WO2005051380A1 - Substituted urea-octahydroindols as antagonists of melanin concentrating hormone receptor 1 (mch1r) - Google Patents

Substituted urea-octahydroindols as antagonists of melanin concentrating hormone receptor 1 (mch1r) Download PDF

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Publication number
WO2005051380A1
WO2005051380A1 PCT/SE2004/001619 SE2004001619W WO2005051380A1 WO 2005051380 A1 WO2005051380 A1 WO 2005051380A1 SE 2004001619 W SE2004001619 W SE 2004001619W WO 2005051380 A1 WO2005051380 A1 WO 2005051380A1
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Prior art keywords
indol
dimethoxyphenyl
benzyl
trifluoroacetate
octahydro
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PCT/SE2004/001619
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French (fr)
Inventor
Martin Scobie
Andrew Browning
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Biovitrum Ab
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Priority claimed from SE0303181A external-priority patent/SE0303181D0/en
Application filed by Biovitrum Ab filed Critical Biovitrum Ab
Publication of WO2005051380A1 publication Critical patent/WO2005051380A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • MCH1R melanin concentrating hormone receptor 1
  • the present invention relates to substituted octahydroindoles that act as antagonist for the melanin concentrating hormone receptor 1 (MCH1R).
  • MCH1R melanin concentrating hormone receptor 1
  • the invention further relates to pharmaceutical compositions comprising these compounds, the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of obesity, and methods for the prophylaxis and treament of obesity.
  • MCH Melanin Concentrating Hormone
  • mice lacking MCH are hypophagic and lean, and have increased energy expenditure (20 % increase over control animals when expressed on a per kg basis) (Shimada M et al., Nature, 1998; 396(6712):670-4).
  • mice overexpressing MCH in the lateral hypothalamus show that these animals are more prone to diet-induced obesity when fed a high fat diet, and they have higher systemic leptin levels (Ludwig DS et al., J Clin. Invest, 2001; 107(3):379-86). Blood glucose levels were increased both preprandially and after intraperitoneal injection of glucose. The animals also had increased insulin levels and insulin tolerance test indicated peripheral insulin resistance. Further support for the role of MCH in metabolic regulation comes from studies showing that, in mice, mRNA for the MCH receptor is upregulated 7-fold by 48h fasting and in genetic leptin deficiency (ob/ob mice).
  • Obesity is also proven to double the risk of hypertension. It is estimated that between 2% and 8% of total health-care costs in the Western world are related to obesity, i.e., in excess of 10 billion USD.
  • Initial treatment for obesity is simple diet and exercise. Initial drug therapy tends to be focused around suppression of appetite. Many of the older appetite-suppressant agents act via the noradrenergic (and possibly dopaminergic) receptors to produce a feeling of satiety.
  • Amphetamine was the archetypal agent in this class, but it has substantial potential for stimulating the central nervous system and consequent abuse. More recent developments, such as Xenical® (orlistat), marketed by Roche, have focused on preventing fat absorption in the gut.
  • Xenical® inhibits the action of the enzyme lipases, thereby reducing the digestion of triglycerides and subsequent absorption by the intestinal tract. Unfortunately, this does not address overeating and excess calorie intake.
  • Other pharmacological approaches for the treatment of obesity include serotonin re-uptake inhibitors, such as Reductil® (sibutramine) marketed by Abbot, which acts as an appetite- suppressant.
  • Reductil® sibutramine
  • MCH1R antagonists for the treatment of obesity has recently been published. A review is presented by Carpenter and Hertzog, ExpertOpin. Ther. Patents, 2002, 12(11): 1639-1646. WOO 1/21169 (Takeda Chemical industries) describes diaryl compounds as MCH- 1R antagonists useful for the treatment of obesity.
  • JP 13226269 (Takeda), describing several piperidine-substituted benzazepines and benzazepinones; WOO 1/82925 (Takeda), disclosing different amines; and WO01/87834 (Takeda) describing piperidine compound with benzene (1:1), claim compounds for the treatment of obesity.
  • WO01/21577 discloses a series of amines claimed to be anorectic, antidiabetic and antidepressant agents.
  • WO01/57070 (Merck) describes in a series of truncated and modified peptidic MCH analogues as either significant agonist or antagonist activity.
  • WO02/10146 GaxoSmithKline
  • WO02/04433 The Neurogen Corporation
  • WO02/06245 a class of dihydropyrimidinones as MCH-IR antagonists for the treatment of feeding disorders, such as obesity and bulimia is disclosed.
  • WO02/051809 Schering Corporation 4-substituted piperidine derivatives are disclosed as MCH antagonists as well as their use in the treatment of obesity.
  • aryl- substituted ureas are disclosed as MCH antagonists as well as their use in the treatment of obesity.
  • the central core in the WO02/057233 is a(n) (hetero)arylene group, whereas the central core in the present compounds is an octahydroindole group.
  • Mesembrine 3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-6H-indol-6-one, is a natural product obtained as an extract of plants of the Mesembryanthemaceae family, including Sceletium tortuosum. In small doses the mesembrine have a meditative or narcotic effect. Hottentots used Sceletium expansum and tortuosum as a psychedelic called "channa". The use of mesembrine as a serotonin-uptake inhibitor for the treatment of an array of mental disorders is disclosed in WO97/46234.
  • novel substituted octahydroindoles have been found that are active towards the MCH1R receptor.
  • the compounds are relatively easy to prepare and can be used for the treatment or prevention of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, modulation of appetite, depression, anxiety or urinary incontinence.
  • the compounds can further be used in conjunction with other compounds acting through other mechanisms, such as MC-4 agonists, 5HT 2c agonists, or 5HT 6 antagonists.
  • the compounds can also be used in conjunction with anti-obesity medicaments.
  • C ⁇ -6 -alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl.
  • C 3-8 -cycloalkyl denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms.
  • examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl.
  • C 3-8 -cycloalkyl For parts of the range "C 3-8 -cycloalkyl” all subgroups thereof are contemplated such as C 3-7 -cycloalkyl, C -6 -cycloalkyl, C 3-5 -cycloalkyl, C 3- -cycloalkyl, C 4- 8 -cycloalkyl, C 4-7 -cycloalkyl, C 4-6 -cycloalkyl, C 4-5 -cycloalkyl, C 5- -cycloalkyl, C 6-7 - cycloalkyl, etc.
  • C ⁇ -6 alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t- butoxy and straight- and branched-chain pentoxy and hexoxy.
  • C] -6 - alkoxy all subgroups thereof are contemplated such as C ⁇ -5 -alkoxy, C ⁇ -4 -alkoxy, C ⁇ -3 - alkoxy, C ⁇ -2 -alkoxy, C 2-6 -alkoxy, C 2-5 -alkoxy, C 2-4 -alkoxy, C 2-3 -alkoxy, C 3-6 -alkoxy, C 4-5 - alkoxy, etc.
  • Halo-C ⁇ -6 -alkoxy means a C ⁇ -6 -alkoxy group substituted by one or more halogen atoms.
  • C 2-6 -alkenyl denotes a straight or branched alkenyl group having from 2 to 6 carbon atoms. Examples of said alkenyl include vinyl, allyl, 1-butenyl, 1-pentenyl, and 1-hexenyl.
  • C 2-6 -alkenyl For parts of the range "C 2-6 -alkenyl" all subgroups thereof are contemplated such as C 2-5 -alkenyl, C -4 -alkenyl, C 2-3 -alkenyl, C 3-6 - alkenyl, C 3- -alkenyl, C 3-4 -alkenyl, C 4-6 -alkenyl, C 4-5 -alkenyl, etc.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • aryl refers to a hydrocarbon ring system having at least one aromatic ring.
  • aryls are phenyl, pentalenyl, indenyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl.
  • the aryl rings may optionally be substituted by C ⁇ -6 -alkyl.
  • substituted aryl groups are benzyl and 2-methylphenyl.
  • heteroaryl refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S.
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups.
  • heterocyclo refers to a hydrocarbon ring system containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or O) as part of the ring. It includes saturated, unsaturated, aromatic, and nonaromatic heterocycles. Suitable heterocyclo groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl, and piperazinyl groups.
  • heteroatom e.g., S, N, or O
  • Suitable heterocyclo groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl,
  • “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Treatment” as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.
  • “An effective amount” refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • prodrug forms means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug.
  • pharmacologically acceptable derivative such as an ester or an amide
  • aryl-C ⁇ -6 alkyl means a C ⁇ -6 -alkyl group that is substituted by an aryl group.
  • halo C ⁇ -6 alkoxy means a C ⁇ -6 -alkoxy group that is substituted by one or more halogen atoms.
  • O means di-tert-butyl carbonate
  • DCM means dichloromethane
  • DIBAL-H means diisobutylaluminium hydride
  • DMF means dimethylformamide
  • HPLC high performance liquid chromatography
  • Hunig's base means N-ethyldiisopropylamine
  • PNP para-nitrophenyl
  • R.T. R.T.
  • (rt) means room temperature
  • TFA means trifluoroacetic acid
  • THF means tetrahydrofuran.
  • the present invention provides a compound of the general formula
  • R 1 is C 1-6 -alkyl
  • R 2 is C ⁇ -6 -alkyl
  • R 1 and R 2 are linked to form C ⁇ -3 -alkylene
  • R 3 is H, C ⁇ - 6 -alkyl, C ⁇ -6 -alkoxycarbonyl, C ⁇ . 6 -alkoxycarbonyl-C ⁇ -6 -alkyl, C ⁇ -6 - alkoxycarbonyl-C 3-6 -cycloalkyl-C 1-6 alkyl, aryl-C ⁇ .
  • R 4 is H or C ⁇ -6 -alkyl
  • R 5 is H, OH, C ⁇ - 6 -alkyl, C ⁇ -6 -alkylaminocarbonyl, or C ⁇ -6 -alkylaminothioxylcarbonyl
  • R 6 is H or C ⁇ _ 6 -alkyl
  • R 7 is H, C ⁇ -6 -alkyl, C 2-6 -alkenyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C ⁇ -6 -alkyl, C ⁇ .g-alkoxy,
  • R 1 and R 2 are methyl. 1 In some embodiments that R and R are linked to form methylene. In some embodiments R 4 is H. In some embodiments R 8 is H.
  • - R 3 is hydrogen; methyl; ethyl; n-propyl; isobutyl; pentyl; tert-butoxycarbonyl; ethoxycarbonylmethyl; ethoxycarbonylcyclopropylmethyl; benzyl, which may be unsubstituted or independently substituted in one or two positions with trifluoromethyl, methoxy, trifluoromethoxy, and nitro; phenylethyl; phenylpropyl; furylmethyl; methyl-furylmethyl; thienylmethyl; methyl-pyrrolylmethyl; pyridylmethyl; methyl- lH-imidazolylmethyl; or quinolinylmethyl; - R 5 is H or methyl; - R 6 is H; and - R 7 is ethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hex
  • X is O: - R 3 is methyl or benzyl; - R 5 is H; - R 6 is H or methyl; - R 7 is ethyl, allyl, benzyl, ethoxycarbonylethyl, piperazinylethyl, piperazinylpropyl, methylbenzyl, fluorobenzyl, bromobenzyl, dichlorobenzyl, methoxybenzyl, trifluoromethylbenzyl, phenylethyl, thienylethyl, pyridinylmethyl, methylpyrazinylmethyl, or 4-methylpiperazin-l-yl; or that - R 6 and R 7 together with the nitrogen to which they are attached form a piperazine, which may be unsubstituted or substituted in one position with methyl.
  • hen X is NH: - R 3 is methyl; - R 5 and R 6 both are H; and - R 7 is n-butyl, n-pentyl, or benzyl.
  • Certain specific embodiments are denoted in Examples 10-76 and 78-95 below. All diastereomeric forms possible (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Such compounds can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms are contemplated.
  • Another object of the present invention is a process for the preparation of a compound above comprising at least one of the following steps: (a) treatment of a nitrile with an alkali amide and then with l-bromo-2-chloroethane to give a cyclopropanecarbonitrile, (b) reduction of a cyclopropanecarbonitrile with diisobutylaluminium hydride to give a cyclopropanecarbaldehyde,
  • Another object of the present invention is a compound as described above for use in therapy.
  • the compound can be used in the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, urinary incontinence, and for modulation of appetite. It may also be used in the treatment or prophylaxis of disorders relating to the MCH1R receptor and for modulation of appetite. Examples of such disorders are obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence.
  • the compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT 2c agonists, or 5HT 6 antagonists.
  • the compound can also be used in conjunction with anti-obesity medicaments.
  • Another object of the present invention is a pharmaceutical formulation containing a compound as described above as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical formulation may be used in the treatment or prophylaxis of obesity wherein the active ingredient is a compound as described above.
  • Another object of the present invention is a method for the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, urinary incontinence, and for modulation of appetite, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment (e.g., including the step of identifying the subject as in need of such treatment) an effective amount of a compound as described above.
  • a subject e.g., mammal, human, or animal
  • an effective amount of a compound as described above e.g., an effective amount of a compound as described above.
  • the compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT 2c agonists, or 5HT 6 antagonists.
  • the compound can also be used in conjunction with anti-obesity medicaments.
  • Another object of the present invention is a method for the treatment or prophylaxis of disorders related to the MCHIR receptor and for modulation of appetite, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above.
  • the MCHIR receptor related disorder is any disorder or symptom wherein the MCHIR receptor is involved in the process or presentation of the disorder or the symptom.
  • the MCHIR related disorders include, but are not limited to obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence.
  • the compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT 2c agonists, or 5HT 6 antagonists.
  • the compound can also be used in conjunction with anti-obesity medicaments.
  • the methods delineated herein can also include the step of identifying that the subject is in need of treatment of the MCHIR receptor-related disorder. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • Another object of the present invention is a method for modulating MCHIR receptor activity (e.g., antagonizing the human MCHIR receptor), comprising administering to a subject (e.g., mammal, human, or animal) in need thereof an effective amount of a compound as described above or a composition comprising a compound as described above.
  • a subject e.g., mammal, human, or animal
  • Another object of the present invention is the use of a compound as described above in the manufacture of a medicament for use in the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence, and for modulation of appetite.
  • Another object of the present invention is the use of a compound as described above in the manufacture of a medicament for use in the treatment or prophylaxis of disorders related to the MCHIR receptor and for modulation of appetite, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above.
  • the MCHIR receptor related disorder is any disorder or symptom wherein the MCHIR receptor is involved in the process or presentation of the disorder or the symptom.
  • the MCHIR related disorders include, but are not limited to obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence.
  • the compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT 2c agonists, or 5HT 6 antagonists.
  • the compound can also be used in conjunction with anti-obesity medicaments.
  • the compounds of the formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof.
  • pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form.
  • Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid.
  • Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like.
  • organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, tolu
  • Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine.
  • the term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.
  • the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients.
  • excipients examples include water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like.
  • Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetring agents, emulsifiers, flavouring agents, buffers, and the like.
  • the formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc.
  • the formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections.
  • Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.
  • the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein.
  • the compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods. The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt.
  • 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 base compounds.
  • addition salt forming acids are mentioned above.
  • the compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers.
  • the separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
  • the chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds.
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • the dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy.
  • the daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
  • NMR nuclear magnetic resonance
  • 13 C NMR were recorded on a Bruker PMR 500 spectrometer at 500.1 MHz and 125.1 MHz, respectively or on a JEOL eclipse 270 spectrometer at 270.0 MHz and 67.5 MHz, respectively, or on a Bruker Advance DPX 400 spectrometer at 400.1 and 100.6 MHz, respectively. All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. . All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. IR spectra were recorded on a Perkin-Elmer Spectrum 1000 FT-IR spectrometer.
  • Electrospray mass spectrometry were obtained using an Agilent MSD mass spectrometer. Accurate mass measurements were performed on a Micromass LCT dual probe. Elemental analyses were performed on a Vario El instrument or sent to Mikro Kemi in Uppsala.
  • Dimethoxyphenyl acetonitrile (4.43 g, 2.5 mmol) was dissolved in DMF (20 mL).
  • Sodium hydride (4 g of a 60% dispersion, 2.4 g, 100 mmol) was added in portions and the mixture was stirred at room temperature for 10 minutes.
  • Bromochloroethane (2.1 mL, 3.62 g, 25.2 mmol) was added, and the mixture stirred at room temperature overnight. The reaction was cautiously quenched by addition of a methanol / water mixture (1 :1, 300 mL) and the reaction products were extracted into ethyl acetate (3 x 200 mL).
  • the resulting mixture was heated to 70°C for 3 hours and then partitioned between water (150 mL) and ethyl acetate (200 mL).
  • the aqueous phase was extracted with a further portion of ethyl acetate (1 x 200 mL) and the combined extracts were washed with brine (1 x 200 mL) and dried (Na 2 SO 4 ).
  • the solvent was removed under reduced pressure, and the crude product dissolved in dichloromethane (30 mL). To this was added HC1 in ether (70 mL of a 1.0 M solution, 70 mmol) and the crude HC1 salt was evaporated to dryness.
  • Example 3 (750 mg, 2.05 mmol) was dissolved in methanol (60 mL). Ammonium acetate
  • COMPARATIVE EXAMPLE 7 (3aS*.6R*.7aS*)-l-methyl-3a-r3.4- dimethox vphenvDoctahydro- 1 H-indol-6-amine and COMPARATIVE EXAMPLE 8 - (3aS*.6S* aS*Vl-methyl-3a-G.4- dimethoxyphenyl octahydro-lH-indol-6-amine
  • the compound was synthesised and purified an analougous method to that described in
  • Example 17 To a solution of Example 17 (600 mg, 1.14 mmol) in DCM (20 mL) was added trifluoroacetic acid (20 mL) and the resulting solution was stirred at rt during 5 min. The volatiles were evaporated under reduced pressure and the residue was partitioned between
  • N-benzyl-lH-pyrazole-1-carboximidamide hydrochloride 50 mg, 0.21 mmol
  • diispropylethylamine (0.03 ml, 0.21 mmol)
  • (3aS*,6S*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyl-octahydro-lH-indol-6-amine (Comparative Example 8, 60 mg, 0.21 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs. The crude mixture was purified by preparative HPLC to give the title compound, 9 mg (8 %) HRMS (El) calc: 422.2682 Found: 422.2676
  • N-butyl- lH-pyrazole-1-carboximidamide hydrochloride 43 mg, 0.21 mmol
  • diispropylethylamine (0.03 ml, 0.21 mmol)
  • (3aS*,6S*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyl-octahydro-lH-indol-6-amine 60 mg, 0.21 mmol
  • 60 mg, 0.21 mmol were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs.
  • the crude mixture was purified by preparative HPLC to give the title compound, 9 mg (9 %)
  • N-pentyl- lH-pyrazole-1-carboximidamide hydrochloride 45 mg, 0.21 mmol
  • diispropylethylamine (0.03 ml, 0.21 mmol)
  • (3aS*,6S*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyl-octahydro-lH-indol-6-amine (Comparative Example 8, 60 mg, 0.21 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs.
  • N-butyl- lH-pyrazole-1-carboximidamide hydrochloride (6 mg, 0.03 mmol), diispropylethylamine (0.01 ml, 0.06 mmol) and (3aS*,6R*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-amine (Comparative Example 7, 10 mg, 0.03 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs. The crude mixture was purified by preparative HPLC to give the title compound, 1 mg (7 %) HRMS (El) calc: 388.2838 Found: 388.2856
  • EXAMPLE 70 N'-butyl-N-r(3aS*.6R* JaS*V3a-(3.4-dimethoxyphenvn-l- methyloctahvdro-lH-indol-6-yll-N-methylthiourea trifluoroacetate and
  • Triethylamine (0.29 mL, 2.07 mmol) was added to a solution of (3aS*,6S*,7aS*)-l- benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-amine (Example 6, 0.38 g, 1.04 mmol) in dry CH 2 C1 2 (20 mL).
  • Triphosgene (0.123 g, 0.415 mmol), dissolved in dry CH 2 C1 2 (3 mL), was added to the reaction mixture dropwise. The mixture was stirred at room temperature under N 2 atmosphere for about 30 minutes. During this time the colour changed from light yellow to darker yellow.
  • Triethylamine (62 ⁇ L, 0.448 mmol) was added to a solution of (3aS*,6R*,7aS*)-3a-(3,4- dimethoxyphenyl)- 1 -methyloctahydro-1 H-indol-6-amine (Comparative Example 7, 65 mg,
  • Triethylamine (305 ⁇ L, 2.19 mmol) was added to a solution of (3aS*,6R*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-amine (Comparative Example 7, 318 mg, 1.097 mmol) dissolved in dry CH 2 C1 2 (5 mL).
  • Triphosgene 130 mg, 0.44 mmol was dissolved in dry CH 2 C1 2 (1 mL) and added dropwise. The solution was stirred under N 2 in room temperature for 3 h.
  • MS (ESI+) m/z 393 (M+H) + The crude isocyanate was partitioned into several reaction vials, to which the appropriate amine (see below) was added).
  • EXAMPLE 80 N-r(3aS*.6R*.7aS*)-3a-r3.4-dimethoxyphenvn-l-methyloctahvdro-lH- indol-6-yll-N'-r(5-methylpyrazin-2-yl)methyllurea trifluoroacetate
  • 2-(Aminomethyl)-5-methylpyrazine 21mg, 0.17mmol
  • Diisopropylamine 44mg, 0.34mmol was added followed by dropwise addition of triphosgene (24mg, 0.08mmol) in ImL of dry CH 2 C1 2 .
  • the mixture was heated at 80 °C for 30 min, whereupon its color changed to green, before a solution of l-bromo-2-chloroethane (11.3 mL, 136 mmol) in DME (50 mL) was added over a period of 20 min. During the course of the addition, the green color of the mixture changed to light brown.
  • the mixture was heated at 80 °C overnight, or until GC indicated >95% consumption of the starting material.
  • the mixture was cooled on an ice/water bath, and water (200 mL) and Et 2 O (400 ml) was then added to destroy the excess of strong base.
  • l-(3,4-methylenedioxyphenyl)cyclopropanecarbonitrile (19.0 g of crude material, 101 mmol), was dissolved in dry toluene (800 mL) and cooled on an ice/water bath. A solution of DIBAL (lM in toluene, 140 mL, 140 mmol) was added dropwise via an addition funnel, over a period of 30 min. The resulting mixture was heated at 50°C overnight. The reaction mixture was cooled to 0°C and cautiously transferred, in small portions and with swirling, to a separatory funnel containing ice-cold aq. HC1 (4M, 0.5L).
  • the isomers were separated by using column chromatography (silica, CHCl 3 /MeOH NH 3 ) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et 2 O (sat.) followed by evaporation.
  • the relative configuration was determined by 1H NMR spectroscopy (NOESY).
  • the isomers were separated by using column chromatography (silica, CHCl 3 /MeOH/NH 3 ) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et O (sat.) followed by evaporation.
  • the relative configuration was determined by 1H NMR spectroscopy (NOESY).
  • the isomers were separated by using column chromatography (silica, CHCl 3 /MeOH/NH 3 ) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl Et 2 O (sat.) followed by evaporation.
  • the relative configuration was determined by 1H NMR spectroscopy (NOESY).
  • the isomers were separated by using column chromatography (silica, CHCl 3 /MeOH/NH 3 ) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et 2 O (sat.) followed by evaporation.
  • the relative configuration was determined by ⁇ NMR spectroscopy (NOESY).
  • the isomers were separated by using column chromatography (silica, CHCl 3 /MeOH/NH 3 ) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et 2 O (sat.) followed by evaporation.
  • the relative configuration was determined by 1H NMR spectroscopy (NOESY).
  • the active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes.
  • the magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
  • the ability of a compound of the invention to bind or act at the MCHIR receptor can be determined using in vitro and in vivo assays known in the art. The biological activity of compounds prepared in the Examples was tested using different tests.
  • the compounds according to the invention were evaluated for their binding to the human MCHIR receptor by the following method:
  • MCH peptide was purchased from Phoenix pharmaceuticals. (Phe 13 , [ I25 I]Tyr 19 Melanine-Concentrating Hormone (human, mouse, rat) ([ 125 I]-MCH) was obtained from NEN life Science Products. Inc. Boston, MA. Wheat germ agglutinine SPA beads (RPNQ 0001) were obtained from Amersham-Pharmacia Biotech. All other reagents used are of highest purity from different resources available. Protein Kits, Micro BCATM Protein Assay Reagent Kit (Cat No. 23235) were purchased from Piece, Rockford, IL, USA. Plastic wares: Cell culture flasks, dishes were from Decton Dickinson Labware, NJ, USA. Scintillation plate, white clear bottom were from Wallac, Finland.
  • CHO-K1 cells expressing hMCHl receptor were purchased from Euroscreen.
  • CHO-K1 hMCHRI Euroscreen, Brussels, Belgium, #ES-370-C
  • Nutrient mixture Ham's F-12 with Glutamax I Ham's F-12 with Glutamax I (Gibco-BRL #31765-027) supplemented with 10% heat-inactivated foetal calf serum (FCS, Gibco-BRL #10108-165) and 400 ⁇ g/ml geniticin (Gibco-BRL #1140-0359).
  • FCS heat-inactivated foetal calf serum
  • FCS Gibco-BRL #10108-165
  • 400 ⁇ g/ml geniticin Gibco-BRL #1140-0359.
  • For membrane preparation the cells were cultured in 500 mm dishes and the cells were harvested when 90% confluent.
  • the homogenized preparation was centrifuged at 40,000g (18500 m with ss-34, No. 5 rotor in Sorvall centrifuge, RC5C, DuPont) for 25 minutes at 4 °C.
  • the pellets were washed once with Buffer A and centrifuged again under the same conditions.
  • the pellets were suspended with Buffer B, which contains Tris.HCl (7.5), MgCl 2 .6H 2 O (12.5), EDTA (0.3), EGTA (1), sucrose (25) in mM with pH 7.5, and gently homogenized for several times with a glass homogenizer.
  • Buffer B which contains Tris.HCl (7.5), MgCl 2 .6H 2 O (12.5), EDTA (0.3), EGTA (1), sucrose (25) in mM with pH 7.5, and gently homogenized for several times with a glass homogenizer.
  • the membrane preparation was aliquoted into Eppendorf tubes, 1 ml/tube and frozen at
  • the protein determination was done as described in the instruction provided with Pierce protein assay kit (Peirce Micro BCA Protein assay reagent kit, No 23235, Pierce, USA). Briefly, the Piece working reagent components A, B and C were mixed in the ratio 25:24:1. BSA (No. 23209, Pierce, USA) provided with the kits was used as standard, which the concentration in the curve is 1, 2, 4, 6, 8, 12, 16 and 24 ⁇ l/ml. The samples from membrane preparation were diluted for 50, 100, 200, 400 times. The standards or the samples 150 ⁇ l and the working reagent 150 ⁇ l were mixed in each well in a Costa 96 well microtiter plate and incubated at 37°C for 2 hours. The plate was cooled down to room temperature and read at 595 nm with a Microplate reader from Molecular Devices, USA.
  • the WGA beads were re-constructed with reaction buffer, which contains Tris (50), MgCl 2 (5), EDTA (2.5) in mM with pH adjusted to 7.4, to 40 mg/ml as a stock suspension.
  • reaction buffer contains Tris (50), MgCl 2 (5), EDTA (2.5) in mM with pH adjusted to 7.4, to 40 mg/ml as a stock suspension.
  • the beads and the membrane will be pre-incubated with for 30 minutes at room temperature with gentle shaking.
  • the suspension of the beads was centrifuged at 3400 ⁇ m for 2 minutes using centrifuge.
  • the amount of the beads used was 0.25 mg/well and the amount of the membrane protein was 4 ⁇ g/well 0.2 nM of labeled MCH was used.
  • the total volume was 200 ⁇ l, which contained 50 ⁇ l [ 125 I]-MCH, 100 ⁇ l substances and 50 ⁇ l beads.
  • the plate was gently shaken for 30 minute and incubated overnight.
  • the samples were counted using Microbeta counter (Wallac Trilux 1450 Micro beta counter, Wallac, Finland) for 2 minutes and the results were calculated by using the computer program Activity Base.
  • the equilibrium time of the binding was investigated at room temperature, 30 and 37°C.
  • the equilibrium time was about 30 minutes at 37 °C but the binding was lower compared with that at room temperature and 30 °C.
  • the equilibrium time was about 2 hours at 30 °C while it took about 4 hours to reach stable binding at room temperature.
  • room temperature was chosen since it is easy condition for experiments.
  • the [ 125 I]-MCH binding to hMCH RI was further characterized by determination of Kd values.
  • the Kd values are same, 0.19 nM, as reported by Chambers J, Ames RS, Bergsma D, Muir A, Fitzgerald LR, Hervieu G, Dytko GM, Foley JJ, Martin J, Liu WS, Park J, Ellis C, Ganguly S, Konchar S, Cluderay J, Leslie R, Wilson S, Sarau HM.
  • Melanin- concentrating hormone is the cognate ligand for the o ⁇ han G-protein-coupled receptor SLC-1. Nature 1999 Jul 15;400(6741):261-5.
  • Kd values from present study were consistent with that from Macdonald D, Murgolo N, Zhang R, Durkin JP, Yao X, Strader CD, Graziano MP..
  • Molecular characterization of the melanin-concentrating hormone/receptor complex identification of critical residues involved in binding and activation. Mol Pharmacol 2000 Jul;58(l):217-25 but were slightly different from that 1.2 nM from Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA, The distribution of the mRNA and protein products of the melanin- concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat.
  • MCH melanin- concentrating hormone
  • K, values for the inhibitors was performed by use of Activity Base.
  • the IC 50 is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance.
  • the compounds of formula (I) exhibit the IC 50 values for the MCHIR receptor in the range from 10 nM to 10 ⁇ M.
  • the following Ki values have been determined in the assay (see Table 1):
  • Table 1 Ki values determined in the assay.

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Abstract

The invention relates to compounds of the general formula (I). (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, and X are as defined in the description, or pharmaceutically acceptable salts, hydrates, geometrical isomers, racemates, tautomers, optical isomers, N-oxides and prodrug forms thereof. The compounds may be used for the treatment or prophylaxis of disorders related to the MCH1R receptor and for modulation of appetite. The invention also relates to such use as well as to pharmaceutical formulations comprising a compound of formula (I).

Description

Substituted urea-octahydroindols as antagonists of melanin concentrating hormone receptor 1 (MCH1R)
RELATED APPLICATIONS This application claims priority to Swedish application number 0303181 -2, filed on
November 26, 2003, and U.S. provisional application 60/549,644, filed on March 3, 2004, the contents of which is incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to substituted octahydroindoles that act as antagonist for the melanin concentrating hormone receptor 1 (MCH1R). The invention further relates to pharmaceutical compositions comprising these compounds, the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of obesity, and methods for the prophylaxis and treament of obesity.
BACKGROUND ART
Melanin Concentrating Hormone (MCH) is a 19 AA cyclic peptide, which is expressed in hypothalamus in the mammalian brain (Nahon JL et al., Endocrinology, 1989; 125(4):2056-65 and Tritos NA, et al., Diabetes, 1998; 47(11): 1687-92). A substantial body of evidence has shown that this peptide plays a critical role in the moderation of feeding behavior and energy expenditure. Studies have shown that ICV administration of MCH directly into rat brains results in a marked increase in food intake (Ludwig DS et al., Am. J. Physiol, 1998; 274(4 Pt l):E627-33). It has also been shown that messenger RNA for the MCH precursor is up-regulated in the hypothalamus of fasted animals and in animals that are genetically obese (Qu D, Ludwig DS et al., Nαtwre, 1996; 380(6571):243-7). Furthermore, mice lacking MCH are hypophagic and lean, and have increased energy expenditure (20 % increase over control animals when expressed on a per kg basis) (Shimada M et al., Nature, 1998; 396(6712):670-4). Studies of transgenic mice overexpressing MCH in the lateral hypothalamus show that these animals are more prone to diet-induced obesity when fed a high fat diet, and they have higher systemic leptin levels (Ludwig DS et al., J Clin. Invest, 2001; 107(3):379-86). Blood glucose levels were increased both preprandially and after intraperitoneal injection of glucose. The animals also had increased insulin levels and insulin tolerance test indicated peripheral insulin resistance. Further support for the role of MCH in metabolic regulation comes from studies showing that, in mice, mRNA for the MCH receptor is upregulated 7-fold by 48h fasting and in genetic leptin deficiency (ob/ob mice). These effects could be completely blunted by leptin treatment (Kokkotou EG et al., Endocrinology, 2001 ; 142(2):680-6.). In addition to its role in regulating feeding behavior, MCH antagonists have been demonstrated to have anxiolytic and antidepressant effects (Borowsky, BD et al., Nature Medicine, 2002. 8(8): 825-830). Obesity is linked to a wide range of medical complications, such as diabetes, cardiovascular disease and cancer. In addition, being overweight can exacerbate the development of osteoporosis and asthma. For example, at least 75% of Type II diabetics are overweight and a clear correlation has been demonstrated between weight and the prevalence of Type II diabetes. Obesity is also proven to double the risk of hypertension. It is estimated that between 2% and 8% of total health-care costs in the Western world are related to obesity, i.e., in excess of 10 billion USD. Initial treatment for obesity is simple diet and exercise. Initial drug therapy tends to be focused around suppression of appetite. Many of the older appetite-suppressant agents act via the noradrenergic (and possibly dopaminergic) receptors to produce a feeling of satiety. Amphetamine was the archetypal agent in this class, but it has substantial potential for stimulating the central nervous system and consequent abuse. More recent developments, such as Xenical® (orlistat), marketed by Roche, have focused on preventing fat absorption in the gut. Xenical® inhibits the action of the enzyme lipases, thereby reducing the digestion of triglycerides and subsequent absorption by the intestinal tract. Unfortunately, this does not address overeating and excess calorie intake. Other pharmacological approaches for the treatment of obesity include serotonin re-uptake inhibitors, such as Reductil® (sibutramine) marketed by Abbot, which acts as an appetite- suppressant. The concept of using MCH1R antagonists for the treatment of obesity has recently been published. A review is presented by Carpenter and Hertzog, ExpertOpin. Ther. Patents, 2002, 12(11): 1639-1646. WOO 1/21169 (Takeda Chemical industries) describes diaryl compounds as MCH- 1R antagonists useful for the treatment of obesity. Also JP 13226269 (Takeda), describing several piperidine-substituted benzazepines and benzazepinones; WOO 1/82925 (Takeda), disclosing different amines; and WO01/87834 (Takeda) describing piperidine compound with benzene (1:1), claim compounds for the treatment of obesity. WO01/21577 (Takeda) discloses a series of amines claimed to be anorectic, antidiabetic and antidepressant agents. WO01/57070 (Merck) describes in a series of truncated and modified peptidic MCH analogues as either significant agonist or antagonist activity. In WO02/10146 (GlaxoSmithKline) the preparation of carboxamide compounds claimed for the treatment of obesity as well as diabetes, depression and anxiety is disclosed. WO02/04433 (The Neurogen Corporation) describes in N-arylpiperazine derivatives and related 4- arylpiperidine derivatives as selective modulators of MCH-IR for the treatment of a variety of metabolic, feeding and sexual disorders. In WO02/06245 (Synaptic Pharmaceutical Corporation) a class of dihydropyrimidinones as MCH-IR antagonists for the treatment of feeding disorders, such as obesity and bulimia is disclosed. In WO02/051809 (Schering Corporation) 4-substituted piperidine derivatives are disclosed as MCH antagonists as well as their use in the treatment of obesity. In WO02/057233 aryl- substituted ureas are disclosed as MCH antagonists as well as their use in the treatment of obesity. The central core in the WO02/057233 is a(n) (hetero)arylene group, whereas the central core in the present compounds is an octahydroindole group. Mesembrine, 3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-6H-indol-6-one, is a natural product obtained as an extract of plants of the Mesembryanthemaceae family, including Sceletium tortuosum. In small doses the mesembrine have a meditative or narcotic effect. Hottentots used Sceletium expansum and tortuosum as a psychedelic called "channa". The use of mesembrine as a serotonin-uptake inhibitor for the treatment of an array of mental disorders is disclosed in WO97/46234. Parkes et al., Journal of Neuroendocrinology 1996, 8, 57-63 has shown that the MCH-peptide acts as a diuretic. Therefore, MCH antagonists should work as anti-diuretics. US 6,288,104 discloses mesembrine-like compounds lacking the urea group in the present compounds. This document relates to serotonin-uptake inhibitors for the treatment of depression and anxiety, whereas the present compounds are antagonists for the MCH- IR. None of the above disclosures discloses the compounds according to the present invention as antagonists for the MCH-IR.
DISCLOSURE OF THE INVENTION According to the present invention, novel substituted octahydroindoles have been found that are active towards the MCH1R receptor. The compounds are relatively easy to prepare and can be used for the treatment or prevention of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, modulation of appetite, depression, anxiety or urinary incontinence. The compounds can further be used in conjunction with other compounds acting through other mechanisms, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists. The compounds can also be used in conjunction with anti-obesity medicaments.
Definitions
The following definitions shall apply throughout the specification and the appended claims. Unless otherwise stated or indicated, the term "Cι-6-alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. For parts of the range "d-6-alkyl" all subgroups thereof are contemplated such as Cι-5-alkyl, Cι-4-alkyl, Cι-3-alkyl, Cι-2-alkyl, C2- 6-alkyl, C2-5-alkyl, C2-4-alkyl, C2-3-alkyl, C3-6-alkyl, C4-5-alkyl, etc. "Halo-Cι-6-alkyl" means a Cι-6-alkyl group substituted by one or more halogen atoms. Unless otherwise stated or indicated, the term "C3-8-cycloalkyl" denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl. For parts of the range "C3-8-cycloalkyl" all subgroups thereof are contemplated such as C3-7-cycloalkyl, C -6-cycloalkyl, C3-5-cycloalkyl, C3- -cycloalkyl, C4- 8-cycloalkyl, C4-7-cycloalkyl, C4-6-cycloalkyl, C4-5-cycloalkyl, C5- -cycloalkyl, C6-7- cycloalkyl, etc. Unless otherwise stated or indicated, the term "Cι-6 alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t- butoxy and straight- and branched-chain pentoxy and hexoxy. For parts of the range "C]-6- alkoxy" all subgroups thereof are contemplated such as Cι-5-alkoxy, Cι-4-alkoxy, Cι-3- alkoxy, Cι-2-alkoxy, C2-6-alkoxy, C2-5-alkoxy, C2-4-alkoxy, C2-3-alkoxy, C3-6-alkoxy, C4-5- alkoxy, etc. "Halo-Cι-6-alkoxy" means a Cι-6-alkoxy group substituted by one or more halogen atoms. Unless otherwise stated or indicated, the term "C2-6-alkenyl" denotes a straight or branched alkenyl group having from 2 to 6 carbon atoms. Examples of said alkenyl include vinyl, allyl, 1-butenyl, 1-pentenyl, and 1-hexenyl. For parts of the range "C2-6-alkenyl" all subgroups thereof are contemplated such as C2-5-alkenyl, C -4-alkenyl, C2-3-alkenyl, C3-6- alkenyl, C3- -alkenyl, C3-4-alkenyl, C4-6-alkenyl, C4-5-alkenyl, etc. Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine. Unless otherwise stated or indicated, the term "aryl" refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryls are phenyl, pentalenyl, indenyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl.
The aryl rings may optionally be substituted by Cι-6-alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl. The term "heteroaryl" refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, and indolyl groups. The term "heterocyclo" refers to a hydrocarbon ring system containing 4 to 8 ring members that have at least one heteroatom (e.g., S, N, or O) as part of the ring. It includes saturated, unsaturated, aromatic, and nonaromatic heterocycles. Suitable heterocyclo groups include thienyl, furyl, pyridyl, pyrrolidinyl, imidazolyl, pyrazolyl, piperidyl, azepinyl, morpholinyl, pyranyl, dioxanyl, pyridazinyl, pyrimidinyl, and piperazinyl groups. "Pharmaceutically acceptable" means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use. "Treatment" as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established. "An effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., Mc-Graw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13- 15. When two of the above-mentioned terms are used together, it is intended thatlthe latter group is substituted by the former. For example, aryl-Cι-6 alkyl means a Cι-6-alkyl group that is substituted by an aryl group. Likewise, halo Cι-6 alkoxy means a Cι-6-alkoxy group that is substituted by one or more halogen atoms. The following abbreviations have been used: (Boc) O means di-tert-butyl carbonate, DCM means dichloromethane, DIBAL-H means diisobutylaluminium hydride, DMF means dimethylformamide, HPLC means high performance liquid chromatography, Hunig's base means N-ethyldiisopropylamine, PNP means para-nitrophenyl, R.T. (rt) means room temperature, TFA means trifluoroacetic acid, THF means tetrahydrofuran.
In a first aspect, the present invention provides a compound of the general formula
(I)
Figure imgf000007_0001
or a pharmaceutically acceptable salt, hydrates, geometrical isomers, racemates, tautomers, optical isomers, N-oxides and prodrug forms thereof, wherein: R1 is C1-6-alkyl; R2 is Cι-6-alkyl; or R1 and R2 are linked to form Cι-3-alkylene;
R3 is H, Cι-6-alkyl, Cι-6-alkoxycarbonyl, Cι.6-alkoxycarbonyl-Cι-6-alkyl, Cι-6- alkoxycarbonyl-C3-6-cycloalkyl-C1-6 alkyl, aryl-Cι.6-alkyl, heteroaryl-Ci-6 alkyl, aryl or heteroaryl, wherein any aryl or heteroaryl may be unsubstituted or independently substituted with Cι-6-alkyl, C]-6-alkoxy, Cι-6-alkoxycarbonyl, Cι-6-alkoxycarbonyl-Cι-6- alkyl, Cι-6-alkoxycarbonyl-C3-6-cycloalkyl-Cι-6 alkyl, halo-Cι-6-alkyl, halo-Cι-6-alkoxy, or nitro;
R4 is H or Cι-6-alkyl; R5 is H, OH, Cι-6-alkyl, Cι-6-alkylaminocarbonyl, or Cι-6-alkylaminothioxylcarbonyl; R6 is H or Cι_6-alkyl; R7 is H, Cι-6-alkyl, C2-6-alkenyl, C3-8-cycloalkyl, C3-8-cycloalkyl-Cι-6-alkyl, C^.g-alkoxy,
Cι_6-alkoxy-Cι-6-alkyl, Cι-6-alkylcarbonyl, Ci.g-alkoxycarbonyl, Cι _6-alkoxycarbonyl-
Cι-6-alkyl, heterocyclo-Cι-6-alkyl, heteroaryl-Cι-6-alkyl, aryl-Cι-6-alkyl, arylcarbonyl, heteroarylcarbonyl, or heterocyclyl, wherein any aryl, heteroaryl and heterocyclyl may be unsubstituted or substituted in one, two or three positions with Cι-6-alkyl, halo-Cι-6-alkyl, Cj.g-alkoxy, or halogen; or R6 and R7 are linked to form C4-6-alkylene or together with the nitrogen atom to which they are attached form a piperazine ring, which may be unsubstituted or substituted in one position with Cι-6-alkyl; R8 is H or Cι-6-alkyl; and X is O, S, NH, CH-NO2, or NCN.
In some embodiments R1 and R2 are methyl. 1 In some embodiments that R and R are linked to form methylene. In some embodiments R4 is H. In some embodiments R8 is H.
In some embodiments when X is S: - R3 is hydrogen; methyl; ethyl; n-propyl; isobutyl; pentyl; tert-butoxycarbonyl; ethoxycarbonylmethyl; ethoxycarbonylcyclopropylmethyl; benzyl, which may be unsubstituted or independently substituted in one or two positions with trifluoromethyl, methoxy, trifluoromethoxy, and nitro; phenylethyl; phenylpropyl; furylmethyl; methyl-furylmethyl; thienylmethyl; methyl-pyrrolylmethyl; pyridylmethyl; methyl- lH-imidazolylmethyl; or quinolinylmethyl; - R5 is H or methyl; - R6 is H; and - R7 is ethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hexyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, allyl, methoxypropyl, morpholinylethyl, furylmethyl, benzyl, phenylethyl, fluorobenzyl, or methoxybenzyl.
In some embodiments when X is O: - R3 is methyl or benzyl; - R5 is H; - R6 is H or methyl; - R7 is ethyl, allyl, benzyl, ethoxycarbonylethyl, piperazinylethyl, piperazinylpropyl, methylbenzyl, fluorobenzyl, bromobenzyl, dichlorobenzyl, methoxybenzyl, trifluoromethylbenzyl, phenylethyl, thienylethyl, pyridinylmethyl, methylpyrazinylmethyl, or 4-methylpiperazin-l-yl; or that - R6 and R7 together with the nitrogen to which they are attached form a piperazine, which may be unsubstituted or substituted in one position with methyl.
In some embodiments hen X is NH: - R3 is methyl; - R5 and R6 both are H; and - R7 is n-butyl, n-pentyl, or benzyl. Certain specific embodiments are denoted in Examples 10-76 and 78-95 below. All diastereomeric forms possible (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Such compounds can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms are contemplated. Another object of the present invention is a process for the preparation of a compound above comprising at least one of the following steps: (a) treatment of a nitrile with an alkali amide and then with l-bromo-2-chloroethane to give a cyclopropanecarbonitrile, (b) reduction of a cyclopropanecarbonitrile with diisobutylaluminium hydride to give a cyclopropanecarbaldehyde,
(c) reaction of a cyclopropanecarbaldehyde with benzylamine to give an imine and further reaction of the imine with a ketone, (d) treatment of a ketone with ammonia, an amine or a salt thereof and then reduction to give an amine,
(e) protection of an amine with a tert-butyloxycarbonyl group,
(f) treatment of an amine with an isocyanate or isothiocyanate,
(g) treatment of a first amine with αra-nitrophenylchloro formate and then with Hunigs base to give a PNP-carbamate, and treatment of a second amine with said PNP-carbamate,
(h) reductive alkylation by treatment of an amine with an aldehyde and subsequent reduction,
(i) deprotection of a tert-butyloxycarbonyl group with trifluoroacetic acid,
(j) treatment of an amine with a carboximidamide, and (k) treatment of a first amine with triphosgene and then with a second amine. Another object of the present invention is a compound as described above for use in therapy. The compound can be used in the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, urinary incontinence, and for modulation of appetite. It may also be used in the treatment or prophylaxis of disorders relating to the MCH1R receptor and for modulation of appetite. Examples of such disorders are obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence. The compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists. The compound can also be used in conjunction with anti-obesity medicaments. Another object of the present invention is a pharmaceutical formulation containing a compound as described above as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier. The pharmaceutical formulation may be used in the treatment or prophylaxis of obesity wherein the active ingredient is a compound as described above. Another object of the present invention is a method for the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, urinary incontinence, and for modulation of appetite, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment (e.g., including the step of identifying the subject as in need of such treatment) an effective amount of a compound as described above. The compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists. The compound can also be used in conjunction with anti-obesity medicaments. Another object of the present invention is a method for the treatment or prophylaxis of disorders related to the MCHIR receptor and for modulation of appetite, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above. The MCHIR receptor related disorder is any disorder or symptom wherein the MCHIR receptor is involved in the process or presentation of the disorder or the symptom. The MCHIR related disorders include, but are not limited to obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence. The compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists. The compound can also be used in conjunction with anti-obesity medicaments. The methods delineated herein can also include the step of identifying that the subject is in need of treatment of the MCHIR receptor-related disorder. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). Another object of the present invention is a method for modulating MCHIR receptor activity (e.g., antagonizing the human MCHIR receptor), comprising administering to a subject (e.g., mammal, human, or animal) in need thereof an effective amount of a compound as described above or a composition comprising a compound as described above. Another object of the present invention is the use of a compound as described above in the manufacture of a medicament for use in the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence, and for modulation of appetite. Another object of the present invention is the use of a compound as described above in the manufacture of a medicament for use in the treatment or prophylaxis of disorders related to the MCHIR receptor and for modulation of appetite, said method comprising administering to a subject (e.g., mammal, human, or animal) in need of such treatment an effective amount of a compound as described above. The MCHIR receptor related disorder is any disorder or symptom wherein the MCHIR receptor is involved in the process or presentation of the disorder or the symptom. The MCHIR related disorders include, but are not limited to obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence. The compound can further be used in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists. The compound can also be used in conjunction with anti-obesity medicaments. The compounds of the formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like. For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetring agents, emulsifiers, flavouring agents, buffers, and the like. The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner. In a further aspect the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods. The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. 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 base compounds. Examples of addition salt forming acids are mentioned above. The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns. The chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective
Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen. The invention will now be further illustrated by the following non-limiting Examples.
The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.
General comments
Η nuclear magnetic resonance (NMR) and 13C NMR were recorded on a Bruker PMR 500 spectrometer at 500.1 MHz and 125.1 MHz, respectively or on a JEOL eclipse 270 spectrometer at 270.0 MHz and 67.5 MHz, respectively, or on a Bruker Advance DPX 400 spectrometer at 400.1 and 100.6 MHz, respectively. All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. . All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. IR spectra were recorded on a Perkin-Elmer Spectrum 1000 FT-IR spectrometer. Electrospray mass spectrometry (MS) were obtained using an Agilent MSD mass spectrometer. Accurate mass measurements were performed on a Micromass LCT dual probe. Elemental analyses were performed on a Vario El instrument or sent to Mikro Kemi in Uppsala.
Analytical HPLC were performed on Agilent 1100. Preparative HPLC was performed on a
Gilson system or on a Waters/Micromass Platform ZQ system. Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh). The compounds were automatically named using ACD6.0. GC-MS analysis were performed on a Hewlett Packard 5890 gas chromatograph with a HP-5MS 15 m*0.25 mm*0.25μm column connected to a 5971 MS detector. Electrospray mass spectrometry (MS) spectra were obtained on a Perkin-Elmer API 150EX mass spectrometer. Accurate mass measurements were performed on a Micromass LCT dual probe.
General procedures for the preparation of compounds of the present invention
Scheme A. General procedure urea and thiourea formation via RNCX
Figure imgf000015_0001
A solution of the amine, (3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyi)octahydro- lH-indol-6-amine, Comparative Example 5 (18.3 mg; 0.05 mmol) in methylene chloride (2.0 ml) was treated with an isocyanate or isothiocyanate (1 equiv.; 0.05 mmol) The mixture was shaken at room temperature for 18 h, then the solvent was removed by evaporation.
The residues were purified by preparative HPLC. Scheme B. General procedure for urea formation via p-nitrophenylchloroformate
Figure imgf000016_0001
A solution of the appropriate amine (1 mmol) in DCM (5.0 ml) was treated withpara- mtrophenylchloroformate (1 mmol). The resulting solution was then treated dropwise at room temperature with Hunigs base (1 mmol). The mixtures were stirred at room temperature for 5h.
An aliquot (0.25 ml; 0.05 mmol) of the crude PNP-carbamate from the reaction mixtures described above was then transferred to a solution of the amine, (3aS*,6R*,7aS*)-l- benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-amine, Comparative Example 5 (18 mg; 0.05 mmol) in methylene chloride (3.0 ml) and the resulting solution shaken at R.T. overnight.
The solvent was removed by evaporation and the crude reaction mixtures purified by preparative HPLC.
Scheme C. General procedure for urea and thiourea formation via RNCX
Figure imgf000016_0002
A solution of the amine, (3aS*,6R*,7aS*)-l-methyl-3a-(3,4-dimethoxyphenyi)octahydro- lH-indol-6-amine, Comparative Example 7 (7.3 mg; 0.025 mmol) in tetrahydrofuran (1.0 ml) was treated with and isocyanate or isothiocyanate (1 equiv.; 0.025 mmol) The mixture was shaken at room temperature for 18 h, then the solvent was removed by evaporation.
The residues were purified by preparative HPLC.
Scheme D
Figure imgf000017_0001
The amine, (3aS*,6R*,7aS*)-l-methyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- amine, Comparative Example 7 (7 mg, 0.024 mmol) and isocyanate (1.3 eq) were dissolved in dry THF (1.5 ml). Reaction in R.T., under N2 and overnight. The solvent was evaporated under reduced pressure. Purification was performed by preparative HPLC.
Scheme E. General procedure for reductive alkylation
Figure imgf000017_0002
To the appropiate amine (0.06 mmol) in EtOH (0.5 ml) and THF (0.5 ml) was added an aldehyde (0.1 mmol) and NaBH3CN (1 mmol). The mixture was stirred overnight and concentrated. 2 M NaOH was added and the aqueous layer extracted with EtOAc. The products were purified by preparative HPLC. Synthesis of starting materials (Examples 1-9)
COMPARATIVE EXAMPLE 1 - l-(3.4-dimethoxyphenvncvclθDropanecarbonitrile
Dimethoxyphenyl acetonitrile (4.43 g, 2.5 mmol) was dissolved in DMF (20 mL). Sodium hydride (4 g of a 60% dispersion, 2.4 g, 100 mmol) was added in portions and the mixture was stirred at room temperature for 10 minutes. Bromochloroethane (2.1 mL, 3.62 g, 25.2 mmol) was added, and the mixture stirred at room temperature overnight. The reaction was cautiously quenched by addition of a methanol / water mixture (1 :1, 300 mL) and the reaction products were extracted into ethyl acetate (3 x 200 mL). The combined extracts were washed with water (4 x 200 mL), brine (1 x 200 mL) and then dried (Na2SO4). The solvent was then removed under reduced pressure and the crude product chromatographed (SiO2, EtOAc / petroleum ether 1:3 as eluent) to give the title compound as an off-white solid (2.4 g, 47 %). 1H NMR (270 MHz, CDC13) δ 1.32 (m, 2H) 1.64 (m, 2H) 3.84 (s, 3H) 3.88 (s 3H) 6.79 (d, J = 1.0 Hz, 2H) 6.84 (s 1H). MS (ESI+) for C,2Hι3NO2: m/z 204.1 (M+1). .
COMPARATIVE EXAMPLE 2 - l-f3.4-dimethoxyphenyl vclopropanecarbaldehvde
l-(3,4-dimethoxyphenyl)cyclopropanecarbonitrile, Comparative Example 1 (2.0 g, 9.84 mmol) was dissolved in THF (30 mL). DIBAL-H (15 mL of a 1.0 M solution in toluene, 15 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction was cautiously quenched by addition of 2 M HC1 and organic components were extracted into dichloromethane (3 x 125 mL). The combined extracts were washed with water (2 x 100 mL), brine (2 x 100 mL) and then dried (Na2SO4), giving the title compound as an off-white sold (1.95 g, 98 %). Η NMR (270 MHz, CDC13) δ ppm 1.38 (m, 2H) 1.53 (m, 2H) 3.87 (s, 6H) 6.81 (s, 1H) 6.84 (d, J = 1.0 Hz, 2H) 9.23 (s, 1H). MS (ESI+) for Cι2Hι4O3: no ion detected
COMPARATIVE EXAMPLE 3 - f3aS*.7aS»Vl-benzyl-3a-(3.4- dimethoxyphenyl")octahvdro-6H-indol-6-one
l-(3,4-dimethoxyphenyl)cyclopropanecarbaldehyde, Comparative Example 2 (3.25 g, 16.0 mmol) was dissolved in dichloromethane (35 mL). Benzylamine (1.77 mL, 1.74 g, 16.2 mmol) was added, followed by sodium sulfate (15 g, 105.6 mmol). The mixture was stirred at room temperature overnight before being filtered and evaporated to yield the crude imine as a clear oil. This material was then dissolved in DMF (15 mL), and sodium iodide (246 mg, 1.64 mmol) and trimethylsilyl chloride (202 μL, 172 mg, 1.58 mmol) were added. The resulting mixture was heated to 70°C for 3 hours and then partitioned between water (150 mL) and ethyl acetate (200 mL). The aqueous phase was extracted with a further portion of ethyl acetate (1 x 200 mL) and the combined extracts were washed with brine (1 x 200 mL) and dried (Na2SO4). The solvent was removed under reduced pressure, and the crude product dissolved in dichloromethane (30 mL). To this was added HC1 in ether (70 mL of a 1.0 M solution, 70 mmol) and the crude HC1 salt was evaporated to dryness. This material was then dissolved in acetonitrile (70 mL), methyl vinyl ketone (1.42 mL, 1.19 g, 17 mmol) was added and the mixture heated to reflux for 16 hours. On cooling the solvent was removed under reduced pressure and the resulting dark oil partitioned between 3M HC1 solution (200 mL) and ether (150 mL). The aqueous fraction was washed with further ether (3 x 150 mL), and then brought to basic pH using 3 M NaOH solution. The organic components were then extracted into diethyl ether (3 x 150 mL) and the combined extracts washed with brine (1 x 200 mL) and dried (Na2SO4). On removal of the solvent under reduced pressure, the crude product was purified by chromatography (SiO2, ethyl acetate / petroleum ether 2:3 as eluent) to give the title compound as a clear oil (3.10 g, 53 %). lH NMR (270 MHz, CDC13) δ ppm: 1.87-2.38 (m, 6H); (2.38-2.82 (m, 3H); 2.82-3.05 (m, 1H); 3.05-3.20 (m, J = 12.6 Hz, 1H); 3.20-3.35 (m, 1H); 3.92 (s, 6H); 3.96-4.19 (m, J= 12.6 Hz, 1H); 6.73-7.03 (m, 3H) 7.09-7.42. 13C NMR (68 MHz, CDC13) δ ppm: 34.80, 36.21, 38.61,40.63, 47.18, 51.67, 53.38, 57.38, 60.32, 68.15, 109.90, 110.95, 117.76, 126.89, 128.15, 128.76, 138.79, 140.32, 147.47, 148.98, 211.36.
COMPARATIVE EXAMPLE 4 - (3aS*.7aS*V3a-(3.4-dimethoχyphenvn-l- methyloctahvdro-6H-indol-6-one l-(3,4-dimethoxyphenyl)cyclopropanecarbaldehyde, Comparative Example 2 (8.0 g, 38.8 mmol) was dissolved in dichloroethane (100 mL). Sodium sulfate (25 g, 176 mmol) was added and methylamine gas was bubbled through the solution for 10 minutes. The reaction vessel was then sealed and the mixture stirred at room temperature overnight before being filtered and evaporated to yield the crude imine as a yellow oil. This material was then dissolved in DMF (30 mL), and sodium iodide (585 mg, 3.90 mmol) and trimethylsilyl chloride (500 L, 426 mg, 3.92 mmol) were added. The resulting mixture was heated to 90° C for 3 hours and then partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous phase was extracted with a further ethyl acetate (2 x 100 mL) and the combined extracts were dried (Na2SO4). The solvent was removed under reduced pressure, and the crude product dissolved in dichloromethane (100 mL). To this was added HC1 in ether (100 mL of a 1.0 M solution, 100 mmol) and the crude HC1 salt was evaporated to dryness. This material was then dissolved in acetonitrile (100 mL), methyl vinyl ketone (3.5 mL, 2.95 g, 42.1 mmol) was added and the mixture heated to reflux for 16 hours. On cooling the solvent was removed under reduced pressure and the resulting dark oil partitioned between 3M HC1 solution (200 mL) and ether (200 mL). The aqueous fraction was washed with further ether (2 x 100 mL), and then brought to basic pH using 3 M NaOH solution. The organic components were then extracted into ethyl acetate (4 x 150 mL) and the combined extracts washed with brine (1 x 200 mL) and dried (Na2SO4). On removal of the solvent under reduced pressure, the crude product was purified by chromatography (SiO2, ethyl acetate as eluent) to give the title compound as a yellow oil (4.5 g, 40 %).
Η NMR (270 MHz, CDC13) δ ppm: 1.99-2.12 (m, 2H); 2.12-2.26 (m, 3H); 2.28 (s, 3H); 2.30-2.47 (m, 2H); 2.52-2.62 (m, 2H); 2.88-2.95 (m, 1H) 3.06-3.15 (m, 1H) 3.85 (s, 3H); 3.87 (s, 3H); 6.76-6.93 (m, 3H). 13C NMR (68 MHz, CDC13) δ ppm: 35.20, 36.16, 38.76, 40.01, 40.48, 47.42, 54.78, 55.82, 55.92, 70.31, 109.84, 110.87, 117.83, 140.12, 147.39, 148.90, 211.40. MS (ESI+) for C17H23NO3 m/z 290.2 (M+H)+. HRMS (El) calcd for C17H23NO3: 289.1678, found 289.1684
COMPARATIVE EXAMPLE 5 - (3aS*.6R*,7aS*Vl-benzyl-3a-f3.4- dimethoxyphenvDoctahydro- 1 H-indol-6-amine and
COMPARATIVE EXAMPLE 6 - (3aS*.6S*.7aS*)-l-benzyl-3a-f3.4- dimethox vphenylloctahydro- 1 H-indol-6-amine
(3 aS * ,7aS *)- 1 -benzyl-3 a-(3 ,4-dimethoxyphenyl)octahydro-6H-indol-6-one (Comparative
Example 3) (750 mg, 2.05 mmol) was dissolved in methanol (60 mL). Ammonium acetate
(1.6 g, 20.8 mmol) was added and the solution allowed to stir at room temperature for 2 hours before sodium cyanoborohydride (100 mg, 1.59 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with 3 M NaOH solution (100 mL) and extracted into dichloromethane (2 x 150 mL). The combined extracts were dried (Na2SO4) and the solvent removed to give the crude mixture of amines (410 mg, 55 %). This crude material was used as a mixture without further purification, or the cis (6R*)- and trans- isomer (6S*) separated by flash chromatography using chloroform saturated with NH3 (g).
COMPARATIVE EXAMPLE 7 - (3aS*.6R*.7aS*)-l-methyl-3a-r3.4- dimethox vphenvDoctahydro- 1 H-indol-6-amine and COMPARATIVE EXAMPLE 8 - (3aS*.6S* aS*Vl-methyl-3a-G.4- dimethoxyphenyl octahydro-lH-indol-6-amine
Same procedure as for Comparative Example 5 and Comparative Example 6 starting from (3aS*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-6H-indol-6-one (Comparative Example 4). This crude material was used as a mixture without further purification, or the cis (6R*)- and trans-isomer (6S*,) separated by flash chromatography using chloroform saturated with NH3 (g).
COMPARATIVE EXAMPLE 9 - tert-butyl (3aS*.7aS*V3a-r3.4-dimethoxyphenvn-6- oxooctahydro-lH-indole-l-carboxylate
Into a solution of Comparative Example 3 (3.0 g, 8.2 mmol) and (Boc)2O (3.0 g, 13.7 mmol) in i-PrOH (200 mL) was suspended 10% Pd on charcoal (0.8 g), and the resulting mixture was vigorously agitated under H2 (1.4 atm) during 4h at rt. The catalyst was filtered off and the filtrate was shaken with PS-trisamine (3.0 g, 4 mmol/g) at rt overnight. The resin was filtered off and the solvent evaporated, leaving the title compound (2.4 g, 80%) as a thick oil, which was used in the next step without further purification. Η NMR (270 MHz, CDC13): δ ppm 1.28-1.51 (m, 9H), 1.96-2.38 (m, 6H), 2.43-2.72 (m, 1H), 2.72-2.89 (m, 1H), 3.14-3.45 (m, 1H), 3.68-3.84 (m, 6H), 4.27-4.58 (m, 1H), 6.60- 6.84 (m, 3H).
13C NMR (270 MHz, CDC13): δ ppm 14.22, 21.04, 28.50, 33.22, 36.59, 44.76, 55.90, 55.96, 60.29, 79.87, 100.00, 109.49, 111.20, 117.99, 137.66, 147.86, 149.08, 210.41. Synthesis of Examples 10-95
EXAMPLE 10 - N-rr3aS*.6S*.7aS* -l-benzyl-3a-(3.4-dimethoχyphenvnoctahvdro-lH- indol-6-yl"|-N'-ethylthiourea and
EXAMPLE 11 - N-r(3aS*.6R*.7aS* -l-benzyl-3a-C3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yl]-N'-ethylthiourea
The compounds were synthesised (starting with 705 mg of the mixture of amines) and purified in an analogous method to that described in Example 14 and 15 to give:
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- ethylthiourea (80 mg, 9%)
MS (ESI+) for C26H35N3O2S: m/z 454.0 (M+1)
HRMS (El) calcd C26H35N3O2S: 453.2450, found 453.2472 N-[(3 aS* ,6S * ,7aS *)- 1 -benzyl-3 a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6-yl] -N'- ethylthiourea (200 mg, 23%)
MS (ESI+) for C26H35N3O2S: m/z 454.0 (M+1)
HRMS (El) calcd C26H35N3O2S: 453.2435, found 453.2450
EXAMPLE 12 - N-rr3aS*.6R*.7aS* -l-benzyl-3a-(3.4-dimethoxyphenyl')octahvdro-lH- indol-6-yl]-N'-butylthiourea and
EXAMPLE 13 - N-r(3aS*.6S*.7aS*Vl-benzyl-3a-(3,4-dimethoxyphenyl)octahvdro-lH- indol-6- yl] -N'-but ylthiourea
Compounds were prepared and purified in an analougous method to that described in
Example 14 and 15 to give:
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N,- butylthiourea (14 mg, 13 %) MS (ESI+) for C28H39N3O2S: m/z 482.1 (M+1)
HRMS (El) calcd C28H39N3O2S: 481.2763, found 481.2765
N-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- butylthiourea (30 mg, 28 %)
MS (ESI+) for C28H39N3O2S: m/z 482.1 (M+1) HRMS (El) calcd C28H39N3O2S: 481.2763, found 481.2742
EXAMPLE 14 - N-benzyl-N,-IY3aS*,6R*.7aS*Vl-benzyl-3a-f3.4- dimethoxyphenyDoctahvdro-lH-indol-6-yl1thiourea and
EXAMPLE 15 - N-benzyl-N'-r(3aS*.6S* aS*)-l-benzyl-3a-(3,4- dimethoxyphenyl)octahydro-lH-indol-6-yllthiourea
The mixture of cis and trans amines from Comparative Example 5 and Comparative Example 6 (82.5 mg, 225 μmol) was dissolved in dichloromethane (5 mL). Benzyl isothiocyanate (39 μL, 43.9 mg, 294 μmol) was added and the mixture stirred at room temperature for 16 hours. The solvent was then removed, and the crude reaction mixture chromatographed (SiO2, petroleum ether / ethyl acetate 5:2 as eluent) to give:
N-benzyl-N'-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea (10 mg, 9 %):
MS (ESI+) for C31H37N3O2S: m/z 516.2 (M+1)
HRMS (El) calcd C3ιH37N3O2S: 515.2606, found 516.2602
N-benzyl-N'-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea (25 mg, 22 %): MS (ESI+) for C31H37N3O2S: m/z 516.2 (M+1)
HRMS (El) calcd C3ιH37N3O2S: 515.2606, found 516.2623
EXAMPLE 16 - N-rf3aS*,6S* aS*Vl-benzyl-3a-(3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yll-N'-ethylurea
The compound was synthesised and purified an analougous method to that described in
Example 14 and 15 to give:
N-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyρhenyl)octahydro-lH-indol-6-yl]-N'- ethylurea (20 mg, 20 %) MS (ESI+) for C26H35N3O3: m/z 438.5 (M+1)
HRMS (El) calcd C26H35N3O3: 437.2678, found 437.2670
EXAMPLE 17 - tert-butyl (3aS*.6R*.7aS* -6-{r(benzylamino carbonothioyl1aminol-3a-
(3.4-dimethoxyphenyl)octahydro-lH-indole-l-carboxylate And
EXAMPLE 18 - tert-butyl r3aS*.6S*.7aS*)-6-{r(benzylamino')carbonothioyllamino}-3a-
(3,4-dimethoxyphenyl)octahydro-lH-indole-l-carboxylate
NH4OAc (2 g) was added to a solution of tert-butyl (3aS*,7aS*)-3a-(3,4- dimethoxyphenyl)-6-oxooctahydro-lH-indole-l-carboxylate (Comparative Example 9, 2.4 g, 6.4 mmol) in MeOH (50 ml), and the solution was stirred at ambient temperature for 2 h before NaBH3CN (400 mg) was added and the mixture stirred overnight. The mixture was diluted with 3 M NaOH (50 ml) and extracted with dichloromethane. The crude mixture of amines was used without further purifications.
Benzyl thioisocyanate (1.5 eqv.) was added to a solution of the amine mixture from above
(O.lg, 0.26 mmol) in CHC13 (50 ml) and the mixture was stirred at ambient temperature overnight. Trisamine-PS (1 g) was added and the mixture stirred for 4 h before filtration and separation of products by flash chromatography (silica, CHCl3/MeOH/NH3). First eluted. tert-butyl (3aS*,6R*, 7aS*)-6-{[(benzylamino)carbonothioyl]amino}-3a-(3,4- dimethoxyphenyl)octahydro-lH-indole-l-carboxylate: 215 mg.
Η NMR (270 MHz, CDC13): δ ppm 1.13-1.53 (m, 10H), 1.65-1.99 (m, 4H), 1.99-2.23 (m,
IH), 2.92-3.31 (m, IH), 3.31-3.66 (m, 3H), 3.77-3.94 (m, 6H), 3.96-4.15 (m, IH), 4.74- 5.01 (m, IH), 5.79-5.96 (m, IH), 6.74-6.91 (m, 3H), 7.18-7.34 (m, 3H), 7.34-7.44 (m, IH),
7.44-7.70 (m, IH). (ESI+) m/z 526 (M+1).
HRMS (El) Calc for C32H36F3N3O3S: 525.2661; found 525.2662.
Relative configuration was determend by NMR.
Second eluted: tert-butyl (3aS*,6S*, 7aS*)-6-{[(benzylamino)carbonothioyl]amino}-3a- (3,4-dimethoxyphenyl)octahydro-lH-indole-l-carboxylate: 300 mg
EXAMPLE 19 - N-benzyl-N'-r(3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenvnoctahydro-lH- indol-6-yllthiourea
To a solution of Example 17 (600 mg, 1.14 mmol) in DCM (20 mL) was added trifluoroacetic acid (20 mL) and the resulting solution was stirred at rt during 5 min. The volatiles were evaporated under reduced pressure and the residue was partitioned between
EtOAc (5mL) and NaOH (aq., 1M, 2 mL). The water phase was extracted with EtOAc and the organic phases were washed with saturated aqueous NaCl (2 mL), dried (MgSO4) and evaporated to give the title compound (0.44 g, 91%) as a colorless oil. 1H NMR (270 MHz, CDC13): δ ppm 1.01-1.15 (m, IH), 1.15-1.42 (m, IH), 1.56-1.68 (m, IH), 1.72-1.89 (m, 2H), 1.90-2.15 (m, 4H), 2.20-2.33 (m, IH), 2.34-2.45 (m, IH), 3.09- 3.22 (m, IH), 3.22-3.40 (m, IH), 3.77-3.97 (m, 6H), 4.17-4.39 (m, IH), 4.59-4.94 (m, 2H), 5.67-6.16 (m, IH), 6.65-6.94 (m, 3H), 7.18-7.40 (m, 5H). MS (ESI+) m/z 426 (M+1). HRMS (El) Calc for C24H3,N3O2S: 425.2137; found 425.2157.
EXAMPLE 20 - N-benzyl-N'-r(3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenylVl-('quinolin-3- ylmethyl')octahvdro-lH-indol-6-yl~|thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro- lH-indol-6- yl]thiourea (Example 19, 20 mg, 0.051 mmol) and quinoline-3-carbaldehyde (0.25 mmol), gave the title compound after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 1.04-1.26 (m, IH), 1.26-2.61 (m, 8H), 2.83-3.20 (m, 3H), 3.20-3.38 (m, IH), 3.69- 3.91 (m, 6H), 4.27-4.67 (m, 3H), 4.77-4.99 (m, 2H), 5.21-5.46 (m, IH), 5.75-6.07 (m, IH), 6.68-6.90 (m, 3H), 7.40-7.58 (m, 2H), 7.58-7.69 (m, IH), 7.72-7.87 (m, IH), 7.99-8.21 (m, 3H), 8.81-8.81-8.92 (m, IH). MS (ESI+) m/z 567 (M+1). HRMS (El) Calc for C34H38N4O2S: 566.2715; found 566.2695.
EXAMPLE 21 - N-benzyl-N'-(f3aS*.6R* aS* -3a-f3.4-dimethoxyphenvn-l-r3- (trifluoromethvDbenzyl] octahydro- 1 H-indol-6-yl I thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea (Example 19, 20 mg, 0.051 mmol) and 3-(trifluoromethyl)benzaldehyde (0.25 mmol), gave the title compound after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 1.01-1.17 (m, IH), 1.24-1.59 (m, 3H), 1.59-1.85 (m, 3H), 1.85-2.51 (m, 4H), 2.81-3.24 (m, 3H), 3.67-3.92 (m, 6H), 4.10-4.33 (m, IH), 4.33-4.70 (m, 3H), 5.20- 5.57 (m, IH), 5.72-6.05 (m, 2H), 6.66-6.91 (m, 3H), 7.19-7.85 (m, 7H). (ESI+) m/z 584 (M+1). HRMS (El) Calc for C32H36F3N3O2S: 583.2480; found 583.2487 EXAMPLE 22 - N-benzyl-N'-((3aS*.6R*.7aS'l')-3a-(3.4-dimethoxyphenylVl-r4- (trifluoromethoxy benzyl]octahydro- 1 H-indol-6- yl I thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea (Example 19, 20 mg, 0.051 mmol) and 4-(trifluoromethoxy)benzaldehyde (0.25 mmol), gave the title compound after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 1.03-1.29 (m, IH), 1.30-1.49 (m, IH), 1.49-1.66 (m, 2H), 1.66-1.91 (m, 3H), 1.91-2.35 (m, 3H), 2.35-2.60 (m, IH), 2.83-3.22 (m, 3H), 3.72-3.97 (m, 6H), 4.09- 4.34 (m, IH), 4.34-4.76 (m, 2H), 5.75-6.02 (m, IH), 6.73-6.95 (m, 3H), 7.05-7.19 (m, 2H), 7.20-7.34 (m, 5H), 7.34-7.49 (m, 2H).
MS (ESI+) m/z 600 (M+1). HRMS (El) Calc for C32H36F3N3O3S: 599.2429; found 599.2443
EXAMPLE 23 - N-benzyl-N'-r(3aS*.6R* aS*)-3a-(3.4-dimethoxyphenvn-l-(3- phenylpropyDoctahvdro- 1 H-indol-6- yl"| thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yljthiourea (Example 19, 20 mg, 0.051 mmol) and 3-phenylpropanal (0.25 mmol), gave the title compound as a colorless after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ ppm 0.95-1.42 (m, 3H), 1.42-1.87 (m, 6H), 1.87-2.35 (m, 5H), 2.35-3.04 (m, 4H), 3.07-3.31 (m, IH), 3.65-3.97 (m, 6H), 4.35-4.80 (m, 2H), 5.28-6.01 (m, IH), 6.60- 6.91 (m, 3H), 6.91-7.44 (m, 10H). MS (ESI+) m/z 544 (M+1). HRMS (El) Calc for C33H41N3O2S: 543.2919; found 543.2902.
EXAMPLE 24 - N-benzyl-N'-r('3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenvn-l-(pyridin-3- ylmethyDoctahvdro- 1 H-indol-6- yl") thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3 aS * ,6R* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6- yl]thiourea (Example 19, 20 mg, 0.051 mmol) and pyridine-3-carbaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ ppm 1.01-1.40 (m, 3H), 1.43-1.60 (m, 2H), 1.67-1.78 (m, 3H), 1.91- 2.04 (m, IH), 2.04-2.26 (m, 2H), 2.37-2.50 (m, IH), 2.83-2.99 (m, IH), 2.99-3.14 (m, 2H), 3.62-3.69 (m, IH), 3.76-3.87 (m, 7H), 4.12-4.27 (m, IH), 4.36-4.62 (m, 2H), 5.77-5.97 (m, IH), 6.71-6.71-6.84 (m, 3H), 6.96-7.00 (m, IH), 7.38-7.42 (m, IH), 7.71-7.85 (m, 5H), 8.40-8.45 (m, IH), 8.47-8.53 (m, IH). MS (ESI+) m/z 517 (M+1). HRMS (El) Calc for C30H36N4O2S: 516.2559; found 516.2557.
EXAMPLE 25 - N-benzyl-N'-[Y3aS*,6R* aS*)-3a-(3,4-dimethoxyphenylVl-(4- methox vbenzvDoctahvdro- 1 H-indol-6- yl]thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea (Example 19, 20 mg, 0.051 mmol) and 4-methoxybenzaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 1.01-1.15 (m, IH), 1.26-1.43 (m, IH), 1.43-1.63 (m, 2H), 1.63- 1.85 (m, 3H), 1.85-2.16 (m, 2H), 2.16-2.43 (m, IH), 2.84-3.20 (m, 3H), 3.66-3.77 (m, 3H), 3.77-3.92 (m, 6H), 3.95-4.18 (m, IH), 4.37-4.73 (m, 2H), 5.28-5.62 (m, IH), 5.62-5.99 (m, IH), 6.62-6.62-6.95 (m, 5H), 7.03-7.44 (m, 7 H). MS (ESI+) m/z 546 (M+1). HRMS (El) Calc for C32H39N3O3S: 545.2712; found 545.2712.
EXAMPLE 26 - ethyl [(3aS*.6R*.7aS*V6-{r(benzylamino carbonothioyllaminol-3a-f3.4- dimethox yphenvDoctahydro- 1 H-indol- 1 -yl] acetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3 aS * ,6R* ,7aS*)-3a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6- yljthiourea (Example 19, 20 mg, 0.051 mmol) and ethyl glyoxalate (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. lH NMR (270 MHz, CDC13): δ ppm 1.04-1.14 (m, 3H), 1.18-1.26 (m, IH), 1.34-1.43 (m, IH), 1.43-1.54 (m, 2H), 1.68-1.76 (m, IH), 1.76-1.85 (m, 2H), 1.89-2.13 (m, 3H), 2.45-2.69 (m, IH), 2.98- 3.50 (m, 4H), 3.64-3.78 (m, IH), 3.78-3.83 (m, 6H), 3.86-3.97 (m, IH), 3.97-4.20 (m, IH), 4.57-4.94 (m, 2H), 5.44-4.94 5.77 (m, IH), 6.66-6.85 (m, 3H), 7.22-7.35 (m, 5H). MS (ESI+) w/z 512 (M+l). HRMS (El) Calc for C28H37N3O4S: 511.2505; found 511.2518.
EXAMPLE 27 - N-benzyl-N'-IY3aS*,6R* aS*)-3a-π.4-dimethoxyphenylVl-(4- nitrobenzvDoctahydro- 1 H-indol-6- yllthiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3 aS * ,6R*,7aS *)-3 a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6- yljthiourea (Example 19, 20 mg, 0.051 mmol) and 4-nitrobenzaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 1.04-1.84 (m, 9H), 1.89-2.28 (m, 3H), 2.33-2.57 (m, IH), 2.72-3.00 (m, IH), 3.00-3.23 (m, 2H), 3.70-3.89 (m, 6H), 4.14-4.67 (m, 4H), 5.19-5.37 (m, IH), 5.67-6.02 (m, IH), 6.51-6.62 (m, IH), 6.69-6.87 (m, 3H), 7.20-7.36 (m, 3H), 7.48-7.64 (m, 2H), 7.70-7.85 (m, IH), 8.04-8.14 (m, 3H), 8.15-8.32 (m, IH). MS (ESI+) m/z 544 (M+1).
EXAMPLE 28- N-benzyl-N'-r(,3aS*.6R*.7aS* -3a-r3.4-dimethoxyphenyl)-l- pentyloctahvdro- 1 H-indol-6- yl]thiourea
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yljthiourea (Example 19, 20 mg, 0.051 mmol) and pentanal (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification.
Η NMR (270 MHz, CDC13): δ ppm 0.70-0.91 (m, 3H), 0.91-1.85 (m, 9H), 1.85-2.09 (m, 3H), 2.09-2.30 (m, 2H), 2.59-2.78 (m, IH), 2.78-2.94 (m, IH), 3.04-3.24 (m, IH), 3.70- 3.88 (m, 6H), 4.48-4.81 (m, IH), 5.64-5.88 (m, IH), 6.64-6.87 (m, 3H), 7.20-7.35 (m, 5H). MS (ESI+) m/z 496 (M+1). HRMS (El) Calc for C29H41N3O2S: 495.2919; found 495.2929.
EXAMPLE 29 - N-benzyl-N'-rf3aS*.6S*.7aS* -3a-(3.4-dimethoxyphenyl)octahydro-lH- indol-6-yl~| thiourea
To a solution of tert-butyl (3aS*,6S*,7aS*)-6-{[(benzylamino)carbonothioyl]amino}-3a- (3,4-dimethoxyphenyl)octahydro-lH-indole-l-carboxylate (Example 18, 10 mg) in DCM (2 mL) was added trifluoroacetic acid (2 mL) and the resulting solution was stirred at rt during 5 min. The volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc (5mL) and NaOH (aq., 1M, 2 mL). The water phase was re- extracted with EtOAc and the organic phases were washed with saturated aqueous NaCl (2 mL), dried (MgSO4) and evaporated to give the title compound as a colourless oil. Η NMR (500 MHz, CDC13): δ ppm 1.34-1.46 (m, IH), 1.61-2.08 (m, 9 H), 2.75-3.04 (m, 2 H), 3.69-3.79 (m, 1 H), 3.79-3.95 (m, 6 H), 4.25-4.79 (m, 3 H), 6.09-6.61 (m, 1 H), 6.78- 6.85 (m, 3 H), 7.27-7.39 (m, 4 H), 8.78-9.64 (m, 1 H). MS (ESI+): m/z 426 (M+1)
EXAMPLE 30 - N-aHyl-N'-r('3aS*,6R*,7aS*)-l-benzyl-3a-(3,4- dimethox vphenyl)octahvdro-l H-indol-6- yllurea trifluoroacetate Reagent: allyl isocyanate Synthetic procedure: Scheme A Yield: 12.7 mg Measured mass: 449.2669 Calc. mass: 449.2678
EXAMPLE 31 - N-r(3aS*.6R*.7aS*)-l-benzyl-3a-('3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yl]-N'-(2-:farylmethyl)thiourea trifluoroacetate
Reagent: 2-(isothiocyanatomethyl)furan
Synthetic procedure: Scheme A
Yield: 0.9 mg Measured mass: 502.2395
Calc. mass: 505.2399
EXAMPLE 32 - N-r(3aS*.6R*.7aS*)-l-benzyl-3a-(3.4-dimethoxyphenyl)octahydro-lH- indol-6-yl]-N'-(2-morpholin-4-ylethyl)thiourea trifluoroacetate Reagent: 4-(2-isothiocyanatoethyl)morpholine Synthetic procedure: Scheme A Yield: 16.9 mg Measured mass: 538.3000 Calc. mass: 538.2978
EXAMPLE 33 - N-benzyl-N,-f(3aS*.6R*.7aS*)-l-benzyl-3a-('3.4- dimethoxyphenyl octahydro-l H-indol-6- yllurea trifluoroacetate Reagent: (isocyanatomethyl)benzene
Synthetic procedure: Scheme A Yield: 17.0 mg Measured mass: 499.2851 Calc. mass: 499.2836
EXAMPLE 34 - N-rf3aS*.6R* aS*)-l-benzyl-3a-(3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yl] -N'-(3 -methoxypropyDthiourea trifluoroacetate Reagent: l-isothiocyanato-3-methoxypropane Synthetic procedure: Scheme A Yield: 12.8 mg Measured mass: 497.2706 Calc. mass: 497.2712
EXAMPLE 35 - N-r(3aS*.6R*.7aS*)-l-benzyl-3a-(3.4-dimethoxyphenyl)octahydro-lH- indol-6- yl] -N'-(cvclopropylmethyl)thiourea trifluoroacetate Reagent: cyclopropylmethyl isothiocyanate
Synthetic procedure: Scheme A
Yield: 14.0 mg
Measured mass: 479.2615
Calc. mass: 479.2606
EXAMPLE 36 - N-allyl-N'-IY3aS*,6R*,7aS*H-benzyl-3a-(3.4- dimethoxyphenvDoctahydro- 1 H-indol-6-yl"| thiourea
Reagent: allyl isothiocyanate
Synthetic procedure: Scheme A Yield: 1.1 mg
Measured mass: 465.2444
Calc. mass: 465.2450
EXAMPLE 37 - N-rπaS*.6R* aS* -l-benzyl-3a-(3.4-dimethoxyphenyl)octahvdro-lH- indol-6-yl]-N'-isobutylthiourea trifluoroacetate
Reagent: isobutyl isothiocyanate
Synthetic procedure: Scheme A
Yield: 14.1 mg
Measured mass: 481.2753 Calc. mass: 481.2763
EXAMPLE 38 - N-r(3aS*.6R* aS*)-l-benzyl-3a-(3.4-dimethoxyphenyl octahvdro-lH- indol-6- yll -N'-(2 -phenyl ethvDthiourea trifluoroacetate
Reagent: 2-phenylethyl isothiocyanate
Synthetic procedure: Scheme A
Yield: 12 mg
Measured mass: 529.2755
Calc. mass: 529.2763
EXAMPLE 39 - ethyl N-((r(3aS*,6R*,7aS*Vl-benzyl-3a-(3.4- dimethoxyphenyl)octahvdro-lH-indol-6-yllaminolcarbonyl)-beta-alaninate trifluoroacetate
Reagent: ethyl 3-isocyanatopropionate Synthetic procedure: Scheme A Yield: 9.0 mg Measured mass: 509.2882 Calc. mass: 509.2890
EXAMPLE 40 - N-butyl-N,-rr3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenylVl- ethyloctahydro-lH-indol-6-yl]thiourea trifluoroacetate
To a solution of mixture of amines, intermediate from Example 17 and 18 (2.2 g, 5.84 mmol) in dichloromethane (50 ml) was added n-butyl thioisocyanate (1.02 g, 8.8 mmol) and the mixture was stirred orvernight. PS-trisamine (2 g) was added and mixture was filtered and purified by flash chromatography using 20-70% EtOAc in hexanes. Yield: 800 mg of cis-compound.
The BOC-protected compound from above was deproteced by stirring in dichloromethane (10 ml) and trifluoroacetic acid (10 ml) for 30 min. The mixture was concentrated and redissolved in chloroform. PS-trisamine was added and the mixture filtered. The crude material was used without further purifications. Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using the deprotected amine from above (20 mg, 0.051 mmol) and acetaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. H NMR (270 MHz, CDC13): δ ppm 0.86-0.98 (m, 3H), 1.25-0.98 1.40 (m, 4H), 1.40-1.57 (m, 5H), 1.67-1.95 (m, 4H), 2.08-2.35 (m, 3H), 2.35-2.49 (m, IH), 2.61-2.78 (m, IH), 3.34- 3.50 (m, 2H), 3.63-3.78 (m, IH), 3.80-3.92 (m, 7H), 4.05-4.16 (m, IH), 4.41-4.60 (m, 2H), 6.93-7.04 (m, 3H). MS (ESI+) m/z 420 (M+1). HRMS (El) Calc for C23H37N3O2S: 419.2606; found 419.2604.
EXAMPLE 41 - N-butyl-N'-r(3aS*.6R*.7aS* -3a-(3.4-dimethoxyphenyl)-l- propyloctahydro- 1 H-indol-6-yllthiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and propanal (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ ppm 0.86-1.01 (m, 3H), 1.24-1.61 (m, 5H), 1.61-2.04 (m, 4H), 2.16-2.39 (m, 2H), 2.39-2.59 (m, IH), 2.67-2.88 (m, IH), 3.05-3.26 (m, 3H), 3.37-3.66 (m, 2H), 3.74-4.00 (m, 7H), 4.11-4.24 (m, IH), 4.44-4.63 (m, 2H), 6.91- 7.06 (m, 3H), 7.20-7.49 (m, 5H). MS (ESI+) m/z 434 (M+1). HRMS (El) Calc for C24H39N3O2S: 433.2763; found 433.2775.
EXAMPLE 42 - N-butyl-N'-r(3aS*.6R*.7aS* -3a-(3.4-dimethoxyphenvn-l- isobutyloctahvdro- 1 H-indol-6- yl"|thiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and isobutyraldehyde (0.25 mmol), gave the title compound as a colorless after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 0.85-0.85-1.01 (m, 3 H), 1.09- 1.24 (m, 5 H), 1.24-1.62 (m, 6 H), 1.62-2.09 (m, 4 H), 2.09-2.47 (m, 5 H), 2.65-2.83 (m, 1 H), 3.07-3.20 (m, 1 H), 3.34-3.53 (m, 3 H), 3.78-3.90 (m, 6 H), 3.90-4.08 (m, 1 H), 4.08- 4.21 (m, 1 H), 4.40-4.61 (m, 2 H), 6.88-7.10 (m, 3 H). MS (ESI+) m/z 448 (M+1). HRMS (El) Calc for C25H41N3O2S: 447.2919; found 447.2808. EXAMPLE 43 - N-butyl-N'-r(3aS*.6R*.7aS*)-3a-r3.4-dimethoxyphenyl -l- pentyloctahvdro-lH-indol-6-yllthiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and pentanal (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 0.85-1.03 (m, 6H), 1.22-1.59 (m, 10H), 1.61-2.00 (m, 7H), 2.10-2.33 (m, 2H), 2.33-2.49 (m, IH), 2.64-2.81 (m, IH), 3.08-3.25 (m, IH), 3.35-3.50 (m, 2H), 3.50-3.70 (m, IH), 3.74-3.89 (m, 7H), 4.06-4.16 (m, IH), 4.38- 4.60 (m, IH), 6.92-7.02 (m, 3H). MS (ESI+) m/z 462 (M+1). HRMS (El) Calc for C26H43N3O2S: 461.3076; found 461.3059.
EXAMPLE 44 - N-butyl-N'-IY3aS*,6R* aS*)-3a-(3.4-dimethoxyphenyl)-l-(2- phenylethvDoctahydro- 1 H-indol-6-yl~|thiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and phenylacetaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 0.84-1.00 (m, 3H), 1.26-1.58 (m, 6H), 1.61-1.82 (m, IH), 1.82-2.03 (m, 2H), 2.15-2.37 (m, 3H), 2.38-2.54 (m, IH), 2.68-2.87 (m, IH), 3.39-3.65 (m, 3H), 3.73-4.00 (m, 11H), 4.13-4.22 (m, 2H), 4.46- 4.61 (m, 2H), 6.92-7.04 (m, 3H), 7.21-7.48 (m, 5H). MS (ESI+) m/z 496 (M+1). HRMS (El) Calc for C29H4,N3O2S: 495.2919; found 495.2914.
EXAMPLE 45 - Ethyl 2-{rGaS*.6R*.7aS* -6-{rrbutylamino)carbonothioyllamino)-3a- (3,4-dimethoxyphenyl)octahvdro- 1 H-indol- 1 -yllmethyl I cyclopropanecarboxylate trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and 2- formyl-cyclopropanecarboxylic acid ethyl ester (0.25 mmol), gave the title compound as a colorless oil in after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ ppm 0.82-0.98 (m, 3H), 1.05-1.42 (m, 9H), 1.42-1.60 (m, 2H), 1.66-2.02 (m, 5H), 2.12-2.36 (m, 2H), 2.36-2.51 (m, IH), 2.59-2.80 (m, IH), 3.14-3.27 (m, 2H), 3.47-3.74 (m, 3H), 3.74-
4.02 (m, 7H), 4.05-4.23 (m, 3H), 4.36-4.57 (m, 2H), 6.89-7.05 (m, 3H).
MS (ESI+) m/z 518 (M+1). HRMS (El) Calc for C28H43N3O4S: 517.2974; found 517.2973.
EXAMPLE 46 - N-butyl-N'-IY3aS*,6R* aS*V3a-(3,4-dimethoxyphenyr)-l-(3- furylmethyDoctahydro- 1 H-indol-6-yllthiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and furan-3-carbaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 0.84-1.01 (m, 3H), 1.24-1.61 (m, 5H), 1.61-2.00 (m, 4H), 2.03-2.34 (m, 3H), 2.34-2.48 (m, IH), 2.68-2.82 (m, IH), 3.25-3.47 (m, IH), 3.47-3.64 (m, 2H), 3.64-3.81 (m, 2H), 3.81-3.89 (m, 6H), 4.09- 4.18 (m, IH), 4.29-4.44 (m, IH), 4.60-4.71 (m, IH), 6.70-6.80 (m, IH), 6.89-7.03 (m, 3H), 7.63-7.71 (m, IH), 7.85-7.93 (m, IH). MS (ESI+) m/z 472 (M+1). HRMS (El) Calc for C26H37N3O3S: 471.2556; found 471.2569.
EXAMPLE 47 - N-butyl-N'-((3aS*.6R*.7aS*)-3a-r3.4-dimethoxyphenvn-l-r(l-methyl- lH-pyrrol-2-yl)methylloctahvdro-lH-indol-6-yl}thiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and 1- methyl-lH-pyrrole-2-carbaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ 0.86-0.97 (m, 3H), 1.25-1.42 (m, 2H), 1.42-1.57 (m, 3H), 1.70-1.98 (m, 5H), 2.14-2.32 (m, 3H), 2.32-2.56 (m, 3H), 2.67-2.82 (m, 2H), 3.27-3.47 (m, 3H), 3.58-3.73 (m, 2H), 3.79-3.89 (m, 6H), 4.15- 4.22 (m, IH), 4.43-4.54 (m, IH), 6.11-6.16 (m, IH), 6.46-6.51 (m, IH), 6.84-6.89 (m, IH), 6.94-7.01 (m, 3H), 7.31-7.31-7.42 (m, IH). MS(ESI+) m/z 485 (M+1). HRMS (El) Calc for C27H40N4O2S: 484.2872; found 484.2880. EXAMPLE 48 - N-butyl-N'-(('3aS*.6R*.7aS*')-3a-(3.4-dimethoxyphenylVl-r(5-methyl-2- furyl)methyl1octahvdro- 1 H-indol-6- vU thiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and 5- methyl-furan-2-carbaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ ppm 0.88-0.99 (m, 3H), 1.25-1.58 (m, 5H), 1.62-1.98 (m, 3H), 2.02-2.18 (m, IH), 2.19-2.32 (m, IH), 2.32-2.38 (m, 3H), 2.38-2.57 (m, 2H), 3.16-3.49 (m, 2H), 3.53-3.69 (m, 2H), 3.70-3.81 (m, IH), 3.81- 3.90 (m, 6H), 4.08-4.19 (m, IH), 4.38-4.52 (m, IH), 4.52-4.71 (m, 3H), 6.10-6.18 (m, IH), 6.65-6.72 (m, IH), 6.87-7.03 (m, 3H). MS (ESI+) m/z 486 (M+1). HRMS (El) Calc for C27H39N3O3S: 485.2712; found 485.2721.
EXAMPLE 49 - N-butyl-N'-rC3aS'|c.6R*.7aS*)-3a-(3.4-dimethoxyphenvn-l-('3- thienylmethvDoctahydro- 1 H-indol-6- yllthiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and thiophene-3-carbaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 0.87-1.01 (m, 3 H), 1.20-1.62 (m, 6 H), 1.62-2.03 (m, 4 H), 2.03-2.31 (m, 3 H), 2.31-2.48 (m, 1 H), 2.59-2.77 (m, 1 H), 3.51-3.76 (m, 2 H), 3.79-3.90 (m, 7 H), 4.09-4.23 (m, 1 H), 4.39-4.59 (m, 2 H), 4.73-4.83 (m, 1 H), 6.87-7.04 (m, 3 H), 7.34-7.45 (m, 1 H), 7.56-7.67 (m, 1 H), 7.78-7.89 (m, 1 H). MS (ESI+) m/z 488 (M+1). HRMS (El) Calc for C26H37N3O2S2: 487.2326; found 487.2327.
EXAMPLE 50 - N-butyl-N'-(f3aS*,6R* aS* -3a-f3.4-dimethoxyphenvn-l-r(4-methyl- lH-imidazol-5-yl)methyl1octahydro-lH-indol-6-ylUhiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and 5- Methyl-3H-imidazole-4-carbaldehyde (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. Η NMR (270 MHz, CDC13): δ ppm 0.86-1.01 (m, 3 H), 1.23-1.60 (m, 6 H), 1.66-2.08 (m, 3 H), 2.12-2.34 (m, 2 H), 2.34-2.48 (m, 1 H), 2.48- 2.59 (m, 4 H), 2.60-2.79 (m, 1 H), 3.16-3.64 (m, 3 H), 3.68-3.95 (m, 8 H), 4.19-4.35 (m, 1 H), 4.41-4.67 (m, 2 H), 6.90-7.08 (m, 3 H), 8.81-8.86 (m, 1 H).
MS (ESI+) m/z 486 (M+1). HRMS (El) Calc for C26H39N5O2S: 485.2824; found 485.2839.
EXAMPLE 51 - N-butyl-N'-r(3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenvn-l-r3- phenylpropyDoctahydro- lH-indol-6-yllthiourea trifluoroacetate
Following the general procedure for reductive alkylation of the pyrrolidine moiety, Scheme E, using deprotected amine, intermediate from Example 40 (20 mg, 0.051 mmol) and 3- phenylpropanal (0.25 mmol), gave the title compound as a colorless oil after preparative HPLC purification. 1H NMR (270 MHz, CDC13): δ ppm 0.86-1.00 (m, 3H), 1.24-1.59 (m, 5H), 1.62-1.97 (m, 3H), 2.10-2.33 (m, 4H), 2.33-2.48 (m, IH), 2.61-2.84 (m, 3H), 3.12- 3.47 (m, 5H), 3.53-3.73 (m, IH), 3.73-3.90 (m, 8H), 4.04-4.16 (m, IH), 4.41-4.59 (m, IH), 6.91-7.02 (m, 3H), 7.16-7.37 (m, 5H). MS (ESI+) m/z 510 (M+1). HRMS (El) Calc for C30H43N3 O2S: 509.3076; found 509.3068.
EXAMPLE 52 - N-r(3aS*.6R*.7aS*Vl-benzyl-3a-('3.4-dimethoxyphenyl)octahvdro-lH- indol-6-vH-N'-(pyridin-4-yrmethyl)urea trifluoroacetate Reagent: 4-(aminomethyl)pyridine
Synthetic procedure: Scheme B
Yield: 2.2 mg
Measured mass: 500.2781
Calc. mass: 500.2787
EXAMPLE 53 - N'-rr3aS*.6R*.7aS*)-l-benzyl-3a-(3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yl]-N-ethyl-N-methylurea trifluoroacetate
Reagent: n-ethylmethylamine
Synthetic procedure: Scheme B Yield: 1.8 mg
Measured mass: 451.2837
Calc. mass: 451.2835 EXAMPLE 54 - N-rf3aS*.6R*.7aS* -3a-(3.4-dimethoxyphenvn-l-methyloctahvdro-lH- indol-6-yll-N'-(4-fluorobenzyl thiourea trifluoroacetate Reagent: 4-fluorobenzyl isothiocyanate Synthetic procedure: Scheme C Yield: 3.9 mg
Measured mass: 457.2197 Calc. mass: 457.2199
EXAMPLE 55 - N-f(3aS*.6R* aS*) a-f3.4-dimemoxyDhenylVl-memyloctahy(iro-lH- indol-6-yl]-N'-r2-(2-thienyl)ethyllurea trifluoroacetate
Reagent: 2-(thien-2-yl)ethyl isocyanate
Synthetic procedure: Scheme C
Yield: 2.8 mg
Measured mass: 443.2258 Calc. mass: 443.2243
EXAMPLE 56 - N-r(3aS*.6R*.7aS*)-3a-r3.4-dimethoxyphenyl)-l-methyloctahvdro-lH- indol-6-yl] -N'-(2-phenylethyl)urea trifluoroacetate Reagent: phenethyl isocyanate Synthetic procedure: Scheme C Yield: 1.7 mg Measured mass: 437.2671 Calc. mass: 437.2678
EXAMPLE 57 - N-r(3aS*.6R*.7aS* -3a-(3.4-dimethoxyphenyl -l-methyloctahvdro-lH- indol-6-yl]-N'-(4-methoxybenzyl)thiourea trifluoroacetate
Reagent: 4-methoxybenzyl isothiocyanate
Synthetic procedure: Scheme C
Yield: 2.8 mg Measured mass: 469.2403
Calc. mass: 469.2399 EXAMPLE 58 - N-allyl-N'-rC3aS*.6R*.7aS*)-3a-('3.4-dimethoxyphenvn-l- methyloctahydro- 1 H-indol-6- yllurea trifluoroacetate Reagent: allyl isocyanate Synthetic procedure: Scheme C Yield: 3.9 mg
Measured mass: 373.2357 Calc. mass: 373.2365
EXAMPLE 59 - N-r(3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenvn-l-methyloctahvdro-lH- indol-6-yl"|-N'-hexyrthiourea trifluoroacetate
Reagent: n-hexyl isothiocyanate
Synthetic procedure: Scheme C
Yield: 6.2 mg
Measured mass: 433.2746 Calc. mass: 433.2763
EXAMPLE 60 - N-rC3aS*.6R*.7aS*)-3a-r3.4-dimethoxyphenyl)-l-methyloctahvdro-lH- indol-6-yl~|-N'-(3-methylbenzyl)urea trifluoroacetate Reagent: 3-methylbenzyl isocyanate Synthetic procedure: Scheme C Yield: 7.3 mg Measured mass: 437.2684 Calc. mass: 437.2678
EXAMPLE 61 - N-rC3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenyl)-l-methyloctahvdro-lH- indol-6-yl]-N'-(4-methoxybenzyl)urea trifluoroacetate
Reagent: 4-methoxybenzyl isocyanate
Synthetic procedure: Scheme C
Yield: 6.3 mg Measured mass: 453.2633
Calc. mass: 453.2628 EXAMPLE 62 - N-benzyl-N'-r(3aS*.6S*.7aS* -3a-f3.4-dimethoxyphenyl)-l- methyloctahydro- 1 H-indol-6-yll guanidine trifluoroacetate
N-benzyl-lH-pyrazole-1-carboximidamide hydrochloride (50 mg, 0.21 mmol), diispropylethylamine (0.03 ml, 0.21 mmol) and (3aS*,6S*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyl-octahydro-lH-indol-6-amine, (Comparative Example 8, 60 mg, 0.21 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs. The crude mixture was purified by preparative HPLC to give the title compound, 9 mg (8 %) HRMS (El) calc: 422.2682 Found: 422.2676
EXAMPLE 63 - N-butyl-N'-rπaS*.6S*.7aS* -3a-(3.4-dimethoxyphenyn-l- methyloctahvdro-lH-indol-6-vH guanidine trifluoroacetate
N-butyl- lH-pyrazole-1-carboximidamide hydrochloride (43 mg, 0.21 mmol), diispropylethylamine (0.03 ml, 0.21 mmol) and (3aS*,6S*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyl-octahydro-lH-indol-6-amine (Comparative Example 8, 60 mg, 0.21 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs. The crude mixture was purified by preparative HPLC to give the title compound, 9 mg (9 %)
HRMS (El) calc: 388.2838 Found: 388.2849
EXAMPLE 64 - N-r(3aS*.6S*.7aS*)-3a-(3.4-dimethoxyphenvn-l-methyloctahydro-lH- indol-6-yll-N'-pentyl guanidine trifluoroacetate
N-pentyl- lH-pyrazole-1-carboximidamide hydrochloride (45 mg, 0.21 mmol), diispropylethylamine (0.03 ml, 0.21 mmol) and (3aS*,6S*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyl-octahydro-lH-indol-6-amine (Comparative Example 8, 60 mg, 0.21 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs. The crude mixture was purified by preparative HPLC to give the title compound, 9 mg (8 %) HRMS (El) calc: 402.2995 Found: 402.2991 EXAMPLE 65 - N-butyl-N'-rf3aS*.6R*.7aS* -3a-(3.4-dimethoxyphenylVl- methyloctahydro- 1 H-indol-6-yll guanidine trifluoroacetate
N-butyl- lH-pyrazole-1-carboximidamide hydrochloride (6 mg, 0.03 mmol), diispropylethylamine (0.01 ml, 0.06 mmol) and (3aS*,6R*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-amine (Comparative Example 7, 10 mg, 0.03 mmol) were mixed in anhydrous DMF (1 ml) and heated at 100 °C for 2 hrs. The crude mixture was purified by preparative HPLC to give the title compound, 1 mg (7 %) HRMS (El) calc: 388.2838 Found: 388.2856
EXAMPLE 66 - N-r(3aS*.6R* aS* -3a-(3.4-dimethoxyphenyl)-l-methyloctahvdro-lH- indol-6-yll-N'-[4-(trifluoromethyl)benzyl"lurea trifluoroacetate Reagent: 1 -(isocyanatomethyl)-4-(trifluoromethyl)benzene Synthetic procedure: Scheme D Measured mass: 491.2406 Calc. mass: 491.2396
EXAMPLE 67 - N-r2.4-dichlorobenzyl -N'-r(3aS*.6R*.7aS*)-3a-f3.4-dimethoxyphenyl)- l-methyloctahydro-lH-indol-6-yllurea trifluoroacetate Reagent: 2,4-dichloro-l-(isocyanatomethyl)benzene Synthetic procedure: Scheme D Measured mass: 491.1766 Calc. mass: 491.1746
EXAMPLE 68 - N-r(3aS*.6R*.7aS* -3a-f3.4-dimethoxyphenyl)-l-methyloctahvdro-lH- indol-6-vH-N'-(4-fluorobenzyl urea trifluoroacetate
Reagent: 4-fluorobenzyl isocyanate
Synthetic procedure: Scheme D
Measured mass: 441.2438 Calc. mass: 441.2428
EXAMPLE 69 - N-(4-bromobenzylVN'-rπaS*.6R*.7aS* -3a-(3.4-dimethoxyphenyl)-l- methyloctahvdro-lH-indol-6-yl"|urea trifluoroacetate
Reagent: 4-bromobenzyl isocyanate Synthetic procedure: Scheme D Measured mass : 501.1641 Calc. mass: 501.1627
EXAMPLE 70 - N'-butyl-N-r(3aS*.6R* JaS*V3a-(3.4-dimethoxyphenvn-l- methyloctahvdro-lH-indol-6-yll-N-methylthiourea trifluoroacetate and
EXAMPLE 71 - N'-butyl-N-r(3aS*.6S*.7aS*V3a-(3.4-dimethoxyphenvn-l- methyloctahvdro- 1 H-indol-6-yl] -N-methylthiourea trifluoroacetate
Mesembrine (250mg, 870 μmol) was dissolved in DCM (4mL). An aqueous solution of methylamine (12mL of a 50% solution) was added, followed by sodium cyanoborohydride (250mg, 3.98 mmol). The mixture was stirred overnight at room temperature and the solvent removed under reduced pressure. The crude product was partitioned between NaOH solution (25mL, 3M) and DCM (25mL). The aqueous portion was extracted with further DCM (2x20mL), the combined extracts dried (Na2SO4), and the solvent was removed under reduced pressure. The oily residue was dissolved in DCM (5mL), and treated with n-butylisothiocyanate (115 μL, 1 lOmg, 960 μmol). After stirring at room temperature for 16 hours, the solvent was removed and the crude products purified by preparative HPLC.
N'-butyl-N-[(3aS*, 6R * 7aS*)-3a-(3, 4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] -N-methylthiourea (29.6mg, 8%):
MS (ESI+) for C23H37N3O2S: m/z 420.3 (M+1). HRMS (El) calcd C23H37N3O2S: 419.2606, found 419.2605 N'-butyl-N-[(3aS*, 6S*, 7aS*)-3a-(3,4-dimethoxyphenyl)-l -methyloctahydro-1 H-indol-6- yl] -N-methylthiourea (40.4mg, 11%): MS (ESI+) for C23H37N3O2S: m/z 420.3 (M+1). HRMS (El) calcd C23H37N3O2S: 419.2606, found 419.2592 EXAMPLE 72 - N'-benzyl-N-r(3aS*.6S*.7aS* -3a-(3.4-dimethoxyphenvn-l- methyloctahydro- 1 H-indol-6- yll -N-methylthiourea and
EXAMPLE 73 - N'-benzyl-N-r(3aS*.6S*.7aS*)-3a-(3.4-dimethoχyphenvn-l- methyloctahvdro-lH-indol-6-yll-N-methylthiourea trifluoroacetate
Compounds were prepared and purified in an analogous method to Example 70 and 71. N'-benzyl-N-[(3aS*,6R*, 7aS*)-3a-(3,4-dimethoxyphenyl)-l -methyloctahydro-1 H-indol-6- yl] -N-methylthiourea (56.3mg, 14%): MS (ESI+) for C26H35N3O2S: m/z 454.2 (M+1). HRMS (El) calcd C26H35N3O2S: 453.245, found 454.2442
N'-benzyl-N-[(3aS*,6S*, 7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] -N-methylthiourea (72.3mg, 18%): MS (ESI+) for C26H35N3O2S: m/z 454.2 (M+1). HRMS (El) calcd C26H35N3O2S: 453.245, found 454.2444.
EXAMPLE 74 - N-rC3aS*.6S*.7aS*)-l-benzyl-3a-r3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yll-4-methylpiperazine- 1 -carboxamide bis(trifluoroacetate)
Triethylamine (0.29 mL, 2.07 mmol) was added to a solution of (3aS*,6S*,7aS*)-l- benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-amine (Example 6, 0.38 g, 1.04 mmol) in dry CH2C12 (20 mL). Triphosgene (0.123 g, 0.415 mmol), dissolved in dry CH2C12 (3 mL), was added to the reaction mixture dropwise. The mixture was stirred at room temperature under N2 atmosphere for about 30 minutes. During this time the colour changed from light yellow to darker yellow. Volatiles were evaporated which gave the crude isocyanate as a yellow solid. MS (ESI+) m/z 393 (M+H)+. 1 -Methyl -piperazine (0.164 mL, 1.48 mmol) was added to the crude isocyanate (0.194 g, 0.494 mmol) dissolved in dry CH2C1 (10 mL), and the mixture was stirred under N2 atmosphere for 3 hours. Volatiles were evaporated and the crude product was purified by preparative HPLC which gave 0.64 mg of the title compound as an off-white solid. MS (ESI+) m/z 493 (M+H)+. HRMS (El) calc for C29H40N4O3: 492.3100 found 492.3076. EXAMPLE 75 - N-rf3aS*.6R* JaS*)-3a-(3.4-dimemoχyphenylVl-memyloctahvdro-lH- indol-6-yl1-4-methylpiperazine-l-carboxamide bis(trifluoroacetate)
Triethylamine (62 μL, 0.448 mmol) was added to a solution of (3aS*,6R*,7aS*)-3a-(3,4- dimethoxyphenyl)- 1 -methyloctahydro-1 H-indol-6-amine (Comparative Example 7, 65 mg,
0.224 mmol) dissolved in dry CH2C12 (3 mL). Triphosgene (26.6 mg, 0.0895 mmol) was dissolved in dry CH2C12 (1 mL) and added dropwise. The solution was stirred under N2 in room temperature for 3 h. 1-Methyl-piperazine (25 μL, 0.224 mmol) was added and the reaction mixture was stirred at room temperature overnight. Volatiles was evaporated and the crude product was purified by preparative HPLC which gave 93 mg (99%) of the title compound. 1H NMR (400 MHz, MeOH-D4) δ ppm 1.18 (s, 3 H), 1.21 (s, 3H), 1.67-1.75
(m, 2H), 2.11 (br s, 2H), 2.26-2.30 (br s, 3 H), 2.77-3.35 (m, 8H), 3.69 (s, 3H), 3.73 (s,
3H), 3.78 (br m, 2 H), 3.99 (br m, 3H), 6.86 (m, 3H).
MS (ESI+) m/z 417 (M+H)+. HRMS (El) calc for C23H36N4O3: 416.2787 found 416.2791.
EXAMPLE 76 - N-r(3aS*.6R* aS*V3a-(3.4-dimethoxyphenvn-l-methyloctahvdro-lH- indol-6-yl1piperazine-l-carboxamide bis(trifluoroacetate)
Piperazine (9.5 mg, 0.1097 mmol) was added to the crude solution of isocyanate (0.1097 mmol) prepared in comparative example 77. The mixture was stirred at room temperature under N atmosphere overnight. Volatiles were evaporated and the crude product was purified by preparative HPLC which gave 5.8 mg (13%) of Example 76.
MS (ESI+) m/z 403 (M+H)+. HRMS (El) calc for C22H34N4O3: 402.2631 found 402.2630.
See also under Comparative Example 77.
COMPARATIVE EXAMPLE 77 - Preparation of isocyanate for small set library:
(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-6-isocvanato-l-methyloctahvdro-lH-indole
Triethylamine (305 μL, 2.19 mmol) was added to a solution of (3aS*,6R*,7aS*)-3a-(3,4- dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-amine (Comparative Example 7, 318 mg, 1.097 mmol) dissolved in dry CH2C12 (5 mL). Triphosgene (130 mg, 0.44 mmol) was dissolved in dry CH2C12 (1 mL) and added dropwise. The solution was stirred under N2 in room temperature for 3 h. MS (ESI+) m/z 393 (M+H)+. The crude isocyanate was partitioned into several reaction vials, to which the appropriate amine (see below) was added).
EXAMPLE 78 - N-rf3aS*.6R* aS*V3a-f3.4-d)memoxyphenylVl-memyloctahvdro-lH- indol-6-yl~|-N'-(2-piperazin- 1 -ylethvDurea trisCtrifluoroacetate)
N-(2-aminoethyl)piperazine (14 μL, 0.1097 mmol) was added to the isocyanate (0.1097 mmol) solution of Comparative Example 77. The mixture was stirred at room temperature under N2 atmosphere overnight. Volatiles were evaporated and the crude product was purified by preparative HPLC, which gave 39 mg (79%) of the title compound. MS (ESI+) m/z 446 (M+H)+. HRMS (El) calc for C24H39N5O3: 445.3053 found 445.3058.
EXAMPLE 79 - N-rf3aS*.6R* aS*)-3a-(3.4-dimethoxyphenvn-l-methyloctahydro-lH- indol-6-yll-N'-[3-(4-methylpiperazin-l-yl)propyllurea tris(trifluoroacetate) l-(3-aminopropyl)-4-methylpiperazine (17 mg, 0.1097 mmol) was added to the isocyanate (0.1097 mmol) solution of Comparative Example 77. The mixture was stirred at room temperature under N2 atmosphere overnight. Volatiles were evaporated and the crude product was purified by preparative HPLC, which gave 22 mg (42%) of the title compound. MS (ESI+) m/z 474 (M+H)+. HRMS (El) calc for C26H43N5O3: 473.3366 found 473.3364.
EXAMPLE 80 - N-r(3aS*.6R*.7aS*)-3a-r3.4-dimethoxyphenvn-l-methyloctahvdro-lH- indol-6-yll-N'-r(5-methylpyrazin-2-yl)methyllurea trifluoroacetate 2-(Aminomethyl)-5-methylpyrazine (21mg, 0.17mmol) was dissolved in ImL dry CH2C12 under N2. Diisopropylamine (44mg, 0.34mmol was added followed by dropwise addition of triphosgene (24mg, 0.08mmol) in ImL of dry CH2C12. Stirred at room temperature for 2hrs, and then (3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol- 6-amine (Comparative Example 7, 50mg, 0.17mmol) was added. Stirred at room temperature overnight and then concentrated. Purification using preparative HPLC gave the product as light yellow oil (7.8mg, 10%). 'HNMR (270MHz, Chloroform-d) ppm 1.04-1.32(m, 5H); 1.76-1.90(m, 3H); 2.00-
2.38(m, 5H); 2.53(s, 3H); 3.46-3.72(m, IH); 3.87(s, 6H); 4.05-4.20(m, IH); 4.48(s, 2H);
5.21(w, IH); 6.70-6.98(m, 2H); 7.30-7.65(m, IH); 8.36-8.40(m, 2H); 8.47(b,lH).
MS (ESf) for C24H33N5O3 m/z 440 (M+H+), HRMS found: 439,2580 calculated: 439,2583 EXAMPLE 81 - N-r(3aS*.6R* aS*V3a-(3.4-dimemoxyphenylVl-memyloctahvdro-lH- indol-6-yl]-N'-(4-methylpiperazin- 1 - vDurea tris(trifluoroacetate)
l-Amino-4-methylpiperazine (13 μL, 0.1097 mmol) was added to the isocyanate (0.1097 mmol) solution of Comparative Example 77. The mixture was stirred at room temperature under N2 atmosphere overnight. Volatiles were evaporated and the crude product was purified by preparative HPLC, which gave 33 mg (69%) of the title compound. MS (ESI+) m/z 432 (M+H)+. HRMS (El) calc for C23H37N5O3: 431.2896 found 431.2875.
EXAMPLE 82 - N-r(3aS*.6R*.7aS*)-l-benzyl-3a-(3.4-dimethoxyphenyl)octahvdro-lH- indol-6-yl"|-N'-cvclopropylthiourea trifluoroacetate
Reagent : i sothiocyanatocycloprop ane
Synthetic procedure: Scheme A
Yield: 2.2 mg Measured mass: 465.2468
Calc. mass: 465.2450
EXAMPLE 83 - N-r(3aS*.6R*.7aS*)-l-benzyl-3a-(3.4-dimethoxyphenvnoctahvdro-lH- indol-6-yll-N'-(sec-butyl)thiourea trifluoroacetate Reagent: 2-isothiocyanatobutane
Synthetic procedure: Scheme A
Yield: 15.5 mg
Measured mass: 481.2767
Calc. mass: 481.2763
EXAMPLE 84 - N-|Y3aS*.6R* aS*)-l-benzyl-3a-(3.4-dimethoxyphenyl)octahydro-lH- indol-6-yl]-N'-cvclopentylthiourea trifluoroacetate
Reagent: cyclopentyl isothiocyanate
Synthetic procedure: Scheme A Yield: 15.4 mg
Measured mass: 493.2786
Calc. mass: 493.2763 EXAMPLE 85 - N-r(3aS*.6R*.7aS*)-3a-(3.4-dimethoxyphenvn-l-methyloctahvdro-lH- indol-6-yll-N'-r(l S)- 1 -phenylethyllurea trifluoroacetate Reagent: (S)-(-)-alpha-methylbenzyl isocyanate Synthetic procedure: Scheme C Yield: 2.3 mg
Measured mass: 437.2691 Calc. mass: 437.2678
EXAMPLE 86 - N-dlyl-NT-r(3aS*.6R*,7aS*V3a-f 1.3-benzodioxol-5-vn-l- benzyloctahydro- 1 H-indol-6- yl"|urea hydrochloride and
EXAMPLE 87 - N-allyl-N'-r(3aS*.6Si|i.7aS* -3a-ri.3-benzodioxol-5-vn-l- benzyloctahydro-lH-indol-6-yl"|urea hydrochloride LiNH2 (7.5 g, 328 mmol) was suspended in DME (200 mL) at ambient temperature and (3,4-methylenedioxy)phenylacetonitrile (20 g, 124 mmol) in DME (50 mL) was added portionwise over 15 min. The mixture was heated at 80 °C for 30 min, whereupon its color changed to green, before a solution of l-bromo-2-chloroethane (11.3 mL, 136 mmol) in DME (50 mL) was added over a period of 20 min. During the course of the addition, the green color of the mixture changed to light brown. The mixture was heated at 80 °C overnight, or until GC indicated >95% consumption of the starting material. The mixture was cooled on an ice/water bath, and water (200 mL) and Et2O (400 ml) was then added to destroy the excess of strong base. The mixture was extracted with DCM (2 x 100 mL), and the combined organic extracts were washed with H2O (100 mL), dried (MgSO ) and evaporated. The residue was purified by flash chromatography (silica, 10-20% EtOAc in n- heptane) to yield l-(3,4-methylenedioxyphenyl)cyclopropanecarbonitrile (19.0 g, 82%) as a yellowish oil. Η NMR (270 MHz, CDC13) δ ppm 1.18-1.32 (m, 2H); 1.57-1.66 (m, 2H); 5.93 (s, 2H); 6.71-6.83 (m, 3H).
l-(3,4-methylenedioxyphenyl)cyclopropanecarbonitrile (19.0 g of crude material, 101 mmol), was dissolved in dry toluene (800 mL) and cooled on an ice/water bath. A solution of DIBAL (lM in toluene, 140 mL, 140 mmol) was added dropwise via an addition funnel, over a period of 30 min. The resulting mixture was heated at 50°C overnight. The reaction mixture was cooled to 0°C and cautiously transferred, in small portions and with swirling, to a separatory funnel containing ice-cold aq. HC1 (4M, 0.5L). The aqueous layer was extracted once with EtOAc (400 mL) and the combined organic portions were washed with water (lx 300 mL) and brine (1 x 200 mL), dried (MgSO4) and concentrated to give the aldehyde (19 g) as a yellowish oil, which was used in the subsequent step without further purification. Η NMR (270 MHz, CDC13) δ 1.32-1.37 (m, 2H); 1.49-1.55 (m, 2H); 5.95 (s, 2H); 6.69-6.83 (m, 3H); 9.18 (s, IH).
To a solution of the aldehyde (19 g of crude material, assumed to be 101 mmol) in dry THF (800 mL) was added benzylamine (11.9 g, 111 mmol) and an excess of MgSO4 (50g) and the resulting mixture was stirred at rt during 24h. The mixture was filtered and evaporated to give the imine (28 g), which was used in the next step without further purification. Η NMR (270 MHz, CDC13) δ 1.12-1.17 (m, 2H); 1.30-1.36 (m, 2H); 4.56 (s, 2H); 5.93 (s, 2H); 6.69-6.89 (m, 3H); 7.14-7.40 (m, 5H); 7.70 (s, IH).
To a solution of imine (lOg of crude material, assumed to be 53 mmol) and benzylamine hydrochloride (lOg, 68 mmol) in MeCN (400 mL) was added Na2SO4 (20 g) and but-3-en- 2-one (3.7g, 53 mmol). The mixture was heated at reflux for 5h and then cooled to rt. The drying agent was filtered off and the filtrate was evaporated to dryness. The residue was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 (100 mL), and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic portions were washed with brine (100 mL), dried (MgSO4) and concentrated to give (3aS*,7aS*)- 3a-benzo[l,3]dioxol-5-yl-l-benzyl-octahydroindol-6-one as a colorless oil (29%) after purification by column chromatography (silica / hexanes: EtOAc 70:30). 1H NMR (270 MHz, CDC13) δ 1.85-2.36 (m, 6H); 2.40-2.82 (m, 3H); 2.87-2.98 (m, IH); 3.10 (d, IH, J = 12.1 Hz); 3.21-3.26 (m, IH); 4.08 (d, IH, J = 12.1 Hz); 5.93 (s, 2H); 6.71- 6.95 (m, 3H); 7.17-7.41 (m, 5H). 13C NMR (67.9 MHz, CDC13) 34.86, 36.08, 38.45, 40.36, 47.24, 51.46, 57.30, 68.24, 100.88, 106.73, 107.86, 118.48, 126.75, 128.02, 128.57, 138.78, 141.52, 145.63, 147.86, 210.96.
To a solution of (3aS*,7aS*)-3a-benzo[l,3]dioxol-5-yl-l-benzyl-octahydroindol-6-one (1.5 g, 4.30 mmol) and ammonium formate (2 g, 38 mmol) in MeOH (100 mL) was added NaBH3CN (2g, 32 mmol) in portions during 5 min. The resulting mixture was stirred at rt for 4 h and then evaporated. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic fractions were washed with brine (50 mL), dried (MgSO4) and evaporated to give (3aS*, 7aS*)-3a-benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6- ylamine as a colorless oil (1.3 g, 87%), which was used in the next step without further purification. Η NMR indicated the formation of approximately a 1 :1 mixture of diastereomers (at C-6).
Η NMR (270 MHz, CDC13) δ 0.89-2.42 (m, 11H); 2.83-3.30 (m, 3H); 4.18 (d, 0.5H, J = 13.7 Hz); 4.30 (d, 0.5H, J = 13.0 Hz); 5.88 (s, 2H); 6.64-7.00 (m, 3H); 7.10-7.53 (m, 5H).
The general procedure for urea/thiourea formation was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine (O.lg, 0.29 mmol) and allyl isocyanate (34 mg, 0.4 mmol), to give 102 mg (74%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl /MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et2O (sat.) followed by evaporation. First eluted: N-allyl-N'-[(3aS*,6R*, 7aS*)-3a- (1 ,3-benzodioxol-5-yl)-l -benzyloctahydro-1 H-indol-6-ylJurea hydrochloride: 23 mg
(17%). 1H NMR (500 MHz, CDC13): δ ppm 1.16-1.34 (m, IH); 1.55-1.68 (m, IH); 1.82 (d, IH, J = 14.1 Hz); 1.91-2.26 (m, 4H); 3.21-3.31 (m, IH); 3.73-4.08 (m, 4H); 4.21 (dd, IH, J = 13.0, 4.9 Hz); 4.45-4.54 (m, IH); 4.56 (d, IH, J = 13.2 Hz); 5.11 (d, IH, J = 10.6 Hz); 5.21 (dd, IH, J = 16.7, 4.8 Hz); 5.44-5.64 (br s, IH); 5.82-5.95 (m, IH, J = 16.7, 10.6, 5.0 Hz); 5.97 (s, 2H); 6.59 (d, IH, J = 8.46 Hz); 6.65 (s, IH); 6.78 (d, IH, J = 8.46 Hz); 6.68- 7.05 (br s, IH); 7.45-7.53 (m, 3H); 7.65 (d, 2H, J = 7.06 Hz); 11.77-12.26 (br s, IH). MS (ESI+): m/z 434 (M+1). HRMS (El) Calc for C26H3ιN3O3: 433.2365; found 433.2553.
Second eluted: N-allyl-N'-[(3aS*,6S*, 7aS*)-3a-(l ,3-benzodioxol-5-yl)-l -benzyloctahydro- lH-indol-6-ylJ rea hydrochloride:greyis gummy solid; 49 mg (36%). The relative configuration was determined by 1H NMR spectroscopy (NOESY). 1H NMR (270 MHz, CDC13): δ ppm 1.23-1.47 (m, 2H); 1.54-1.70 (m, IH); 1.77-1.96 (m, 2H); 1.98-2.34 (m, 2H); 2.35-2.38 (m, IH); 3.04-3.17 (m, IH); 3.20-3.35 (m, 2H), 4.21 (d, IH, J = 13.0 Hz); 4.35-4.50 (m, IH); 4.63-4.80 (m, IH); 4.94-5.23 (m, 2H); 5.65-5.88 (m, IH); 5.93 (s, 2H); 6.67-6.87 (m, 3H); 7.23-7.37 (m, 5H). MS (ESI+): m/z 434 (M+1). HRMS (El) Calc for C26H3,N3O3: 433.2365; found 433.2358. EXAMPLE 88 - N-IY3aS*.6R* aS*V3a-(T.3-benzodioxol-5-yiyi-benzyloctahydro-lH- indol-6- yl] -N'-ethylthiourea hydrochloride and
EXAMPLE 89 - N-r(3aS*.6S*.7aS*)-3a-ri.3-benzodioxol-5-vn-l-benzyloctahvdro-lH- indol-6-yl~|-N'-ethylthiourea hydrochloride
The general procedure for urea/thiourea formation was used, starting from from (3aS*,7aS*)-3a-benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (O.lg, 0.29 mmol) and ethyl isothiocyanate (36 mg, 0.4 mmol), to give 111 mg (81%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl3/MeOH NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et2O (sat.) followed by evaporation. N-[(3aS*,6R*, 7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol- 6-yl] -N'-ethylthiourea hydrochloride (slower elute): greyish gummy solid; 30 mg (20%). The relative configuration was determined by 1H NMR spectroscopy (NOESY).
1H NMR (270 MHz, CDC13): δ ppm 0.81-0.96 (m, IH); 1.03 (t, 3H, J = 7.05 Hz); 1.10- 1.52 (m, 2H); 1.55-1.75 (m, 2H); 1.75-2.10 (m, 5H); 2.18 (d, IH, J = 15.6 Hz); 2.56-2.71 (m, IH); 2.87-3.54 (m, 3H); 4.03-4.50 (m, IH); 5.12-5.26 (br s, IH); 5.94 (s, 2H); 6.69- 6.89 (m, 3H); 7.23-7.44 (m, 5H). MS (ESI+): m/z 438 (M+1). HRMS (El) Calc for C25H3,N3O2S: 437.2137; found 437.2151.
Faster elute: N-[(3aS*,6S*, 7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol- 6-yl] -N'-ethylthiourea hydrochloride: greyish gummy solid; 58 mg (40%). The relative configuration was determined by 1H NMR spectroscopy (NOESY). 1H NMR (270 MHz, CDC13): δ ppm 1.03-1.16 (m, 4H); 1.16-1.32 (m, 3H); 1.36-1.52 (m, IH); 1.60-1.93 (m, 3H); 1.94-2.06 (m, IH); 2.10-2.48 (m, 2H); 2.95-3.13 (m, 2H); 3.16-3.38 (m, 2H); 4.15- 4.28 (m, IH); 5.27-5.51 (br s, IH); 5.94 (s, 2H); 6.69-6.89 (m, 3H); 7.27-7.48 (m, 5H). MS (ESI+) m/z 438 (M+1). HRMS (El) Calc for C25H31N3O2S: 437.2137; found 437.2124. EXAMPLE 90 - N-r(3aS*.6S*.7aS*)-3a-fl.3-benzodioxol-5-vn-l-benzyloctahvdro-lH- indol-6-yl1-N'-benzylthiourea hydrochloride and
The general procedure for urea/thiourea formation was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (0.9g, 2.57 mmol) and benzyl isothiocyanate (500 mg, 3.3 mmol), to give 960 mg (65%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl3/MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et O (sat.) followed by evaporation. N-[(3aS*, 6S*, 7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol- 6-yl] -N'-benzylthiourea hydrochloride (faster eluting): colorless gummy solid; 500 mg (17%). The relative configuration was determined by 1H NMR spectroscopy (NOESY). 1H NMR (270 MHz, CDC13) δ ppm 0.81-0.96 (m, IH); 1.16-1.47 (m, 2H); 1.53-2.48 (m, 10H); 2.92-3.26 (m, 2H); 4.09-4.23 (m, 2H); 4.53-4.63 (br s, IH); 5.94 (s, 2H); 6.71-6.90 (m, 3H); 7.15-7.42 (m, 10H). MS (ESI+) m/z 500 (M+1). HRMS (El) Calc for C30H33N3O2S : 499.2293; found: 499.2277
EXAMPLE 91 - N-r(3aS*.6R* aSi|i)-3a-π.3-benzodioxol-5-vn-l-benzyloctahvdro-lH- indol-6-yll -N'-butylthiourea hydrochloride
The general procedure for urea/thiourea formation was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (O.lg, 0.29 mmol) and n-butyl isothiocyanate (46 mg, 0.4 mmol), to give 95 mg (68%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl3 MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et2O (sat.) followed by evaporation. The title compound (slower elute): greyish gummy solid; 48 mg (33%). The relative configuration was determined by Η NMR spectroscopy (NOESY). Η NMR (270 MHz, CDC13) δ ppm 0.86 (t, 3H, J = 7.3 Hz); 1.06-2.06 (m, 12H); 2.18 (d,
IH, J = 16.0 Hz); 2.55-2.70 (m, IH); 2.85-3.33 (m, 3H); 3.45 (d, IH, J = 13.3 Hz); 4.04-
4.14 (m, IH); 4.58-4.75 (br s, IH); 5.19-5.33 (br s, IH); 5.93 (s, 2H); 6.70-6.87 (m, 3H);
7.23-7.45 (m, 5H) 8.43-8.59 (br s, IH). MS (ESI+): m/z 466 (M+1). HRMS (El) Calc for
C27H35N3O2S: 465.2450; found 465.2435. EXAMPLE 92 - N-r(3aS*.6R*.7aS*)-3a-(1.3-benzodioxol-5-yl)-l-benzyloctahvdro-lH- indol-6- yll -N'-(tert-butyl)thiourea hydrochloride
The general procedure for urea/thiourea formation was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (O.lg, 0.29 mmol) and t-butyl isothiocyanate (46 mg, 0.4 mmol), to give 103 mg (74%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl3/MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl Et2O (sat.) followed by evaporation. The title compound (slower elute): colorless gummy solid; 19 mg (14%). The relative configuration was determined by 1H NMR spectroscopy (NOESY). 1H NMR (270 MHz, CDC13) δ ppm 0.80-0.97 (m, IH); 1.16-1.47 (m, 11H); 1.62-2.32 (m, 7H); 2.57 (d, IH, J = 14.0 Hz); 2.88-3.20 (m, 2H); 4.59-4.80 (br s, IH); 5.29 (d, IH, J = 9.0 Hz); 5.78-5.90 (br s, IH); 5.93 (s, 2H); 6.72-6.91 (m, 3H); 7.16-7.49 (m, 5H). MS (ESI+): m/z 466 (M+1). HRMS (El) Calc for C27H35N3O2S: 465.2450; found 465.2448.
EXAMPLE 93 - N-r(3aS*.6S*.7aS*)-3a-(1.3-benzodioxol-5-vn-l-benzyloctahvdro-lH- indol-6-yll-N'-(tert-butyl)thiourea hydrochloride
The general procedure for urea/thiourea formation was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (O.lg, 0.29 mmol) and t-butyl isothiocyanate (46 mg, 0.4 mmol), to give 103 mg (74%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl /MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et2O (sat.) followed by evaporation. Example 91 (faster elute): colorless gummy solid; 48 mg (34%). The relative configuration was determined by Η NMR spectroscopy (NOESY). 1H NMR (270 MHz, CDC13) δ ppm 1.20-1.32 (m, IH); 1.42 (s, 9H); 1.58-1.73 (m, IH);
1.49-2.05 (m, 6H); 2.24 (d, IH, J = 16.5 Hz); 2.62-2.79 (m, IH); 3.10-3.23 (m, 2H); 3.70
(d, IH, J = 13.8 Hz); 4.00 (d, IH, J = 13.8 Hz); 5.55-5.65 (br s, IH); 5.93 (s, 2H); 6.68-
6.80 (m, 3H); 7.25-7.40 (m, 5H); 7.94-8.11 (br s, IH). MS (ESI+): m/z 466 (M+1). HRMS
(El) Calc for C27H35N3O2S: 465.2450; found 465.2450. EXAMPLE 94 - N-r(3aS*.6S*.7aS*)-3a-fl.3-benzodioxol-5-vn-l-benzyloctahvdro-lH- indol-6-yl1-N'-butylthiourea hydrochloride
The general procedure for urea/thiourea formation was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (O.lg, 0.29 mmol) and n-butyl isothiocyanate (46 mg, 0.4 mmol), to give 95 mg (68%) of the mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl3/MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et2O (sat.) followed by evaporation. The title compound (faster eluting): colorless gummy solid; 30 mg (21%). The relative configuration was determined by Η NMR spectroscopy (NOESY). Η NMR (270 MHz, CDC13) δ ppm 0.82-0.96 (m, 4H); 1.14-2.52 (m, 14H); 2.96-3.36 (m, 4H); 4.20-4.31 (m, 2H); 5.32-5.61 (br s, IH); 5.93 (s, 2H); 6.71-6.90 (m, 3H); 7.24-7.50 (m, 5H). MS (ESI+) m/z 466 (M+1). HRMS (El) Calc for C27H35N3O2S: 465.2450; found 465.2451.
EXAMPLE 95 - N-r(3aS*.6R*.7aS*)-3a-(1.3-benzodioxol-5-yl)-l-benzyloctahvdro-lH- indol-6-yl"l-N'-benzylthiourea hydrochloride
The general procedure for urea thiourea was used, starting from (3aS*,7aS*)-3a- benzo[l,3]dioxol-5-yl-l-benzyl-octahydro-indol-6-ylamine, intermediate from Example 86 and 87 (0.9g, 2.57 mmol) and benzyl isothiocyanate (500 mg, 3.3 mmol), to give 960 mg (71%) of a mixture of isomers. The isomers were separated by using column chromatography (silica, CHCl3/MeOH/NH3) and converted to the corresponding hydrochlorides via treatment of DCM solutions with HCl/Et2O (sat.) followed by evaporation. The title compound (slower elute): colorless gummy solid; 350 mg (12%). The relative configuration was determined by 1H NMR spectroscopy (NOESY). Η NMR (270 MHz, CDC13) δ ppm 0.79-0.93 (m, IH); 1.14-2.60 (m, 8H); 3.00-3.15 (m, IH); 3.38 (IH, d, J - 13.3 Hz); 3.95-4.78 (m, 4H); 4.64-4.75 (br s, IH); 5.53-5.56 (br s, IH); 5.94 (s, 2H); 6.68-6.86 (m, 3H); 7.16-7.41 (m, 10H). MS (ESI+) m/z 500 (M+1). HRMS (El) Calc for C30H33N3O2S : 499.2293; found: 499.2283 PREPARATION OF A PHARMACEUTICAL COMPOSITION
EXAMPLE 96: Preparation of tablets ingredients mg/tablet
1. Active compound of formula (I) 10.0
2. Cellulose, microcrystalline 57.0
3. Calcium hydrogen phosphate 15.0
4. Sodium starch glycolate 5.0
5. Silicon dioxide, colloidal 0.25
6. Magnesium stearate 0.75
The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
BIOLOGICAL METHODS
The ability of a compound of the invention to bind or act at the MCHIR receptor can be determined using in vitro and in vivo assays known in the art. The biological activity of compounds prepared in the Examples was tested using different tests.
Binding assay
The compounds according to the invention were evaluated for their binding to the human MCHIR receptor by the following method:
Materials and methods
Materials Compounds: MCH peptide was purchased from Phoenix pharmaceuticals. (Phe13, [I25I]Tyr19 Melanine-Concentrating Hormone (human, mouse, rat) ([125I]-MCH) was obtained from NEN life Science Products. Inc. Boston, MA. Wheat germ agglutinine SPA beads (RPNQ 0001) were obtained from Amersham-Pharmacia Biotech. All other reagents used are of highest purity from different resources available. Protein Kits, Micro BCA™ Protein Assay Reagent Kit (Cat No. 23235) were purchased from Piece, Rockford, IL, USA. Plastic wares: Cell culture flasks, dishes were from Decton Dickinson Labware, NJ, USA. Scintillation plate, white clear bottom were from Wallac, Finland.
Cells and culture conditions
CHO-K1 cells expressing hMCHl receptor were purchased from Euroscreen. CHO-K1 hMCHRI (Euroscreen, Brussels, Belgium, #ES-370-C) were cultivated in
Nutrient mixture Ham's F-12 with Glutamax I (Gibco-BRL #31765-027) supplemented with 10% heat-inactivated foetal calf serum (FCS, Gibco-BRL #10108-165) and 400 μg/ml geniticin (Gibco-BRL #1140-0359). The cells were sub-cultivated twice weekly with split ratio= 1 :20-l :30. For membrane preparation the cells were cultured in 500 mm dishes and the cells were harvested when 90% confluent.
Membrane preparation
When the cells reached more than 90% confluence, dishes (500 cm2 ) were rinsed twice with 20 ml PBS (Ca2+ and Mg2+ free). Buffer A, which contains Tris.HCl (15), MgCl2.6H2O (2), EDTA (0.3), EGTA (1) in mM with pH 7.5, 25ml was added and cells were suspended using a window scraper. The cells were collected in 50 ml Falcon tube pre-cooled on ice and then centrifuged for 3 minutes at 1500g at 4 °C. The supernatant was discarded and the cells were suspended again with Buffer A. The cells were homogenized using a Polytron homogenizer at setting 4 for 4 times for 30 seconds with 1 minute pause between the cycles. The homogenized preparation was centrifuged at 40,000g (18500 m with ss-34, No. 5 rotor in Sorvall centrifuge, RC5C, DuPont) for 25 minutes at 4 °C. The pellets were washed once with Buffer A and centrifuged again under the same conditions. The pellets were suspended with Buffer B, which contains Tris.HCl (7.5), MgCl2.6H2O (12.5), EDTA (0.3), EGTA (1), sucrose (25) in mM with pH 7.5, and gently homogenized for several times with a glass homogenizer. The membrane preparation was aliquoted into Eppendorf tubes, 1 ml/tube and frozen at -70 °C. Membrane protein determination
The protein determination was done as described in the instruction provided with Pierce protein assay kit (Peirce Micro BCA Protein assay reagent kit, No 23235, Pierce, USA). Briefly, the Piece working reagent components A, B and C were mixed in the ratio 25:24:1. BSA (No. 23209, Pierce, USA) provided with the kits was used as standard, which the concentration in the curve is 1, 2, 4, 6, 8, 12, 16 and 24 μl/ml. The samples from membrane preparation were diluted for 50, 100, 200, 400 times. The standards or the samples 150 μl and the working reagent 150 μl were mixed in each well in a Costa 96 well microtiter plate and incubated at 37°C for 2 hours. The plate was cooled down to room temperature and read at 595 nm with a Microplate reader from Molecular Devices, USA.
Receptor binding by SPA
The WGA beads were re-constructed with reaction buffer, which contains Tris (50), MgCl2 (5), EDTA (2.5) in mM with pH adjusted to 7.4, to 40 mg/ml as a stock suspension. To link the membrane with the bead, the beads and the membrane will be pre-incubated with for 30 minutes at room temperature with gentle shaking. The suspension of the beads was centrifuged at 3400 φm for 2 minutes using centrifuge. The supernatant was discarded and the beads were re-suspended with binding buffer, HEPES (25mM), MgCl2 (5mM), CaCl2 (ImM), BSA (0.5%) with peptidase inhibitors (lμg/ml) Leupeptin, Aprotinin and pepstatin, pH 7.4.
Since appropriated beads and membrane construction is needed for SPA, the ratio of beads and membrane in link were tested and it will be indicated where the experiments are described. The radio labeled [125I]-MCH was diluted with cold MCH in ratio 1 :3. In Kd determination, the concentrations of labeled peptide were 3 nM with 1 :2 series dilution for 11 samples. The amount of the beads was 0.25 mg/well. The results were calculated using Excel program and the curves were drawn using a program GraphPad Prism.
For screening of the substances the amount of the beads used was 0.25 mg/well and the amount of the membrane protein was 4 μg/well 0.2 nM of labeled MCH was used. The total volume was 200 μl, which contained 50 μl [125I]-MCH, 100 μl substances and 50 μl beads. The plate was gently shaken for 30 minute and incubated overnight. The samples were counted using Microbeta counter (Wallac Trilux 1450 Micro beta counter, Wallac, Finland) for 2 minutes and the results were calculated by using the computer program Activity Base.
Results
The equilibrium time of the binding was investigated at room temperature, 30 and 37°C. The equilibrium time was about 30 minutes at 37 °C but the binding was lower compared with that at room temperature and 30 °C. The equilibrium time was about 2 hours at 30 °C while it took about 4 hours to reach stable binding at room temperature. Thus, room temperature was chosen since it is easy condition for experiments.
The [125I]-MCH binding to hMCH RI was further characterized by determination of Kd values. The Kd values are same, 0.19 nM, as reported by Chambers J, Ames RS, Bergsma D, Muir A, Fitzgerald LR, Hervieu G, Dytko GM, Foley JJ, Martin J, Liu WS, Park J, Ellis C, Ganguly S, Konchar S, Cluderay J, Leslie R, Wilson S, Sarau HM. Melanin- concentrating hormone is the cognate ligand for the oφhan G-protein-coupled receptor SLC-1. Nature 1999 Jul 15;400(6741):261-5.
In all displacement experiments, 0.2 nM [125I]-MCH was used for total binding and 300 nM MCH used as non-specific binding. The background is low and the signal is good. The Z' factor was 0.83 which is considered very good for screening.
Kd values from present study were consistent with that from Macdonald D, Murgolo N, Zhang R, Durkin JP, Yao X, Strader CD, Graziano MP.. Molecular characterization of the melanin-concentrating hormone/receptor complex: identification of critical residues involved in binding and activation. Mol Pharmacol 2000 Jul;58(l):217-25 but were slightly different from that 1.2 nM from Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA, The distribution of the mRNA and protein products of the melanin- concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat. Eur J Neurosci 2000 Apr; 12(4): 1194-216. The reason for this is unknown but might be caused by different clones of the cells. The calculation of the K, values for the inhibitors was performed by use of Activity Base. The K, value is calculated from IC 0 and the Km value is calculated using the Cheng Prushoff equation (with reversible inhibition that follows the Michaelis-Menten equation): K, = IC5o(l+[S]/Km) [Cheng, Y.C.; Prushoff, W.H. Biochem. Pharmacol. 1973, 22, 3099- 3108]. The IC50 is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance.
The compounds of formula (I) exhibit the IC50 values for the MCHIR receptor in the range from 10 nM to 10 μM. Illustrative of the invention, the following Ki values have been determined in the assay (see Table 1):
Table 1 : Ki values determined in the assay.
Figure imgf000057_0001

Claims

Claims
1. A compound of the general formula (I)
Figure imgf000058_0001
or a pharmaceutically acceptable salt, hydrates, geometrical isomers, racemates, tautomers, optical isomers, N-oxides and prodrug forms thereof, wherein:
R1 is Cι-6-alkyl; R2 is Cι-6-alkyl; or R1 and R2 are linked to form Cι-3-alkylene;
R3 is H, Cι-6-alkyl, Cι-6-alkoxycarbonyl, Cι-6-alkoxycarbonyl-C1-6-alkyl, Cι-6- alkoxycarbonyl-C3-6-cycloalkyl-Cι-6 alkyl, aryl-Cι-6-alkyl, heteroaryl-Cι-6 alkyl, aryl or heteroaryl, wherein any aryl or heteroaryl may be unsubstituted or independently substituted with Cι-6-alkyl, C1-6-alkoxy, Cι-6-alkoxycarbonyl, Cι-6-alkoxycarbonyl-Cι-6- alkyl, Ci-e-alkoxycarbonyl-C^ό-cycloalkyl-Ci-e alkyl, halo-C1-6-alkyl, halo-Cι-6-alkoxy, or nitro;
R4 is H or Cι-6-alkyl;
R5 is H, OH, Cι-6-alkyl, Cι-6-alkylaminocarbonyl, or Cι-6-alkylaminothioxylcarbonyl; R6 is H or Cι-6-alkyl;
R7 is H, Cι-6-alkyl, C2.6-alkenyl, C3-8-cycloalkyl, C -8-cycloalkyl-Cι-6-alkyl, Cι_6-alkoxy,
Ci.g-alkoxy-Ci-δ-alkyl, Cι-6-alkylcarbonyl, Ci .g-alkoxycarbonyl, C^.g-alkoxycarbonyl-
Cι-6-alkyl, heterocyclo-Cι-6-alkyl, heteroaryl-Cι-6-alkyl, aryl-Cι-6-alkyl, arylcarbonyl, heteroarylcarbonyl, or heterocyclyl, wherein any aryl, heteroaryl and heterocyclo may be unsubstituted or substituted in one, two or three positions with Cι-6-alkyl, halo-Cι-6-alkyl, Cχ-6-alkoxy, or halogen; or R6 and R7 are linked to form C4-6-alkylene or together with the nitrogen atom to which they are attached form a piperazine ring, which may be unsubstituted or substituted in one position with Cι-6-alkyl; R8 is H or Cι-6-alkyl; and X is O, S, NH, CH-NO2, or NCN.
2. The compound according to claim 1 wherein R1 and R2 are methyl.
3. The compound according to claim 1 wherein R and R are linked to form methylene.
4. The compound according to any one of claims 1 to 3 wherein R4 is H.
5. The compound according to any one of claims 1 to 4 wherein R8 is H.
6. The compound according to any one of claims 1 to 5 wherein X is S.
7. The compound according to claim 6 wherein R is hydrogen; methyl; ethyl; n-propyl; isobutyl; pentyl; tert-butoxycarbonyl; ethoxycarbonylmethyl; ethoxycarbonylcyclopropylmethyl; benzyl, which may be unsubstituted or independently substituted in one or two positions with trifluoromethyl, methoxy, trifluoromethoxy, and nitro; phenylethyl; phenylpropyl; furylmethyl; methyl-furylmethyl; thienylmethyl; methyl- pyrrolylmethyl; pyridylmethyl; methyl- lH-imidazolylmethyl; or quinolinylmethyl;
8. The compound according to claim 6 wherein R is H or methyl.
9. The compound according to claim 6 wherein R 6 i ■s H
10. The compound according to claim 6, wherein R7 is ethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hexyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, allyl, methoxypropyl, moφholinylethyl, furylmethyl, benzyl, phenylethyl, fluorobenzyl, or methoxybenzyl.
11. The compound according to any one of claims 1 to 5 wherein X is oxygen.
12. The compound according to claim 11 wherein R3 is methyl or benzyl.
13. The compound according to claim 11 wherein R5 is H.
14. The compound according to claim 11 wherein R6 is H or methyl.
15. The compound according to claim 11 wherein R7 is ethyl, allyl, benzyl, ethoxycarbonylethyl, piperazinylethyl, piperazinylpropyl, methylbenzyl, fluorobenzyl, bromobenzyl, dichlorobenzyl, methoxybenzyl, trifluoromethylbenzyl, phenylethyl, thienylethyl, pyridinylmethyl, methylpyrazinylmethyl, or 4-methylpiperazin-l-yl.
16. The compound according to claim 11 wherein R6 and R7 together with the nitrogen to which they are attached form a piperazine, which may be unsubstituted or substituted in one position with methyl.
17. The compound according to any one of claims 1 to 5 wherein X is NH.
18. The compound according to claim 17 wherein R3 is methyl.
19. The compound according to claim 17 wherein R5 and R6 both are H.
20. The compound according to claim 17 wherein R7 is n-butyl, n-pentyl, or benzyl.
21. The compound according to any one of claims 1 to 20, which is a compound selected from the group of: N-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- ethylthiourea,
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N- ethylthiourea,
N-[(3aS * ,6R* ,7aS *)- 1 -benzyl-3a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6-yl] -N'- butylthiourea,
N-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- butylthiourea,
N-benzyl-N'-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yljthiourea, N-benzyl-N'-[(3 aS * ,6S *,7aS*)- 1 -benzyl-3 a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6- yljthiourea,
N-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- ethylurea, tert-butyl (3 aS * ,6R*,7aS *)-6- { [(benzylamino)carbonothioyl] amino } -3a-(3 ,4- dimethoxyphenyl)octahydro-lH-indole-l-carboxylate, tert-butyl (3 aS* ,6S * ,7aS *)-6- { [(benzylamino)carbonothioyl] amino } -3a-(3 ,4- dimethoxyphenyl)octahydro- 1 H-indole- 1 -carboxylate,
N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea,
N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyρhenyl)-l-(quinolin-3- ylmethyl)octahydro- 1 H-indol-6-yl]thiourea,
N-benzyl-N'-{(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-[3-
(trifluoromethyl)benzyl] octahydro- 1 H-indol-6-yl} thiourea, N-benzyl-N'-{(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-[4-
(trifluoromethoxy)benzyl] octahydro- lH-indol-6-yl} thiourea,
N-benzyl-N'-[(3 aS* ,6R* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -(3 -phenylpropyl)octahydro- lH-indol-6-yl]thiourea,
N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyρhenyl)-l-(pyridin-3- ylmethyl)octahydro- 1 H-indol-6-yl]thiourea,
N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-(4-methoxybenzyl)octahydro- lH-indol-6-yl]thiourea, ethyl [(3aS*,6R*,7aS*)-6-{[(benzylamino)carbonothioyl]amino}-3a-(3,4- dimethoxyphenyl)octahydro- 1 H-indol- 1 -yl] acetate, N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-(4-nitrobenzyl)octahydro-lH- indol-6-yl]thiourea,
N-benzyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-pentyloctahydro-lH-indol-6- yl] thiourea,
N-benzyl-N'-[(3 aS * ,6S * ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6- yl] thiourea,
N-allyl-N'-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]urea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'-(2- furylmethyl)thiourea trifluoroacetate, N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'-(2- moφholin-4-ylethyl)thiourea trifluoroacetate,
N-benzyl-N'-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]urea trifluoroacetate, N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'-(3- methoxypropyl)thiourea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'-
(cyclopropylmethyl)thiourea trifluoroacetate,
N-allyl-N'-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl]thiourea,
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- isobutylthiourea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'-(2- phenylethyl)thiourea trifluoroacetate, ethyl N-({[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6- yl] amino } carbonyl)-beta-alaninate trifluoroacetate,
N-butyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-ethyloctahydro-lH-indol-6- yl]thiourea trifluoroacetate,
N-butyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-proρyloctahydro-lH-indol-6- yl]thiourea trifluoroacetate,
N-butyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-isobutyloctahydro-lH-indol-6- yl]thiourea trifluoroacetate,
N-butyl-N'- [(3aS * ,6R*,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -pentyloctahydro- 1 H-indol-6- yl]thiourea trifluoroacetate, N-butyl-N*- [(3aS * ,6R* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -(2-phenylethyl)octahydro- 1 H- indol-6-yl]thiourea trifluoroacetate, ethyl 2- { [(3 aS * ,6R*,7aS *)-6- { [(butylamino)carbonothioyl] amino } -3a-(3 ,4- dimethoxyphenyl)octahydro-lH-indol-l-yl]methyl}cyclopropanecarboxylate trifluoroacetate, N-butyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-(3-furylmethyl)octahydro-lH- indol-6-yl]thiourea trifluoroacetate,
N-butyl-N'-{(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-[(l-methyl-lH-pyrrol-2- yl)methyl]octahydro- 1 H-indol-6-yl} thiourea trifluoroacetate, N-butyl-N'-{(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-[(5-methyl-2- furyl)methyl]octahydro-lH-indol-6-yl}thiourea trifluoroacetate,
N-butyl-N'-[(3aS * ,6R* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -(3 -thienylmethyl)octahydro-
1 H-indol-6-yl]thiourea trifluoroacetate, N-butyl-N"-{(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-[(4-methyl-lH-imidazol-5- yl)methyl]octahydro-lH-indol-6-yl}thiourea trifluoroacetate,
N-butyl-N'- [(3 aS * ,6R* ,7aS *)-3a-(3 ,4-dimethoxyphenyl)- 1 -(3-phenylpropyl)octahydro- 1 H- indol-6-yl]thiourea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- (pyridin-4-ylmethyl)urea trifluoroacetate,
N'-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N- ethyl-N-methylurea trifluoroacetate,
N-[(3 aS * ,6R*,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6-yl] -N'-(4- fluorobenzyl)thiourea trifluoroacetate, N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-[2-
(2-thienyl)ethyl]urea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-(2- phenylethyl)urea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-(4- methoxybenzyl)thiourea trifluoroacetate,
N-allyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl]urea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'- hexylthiourea trifluoroacetate, N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-(3- methylbenzyl)urea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N,-(4- methoxybenzyl)urea trifluoroacetate,
N-benzyl-N'-[(3aS*,6S*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] guanidine trifluoroacetate,
N-butyl-N'-[(3aS*,6S*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] guanidine trifluoroacetate,
N-[(3aS*,6S*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'- pentylguanidine trifluoroacetate, N-butyl-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] guanidine trifluoroacetate,
N-[(3 aS * ,6R* ,7aS*)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6-yl] -N'- [4-
(trifluoromethyl)benzyl]urea trifluoroacetate, N-(2,4-dichlorobenzyl)-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l- methyloctahydro- 1 H-indol-6-yl]urea trifluoroacetate,
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-(4- fluorobenzyl)urea trifluoroacetate,
N-(4-bromobenzyl)-N'-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro- lH-indol-6-yl]urea trifluoroacetate,
N'-butyl-N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] -N-methylthiourea trifluoroacetate,
N'-butyl-N-[(3aS*,6S*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6- yl] -N-methylthiourea trifluoroacetate, N'-benzyl-N- [(3 aS *,6S* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6- yl] -N-methylthiourea,
N'-benzyl-N-[(3 aS * ,6S* ,7aS*)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6- yl] -N-methylthiourea trifluoroacetate,
N-[(3aS*,6S*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-4- methylpiperazine-1-carboxamide bis(trifluoroacetate),
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-4- methylpiperazine- 1 -carboxamide bis(trifluoroacetate),
N-[(3aS * ,6R* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6- yl]piperazine- 1 -carboxamide, bis(trifluoroacetate), N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-(2- piperazin- 1 -ylethyl)urea, tris(trifluoroacetate),
N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-[3-
(4-methylpiperazin- 1 -yl)propyl]urea, tris(trifluoroacetate),
N-[(3 aS *,6R* ,7aS*)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6-yl] -N'- [(5 - methylpyrazin-2-yl)methyl]urea trifluoroacetate,
N-[(3 aS * ,6R* ,7aS *)-3 a-(3 ,4-dimethoxyphenyl)- 1 -methyloctahydro- 1 H-indol-6-yl] -N'-(4- methylpiperazin- 1 -yl)urea tris(trifluoroacetate),
N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'- cyclopropylthiourea trifluoroacetate, N-[(3aS*,6R*,7aS*)-l-benzyl-3a-(3,4-dimethoxyphenyl)octahydro-lH-indol-6-yl]-N'-
(sec-butyl)thiourea trifluoroacetate,
N-[(3 aS *,6R* ,7aS*)- 1 -benzyl-3 a-(3 ,4-dimethoxyphenyl)octahydro- 1 H-indol-6-yl] -N'- cyclopentylthiourea trifluoroacetate, N-[(3aS*,6R*,7aS*)-3a-(3,4-dimethoxyphenyl)-l-methyloctahydro-lH-indol-6-yl]-N'-
[(lS)-l-phenylethyl]urea trifluoroacetate,
N-allyl-N'-[(3aS*,6S*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6- yl]urea hydrochloride,
N-allyl-N*-[(3aS*,6R*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6- yl]urea hydrochloride,
N-[(3aS*,6R*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N'- ethylthiourea hydrochloride,
N-[(3aS*,6S*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N- ethylthiourea hydrochloride, N-[(3aS*,6S*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N'- benzylthiourea hydrochloride,
N-[(3aS*,6R*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N- butylthiourea hydrochloride,
N-[(3aS*,6R*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N'-(tert- butyl)thiourea hydrochloride,
N-[(3aS*,6S*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N'-(tert- butyl)thiourea hydrochloride,
N-[(3aS*,6S*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N'- butylthiourea hydrochloride, and N-[(3aS*,6R*,7aS*)-3a-(l,3-benzodioxol-5-yl)-l-benzyloctahydro-lH-indol-6-yl]-N'- benzylthiourea hydrochloride.
22. A process for the preparation of a compound according to anyone of claims 1 to 21 comprising at least one of the following steps: (a) treatment of a nitrile with an alkali amide and then with l-bromo-2-chloroethane to give a cyclopropanecarbonitrile,
(b) reduction of a cyclopropanecarbonitrile with diisobutylaluminium hydride to give a cyclopropanecarbaldehyde, (c) reaction of a cyclopropanecarbaldehyde with benzylamine to give an imine and further reaction of the imine with a ketone,
(d) treatment of a ketone with ammonia, an amine or a salt thereof and then reduction to give an amine, (e) protection of an amine with a tert-butyloxycarbonyl group,
(f) treatment of an amine with an isocyanate or isothiocyanate,
(g) treatment of a first amine with /rørα-nitrophenylchloro formate and then with Hunigs base to give a PNP-carbamate, and treatment of a second amine with said PNP-carbamate, (h) reductive alkylation by treatment of an amine with an aldehyde and subsequent reduction,
(i) deprotection of a tert-butyloxycarbonyl group with trifluoroacetic acid,
(j) treatment of an amine with a carboximidamide, and
(k) treatment of a first amine with triphosgene and then with a second amine.
23. A compound according to anyone of claims 1 to 21 for use in therapy.
24. A compound according to anyone of claims 1 to 21 for medical use in the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence, and for modulation of appetite.
25. A compound according to anyone of claims 1 to 21 for medical use in the treatment or prophylaxis of disorders relating to the MCHIR receptor and for modulation of appetite.
26. A compound according to claim 25, wherein the disorders are selected from obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence.
27. A compound according to anyone of claims 1 to 21 for use in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists.
28. A compound according to anyone of claims 1 to 21 for use in conjunction with antiobesity medicaments.
29. A pharmaceutical formulation containing a compound according to anyone of claims 1 to 21 as an active ingredient, in combination with a pharmaceutically acceptable diluent or carrier.
30. A pharmaceutical formulation for use in the treatment or prophylaxis of obesity wherein the active ingredient is a compound according to anyone of claims 1 to 21.
31. A method for the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, urinary incontinence, and for modulation of appetite, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to anyone of claims 1 to 21.
32. A method for the treatment or prophylaxis of disorders related to the MCHIR receptor and for modulation of appetite, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to anyone of claims 1 to 21.
33. A method according to claim 32, wherein the disorders are selected from obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence.
34. A method for modulating MCHIR receptor activity, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 21.
35. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for use in the treatment or prophylaxis of obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence, and for modulation of appetite.
36. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for use in the treatment or prophylaxis of disorders related to the MCHIR receptor and for modulation of appetite.
37. Use according to claim 36, wherein the disorders are selected from obesity, diabetes mellitus, hyperlipidemia, hyperglycemia, depression, anxiety, and urinary incontinence.
38. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for use in conjunction with other compounds active towards other receptors, such as MC-4 agonists, 5HT2c agonists, or 5HT6 antagonists.
39. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for use in conjunction with anti-obesity medicaments.
PCT/SE2004/001619 2003-11-26 2004-11-09 Substituted urea-octahydroindols as antagonists of melanin concentrating hormone receptor 1 (mch1r) WO2005051380A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015157A2 (en) * 2005-08-01 2007-02-08 Pfizer Limited Mc4r-ag0nists for the treatment of urinary tract dysfunction
WO2017040234A1 (en) 2015-08-31 2017-03-09 3M Innovative Properties Company IMIDAZO[4,5-c] RING COMPOUNDS CONTAINING SUBSTITUTED GUANIDINE GROUPS
WO2018038877A1 (en) 2016-08-26 2018-03-01 3M Innovative Properties Company FUSED [1,2]IMIDAZO[4,5-c] RING COMPOUNDS SUBSTITUTED WITH GUANIDINO GROUPS
WO2018121770A1 (en) * 2016-12-30 2018-07-05 中国科学院上海药物研究所 Antidepressant compound and preparation method and application thereof
US10150768B2 (en) 2015-08-31 2018-12-11 3M Innovative Properties Company Guanidine substituted imidazo[4,5-c] ring compounds
US10766896B2 (en) 2017-03-01 2020-09-08 3M Innovative Properties Company Imidazo[4,5-c] ring compounds containing guanidine substituted benzamide groups
WO2023187421A1 (en) * 2022-04-01 2023-10-05 Kanna Health Limited Salt forms of mesembrine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024026059A2 (en) * 2022-07-29 2024-02-01 Sensorium Therapeutics, Inc. Delivery of therapeutic alkaloid compounds
WO2024206823A1 (en) * 2023-03-31 2024-10-03 Sensorium Therapeutics, Inc. Therapeutic alkaloid compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3028394A (en) * 1960-03-28 1962-04-03 Boehringer & Soehne Gmbh 9-phenyl octahydroindole compounds and process of making same
US6288104B1 (en) * 1996-06-04 2001-09-11 African Natural Health Cc Pharmaceutical compositions containing mesembrine and related compounds
WO2002057233A1 (en) * 2000-12-01 2002-07-25 Schering Corporation Mch antagonists and their use in the treatment of obesity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3028394A (en) * 1960-03-28 1962-04-03 Boehringer & Soehne Gmbh 9-phenyl octahydroindole compounds and process of making same
US6288104B1 (en) * 1996-06-04 2001-09-11 African Natural Health Cc Pharmaceutical compositions containing mesembrine and related compounds
WO2002057233A1 (en) * 2000-12-01 2002-07-25 Schering Corporation Mch antagonists and their use in the treatment of obesity

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JEFFS P.W. ET AL: "Total Syntheses of Mesembrine, Joubertinamine, and N-Demethylmesembrenone", J ORG CHEM, vol. 48, 1983, pages 3861 - 3863, XP002040520 *
SMITH M.T. ET AL: "Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae", JOURNAL OF ETHOPHARMACOLOGY, vol. 50, 1996, pages 119 - 130, XP002040528 *
TABER F. ET AL: "Enantioselective Construction of Cyclic Quaternary Centers: (-)-Mesembrine", J ORG CHEM, vol. 66, 2001, pages 143 - 147, XP002986103 *
TAGUCHI H. ET AL: "Synthesis of octahydroindole derivatives", TETRAHEDRON LETTERS, no. 55, 1968, pages 5763 - 5766, XP002040523 *

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* Cited by examiner, † Cited by third party
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WO2007015157A3 (en) * 2005-08-01 2007-05-18 Pfizer Ltd Mc4r-ag0nists for the treatment of urinary tract dysfunction
WO2007015157A2 (en) * 2005-08-01 2007-02-08 Pfizer Limited Mc4r-ag0nists for the treatment of urinary tract dysfunction
US10150768B2 (en) 2015-08-31 2018-12-11 3M Innovative Properties Company Guanidine substituted imidazo[4,5-c] ring compounds
WO2017040234A1 (en) 2015-08-31 2017-03-09 3M Innovative Properties Company IMIDAZO[4,5-c] RING COMPOUNDS CONTAINING SUBSTITUTED GUANIDINE GROUPS
US10487081B2 (en) 2015-08-31 2019-11-26 3M Innovation Properties Company Guanidine substituted imidazo[4,5-c] ring compounds
US10118925B2 (en) 2015-08-31 2018-11-06 3M Innovative Properties Company Imidazo[4,5-c] ring compounds containing substituted guanidine groups
WO2018038877A1 (en) 2016-08-26 2018-03-01 3M Innovative Properties Company FUSED [1,2]IMIDAZO[4,5-c] RING COMPOUNDS SUBSTITUTED WITH GUANIDINO GROUPS
US10414779B2 (en) 2016-08-26 2019-09-17 3M Innovative Properties Company Fused [1,2]imidazo[4,5-C] ring compounds substituted with guanidino groups
EP3889158A1 (en) 2016-08-26 2021-10-06 3M Innovative Properties Company Fused [1,2]imidazo[4,5-c] ring compounds substituted with guanidino groups
WO2018121770A1 (en) * 2016-12-30 2018-07-05 中国科学院上海药物研究所 Antidepressant compound and preparation method and application thereof
US11142543B2 (en) 2016-12-30 2021-10-12 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Antidepressant compound and preparation method and application thereof
US10766896B2 (en) 2017-03-01 2020-09-08 3M Innovative Properties Company Imidazo[4,5-c] ring compounds containing guanidine substituted benzamide groups
WO2023187421A1 (en) * 2022-04-01 2023-10-05 Kanna Health Limited Salt forms of mesembrine
US11970446B2 (en) 2022-04-01 2024-04-30 Kanna Health Ltd Crystalline salt forms of mesembrine

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