CA2118920A1 - Benzo-isoquinoline derivatives and analogs and their use in therapeutics - Google Patents

Abstract

The present invention encompasses: 1) compounds of formula (I), wherein p and s are independent and may be either 1 or 2, wherein R1 is -H, -Halo, -CN, -CO2H, -CO2R1-1, -CONH2, -CONHR1-1, -CON(R1-1)2, -SH, -SR1-1, -SO2R1-1, -SO2NH2, -SO2NHR1-1, -SO2N(R1-1)2, -OR1-1, -OSO2CF3, -OSO2R1-1, -NH2, -NHR1-1, or -N(R1-1)2; wherein R1-1 is -H, -(C1-C8 alkyl), -(C1-C8 alkenyl), -(C3-C10 cycloalkyl), -(C6 aryl), -5 or 6 member heterocyclics, -(C1-C8 alkyl)-(5 or 6 member heterocyclics), wherein R2 is -H, -Halo, -CN, -CF3, -SH, or -SR2-1; wherein R2-1=R1-1, wherein R3 is -H, -(C1-C8 alkyl), -(C1-C8 alkenyl), -(C6 aryl), -(C3-C10 cycloalkyl), -(5 or 6 member heterocyclics), -(C1-C8 alkyl)-5 or 6 member heterocyclics), wherein R3-1=R1-1 or a pharmacologically acceptable salt thereof; 2) a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I);
3) 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.

Description

'~O 93/08166 2 1 1 ~ PCT/US92/07314 THEIR USE IN THERAPEUTICS
The present invention relates to novel compositions of matter. More particularly, the present invention relates to new isoguinoline and pyridine derivatives, processes for preparing these S 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.
BACKGROUND OF THE INVENTION
Psychiat~ic diseases are thought to be due to dysfunctions in monoaminergic neuronal 10 systems, particularly those involving serotonin (5-HT,) and dopamine (DA).
Serotonin (5 HT~2 Anxiety is associated with increased activity in 5-HT systems. In animals where 5-HT hæ
been depleted, benzodiazepine anxiolytics are not active in anti-anxiety assays that they otherwise are effeclive in. Serotonin neurons have autoreceptors that, when activated by agonists, depress 15 firing ra~es of 5-HT cells. These receptors are of the S-HT,A subtype. Because they depress 5-HT
neuronal activity, it can be expected that 5 HTIA agonists will be an effective anxiolytic. Clinical1y, S-HTIA agonists have demonstrated anxioly~ic properties. The drug buspirone is the only currently available marketed 5-HT,~ agonist having anxiolytic activity. This compound antagonizes dopamine receptors at the same dose it stimulates S-HT,~ receptors. A similar drug, gepirone, also has 20 dopamine antagonist properties. These dopamine antagonist properties reduce the clinical utility of these compounds because long term treatment with dopamine antagonists can p~duce 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 25 re-uptake into nenre terminals. Since some 5-HT", receptors are activated postsynaptically by 5-HT, 5-HT~ agonists may also be anti-depressants. Since the postsynaptic 5~ receptor may be less sensitive than the autoreceptor, high doses of 5~ agonists, panicularly ve~ effective ones (i.e.~
those causing greater stimulation of the 5-HT,~ receptor~ a parameter referred to as "efficacy")~ can be expected to be effective anti-depressants. Gepirone has already been demonstrated to have 30 ameliorative effccts on some depressive end points in some patients.
Serotonin is also involved in the regulation of feeding and sexual behavlor and in cardiovascular regulation. Thus~ 5~HT~ agonists may be useful in treating overealing and sexual dysfunction. These compounds have been shown to alter feeding and sexual behavior in animals.
5-HT,~ agonists are also known to depress sympathetic nerve discharge and thus lower blood 35 pressure. Thus, they may be useful in treating hypenension~ congestive heart failure by reducing cardiovascular afterload and hean attack by removing sympathetic drive to the heart.

2 ~ 7 a W O 93/08166 PC~r/US92/07314 "

DoDamine(DA) Schizophrenia is thought to be due to hyperactivity in DA systems. Thus, currently available anti-psychotics are DA antagonists. Dopamine autoreceptors depress DA neuron firing rates, DA synthesis and release. Thus DA autoreceptor agonists can also be expected to be anti-5 psychotics. DA agonists are also useful for ~:a~ng Parkinsonism, a disease caused by degenerationof DA neurons, and hyperprolactinemia, since DA agonists depress prolactin release.
Dopamine autoreceptor antagonists are a new clæs of drug that increæe releæe of DA by releæing 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 rclease DA.
10 Dopamine autoreceptor agonists are expected to be much milder stimulants than amphetamines because they simply increase the release æsociated 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 parkinsonism, schizophrenia, and manic-depressive illness.
In parkinsonism, for example, the nigro-neostriatal hypofunction can be restored by an increase in postsynaptic DA receptor stimulation. In schizophrenia, the condition can be normalized by achieving a decrease in postsynaptic DA receptor stimulation. Classical anti-psychotic agents 20 directly block the postsynaptic DA receptor. The same effect can be achieved by inhibition of in-traneuronal presynaptic events essential for the maintenance of adequate neurotransmission, transporl mechanism and transmitter synthesis.
In recent years a large body of pharmacological, biochemical and electrophysical evidence hac provided considerable support in favor of the existence of a specific population of central 25 autoregulatory DA receptors located in the dopaminergic neulon it~elf. These receptors are part of a homeostatic mechanism that modulates nerve i~pulse flow and transmitter synthesis and regulates the amount of DA released from the nerve endings.
Direct DA receptor agonists, like apomorphine, are able to activate the DA autoreceptors as well as the p~st synaptic DA receptors. The effects of autoreceptor stimulation appear to 30 predominate when apomorphine is administcred at low doses, whereas at higher doses the attenuation of DA transmission is outweighed by the enhancement of postsynapdc 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 Icnowledge indicates DA receptor stimulants with a high selectivity for central nervous DA
35 autoreceptors would be valuable in treating psychiatric disorders. The compounds of the present invention have a variety of effects at S-HTI~ and DA receptors, and offer a variety of utilities 2 ~ 2 ~
`;1VO 93/08166 PCr/lJS92/07314 associated with those activities.
DESCRlPrION OF RELATED ART
The compounds of this invention may be described as having tricyclic moieties, or rings.
These rings, have been labeled A, B, C, in Formula 1, below, in the summary of invention section.
S 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 ling, S 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 -r ng is nitrogelL A 6-6-6 ring system where the A ring is arom~tic that contains a 6-atom C ring which contains nitrogen might also be called a benzo-quinoline structure. Included below are 10 documents thal represent the h~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 ~is disclosure.
Some documents cited below describe compounds that belong in more than one group, but gencrally the following groups are observed: The first group, SET A, contains 6-6-6 ring systems 15 or benzo-quinolone structures; the second gr~up, 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.
These documents are described below:
SET A (6-6-6 ring systems) European Patent Application, EP 410,535-A, application published 30 January 1991~
Derwent No. 91-030926/05, discloses octahydrobenzisoquinoline derivatives as antipsychotic agents.
Published PCI application, international publication number WO 90/06927, PCI`IUS89/05512, intemational publication date, 28 une 1990, DeJwent No. 9~224487129, discloses 25 hexahydroindeno[l,2-c]pynoles, hexahydroindenopyrodines and hexahydrobenz[e]isoindoles as selective S-HT receptor agents; United States Patent, US 4,341,786, issued 27 July 1982, discloses octahydrobenzo[flquinoline compounds. Great Britain Pate~ GB 1,596,170, published 19 August 1981, Den~ent No. 55370A/31 discloses hexahydro-benz[flisoquinolines~ Great Britain Patent Application, GB 2,126,58~A, application published 28 March 1984, Derwent No. 84-077373/13, 30 discloses octahydrobenzlflisoquinolines as psychotropic and analgesic agents. Great Britain Patent, GB 2138-815-A, published 27 April 1983, Derwent No. 84-271,830 discloses benzo[flquinolines.
German Patent, DE 2,801,576, DenNent No. 55370/31~ discloses hexahydrobenz[f~isoquinolines.
SET B (~-5-6 ring systems) Soviet Union Patent. SU 327193, Derwent No. 63503T-B~ discloses isoquinolines; and 35 Gelman Patent, DE 2.501.930. Derwent No. 58024X/31, discloses hexahydro-indeno wridines as antidepressants.

WO 93/08166 PCr/US92/07314 "

SET C (6-6-5 ring systems) Published PCT application, WO91/13872, published 19 September 1991, intemationalapplication No. PCT/US91/00117 discloses heterocyclic indole compounds. Published PCT
application WO91/11435, published 8 August ~ intemational application No. PCI`/US91/00018 S discloses benz(e)indole heterocyclic compounds. Published PCT application WO91/00856, published 24 January 1991, intemational application No. PCI`/US90/03551 discloses carbocyclic-2-amino tetralin derivatives. United States Patent, US 4,618,683, issued 21 Octnber 1986, Derwent No. 86-298,374/45 discloses tetrahydro-benzole~indolines. European Patent, EP 95-666-A, published I June 1980, Der vent No. 83-840180, discloses tetra:hydro-benzo-isoindolines.
10 Netherland Patent, NL 7216762, published 8 December 1981, Derwent No. 36797U-B discloses benzolf]isoindolines. Belgium, BE 827,087, published 26 March 1974, Denvent No. 67323W/41, discloses benz~isoindolines.
SET D (6-5-5 nng systems) European Patent 170,093-A, published 25 luly 1984, Der vent No. 86-036877/06 discloses 15 indeno-wrroles.
SET E ~6-7-5 ring systems) U.S. Patent 4,024,265, May 17, 19M, discloses benzolS,6~ cycloheptal1,2-clpyridines and their use for treating depreæion.
SUMMARY OF INVENTION
20The present invention encompasses: I) compounds of fonnula I below, ~s (~)p FormuJa l wherein p and s ar~ independent and may be either I or 2, 30 wherein Rl is -H, -Halo, -CN, -CO2H, -CO2Rl.,, -CONH2, -CONHR~.~, -CON(Rl.1)2, -SH, -SRl " -SO2Rl l, -SO2NH2, -SO2NHR~," -SO2N(Rl,~)2, -ORl.l, -OSO2CF3, -OSO2Rl.l, -NH2, -NHRl ~, or -N(R")2; wherein Rl.~ is -H, -(Cl-C~ alkyl), -(C,-C~, alkenyl), -(C3-CIo sycloalkyl), -(C6 aryl), -5 or 6 member heterocyclics, -(C,-C, alkyl)-(5 or 6 member heterocyclics), wherein R2 is -H, -Halo, -CN, -CF3 -SH, or -SR2.,; wherein R2, = R, ~, wherein R3 is -H, -(C,-C8 alkyl), -(C,-C8 alkenyl), -35 (C6 aryl), -(C3-Clo cycloalkyl), -(S or 6 member heterocyclics), -(C,-C8 alkyl)-5 or 6 member heterocyclics), wherein R3., = R,, or a pharm~cologically acceptable salt thereof. 2. A

2it 8~?JQ
; ~W O 93/08166 PC~r/~S92/07314 pharmaceutical composition consisting essentially of a pharmaceutically acceptable carlier and an effective amount of a compound of formula 1.
3. 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 5 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. Other central nervous system 10 disorders and conditions related to central dopamine transmission such as parkinsonism. schizophre-nia, and manic-depressive illness may also be treated with the compounds of this invention. The compounds of this invention are also useful to alle~/iate aggressive behavior, confusional delirious states and impotence. In addition to tneir central nervous system pharmacological activities, the compounds of this invention are also anti-diabetic, anti-obesity,anti-atherosclerotic, and anti-15 hyper~ensive agents. Processes for preparation of these compounds, their pharmaceutical use andpharmaceutical preparations employing such compounds constitute funher aspects of the in vention.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a therapeutic activity in the cent al nervous system. Another object is to provide compounds having an effect on the 5-HTI~ receptor in mammals including man. A funher object 20 of this invention is to provide compounds having an effect on the subclass of dopamine receptors known as the D2 receptor.
The compounds of formula I where R3 equals H are novel and useful as intermediates in the preparation of the compounds of formula 1.
DETAILED DESCRIPI ION OF THE INVENTION
The compounds of this invention are identified in two ways: by the descriptive name and reference to labeled structures contained in appropriate charts. In app~priate situadons, the proper stereochemistry is also represented in the charts.
ln this document the parenthetical term (Cn-Cm) is inclusive such that a compound of (Cl-C~) would include compounds of one to 8 carbons and their isomeric forms. The vsuious carbon ....
30 moieties are defined as follows: Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-p~pyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl~ and n-octyl.
Alkoxy as represented by -ORI when R~ is (Cl-C~) alkyl refers to an alkyl radical which is attached to the remainder of the molecule by oxygen and includes branched or unbranched fonns 35 such as methoxy~ ethoxy~ n-propoxy~ isop~poxy, n-butoxy~ isobutoxy~ sec-butoxy~ t-butoxy~ n-pentoxy~ isopentoxy, n-hexoxy~ isohexoxy~ n-heptoxy~ isoheptoxy~ and n-octoxy.

S~ 18~2~
WO 93/08166 PCr/US92/07314 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, I-methyl-l-e~henyl, I-propenyl, 2-propenyl, I-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, l-pentenyl, allyl, 3-pentenyl, 4-pentenyl, I-methyl~pentenyl, 3-methyl-1-pentenyl, 3-methyl-allyl, I-hexenyl, 2-hexenyl, 3-hexenyl, 4hexenyl, I-methyl~-hexenyl, 3-me~hyl-1-hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, l-methyl~heptenyl, 3-methyl-1-heptenyl, 3-methyl-2-heptenyl, I-octenyl, 2-octenyl, or 3-octenyl.
(C3-CI~)cycloalkyl 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-methylcyclobutyl, 3-propylcyclobutyl, cydopentyl, 2,2-dimethylcyclopentyl, cyclohexyl, cydoheptyl, or cyclooctyl.
Examples of aryl include phenyl, naphthyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-e2hyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(v-, m-, or p-)-tolyl, 4-isopropyl-2,6-xylyl, 3-propyl~ethylphenyl, (2,3,4, 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, (o-, m-, or p-trifluoromethyl)phenyl, ~fluoro-2~5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluo~ophenyl, (o-, m-, or p-)chlorophenyl, 2-chloro ~tolyl, (3-, ~, 5- or 6-)chloro~-tolyl, ~
chloro-2-propylphenyl, 2-isopropyl~chlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m-, or p-,)trifluorophenyl, (o-, m-, p-)ethoxyphenyl, (~ or 5-)chloro-2-methoxy-phenyl, and 2,4-dichloro(5- or 6-)methylphenyl.
Examples of heterocyclics include: (2-, 3-, or 4-)pyridyl, imidazolyl, indolyl, NU'-formyl-indolyl~ NU'-C2-C~alkyl-C(O)-indolyl, [1,2,41-triazolyl, (2-, 4-, S-)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, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, and benzothienyl.
Each of these moieties may be substituted as appropriate.
Halo is halogen (fluoro, chloro, bromo or iodo) or trifluoromethyl.
LAH is lithilun aluminum hydride LDA is !itluum diisopropylamide THF is tet~hydrofuran 9-BBN-H or 9-BBN is 9-Borabicyclo[3.3.11nonane dimer It will be apparent to those skilled in the art that 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 forrnula 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 2118~2~
`~0 93/08166 PCr/US92/0731 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. ]llustrative acids are sulfuric, 5 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.
In clinical practice the compounds of the present invention will normally be administered orally, rectally, or by injection, in the form of phalmaceutical preparations comprising the activc 10 ingredient either as a free bæe or æ 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. The use and administration to a patient to be treated in the clinic would be leadily apparent to a physician or phamlacist of ordinary skill in the art.
I5 In therapeutical treatment the suitable daily doæs of the compounds of the invention are I - 2000 mgApatient for oral application, and 0.001 - 20 mg/kg for intramuscular, intravenous or subcutaneous application. The precise dosage will be apparent to an ordinarily skilled physician or pharmacologist taking into account factors such as the age, weight, sex, and medical condidon of the patient being treated. Also relevant is the potency of the particular compound. The potency of a compound may be suggested by the standard tests described below.
These compounds are particularly effective anxiolytic and antidepressant agents. Central nervous system disorders and conditions related to central dopamine transmission such as parkinsonism, schizophrenia, and manic-depressive illness may also be treated with the compounds of this invendon. Other uses for these compounds include panic attacks, obsessive-compulsive disturbances, and senile dementia, particularly the emotional disturbances seen in dementia disorders. In addition, 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 1~
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 1, the compounds of CHARTS A and B are claims 14 - 24. Part Il contains the COMPOIJNDS that correspond to CHART C. the reactions. the corresponding biological data and the detailed ~11892~
WO 93/08166 PCr/US92/07314 preparations. The compound claims that correspond to PART Il are claims 2 - 13.
PART I
Reactions of CHART A
Step I, the s~ting ketone, Al, is refluxed wi~ the sodium salt of triethyl phosphonoacetate to give the ester, A~, along with some of its exo double bond isomer. The undesired isomer is removed by treating the isomeric mixture wi~ 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 t-butyldimethylsilyl ether A4.
Step 4, the silyl ether, A4, is refluxed with 9-E~BN-H in TH~ and then treated with a mixture of bromo ethylacetate and potassium 2,6-di-J-butylphenoxide to give the ester, A5. Step 5, the silyl gr~up is removed with aqueous acid to afford the alcohol, A6. Step 6, A6 is reduced with lithium borohydride to afford the diol, A7. Step 7, the diol is converted into the dibromide, A8, with NBS and triphenylphosphine. Step 8, the dibromide is heated with optically pure o~-methylbenzylamine to afford a mixture of diastereomeric a~epines, 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 t~eated with t-butyllithium followed by trimethylsilylisocyanate to afford the carboxamido azepine, A10. Step 10, hydrogenation over palladium hydroxide afforded All. Step 11, the hydrogenated azepine was alkylated with bromopropane to afford A12. Step 12, the carboxamido group is replaced with a cyano group, A13.
Structures are shown in CHART A.
Reactions of CHART B
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 ca~boxylate, B3. Step 3, the 2~5 carboxylate undergoes a Reformatsky reaction with ethyl bromoacetate to afford the diester, B4.
Step 4, the diester is reduced with triethylsilane 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).
Structures are shown in CHART B.
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.
35 One preferred compound is (-)-trans-l~carboxamido-5alO~dihydro-3N-n-propyl-6H-indeno~1,2-d~azepine. compound number 3, below.

21~ .g~Q
`~0 g3/08166 P~r/US92/07314 g 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.
S CNS Receptor Binding Assay (PART 1 - TABLE 1): The Central Nervous System Binding Assay measures the percent inhibition from experiments employing test compounds at I microMolar concentration competing with valious radioligands for binding to whole brain membranes, membranes prepared from specific brain structures, or membranes prepared from cel1 lines expressing cloned receptors. When percent inhibition is equal to 10û the test compound binds as 10 well as the standard compound. The standard compound for the 5-HT,A receptor is 8-OH-DPAT.
The standard compo~nd for the dopamine Dl receptor is SCH 23390.
5-HT and DA Cell Flring (PART I - TABLE Il): Glass microelectrodes filled with pontamine sky blue in 2M NaCI were used for extracellular recordings from Sprague-Dawley rats anesthetized with chloral hydrate (400 mg~lcg i.p.). Drugs were injected intravenous and five 15 neurons were located in the dorsal raphe nucleus according to Aghajaruan et al., J. Pharmacol. Exp.
Ther. 137:178 (1970). DA neurons werc located in the substantia nigra pars compacta (SNPC) and identified according to Bunney et al., l. Pharmacol. Exp. Ther. 185:560 (1973). For S HTIA agonist effects, 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). For DA agonist 20 effects, 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 atlainable. Piercey and Hoffmann, l. Pharmacol. Exp. Ther. 243:391, (1987). For DA
antagonists, the ED50 is the dose reguired to reverse the depression of SNPC neuron firing caused by a DA agonist (usually either 1-3 mgJkg amphetamine, or 100 ugQcg apomorphine). For partial DA agonists, 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 Hoffmarm, J. Pharmacol. Exp.
Ther., 243:391 (1987).
Sympathetic Nerve Discharge (SND) (PART I - TABLE III): SND ED50 (m~lkR): The i.v. mg~lcg dose causing a 509'o depression in SND in chloralose anesthetized cats. Max. Decr. SND
qo Control: The maximum inhibition of sympathetic activity observed in the dose range tested (0.001-1.0 mg/kg i.v.). 9bBP at SND ED50: The blood pressure of the chloralose anesthetized cats in percent control at the dose causing 50% depression in SND. Max Decr. 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 mglkg i.v.).
Metabolism (PART I - TABLE IV): Intrinsic clearance of 3 concentrations of compound (2, 5 and 15 ug/ml) foDowing a 60 minute incubation at 37C in the presence of a suspension of ;` 2 ~J
WO 93/OB166 PCr/US92/07314 ~

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. lntrinsic clearance is expressed as ml/minlS million cells. Metabolic stability relative to the control, ( ~ 1-formyl-6,7,8,9-tetrahydro-N-di-n-propyl-8-amino-3H-benzle]indole, is determined.S Hypothermia (PART I - TABLE IV)- Starting with a dose of 30 mg/lcg, four mice are injected subcutaneously with test compound. Twenty minutes latert the number of animals whose body temperature has decreased by 2C 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 signific3nt drug effect on mean body 10 temperature is indicated u~ minutes. For all "active" compounds, doses are lowered by 0.5 Iog intervals until a dose which does not lower body temperature by 2C in any animal is found.
Potency is given as mglkg ED50 (dose requi~ed to depress temperature in two of four mice) as measured by Spealman-Karber statistics.
The compounds below have been subjected to one or more of the biological tests described 15 above. PART I - TABLES I - IV use the arbitrary numbers æsigned below.
Com~ound Number Name cis-7-chloro-10-methoxy-5a,10b-dihydro-3N-n-propyl-GH-indenoll,2-dlazepine, see CHART B stn~cture B9.
2 rrans-7-chloro-10-methoxy-5a,10b-dihydro-3N-n-propyl-6H-indenoll,2-dlazepine, see CHART B structure B9.
3 (-~trans-lO carboxamido-5a910b-dihydro-3N-n-propyl-6H-indeno~ dlazepine, see CHART A structure A12.

4 (+)-trans-10-carboxamido-5a,10b-dihydro-3N-n-propyl-6H-indenol1,2-d)azepine, see CHART A st~ucnlre A12.
(-)-trans-7-carboxamido-5a,10b-dihydro-3N-n-propyl-6H-indenoll,2-dlazepine, see CHART A stn~cture A12.
6 (I)-trans-7-carboxamido-5a,10b-dihydro-3N n-propyl-6H-indeno[1,2-dlazepine, see CHART A structure A12.
7 (-)-trans~7~cyano-5a,10b-dihydro-3N-n~propyl-6H~indenoll,2-dlazepine, see CHART A stlucnlre Al3.
8 (+)-trans-7~cyano-5a,10b-dihydro-3N-n-propyl-6H-indenol1,2-d]azepine~ see CHART A structure A13.

2118~
WO 93/08166 PCr/US92/07314 PART I - TABLE I
BIOLOGICAL DATA - CNS Receptor Binding 5-HTIA Dopamine - Dl Dopamine - D2 Compound No. % inhibition % inhibition % inhibition 8 15 7 3s 1 5 ~ ~ _ .. ~ _ PART I - TABLE Il BIOLOGICAL DATA - 5HT and DA Cell Firing S-HTIA Piri;ng DA Firing Compound No.(mglkg) (m~g) 2 -- 0.065 _ _ _ _ PART I - TABLE III
BIOLOGICAL DATA - Sympathetic Nelve Discharge (SND) SNDED50 Max. Decr. SND %BP at Max. Decr. BP BP
Compound No. (mg/kg) % contsol SNDED50 % control 3 1.0 1.0 66.0 66.0 PART I - TABLE IV
BIOLOGICAL DATA - Metabolism and Hypothermia Metabolic Stability Hypolhermia Duration Compound No. (control is 1.0) (mg/kg) (minutes) 3 0.95 0.97 (subcutaneous) --3 1.3 (oral) 4 0.39 --.~

Wo 93/08166 2 1 1 Q ~1 2 ~ PCr/US92/07~14 Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding S disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

PREPARATIONS AND EXAMPLES FROM CHART A

Preparation Al(a): 7-bromo~4chloro-1-carboethoxymethyl-3H-indene, see CHART A, S'l~P 1, compound A2.
Tnethyl phosphonoacetate t34.2 ml) and sodium hydride (7.92 g of 50 % slurry in oil) are placed sequentially in a flask with T~ (300 ml). After hydrGgen evolution ceases, the solution is cooled to 0C and a THF (50 ml) solution of 7-bromo~chloroindanone is added. The solution 15 is brought to reflux and kept the~e 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 elldo olefin to the exo.
This mixture is added to a T~ solution of lithium diisopropylamide (1 eq.) at -78C. After five minutes ~cetic acid (1 eq.) is added in THF (10 rnl) and the solution is allowed to warm to 25C
20 where it is partitioned between water and ether. The ether layer is washed with 2N aqueous hydrochloric acid followed by water, saturated aqueous sodium bicarbonaee, and bnne. The ether solution is dried over anhydrous sodium sulfate and the solvent removed in vacuo to afford 31 g cf the title compound after chromatography with ethyl acetate/hexane ~2:98).

Preparation A1(b): 4bromo-1-carboethoxymethyl-3H-indene, see CHART A, STEP 1, compound A2.
Use preparation A1(a), only start with ~brom~l-indanone.

. .
Preparation A2(a), 7-bromo-4chloro-1-(hydroxyeth~2-yl)-3H-indene, see CHART A, STEP 2, compound A3.
A solution of 7-bromo~chloro-1-carboethoxymethyl-3H-indene (25.61 g, 81.2 mmol) in diethylether ( 150 ml) is added over a 10 minute period to a suspension of lithium aluminum hydride (10.0 g, 0.263 mol) in die~ylether (250 ml) with stirring at 0DC. The cold bath is removed, and 35 the mixture is stirred for 15 minutes. The mixture again is cooled to 0DC, and water (10 ml), 159h NaOH (10 ml), and water ~30 ml) are added in succession. The cold bath is removed, and the 211~92~ `
WO 93/0816S PCr/~S92/07314 mixture is stirred for 10 minutes. The mixture is filtered, and the precipitate is washed well with diethylether. The filtrate is dried (MgS04), and the solvent is removed under vacuum to leave the title compound as a yellow solid (21.67 g, 98%).
.

S Preparation A2(b): 4-bromo-1-(hydroxyeth-2-yl)-3H-indene, see CHART A, SI'EP 2, compound A3.
Use preparation A2(a), only start wi~h 4-bromo-1-carboethoxymethyl-3H-indene.

STEP ~
P~epa~ionA3(a): 1-(t-butyldimethylsilyloxyeth-2-yl)~7-bromo-4-chloro-3H-indene,see CHART A, STEP 3, compound A4.
In this procedure 7-Bromo~chloro-l-(hydroxyeth-2-yl)-3H-indene (28.23 g, 103.2 mmol) and imidazole (lSA g, 0.226 mol) are dissolved in dimethylformamide (200 ml), cooled to 0C, and t-butyldimethylsilyl chloride (1~.08 g, 0.113 mol) is added. The mixture is stirred at room 15 temperature for 12 hours, and partitioned between diethylether and water. The ether solution is wæhed several times wi~ water and once wilh brine. The solution is dried (Na2SO4~, and the solvent is removed under vacuum to leave an amber oil (3g.94 g). Purification by flæh chromatogra~hy ~230400 mesh silica gel; 10% toluene in hexane) gives the title compound as an amber oil (37.26 g).
PreparationA3(b): 1-(t-butyldimethylsilyloxyeth-2-yl)-4-bromo-3H-indene,seeCHARTA, STEP 3, compound A4.
Vse Preparation A3(a) only start with 4-bromo-1-(hydroxyeth-2-yl)-3H-indene.

Sl'EP 4 PreparationA4(a): trans-7-bromo-1-(t-butyldimethylsilyloxyeth-2-yl)-2-carboethoxyme-thyl-4-chloro-2,3-dihydro-3H-indene, see CHART A, STEP 4, compound AS.
Add 9-Borabicyclo[3.3~1~nonane (9-BBN-H) dimer (11.0 g, 0.045 mol, 1.05 eq.) to a solution of l-(t-butyldimethylsilyloxyeth-2-yl)-7-bromo 4 chloro-3H-indene (33.28 g~ 85.8 mmol) 30 in dry tetrahydrofuran. Heat the mixture at reflux under argon in an oil bath maintained at 100C
for 41 hours and cooled in ice. A solution of 2,6-di-t-butylphenol (23.02 g, 0.112 mol) in dry tetrahydrofuran (200 ml) is cooled to 0C, and a solution of potassium t-butoxide in tetrahydrofuran (1.0 M, 90.1 ml, 9QI mmol) is added over 10 minutes. The mixture is stirred at room temperature for 15 minutes and again cooled in ice. The solution is added to the borane solution above via 35 needlestock. Ethyl bromoacetate (15.1 g. 90.2 mmol) is added dropwise, and the mixture is stirred at O~C for 30 minutes, room temper~ture for 2 hours, and at reflux for lS minutes. The mixture 2li~.~2a WO 93/08166 PCr/US92/07314 is diluted with diethylether and washed with water, 10% sodium carbonate solution, and brine. The solution is dried (MgSO4), and the solvent is removed under vacuwn to leave an oil. Purification by flash chromatography (230400 mesh silica gel; pure hexane to 2% ethyl acetate in hexane) gives the title compound as an oil (30.2 g, 74% yield).
s PreparationA4(b): t7ans-4bromo-l~(t-butyldimethylsilyloxyeth-2-yl)-2-carboethoxyme-thyl-2,3~dihydro-3H-indene, see CHART A, STEP 4, compound A5.
Use procedure A4(a) with the following modifications. 1-(t-Butyldimethylsilyloxyeth-2-yl)-4-bromo-3H-indene ~38.8 g, 109.9 mmol) and 9-BBN-H (dimer) (14 g, 115.4 mmol) are dissolved in T~ (10û ml) under a nitrogen atmosphere. This solution is refluxed for 48 hours and then cooled. A slurry of potassium 2,6-di-t-butylphenoxide in THF is prepared by dissolving 2,6-di-t-butylphenol (29.5 g) in THF (50 ml) and adding a 1.0 M TH~ solution of potassium t-butoxide (115.4 ml). The slurry is stirred for 10 minutes and then cooled to 0C. The solution of the organoborane is then added. Ethyl bromoacetate (12.8 ml) is added over a 3 minute period. The slurry is stirred at 0C for 1 hour and then allowed to stir at 25C for I hour. The flask is cooled to 0C and quenched with water and then partitioned between water and ether. The ether layer is washed with water (2X) and bnne, then d~ied over sodium sulfate and the solvent removed in vacuo. The resulting oil is placed on flash silica gel (6 cm X 45 cm) and eluted with ether/hexane (0.5:99.5). This is raised to 5:95 to elute off the product which is obtained as an oil (18.7 g~ 38%
yield).

STEP S
Preparation A5(a): ~ans-7-bromo-2-carboethoxymethyl-4-chloro-2,3-dihydro-1-(hydroxyeth-2-yl)-3H-indene, see CHART A, SIEP 5, compound A6.
Acetic acid (180 ml) is added to a solution of mans-7-bromo-1-(t-butyldimethylsilyloxyeth-2-yl)-2-carboethoxymethyl~chloro-2,3-dihydro-3H-indene (29.2 g, 61.3 mmol) in tetrahydrofuran (60 ml). Water (60 ml) is added, and the mixture is stirred at room temperature for 18 hours. The solvent is removed under vacuum, and the oil is dissolved in diethylether, washed twice with 109h aqueous sodium carbonate followed by brine, and the solution is dried overmagnesium sulfate. The solvent is removed under vacuum leaves a yellow oil (24.5 g). Purification by flash chromatography (230-400 mesh silica gel, 20% ethyl acetate in hexane) gives the title compound as a colorless oil (18.4 g, 60% yield from the olefin).

Prepara~ionAS(b): nans~bromo-2-carboetho~ymethyl-2,3-dihydro-l-(hydroxyeth-2-yl)~
3H-indene, see CHART A~ SrEP 5, compound A7.
Use prepa~ation AS(a) with the following modifications. Trans4-bromo- I-(t-3 ` ~
WO 93~08166 PCr/USg2/07314 butyldimethylsilyloxyeth-2-yl)-2-carboethoxymethyl-2,3-dihydro-3H-indene (46 g) is dissolved in acetic acid/IHF/water (3:1:1, 250 ml) and stirred for 16 hours. The solvent is removed in vacuo to obtain 22.3 g of pure oil.

Preparation A6(a): bans-7-bromo-4-chloro-2,3-dihydro-1,2-di(hydroxyeth-2-yl)-3H-indene, see CHART A, STEP 6, compound A7.
Lithium borohydride (2.0 M in tetrahydrofuran, 45 ml, 90 mmol) is added to a solution of trans-7-bromo-2-carboethoxymethyl~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 stined for 3 hours, allowed to stand at 0C for 155 hours, and ~efluxed for 30 minutes. The mixture is cooled in ice, and water (100 ml) is slowly added. When the reaction subsided, 10% hydrochloric acid (100 ml) is slowly added, and the mixture is stirred for 30 minutes. The layers are separated, and the aqueous layer is extracted with diethylether. The combined ether solution is washed with water, saturated aqueous sodium bicarbonate, and brine. The solution is dFied over magnesium sulfate, and the solvent removed under vacuum to leave the title compound as a cololless oil (15.0 g, 100%).

Preparation A6(b): ~ans-4bromo-273-dihydro-1,2-di(hydroxyeth-2-yl)-3H-indene, see CHART A, STEP 6, compound A7.
Use preparation A6(a) only start with trans~bromo-2-carboethoxymethyl-2,3-dihydro-1-(hydroxyeth-2-yl)-3H-indene.

Prepara~on A7(a): Irans-7-bromo-4chloro-2~dihydro-1,2-di(bromoeth-2-yl)-3H-indene, see CHART A, STEP 7, compound A8.
ln this procedwe, srans-7-bromo~chloro-z~3-dihydro-l~2-di(hydroxyeth-2-yl) 3H-indene ( 19.7 g) is dissolved in methylene chloride (300 ml) and TH~ (500 ml) with triphenylphosphine (38 g) and cooled to 0C. N-Bromosuccinimide (25 g) is added in portions. The solution is stirred for 20 minutes and the solvent removed in vucuo~ The residue is dissolved in ethyl acetate (200 ml) and silica gel (300 g) is added. With swirling. hexane (800 ml) is added. The slurry is filtered and the solvent removed in vacuo. The residue is eluted do~,vn a flash silica gel column (4 cm X 25 cm) with ethyl acetatel hexane (10:90). Solvent removal in vacuo afforded the dibromide in 89%
yield.
Prepalation A7(b): ~rans-4bromo-1,2-di(bromoeth-2-yl)-2,3-dihydro-3H-indene~ see Wo 93/~ 3 ~ 2 ~) PCl/US92/07314 CHART A, STEP 7, compound A8.
Use preparation A7(a) only start with trans-4bromo-2,3-dihydro-1,2-di(hydroxyeth-2-yl)-3H-indene (19.7 g, 69.1 mmol). Title compound is afforded in 89% yield (25.~ g of an oil).

Preparation A8(a): preparation and separation of the diastereomers of A9, ~ans 10-bromo-7-chloro-3N-[(S)-methylbenzyl]-6H-Sa,lOb-dih~droindeno[l,2-d]azepine, see CHART A, STEP
8, compound A9.
A mixture of tran3-7-bromo~chloro-2,3-dihydro-1,2-di(bromoeth-2-yl)-3H-indene (19.31 g, 0.0307 mol), ~S)-(-)-a-methylbenzylamine (3.91 g, 0.0323 mol), and potassium car'oonate (12.73 g, Q0921 mol) in acetonitrile (200 ml) is stirred at reflux on the steambath for 48 hours. The solvent is removed under vacuum, and the residue îs partitioned between water and diçthylether.
The aqueous layer is extracted with diethylether, and the com~ined organics ale washed with brine and dried (MgSO4). The solvent is removed under ~acuum to leave an orange oil (14.22 g).
Purification by flash chromatography (230 400 mesh silica gel, 5-30% ethyl acetate in hexane~ give the desired amine as a mixture of diastereomers (7.05 g). Fu~er purification by mediwn pressure liquid chromatography in a Michell-Miller column (230 400 mesh silica gel, 2-2.5% ethyl acetate in hexane) gives hVO diastereomers. Mastereomer I ~higher Rf)(2.88 g). Diastereomer 2 (lower Rf) (2.52 g~.
Preparation A8(b): preparation and separation of the diastereomers of A9, ~rans-7-bromo 3N-I~S)-methylben~yl]-6H-5a,l0b-dihydroindenol~ d]aæpine, see CHART A, STEP 8.
compound A9.
Use procedure A8(a) only start with trans-4-bromo-1,2-di(bromoeth-2-yl~2,3-dihydro-3H-indene (25.3 g). The reaction is refluxed for 48 hours to afford compound. The diastereomers are separated with flash silica gel ch~matography (Scm X 30cm) eluting with ether/hexane (1:99). The higher Rf fraction is isolated æ a crystalline solid (m.p. 117) by crystallizing from hexaneltoluene (7.2 g) la]25589 = -8.45 (c = 0.355, chloroform). The lower Rf diastereomer remains an oil (8.75 g)- 1]25589 = +5.82 (c = 1.545, chloroform). The remainder is a mixture of starting material and diastereomeric products which are resubjected to the reaction conditions.

Preparation A9(a)(1-2): preparation of two diastereomers of A10, see CHART A~ STEP

9, compound A10. follow the appropriate paragraph below.
Preparation A9(a)(1): preparation of Irans-lO-carboxamido-7-chloro-5a.10b-dihydro-3N-- `~1VO 93/08166 2 1 1 8 ~ 2 0 PCr/US92/07314 [(S)-methylbenzyl]-6H-indenol1~2-d~azepine from diastereomer 1. A solution of ~rans- 10-bromo-7-chloro-3N-l(S)-methylbenzyl]-6H-Sa,lOb-dihydroindeno[1,2-d]azepine (diastereomer 1; 2.88 g, 7.12 mmol) in dry, argon degassed tetrahydrofuran (30 ml) is cooled to -78C, and t-butyllithium (1.7 M in pentane, 8.4 ml, 14.3 mmol) is added over 15 seconds. The mixture is stirred at -78C
S for S minutes and added via needle stock to a solution of trimethylsilylisocyanate (2.42 g of 85%, 17.9 mmol) in dry tetrahydrofuran (10 ml) and dioxane (15 ml) at -78C. The cold bath is removed and the mixture is allowed to warm to room temperature. Water is added, the mixture is stirred for 15 minutes, and the volatiles were removed under vacuum. The residue is shaken with diethylether and water, the precipitate is filtered, washed with diethylether, and dried under vacuum at 60C to 10 give a solid (1.86 g). A sample (Q20 g) is crystaUized from ethanol to give the title compound as a colorless solid (0.15 g, m.p. 231-232C).

- Preparation A9(a)(2): p~eparation of trans-1O-carboxamido-7~hloro-5a,l0b-dihydro-3N-l(S)-methylbenzyll-6H-indenoll,2-d~azepine from diætereomer 2, see CHART A, STEP 9, 15 compound A10.
The amide is prepared in a manner similar to that for diastereomer 1, using procedure A9(a)(1), except stalting with diastereomer2 of trans-10-bromo-7-chloro 3N-l(S~methylbenzyll-6H-5a,10~dihydroindeno[1,2-d]azepine. The product is a colorless solid. A sample may be crystallized from acetonitrile (m.p. 192-193C).
Preparation A9(b)(1-2): preparation of two diastereomers of A10, see CHART A, STEP
9, compound A10, follow the appropriate paragraph below.

Prepa~ion A9(b)(1), prepa~ation of (+)-trans-7-carboxamido-Sa,lOb-dihydro-3N-[(S)-25 methylbenzyll-6H-indenol1,2-dlazepine.
Use preparation A9(a)(1) only start wi~ (+)-~rans-7-bromo-3N-[(S)-methylbenzyll-6H-Sa,lOb-dihydroindenol 1,2-d]azepine (7.26 g). This produces 5.57 g of ~e isomer as solid. [ocl~S589 = +29.11 (c = 0.56 methanol).

....
30 Prepa~ion A9(b)(2): (-)-bns-7 carboxamido-5a,10b-dihydro-3N-I(S)-methylbenzyll-6H-indenol1,2-dlaupine.
- Use preparation A9(a)(1) only start with (-~trans-7-bromo-3N-[(S)-methylbenzyll-6H-5a,10b dihydroindeno[t,2-d]azepine (8.75 g). Afforded 6.7 g of the title compound as a solid.
Ia]25589 = -25.97~ (c = 1.525 methanol).

Preparation A9(c): trans-10-aminosulfonyl-7-chloro-5a,l0b-dihydro-3N-l(S)-WO g3/08166 2 1 1 ~ ~ 2 t~ P~/US92/0~31~ ~ ;

methylbenzyl]-6H-indenol1,2-d]azepine, CHART A, STEP 9, compound A10.
The diastereomeric title sulfonamide is prepared from the diastereomerof ~rans-10-bromo-7-chloro-3N-l(S)-methylbenzyl]-6H-Sa,lO~dihydroindeno[1,2-dlazepine, see procedure A8(a), by performing a metal-halogen exchange with t-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., J. Med. Chem., 32:2548 (1989).

Preparation AlO(a)(1-2), Examples 1-2: preparation of two diastereomers of All, see CHART A, STEP 10, compound All, follow the appropriate paragraph below.

P~leparation AlO(a)(l), Example- 1: (+)-~rans-1O carboxamido-5a,10b-dihydro-6H-indenoll,2-dlazepine.
A mixture of (+~rans-10-carboxamido-Sa,lO~dihydro-3N-[(S)-methylbenzyl]-6H-indeno[l,2-d]azepine (1.70 g, 4.61 mmol), 20% palladium hydroxide on carbon (0.65 g), 12 N
hydrochloric acid (0.4 ml) in water (15 ml), and absolute ethanol (75 ml) is hydrogcnated in a Parr appa~anls for 16 hours with an initial hydrogen pressure of 50 psi. The mixture is filteled through H diatomaceous earlh and washed well with ethanol. The combined filtrate is evaporated leaving a foam (1.37 g).
Procedure AlO(a)(2), Example 2: (-)-tr~ns-10-carboxamido-5a,10b-dihydro-6H-` indenoll,2-dlaupine.
Use the same procedure as AlO(a)~l), except substituting (-~trans-10 calboxamido-Sa,lOb-dihydro-3N-[(S)-methylbenzyll-6H-indenol1,2-d]azepine in place of the equivalent (+) isomer.
Preparation AlO(b), Examples 34, preparation of two diastereomers of Al l, see CHART
A, STEP 10, compound Al l, from the appropriate paragraph below.

Preparation AlO(b)(l), Example 3: (+)-trans-7-carbo~amido 5a,10b-dihydro~6H-30 indenoll,2-dlazepine.
Use procedure AlO(a)(l) only start with (+)-trans-7-carboxamido-5a,10b-dihydro-3N-[(S)-methylbenzyl]-6H-indeno[1,2-dlazepine (5.5 g). The isomer is produced as a white solid, m.p.
222C decomp. ~al255~9 = +28.68 (c = 0.68 methanol).

Prepa~ion AlO(b)(2), Example 4: (-)-trans-7-carbo~amido-5a,l0b-dihydro-6H-indeno[l,2-dlazepine.

JI~ ' VO 93/08166 PCr/US92/07314 _19_ UsepreparationA10(a)(1)onlystartwith~-)-trans-7-carboxamid~Sa,lOb-dihydro-3N-[(S)-methylbenzyl]-6H-indeno[1,2-d]azepine. The title compound is produced æ a white solid, m.p.
223C, decomp. [ak55B9 = -29.43 (c = 0.72 methanol).

S Preparation A10(c): ~ans~ aminosulfonyl-Sa,lOb-dihydro-6H-indeno[l,2-dlazepine, see CHART A, ST~P lQ compound All.
Use procedure lO(a)(l) only start with trans-10-aminosulfonyl-7-chloro-5a,10b-dihydro-3N~[(S)-methylbenzyl]-6H-indeno[l,2-d]azepine, from preparation 9~c).

Prepas~tion All(a)(1-2), Examples S-6: prcparation of two diastereomers of A12, see CHART A, Sl~P 11, compound A12, follow the appropriate paragraph below.

Prepar~tion All(a)(l), Example 5: (+)-trans-1~carboxan~ido-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-dlazepine.
A mixture of (+)-~rans- 10-carboxamido^5a,10hdihydro-6H-indenol l ,2-dlazepine hydrochloride (1.37 g,4.61 mmol), l-bromopropane (1.76 g,14.3 mmol), potassium carbonate (1.91 g, 13.8 mmol), triethylamine (0.73 g, 7.2 mmol), and acetonitrile (SO ml) is stirred at reflux for 17 hours. The solvent is removed under vacuum, and the residue is partitioned between water and 1:1 20 THFldiethylether. The aqueous layer is extracted again with the same solvent, and the combined extracts were washed with brine and dried (MgSO4). The solvent is removed under vacuum to leave a solid (1.04 g). Crystallization from acetonitrile gives colorless crystals ~m.p. 198-199C).
la]D= +218.7 (c = 0.785, 25C, T~

Preparation All(a)(2), Example 6~ bans-10-carboxamido-Sa,lOb-dihydro-3N-n-propyl-6H-indenoll,2-d]azepine.
Use the same preparation as above except substituting (-)-trans-10-carboxamido-Sa,10~
dihydro-6H-indeno~1,2-d~azepine hydrochloride for the equivalent (+) isomer (0.85 g, m.p. 198-199C). 1OC~D = -222.3 (c = 0.865, 25C, THI:~.
Preparation All(b)(1-2), Examples 7-8: preparation of t~,vo diastereomers of A12, see CHART A, STEP 11, compound A12, f~m the appropriate paragraph below.

P~paration Al l(b)(l). Example 7: (+)-bans-7-carboxamido-5a,10b-dihydro.3N-n-propyl-35 6H-indeno~ d)azepine.
Use preparation Al l(a) only start wi~ (+)-trans-7-carbox~nido-Sa,lO~dihydro-6H~

WO 93/OB166 PCI /US92/07314 / ' -2~-indeno[l,2-d~azepine. The isomer is isolated as a white solid which is converted into the fumaric acid salt with one equal of acid in methanol/ether (m.p. 185C). [a]25589 - +26.47 (c = 0.665 methanol).

Preparation Al l(b)(2),Example 8~ rans-7-carboxan~ido-Sa,lOb-dihydro-3N-n-propyl-6H-indenol1,2 dlazepine.
Use preparation All(a) only start with (-)-trans-7-carboxamido-Sa,lOb-dihydro-6H-indeno[1,2-d~azepine. The isomer is isolated as a white solid which is converted into the fumaric acid salt with one equal of acid in methanollether (m.p. 185~ a]2S589 = -23.84~ (c = 0.99 10 methanol).

PrepasationAll(c): ~ns~ aminosulfonyl-5a,l0b-dihydro-3N-n-propyl-6H-indenol1,2-dlazepine, see CHART A, STEP 10, compound Al l.
Use procedure All(a) only start with trans-1~aminosulfonyl-Sa,10~dihydro-6H-indeno[1,2-15 d~azepine, from procedure AlO(c~.

Preparation A12(a)(1-2): preparation of t vo diastereomers of A13, see CHART A, STEP
12, compound A13, follow the appropriate paragraph below.
PreparationA12(a)(1): (+)-trans-10-cyano-5a,10b-dihydro-3N-n-propyl-6H-indenoll,2-dlazepine. (+)-trans-lO-calboxamido-5a,10~dihydro-3n-n-propyl-6H-indeno~1,2-d]azepine (0.33 g, 1.22 mmol) is dissolved in THF (lS mL) and t~iethylamine (1.0 mL, 7.42 mmol) then cooled to O~C. Titanium (IV) Chloride (0.33 mL, 3.04 mmol) is added. After stirdng at 20C for 2 hours, it 25 is partitioned between methylene chloride and dilu~e aqueous sodium carbonate. The organic layer is washed with water and brine, then dried over sodium sulfate. Product is dissolved in ether and hydrochloric acid in ether is added. Product is recrystallized from methanol and ether.
Preparation A12(a)(2)~ rans~ cyano-Sa,lOb-dihydro-3N-n-propyl-6H-indenop,2-d]azepine. (-)-trans-10-carboxamido-5a,10b-dihydro-3n-n-propyl-6H-indeno[1,2-d]Dzepine (0.28 . . .
30 g, 1.02 mmol) is dissolved in THP (15 mL) and triethylamine (0.87 mL, 6.24 mmol) then cooled to 0C. Titanium (IV) Chloride (0.28 mL, 2.56 mmol) is added. After stirring at 20C for 2 hours, it is partitioned between methylene chloride and dilute aqueous sodium carbonate. The organic Iayer is washed with water and brine. The product is dissolved in ether and hydrochloric acid in ether is added. Product is recrystallized from methanol and ether.
Prepa~tion A12(b)(1-2). Examples 9-10: preparation of two diastereomers of A13, see 21~8~2~
~VO 93/08166 PCr/US92/07314 CHART A, STEP 12, compound A13, follow the appropriate paragraph below.
Preparation A12(b)(1), Example 9: ~+)-trans-7-cyano-5a,10b~dihydro-3N-n-propyl-6H-indenoll,2-dlazepine.
The title compound is prepared from (+)-trans-7-carboxamido-Sa,lOhdihydro-3n-n-propyl-6H-indeno[1,2-d]azepine (0.33 g, 1.22 mmol) is dissolved in T~ (lS mL) and triethylamine (1.0 mL, 7.42 mmol) then cooled to 0C. Titanium (IV) Chloride (0.33 mL, 3.04 mmol) is added. After stirring at 20C for 2 hours, it is partitioned between methylene chloride and dilute aqueous sodium carbonate. The organic Iayer 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 hydr~chloric acid in ether is added. The tan solid is recrystallized from methanol and ether to give a gray solid (0.22 g, m.p. 252C).

Preparation A12(b)(2), Example 10: (-}~ans-7-cyano-5a,10b-dihydro-3N-n-prop~1-6H-indenoll,2-dlazepine.
The title compound is prepared from (-)-trans-7-carboxamido-Sa,lOb-dihydro-3n-n-propyl-6H-indenol 1,2-d]azepine (0.28 g, 1.02 mmol) is dissolved in THF (IS mL) and triethylamine (0.87 mL, 6.24 mmol) then cooled to 0C. Titanium aV) Chloride (0.28 mL, 2.56 mmol) is added. After stirring at 20C for 2 hours, it is partitioned hetween methylene chloride and dilute agueous sodium carbonate. The organic layer is washed with water and b~ine, 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. 252C).

Preparation A12(c): ~ans-7-aminosulfonyl-5a,10b-dihydr~3N-n-propyl-6H-indenoll,2-dlazepine, see CHART A, STEP 12, compound A13.
The title compound is preparcd from t~ans-7-aminosulfony1-Sa,lO~dihyd~6H-indenol1,2-2S d]azepine in a manner similar to that for the preparation of n ans- l~aminosulfonyl-Sa,lO~dihyd~
3N-n-propyl-6H-indeno[1,2-d]azepine, see preparation Al l(c).

PREPARATIONS AND EXAMPLES FROM CHART B
STEP I
Preparation Bl(a): 4Chloro-7-melhoxy-l-(N-pyrrolidinyl)indene. see CHART B, SrEP1, compound B2.
A solution of the ~chloro-7-methoxy- I-indanone t3S.OO g, 0.178 mol~ and pynolidine (76.0 g, 1.07 mol) in dry tetrahydrofuran (800 ml) is cooled to 7~C, and a solution of titanium tetlachloride (18.6 g, 0.098 mol) in pentane (SO ml) is added over a period of 7 minutes. The mixture is stirred at 10C for 30 minutes at room temperature for 3.5 hours. The mixture i~ filtered~
and the fil~e is evaporated under vacuwn to leave the title compound as a green oil (44.4 g).
.,.

WO 93/081q~ 3 9 ~ PCr/US92/07314 S~EP 2 Preparation B2(a): 2-(Carboethoxymethyl)-4-chloro-7-methoxy-1-indanone, see CHART
B, SrEP 2, compound B3.
S A solution of the 4-chloro-7-methoxy-1-(N-pyrrolidinyl)indene (44.4 g, 0.178 mol). ethyl bromoacetate (32.7 g, 0.196 mol), and diisopropylethylamine (34.5 g, 0.267 mol) in acetonitrile (150 ml~ is stirred at reflux in an oil bath maintained at 95C for 4 hours and at room temperature for 15 hours. The mixture is titrated with water, and 10% hydrochloric acid is added to adjust the pH to 4-5. The m~xture is heated on the steam bath for 15 minutes, cooled, and extracted with diethylether and with 1:1 diethylether/tetrahydrofuralL The combined extracts are washed with 10%
hydrochloric acid (3 times), saturated sodium bicarbonate, and brine. The solution is dried (MgSO4), and the solvent is removed under vacuum to leave an amber oil (41.3 g). Crystallization from ethyl acetate/hexane gives title compound as yellow erystals (28.g g). The filtrate is purified by flash chromatography (230400 mesh silica gel, 4:1 hexane/ethyl acetate) to give title compound as a solid (4.70 g, total yield 68%).

Preparation B3(a): 1,2-Bis(carboethoxymethyl)-4-chloro-2-hydroxy-7-methoxyindane, see CHART B, SI'EP 3, compound B4.
- 20 A few crystals of iodine were added to a mixture of 2-(ca~boethoxymcthyl~chloro-7-met-hoxy-l-indanone (8.48 g, 30.0 mmol), ethyl bromoacetate (10.0 g, 60.0 mmol), and zinc dust (5.~9 g. 90.1 mmol) in diethylether (50 ml) and benzene (100 ml) at room temperature, and the mixture is heated to reflux. After 30 minutes, no significant reaction occurred. A few more crystals of iodine are added, and the reflux is continued. The reaction is started a~er 30 minutes, and the 2S mixture is refluxed for an additional 1.5 hours. The mixture is cooled, diluted with water, and washed with 10% hydrochloric acid, saturated sodium bicarbonate, and brine. The solution is dried (MgSO4), and the solvent is removed under vacuum to leave the compound, B4(a), as an oil (10.89 g)-Preparation B4(a)~ Bis(carboethoxymethyl)-4-chloro-7 methoxyindane, see CHART
B, SI~P 4, compound BS.
Trifluoroacetic acid (~0 ml) is added to a mixture of 1,2-bis(carboethoxyme~hyl)~chloro-2-hydroxy-7-methoxyindane (9.75 g, 0.026 mol) and triethylsilane (6.1 g, 0.052 mol) at room 35 temperature with stirring. The mixture is sdrred at ~oom temperature for 3 hours, and the solvent is removed under vacuum. The material is dissolved in diethylether and washed with saturated ~ ~WO 93/08166 2 1 1 8 9 2 0 PCI/US92/07314 sodium bicarbonate (twice) and brine. The solvent is removed under vacuum to leave an oil (8.9 g). Purification by flæh chromatography (230400 mesh silica gel, 10-20% ethyl acetate in hexane) gives the title compound æ a mixture of cis-trans isomers (1.57 g).

Preparation B5(a): 1,2-Bis(2-hydroxyethyl)-4chloro-7-methoxyindane, see CHARTB, STEP 5, compound B6.
A solution of 1,2-bis(carboethoxymethyl)~chloro-7-methoxyindane (1.72 g, 4.85 mmol) in diethylether (50 ml) is added to a suspension of lithium aluminum hydride (1.5 g, 39.5 mmol) at room temperature. The mixture is stirred for 45 minutes, cooled in ice, and water (1.5 ml), 15%
sodium hydroxide (1.5 ml), and water (4.5 ml) were added in succession. The mixture is stirred at room temperature for 15 minutes, and the precipitate is filtered and washed with tetrahydrofuran.
The filtrate is dried (MgSO~), and the solvent is removed under vacuum to leave the title compound (1.34 g) as a mixture of cis-trans isomers.

Preparation B6(a)~ Bis(p-toluenesulfonyloxyeth-2-yl)-4chloro-7-methoxyindane, see CHART B, STEP 6, compound B7.
A solution of the 1,2-bis(2-hydroxyethyl)~chloro-7-methoxyindane (1.57 g, 5.80 mmol) is cooled in ice, and p-toluenesulfonyl chloride (3.32 g, 17.4 mmol) is added. The mixture is stirred at 0C for I hour and allowed to stand at 0C for 20 hours. Water (12 ml) is added, and the mixturc is stirred at room tcmperature for 45 minutes. The mixture is diluted with diethylether, washed with 10% hydrochloric acid (3 times), sa~urated sodium Wcarbonate, and brine~ The solution is dried (MgSO,), and the solvcnt is removed under vacuum to leave the title compound 25 as a yellow oil (2.9 g).

Preparation B7(a), Examples 11-12: preparation of the diastereomers, cis and Irans-7-chloro~ metho~y-Sa,lOb-dihydro-3N-n-propyl-6H-indenoll,2-dlazepine, see CHART B, S~EP
.~
30 7, compound B8. A mixture of 1,2-bis~-tolucnesulfonyloxyeth-2-yl~chloro-7-methoxyindane (2.9 g, 5.0 mmol), n-propylamine (0.33 g, 5~6 mmol), and potassium carbonate (2.07 g, IS.0 mmol) in acetonitrile is sdrred at reflux in an oil bath maintained at 90C for 3 hours. n-P~pylamine (0.72 g, 12.2 mmol) is added. and the reflux contDued for 19 hours. The mixture is diluted with diethylether and washed with water, 10% sodium carbonate, and brine. The solution is dried 35 (MgSO4), and the solvent is removed undervacuum to leave an oil (1.45 g). Purification by gravity cl~matography (7~230 mesh siUca gel, 0.7% isopropylamine and 10% ethyl acet~te in hexane) WO 93/08166 ~ 2 -~ - PCr/l,'S92/07314 gives two compounds. The faster moving compound (0.70 g) is dissolved in diethylether and acidified with excess e~hereal hydrochloric acid. The precipitate is centrifuged. washed with diethylether, and crystallized fivm methanoVdiethylether to give the trans-compound as a colorless solid (0.69 g, m.p. 195-196C). The slower moving compound (O.S5 g) is converted to the S hydrochloride salt in a similar manner giving the cis-compound as an off-white solid (0.47 g, m.p.
245-246C).

WO 93/08166 2 1 1 8 ~ 2 (1 PCr/US9~/07314 CE~ART A page 1 step 1 1 Rl rC ~2CII3 R~

Step 2 1 :~
o~

R
~ .

Step 3 211 ~?~13 WO 93/08166 PCI~/US92/07314 C~9RT A page 2 Step 3 Xl ~Si-~e2t-Butyl ~ ' ~4 Step4 2t-B3tyl ~"c'~C l2CII3 Step 5 Rl ~O~o ~G c~ 2~3 Step 6 ;~N0 93/08166 2 i l ~ ~ 2 Q Pcr/US92/07314 CHART A page 3 Step 6 R

R

Step ~ 1 A 7 R
~~'~EIr R~

Step 8 C~3 ~2 Step 9 W~ 93/08166 2 ~ 2 n PCI/lJS92/0731 G~[ART A pa~e 4 Step 9 ¦
c~

Rl~

Step 10 Seep 11 N~' Rl~J

Step 12 2 ~
;~0 93/08166 PCI`/US92/07314 CIIART A page 5 Step 12 R , R,.

WO 93/08166 211 g 3 2 ~ PCI`/US92~07314 CEART B pa8e 1 R~

step R

Ste~ 2 I~d 0~2C33 Ste~ 3 , W093/08166 2~ 20 PCI/US92/07314 C~ART B page 2 Step3 Rl~ o_ C~2C~3 R~--b-~2C~3 Ste,o 4 1 3 4 Rl ~C~ 2C~3 ~g~ 3 B S

Step 5 Rl ~
~~

. Step 6 ~3~

WO 93/08166 ~ 2 {~ pcr~us92/o7314 CHART B page 3 Step6 OSO2Tolue~e Rl ~ :
~~~OSO2Tol~

Step 7 Rl f N~

`~O 93/08166 211 ~ ~ 2 ~ PCl'/US92/07314 Reactions of CHART C
Step 1, carboxylic acid, Cl, 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 S NBS and triphenylphosphine. Step 3, the benzylic bromide, C3 is alkylated with the enolate of - ethyl acetate to give C4. Step 4, C4 is reduced to the alcohol, C5, with LAH. Step 5, the alcohol, C5, is oxidized under Swem conditions to afford the aldehyde, C6.
Step 6, the atdehyde, C6, is treated with vinylmagnesium bromide to afford the allylic alcohol, C7. Step 7, the atlylic alcohol, C7, is treated with triethylorthoacetate to cause a Claisen 10 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 cycliz'ed to the 1,2,3,4,4a,5,6,10b-transoctahydrobenzo[f~isoquinoline, Cll, using paJaformaldehyde and borontrifluoride-etherate.
15 Step 11, the carbamate, Cl 1, 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 crystaDization with opticatly active di-~toluoyltartaric acid in methanol. From this point, step 12, each enantiomer is independently converted through the subsequent steps to afford opticatly pure products.
Step 13, the amine, now the pure enantiomer, C13, is converted into the propionamide, C14, 20 with propionylchloride. Step 14, the propionamide, C14, is reduced with LAH to give C15.
Altematively, from Step 13, the amine, the pure enantiomer, C13, can be converted directly into C15 by atkylation with bromopropane. Step 15, C15 is converted into the carboxamide, C16, by subsequent treatment with t-butyllithium and trimethylsilylisocyanate. The hydro-debrominated anatog, C17, was isolated as a side product. The hydro-debrominated analog, C17, can be 25 synthesized in high yield by treatment with t-butyllithium followed by a water quench.
Step 16, the carboxamide, C16, is dehydra~ed to the nitrile, C20, with the aid of Burgess' reagent. Step 17, the carboxamide, C16, is hydrogenated to remove the chlorine using palladi-um/carbon, affording C18. Step 18, the compound, C18. is dehydrated using Burgess' reagent to afford the nitrile, C19.
30 Structures are shown in CHART C.
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 II are not only active but have incre~sed bioavailability as shown by metabolism studies. See PART 11- TABLES I-II, below.
35 The preferred compounds from the list below and PART 11 - TABLES I and Il are compounds numbered 1, 2~ 7~ and 11.

WO 93/08166 2 1 ~ ~ ~ 2 ~ PCI`/US92~07314 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.
CNS Receptor Binding Assay (PART Il - TABLE 1): The Central Nervous System Binding 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 lO0 the test compound binds as well as the standard compound. The standard compound for the dopamine Dl receptor is SCH
23390.
Metabolism (PART n - TABLE Il):
HeDatocvte. Intrinsic clea~nce of 3 concentrations of compound ~2, 5 and 15 ug/ml) following a 60 rninute incubation at 3rC in the presence of a suspension of freshly prepared rat hepatocytes (5.0 million cellslml). Aliquots of each incubate were withdrawn during the incubation and analyzed for parent compound using HPLC methodology. lntrinsic clearance is expressed as ml/min/5 million cells. Metabolic stability relative to the control, ( ~) l-fonnyl-6,7,8,9-tetrahydro-N-di-n-propyl-8-amino-3H-benzle]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-(dipropylamino)-5,~dihydro~H-imidazo(4,5,l-y~quinoline-2(1H)~ne, (-), monohydrobromide hydrate to give relative metabolic half lives.
The compounds below have been subjected to one or more of the biological tests described above. PART n - TABLES I -11 use the numbers assigned below.

WO 93/08166 213~ ~ ~ ? PCl/US92J07314 Compound Number Name 1. (-)-10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f~isoquinoline, See CHART C STEP 14 compound C15, EXAMPLE 1.
2. (+)-10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans~octahydro-3N-5 propylbenzolfJisoquinoline, See CHART C STEP 14 compound C15, EXAMPLE 2.
3. (-)-7-Chloro-10-carboxamido-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzolt~;soquinoline, See CHART C, STEP 15, compound C16, EXAMPLE 3.
4. ~+)-7-Chloro-10-carboxamido-1,2,3,4~4a,5,6,10b-~rans-octahydro-3N-prnpylbenzolf~isoquinoline, See CHART C, STEP 15, compound C16, EXAMPLE 4.
5. (-)-7-Chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[fpsoquinoline,compound C17, from prepara~ion C15, EXAM~LE 5.
6. (+)-7-Chloro-1,2,3,4,4a,5,6,10b-t~ans-octahydro-3N-propylbenzolfJisoquinoline, compound C17, from preparation C15, EXAMPLE 6.
7. (-)-7-Chloro-10-cyano-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-15 propylbenzolf~isoquinoline. see CHART C, STEP 16, cornpound C20 EXAMPLE 7.
8. (+)-7-Chloro-10-cyano-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[fJisoquinoline. see CHART C, STEP 16, compound C20, EXAMPLE 8.
~ . (-)-10-Carboxamido-1 ,2,3,4,4a,5,6,1 Ob-octahydro-trans-3N-propylbenzol~isoquinoline, see CHART C, STEP C17, compound C18. EXAMPLE 9.
10. (+)-10-Carboxamido-1,2,3,4,4a,5,fi,10b-octahydro-tr~ns-3N-propylbenzo[f~isoquinoline, see CHART C, STEP 17, compound C18, EXAMPLE 10.
I 1. (-)-lO Cyano-1,2,3,4,4a,5,6,10b-octahydro-tr~ns-3N-propylbenzo[~isoquinoline.
see CHART C. STEP 18. compound Cl9. EXAMPLE 11.
12. ~+)~ Cyano-1,~,3,4,4a,~,6,10b-octahydro-trans-3N-propylbenzo[flisoquirloline, see CHART C, STEP 18, compound Cl9, EXAMPLE 12.

2~?
WO 93/08166 PCI/US~2~07314 PART Il - TABLE I
BIOLOGICAL DATA - CNS Receptor Binding Dopamine - D1 I)opamine - D2 Compound No % inhibition % inhibition 92.09 97.06 2 16.00 81.~4 3 14.54 ~3.42 4 3.18 27.37 25.08 89.87 6 40.95 95.92 7 83.17 100.00 8 9.40 24.67 9 24.77 2.90 10 48.35 4.87 11 36.66 100.0~

12 15.14 90.18 _ . . . ~

BIOLOGICAL DATA - Metabolism ~hepatocyte and microsome) Hepatocyte Microsome Compound No. (control is 1.0) ~control is 1.0) . ~ _ . 0.120 --2 0.140 --, 0.120 0.20 6 0.040 7 0.~30 0.91 8 0.200 -9 0.500 1.30 1.610 --1l 0,130 0.48 12 0.070 0.28 ~ ..... --............ .. _ .

.
Without fur~er elaboration, it is believed that one skilled in the art can, using the preceding description~ practice the present invention to its fullest extent. The following detaiied examples describe how to prepare the vanous compounds and/or pçrform the various processes of the 50 invention and are to be construed as merely illustrative, and not limitations of the preceding WO 93/08166 2 ~ 2 0 PCI`/US92/07314 disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reac~on conditions and techniques.

PREPARATIONS AND EXAMPLES FROM CHART C

Preparation Cl, Bromo-2-chlorobenzyl alcohol, see CHART C, STEP 1, compound C2.
S-Bromo-2-chlorobenzoic acid (107.9 g, 4S8.2 mmol) in THF (1000 mL) is cooled to 0C.
Borane-methyl sulfide complex (1.3 eq) is added. After 25 minutes at room temperature the solution is refluxed for 30 minutes. Water, 300 mL, is added at 0C, then 2N hydrochloric acid is 10 added. After stirring 45 minutes ~ room temperature, additional acid is added and the mixture extracted with ether/methylene chloride. The organic layer is washed successively with more aqueous acid, water, saturated aqueous sodium bicarbonate and brine. The organic layer is then dned over sodiurn sulfate, filtered, and stripped of solvent to yield a white solid, 100.9 g (99%), mp 90.0-92.0C.

Preparation C2, 5-Bromo-2-chloroben~yl bromide, see CHART C, STEP 2, compound C3.
5^Bromo-2-chlorobenzyl alcohol (106.6 g, 481.4 mmol) in methylene chloride (1000 mL) is cooled to 0C. N-Bromo-succinimide (1.2 eq) is added over 60 minutes and the ice bath is 20 removed. After 2 hours, methanol (8 mL) is added. The solution is poured into 40~0 ether in hexane (2100 mL); silica gel (800 mL, 230~00 mesh) is added. The mixture is f;ltered through another 200 mL of silica gel and the silica gel plug is rinsed with 40% ether in hexane (1050 mL~.
Solvents are removed and the residue is flash chromatographed on a silica gel column (24 x 7 cm), followed by elution with methylene chloride/ethyl acetate/hexane ~2:10:88) to yield a red solid, 25 108.9 g (79%), mp 72.5-74.5C.

Preparation C3, ethyl 3-(5-bromo-2-chlorophenyl)propiw~ate, see CHART C, STEP 3,compound C4. `
S-Bromo-2-chlorobenzyl bromide (108.9 g, 382.9 mmol) in TH~ (475 mL) is added to ethyl ....
30 acetate (60.0 mL, 612.7 mmol) in lithium diisopropylamide (1.5 eq in TH~, 650 mL) at -78C.
After sdr ing for 2 hours, glacial acetic acid (I equivalent) is added. The mixture is pardtioned between ether and 2N hydrochloric acid. The organic layer is washed with water, saturated aqueous sodium bicarbon~te, and brine. lt is dried over sodium sulfate, filtered, and the solvents removed under vacuum. The residual oil is flash cl~omatographed on a 20x7 cm silica gel column. The 35 silica gel column is eluted with 7.5% ethyl acetate in hexane to yield 87.2 g (78%) orange oil.

2 ~ t ~ ~ 2 s) WO 93/08166 PCr/US92/07314 '' -3g-Preparation C4, 3-(5-Bromo-2-chlorophenyl)propanol, see CHART C, STEP 4, compound CS.
Ethyl 3-(S-bromo-2-chlorophenyl)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 0C. After 30 S minutes, water (10 mL), sodium hydroxide (10 mL, 15% aqueous), and water (30 mL) are added successively and stirred at room temperature for lS minutes. The slurry is filtered and the filtrate is d~ied over sodium sulfate to yield a pale orange oil (68.9 g, 92%).
STEP S
P~paration C5, 3-(5-Bromo-2-chlorophenyl)propionaldehyde, see CHART C, STEP S, compound C6.
Dimethyl sulfoxide (43.1 mL, 0.61 M) in methylene chloride (300 mL) is cooled to -78C.
Oxalyl chloride (26.5 mL, 0.30 M) is added. After 30 minutes, 3-(S-bromo-2-chlorophenyl)-propanol (68.9 g, 0.28 M~ in methylene chloride (250 mL) is added. After 20 minutes, tAethyl-amine (192 mL, 1.38 M) is added. The slurry is warmed to room temperature. Water is added and the mixture is extracted with ether. The organic layer is successively wæhed with 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine. It is dried over sodium sulfate and yields 68.3 g (100%) pale oil.

Preparation C6, 5-(S-Bromo-2-chbrophenyl)penten-3-ol, see CHART C, SlEP 6 compound C7.
Vinylmagnesium bromide (339 mmol) in THF (900 mL) is cooled to 0C. 3-(5-Bromo-2-chlorophenyl)propionaldehyde (68.3 g, 276 mmol) in TH~ (500 mL) is added and the solution stirred at room temperature for 2.5 hours. Saturated aqueous ammonium chloride is added, then 2N hydrochloric acid is added. The mixture is extracted with ether. The ether layer is washed with water then with brine. The washed ether layer is dried over sodium sulfate and yielded 71.6 g (g4%) yellow oil.

Preparation C7(a). ethyl 7-(5-bromo-2-chlorophenyl)-~rans-hept-~enoate, see CHART
C, STEP 7, compound C8.
S-(S-Bromo-2-chlorophenyl)penten-3-ol (71.6 g~ 260 mmol~, triethylorthoacetate (164 mL
885 mmol)~ and propionic acid (1~1 mL, 099 mmol) are combined and heated at tS0C for 2 hours with removal of ethanol. The solution is cooled to 0C and 2N hydrochloric acid is added. The mixture is extracted with ether. The ether layer is washed with water then with brine. The either layer is then dried over sodium sulfate and yields 84.12 ~ (94%) of yellow oil.

Preparation C8~ 7-(5-Bromo-2-chlorophenyl~-~ans-hept-~enoic acid~ see CHART C.

``VO 93/08166 2 1 1 ~ ~ 2 ~ PC,/US92~073l4 STEP 8 compound C9.
Ethyl 7-(5-bromo-2-chlorophenyl)-trans-hept4-enoate (~4.1 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.
S The aqueous layer is acidified with hydrochloric acid and extracted with ether. The ether layer is washed with waler and brine and is dried over sodium sulfate. It yields 57.8 g (7~%) yellow solid.
A portion is rec~ystallized from ethyl acetate, mp 53.5-55.0C.
.STEP 9 Prepa~ation C9, 6-(5-Bromo-2-chlorophenyl)-~rans-hex-3-enyl ethyl carbamate, seeCHART C, STEP 9, compound C10.
7-(5-Bromo-2-chlor~phenyl)-trans-hept~enoic acid (57.8 g, 182 mmol), 1,4-dioxane (600 mL), diphenylphosphoryl azide (39.2 mL, 182 mmol),and triethylamine (25.4 ml,, 182 mmol) are stirred at room temperature for I hour, then refluxed 30 minutes. Nitrogen evolves. Ethanol (æ.l mL, 364 mmol) is added and refluxing continues for 2 hours. The solution is cooled to O~C and sodium hydroxide (1.1 equivalent) and water are added. After 30 minutes, the mixh~re is partitioned between ether and water. The e~er layer is washed successively with water, 2N hyd~chloric acid, water, saturated aqueous sodium bicarbonate and brine. The solution is dried over sodium sulfate.
The yellow oil is flash ch~matogra~hed on a 16 x 7 cm silica gel column and eluted with 5%
followed by 10% ethyl acetate in hexane to yield 37.2 g (57%) yellow oil.

Preparation C10, 10-Bromo-3N-carboethoxy-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydrobenzo[f]isoquinoline, see CHART C, STEP 10, compound Cll.
6-(5-Bromo-2-chlorophenyl)-~rans-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 wasmed to 30C 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 x 7 cm silica gel column and eluted with 2% acetone in hexane to yield 41.6 g (83%) of pale oil.
STEP I I
Preparation Cl l, 10-Bromo-7-chloro-l,2,3,4,4a,5,6,10b-t~uns-octahydrobenzolf]-isoquinoline, See CHART C. STEP 11, compound C12.
l~Bromo-3N-calboethoxy-7-chloro 1,2,3,4,4a.5,6,10~trans-octahydrobenzn[~isoquinoline (41.1 g. 110 mmol) is refluxed with potassium hydroxide (28.5 g~ 441 mmol), methanol (200 mL).
and-water (20 mL) for 65 hours. The solvents are removed under vacuum and the residue is partitioned between water and ether/methylene chloride. The organic layer is washed with water Wo 93~08~ ) 2 ~ PCr/US92/07314 ~ ~

twice and then with brine. The organic layer is dried over sodium sulfate to yield 30.9 g (93%
crude) of pale oil.

Preparation C12, enantiomeric separation of 10-bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-S octahydrobenzo[f)isoquinoline, see CHART C, STEP 12, compound C13.
A hot methanol solution (650 mL) of 10-bromo-7-chloro- 1,2,3,4,4a,5,6,10b-~rans-octahydrobenzo[flisoquinoline (30.9 g, 103 mmol) is combined with di-p-toluoyl-D-tartaric acid (22.5 g, 56.5 mmol). Upon cooling, the resultant white solid is filtered. The filtrate is dried of solvent under vacuum, then pa~titioned 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 the L folms of ~e acid. Thc combined ~salts are then converted to free base and converted back to the v-sa1ts as described above. A second cycle yielded the free base as a white waxy solid, 9.0 g (29%). ~a]~5589=
-212.9 (c= 0.68, MeOH).
NOTATION COMMENT
Steps 13 - 19, below, show how ~e enantiomers, "~a)" and "(b)" are independentlyconvelted to give optically pure products. Enantiomer~ for aminosulfonyl deriva~ives are labeled with preparation numbers that include the letters "(c)" and "(d)."

Pleparation C13(a), (-)-10-Bromo-7-chloro-1,2,3,4,4a,~,6,10b-trans-octahydro-3N-propionylbenzo[t~isoquinoline, See Chart C, STEP 13, compound Ct4.
(-)-1 0-Bromo-7-chloro- 1 ,2,3,4,4a,S,6,10b-tr~ans-octahydro benzolf~isoquinoline ( 1.75 g, 5.82 mmol), triethylamine (0.97 mL, 6.98 mmol), and methylcne chloride (12 mL) are combined and cooled to 0C. Propionyl chloride (0.57 mL, 6.40 mmol) is added. Af~r I hour water is added and the mixture is extracted with ether. The ether layer is washed with 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and brine. The ether layer is dried over sodium sulfate to yield 2.17 g (100%) thick oil.
Preparation C13(b), (+)-10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propionylbenzolfJisoquinoline, See Chart C, STEP 13, compound C14.
Use the same procedure as above, for C13(a), only start with (+)-10-Bromo-7-chloro 1,2,3,4,4a,S,6,10~t~ans-octahydro benzolflisoquinoline.

Preparation C14(a), EXAMPLE 1, (-)-10-Bromo-7-chloro-1,2,3,4,4a,S,6,10b-trans-octahydro-3N-propylbenzolf]isoquinoline, See CHART C, ST~P 14. compound CIS.
(-)-1~Bromo-7-chloro-1.2,3,4,4aS,6,10~rans-oc~ahydro 3N-propionylbenzo[flisoquinoline (2.17 g, 6.08 mmol) in ether (6 mL) is added to lithium aluminum hydride (0.23 g, S.82 mmol) in ~ WO 93/08166 2 1 1 8 ~ 2 0 PCr/US9~/07314 ether (6 mL) at O~C. The mixture is refluxed for I hour, then water (0.20 mL), sodium hydroxide (0.20 mL, 15% aqueous), and water (0.60 mL) are se~guentially added. The mixture is filtered and the fil~ate is dried over sodium sulfate tO yield 1.88 g thick oil. The oil is flash chromatographed on a 2.2 x 15 cm silica gel column and eluted with 15% ethyl acetate in hexane to yield 1.77 g 5 (89%) of an oil. la]25589= -176.55~ (c=1.70 CHC13). The oil is dissolYed in ether and is acidified with hydrochloric acid in ether. The resulting white solid is recrystallized from methanol and ether to yield a white solid, m.p. 277C (decomposition).
Preparation C14(b), EXAMPLE 2, (+)-10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-~ans-octahydro-3N-propylbenzo[f3isoquinoline, See CHART C, STEP 14, compound C15.
Use the same procedure as above, for C14(a), only start wlth (+)-1~Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propionylbenzo[f3isoquinoline.

Preparation Cl5(a),EXAMPLE 3, (-)-7-Chloro-l~carboxamido-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f3isoquinoline, See CHART C, STEP 15, compound C16.
(-)-1~Bromo-7-chloro-1,2,3,4,4a,5,6,1Ob-trans-octahydro-3N-propylbeni~o[f3isoquinoline (1.20 g, 3.50 mmol) in THF ~10 mL) is cooled to -78C and t-butyllithium (4.1 mL, 1.7 M in pentane) is added. Trimethylsilylisocyanate (1.1 mL, ?.ûO mmol) is added. After 75 minutes at room temperature, water is added and the mixture extracted wi~ ether. The ether layer is washed with saturated a~ueous sodium bicarbonate and brine. The washed ether layer is dried over sodium 20 sulfate. The ctude product is flash chromatographed on a 2.2 x 15 cm silica gel column and eluted with 5:1 methylene chloride:methanol. Product obtained is 0.86 g (80%) of a white solid, m.p.
220C (decomposition). [a]~5589 = -255.82 (c-0.455 CHCI3~. This solid is dissolved in isopropanol and ether, therl hydrochloric acid in ether is added. The white solid is recrystallized from isopropanol and ether, m.p. 165C (decomposition).
Preparation C15(b), EXAI~PLE 4, (+)-7-Chloro-l~carboxamido-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[t~isoquinoline, See CHART C, STEP 15, compound C16.
Use the same procedure as above, for Cl5(a~, only start with (+)-10-bromo-7-chloro-1 ,2,3.4,4a,5,6.10b-trans-octahydro-3N-propylbenzo[f]isoquinoline.

EXAMPLE 5, isolation of ~-~-7-Chloro-1,~,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenz-olflisoquinoline, compound C17, from preparation C15. This compound is isolated from (-)-7-chloro- I O-carboxamido- 1 ,2,3,4,4a,5 ,6.1 Ob-trans-octahydro-3N-propylbenzolf]isoquinoline chromatography using an initial elution of 20:1 methylene chloride:methanol to yield 0.30 g (1.14 mmol) pale paste. This is dissolved in methanol and ether and hydrochloric ~cid in ether is added.
35 The white solid is recrystallized from methanol and ether to yiçld 0.14 g white solid. m.p. 250C
(decomposition), lal2558~ -92.73 (c= 0.33 MeOH).

211~2~
WO 93/08166 PCr/lJS92/07314 EXAMPLE 6. isolation of (+)-7-Chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzolflisoquinoline, compound C17, from preparation C15. This compound is isolated from (-)-7-ch1Or~-10-carboxamido-1,2,3,4,4a,5,6,10~trans-octahydro 3N-propylbenzo[flisoquinoline using the same procedure as above.
Preparation C15(c) and Cl5(d) ~+) and (-)-7-chloro-10-aminosulfonyl-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzolfJisoquinoline, See CHART C, STEP 15, compound C16. The title sulfonamides are prepared from the enantiomers of 10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzolflisoquinoline, compound C15, via metal-halogen exchange with t-10 butyllithium, followed by conversion of the aryllithium to the sulfonamide according to thereference: S.L. Graham, ct al., J. Med. Chem., 32:2548 (1989).

Prepa~ation C16(a), EXAMPLE 7, (-)-7-Chloro-10-cyano-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[l~isoquinoline. see CHART C, Sl'EP 16, compound C20.
(-)-7-Chloro-10-carboxamido-1,2,3,4,4a,5,6,10~trans-octahydro-3N-propylbenzolflisoqu-inoline (0.45 g, 1.47 mmol) is dissolved in THF (7.5 mL) and methylene chloride (9.0 mL) and Burgess' reagent (0.87 g, 3.67 mmol) are added. After 3 hours at room temperature it is poured onto 10% aqueous sodium carbonate at 0C and extracted with ether. The ether layer is wæhed with brine and dried over sodium sulfate. The amber pæte is flash chromatographed on a 1.2 x 16 20 cm silica gel column, eluted with 10:1 methylene chloridehnethanol to yield 0.41 g (97%) opaque tan oil, la]255S9 -209.6, (c = 1.09 MeOH). This is dissolved in methanol and ether and hydrochloric acid in ether is added. The white solid is recrystallized f~m methanol and ether, m.p.
275C (decomposition).
Prepa~ation C16(b), EXAMPLE 8, (+)-7-Chloro l0-cyano-1,2,3,4,4a,5,6,10b-~ns-25 octahydro-3N-propylbenzolflisoquinoline. see CHART C, STEP 16, compound C20.
Use the same procedure æ above, for C16(a), only start with (+)-7-chloro-10-calboxamido-1,2,3,4,4a,5,6,10~trans-octahydro-3N-propylbenzolflisoquinoline.

PrepD~ion C17(a), EXAMPLE 9, (-)-10 Carboxamido-1,2,3,4,4a,5,6,10b-octahydro-tr~ns-30 3N-propylbenzotflisoquinoline, see CHART C, STEP C17, compound C18.
(-)-7-Chloro- 10-carboxamido- 1,2,3,4,4a,5,6,10b octahydro-trQns-3N-propylbenzotflisoqu-inoline (I.Sg) is placed in a hydrogenation flask with palladium hydroxide/carbon (0.45g) and ethanol (120 ml). This is hydrogenated under 50 p.s.i. for 12 hours then filtered through diatomaceous earth. Solvent evaporation is followed by dissolving the residue in methylene 35 chloride and 10% aqueous sodium carbonate. The organic layer is separated and washed with water and then brine. and dried over sodium sulfate. Solvent removal affords a white solid. 10~1255w = -21~ 2~
WO 93/~8166 ` PCr/~S92/07314 307.80 (c = 0.68 methanol). The amine is converted into the crystalline maleate salt with maleic acid in methanollether (needles) []25S89 = -214.95 (c = 1.07 methanol), m~p. 240C (decomposi-tion).
Preparation C17(b), EXAMPLE 10, (+)-10-Carboxamido-1,2,3,4,4a,5,6,10b-octahydro-S trans-3N-propylbenzolflisoquinoline, see CHART C, STEP 17, compound C18. Use the same procedure as above, for C17(a), only start with (+)-7-chlor~-10-casboxamido-1,2,3,4,4a,5,6,10b-octahydro~trans-3N-propylbenzolf~isoquinoline.
Prepa~ion C17(c) and C17(d), (+) and (-) -(10)-aminosulfonyl-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[flisoquinoline, see CHART C, SrEP 17, compound C18.

Preparation C18(a), EXAMPLE 11, (-)-10-Cyano-1,2,3,4,4a,S,6,10b-octahydto-~rans-3N-propylbenzo[~isoguinoline, see CHART C, STEP 18, compound Cl9. (-)-10-Carboxamido-1,2,3,4,4a,5,6,10hoctahydro-trans-3N-propylbenzo[flisoquinoline (300 mg, 1.1 mmol) is dissolved in methylene chloride. Burgess' reagent (3 eq. 785 mg) is added and ~e solution is stirred for two 15 hours. The solution is poured into 10 % aqueous sodium carbonate and extracted. The organic layer is washed with water and then brine. Drying over sodium sulfate and solvent removal affords an oil [0~5589 = -202.64 (c = 1.89 chloroform). l'his is converted to the crystalline hydrochloride salt witb etheral hydrogen chloride and methanol, m.p. 325C (decomposition).
Preparation C18(b), EXAMPLE 12, (+)-10-cyano-1~2,3,4,4a,S,6,10b-octahydro-~rans-3N-20 propylbenzo[flisoquinoline, see CHART C, STEP 18, compound Cl9. Use the same procedureas above, for C18(a), only s~art with (+)-10-carboxamido-1,2,3,4,4a,5,6,10b-octahydro-Jrans-3N
-propylbenzo[f~isoquinoline.

The follow~ng altemative procedures are provided fnr the synthesis of some compounds.25 The following synthesis steps begin in place of step 13 and are numbered 131, 132 etc., see page S of CHART C.

Preparation C131, Example 13, (-)-10-Bromo-7-chloro-1,2,3,4,4a,~,6,10b-1rans-octahydro-3N-benzylbenzolfJisoquinoline, see CHART C, STEP 131, compound C132~ Begin with staning 30 materials for preparation C13 from STEP 13 above. Benzyl ch1oride (5.4 mL~ 45.4 mmol) is added to triethylamine ~6.6 mL, 47.6 mmol), (-)-l~bromo^7-chloro 1,2,3,4,4aS,6,10b-~rans-octahydrobenzo[flisoquinoline (13.0 g~ 43.24 mmol)~
and dime~ylformamide (90 mL~ at 0C. After 30 minutes, the ice bath is removed and the slurry stirred at room temperatur~ for two days. Water and e~her are added. The organic layer is washed 35 with water and brine and is dried with sodium sulfate to yield an amber oil.
[0~]25589--139.32 (c= 1.04~ MeOH).

211~ 2ii Notation comment. In the compounds of this series the preparations followed by a lower case (a) are where R = H, lower case (b) indicates R = CH3.

Preparation C132(a), Example 14, (-)-7-Chloro-10-sulfonamido-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-benzylbenzolfJisoquinoline, see CHART C, STEP 132, Compound C133, R = H.
tert-Butyllithium (8.0 mL, 1.7 M in pentane) is added to (-)-10-bromo-7-chloro-1,2,3,4,4a,5,6,10~
trans-octahydro-3N-berl2ylbenzo[flisoquinoline (2.58 g, 6.60 mmol) in THF (15 mL) at -78C.
After 10 minutes, sulfuryl chloride (0.8 mL, 9.90 mmol) is added in a quick dose and the cold bath 10 removed. After 1 hour, the solvents are removed under vacuum. THl~ (15 mL) is added and the mixture cooled on an ice bath and ammonia sah~rated THF (15 mL) added in a quick dose to the slurry, and the ice bath removed. Ammonium hdyroxide (10 mL) is then added. After 2 hours, water and ether are added. The organic layer is washed wi~ water and brine and dried over sodium sulfate to yield an ~nber foam, m.p. 97- 1~2C. [a]25589~ -158.2 (c= 0.56, MeOH).

Preparation Cl 32(b), Example 15, ~ 7-Chloro-10-methylsulfonamido-1,2,3,4,4a,~,6,10b-trans-octahydro-3N-benzylbenzolf]isoquinoline, see CHART C, STEP 132, Compound C133, R
= CH3. tert-Butyllithium (9.3 mL, 1.7 M in pentane) is added to (-)-l~bromo-7-chloro-1,2,3,4,4a,5.6,10~trans-octahydro-3N-benzylbenzo~f~isoquinoline (3.0 g, 7.68 mmol) in THF (7.5 20 mL) at -78C. After 10 mimltes, 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 I hour, the solvents are removed w~der vacuum. TH~ (15 mL) is added and methylamine saturated TH~; is added. After 50 minutes, water and ethyl acetate are added. The organic layer is washed with water and brine and dned over sodium sulfate to yield a yellow foam. The foam is flash chromatographed on a 19 x 2 cm silica 25 gel column and eluted with 10% me~ylene chloride and 25% ethyl acetate in hexane to yield a yellow foam, m.p. 99C. [oc]25589= -148.5D (c= 0.60, MeOH).

Preparation 133(a), ~xample 16, (-)-10-Sulfonamido-1,2.3,4,4a,5,6,10b-~rans-30 octahydrobenzolf]isoquinoline hydrochloride, see CHART C, STEP 133, Compound C134, R =
H. (-)-7-Chloro-l~sulfonamido-1,2,3.4,4a,5,6,10~trans-octahydro-3N-benzylbenzo-[f]isoquinoline (0.20 g, 0.51 mmol), ethanol (50 mL), and palladium hydroxide, 20% on carbon (0.40 g) are shaken under hydrogen (48 PSI) for 6 hours. The mixture is filtered through diatomaceous earth and solvents removed wlder vacuum to yield a white solid. 0.18 g. Recrystallization from ether and 35 methanol yields a pink solid. 216C m.p.

WO 93/08166 2 1 1 g ~ ~ Q PCl/US92/07314 Preparation 133(b), Ex~nple 17, (-,1-10-Methylsulfonamido-1,2,3,4,4a,5,6,10b-trans-octahydrobenzo[tlisoquino-line hydrochloride, see CHART C, STEP 133, Compound C134, R
CH3. (-)-7-Chloro- I O-methylsulfonamido- 1,2~3 ,4,4a,5,6, 1 Ob-trans-octahydro-3N-benzylbenzolf~isoquinoline (0.78 g, 1.93mmol), ethanol (50 mL). and palladium hydroxide. 20%
5 on carbon (0.69 g) are shaken under hydrogen (43 PSI) for 21 hours. The mixture is filtered through diatomaceous earth and solvents removed under vacuum to yield a pale foam, m.p. 95C.
a]2558~ -148.1 (c= 0.96).

Preparation 134(a), Example l 8, (-)-10-Sulfonan~ido-1,2,3,4,4a,~36,l0btrans-octahydro-3N-propylbenzolfJiso-quinoline, see CHART C, STEP 134, Compound C135, R = H.
Bromopropane (0.02 mL, 0.25 mmol) is added to (-)-10-sulfonamido-1,2,3,4,4a,5,6,10b-Jrans-octahydrobenzo[f~isoquinoline hydrochloride (0.077 g, 0.25 mmol) and triethylamine (0.08 mL, 0.56 mmol) in a~etonitrile (5 mL3 and DMF (2 mL). After heating at 80C for 4 hours, e~her and 15 aqueous sodium carbonate are added. The organic layer is washed with water and brine and dried over sodiurn sulfate to yield an amber oil.

Preparation 134(b), Example 19, ~ 10-Methylsulfonan~ido-1,2,3,4,4a,5,6,10b-~ns-octahydro-3N-propyl-benzo[flisQquinoline, see CHART C, STEP 134, Compound C135, R =
20 CH3. Bromopropane (0.05 mL, 0.50 mmol) is added to ~-)-10-methylsulfonamido-1,2,3,4,4a,5,6,10b-trans-octahyd~benzo[flisoquinoline hydrochloride (0.15 g, 0.50 mmol) and triethylarnine (0.14 mL, 1.00 rnmol) in acetonitrile (4 mL) and DMF ( I mL). After heating at 50C
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. g4- 100C. la]25589= -187.6 25 (c= 0.47). This foam is dissolved in methanol and ether, then hydrochloric acid in ether is added.
The solid is recrystallized from methanol and e~er to yield gray crystals, m.p. 299-301 C.

CHART C begins next page.

2 1 ~ 2 ~
WO 93/08166 PCI`/US92/07314 G~RT C (6-6-6 ring system) page 1 ~c"
~2 0 Step 1 l C

Rl x2 oa c a Step2 ~, R2 ~r c 3 ~tep3 (c~ntinued) WO 93/08166 2 1 1 ~ ~ 2 û Pcr/uS9~/07314 CHART C page 2 Step3 ~2 C 4 step 4 Rl~

R2 c 5 StepS

Rl~ `C

~2 Step 6 ....

(continued) '2 1 ~
WO 93/08166 Pcr/US92/~7314 .

C~ART C page 3 Step 6 Rl~OE C 7 Step~ I

~C~ ~ C~3 ~ O

Step8 R
~0 Step 9 (continued) . WO 93/08166 2 ~ ?
Pcr/US92/07314 CHQRT C page 4 Step 9 R~CN O~\c33 Sl;ep 10 c 10 R2 `N~C~O~ CH3 Stepll 1 R2 c 12 Step 12 (co~tinued) CHART C page 5 Step 12 1ll~) C 13 Step 130 Step13 /

c~ c N'C~3 Step 131 R~ C 14 ¦~

step 14 Cl c 132 ~ r Step 132 r Rz N~c~3 R~N

Step 15 Step 133 r .. R~IN
~ ~N~

(co~tinued) ¢~.~cl WO 93/08166 2 1 1 ~ !1 2 ~) PCr/US92/07314 C~ART C page 6 Step 15 ~ 3~&N C ~

, ~ N~c~3 R

Step 16 ~ \

R~ C ~D Cll3 Step 17~

R2 Rl~&N~cll3 Step 18 ~c~tlnued) 2 ~
WO 93/08166 PCI`/US92/07314 C~RT C page 7 Step 18 ~~C~;

Claims (31)

-53-

1. A compound of formula I, below, Formula I

wherein p and s are independently related and may be either 1 or 2, wherein R1 is a) -H, b) -Halo, c) -CN, d) -CO2H, -CO2R1-1, e) -CONH2, -CONHR1-1, -CON(R1-1)2.
g) -SH, -SR1-1, h) -SO2R1-1, i) -SO2NH2. -SO2NHR1-1, -SO2N(R1-1)2, j) -OR1-1 k) -OSO2CF3, -OSO2R1-1, l) -NH2, -NHR1-1, or -N(R1-1)2;
wherein R1-1 =
a) -H, except where p = 1 and s = 2 b) -(C1-C8 alkyl), c) -(C1-C8 alkenyl), d) -(C6 aryl), e) -(C3-C10 cycloalkyl), f) -5 and 6 member heterocyclics, g) -(C1-C8 alkyl)-(5 or 6 member heterocyclics) wherein R2 is a) -H, b) -Halo, c) -CN, d) -CF3 e) -SH, or -SR2-1;

wherein R2-1 =
a) -H, b) -(C1-C8 alkyl), c) -(C1-C8 alkenyl), d) -(C6 aryl), e) -(C3-C10 cycloalkyl), f) -5 or 6 member heterocyclics, g) -(C1-C8 alkyl)-(5 or 6 member heterocyclics) wherein R3 is a) -H, except where p = 1 and s = 2 b) -(C1-C8 alkyl), c) -(C1-C8 alkenyl), d) -(C6 aryl), e) -(C3-C10 cycloalkyl), f) -5 or 6 member heterocyclics, g) -(C1-C8 alkyl)-(5 or 6 member heterocyclics) or a pharmacologically acceptable salt thereof.

2. A compound of claim 1, wherein p - 2 and s = 1.

3. A compound of claim 2, wherein R1 is a) -Halo, b) -CN, c) -CONH2, -CONHR1-1, or -CON(R1-1)2.

4. A compound of claim 2, wherein R2 is a) -Halo, b) -CN, c) -CONH2, -CONHR2-1, or -CONR2-1.

5. A compound of claim 2, wherein R3 is a) -H, b) -(C1-C8) alkyl c) -(C1-C8) alkenyl d) -(C3-C10) cycloalkyl, e) -(C6-C12 aryl), f) 5 or 6 member heterocyclics, or a pharmacologically acceptable salt thereof.

6. A compound of claim 3, wherein R2 is a) -Halo, b) -CN, c) -CONH2, -CONHR2-1, or -CON(R2-1)2.

7. A compound of claim 6, wherein R3 is a) -H, b) -(C1-C8) alkyl c) -(C1-C8) alkenyl d) -(C3-C10) cycloalkyl, e) -(C6-C12 aryl).
f) 5 and 6 member heterocyclics, or a pharmacologically acceptable salt thereof.

8. A compound of claim 7 wherein R1 is CONH2.

9. A compound of claim 8 selected from, (-)-7-Chloro-10-carboxamido-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]is-oquinoline, (+)-7-Chloro-10-carboxamido-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]is-oquinoline, (-)-10-Carboxamido-1,2,3,4,4a,5,6,10b-octahydro-trans-3N-propylbenzo[f]isoquinoline.
or (+)-10-Carboxamido-1,2,3,4,4a,5,6,10b-octahydro-trans-3N-propylbenzo[f]isoquinoline.

10. A compound of claim 7 wherein R1 is CN.

11. A compound of claim 10 selected from (-)-7-Chloro-10-cyano-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]isoquinoline, (+)-7-Chloro-10-cyano-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]isoquinoline (-)-10-Cyano-1,2,3,4,4a,5,6,10b-octahydro-trans-3N-propylbenzo[f]isoquinoline, or (+)-10-Cyano-1,2,3,4,4a,5,6,10b-octahydro-trans-3N-propylbenzo[f]isoquinoline.

12. A compound of claim 7 wherein R1 is Halo, or H.

13. A compound of claim 12 selected from, (-)-10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]isoquinoline.
(+)-10-Bromo-7-chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]isoquinoline, (-)-7-Chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]isoquinoline, or (+)-7-Chloro-1,2,3,4,4a,5,6,10b-trans-octahydro-3N-propylbenzo[f]isoquinoline.

14. A compound of claim 1, wherein p = 1 and s = 2.

15. A compound of claim 14, wherein R1 is a) -Halo, b) -CN, c) -CONH2, -CONHR1-1, or -CON(R1-1)2.

16. A compound of claim 14, wherein R2 is a) -Halo, or b) -CN.

17. A compound of claim 14 wherein R3 is a) -(C1-C8) alkyl b) -(C1-C8) alkenyl c)-(C3-C10) cycloalkyl, d) -(C6 aryl), e) 5 or 6 member heterocyclics.

18. A compound of claim 15, wherein R2 is a) -Halo, or b) -CN, wherein R3 is a) -(C1-C8) alkyl b) -(C1-C8) alkenyl c) -(C3-C10) cycloalkyl, d) -(C6-C12 aryl), e) 5 and 6 member heterocyclics.

19. A compound of claim 18 wherein R1 is -CONH2, -CONHR1-1, or -CON(R1-1)2.

20. A compound of claim 19 selected from, (+)-trans-10-carboxamido-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine (-)-trans-10-carboxamido-5a,10b dihydro-3N n-propyl-6H-indeno[1,2-d]azepine (+)-trans-7-carboxamido-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine (-)-trans-7-carboxamido-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine.

21. A compound of claim 18 wherein R2 is CN.

22. A compound of claim 21 selected from (+)-trans-7-cyano-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine (-)-trans-7-cyano-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine.

23. A compound of claim 18 wherein R1 is OR3, R2 is Cl.

24. A compound of claim 23 selected from, cis-7-chloro-10-methoxy-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine trans-7-chloro-10-methoxy-5a,10b-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine.

25. A compound of claim 14, wherein R3 = H.

26. A compound of claim 25 selected from (+)-trans-10-carboxamido-5a,10b-dihydro-6H-indeno[1,2-d]azepine (-)-trans-10-carboxamido-5a,10b-dihydro-6H-indeno[1,2-d]azepine (+)-trans-7-carboxamido-5a,10b-dihydro-6H-indeno[1,2-d]azepine (-)-trans-7-carboxamido-5a,10b-dihydro-6H-indeno[1,2-d]azepine.

27. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1.

28. A pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and an effective amount of a compound of claim 2 - 28.

29. 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 claim 1 to a patient in need thereof.

30. 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 claim 2-28 to a patient in need thereof.

31. Use of a compound of any of claims 1 to 26, for the manufacture of a medicament for use in treating central nervous system disorders associated with serotonin and/or dopamine receptor activity.