Classifications

• • 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
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to pharmaceutically active compounds which inhibit Fab I and are useful for the treatment of bacte ⁇ al infections
• Fab I functions as an enoyl-ACP reductase (Bergler, et al, ( 1994), J Btol Chem 269, 5493-5496) in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis
• the first step is catalyzed by ⁇ -ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA (FabH, synthase III)
• FabH acetyl-CoA
• FabB and FabF synthases I and II, respectively
• the second step in the elongation cycle is ketoester reduction by NADPH-dependent ⁇ -ketoacyl-ACP reductase (FabG)
• ⁇ -hydroxyacyl-ACP dehydrase leads to trans-2-
• Fab I is also the target for the broad spectrum antibacterial agent triclosan (McMurry, et al, (1998) Nature 394, 531-532).
• a crystal structure of the E. Coli Fab I complexed with NAD and triclosan shows that triclosan acts as a site-directed, very potent inhibitor of Fab I by mimicking its natural substrate (Levy, et al, (1999) Nature 398, 383-384). Ward, et al ((1999) Biochem.
• This invention comprises compounds of the formula (I), as described hereinafter, which inhibit Fab I and are useful in the treatment of bacterial infections.
• This invention is also a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
• This invention is also a method of treating bacterial infections by inhibiting Fab I.
• the compounds of this invention are useful as antibacterial agents.
• This invention comprises compounds of formula (I):
• R 1 is C ⁇ _4al yl
• R 2 is C ⁇ _4alkyl
• R 3 is -C ) _4alkyl, -C ⁇ -4alkyl-Ar or -C ⁇ -4alkyl-Het;
• R 4 is -C ] .4alkyl, -(CH ⁇ OH, -OCj ⁇ alkyl, -SC j ⁇ alkyl, -N(C 1 . 4 alkyl) 2 , -C 0 . 4 alkyl-Ar, -C 0 . 4 alkyl-Het, -C 0 . 4 alkyl-C3-6cycloalkyl, -CH(OH)-CH 2 -R* or -(CH 2 ) ⁇ .3S0 2 Ar;
• R* is C ⁇ alkyl, Ar or Het
• X is H, C ]. 4 alkyl, OR ' , SR ' , CN, N(R ) 2 , CH 2 N(R ' ) 2 , NO 2 , CF 3 , CO 2 R', CON(R ) 2 , COR ' , NR C(0)R ' , F, CI, Br, I, or -S(0) r CF 3 ; R' is H, Ci-6alkyl or -C ⁇ -6alkyl-Ar; and r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
• this invention includes each unique racemic compound, as well as each unique nonracemic compound.
• O compounds may exist in tautomeric forms, such as keto-enol tautomers, such as - ⁇ - OFT and -- ⁇ t::: ⁇ , each tautomeric form is contemplated as being included within this invention, whether existing in equilibrium or locked in one form by appropriate substitution with R ⁇
• prodrugs of the compounds of this invention are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
• the compounds of formula (I) inhibit Fab I. Inhibition of this enzyme is useful in the treatment of bacterial infections. Also, the compounds of this invention may be useful as antifungal agents. Additionally, the compounds may be useful in combination with known antibiotics.
• this invention preferably includes compounds of formula (la):
• R 3 is -C ⁇ alkyl or -Cn-2alkyl-Ph and R 4 is -C j _ 4 alky 1, -CH 2 OH, -OC j _ 4 alky 1, -C 0 . 2 alkyl-Ph, -C 0 . 2 alkyl-C3-6cycloalkyl, - CH(OH)-CH 2 -R* or -(CH 2 ) 2 S0 2 Ph, in which R* is as defined for formula (I) compounds
• novel compounds of this invention are the following N-[(2-am ⁇ no-5- ⁇ N-methyl-N-[(l-methyl ⁇ ndol-2-yl)methyl]carbamoyl ⁇ phenyl)methyl]-N-methylacetam ⁇ de,
• C ] _4alkyl as applied herein means an optionally substituted alkyl group of 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
• C j _6alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
• Co-4al yl and Co- ⁇ lkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
• Any C]_4alkyl or C j.g alkyl may be optionally substituted with the group R x , which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques.
• Suitable groups for R x are C j ⁇ alkyl, OR , SR , CN, N(R')2, CH 2 N(R ' ) 2 , -N0 2 , -CF 3 , -C0 2 R' -C0N(R') 2 , -COR', -NRC(O)R ' , F, CI, Br, I, or -S(0) r CF3, wherein R' and r are as defined for formula (I) compounds.
• Halogen or halo means F, CI, Br, and I.
• Ar or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, or substituted by methylenedioxy.
• Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
• heterocycles are benzofuryl, benzimidazolyl, benzopyranyl, benzothienyl, furyl, imidazolyl, indolinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, pynolidinyl, tetrahydropyridinyl, pyridinyl, thiazolyl, thienyl, quinolinyl, isoquinolinyl, and tetra- and perhydro- quinolinyl and isoquinolinyl. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl, that are available by chemical synthesis and are stable are within the scope of this invention.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical
• Bn refers to the benzyl radical.
• Me refers to methyl
• Et refers to ethyl
• Ac refers to acetyl
• Alk refers to Cj ⁇ alkyl
• Nph refers to 1- or 2-naphthyl
• cHex refers to cyclohexyl.
• Tet refers to 5-tetrazolyl.
• DCC refers to dicyclohexylcarbodiimide
• DMAP refers to dimethylaminopyridine
• EDC refers to l-(3-dimethylaminopropyl)-3- ethylcarbodiimide
• hydrochloride HOBt refers to 1-hydroxybenzotriazole
• THF refers to tetrahydrofuran
• DIEA refers to diisopropylethylamine
• DEAD refers to diethyl azodicarboxylate
• PPh 3 refers to triphenylphosphine
• DIAD refers to diisopropyl azodicarboxylate
• DME refers to dimethoxyethane
• DMF refers to dimethylformamide
• NBS refers to N-bromosuccinimide
• Pd/C refers to a palladium on carbon catalyst
• PPA refers to polyphosphoric acid
• DPPA diphenylphosphoryl
• the compounds of formula (I) are prepared by reacting a compound of formula (II) with a compound of formula (III):
• R l , R2, R3, R4 anc j x are as defined in formula (I), with any reactive functional groups protected, in the presence of EDC and HOBT; and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
• Reagents and conditions (a) PhS0 Cl, pyridine, t-BuOH; (b) N-bromosuccinamide, benzoyl peroxide, CH 2 C1 2 ; (c) 40% CH NH 2 in H 2 O; (d) (CH 3 CO) 2 O, ( -Pr) NEt, CH 2 C1 2 ; (e) H 2 , 10% Pd/C, MeOH; (f) TFA, CH 2 C1 2 ; (g) l-methyl-2- (methylaminomethyl)indole, EDC, HOBt ⁇ H 2 0, ( -Pr) 2 NEt, DMF.
• 3-methyl-4-nitrobenzoic acid (1-1) is protected at the carboxylic acid functionality with a suitable protecting group, for instance a tertiary butyl (r-Bu) group, to afford 1-2.
• a suitable protecting group for instance a tertiary butyl (r-Bu) group
• protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, "Protective Groups in Organic Synthesis” (published by Wiley-Interscience).
• the benzylic position is brominated under radical conditions using N- bromosuccinamide (NBS) and the radical initiator benzoyl peroxide affording 1-3. Halogenation of reactive positions, such as the benzylic position of 1-2, is well known.
• Nucleophilic substitution of the bromide is accomplished with an excess of aqueous methyl amine, for instance 40% methylamine in water, providing the benzyl amine 1-4.
• Acylation of the pendent nitrogen is accomplished with a suitable acylating reagent such as an acyl halide, or an acid anhydride, to afford N-acyl-substituted de ⁇ vatives
• the benzyl nitrogen can be acylated with acetic anhydride, to afford the amide derivative 1-5
• the aryl nitro compound 1-5 is converted under hydrogenation conditions, in the presence of a catalytic amount of palladium metal on activated carbon (Pd/C), to the amine 1-6
• Aromatic nitro groups can be reduced by a number of methods involving the use of metals and example procedures can be found in standard chemistry texts such as, "Reductions in Organic Chemistry” published by the (American Chemical Society)
• the r-butyl ester is removed to reveal the carboxylic acid functionality with a suitable acid reagent such as tnfluoroacetic acid (TFA) to give 1-7
• a suitable acid reagent such as tnfluoroacetic acid (TFA)
• TFA tnfluoroacetic acid
• Other standard methods for removal of a r-butyl protecting group are described by Greene (see above)
• the carboxylic acid denvative is then converted to amide 1-8 by reaction with an activating agent and a suitable amine species
• acid 1-7 is converted to an activated form by reaction with EDC and HOBt, and the activated form is subsequently reacted with amine [l-methyl-2- (methylam ⁇ nomethyl) ⁇ ndole ] in a
• an added base such as tnethylam e (Et N), diisopropylethylamine (( ⁇ -Pr) 2 NEt), or pyndine, may be used
• Amide coupling reagents as used herein denote reagents which may be used to form peptide bonds Typical coupling methods employ carbod ⁇ mides, activated anhyd ⁇ des and esters and acyl halides Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical
• the amine is coupled via its free ammo group to an appropriate carboxylic acid substrate using a suitable carbod ⁇ mide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1- hydroxybenzotnazole (HOBt) and dimethylamino pyndine (DMAP)
• a carbod ⁇ mide coupling agent such as N,N' dicyclohexyl carbodiimide (DCC)
• catalysts such as 1- hydroxybenzotnazole (HOBt) and dimethylamino pyndine (DMAP)
• HABt 1- hydroxybenzotnazole
• DMAP dimethylamino pyndine
• a benzoic acid is treated in an anhydrous solvent, such as methylene chlo ⁇ de or tetrahydrofuran (THF), in the presence of a base, such as N-methylmorpholine, DMAP or a
• these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration
• Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition
• Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stea ⁇ c acid, talc, pectin, acacia, agar or gelatin
• Liquid carriers include syrup, peanut oil, olive oil, saline and water
• the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax
• the amount of solid earner vanes but, preferably, will be between about 20 mg to about 1 g per dosage unit
• the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms, or milling, mixing and filling for hard gelatin capsule forms When
• the compounds of this invention may be combined with diluents to take the form of ointments, gels, pastes, creams, powders or sprays.
• the compositions which are ointments, gels, pastes or creams contain diluents, for example, animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances.
• the compositions which are powders or sprays contain diluents, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances.
• the typical carriers are water, mixtures of water and water miscible solvents, such as lower alkanols or vegetable oils, and water-soluble non-toxic polymers, for example cellulose derivatives, such as methyl cellulose.
• the compounds described herein are inhibitors of Fab I, and are useful for treating bacterial infections.
• these compounds are useful for the treatment of bacterial infections, such as, for example, infections of upper respiratory tract (e.g. otitis media, bacterial tracheitis, acute epiglottitis, thyroiditis), lower respiratory (e.g. empyema, lung abscess), cardiac (e.g. infective endocarditis), gastrointestinal (e.g.
• the compounds of this invention may be useful as antifungal agents. Additionally, the compounds may be useful in combination with known antibiotics.
• the compounds of this invention are administered to the patient, in a manner such that the concentration of drug is sufficient to treat bacterial infections.
• the pharmaceutical composition containing the compound is administered at an oral dose of between about 10 mg to about 1000 mg, taken once or several times daily, in a manner consistent with the condition of the patient.
• the oral dose would be about 50 mg to about 500 mg, although the dose may be varied depending upon the age, body weight and symptoms of the patient.
• parenteral administration is prefened.
• An intravenous infusion of the compound of formula (I) in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
• the precise level and method by which the compounds are administered is readily determined by one skilled in the art.
• the compounds may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
• the fabl gene was cloned from the chromosomal DNA of 5. aureus strain WCUH29 using the polymerase chain reaction. Amplification was performed using Taq DNA polymerase (BRL) and the following primers: 5 - CGCCTCGAGATGTTAAATCTTGAAAACAAAACATATGTC-3' and 5 - CGCGGATCCAATCAAGTCAGGTTGAAATATCCA-3' (Xhol and Bam l sites underlined). The resulting fragment was then digested with Xhol and BamHl and ligated into Xhol- and ⁇ mHI-digested expression vector pET-16b (Novagen), producing pET- His]Q-/ ⁇ W.
• BBL Taq DNA polymerase
• the gene sequence of fabl was confirmed by automated cycle sequencing using an Applied Biosystems model 377 machine.
• the untagged version of pKT-fabl was constructed by digesting pET-His jQ -/ ⁇ W with Ncol and Ndel to remove a 97 bp fragment encoding the His 10 tag, the factor Xa cleavage site and the first 8 amino acids of Fabl, and replacing it with a linker encoding the first 8 amino acids of Fabl plus a glycine residue between the initiator methionine and the lysine at position 2.
• This plasmid was called pET- fabl.
• the linker was made by annealing the following two oligonucleotides: 5 - CATGGGCTTAAATCTTGAAAAC AAAAC A-3 ' and 5 '-
• S. aureus Fabl was expressed as soluble protein to 10% of total cell protein, 400g cells being recovered from 15L fermentation in tryptone phosphate medium. The cells were lysed and the sample centrifuged. The resulting supernatant was filtered and purified using three consecutive chromatography columns: ion-exchange (Sourse 15Q), dye-affinity (Blue sepharose), and size exclusion chromatography columns (Superose 12). After each column the Fabl containing fractions were pooled, concentrated, and checked for purity and biological activity. Cloning of E. coli Fabl
• a PCR fragment of correct size for E. coli Fabl was PCR amplified from E. coli chromosomal DNA, subcloned into the TOPO TA cloning vector, and verified by colony PCR + restriction endonuclease analysis.
• the presumptive E. coli Fabl PCR fragment was subcloned into the expression vector pBluePet.
• the Fabl clone was transformed into E. coli strain BL21(DE3) Small Scale expression studies show an over-expressed protein band of correct molecular weight (-28 Kda) for E. coli Fabl clearly visible following Coomassie staining of SDS PAGE gels DNA sequencing of the E. coli Fabl expression constructs illustrated that no errors were apparent. N' terminal amino acid sequencing has confirmed the over-expressed protein band to be E. coli Fabl
• E. coli Fabl was expressed as soluble protein to 15% of total cell protein, 120g cells being recovered from 3L fermentation in shake flasks in modified ternfic broth. The cells were lysed and the sample centnfuged. The resulting supernatant was filtered and punfied using three consecutive chromatography columns: ion-exchange (Sourse 15Q), dye-affinity (blue sepharose), and size exclusion (superose 12). After each column the Fabl containing fractions were pooled, concentrated and checked for purity and biological activity.
• Reactions contained 5 mg/mL E coli apo-ACP, 0 8 mM crotonoyl-CoA (Fluka), 10 mM MgCl 2 , and 30 uM S pneumoniae ACP synthase in 50 mM NaHEPES, pH 7 5
• the mixture was gently mixed on a magnetic stmer at 23 °C for 2 hr, and the reaction was terminated by the addition of 15 mM EDTA
• the reaction mixture was filtered through a 0 2 micron filter (Millipore) and applied to a MonoQ column (Pharmacia) equilibrated with 20 mM T ⁇ s-Cl, pH 7 5 The column was washed with buffer until all non-adherent matenal was removed (as observed by UV detection), and the crotonoyl-ACP was eluted with a linear gradient of 0 to 400 mM NaCl
• Test organisms were selected from the following laboratory strains Staphylococcus aureus Oxford, Staphylococcus aureus WCUH29, Streptococcus pneumoniae ERY2, Streptococcus pneumoniae 1629, Streptococcus pneumomae N 1387, Enterococcus faecahs I, Entewcoccus faecahs 7, Haemoph ⁇ us influenzae Ql,
• the compounds used in the antimicrobial assays of the present invention have a MIC value of less than 128 ⁇ g/mL Most preferably, said compounds have a MIC value of less than 64 ⁇ g/mL
• Example 2 According to the procedure of Example 2, except substituting 4-amino-3-[(N- phenethylacetylamino)methyl]benzoic acid (0.60 g, 1.92 mmole) for 4-amino-3-[(N- methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (0.83 g, 92 %) was prepared as a yellow solid following chromatography on silica gel (CHCI3/CH3OH, 95:5): MS (ES) m/e 469 (M+H)+.
• Example 5 According to the procedure of Example 2, except substituting 4-amino-3-[(2- hydroxy-4,N-dimethylpentanoylamino)methyl]benzoic acid trifluoro acetate (2.1 g, 5.1 mmole) for 4-amino-3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (2.06 g, 90 %) was prepared as a yellow foam following chromatography on silica gel (CHCI3/CH3OH, 95:5): MS (ES) m/e 451 (M+H)+.
• Example 5 Example 5
• Example 2 According to the procedure of Example 2, except substituting 4-amino-3-[(ethoxy- N-methylcarbonylamino)methyl]benzoic acid trifluoro acetate (0.75 g, 2.05 mmole) for 4- amino-3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (0.75 g, 90 %) was prepared as a tan foam following chromatography on silica gel (CHCl 3 /CH 3 OH, 95:5): MS (ES) m/e 409 (M+H)+.
• Example 2 According to the procedure of Example 2, except substituting 4-amino-3-[(2- hydroxy-N-methylacetylamino)methyl]benzoic acid (1.0 g, 2.84 mmole) for 4-amino-3- [(N-methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (0.99 g, 88 %) was prepared as an off-white solid following chromatography on silica gel (CHCI3/CH3OH, 95:5): MS (ES) m/e 395 (M+H)+.
• Example 8 According to the procedure of Example 2, except substituting 4-amino-3-[(N- methylacetylamino)methyl]benzoic acid trifluoroacetate (0.44 g, 1.31 mmole) for 4-amino- 3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (0.45 g, 92 %) was prepared as an off-white solid following chromatography on silica gel (CHCI3/CH3OH, 95:5): MS (ES) m/e 379 (M+H +.
• Example 8 Example 8
• Example 2 According to the procedure of Example 2, except substituting 4-amino-3-[(2- hydroxy-3-indol-3-yl-N-methylpropanoylamino)methyl]benzoic acid trifluoro acetate (0.41 g, 1.12 mmole) for 4-amino-3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (0.46 g, 78 %) was prepared as an off-white solid following chromatography on silica gel (CHCI3/CH3OH, 95:5): MS (ES) m/e 524 (M+H) + .
• Example 2 According to the procedure of Example 2, except substituting 4-amino-3-[(2- cyclopentyl-N-methylacetylamino)methyl]benzoic acid trifluoro acetate (1.05 g, 3.60 mmole) for 4-amino-3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate, the title compound (1.45 g, 90 %) was prepared as an off-white solid following chromatography on silica gel (hexanes/EtOAc, 1 :2): MS (ES) m/e 448 (M+H) + .
• Example 1 According to the procedure of Example 2, except substituting 4-hydroxybenzoic acid (0.23 g, 1.64 mmole) for 4-amino-3-[(N-methylacetylamino)methyl]benzoic acid trifluoro acetate and substituting ⁇ 4-amino-3-[(methylaminomethyl]phenyl ⁇ -N-methyl-N- [(l-methylindol-2-yl)methyl]carboxamide (0.50 g, 1.49 mmole) for l-methyl-2- (methylaminomethyl)indole, the title compound (0.62 g, 92 %) was prepared as an off- white solid following chromatography on silica gel (CHCI3/CH3OH, 95:5): MS (ES) m/e 457 (M+H)+.
• Example 1 1
• Example 2 According to the procedure of Example 2, except substituting 3- (phenylsulfonyl)propionic acid (0.35 g, 1.64 mmole) for 4-amino-3-[(N- methylacetylamino)methyl]benzoic acid trifluoro acetate and substituting ⁇ 4-amino-3- [(methylaminomethyl]phenyl ⁇ -N-methyl-N-[(l-methylindol-2-yl)methyl]carboxamide (0.50 g, 1.49 mmole) for 1 -methyl-2-(methylaminomethyl)indole, the title compound (0.72 g, 91 %) was prepared as an off-white solid following chromatography on silica gel (CHC1 /CH 3 0H, 95:5): MS (ES) m/e 533 (M+H) + .
• a preparation which contains 20 mg of the compound of Example 1 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
• D5W dextrose in water
• a capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
• a tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 with a 10% gelatin solution
• the wet granules are screened, dned, mixed with 10 mg starch, 5 mg talc and 3 mg stea ⁇ c acid; and compressed into a tablet.

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