amines followed by hydrolysis of the ester moiety (Scheme 1).
• the starting materials or intermediates are available commercially or can be prepared by standard literature procedures.
• 4-oxo l,3,4,9-tetrahydropyrano[3,4-b]indole-l-alkanoic acids can be prepared by oxidation of the corresponding l,3,4,9-tetrahydropyrano[3,4-b]indole (prepared, in turn, via cyclization of the appropriately substituted tryptophol with an alkoxy enol ether) with either 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) or 2,2,6,6- tetramethyl-piperidine-1-oxonium tetrafluoroborate (TEMPO BF4); the related 4-imino analogs can be preferably prepared by reaction of the 4-oxo esters with various substituted amines followed by hydrolysis of the ester moiety (Scheme 2). Scheme 2
• the compounds of this invention inhibit the COX-2 enzyme which is believed to be responsible for the production of high levels of prostaglandins in inflammation and colorectal cancer (Tables 1-3). It has been shown that selective inhibition of the COX-2 enzyme relative to COX-1 inhibition leads to an antiinflammatory effect without G.I. toxicity (Chan et. al., /. Pharmacol Exp.Ther. 274, 1531-1537 (1995); Masferrer et. al., Proc. Natl. Acad. Sci. USA , 91, 3228-3232 (1994); Seibert et al., Proc. Natl. Acad. Sci. USA , 91, 12013-12017 (1994)). Therefore, the compounds of this invention are useful for the treatment of inflammatory diseases such as rheumatoid arthritis. In addition, compounds that selectively inhibit the COX-2 enzyme are expected to have a greater margin of safety.
• the compounds of this invention were evaluated for inhibition of COX-2 and COX-1 as follows: human COX-1 and COX-2 cDNAs were cloned from human monocytes, untreated and LPS treated , respectively, by RT-PCR using oligonucleotide primers based on published rhCOX-1 and rhCOX-2 sequences (Jones et al, J. Biol. Chem., 268, 9049 (1993)). The cDNAs were then transfected into either Sf9 or CHO cells and subsequently converted into a microsomal preparation as described by Glaser et al (Eur. J. Pharmacol. 281, 107-111 (1995)).
• microsomal human recombinant enzymes were diluted with buffer (100 mM Tris, pH 7.8 at 37°C) containing 0.5 mM phenol (964 ⁇ l total volume).
• the enzyme preparations were preincubated with vehicle (DMSO) or compounds in DMSO (1% DMSO in final assay) for 30 min at 37°C. Excess hematin was added 1 min prior to initiation of reaction (1.25 ⁇ M final hematin) with 30 ⁇ M arachidonic acid (sodium salt).
• Final assay volume was 1.0 ml (100 mM Tris (pH7.8), 0.5 mM phenol, 1.25 ⁇ M hematin and 30 ⁇ M arachidonic acid at 37°C).
• the compounds of this invention demonstrated high inhibition of the human COX-2 isozyme and are therefore useful for the treatment of inflammation .and inflammation-associated disorders, as an anticancer agent, and other disease states where a role for the COX-2 enzyme in producing high levels of prostaglandins has been proposed.
• the compounds of this invention are useful in treating arthritic disorders, such as rheumatoid arthritis; Alzheimers disea.se; and colorectal cancer .
• the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
• Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably, contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
• the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
• cellulose derivatives preferably sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
• oils e.g. fractionated coconut oil and arachis oil
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
• the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
• the amount of therapeutically active compound that is administered and the dosage regimen for treating a specific arthritic disorder or colorectal cancer with the compound and/or compositions of this invention depends on a variety of factors, including the weight, age, sex, medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, .and thus may vary widely.
• the pharmaceutical compositions may contain active ingredient in the range of 0.1 to 2000 mg, preferably in the range of 0.5 to 500 mg and most preferably between 1 and 100 mg. Projected daily dosages of active compound are 0.01 to 100 mg/kg body weight. The daily dose of can be administered in one to four doses per day.
• Gal ⁇ iM C, 66.89; H, 5.96; N, 4.87. Found: C, 66.74; H, 5.95; N, 4.73.
• JR KBr, cm" 1 3400, 2950, 1710, 1620, 1460.
• step A The ester produced in step A (0.5g, 1.66mmol) was dissolved in 5 ml of a 90% THF/water solution, and to this was added 2,3-dichloro-5,6-dicyano-l,4-benzo- quinone (0.75 g, 3.3 mmol., previously dissolved in 5 ml THF). This mixture was stirred overnight. The solvent was evaporated and 50 ml of ethyl acetate was added. The organic phase was extracted sequentially with 2.5N NaOH, distilled water and brine. The organic layer was separated, dried (MgSO4) and evaporated to produce 0.56 g of crude oil.
• -____M (DMSO-d ⁇ , 400 MHz): ⁇ 0.615 (t, 3H, CCH 3 ), 1.95 (q, 2H, CCH 2 CH 3 ), 2.76 (d, IH, CCH 2 CO), 2.96 (m, 3H, CCH 2 ), 3.32 (s, 3H, OCH 3 ), 3.9 (m, 2H, CCH 2 O), 6.93 (t, IH, ArH), 7.11 (d, IH, ArH), 7.32 ( d, IH, ArH), 11.148 (s, IH, NH)._ MS (m/z, El): 351/353 (M) + , 322/324 (M-C 2 H 5 ) + , 278/280 (b.p., M-CH 2 COOH) + .
• the title compound was prepared according to the method of Example 9 using 0.490 (1.71 mmole) of l,8-diethyl-l,2,3,4-tetrahydrocarbazole-l -acetic acid (Asselin et al., J.Med. Chem 19, 787-792 (1976)). The title compound was obtained as a light yellow solid (0.027 g, 55%), having a melting point of 240-242°C. Analysis for: C19 H23 N O3
• Step B (0.5 g, 1.6 mmol) was added 10 ml MeOH, 0.4 ml IN HCl and 0.37 ml H2O. The mixture was stirred one minute followed by .addition of CH3SO2NHNH2 all at once. After overnight stirring, the MeOH was evaporated and additional water was added. This aqueous phase was twice extracted with CH2CI2. The organic phase was concentrated to a crude solid and purified by flash chromatography using CH2 ⁇ 2-EtOAc 95-5 as eluent. The product 0.33 g, was obtained as a solid m.p. 80-82°C. MS_(EI, m/z): 407 (M) + .

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