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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • 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
  • A61P13/00—Drugs for disorders of the urinary system
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • A61P25/06—Antimigraine agents
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  • A61P25/24—Antidepressants
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to indazole derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use.
• the active compounds of the present invention are useful in treating obesity and other disorders.
• BMI body mass index
• m body weight index
• Overweight is defined as a BMI in the range 25-30 kg/m
• obesity is a BMI greater than 30 kg/m 2 .
• body fat content is also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
• Compounds marketed as anti-obesity agents include Orlistat (Reductil ® ) and
• Sibutramine a lipase inhibitor
• Orlistat a lipase inhibitor
• Sibutramine a mixed 5-HT/noradrenaline reuptake inhibitor
• the serotonin releaser/reuptake inhibitors fenfluramine (Pondimin ® ) and dexfenfluramine (ReduxTM) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
• mCPP m- chlorophenylpiperazine
• TFMPP trifluoromethylphenylpiperazine
• CA-2132887 and CA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives and tricyclic 1 -aminoethyl pyrazole derivatives bind to 5-HT 2 c receptors and may be used in the treatment of obesity.
• WO-A-98/30548 discloses arninoalkylindazole compounds as 5-HT 2 c agonists for the treatment of CNS diseases and appetite regulation disorders.
• Ri to R 3 are independently selected from hydrogen and alkyl; 4 to R are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, monoalkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, arylthio, arylsulfoxyl, arylsulfonyl, alkylsulfoxyl, alkylsulfonyl, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylarnino and dialkylaminocarbonylamino; and R is selected from alkyl and alkoxy, and pharmaceuticaly acceptable salts and prodrugs thereof
• alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
• the alkyl group is preferably C 3 to C 12 , more preferably C 5 to C JO , more preferably C 5 , C 6 or C 7 .
• the alkyl group is preferably Ci to do, more preferably d to C 6 , more preferably methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl), more preferably methyl.
• lower alkyl means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
• aryl means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably one, heteratom, such as pyridyl, pyrrolyl, furanyl and thienyl.
• alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent.
• Substituents may include: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl), ethers (e.g.
• alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g.
• aminocarbonyl mono- or di- alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl
• carbamates e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy
• ureas e.g. mono- or di-alkylaminocarbonylamino or arylaminocarbony lamino
• nitrogen-containing groups such as amines (e.g.
• alkoxy means alkyl-O- and "alkoyl” means alkyl- CO-.
• Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
• halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a fluorine or chlorine radical.
• prodrug means any pharmaceutically acceptable prodrug of the compound of formula (I).
• salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfomc, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
• acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfomc, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydro
• Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
• the compounds of formula (I) are selected from compounds in which Ri is the same as R .
• Ri and R 2 are both hydrogen.
• Ri is hydrogen and R 2 is alkyl, preferably lower alkyl, preferably methyl. In a further embodiment, Ri is hydrogen and R 2 is arylalkyl, preferably arylmethyl. Where R 2 is arylalkyl, it is preferred that said aryl substituent is a substituted or unsubstituted phenyl or thienyl group.
• the compounds of formula (I) are selected from compounds in which R 3 is alkyl, preferably lower alkyl, preferably methyl.
• R 3 is alkyl
• the carbon atom to which R 3 is attached is an asymmetric carbon atom. It is preferred that this asymmetric carbon is in the (S)-configuration, wherein the stereochemical assignment is defined with respect to a compound wherein R 3 is an unsubstituted alkyl group.
• R 4 to R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl
• aryl amino, monoalkylamino, dialkylamino, alkoxy (including arylalkoxy), aryloxy, alkylthio, arylthio, arylsulfoxyl, arylsulfonyl, alkylsulfoxyl, alkylsulfonyl, nitro, cyano, carboxaldehyde, alkylcarbonyl, arylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, monoalkylaminocarbonylamino and dialkylaminocarbonylamino.
• R4 to R 7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, alkoxy (including arylalkoxy), aryloxy, alkylthio, alkylsulfoxyl and alkylsulfonyl.
• the compounds of formula (I) are selected from compounds in which one or more of R ⁇ R 5 , R and R is/are hydrogen.
• one or both of t and R 7 are hydrogen.
• one or more, preferably one or two, of Ri, R 5 , R ⁇ and R 7 are selected from halogen, preferably fluoro, chloro and bromo.
• halogen preferably fluoro, chloro and bromo.
• R 5 and R ⁇ are selected from halogen.
• R 5 is selected from halogen, alkoxy (preferably lower alkoxy), alkylthio (preferably lower alkylthio) and alkyl (preferably trifluoromethyl).
• R G is selected from hydrogen and halogen (preferably fluoro).
• the compounds of formula (I) are selected from compounds in which Rs is alkyl, preferably methyl or ethyl, more preferably ethyl.
• the compounds of formula (I) are selected from l-(6-me oxy-3-methylmdazol-l-yl)-2-propylamine, l-(5,6-difluoro-3- methylindazol-l-yl)-2-propylamine, l-(6-chloro-5-fluoro-3-methylindazol-l-yl)-2- propylamine, 1 -(3-ethyl-6-trifluoromethyhndazol- 1 -yl)-2-propylarnine, 1 -(6-bromo-3- ethyUndazol-l-yl)-2-propylamine and l-(3-ethyl-6-methylthioindazol-l-yl)-2- propylamine.
• l-(3-Ethyl-6-methylthioindazol-l-yl)-2-propylamine and l-(6-bromo-3- emyl dazol-l-yl)-2-propylamine are particularly preferred. It is preferred that the compounds are the (S)-enantiomers thereof. Where the compounds of formula (I) are in salt form, the fumarate salt is particularly preferred.
• the compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
• the compounds can be, for example, racemates or optically active forms.
• the optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
• a compound of formula (I) is in the form of its (S)-enantiomer, substantially free of its (i?)-enantiomer.
• the term "substantially free of its (i?)-enantiomer” means that a composition comprising a compound of formula (I) contains a greater proportion of the (S)-enantiomer of the compound of formula (I) in relation to the (i?)-enantiomer of the compound of formula (I).
• the term "substantially free of its (i?)-enantiomer”, as used herein, means that the composition contains at least 90 % by weight of the (S)-enantiomer and 10 % by weight or less of the (i?)-enantiomer. In a further preferred embodiment, the term “substantially free of its (i?)-enantiomer” means that the composition contains at least 99 % by weight of the (S)-enantiomer and 1 % or less of the (/?)-enantiomer. In another preferred embodiment, the term “substantially free of its (i?)-enantiomer” means that the composition contains 100 % by weight of the (S)-enantiomer. The above percentages are based on the total amount of a compound of formula (I) present in the composition.
• the compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT receptor function.
• the compounds may act as receptor agonists or antagonists.
• the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT 2 ⁇ and/or 5-HT 2C receptor function.
• the compounds may be used in the treatment (including prophylactic treatment) of disorders where a 5-HT 2 c receptor agonist is required.
• the compounds of formula (I) may be used in the treatment or prevention of central nervous disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa or premenstrual tension; damage of the central nervous system such as by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases such as encephalitis or meningitis; cardiovascular disorders such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus; and sleep apnea.
• central nervous disorders such as depression, atypical depression, bipolar disorders,
• a method of treatment (including prophylaxis) of a disorder selected from the group consisting of the above-mentioned disorders comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I).
• a method of treatment (including prophylaxis) of obesity comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I).
• a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
• the (indazolyl)-alkylethanol (III) may be prepared by reaction of the substituted indazole (II) with an alkylene oxide in the presence of a strong base such as sodium hydride in a solvent such as tetrahydrofuran.
• the corresponding azido derivative (N) can be formed in a two step procedure from the derivative (III) by formation of the mesylate (IN), obtained by reaction of (III) with methanesulfonyl chloride in the presence of a base such as triethylamine, and subsequent treatment of the mesylate (IV) with sodium azide in a solvent such as dimethyl formamide.
• compounds of the invention may be prepared according to Reaction Scheme 2.
• Ri to R 8 are as previously defined.
• the hydrazone (VII) may be prepared by reaction of the alkyl- aryl ketone (VI) with hydrazine.
• the indazole (II) can be formed from the hydrazone (VII) by thermally-induced cyclisation with elimination of hydrogen fluoride.
• the carbamate (VIII) may be formed by reaction of the indazole (II) with a 2-carbamylethylsulfonate in the presence of a strong base such as potassium hydroxide in a solvent such as methyl sulfoxide.
• the substituent group R 4 , R 5 , R ⁇ , R 7 or Rs is other than the one required, the substituent group may be converted to the desired substituent by known methods.
• the substituents R 4 , R 5 , R ⁇ , R or R 8 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
• a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
• compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
• the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral
• transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
• the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate).
• binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose
• fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
• lubricants e.g. magnesium stearate, talc or silica
• disintegrants e.g. potato starch or sodium starch glycollate
• Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p- hydroxybenzoates or sorbic acid).
• suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
• emulsifying agents e.g. lecithin or acacia
• non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
• preservatives e.
• composition may take the form of tablets or lozenges formulated in conventional manner.
• the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
• Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
• the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
• a suitable vehicle e.g. sterile pyrogen-free water
• the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
• the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• the pressurized container or nebulizer may contain a solution or suspension of the active compound.
• Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
• a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
• the affinity of the compounds for human 5-HT 2 B receptors in a CHO cell line was determined according to the procedure of K. Schmuck, C Ullmer, P. Engels and H. Lubbert, FEBSLett., 1994, 342, 85-90.
• Fluorimetric Imaging Plate reader FLLPR. CHO cells expressing the human 5-HT c or human 5-HT 2A receptors were counted and plated into standard 96 well microtitre plates on the day before testing to give a confluent monolayer. The cells were then dye loaded with the calcium sensitive dye, Fluo-3-AM. Unincorporated dye was removed using an automated cell washer to leave a total volume of 100 ⁇ L/well of assay buffer (Hanks balanced salt solution containing 20 mM Hepes and 2.5 mM probenecid). The drug (dissolved in 50 ⁇ L of the assay buffer) was added at a rate of 70 ⁇ L/sec to each well of the FLIPR 96 well plate during fluorescence measurements.
• assay buffer Hors balanced salt solution containing 20 mM Hepes and 2.5 mM probenecid
• 6-Chloro-5-fluoro-3-methyl-lH-indazole was prepared according to the method described in Example 2 using 4'-chloro-2',5'-difluoroacetophenone (2.0 g, 10 mmol) to produce 0.83 g (45% yield) of the product as a beige solid:
• IR v max (Nujol/cm -1 ) 3221, 1457, 1306, 1294, 1071, 1012 and 856;
• 2',4'-Difluorophenylpropiohydrazone was prepared according to the method described in Example 5 using 2',4'-difluoropropiophenone (5.0 g, 30 mmol) to produce 2.6 g (48%) of the product as a colourless oil: LR v max (Nujol/cm -1 ) 3385, 1614, 1502, 1420, 1267, 1140, 968 and 850; NMR ⁇ H (400 MHz, CDC1 3 ) 1.03-1.15 (3H, m), 2.48 (0.7H, q, J 7.5 Hz), 2.58 (1.3H, q, J 7.5 Hz), 5.04 (0.7H, br s), 5.46 (1.3H, br s), 6.76-7.01 (2H, m), 7.16-7.23 (0.4H, m) and 7.4-7.47 (0.6H, m).
• 6-Bromo-3-ethylindazole was prepared according to the method described in Example 5 using 4'-bromo-2'-fluorophenylpropiohydrazone (0.6 g, 2.5 mmol) to produce 0.3 g (54%) of the product as a white solid: LR v m (Nujol/cm -1 ) 3204, 1616, 1461, 1377, 1340, 1036 and 800; NMR ⁇ H (400 MHz, CDCI 3 ) 1.42 (3H, t, J 7.5 Hz), 3.01 (2H, q, J 7.5 Hz), 7.23-7.27 (IH, m), 7.57 (IH, d, J 8.5 Hz) and 7.62 (IH, br s).
• 2' -Fluoro-4 '-methylthiophenylpropiohydrazone was prepared according to the method described in Example 5 using 2 '-fluoro-4' -methylthiopropiophenone (3.3 g, 17 mmol) to produce 2.3 g (68%) of the product as a colourless oil:
• IR v max (Nujol/cm -1 ) 3386, 1486, 1400, 1209, 891 and 818;
• NMR ⁇ H 400 MHz, CDC1 3 ) 1.06 (IH, t, J 7.5 Hz), 1.12 (2H, t, J 7.5 Hz), 2.48 (0.6H, q, J 7.5 Hz), 2.58 (1.4H, q, J 7.5 Hz), 5.06 (0.5H, br s), 5.45 (1.5 H, br s), 6.89-7.13 (2.3H, m) and 7.38 (0.7 H, t, J8 Hz).

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