WO1993008166A1 - Benzo-isoquinoline derivatives and analogs and their use in therapeutics - Google Patents

Benzo-isoquinoline derivatives and analogs and their use in therapeutics Download PDF

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Publication number
WO1993008166A1
WO1993008166A1 PCT/US1992/007314 US9207314W WO9308166A1 WO 1993008166 A1 WO1993008166 A1 WO 1993008166A1 US 9207314 W US9207314 W US 9207314W WO 9308166 A1 WO9308166 A1 WO 9308166A1
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compound
trans
dihydro
octahydro
indeno
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PCT/US1992/007314
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English (en)
French (fr)
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Arthur Glenn Romero
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The Upjohn Company
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Priority to CA002118920A priority Critical patent/CA2118920A1/en
Priority to JP5507668A priority patent/JPH07500333A/ja
Priority to EP92309695A priority patent/EP0539209A1/en
Publication of WO1993008166A1 publication Critical patent/WO1993008166A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/32—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to novel compositions of matter. More particularly, the present invention relates to new isoquinoline and pyridine derivatives, processes for preparing these compounds, and pharmaceutical compositions containing these compounds. The present invention further relates to the use of these compounds in the treatment of certain psychiatric disorders, such as anxiety, depression, sexual dysfunction schizophrenia and parkinsonism.
  • Psychiatric diseases are thought to be due to dysfunctions in monoaminergic neuronal systems, particularly those involving serotonin (5-HT) and dopamine (DA).
  • Anxiety is associated with increased activity in 5-HT systems.
  • benzodiazepine anxiolytics are not active in anti-anxiety assays that they otherwise are effective in.
  • Serotonin neurons have autoreceptors that, when activated by agonists, depress firing rates of 5-HT cells. These receptors are of the 5-HT 1A subtype. Because they depress 5-HT neuronal activity, it can be expected that 5-HT 1A agonists will be an effective anxiolytic. Clinically, 5-HT 1A agonists have demonstrated anxiolytic properties.
  • the drug buspirone is the only currently available marketed 5-HT 1A agonist having anxiolytic activity.
  • This compound antagonizes dopamine receptors at the same dose it stimulates 5-HT 1A receptors.
  • a similar drug, gepirone also has dopamine antagonist properties. These dopamine antagonist properties reduce the clinical utility of these compounds because long term treatment with dopamine antagonists can produce tardive dyskinesia.
  • Depression is a psychiatric condition thought to be associated with decreased 5-HT release. Most anti-depressants potentiate the effects of 5-HT by blocking the termination of activity through re-uptake into nerve terminals. Since some 5-HT 1A receptors are activated postsynaptically by 5-HT, 5-HT 1A agonists may also be anti-depressants. Since the postsynaptic 5-HT 1A receptor may be less sensitive than the autoreceptor, high doses of 5-HT 1A agonists, particularly very effective ones (i.e., those causing greater stimulation of the 5-HT 1A receptor, a parameter referred to as "efficacy"), can be expected to be effective anti-depressants. Gepirone has already been demonstrated to have ameliorative effects on some depressive end points in some patients.
  • 5-HT 1A agonists may be useful in treating overeating and sexual dysfunction. These compounds have been shown to alter feeding and sexual behavior in animals. 5-HT 1A agonists are also known to depress sympathetic nerve discharge and thus lower blood pressure. Thus, they may be useful in treating hypertension, congestive heart failure by reducing cardiovascular afterload and heart attack by removing sympathetic drive to the heart.
  • Dopamine (DA) is also known to depress sympathetic nerve discharge and thus lower blood pressure. Thus, they may be useful in treating hypertension, congestive heart failure by reducing cardiovascular afterload and heart attack by removing sympathetic drive to the heart.
  • Schizophrenia is thought to be due to hyperactivity in DA systems.
  • DA antagonists Dopamine autoreceptors depress DA neuron firing rates, DA synthesis and release.
  • DA autoreceptor agonists can also be expected to be anti- psychotics.
  • DA agonists are also useful for treating Paridnsonism, a disease caused by degeneration of DA neurons, and hyperprolactinemia, since DA agonists depress prolactin release.
  • Dopamine autoreceptor antagonists are a new class of drug that increase release of DA by releasing the DA neuron from autoreceptor control. Thus, these drugs can be expected to be useful in conditions treatable with amphetamine and other similar stimulants which directly release DA. Dopamine autoreceptor agonists are expected to be much milder stimulants than amphetamines because they simply increase the release associated with the normal DA activity, by releasing the cell from autoreceptor control, rather than directly releasing DA. Thus, DA autoreceptor antagonists can be expected to be useful in treating overeating, attention deficit disorders, psychiatric, cognitive and motor retardation in demented and elderly patients, and in treating nausea and dizziness.
  • Drugs acting on central DA transmission are clinically effective in treating a variety of central nervous system disorders such as paridnsonism, schizophrenia, and manic-depressive illness.
  • the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic DA receptor stimulation.
  • the condition can be normalized by achieving a decrease in postsynaptic DA receptor stimulation.
  • Classical anti-psychotic agents directly block the postsynaptic DA receptor. The same effect can be achieved by inhibition of intraneuronal presynaptic events essential for the maintenance of adequate neurotransmission, transport mechanism and transmitter synthesis.
  • Direct DA receptor agonists like apomoiphine, are able to activate the DA autoreceptors as well as the post synaptic DA receptors.
  • the effects of autoreceptor stimulation appear to predominate when apomoiphine is administered at low doses, whereas at higher doses the attenuation of DA transmission is outweighed by the enhancement of postsynaptic receptor stimulation.
  • the anti-psychotic and anti-dyskinetic effects in man of low doses of apomorphine are likely due to the autoreceptor-stimulator properties of this DA receptor agonist
  • This body of knowledge indicates DA receptor stimulants with a high selectivity for central nervous DA autoreceptors would be valuable in treating psychiatric disorders.
  • the compounds of the present invention have a variety of effects at 5-HT 1A and DA receptors, and offer a variety of utilities associated with those activities.
  • the compounds of this invention may be described as having tricyclic moieties, or rings. These rings, have been labeled A, B, C, in Formula I, below, in the summary of invention section.
  • the tricyclic moieties may be designated by the number of atoms in each ring. Thus, a 6-5-7 ring system would have 6 atoms in the A ring, 5 atoms in the B ring, and 7 atoms in the C ring.
  • the compounds of this invention have a 6-6-6 ring system.
  • One of the atoms in the C -ring is nitrogen.
  • a 6-6-6 ring system where the A ring is aromatic that contains a 6-atom C ring which contains nitrogen might also be called a benzo-quinoline structure.
  • SET A documents that represent the 6-6-6 system, "SET A,” in addition to other systems. These other systems are grouped and listed below for the sake of completeness. The first two references cited in "SET A" are considered most relevant to this disclosure.
  • the first group, SET A contains 6-6-6 ring systems or benzo-quinolone structures; the second group, SET B, contains 6-5-6 ring systems or indeno-pyridine structures; the third group, SET C, contains 6-6-5 ring systems or benzo-indolines; the fourth group, SET D, contains 6-5-5 ring systems or indeno-pyrroles, and the fifth group SET E, contains 6-7-5 ring systems or benzo-cyclohepta-pyridines.
  • German Patent, DE 2,801,576, Derwent No. 55370/31 discloses hexahydrobenz[f]isoquinolines.
  • the present invention encompasses: 1) compounds of formula I below,
  • p and s are independent and may be either 1 or 2,
  • R 1 is -H, -Halo, -CN, -CO 2 H, -CO 2 R 1-1 , -CONH 2 , -CONHR 1-1 , -CON(R 1-1 ) 2 , -SH, -SR 1-1 , - SO 2 R 1-1 , -SO 2 NH 2 , -SO 2 NHR 1-1 , -SO 2 N(R 1-1 ) 2 , -OR 1-1 , -OSO 2 CF 3- -OSO 2 R 1-1 , -NH 2 , -NHR 1-1 , or -N(R 1-1 ) 2 ; wherein R 1-1 is -H, -(C 1 -C 8 alkyl), -(C 1 -C 8 alkenyl), -(C 3 -C 10 cycloalkyl), -(C 6 aryl), -5 or 6 member heterocyclics, -(C 1 -C 8 alkyl)-(5 or
  • a method of treating central nervous system disorders, associated with serotonin and or dopamine receptor activity comprising: administering an effective amount of a compound of formula I to a patient in need thereof.
  • the compounds of this invention possess selective pharmacological properties and are useful in treating central nervous system disorders including anti-depression symptoms, anxiolytic symptoms, panic attacks, obsessive-compulsive disturbances, senile dementia, emotional disturbances related to dementia disorders, and stimulation of sexual activity.
  • central nervous system disorders and conditions related to central dopamine transmission such as paridnsonism, schizophrenia, and manic-depressive illness may also be treated with the compounds of this invention.
  • the compounds of this invention are also useful to alleviate aggressive behavior, confusional delirious states and impotence.
  • the compounds of this invention are also anti-diabetic, anti-obesity,anti-atherosclerotic, and anti-hypertensive agents. Processes for preparation of these compounds, their pharmaceutical use and pharmaceutical preparations employing such compounds constitute further aspects of the invention.
  • An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the central nervous system. Another object is to provide compounds having an effect on the 5-HT 1A receptor in mammals including man. A further object of this invention is to provide compounds having an effect on the subclass of dopamine receptors known as the D 2 receptor.
  • the compounds of this invention are identified in two ways: by the descriptive name and reference to labeled structures contained in appropriate charts. In appropriate situations, the proper stereochemistry is also represented in the charts.
  • Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl.
  • Alkoxy as represented by -OR 1 when R 1 is (C 1 -C 8 ) alkyl refers to an alkyl radical which is attached to the remainder of the molecule by oxygen and includes branched or unbranched forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy, and n-octoxy.
  • Alkenyl refers to a radical of an aliphatic unsaturated hydrocarbon having at least one double bond and includes both branched and unbranched forms such as ethenyl, 1-methyl-1-ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyI, 1-pentenyl, allyl, 3- pentenyl, 4-pentenyl, 1-methyI-4-pentenyl, 3-melhyI-1-pentenyl, 3-methyl-allyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 1-methyI-4-hexenyl, 3-methyl- 1-hexenyl, 3-methyl-2-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyI-4-heptenyl, 3-methyl
  • (C 3 -C 10 )cyclo alkyl refers to a radical of a saturated cyclic hydrocarbon which includes alkyl- substituted cycloalkyl, such as cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3 diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcycIobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dimethyIcyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • alkyl- substituted cycloalkyl such as cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3 diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcycIobutyl, 3-propyl
  • aryl examples include phenyl, naphthyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl- tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(o-, m-, or p-)-tolyl, 4- isopropyl-2,6-xylyl, 3-propyI-4-ethyIphenyl, (2,3,4-, 2,3,6-, or2,4,5-)trimethylphenyl, (o-, m-, or p- )fluorophenyl, (o-, m-, or p-trifluoromethyl)phenyl, 4-fluoro-2,5-xyIyl, (2,4-, 2,5-, 2,6-, 3,4-,
  • heterocyclics include: (2-, 3-, or 4-)pyridyl, imidazolyl, indolyl, N in -formyl-indolyl, N in -Q-Qalkyl-C ⁇ -indolyl, [1,2,4]-triazolyl, (2-, 4-, 5-)pyrimidinyl, (2-, 3-)thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, is
  • Halo is halogen (fluoro, chloro, bromo or iodo) or trifluoromethyl.
  • LAH is lithium aluminum hydride
  • LDA lithium diisopropylamide
  • THF is tetrahydrofuran
  • 9-BBN-H or 9-BBN is 9-Borabicyclo[3.3.1]nonane dimer
  • compounds of this invention may contain chiral centers.
  • the scope of this invention includes all enantiomeric or diastereomeric forms of formula I compounds either in pure form or as mixtures of enantiomers or diastereomers.
  • the compounds of formula I contain two asymmetric carbon atoms in the aliphatic ring moiety, including the ring carbon atoms adjacent to the nitrogen atom.
  • the therapeutic properties of the compounds may to a greater or lesser degree depend on the stereochemistry of a particular compound.
  • Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
  • Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, methanesulfonic, ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid.
  • These salts are readily prepared by methods known in the art.
  • the compounds of the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, mesylate, methanesulfonate, or sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable non-toxic, acid addition salt such as the hydrochloride, lactate, acetate, mesylate, methanesulfonate, or sulfamate salt
  • These compounds are particularly effective anxiolytic and antidepressant agents.
  • Central nervous system disorders and conditions related to central dopamine transmission such as paridnsonism, schizophrenia, and manic-depressive illness may also be treated with the compounds of this invention.
  • Other uses for these compounds include panic attacks, obsessive-compulsive disturbances, and senile dementia, particularly the emotional disturbances seen in dementia disorders.
  • central 5-HT receptor activation are believed to be involved in mediating sexual disorder. These compounds would be useful to stimulate sexual activity and to alleviate impotence.
  • the compounds of this invention are also useful to alleviate aggressive behavior and confusional delirious states.
  • the compounds of this invention can be made in accordance with the processes illustrated in CHARTS A, B and C.
  • the reactions and properties are divided into two parts.
  • PART I immediately below, contains compounds related to CHARTS A and B.
  • the reactions of compounds of CHARTS A and B are followed by the biological data for the compounds of CHARTS A and B followed by detailed preparation steps.
  • the compound claims that correspond to PART I, the compounds of CHARTS A and B are claims 14 - 24.
  • Part II contains the COMPOUNDS that correspond to CHART C, the reactions, the corresponding biological data and the detailed preparations.
  • the compound claims that correspond to PART H are claims 2 - 13.
  • Step 1 the starting ketone, A1, is refluxed with the sodium salt of triethyl phosphonoacetate to give the ester, A 2 , along with some of its exo double bond isomer.
  • the undesired isomer is removed by treating the isomeric mixture with LDA followed by quenching with acetic acid.
  • Step 2 the ester, A2, is reduced to the alcohol, A3, with LAH.
  • Step 3 the alcohol, A3, is treated with silylchloride to protect the alcohol as the /-butyldimethylsilyl ether A4.
  • Step 4 the silyl ether, A4, is refluxed with 9-BBN-H in THF and then treated with a mixture of bromo ethylacetate and potassium 2,6-di-t-butylphenoxide to give the ester, A5.
  • Step 8 the dibromide is heated with optically pure ⁇ - methylbenzylamine to afford a mixture of diastereomeric azepines, A9, which are separated by chromatography. The diastereomers are separately carried on to the final optically pure enantiomers using the following procedures.
  • Step 9 optically active azepine, A9, is treated with t-butyllithium followed by trimethylsilylisocyanate to afford the caiboxamido azepine, A10.
  • Step 10 hydrogenation over palladium hydroxide afforded A1l.
  • Step 11 the hydrogenated azepine was alkylated with bromopropane to afford A12.
  • Step 12 the carboxamido group is replaced with a cyano group, A13.
  • Step 1 indanone, B1, is treated with pyrrolidine to convert it into the eneamine, B2.
  • Step 2 the eneamine is alkylated with ethyl bromoacetate to afford the caiboxylate, B3.
  • Step 3 the caiboxylate undergoes a Reformatsky reaction with ethyl bromoacetate to afford the diester, B4.
  • Step 4 the diester is reduced with triethylsil ane in trifluoroacetic acid to obtain the reduced diester, B5.
  • Step 5 the reduced diester is further reduced with LAH to afford the diol, B6.
  • Step 6 the diol is converted into the di-p-toluenesulfonate, A7.
  • Step 7 the di-p-toluenesulfonate is converted into the azepines B8 and B9 (trans and cis- fused rings, respectively).
  • the compounds of this invention have high oral potency and a long duration of action. This exceptionally good bioavailability combined with a long period of activity are beneficial to effective clinical treatment
  • the preferred compounds of PART I are not only active but have increased bioavailability as shown by metabolism studies. See PART I - TABLES I-IV, below.
  • One preferred compound is (-)-t ⁇ ans-10-carboxamido-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine, compound number 3, below.
  • the compounds of this invention are useful both as intermediates to produce other compounds and they are useful to treat central nervous system disorders.
  • the utility of the compounds of this invention to treat central nervous system disorders is shown in behavioral, physiological and biochemical tests. These tests are described below.
  • Assay measures the percent inhibition from experiments employing test compounds at 1 microMolar concentration competing with various radioligands for binding to whole brain membranes, membranes prepared from specific brain structures, or membranes prepared from cell lines expressing cloned receptors. When percent inhibition is equal to 100 the test compound binds as well as the standard compound.
  • the standard compound for the 5-HT 1A receptor is 8-OH-DPAT.
  • the standard compound for the dopamine D1 receptor is SCH 23390.
  • 5-HT and DA Cell Firing (PART I - TABLE II): Glass microelectrodes filled with pontamine sky blue in 2M NaCl were used for extracellular recordings from Sprague-Dawley rats anesthetized with chloral hydrate (400 mg/kg i.p.). Drugs were injected intravenous and five neurons were located in the dorsal raphe nucleus according to Aghajanian et al., J. Phaimacol. Exp. Then 137:178 (1970). DA neurons were located in the substantia nigra pars compacta (SNPC) and identified according to Bunney et al., J. Pharmacol. Exp. Then 185:560 (1973).
  • SNPC substantia nigra pars compacta
  • the ED50 is the dose required to depress dorsal raphe neuron firing by 50% of the maximal depression obtainable. Lum and Piercey, Eur. J. Pharmacol. 149:9-15 (1988).
  • the ED50 is the dose required to depress SNPC neuron firing by 50% for full agonists, or for partial agonists, the dose required to depress SNPC neuron firing by 50% of the maximal depression attainable. Piercey and Hoffmann, J. Pharmacol. Exp. Then 243:391, (1987).
  • the ED50 is the dose required to reverse the depression of SNPC neuron firing caused by a DA agonist (usually either 1-3 mg/kg amphetamine, or 100 ug/kg apomorphine).
  • a DA agonist usually either 1-3 mg/kg amphetamine, or 100 ug/kg apomorphine.
  • the antagonist ED50 is the dose required to reverse the agonist-induced depression of SNPC neuron firing by 50% of the maximum reversal. Piercey and Hoffmann, J. Pharmacol. Exp. Then, 243:391 (1987).
  • SND ED50 (mg/kg): The i.v. mg/kg dose causing a 50% depression in SND in chloralose anesthetized cats. Max. Deer. SND % Control: The maximum inhibition of sympathetic activity observed in the dose range tested (0.001-1.0 mg/kg i.v.). %BP at SND ED50: The blood pressure of the chloralose anesthetized cats in percent control at the dose causing 50% depression in SND. Max Deer. BP % Control: The maximum reduction in blood pressure as percent of the control blood pressure in the same animals observed in the dose range tested (0.001-1.0 mg/kg i.v.).
  • hypothermia (PART I - TABLE IV): Starting with a dose of 30 mg/kg, four mice are injected subcutaneously with test compound. Twenty minutes later, the number of animals whose body temperature has decreased by 2°C or more are counted. If all four animals reach criteria, the drug is considered "active," and subsequent readings are taken at 60 and 120 minutes after administration of the drug. The time for the last statistically significant drug effect on mean body temperature is indicated in minutes. For all "active" compounds, doses are lowered by 0.5 log intervals until a dose which does not lower body temperature by 2°C in any animal is found. Potency is given as mg/kg ED50 (dose required to depress temperature in two of four mice) as measured by Spearman-Karber statistics.
  • Triethyl phosphonoacetate (34.2 ml) and sodium hydride (7.92 g of 50 % slurry in oil) are placed sequentially in a flask with THF (300 ml). After hydrogen evolution ceases, the solution is cooled to 0°C and a THF (50 ml) solution of 7-bromo-4-chloroindanone is added. The solution is brought to reflux and kept there for 18 hours. The solution is then cooled and partitioned into ether and water. The ether layer is washed with water (2X) and dried over anhydrous sodium sulfate and the solvent removed in vacuo. NMR shows a 3:1 ratio of the endo olefin to the exo.
  • Lithium borohydride (2.0 M in tetrahydrofuran, 45 ml, 90 mmol) is added to a solution of trans-7-bromo-2-carboethoxymethyl-4-chloro-2,3-dihydro-1-(hydroxyeth-2-yl)-3H-indene ( 16.07 g, 0.0444 mol) in diethylether (400 ml) at room temperature. The mixture is stirred for 3 hours, allowed to stand at 0°C for 15.5 hours, and refluxed for 30 minutes. The mixture is cooled in ice, and water (100 ml) is slowly added.
  • Use preparation A6(a) only start with trans-4-bromo-2-carboethoxymethyl-2,3-dihydro-1-(hydroxyeth-2-yl)-3H-indene.
  • trans-7-bromo-4-chloro-2,3-dihydro-1,2-di(hydroxyeth-2-yl)-3H-indene (19.7 g) is dissolved in methylene chloride (300 ml) and THF (500 ml) with triphenylphosphine (38 g) and cooled to 0°C.
  • N-Bromosuccinimide 25 g is added in portions. The solution is stirred for 20 minutes and the solvent removed in vacuo. The residue is dissolved in ethyl acetate (200 ml) and silica gel (300 g) is added. With swirling, hexane (800 ml) is added.
  • the amide is prepared in a manner similar to that for diastereomer 1, using procedure A9(a)(1), except starting with diastereomer 2 of trans-10-bromo-7-chloro-3N-[(S)-methylbenzyl]-6H-5a,10b-dihydroindeno[1,2-d]azepine.
  • the product is a colorless solid.
  • a sample may be crystallized from acetonitrile (m.p. 192-193°C).
  • the diastereomeric title sulfonamide is prepared from the diastereomer of trans-10-bromo-7- chloro-3N-[(S)-methylbenzyl]-6H-5 a,10b-dihydroindeno[1,2-d]azepine, see procedure A8(a), by performing a metal-halogen exchange with f-butyllithium, as in procedure A9(a)(1), followed by conversion of the aryllithium to the sulfonamide according to the reference: S. L. Graham, et al.,
  • the title compound is prepared from (+)-trans-7-carboxamido-5a,10b-dihydro-3n-n-propyl-6H-indeno[1,2-d]azepine (0.33 g, 1.22 mmol) is dissolved in THF (15 mL) and triethylamine (1.0 mL, 7.42 mmol) then cooled to 0°C. Titanium (IV) Chloride (0.33 mL, 3.04 mmol) is added. After stirring at 20°C for 2 hours, it is partitioned between methylene chloride and dilute aqueous sodium carbonate. The organic layer is washed with water and brine, then dried over sodium sulfate to yield brown oil (0.29 g). The oil is dissolved in ether and hydrochloric acid in ether is added. The tan solid is recrystallized from methanol and ether to give a gray solid (0.22 g, m.p. 252°C).
  • the title compound is prepared from (-)-trans-7-carboxamido-5a,10b-dihydro-3n-n-propyl-6H-indeno[1,2-d]azepine (0.28 g, 1.02 mmol) is dissolved in THF (15 mL) and triethylamine (0.87 mL, 6.24 mmol) then cooled to 0°C. Titanium (IV) Chloride (0.28 mL, 2.56 mmol) is added. After stirring at 20°C for 2 hours, it is partitioned between methylene chloride and dilute aqueous sodium carbonate. The organic layer is washed with water and brine, then dried over sodium sulfate to yield brown oil (0.23 g). The oil is dissolved in ether and hydrochloric acid in ether is added. The tan solid is recrystallized from methanol and ether to give a gray solid (0.21 g, m.p. 252°C).
  • the title compound is prepared from trans-7-aminosulfonyl-5a,10b-dihydro-6H-indeno[1,2-d]azepine in a manner similar to that for the preparation of trans-10-aminosulfonyl-5a,10b-dihydro- 3N-n-propyl-6H-indeno[1,2-d]azepine, see preparation A11(c).
  • Trifluoroacetic acid 80 ml is added to a mixture of 1,2-bis(carboethoxymethyl)-4-chloro-2-hydroxy-7-methoxyindane (9.75 g, 0.026 mol) and triethylsilane (6.1 g, 0.052 mol) at room temperature with stirring. The mixture is stirred at room temperature for 3 hours, and the solvent is removed under vacuum. The material is dissolved in diethylether and washed with saturated sodium bicarbonate (twice) and brine. The solvent is removed under vacuum to leave an oil (8.9 g). Purification by flash chromatography (230-400 mesh silica gel, 10-20% ethyl acetate in hexane) gives the title compound as a mixture of cis-trans isomers (1.57 g). STEP 5
  • Step 1 carboxylic acid, C1, is reduced with borane/dimethylsulfide to give the benzylic alcohol, C2.
  • Step 2 the benzylic alcohol, C2, is converted into the benzylic bromide, C3, with NBS and triphenylphosphine.
  • Step 3 the benzylic bromide, C3 is alkylated with the enolate of ethyl acetate to give C4.
  • Step 4 is reduced to the alcohol, C5, with LAH.
  • Step 5 the alcohol, C5, is oxidized under Swern conditions to afford the aldehyde, C6.
  • Step 6 the aldehyde, C6, is treated with vinylmagnesium bromide to afford the allylic alcohol, C7.
  • Step 7 the allylic alcohol, C7, is treated with triethylorthoacetate to cause a Claisen rearrangement to give the ester, C8.
  • Step 8 the ester, C8, is saponified with sodium hydroxide in aqueous methanol to afford the acid, C9.
  • Step 9 the acid, C9, underwent a Curtus rearrangement with the aid of diphenylphosphorylazide to afford the carbamate, C10.
  • Step 10 the carbamate, C10, is cyclized to the 1,2,3,4,4a,5,6,10b-transoctahydrobenzo[f]isoquinoline, C11, using paraformaldehyde and borontrifluoride-etherate.
  • Step 11 the carbamate, C11, is saponified by refluxing potassium hydroxide in aqueous ethanol to afford the amine C12.
  • Step 12 the amine, C12, is resolved into pure enantiomers by crystallization with optically active di-p-toluoyltart aric acid in methanol. From this point, step 12, each enantiomer is independently converted through the subsequent steps to afford optically pure products.
  • Step 13 the amine, now the pure enantiomer, C13, is converted into the propionamide, C14, with propionylchloride.
  • Step 14 the propionamide, C14, is reduced with LAH to give C15.
  • the amine, the pure enantiomer, C13 can be converted directly into C15 by alkylation with bromopropane.
  • Step 15 C15 is converted into the carboxamide, C16, by subsequent treatment with t-butyllithium and trimethylsilylisocyanate.
  • the hydro-debrominated analog, C17 was isolated as a side product.
  • the hydro-debrominated analog, C17 can be synthesized in high yield by treatment with t-butyllithium followed by a water quench.
  • Step 16 the carboxamide, C16, is dehydrated to the nitrile, C20, with the aid of Burgess' reagent.
  • Step 17 the carboxamide, C16, is hydrogenated to remove the chlorine using palladium/carbon, affording C18.
  • Step 18 the compound, C18, is dehydrated using Burgess' reagent to afford the nitrile, C19.
  • the compounds of this invention have high orrl potency and a long duration of action. This exceptionally good bioavailability combined with a long period of activity are beneficial to effective clinical treatment.
  • the preferred compounds of PART II are not only active but have increased bioavailability as shown by metabolism studies. See PART II - TABLES I-II, below.
  • the preferred compounds from the list below and PART II - TABLES I and II are compounds numbered 1, 2, 7, and 11.
  • the compounds of this invention are useful both as intermediates to produce other compounds and they are useful to treat central nervous system disorders.
  • the utility of the compounds of this invention to treat central nervous system disorders is shown in behavioral, physiological and biochemical tests. These tests are described below.
  • Assay measures the percent inhibition from experiments employing test compounds at 1 microMolar concentration competing with various radioligands for binding to whole brain membranes, membranes prepared from specific brain structures, or membranes prepared from cell lines expressing cloned receptors. When percent inhibition is equal to 100 the test compound binds as well as the standard compound.
  • the standard compound for the dopamine D1 receptor is SCH 23390.
  • Hepatocyte Intrinsic clearance of 3 concentrations of compound (2, 5 and 15 ug/ml) following a 60 minute incubation at 37°C in the presence of a suspension of freshly prepared rat hepatocytes (5.0 million cells/ml). Aliquots of each incubate were withdrawn during the incubation and analyzed for parent compound using HPLC methodology. Intrinsic clearance is expressed as ml/min/5 million cells. Metabolic stability relative to the control, (+) 1-formyl-6,7,8,9-tetrahydro-N-di-n-propyI-8-amino-3H-benz[e]indole, is determined.
  • Microsome Micromes prepared from Sprague Dawley rat livers were incubated at 37 C with 5 or 12.5 micromolar substrate. The metabolic half-lives of the test compounds were determined from the HPLC from plots of LN(peak area) vs time. These were ratioed with the corresponding half-life of 5-(dipropyIamino)-5,6-dihydro-4H-imidazo(4,5,1-ij)-quinoline-2(1H)-one, (-), monohydrobromide hydrate to give relative metabolic half lives.
  • BIOLOGICAL DATA - Metabolism hepatocyte and microsome
  • Ethyl 3-(5-bromo-2-chlorophenyI)propionate (87.2 g, 299.1 mmol) in ether (300 mL) is added to lithium aluminum hydride (12.0 g, 299.1 mmol) in ether (300 mL) at 0°C. After 30 minutes, water (10 mL), sodium hydroxide (10 mL, 15% aqueous), and water (30 mL) are added successively and stirred at room temperature for 15 minutes. The slurry is filtered and the filtrate is dried over sodium sulfate to yield a pale orange oil (68.9 g, 92%).
  • Ethyl 7-(5-bromo-2-chlorophenyl)-trans-hept-4-enoate (84.1 g, 243 mmol), potassium hydroxide (47 g, 730 mmol), methanol (400 mL), and water (50 mL) are refluxed for 2.5 hours.
  • the solvents are removed under vacuum and the residue is partitioned between ether and water.
  • the aqueous layer is acidified with hydrochloric acid and extracted with ether.
  • the ether layer is washed with water and brine and is dried over sodium sulfate. It yields 57.8 g (75%) yellow solid.
  • a portion is recrystallized from ethyl acetate, mp 53.5-55.0°C.
  • the ether layer is washed successively with water, 2N hydro-chloric acid, water, saturated aqueous sodium bicarbonate and brine.
  • the solution is dried over sodium sulfate.
  • the yellow oil is flash chromatographed on a 16 ⁇ 7 cm silica gel column and eluted with 5% followed by 10% ethyl acetate in hexane to yield 37.2 g (57%) yellow oil.
  • 6-(5-Bromo-2-chlorophenyl)-trans-hex-3-enyl ethyl carbamate (46.4 g, 129 mmol) is dissolved in methylene chloride (250 mL).
  • Paraformaldehyde (4.3 g, 135 mmol) is added and then boron trifluoride etherate (17.4 mL, 142 mmol).
  • the slurry is warmed to 30°C and after 5 minutes it is poured onto sodium carbonate and ice.
  • the slurry is extracted with ether.
  • the ether layer is washed with brine and then dried over sodium sulfate. This produces a thick orange oil which is flash chromatographed on a 19 ⁇ 7 cm silica gel column and eluted with 2% acetone in hexane to yield 41.6 g (83%) of pale oil.
  • a hot methanol solution (650 mL) of 10-bromo-7-chIoro-1,2,3,4,4a,5,6,10b-trans- octahydrobenzo[f]isoquinoIine (30.9 g, 103 mmol) is combined with di-p-toluoyl-D-tartaric acid (22.5 g, 56.5 mmol).
  • the resultant white solid is filtered.
  • the filtrate is dried of solvent under vacuum, then partitioned between aqueous sodium hydroxide and ether.
  • the ether layer is washed with water and brine, then dried over sodium sulfate to yield a pale oil.
  • the above procedure is repeated five more times alternating between the D and die L forms of the acid.
  • Steps 13 - 19, below, show how the enantiomers, "(a)” and “(b)” are independently converted to give optically pure products.
  • Enantiomers for aminosulfonyl derivatives are labeled with preparation numbers that include the letters “(c)” and "(d).”
  • the title sulfonamides are prepared from the enantiomers of 10-Bromo-7-chloro-l,2,3,4,4a,5,6,10b-trans- octahydro-3N-propylbenzo[f] ⁇ soquinoline, compound C15, via metal-halogen exchange with t- butyllithium, followed by conversion of the aryllithium to the sulfonamide according to the reference: S.L. Graham, et al., J. Med. Chem., 32:2548 (1989).
  • tert-Butyllithium (9.3 mL, 1.7 M in pentane) is added to (-)-10-bromo-7-chloro- 1,2,3,4,4a,5,6,10b-trans-octahydro-3N-benzylbenzo[f]isoquinoline (3.0 g, 7.68 mmol) in THF (7.5 mL) at -78°C. After 10 minutes, sulfuryl chloride (2.6 mL, 15.8 mmol) is added in a quick dose and the cold bath removed. THF (7.5 mL) is added and after 1 hour, the solvents are removed under vacuum. THF (15 mL) is added and methylamine saturated THF is added.
  • Bromopropane (0.02 mL, 0.25 mmol) is added to (-)- 10-sulfonamido- 1,2,3, 4,4a,5, 6,10b-trans- octahydrobenzo[f]isoquinoline hydrochloride (0.077 g, 0.25 mmol) and triethylamine (0.08 mL, 0.56 mmol) in acetonitrile (5 mL) and DMF (2 mL). After heating at 80°C for 4 hours, ether and aqueous sodium carbonate are added. The organic layer is washed with water and brine and dried over sodium sulfate to yield an amber oil.
  • Bromopropane (0.05 mL, 0.50 mmol) is added to (-)-10-methylsulfonamido- 1,2,3,4,4a,5,6,10b-trans-octahydrobenzo[f]isoquinoline hydrochloride (0.15 g, 0.50 mmol) and triethylamine (0.14 mL, 1.00 mmol) in acetonitrile (4 mL) and DMF (1 mL). After heating at 50°C for 4 hours, ether and aqueous sodium carbonate are added. The organic layer is washed with water and brine and dried over sodium sulfate to yield a white foam, m.p. 94- 100°C.

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WO1995011903A1 (en) * 1993-10-25 1995-05-04 Ortho Pharmaceutical Corporation Tricyclic compounds having affinity for the 5-ht1a receptor
US6472422B2 (en) * 1997-04-07 2002-10-29 Georgetown University Analogs of cocaine
US8518933B2 (en) 2009-04-23 2013-08-27 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8546377B2 (en) 2009-04-23 2013-10-01 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof

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TW200924752A (en) * 2007-09-17 2009-06-16 Organon Nv Tricyclic heterocyclic derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011903A1 (en) * 1993-10-25 1995-05-04 Ortho Pharmaceutical Corporation Tricyclic compounds having affinity for the 5-ht1a receptor
US6472422B2 (en) * 1997-04-07 2002-10-29 Georgetown University Analogs of cocaine
US8518933B2 (en) 2009-04-23 2013-08-27 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8546377B2 (en) 2009-04-23 2013-10-01 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US8846663B2 (en) 2009-04-23 2014-09-30 Abbvie Inc. Modulators of 5-HT receptors and methods of use thereof
US9701679B2 (en) 2009-04-23 2017-07-11 Abb Vie Deutschland GmbH & Co. KG Modulators of 5-HT receptors and methods of use thereof

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