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WO1996038435A1 - Agonistes de dopamine - Google Patents

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Publication number
WO1996038435A1
WO1996038435A1 PCT/US1996/007361 US9607361W WO9638435A1 WO 1996038435 A1 WO1996038435 A1 WO 1996038435A1 US 9607361 W US9607361 W US 9607361W WO 9638435 A1 WO9638435 A1 WO 9638435A1
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WIPO (PCT)
Prior art keywords
alkyl
solution
dihydroxy
dihydro
aminomethyl
Prior art date
Application number
PCT/US1996/007361
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English (en)
Inventor
Robert W. Schoenleber
Michael P. Deninno
Fatima Z. Basha
Paul P. Ehrlich
Richard J. Perner
Michael D. Meyer
James R. Campbell
Yvonne C. Martin
David M. Stout
John F. Debernardis
Howard E. Morton
Michael R. Michaelides
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Abbott Laboratories
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Publication of WO1996038435A1 publication Critical patent/WO1996038435A1/fr

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Definitions

  • This invention relates to novel compounds which are selective dopamine agonists useful for treating dopamine-related neurological, psychological, cardiovascular, cognitive and behavioral disorders.
  • Dopamine is an important neurotransmitter in the central nervous system (CNS), and also has several important roles in the peripheral nervous system such as in the control of the supply of blood to the kidneys and in autonomic ganglion transmission.
  • dopamine receptors in the CNS can be divided into two general categories, designated D-1 and D-2 receptors.
  • the division was originally based on biochemical and pharmacological differences between the two receptor types, but further evidence supporting this division has recently come from study of the molecular biology of dopamine receptors in the CNS.
  • the dopamine D-1 receptor is linked to the enzyme adenylate cyclase through a stimulatory G protein, such that stimulation of this receptor by dopamine or a dopamine D-1 receptor agonist causes an increase in the production of 3',5'-cyclic adenosine monophosphate (cAMP).
  • cAMP 3',5'-cyclic adenosine monophosphate
  • the D-2 receptor also regulates important functional activity within the CNS, although the biochemical events which follow stimulation of this receptor by dopamine or a D-2 receptor agonist are not as well understood.
  • Autoreceptors on dopaminergic neurons which have the pharmacological properties of D-2 receptors are thought to control both the firing rate of these cells as well as the release of dopamine from the nerve terminals. It is also known that stimulation of the D-2 receptors in the intermediate lobe of the pituitary gland causes a decrease in cAMP production and that stimulation of the D-2 receptors on the mammotrophs of the anterior pituitary gland suppresses prolactin secretion.
  • Dopaminergic neurons are also affected by and interact with other neurotransmitter systems in the CNS, as for example D-2 receptors on the cholinergic interneurons in the striatum (one of the components of the basal ganglia) regulating the release of acetylcholine from these cells.
  • Dopamine involvement has been proposed for several diverse neurological and psychological disorders.
  • One disorder involving dopamine is Parkinson's Disease.
  • Dopamine occurs at high concentration within the nerve terminals in the basal ganglia of the mammalian brain.
  • the loss of striatal dopamine was established as a chemical marker of Parkinson's Disease. This deficiency is still thought to be primary to the etiology of the disease state.
  • L-DOPA (3,4-dihydroxyphenylalanine), which is used in conjunction with a peripheral aromatic amino acid decarboxylase inhibitor and often supplemented with anticholinergic agents, has been shown to be useful in the treatment of Parkinson's Disease.
  • the response to L-DOPA is thought to be a result of the conversion of L-DOPA to dopamine within the striatum, and is linked to stimulation of both the D-1 and D-2 receptors.
  • L-DOPA therapy has led to the testing of other compounds capable of mimicking the post-synaptic receptor actions of dopamine.
  • Such direct-acting agents might offer the therapeutic advantages of greater potency, increased duration of action, or fewer side effects over L-DOPA.
  • bromocryptine the direct-acting dopamine agonist most widely used in the treatment of Parkinson's Disease, lowers the amount of L-DOPA required to achieve the maximal therapeutic response and allows for a delay in the onset of L-DOPA therapy.
  • the response to bromocryptine alone is not as great as that observed with L-DOPA.
  • schizophrenia Another disorder in which dopamine has been implicated is schizophrenia.
  • Psychoses are serious psychiatric illnesses characterized by abnormal behavior which may include delusions, hallucinations, violence, mania and serious long-lasting depression.
  • schizophrenia is the most common, involving disturbance of thought processes, hallucinations and loss of touch with reality.
  • the theory of schizophrenia as a disease of the CNS was first formahzed by Kraepelin and Bleuler in the early 1900's. It was not until chlorpromazine was discovered by Delay and Daniker in the early 1950's, however, that drug management of this disease was possible.
  • depressive conditions and related affective disorders result from a reduction in the central nervous system of certain biogenic amine neurotransmitters such as dopamine (D), noradrenaline (NA) and serotonin (5-HT).
  • Affective disorders are characterized by changes in mood as the primary clinical manifestation. Disturbances of mood are the most common psychiatric disorders in adults, with 18-23% of women and 8-11% of men experiencing at least one major depressive episode.
  • Currently-available antidepressant drugs work primarily by raising the levels of the biogenic amine neurotransmitters either by inhibition of the neuronal uptake of the neurotransmitters or by inhibition of the metabolic enzymes responsible for converting the biogenic amines to inactive metabolites.
  • a role for dopamine has been established in several other neurological functions, such as cognitive function and attention mechanisms. Animal studies implicate dopamine in attention-related behaviors involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. A therapeutic role in the treatment of cognitive impairment and attention deficit disorders has therefore been proposed and is under active investigation for compounds which mimic the receptor activity of dopamine.
  • Dopamine has been also used in the treatment of shock, congestive heart failure and renal failure. Stimulation of the peripheral D-1 receptors causes vasodilation, particularly in the renal and mesenteric vascular beds where large numbers of these receptors are found.
  • the utility of dopamine has been limited, however, by its ability to cause vasoconstriction at higher concentrations, presumably due to its secondary effects on adrenergic receptors and by its emetic effects due to peripheral D-2 stimulation.
  • Agents selective for the peripheral D-1 receptors may offer significant advantages over currently used treatments for these and other related disorders.
  • dopamine also has a central role in the brain's reward system. For example, it has been reported that animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist It was proposed that the animals would increase the amount of cocaine administered in order to maintain the elevated dopamine levels responsible for the drugs euphorigenic and reinforcing properties.
  • the dopamine D-1 agonist, SKF 38393 has been reported to decrease food intake by rats presumably by direct action of the drug on neural feeding mechanisms. Because of this interrelationship between dopamine and reward, dopaminergic agents could be useful for the treatment of substance abuse and other addictive behavior disorders including cocaine addiction, nicotine addiction and eating disorders.
  • Dopaminergic agents such as the compounds of the present invention that mimic the actions of dopamine and show selectivity for the different dopamine receptor subtypes are needed in order to obtain the anticipated physiological responses discussed above, separate from other possibly less desirable effects.
  • tetrahydronaphthalene derivatives of EP 0321968 are unsubstituted at the 3-position and are substituted on the amino group with an n-propyl group or an n-propyl and an additional phenoxyethyl group; the 1-aminomethyl tetrahydronaphthalene derivatives of EP 0325963 are substituted on the amino group with an aryl-substituted or heterocycle-substituted alkyl group; and in the 1-aminoalkyl-substituted isochroman and thioisochroman compounds of the French Patent, the amino group of the 1-amino alkyl group must be in a 6-membered ring containing one or two nitrogen atoms and is further substituted with a nitrogen substituent, an aryl group or a benzimidazole group.
  • dopaminergic compounds of the formula I as well as pharmaceutically acceptable salts, esters and amides thereof,
  • A is -O-, -S-, or -CR 2 R 8 -, where R 2 and R 8 are as defined below, preferably -O- ;
  • R1 is selected from hydrogen and a readily-cleavable group, as defined below; or is a catechol-protecting group, as defined below;
  • R 2 is selected from hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, halomethyl, haloethyl, aminomethyl and aminoethyl, or, taken together with R 5 and the atoms to which each is attached (as well as any intervening atoms) forms a 5- or 6-membered ring containing only one heteroatom, the nitrogen shown above in formula I;
  • R 3 is selected from:
  • carbocyclic-C 6 -C 10 -aryloxy-C 1 -C 5 -alkyl as defined below
  • carbocyclic-C 6 -C 10 -aryl-C 1 -C 5 -alkyl as defined below
  • Het-C 1 -C 5 -alkyl as defined below, and substituted Het-C 1 -C 5 -alkyl, as defined below,
  • R 4 is selected from hydrogen and C 1 -C 10 -alkyl, or, taken together with R 3 and the atom to which both are attached, forms a spirocyclo-C 3 -C 10 -alkyl ring, or, taken together with R 9 , forms a bond;
  • R5 is selected from :
  • R 6 is selected from hydrogen and C 1 -C 3 -alkyl; or, taken together with R5 and the atom to each is attached, forms a pyrrolidine ring;
  • R 7 is hydrogen or C 1 -C 5 -alkyl; or, taken together with R5 and the atoms to which each is attached (as well as any intervening atoms), forms a pyrrolidine ring; or, taken together with Y and the atoms to which each is attached (as well as any intervening atoms), forms a 5-, 6- or 7-membered carbocyclic ring;
  • R 8 is hydrogen or, taken together with R 10 , forms a bond
  • R 9 is hydrogen or, taken together with R 4 , forms a bond
  • R 10 is hydrogen or, taken together with R 8 , forms a bond
  • X is selected from hydrogen, halogen, methyl and ethyl
  • Y is selected from hydrogen, halogen, methyl and ethyl; or, taken together with R7 and the atoms to which each is attached (as well as any intervening atoms), forms a 5-, 6- or 7-membered carbocyclic ring, with the proviso that (i) X and Y are not both hydrogen; (ii) at least one of X and Y must be hydrogen when Y is not combined in a ring; and (iii) only one of the following combinations of groups and the atoms to which they are attached may be taken together to form a ring as described above: (a) R 2 and R 5 , (b) R 5 and R 6 , (c) R 5 and R 7 , (d) R 6 and R 7 , and
  • the compounds of formula I have the ability to bind and activate dopamine receptors in the central and peripheral nervous systems, thus mimicing the activity of dopamine, and are therefore expected to be useful in the treatment of dopamine-related neurological,
  • compositions which comprise a therapeutically-effective amount of the compound of formula I and a pharmaceutically-acceptable carrier or diluent
  • Representative of the compounds of the invention are those compounds of formula I in which A is -O- (thus, benzopyran dreivaties); R9 is hydrogen; and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , X and Y are as defined above.
  • preferred compounds include (i) those in which
  • R 3 is selected from C 4 -C 10 -alkyl, substituted C 1 -C 5 -alkyl, cyclo-C 3 -C 10 -alkyl, substituted cyclo-C 3 -C 10 -alkyl, carbocyclic-C 6 -C 10 -aryl, substituted carbocyclic-C 6 -C 10 -aryl, carbocyclic-C 6 -C 10 -aryl-C 1 -C 5 -alkyl, substituted carbocyclic-C 6 -C 10 -aryl-C 1 -C 5 -alkyl, Het, substituted Het, Het-C 1 -C 5 -alkyl, and substituted Het-C 1 -C 5 -alkyl, or, taken together with R4 and the atom to which R 3 and R 4 are both attached, forms a spirocyclo-C 3 -C 10 -alkyl ring, and/or (ii) those in which
  • [1R,3R] 1-Methylaminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2- benzopyran; [1R,3R] 1-Methylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2- benzopyran;
  • A is -O- or -S-;
  • R 1 is a catechol-protecting group
  • R 3 is selected from C 4 -C 10 -alkyl, substituted C 1 -C 5 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, cyclo-C 3 -C 10 -alkyl, carbocyclic-C 6 -C 10 -aryl, carbocyclicC 6 -C 10 -aryl- C 1 -C 5 -alkyl, and Het; and
  • R 4 is selected from hydrogen and C 1 -C 10 -alkyl
  • R 3 and R 4 and the carbon atom to which both are attached form a spiro- C 3 -C 10 -cycloalkyl ring.
  • N-formylaminoacetaldehyde dimethyl acetal in the presence of an acid catalyst selected from boron trifluoride etherate, zinc triflate, trimethylsilyl triflate and methanesulfonic acid.
  • an acid catalyst selected from boron trifluoride etherate, zinc triflate, trimethylsilyl triflate and methanesulfonic acid.
  • R 1 is a catechol-protecting group, with a strong base to form a chiral epoxide of the formula:
  • Certain compounds of this invention may possess one or more asymmetric centers and may exist in optically active forms. Additional asymmetric centers may be present in a substituent group, such as an alkyl group. Pure d -isomers and pure l -isomers, racemic mixtures of the isomers, and mixtures thereof are intended to be within the scope of this invention.
  • the stereochemistry at the 1- and 3-positions, as shown in formula I may independently be either [R] or [S] unless specifically noted otherwise. Chiral forms of certain compounds of this invention are contemplated and are specifically included within the scope of this invention.
  • alkanoyl as used herein, means a carbonyl group linked to an alkyl group, as defined below, of the size indicated.
  • alkanoylamino means an alkanoyl group, as defined above, of the size indicated, connected to an amino group.
  • alkenyl means straight or branched carbon chain radicals of the size indicated containing at least one carbon-to-carbon double bond. Representative of such radicals are ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, 2-ethylhexenyl, n-octenyl, 2,4- dimethylpentenyl, and the like.
  • alkoxy means an oxygen atom linked by an ether bond to an alkyl group, as defined below, of the size indicated.
  • alkoxy groups are methoxy, ethoxy, t- butoxy, and the like.
  • alkyl means a straight- or branched-chain carbon radical of the size indicated. Representative of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, t-butyl, 2-ethylhexyl, n-octyl, 2,4-dimethylpentyl, and the like.
  • alkylamino means an alkyl group, as defined above, of the size indicated, attached to an amino group. This definition includes the dialkylamino group. Examples include methylamino, ethylamino, dimethylamino, and the like.
  • alkynyl is used herein to mean straight or branched carbon chain radicals of the size indicated containing at least one carbon-to-carbon triple bond. Representative of such radicals are ethynyl, n-propynyl, butynyl, 3-ethylhexynyl, n-octynyl, 4-methylpentynyl, and the like.
  • amino acid and "dipeptide”, as used herein, refer, respectively, to a single ⁇ -amino acid or two alpha-amino acids joined by an amide (peptide) bond.
  • the amino acids may be any of the naturally-occurring amino acids such as, for example, valine, glycine, norvaline, alanine, glutamic acid, glutamine, aspartic acid, leucine, isoleucine, proline, methionine, phenylalanine, or the like, or they may be synthetic amino acids such as cyclohexylalanine, for example.
  • the amino acids may be in the L or D configuration or may be represented by a mixture of the two isomers. If not specified, amino acid substituents are optically active and have the L configuration.
  • Carbocyclic-C 6 -C 10 -aryl refers to aromatic radicals having six to ten carbon atoms in a single or fused ring system. Representative examples include phenyl, 1-naphthyl, 2-naphthyl, and the like.
  • carbocyclic C 6 -C 10 -aryloxy means an oxygen atom linked by an ether bond to a carbocyclic-C 6 -C 10 -aryl group, as defined above, and exemplified by phenoxy, benzyloxy, and the like.
  • carrier C 6 -C 10 -aryloxyalkyl means a carbocyclic C 6 -C 10 -aryloxy group, as defined above, attached to an alkyl group, as defined above.
  • carbocyclic arylalkyl means an alkyl group, as defined above, of the size indicated substituted with a carbocyclic-C 6 -C 10 -aryl group, as defined above.
  • Representative examples of carbocyclic-C 6 -C 10 -arylalkyl groups are benzyl and phenylethyl groups.
  • catechol-protecting groups refers to groups used to derivatize catechol hydroxyl oxygen atoms in order to prevent undesired reactions or degradation during a synthesis.
  • protecting group is well known in the art and refers to substituents on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H. Greene, Protective Groups in Organic Synthesis. John Wiley & Sons, New York (1981).
  • derivatizing groups may be selected from phenol-protecting groups or they may be selected from those groups which are particularly suitable for the protection of catechols because of the proximity of the two hydroxyl functions on the catechol ring.
  • catechol-protecting groups include dimethyl ethers, dibenzyl ethers, cyclohexylidene ketals, methylene acetals, acetonide derivatives, diphenylmethylene ketals, cyclic borate esters, cyclic carbonate esters, cyclic carbamates and the like.
  • cycloalkyl refers to a C 3 -and-up monocyclic, C 4 -and-up bicyclic or C 5 -and-up tricyclic cyclic group, of the size indicated, that are fully saturated or partially unsaturated, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, cycloctadiene, bicycloheptane, bicyclooctane, adamantane, norbomane, norbornene, camphene, pinene, and the like.
  • cycloalky1-alkyl means a cycloalkyl group of the size indicated attached to an alkyl of the size indicated, for example cyclo-C 3 -C 8 -alkyl-C 1 -C 10 -alkyl.
  • fused is used herein to mean two cyclic groups having at least two atoms in common to both rings.
  • haloalkyl refers to a alkyl group of the size indicated, as defined below, bearing at least one halogen substituent, for example chloroethyl and trifluoromethyl.
  • halo or halogen refer to bromo, chloro, fluoro and iodo.
  • Het refers to a three- to twelve-atom monocyclic or four- to twelve-atom bicyclic ring containing one-to-three heteroatoms independently selected from N, O and S, with the remaining atoms being carbon.
  • Het examples include furan, tetrahydrofuran, thiophene, pyrrolidine, pyridine, piperidine, isoxazole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran and the like.
  • Het-alkyl means a Het, as defined above, attached to an alkyl of the size indicated, for example, Het-C 1 -C 5 -alkyl.
  • readily-cleavable group is used herein to mean substituents which are rapidly cleaved in vivo, for example, by hydrolysis in blood, to yield the parent compounds of formula I.
  • Readily-cleavable groups include those substituents commonly referred to as "prodrug moieties". T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in Pro-drugs as Novel Delivery Systems. Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975).
  • Examples of readily-cleavable groups include acetyl, trimethylacetyl, butanoyl, methyl succinoyl, t-butyl succinoyl, ethoxycarbonyl,
  • spirocycloalkyl means a cycloalkyl ring, as defined above, of the size indicated bonded to another ring in such a way that a single carbon atom is common to both rings.
  • substituted alkenyl means an alkenyl group, as defined above, mono- substituted with cyclo-C 3 -C 8 -alkyl, carbocyclic C 6 -C 10 -aryl, amino, hydroxy, C 1 -C 4 -alkoxy or with a pyrrolidine, piperidine, pyridine, quinoline, isoquinoline, thiophene or isoxazole heterocycle.
  • substituted alkoxy means an oxygen atom linked by an ether bond to a substituted alkyl group, as defined below, of the size indicated.
  • substituted alkyl refers to an alkyl group, as defined above, of the size indicated, that may be mono- or independently di-substituted with a group selected from selected from halogen, hydroxy, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkyl amino, C 3 -C 8 - cycloalkyl and C 1 -C 4 -alkanoylamino.
  • substituted alkylamino means a substituted alkyl group, as defined above, of the size indicated, attached to an amine group.
  • substituted alkynyl means an alkynyl group mono-substituted with cyclo- C 3 -C 8 -alkyl, carbocyclic C 6 -C 10 -aryl, or with a Het as defined below.
  • substituted carbocyclic-C 6 -C 10 -a ⁇ yl means a carbocyclic-C 6 -C 10 -aryl group, as defined above, substituted with 1-to-5 non-hydrogen substituents, for example, halogen, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, or one phenyl group or one trifluoromethyl group in conjunction with 0-to-4 of the said non-hydrogen substituents.
  • substituted carbocyclic- C 6 -C 10 -arylalkyl means a substituted carbocyclic- C 6 -C 10 -aryl, as defined above, attached to an alkyl group, as defined above, of the size indicated.
  • substituted carbocyclic- C 6 -C 10 -aryloxy means an oxygen atom linked by an ether bond to a substituted carbocyclic C 6 -C 10 -aryl group, as defined above.
  • substituted carbocyclic C 6 -C 10 -aryloxyalkyl means a substituted carbocyclic C 6 -C 10 -aryloxy group, as defined above, attached to an alkyl group, as defined above.
  • substituted cycloalkyl means a cycloalkyl group, as defined above, of the size indicated, that may be mono- or di-substituted with a group selected from halogen, hydroxy, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkyl amino, and C 1 -C 4 -alkanoylamino.
  • substituted Het refers to a Het, as defined above, that may possess 1 to 3 substituents selected from halogen, hydroxy, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkyl amino, and C 1 -C 4 -alkanoylamino.
  • substituted Het-alkyl means a Het-alkyl group, as defined above, that may possess 1 to 3 substituents selected from halogen, hydroxy, C 1 -C 10 -alkoxy, amino, C 1 -C 4 - alkyl amino, and C 1 -C 4 -alkanoylamino.
  • administration refers to systemic use as when taken orally, parenterally, by inhalation spray, by nasal, rectal or buccal routes, or topically in dosage form unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
  • parenteral includes intravenous, intramuscular, and
  • salts are, within the scope of sound medical judgement suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio, effective for their intended use in the treatment of psychological, neurological, cardiovascular and addictive behavior disorders.
  • Pharmaceutically acceptable salts are well known in the art . For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in /. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of formula I, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulfate salts and the like.
  • Representative alkali or alkaline earth metal salts include sodium, calcium, potassium, magnesium salts and the like.
  • Examples of pharmaceutically acceptable, nontoxic amides of the compounds of formula I include amides derived from C 1 -C 6 -alkyl carboxylic acids wherein the alkyl groups are straight or branched chain, aromatic carboxylic acids such as derivatives of benzoic acid and heterocyclic carboxylic acids such as furan-2-carboxylic acid or nicotinic acid.
  • Amides of the compounds of formula I may be prepared according to conventional methods. It is understood that amides of the compounds of the present invention include amino acid and polypeptide derivatives of the amines of formula I.
  • the term "pharmaceutically acceptable carriers” means a non-toxic, inert solid, semi-solid or liquid filler, diluent encapsulating material or formulation auxiliary of any type.
  • Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator.
  • antioxidants examples include water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propy
  • a “therapeutically effective amount” of the dopaminergic agent is meant a sufficient amount of the compound to treat dopamine-related disorders at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidently with the specific compound employed; and like factors well known in the medical arts.
  • cognate disorder refers to disorders that are characterized by changes in mood as the primary clinical manifestation, for example, depression.
  • antipsychotic agent refers to drugs used extensively in the symptomatic management of all forms of schizophrenia, organic psychosis, the manic phase of manic depressive illness and other acute idiopathic illnesses and occasionally used in depression or in severe anxiety.
  • neuropsychiatric disorder characterized by inattention, impulsivity, distractibility and sometimes hyperactivity, which replaces the less formal diagnoses of hyperactivity syndrome, hyperkinetic syndrome, minimal brain dysfunction and specific learning disability.
  • the disorder is prevalent among pre-adolescent children and is reflected in poor school performance and social behavior and has been described in experimental reports of impaired perceptual, cognitive and motor function.
  • cognitive impairment refers to a deficiency in any of the aspects of the cognitive (information processing) functions of perceiving, thinking and remembering.
  • dopamine-related cardiovascular disorders refers to conditions which can be reversed or improved by administration of dopamine or a
  • dopaminergic agent either alone or in combination therapy with other classes of cardiovascular agents.
  • the usefulness of dopaminergic agents in cardiovascular diseases is based on the known, but incompletely understood, role of dopamine in the cardiovascular system, especially the effects of dopamine on the heart and the ability of dopamine to produce vasoconstriction while maintaining blood flow through renal and mesenteric beds.
  • other related, potential uses for dopaminergic agents which, because the role of dopamine in the cardiovascular system is presently incompletely defined, are still under investigation, for example use in renal failure.
  • dopamine-related neurological and psychological disorders refers to behavioral disorders, such as psychoses and addictive behavior disorders; affective disorders, such as major depression; and movement disorders such as Parkinson's Disease, Hunrington's Disease and Gilles de la Tourette's syndrome; which have been linked, pharmacologically and/or clinically, to either insufficient or excessive functional dopaminergic activity in the CNS.
  • miscellaneous indications for which dopaminergic agents have been found to be clinically useful are disorders characterized by vomiting, such as uremia, gastroenteritis, carcinomatosis, radiation sickness, and emesis caused by a variety of drugs; intractable hiccough and alcoholic hallucinosis.
  • Normal dopamine levels are those levels of dopamine that are found in the brains of control subjects and are usually measured as levels of the dopamine metabolites homovanillic acid (3-methoxy-4-hydroxyphenylacetic acid) and 3,4-dihydroxyphenylacetic acid.
  • Abnormal dopamine levels are those levels that are not within the range of dopamine levels found in the brains of control subjects.
  • substance abuse is used herein to mean periodic or continued self- administration of psychoactive substances in the absence of medical indications and despite the presence of persistent or recurrent social, occupational, psychological or physical problems that the person knows are caused by or may be exacerbated by continued use of the substance.
  • the total daily dose of the compounds of this invention administered to a host in single or in divided doses can be in amounts, for example, from 0.01 to 25 mg/kg body weight or more usually from 0.1 to 15 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in multiple doses or in a single dose of from 10 mg to 1000 mg.
  • the compounds of the present invention may be administered alone or in combination or in concurrent therapy with other agents which effect the dopaminergic system such as L- dopa, amantadine, apomorphine or bromocryptine; and with cholinergic agents, for example, benztropine, biperiden, ethopromazine, procyclidine, trihexylphenidyl and the like.
  • the compounds of the present invention may also be co-administered with agents, for example enzyme inhibitors, which block their metabolic transformation outside the CNS.
  • This invention also provides pharmaceutical compositions in unit dosage forms, comprising a therapeutically effective amount of a compound (or compounds) of this invention in combination with a conventional pharmaceutical carrier.
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubihty
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying abso ⁇ tion of a drug is to administer the drug as a solution or suspension in oil.
  • Injectable depot forms can also be made by forming microcapsule matrices of drugs and biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly-orthoesters and polyanhydrides.
  • the depot injectables can also be made by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release-controlling coatings.
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such exipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; sweetening, flavoring and perfuming agents.
  • the compounds of the present invention can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by
  • sterilizing agents in the form of sterile solid compositions which can dissolve in sterile water, or some other sterile injectable medium immediately before use.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art
  • They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of this invention are synthesized by reaction schemes I through XNI as illustrated below. It should be understood that Rl- R ⁇ as used herein correspond to the R groups identified by formula I.
  • the oxygens of the catechol groups can be derivatized with "protecting groups” or “leaving groups” which are known in the art and can be prepared by conventional methods. These derivatizing groups can be selected from among phenol derivatives and derivatives which are suitable to catechols because of the proximity of the two hydroxyl functions.
  • phenol derivatives are ethers, for example alkyl, alkenyl, and cycloalkyl ethers (such as methyl, isopropyl, t-butyl, cyclopropylmethyl, cyclohexyl, allyl ethers and the like); alkoxyalkyl ethers such as methoxymethyl or
  • alkylthioalkyl ethers such as methylthiomethyl ether; tetrahydropyranyl ethers, arylalkyl ethers (such as benzyl, o-nitrobenzyl, 9-anthrylmethyl, 4- picolyl ethers and the like); trialkylsilyl ethers such as trimethylsilyl, triethylsilyl, t- butyldimethylsilyl ethers and the like; alkyl esters such as acetates, propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates and the like; substituted alkyl esters such as 3- (methoxycarbonyl)propionate, 3-aminopropionate, 3-(t-butoxycarbonyl)propionate and the like; carbonates such as methyl ethyl, 2,2,2-trichloroethyl, vinyl,
  • carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl, and the like; and sulfonates such as methanesulfonate, trifluoromethanesulfonate, toluenesulfonate and the like.
  • catechol derivatives include cyclic acetals and ketals such as methylene acetal, acetonide derivatives, cyclohexylidene ketal, diphenylmethylene ketal and the like; cyclic esters such as borate esters, cyclic carbonate esters and the like.
  • the condensation of amino groups (such as those present in the certain of the compounds of this invention) with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimide) method, the active ester method ( p-nitrophenyl ester method, ⁇ -hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in "Peptide Synthesis” Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).
  • branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary.
  • the protecting groups for amino groups which can be used involve, for example,
  • benzyloxycarbonyl (Z), o-chloro-benzyloxycarbonyl ((2-C1)Z), p-nitrobenzyloxycarbonyl (Z(NO2)), p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc), t- amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4- biphenyl)-2-propyloxy carbonyl (Bpoc), 9-fluorenylmethoxycarbonyl (Fmoc),
  • Msc methylsulfonylethoxy carbonyl
  • Mpt diphenylphosphinothioyl
  • Mpt dimethylphosphinothioyl
  • protecting groups for carboxyl groups involve, for example, benzyl ester (OBn), cyclohexyl ester, 4-nitrobenzyl ester (OBnNO2), t-butyl ester (OtBu), 4- pyridylmethyl ester (OPic) and the like.
  • the guanidino group (NG ) in arginine may be protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-dimethyl- benzenesulfonyl (Mts) and the like
  • the thiol group in cysteine may be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetomidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBn, 2,4,6,-trimethylbenzyl (Tmb) and the like
  • the hydroxy group in serine may be protected with benzyl (Bn), t-butyl, acetyl, tetrahydropyranyl (THP) and the like.
  • the compounds of formulae I A and I B are synthesized by the method discussed herein.
  • 2,3-Dihydroxybenzaldehyde which has the two catechol hydroxy groups protected by, for example, alkyl groups preferably methyl groups
  • a substituted acetic acid derivative such as phenyl acetic acid
  • a dehydrating agent such as acetic anhydride
  • a proton acceptor such as triethylamine (TEA)
  • the carboxylic acid (or acid derivative such as the methyl or ethyl ester) of compound 2 is reduced by a reducing agent such as lithium aluminum hydride (LAH) preferably in an ether solvent such as tetrahydrofuran (THF).
  • LAH lithium aluminum hydride
  • THF tetrahydrofuran
  • the leaving group ability of the hydroxyl group of compound 3 is enhanced by derivatizing it with, for example, methanesulfonyl chloride, in the presence of a proton acceptor such as TEA, and it is then converted to the cyano compound 4 by nucleophilic displacement with a salt of cyanic acid such as sodium cyanide in a polar solvent such as dimethyl sulf oxide (DMSO).
  • DMSO dimethyl sulf oxide
  • the cyano group is hydrolyzed to the corresponding carboxylic acid group under basic conditions using, for example, aqueous sodium hydroxide, and the naphthalenone derivative
  • Compound I A is produced when the catechol hydroxyl groups of compound 7 are deprotected with, for example, boron tribromide or boron trichloride in an inert solvent such as dichloroethane or methylene chloride.
  • Compound 7 is also hydrogenated to the corresponding tetrahydronaphthalene derivative in the presence of a catalyst such as palladium or platinum on carbon and then deprotected with e.g. boron tribromide or boron trichloride to produce IB.
  • R ⁇ is phenyl or cyclohexyl and X is bromo or chloro.
  • the compounds of formula I are alternately synthesized by the method discussed herein.
  • 2,3-Dihydroxybenzaldehyde with both the catechol hydroxyl protected as described in Example I and the aldehyde group derivatized as its dithiane is treated with a base such as n- butyl lithium to generate the anion (compound 8), and condensed with an alpha-beta unsaturated acid derivative such as ethyl cinnamate in the presence of dimethyl-2- imidizolidinone to produce compound 9.
  • the dithiane group is removed from compound 9 by treatment with hydrogen in the presence of a catalyst such as Raney nickel and converted to compound 5 as described in Scheme LA.
  • Compound 5 is further converted to IA and IB as described in Scheme IA.
  • the compounds of formulae II A and ⁇ B are prepared by the method illustrated in Scheme H
  • the naphthalenones of formula 5 are treated sequentially with a suitable base such as lithium bis(trimethylsilyl)amide and a haloacetic acid ester, for example ethyl bromoacetate, to afford the compounds of formula 10.
  • a suitable base such as lithium bis(trimethylsilyl)amide and a haloacetic acid ester, for example ethyl bromoacetate
  • Compounds of formula 10 are converted to compounds of formula 11 by treatment with diethylaluminum cyanide under anhydrous conditions, followed by cyclization in aqueous mineral acid, for example aqueous hydrochloric acid.
  • Compounds of formula 11 are reduced using a suitable reagent such as LAH followed by elimination with an acid such as hydrogen chloride in isopropanol to afford compounds of formula 12.
  • Compounds of formula 12 are treated with a suitable reagent for removal of the cate
  • compounds of formula 11 are converted to compounds of formula 13 by treatment with a mineral acid in anhydrous alcohol.
  • the compounds of formula 13 are, in turn, converted to compounds of formula 14 by treatment with magnesium followed by aqueous mineral acid and reduction using a suitable reagent such as LAH.
  • the compounds of formula 14 are then treated with a suitable reagent for the removal of the catechol protecting groups, for example boron tribromide to afford the compounds of formula II B.
  • Naphthalenones of formula 5 are alkylated to afford the compounds of formula 15 by treatment with a suitable base(for example lithium bis(trimethylsilyl)amide and a suitable alkylating agent such as allyl bromide.
  • the compounds of formula 15 are converted to the compounds of formula 16 by sequential treatment with trimethylsilyl cyanide and a suitable reducing agent such as LAH.
  • the compounds of formula 16 are, in turn, cyclized to the compounds of formula 17 by treatment with a suitably reactive carbonic acid derivative such as 1,1'-carbonyldiimidazole.
  • Compounds of formula II I A are prepared by reduction of compounds of formula 17 with a suitable reagent (for exampll by hydrogenation using a suitable catalyst such as palladium on carbon), followed by treatment with a suitable reagent for removal of the catechol protecting groups such as boron tribromide resulting in simultaneous elimination of carbon dioxide to afford the desired amines.
  • a suitable reagent for exampll by hydrogenation using a suitable catalyst such as palladium on carbon
  • Compounds of formula III B are prepared by hydrogenation of compounds of formula 17 using a suitable catalyst such as palladium hydroxide on carbon, followed by treatment with a suitable reagent for removal of the catechol protecting groups such as boron tribromide.
  • a suitable catalyst such as palladium hydroxide on carbon
  • Compounds of formula 20 are converted to compounds of formula III D by treatment with 4.5 equivalents of boron tribromide.
  • Compounds of formula 20 are converted to compounds of formula II I E by reductive opening of the oxazolidinone ring followed by treatment with a suitable reagent for removal of the catechol protecting groups such as boron tribromide.
  • a catechol (compound 22 wherein Rl is selected from alkyl groups such as methyl or both Rl groups together form a spiro cycloalkyl group such as cyclohexyl) is reacted in the presence of a base, such as n-butyl lithium, with an epoxide such as compound 23 (wherein R 4 is hydrogen and R 3 is preferably selected from cyclohexyl, phenyl, ethyl, p- methoxyphenoxymethyl, phenoxymethyl, o-phenylphenoxymethyl, p-t-butylphenoxymethyl, p-bromophenoxymethyl, adamantyl, benzyl, phenylethyl, n-octyl, n-hexyl, 1-hex-5-enyl, n- decyl, t-butyl or benzyloxy
  • Compound 24 can be oxidized to the co ⁇ esponding ketone with an oxidizing agent such as pyridinium chlorochromate (PCC) and the resultant ketone can be stereoselectively reduced with, for example, B-chlorodiisopinocampheylborane (as described in Example 46) to give the optically active isomers of compound 24.
  • PCC pyridinium chlorochromate
  • Compound 24 is condensed with a bromoaldehyde such as bromoacetaldehyde dimethyl acetal or 3-bromopropionaldehyde dimethyl acetal to form the substituted benzopyran derivative 26.
  • Compound 26 is converted to compound 27 by treatment with a nucleophilic azide such as lithium azide in a polar solvent such as dimethyl formamide, followed by reduction of the azido compound , for example with LAH.
  • Compound 27 is converted to IV A by generation of the amine salt in acidic solution and deprotection of the catechol hydroxyl groups in acid solution.
  • Compound 27 is converted to compound TV B by treatment with ethyl formate followed by reduction with, for example LAH and generation of the amine salt with deprotection of the catechol hydroxyl groups in acidic solution.
  • Compound 26 is converted to IV C by treatment with an amine such as allyl amine, cyclopropylamine or py ⁇ olidine, followed by deprotection of the catechol hydroxyl groups and generation of the amine salt in acidic solution.
  • an amine such as allyl amine, cyclopropylamine or py ⁇ olidine
  • Compounds of formula 30 are condensed with N-formylamino-acetaldehyde dimethyl acetal in the presence of a catalyst selected from boron trifluoride etherate, zinc triflate, trimethylsilyl triflate, methanesulfonic acid, p-toluenesulfonic acid and polyphosphoric acid to afford the isochromans of formula 31.
  • a catalyst selected from boron trifluoride etherate, zinc triflate, trimethylsilyl triflate, methanesulfonic acid, p-toluenesulfonic acid and polyphosphoric acid to afford the isochromans of formula 31.
  • the formyl group is removed and replaced with a t- butyloxycarbonyl protecting group and the hydroxy group is deprotected preferably by hydrogenolysis to afford the compounds of formula 32.
  • Compounds of formula V A are prepared by removal of the amino and catechol protecting groups from the compounds of formula 32 in acidic solution.
  • Compounds of formula V B are prepared from the compounds of formula 32 by the following sequence of reactions: activation of the hydroxymethyl group, for example by reaction with methanesulfonyl chloride; displacement with a nucleophilic azide such as lithium azide to give the azidomethyl compound; followed by reduction of the azido group to give the compounds of formula 33 and deprotection of the amine and the catechol hydroxyls with an acid such as hydrochloric acid in alcohol.
  • Compounds of formula V C are prepared from the compounds of formula 33 by acylation of the free amino group followed by simultaneous removal of the amine and catechol protecting groups in acidic solution.
  • compounds of formula 31 are converted to compounds of formula 34 by hydrogenolysis followed by activation of the hydroxymethyl group, for example by reaction with methanesulfonyl chloride and displacement with a nucleophilic azide such as lithium azide.
  • the compounds of formula 34 are, in turn, converted to compounds of formula V D by reduction of the formyl group and the azido group followed by removal of the catechol protecting groups in acidic solution.
  • the compounds of formula 34 are also converted to the compounds of formula V E by reduction of the azido group, formylation of the free amino, simultaneous reduction of both formyl groups to methylamino groups and treatment with a suitable reagent for the removal of the catechol protecting groups.
  • compounds of formula 32 are converted to compounds of formula V F by activation of the 3-hydroxymethyl group, for example by reaction with methanesulfonyl chloride followed by displacement with a nucleophilic amine, NHR 9 R 10 , in which R 9 and R 10 are independently selected from H and lower alkyl or R 9 and R 10 together form a ring containing a nitrogen atom such as py ⁇ olinyl or piperidinyl or morpholino, followed by deprotection of the amino group and the catechol hydroxyls in acidic solution.
  • a nucleophilic amine NHR 9 R 10
  • R 9 and R 10 are independently selected from H and lower alkyl or R 9 and R 10 together form a ring containing a nitrogen atom such as py ⁇ olinyl or piperidinyl or morpholino
  • Chiral compounds may be prepared according to Scheme VI B, wherein compounds of formula 22, wherein R1 is as defined in Scheme IV, are converted into compounds of formula 38 by treatment with a strong base, such as n-butyl lithium, followed by reaction with chiral epichlorohydrin.
  • the chiral compounds of formula 38 are converted into the chiral epoxides of formula 38 A by treatment with a strong base, such as NaOH or KOH in a polar organic solvent, such as a mixture of ether and alcohol.
  • the chiral 38A is then reacted with an organometallic compound, for example, an alkyl magnesium halide, an organocuprate or a lithium acetyhde, for example, in a non-polar organic solvent, to prepare the chiral alcohol of formula 38B.
  • the compound 38B is reacted with N-formylaminoacetaldehyde dimethyl acetal in the presence of an acid catalyst as described in Scheme XVIA below, followed by hydrolysis of the formyl group to give chiral compounds of formula 39.
  • Compounds of formula 39 can be either hydrolyzed or reduced followed by conversion to the HCl salt to give certain chiral compounds of formula NIB directly.
  • the formyl group can be replaced with an amino protecting group and the intermediate further modified to give other compounds of formula I, for example as illustrated in Scheme N above.
  • cyanohydrin by treatment with a nucleophilic cyano derivative such as trimethylsilyl cyanide in the presence of a catalyst such as aluminum trichloride.
  • the cyanohydrin is dehydrated to the a,b-unsaturated nitrile by treatment with a dehydrating agent such as TFA/p-toluenesulfonic acid and the unsaturated nitrile reduced to the saturated nitrile (compound 46) by treatment with a reducing agent such as sodium borohydride.
  • the nitrile group is hydrolyzed to a carboxylic acid group (compound 47) and the acid converted to the N-methoxy-N-methyl amide 48 by sequential treatment with an activating agent such as oxalyl chloride, to generate the acid chloride, and N-methoxymethylamine.
  • an activating agent such as oxalyl chloride
  • Compound 48 is converted to a mixture of the diastereomeric pyrrolidinyl derivatives 49 and 50 by treatment with 2,2,5,5-tetramethyl-1-aza- 2,5-disilacyclopentane-1-propyl magnesium bromide (by the procedure given in Tetrahedron Letters 25:5271-5271-4 (1984)) followed by reduction with a reducing agent such as sodium borohydride, and the diastereomers are separated chromatographically.
  • the separated isomers 49 and 50 are converted to IX A and IX B, respectively, by treatment with boron trihalide, preferably boron tribromide.
  • the compounds X A and X B are synthesized by the method discussed herein.
  • R 1 - R 3 are defined in Scheme I.
  • Compound 5 is converted to compound 51 by treatment with dimethyl succinate in the presence of a base such as potassium t-butoxide.
  • Compound 51 is reduced to the co ⁇ esponding 1,2,3,4-tetrahydronaph-thalene and the tricyclic ring system is formed by treating compound 51, with a dehydrating agent such as polyphosphoric acid.
  • a dehydrating agent such as polyphosphoric acid.
  • Four isomeric products are obtained.
  • Two of the isomers, compounds 52 and 53 are carried on to X A and X B, respectively.
  • Reduction of the 3-keto group,of compounds 52 and 53 with, for example hydrogen in the presence of a catalyst such as palladium on carbon support is followed by hydrolysis of the ester in basic solution to give compounds 54 and 55, respectively.
  • Compounds 54 and 55 are each treated with diphenylphosphoryl azide and benzyl alcohol in the presence of a base such as triethylamine to give the carbobenzyloxy protected amino derivatives, which are deprotected by hydrogenolysis using, for example, palladium on carbon support as a catalyst, and demethylation using, for example, boron tribromide to give X A and X B.
  • a base such as triethylamine
  • R 1 - R 3 are defined in Scheme I.
  • Compound 5 is converted to the ⁇ -bromoketone by treatment with a brominating agent such as phenyltrimethylammonium tribromide.
  • a brominating agent such as phenyltrimethylammonium tribromide.
  • the bromide undergoes nucleophilic displacement for example, with the anion of thiophenol to give the
  • ⁇ -thiophenylketone compound 56 The ketone is reduced to the alcohol with a reducing agent such as sodium borohydride and the hydroxy group is eliminated with a dehydrating agent such as p-toluenesulfonic acid to give the thio-enolether.
  • the sulfur atom of the thio-enolether is oxidized to the sulfoxide with an oxidizing agent such as mCPBA to give compound 57.
  • the amine component is made by a nucleophilic displacement on chloromethylrrimethylsilane by an amine (compound 58), such as benzylamine.
  • the imine is formed by treatment of the amine with an aldehyde such as formaldehyde and then an alcohol, such as methanol, is added to form the alkoxymethyl amine compound 60.
  • Compound 60 is then reacted with the sulfoxide (compound 57) in the presence of an acid, such as TFA to generate the azomethine ylid in situ which traps the activated double bond of the a, b-unsaturated sulfoxide to give a 1,3-dipolar addition adduct which, on heating, spontaneously undergoes elimination to give the cyclization/elimination product compound 61.
  • the nitrogen can be deprotected by treatment with an acylating agent such as l-chloroethylchloroformate followed by acyl group removal with a nucleophile, such as methanol to give compound 62.
  • an acylating agent such as l-chloroethylchloroformate
  • a nucleophile such as methanol
  • the catechol is deprotected by treatment with a boron trihalide, preferably boron tribromide to give XI.
  • the compounds of formulae XII A, XII B and XII C are synthesized by the methods described herein.
  • R 1 and R 3 are defined in Scheme I.
  • Compounds of the formula 12 are reduced by catalytic hydrogenation using a suitable catalyst such as palladium hydroxide to afford the compounds of formula 63.
  • the compounds of formula 63 are treated with a suitable reagent for protecting the amino group, for example benzyloxycarbonyl chloride, followed by a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride to afford the compounds of formula 64.
  • the compounds of formula 64 are, in turn, cyclized by treatment with a suitable base for example sodium hydride in DMF and deprotected with acid, for example by treatment with hydrogen bromide in acetic acid, to afford the compounds of formula XII B.
  • a suitable base for example sodium hydride in DMF
  • acid for example by treatment with hydrogen bromide in acetic acid
  • the compounds of formula 12 are converted to the compounds of formula 65 by treatment with a suitable reagent for protecting the amino group, for example benzyloxycarbonyl chloride, followed by a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride to afford the compounds of formula 65.
  • a suitable reagent for protecting the amino group for example benzyloxycarbonyl chloride
  • a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride
  • the compounds of formula 65 are, in turn, cyclized by treatment with a suitable base for example sodium hydride in DMF and deprotected with acid, for example by treatment with hydrogen bromide in acetic acid, to afford the compounds of formula XII A.
  • the compounds of formula 11 are treated with a suitable reducing agent such as LAH to afford the compounds of formula 66.
  • the compounds of formula 66 are treated with an appropriately reactive carbonic acid derivative, for example carbonyl diimidazole to afford the oxazolidinones of formula 67.
  • the compounds of formula 67 are reduced by catalytic hydrogenation using a suitable catalyst such as palladium hydroxide to afford the compounds of formula 68.
  • the compounds of formula 68 are treated with a suitable reagent for protecting the amino group, for example benzyloxycarbonyl chloride, followed by a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride to afford the compounds of formula 69.
  • the compounds of formula 69 are, in turn, cyclized by treatment with a suitable base for example sodium hydride in DMF and deprotected with acid, for example by treatment with hydrogen bromide in acetic acid, to afford the compounds of formula XII C.
  • a suitable base for example sodium hydride in DMF
  • acid for example by treatment with hydrogen bromide in acetic acid
  • the compounds of formulae X III A and XIII B are synthesized by the methods described herein.
  • R 1 and R 3 are defined in Scheme I.
  • the compounds of formula 20 are treated with a suitable acid such as hydrogen chloride in a suitable solvent, for example isopropyl alcohol or ethyl alcohol or diethyl ether, in order to open the oxazolidinone ring with the elimination of carbon dioxide.
  • the resultant amino alcohols are treated with a suitable reagent for protecting the amino group, for example benzyloxycarbonyl chloride, followed by a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride to afford the compounds of formula 70.
  • the compounds of formula 70 are, in turn, cyclized by treatment with a suitable base for example sodium hydride in DMF and deprotected with acid, for example by treatment with hydrogen bromide in acetic acid, to afford the compounds of formula Xm A.
  • the compounds of formula 21 are treated with a suitable reagent for protecting the amino group, for example benzyloxycarbonyl chloride, followed by a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride to afford the compounds of formula 71.
  • a suitable reagent for protecting the amino group for example benzyloxycarbonyl chloride
  • a suitable reagent for activating the hydroxyl group such as methanesulfonyl chloride
  • the compounds of formula 71 are, in turn, cyclized by treatment with a suitable base for example sodium hydride in DMF and deprotected with acid, for example by treatment with hydrogen bromide in acetic acid, to afford the compounds of formula X II I B.
  • the compounds of formulae XTV A and XTV B are synthesized by the methods described herein.
  • Compounds of formula 5 are converted to compounds of formula 72 by treatment with dimethyl malonate in the presence of a base such as potassium t-butoxide.
  • the tricyclic ring system is formed by treating a compound of formula 72, with an acid such as polyphosphoric acid, followed by reduction of the keto group with, for example, triethylsilane in trifluoroacetic acid to afford a compound of formula 73.
  • Hydrolysis of the ester group in basic solution affords compounds of formula 74.
  • the compounds of formula 72 are reduced by catalytic hydrogenation using a suitable catalyst such as palladium hydroxide to afford the compounds of formula 75.
  • the compounds of formula 75 are, in turn, converted to the compounds of formula XIV B by the same series of chemical tranformations described above for the conversion of compounds of formula 72 to compounds of formula XIV A.
  • the compounds of formulae XN A and XN B are synthesized by the methods described herein.
  • R 1 and R 3 are defined in Scheme I.
  • the compounds of formula 5 are converted to compounds of formula 51 by treatment with dimethyl succinate in the presence of a base such as potassium t-butoxide.
  • the compounds of formula 51 are, in turn, treated with a suitable reducing agent for reducing the acid, for example borane, to afford the co ⁇ esponding hydroxy compounds of formula 78.
  • the compounds of formula 78 are treated with a suitable reagent to activate the hydroxyl group, for example methanesulfonyl chloride, followed by displacement with a nucleophic cyano derivative such as sodium cyanide to afford the compounds of formula 79.
  • the rricyclic ring structure is formed by an intramolecular Houben-Hoesch reaction using hydrogen chloride and zinc dichloride to give the compounds of formula 80.
  • Reduction of the keto group using, for example, triethylsilane in trifluoroacetic acid, followed by hydrolysis of the ester group in basic solution affords compounds of formula 81.
  • Compounds of formula 81 are treated with diphenylphosphoryl azide and benzyl alcohol in the presence of a base such as triethylamine to give the carbobenzyloxy protected amino derivatives, which are deprotected along with the catechol hydroxyls using, for example, hydrogen bromide in acetic acid, to give XN A.
  • the compounds of formula 78 are reduced by catalytic hydrogenation using a suitable catalyst such as palladium hydroxide to afford the compounds of formula 82.
  • the compounds of formula 82 are, in turn, converted to the compounds of formula XV B by the same series of chemical tranformations described above for the conversion of compounds of formula 78 to compounds of formula XIV A.
  • Scheme XVIA
  • Reaction Scheme XVIA is a novel and practical method for ring closure in the synthesis of the isochroman and thioisochroman compounds of the present invention.
  • Compounds of the formula 24 are condensed with ⁇ -formylamino-acetaldehyde dimethyl acetal in the presence of an acid catalyst to afford the compounds of formula XVIA.
  • the reaction is carried out in an inert solvent for example a chlorinated solvent such as methylene chloride or 1,2-dichloroethane, an ether solvent such as diethyl ether or THF, or a polar aprotic solvent such as acetonitrile.
  • the reaction is carried out in the temperature range of from about 0°C to about 100°C.
  • the prefe ⁇ ed reaction temperature is determined by the choice of solvent the choice of catalyst and the amount of catalyst present In general, reactions in chlorinated solvents are carried out at lower temperatures than reactions in more polar solvents and larger amounts of catalyst require lower reaction temperatures.
  • the formylamino reagent (compounds of formula 86) is present in the reaction mixture at from about 1 to about 4 equivalents, preferably from about 1.5 to about 2.0 equivalents.
  • the catalyst is preferably selected from boron trifluoride etherate, trimethylsilyl triflate, zinc triflate, polyphosphoric acid, methanesulfonic acid and p-toluene sulfonic acid. The amount of catalyst present in the reaction mixture depends on the catalyst used, the solvent and reaction temperature.
  • the catalyst is present in the range of from about 1 mole % to about 3 equivalents. Most preferably the reaction is carried with either 1 mole % trimethylsilyl triflate in refluxing acetonitrile or with 5 mole % boron trifluoride etherate in refluxing acetonitrile. The reactions are monitored by TLC analysis to determine the optimum reaction time for good yields with minimum product degradation and this time varies with choice of solvent, catalyst and reaction temperature.
  • the compounds of formula XVI A are valuable intermediates in the synthesis of the compounds of formula I in which A is an oxygen or a sulfur atom (isochromans and thioisochromans).
  • Compounds of formula XVI can be either hydrolyzed or reduced to give certain compounds of formula I directly.
  • the formyl group can be replaced with an amino protecting group and the intermediate further modified to give other compounds of formula I, for example as illustrated in Scheme V below.
  • Compounds of formula XVI A can be either hydrolyzed or reduced to give certain compounds of formula I directly.
  • the process illustrated in Scheme XVIB is a practical method for preparing isochroman or thioisochroman compounds substituted with py ⁇ olidine at the 1 -position.
  • the compounds of formula 24 are condensed with the dimethyl acetal of prolinaldehyde in the presence of an acid catalyst to afford the compounds of formula XVI B.
  • Chiral or racemic proline aldehyde may be used.
  • the reaction is carried out in an inert solvent for example a chlorinated solvent such as methylene chloride or 1,2-dichloroethane, an ether solvent such as diethyl ether or THF, or a polar aprotic solvent such as acetonitrile.
  • the reaction is carried out in the temperature range of from about 0°C to about 100°C.
  • the prefe ⁇ ed reaction temperature is determined by the choice of solvent, the choice of catalyst and the amount of catalyst present. In general, reactions in chlorinated solvents are carried out at lower temperatures than reactions in more polar solvents and larger amounts of catalyst require lower reaction temperatures.
  • the formylamino reagent (compounds of formula 86) is present in the reaction mixture at from about 1 to about 4 equivalents, preferably from about 1.5 to about 2.0 equivalents.
  • the catalyst is preferably selected from boron trifluoride etherate, trimethylsilyl triflate, zinc triflate, polyphosphoric acid, methanesulfonic acid and p-toluene sulfonic acid.
  • the amount of catalyst present in the reaction mixture depends on the catalyst used, the solvent and reaction temperature. Generally, the catalyst is present in the range of from about 1 mole % to about 3 equivalents. Most preferably the reaction is carried with either 1 mole % trimethylsilyl triflate in refluxing acetonitrile or with 5 mole % boron trifluoride etherate in refluxing acetonitrile. The reactions are monitored by TLC analysis to determine the optimum reaction time for good yields with minimum product degradation and this time varies with choice of solvent catalyst and reaction temperature.
  • the compounds of formula XNI B are valuable intermediates in the synthesis of the compounds of formula I in which A is an oxygen or a sulfur atom (isochromans and thioisochromans).
  • Compound 88 is selectively oxidized to the aldehyde 89, prefe ⁇ ably by reaction with sulfur trioxide-pyridine, triethylamine and DMSO.
  • Compound 89 is reacted with LiTMS- dithiane to form the thiane derivative of the aldehyde.
  • This intermediate is made to undergo an internal ring closure by reacting it with HgCl 2 , 5% aqueous methyl cyanide to produce compound 90.
  • the tetralone compound 90 is then converted to the aminomethyl compound 91 by reactions described in Scheme I for conversion of compound 5 to compound 7.
  • Compound 91 may then be converted to the free catechol compound XVH A as described in Scheme I, or it may be converted to compound 92, where R 5 is not hydrogen, as described in Scheme IV, or by additional alkanoylation followed by reduction to give the amino-disubstituted compounds similar to compounds IVC as described in Scheme IV.
  • compound 97 is converted into compound 100 by catalytic hydrogenation over a catalyst as described earlier, which may then be deprotected to give compound XV II I D.
  • Compound 99 may be formed by the alkylation of compound 100 or alternately by catalytic reduction of compound 98. Deprotection of compound 99 produces compound
  • Step 1 (E,Z)-3-(2',3'-Dimethoxyphenyl)-2-phenylpropenoic acid
  • the reaction mixture was heated at reflux temperature for 2 h and then cooled to 0°C .
  • the reaction was quenched by the sequential addition of 15 mL of water, 15 mL of 15% aqueous sodium hydroxide solution and 45 mL of water.
  • Step 4 4-(2',3'-Dimethoxyphenyl)-3-phenylbutanenitrile
  • Step 5 4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid
  • Step 1 2-(2',3'-Dimethoxyphenyl)-1,3-dithiane
  • Step 2 Ethyl 4-(2',3'-dimethoxyphenyl)-4-(1",3"-dithiane)-3-phenylbutyrate
  • Step 4 4-(2',3'-Dimethoxyphenyl)3-phenylbutyric acid
  • N-t-Butoxycarbonyl-alanyl-alanine (BocAla-Ala) (2.01 g, 7.74 mmol) was added to a stirred solution of 1-aminomethyl-5,6-bis(acetoxy)-3-phenyl-3,4-dihydronaphthalene hydrochloride (3 g, 7.74 mmol), the product of Example 3, in 35 mL of DMF. The resultant solution was cooled to 0°C.
  • the foam (5.06 g) was purified by flash chromatography using C 1 8 ODS (C 1 8 -octadecylsilane) on silica as the solid phase and a 50% solution of 1% aqueous trifluoroacetic acid (TFA) in acetonitrile as the eluent to give 2.03 g (44% yield) of the title compound as a light yellow colored solid, m.p.
  • C 1 8 ODS C 1 8 -octadecylsilane
  • TFA trifluoroacetic acid
  • Step 1 N-t-Butyloxycarbonyl-1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4- dihydronaphthalene
  • Triethylamine (7 mL) was added to a solution of 15 g (56 mmol) of 1-aminomethyl- 5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, from Example 2 in 100 mL of dimethylformamide (DMF).
  • the solution was cooled to 0 °C and a solution of di-t-butyl- dicarbonate (18 g, 82.5 mmol) in 50 mL of DMF was added over a period of 1 h. After the addition was complete, 250 mL of water was added to the reaction mixture and it was extracted with ethyl acetate.
  • Step 2 N-t-Butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4- dihydronaphthalene
  • N-t-Butyloxycarbonyl-1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4- dihydronaphthalene (3 g, 8.16 mmol), from Step 1, and 11 mL of triethylamine were combined and cooled to 0°C.
  • a solution of trimethylacetyl chloride (2.1 mL, 17 mmol) in 13 mL of dioxane was added to the cooled solution dropwise.
  • the reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 2 h. Water (25 mL) was added to the reaction mixture and the pH was adjusted to 4 with concentrated phosphoric acid.
  • the reaction mixture was extracted with diethyl ether.
  • N-t-Butyloxycarbonyl-1-aminomemyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4- dihydronaphthalene (14 g, 26 mmol), from Step 2, was dissolved in 75 mL of dioxane and saturated with anhydrous hydrogen chloride. The reaction mixture was stirred for 2 h and concentrated in vacuo. The solid residue was dissolved in a minimum amount of methanol and the methanol solution was added dropwise to an excess amount (500 mL) of diethyl ether.
  • Example 5 Following the procedures described in Example 4 using the appropriate aminomethyl compound of formula I with both catechol hydroxyl group protected as shown in the table and the appropriate (D) or (L) amino acid or peptide having the N-terminal amino group protected preferably as a carbamate, and more preferably as the t-butoxycarbonyl derivative, Examples 5 - 14 were prepared as disclosed below in Table 1.
  • Examples 16 - 34 were prepared as disclosed below in Table 1.
  • This ketone was treated with trimethylsilylcyanide in the presence of aluminum chloride and reduced with lithium aluminum hydride as described in Step 1 of Example 2 to give 1-aminomethyl-5,6-dimethoxy-1-hydroxy-3-cyclohexyl-1,2,3,4- tetrahydronaphthalene.
  • the hydroxy group was eliminated by treatment with anhydrous hydrogen chloride in isopropyl alcohol as described in Step 2 of Example 2 to give 1- aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride, m.p.
  • Step 3 1-Aminomethyl-3-cyclohexyl-5,6-dihydroxy-3,4-dihydronaphthalene hydrobromide
  • Boron tribromide 36 mL of a 1 M solution in methylene chloride
  • the reaction mixture was warmed to 0°C for 1 h.
  • the reaction mixture was cooled again to -78° C and 30 mL of methanol was added.
  • Step 1 [1R, 3S1 1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene hydrochloride
  • Examples 38 - 43 were made, as their hydrochloride salts, as disclosed in Table 2. The structure of each was confirmed by melting point (m.p.), elemental analysis and mass spectra as designated. Examples 42 and 43, as disclosed in Table 2, were prepared, using the appropriate aldehyde, following sequentially the procedures described in Examples 37 and 38, as their hydrochloride salts. The structure of each was confirmed by melting point (m.p.), elemental analysis and mass spectra as designated.
  • Step 2 9b-Cyano-6,7-dimethoxy-2-oxo-4-phenyl-2,3,3a,4,5,9b- hexahydronaphtho[1,2b]furan
  • the reaction was quenched by the addition of excess sodium sulfate decahydrate.
  • the resultant suspension was filtered through Celite ® filter aid and the filter cake was washed with 100 mL of hot THF.
  • the filtrate was concentrated to a light amber colored foam. This foam was dissolved in a solution of 3 M anhydrous
  • Step 4 1-Aminomethyl-5,6-dihydroxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-3,4- dihydronaphthalene hydrobromide
  • Step 3 [1-2-trans] 1-Aminomethyl-5,6-dihydroxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-1,2,3,4- tetrahydronaphthalene formic acid salt
  • Triethylamine (0.33 mL, 2.37 mmol) was added to a cold solution of 1 g (2.58 mmol) of 1-aminomethyl-5,6-bis(acetoxy)-3-phenyl-3,4-dihydronaphthalene hydrochloride, the product of Example 3, in 10 mL of DMF.
  • the resultant solution was added dropwise to a solution of 1.27 mL (5.52 mmol) of trimethylacetic anhydride (commercially available from Aldrich
  • Sodium hydride (4.5 g, 187.5 mmol) and trimethylsulfoxonium iodide (41.25 g, 187.5 mmol) were combined in a 3-neck flask equipped with a mechanical stirrer and an addition funnel.
  • Dimethyl sulfoxide (DMSO) was added slowly, over a 30 min period, until 200 mL had been added. Gas was evolved throughout the addition.
  • a solution of cyclohexane carboxaldehyde (21.8 mL, 180 mmol) in 50 mL of DMSO was added dropwise to the reaction mixture over a 15 min period. The reaction mixture was heated to 55 C and stirred at 55 C for 30 min.
  • the reaction mixture was cooled to ambient temperature and poured into 500 mL of water.
  • the aqueous solution was extracted with 3 X 100 mL of diethyl ether.
  • the combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo.
  • the crude product was distilled (44 C, 0.1 mm) to give 14 g (62% yield) of 1-cyclohexyl ethylene oxide as a clear colorless liquid.
  • n-Butyl lithium (12.6 mL of 2.5 M solution in hexane, 32 mmol) was added to a solution of spiro[1,3-benzodioxole)-2,1'-cyclohexane] (5 g, 26.3 mmol), prepared as described by Boeckmann and Schill in Chemische Berichte, 110:703 (1977), in 40 mL of THF at 0 °C.
  • 3,3-dimethyl-1,2-epoxybutane (2.5 g, 25 mmol), commercially available from Aldrich Chemical Company, was added dropwise and .the reaction mixture was warmed to 25 °C.
  • Step 3A [1,3-cis]-1-Bromomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2- benzopyran
  • Lithium azide (1.6 g, 31 mmol) was added to a solution of the product of Example 47 (2.5 g, 6.35 mmol) in 12 mL of dimethylformamide (DMF) at 25°C.
  • the reaction mixture was heated at 75°C for 2h then cooled and poured into 50 mL of water.
  • the aqueous solution was extracted with 3 X 50 mL of diethyl ether.
  • the combined ether extracts were washed with 50 mL of water, 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and
  • Step 2 [ 1,3-cis] 1-Aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2- benzopyran hydrochloride
  • LAH Lithium aluminum hydride
  • Examples 49 - 106 were made as disclosed in Table 3. The structure of each was confirmed by melting point (m.p), elemental analysis and mass spectra as designated.
  • Oxalyl chloride (0.45, 5.1 mmol) and 2 - 3 drops of N,N-dimethylformamide (DMF) were added to a chilled (0°C) solution of 2,3-dimethoxyphenylacetic acid in 25 mL of THF.
  • the resultant solution was allowed to warm to ambient temperature over a 4 h period.
  • the solvent was removed in vacuo and the residue was dissolved in 50 mL of chloroform.
  • N- methoxy-N-methyl-hydroxylamine hydrochloride (0.55 g, 5.61 mmol) was added and the resultant solution was chilled to 0°C.
  • Pyridine (0.91 mL, 11.23 mmol) was added and the solution was stirred for 2 h at 0°C.
  • n-Butyl lithium (1.87 mL, 3.76 mmol of a 1.75 M solution in hexanes) was added to a chilled (0°C) solution of furan (0.2 mL, 2.72 mmol) in 5 mL of THF. The mixture was allowed to warm to ambient temperature over a 4 h period. The mixture was then chilled again to 0°C and a solution of 0.65 g (2.72 mmol) of 1-(2',3'-dimethoxyphenyl)-N-methoxy-N-methyl- acetamide, from Step 1, was added. The reaction mixture was allowed to warm to ambient temperature over a 2 h period and was then quenched with a saturated aqueous ammonium chloride solution.
  • n-Butyl lithium (30 mL of 2.5 M solution in hexane, 75 mmol) was added dropwise to a solution of spiro[1,3-benzodioxole)-2,r-cyclohexane] (5 g, 26.3 mmol), prepared as described by Boeckmann and Schill in Chemische Berichte 110:703 (1977), in 125 mL of anhydrous THF at 0°C.
  • the solution was stirred at 0°C for 2 h and then a solution of 4.8 g (52 mmol) of epichlorohydrin in 10 mL of THF was added via cannula over a 15 minute period.
  • the reaction mixture was heated to ambient temperature and stirred for 60 minutes at ambient temperature and heated at 65°C for 75 minutes.
  • the reaction mixture was cooled to ambient temperature and poured into 150 mL of water.
  • the aqueous layer was extracted with 2 X 75 mL of diethyl ether.
  • the combined ether layers were washed with 75 mL of saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to an amber colored oil.
  • the oil was purified by flash chromatography on silica gel eluted with 8% ethyl acetate in hexane to give 6.81 g (53% yield) of the title compound as a clear oil.
  • Step 2 1-(Spiro-[(1,3-benzodioxole)-2,1-' cyclohexane])-4-pentvn-2-ol
  • the methylene chloride layer was concentrated under reduced pressure and the residue was dissolved in 25 mL of ethyl formate.
  • the ethyl formate solution was heated to reflux temperature. After 1 h at reflux temperature, the reaction mixture was concentrated to a white solid. The solid was dissolved in 15 mL of THF and 175 mg (4.6 mniol) of lithium aluminum hydride (LAH) was added. The reaction mixture was heated at reflux temperature for 3 h then cooled to 0 °C. The reaction was quenched by the sequential addition of 0.175 mL of water, 0.175 mL of 15% aqueous sodium hydroxide solution and 0.525 mL of water.
  • LAH lithium aluminum hydride
  • Step 1 [1 ,3-cis] 1-(N- Allyl)aminomethyl-3-cyclohexyl-5,6-cyclohexyhdenedioxy-3,4- dihydro-1H-2-benzopyran
  • Step 2 [1,3-cis] 1-(N-Allyl)aminomethyl-3-cyclohexyl-3,4-dihtdro-5,6-dihydroxy-1H-2- benzopyran hydrochloride
  • Examples 114 - 131 were prepared as disclosed in Table 4.
  • Examples 123, 124 and 127 were prepared by replacing the bromoacetaldehyde dimethyl acetal of Example 47 step 3 with the appropriate Z-protected prolinal dimethyl acetal as indicated, followed by deprotection.
  • the chiral prolinals were prepared from the chiral amino acid alcohols following the prcedures given in Chem. Pharm. Bull (1982), 30, 1921 and Tetrahedron Letters (1986), 27, 6111.
  • Examples 132 - 146 were prepared by the procedures described in Examples 47, 48 and 111.
  • Examples 147 and 148 were prepared were prepared by the procedures described in Examples 47, 48 and 111, repeating the procedure of Example 111 in order to place the second methyl group on the amino function. The structure of each was confirmed by melting point, mass spectra and elemental analysis as designated.
  • Example 149
  • Examples 151 - 153 were prepared with the catechol hydroxyl groups protected as dimethyl ethers.
  • the 1 -aminomethyl compounds were N-acylated.
  • the N-acyl derivatives reduced as described in Example 111 and deprotected as described in Step 4 of Example 2, using the appropriate acylating agent and hthium aluminum hydride (LAH) as the reducing agent to give Examples 151 -153 as their hydrochloride salts unless otherwise noted.
  • LAH hthium aluminum hydride
  • Example 152 the acylation/reduction sequence was repeated to give the dialkylamino derivative.
  • Examples 151 - 153 are disclosed in Table 5. The structure of each was confirmed by melting point (m.p.), elemental analysis and mass spectra, as designated.
  • Step 1 1-Benzyloxy-3-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-2-propanol
  • N-Butyl Hthium (18.5 mL of 2.5 M solution in hexane, 46 mmol) was added to a solution of spiro[(1,3-benzodioxole)-2,1'-cyclohexane] (7.4 g, 39 mmol) in 75 mL of THF at 0° C. After 4 h, the protected glycidol (5.3 g, 32 mmol) in 10 mL of THF was added dropwise and the reaction mixture was allowed to warm to ambient temperature. After 1.5 h, the reaction mixture was poured into 10% aqueous ammonium chloride solution and extracted with 2 X 50 mL of diethyl ether.
  • Step 3 [ 1,3-cis] l-Bromomethyl-3-hydroxymethyl-5,6-cyclohexyhdenedioxy-3,4-dihydro- 1 H-2-benzopyran
  • Lithium azide (1.0 g, 20 mmol) was added to a solution of [1,3-cis] 1-bromomethyl- 5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4-dihydro-1H-2-benzopyran (2.17 g, 5.87 mmol), from Step 3, in 20 mL of DMF.
  • the reaction mixture was heated to 70 °C for 1.5 h then cooled to ambient temperature and poured into 50 mL of diethyl ether and 50 mL of water. The layers were separated and the aqueous layer was extracted with 2 X 50 mL of diethyl ether.
  • Methanesulfonyl chloride (0.128 mL, 1.65 mmol) was added dropwise to a solution of 1,3-cis 1-azidomethyl-5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4-dihydro-1H-2- benzopyran (500 mg, 1.5 mmol), from Step 4, and 0.314 mL (2.25 mmol) of triethylamine (TEA) in 15 mL of methylene chloride at 0 °C. After stirring for 30 min at 0 °C, the reaction mixture was transferred to a separatory funnel and diluted with diethyl ether.
  • TAA triethylamine
  • the layers were separated and the organic layer was washed with 2 X 20 mL of water, 2 X 15 mL of 1 N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a white foam.
  • the foam was dissolved in 20 mL of DMF and 440 mg (9 mmol) of hthium azide was added. The reaction mixture was heated to 80°C and stirred at 80° C for 4 h then cooled and poured into 50 mL of water.
  • Lithium aluminum hydride (2.4 mL of 1.0 M solution in diethyl ether, 2.4 mmol) was added dropwise to a solution of [1,3-cis] 1,3-bis(azidomethyl)-5,6-cyclohexylidenedioxy-3,4- dihydro-1H-2-benzopyran (430 mg, 1.2 mmol), from Step 5, in 10 mL of anhydrous diethyl ether at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 45 min. The reaction was then quenched by the sequential addition of 91 ⁇ L of water, 91 ⁇ L of 15% aqueous sodium hydroxide solution and 273 ⁇ L of water.
  • Step 7 [ 1,3-cis] 1,3-Bis(am inomethyl)3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran dihydrochloride
  • Absolute ethyl alcohol was saturated with anhydrous hydrogen chloride and added to 212 mg (0.96 mmol) of [1,3-cis] 1,3-bis(aminomethyl)-5,6-cyclohexylidenedioxy-3,4- dihydro-1H-2-benzopyran from Step 6.
  • the solution was heated to reflux temperature. After 45 min at reflux temperature, a precipitate formed and the volume of the reaction mixture was reduced to 5 mL. Diethyl ether was added until precipitation was complete and the precipitate was collected by vacuum filtration. The solid was washed with diethyl ether and dried in a vacuum oven at 80 °C overnight to give 280 mg (96% yield) of the title compound as a fine white powder, m.p.
  • Lithium aluminum hydride (1.1 mL of 1.0 M solution in diethyl ether, 1.1 mmol) was added dropwise to a solution of 370 mg (1.1 mmol) of 1-azidomethyl-5,6- cyclohexylidenedioxy-3,4-dihydro-3-hydroxymethyl-1H-2-benzopyran, the product of Step 4 of Example 154, in 10 mL of anhydrous diethyl ether at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 40 min. The reaction mixture was cooled to 0 °C and quenched by the sequential addition of 42 ⁇ L of water, 42 ⁇ L of 15% aqueous sodium hydroxide solution and 126 ⁇ L of water.
  • Absolute ethyl alcohol was saturated with anhydrous hydrogen chloride and added to a suspension of 256 mg (0.83 mmol) of [1,3-cis] 1-aminomethyl-5,6-cyclohexylidenedioxy-3,4- dihydro-3-hydroxymethyl-1H-2-benzopyran from Step 1 in 2 mL of ethanol.
  • the reaction mixture was heated to reflux temperature. After 1.5 h at reflux temperature, a precipitate had formed.
  • the solvents were evaporated down under reduced pressure to approximately 5 mL.
  • the layers were separated and the organic layer was washed with 2 X 20 mL of water, 2 X 20 mL of 1 N hydrochloric acid and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to 405 mg of white foam.
  • the foam was dissolved in 20 mL of dimethyl formamide (DMF) and an excess amount of pyrrolidine was added to this solution.
  • the reaction mixture was heated at 95°C for 2.5 h then poured into 75 mL of water.
  • the aqueous solution was extracted with 3 X 40 mL of diethyl ether.
  • Step 2 [ 1,3-cis] 1-Ami nomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl- 1H-2-benzo ⁇ yran
  • Lithium aluminum hydride (0.52 mL of a 1.0 M solution, 0.52 mmol) was added dropwise to a solution of 20 mg (0.52 mmol) of 1,3-cis 1-azidomethyl-5,6- cyclohexyhdenedioxy-3,4-dihydro-3-pyrrohdinylmethyl-1H-2-benzopyran, from Step 1, in 10 mL of anhydrous diethyl ether at 0°C. The reaction mixture was allowed to warm to ambient temperature and it was stirred at ambient temperature for 40 min.
  • reaction mixture was then cooled to 0°C and quenched by the sequential addition of 20 ⁇ L of water, 20 ⁇ L of 15% aqueous sodium hydroxide solution and 60 ⁇ L of water.
  • the resultant solution was dried over anhydrous magnesium sulfate and the precipitate filtered.
  • Example 156 Following the synthesis described in Example 156, using 3-(benzyloxy)propylene oxide and the appropriate alkyl or cycloalkyl amine, Examples 157 and 158 were prepared as disclosed in Table 6, as their dihydrochloride salts. Following the procedures described in Examples 154 and 155, using 4-(benzyloxy)butylene oxide, Examples 159 and 160 were prepared as disclosed in Table 6. The structure of each was confirmed by melting point, mass spectra and elemental analysis as designated.
  • Examples 161- 172 were prepared as disclosed in Table 7, as their hydrochloride salts. The structure of each was confirmed by melting point, mass spectra and elemental analysis as designated.
  • Examples 173- 175 Following the synthesis described in Examples 154 and 155, using 4-(benzyloxy)- butylene oxide and the procedure for N-methylation described in Example 111, Examples 173-175 were prepared as shown below in Table 8, as their hydrochloride salts. The structure of each was confirmed by melting point, mass spectra and elemental analysis as designated.
  • Step 1 Spiro[(4-methyl-1,3-benzodioxole)-2,1'-cyclohexanel
  • a catalytic amount of p-toluenesulfonic acid (approximately 50 mg) was added to a solution of 2,3-dihydroxytoluene (10g, 80.7 mmol) and cyclohexanone (8.3 mL, 81 mmol) in 150 mL of cyclohexane.
  • the reaction mixture was heated to reflux temperature and the water produced in the condensation reaction was removed using a Dean Stark trap.
  • Step 2 1-Cyclohexyl-2-(2',3'-cyclohexylidenedioxy-4'-methylphenyl)ethanol
  • N-Butyl lithium (23 mL of a 2.1 M solution in hexane, 49 mmol) was added dropwise to a solution of spiro[(4-methyl-1,3-benzodioxole)-2,1'-cyclohexane] (9 g, 44 mmol), from Step 1, in 60 mL of THF at 0 °C.
  • the reaction mixture was allowed to warm to 25 °C and stirred at ambient temperature for 4 h.
  • the reaction mixture was then cooled to 0 °C and 1- cyclohexylethylene oxide was added.
  • reaction mixture was stirred for 2 h at 25 °C and 30 min at 50°C then poured into 100 mL of saturated aqueous ammonium chloride solution and extracted with 3 X 100 mL of diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
  • reaction mixture was then diluted with 100 mL of diethyl ether and washed with 2 X 50 mL of aqueous sodium carbonate solution and 50 mL of brine.
  • the organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
  • the residue was purified by column chromatography on sihca gel eluted with 2% ethyl acetate in hexane to give 1.2 g (46% yield) of the title compound as a colorless foam.
  • Step 4 [1,3-cis] 1-Arminomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro- 2-benzoxepin hydrochloride
  • Lithium azide (590 mg, 12 mmol) was added to a solution of 1.05 g (2.4 mmol) of [1,3-cis] 1-bromomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro-2- benzoxepane hydrochloride, from Step 3, in 10 mL of DMF at 25 C.
  • the reaction mixture was heated to 65 °C, stirred at 65 C for 2.5 h, cooled to ambient temperature and poured into 100 mL of water.
  • the aqueous solution was extracted with 3 X 50 mL of diethyl ether.
  • This azide intermediate was dissolved in 25 mL of diethyl ether and hthium aluminum hydride (2.1 mL of a 1 M solution in diethyl ether) was added to the solution at 0°C. After warming the reaction mixture to ambient temperature and stirring for 1 h, the reaction mixture was cooled to 0 °C and the reaction quenched by the sequential addition of 80 ⁇ L of water, 80 ⁇ L of 15% aqueous sodium hydroxide solution and 240 ⁇ L of water. The precipitate was filtered and washed with diethyl ether. The filtrate was concentrated and the residue redissolved in diethyl ether. The ether solution was treated with diethyl ether saturated with anhydrous hydrogen chloride.
  • Step 1 2-(2',3'-Cyclohexylidenedioxyphenyl)-1-phenylethanone
  • Diphenyl-(2R-2'-pyrrolidinyl)methanol (610 mg, 2.41 mmol) and phenylboronic acid (294 mg, 2.41 mmol) were taken up in 25 mL of toluene.
  • the diphenyl-(2R-2'- pyrrolidinyl)methanol was prepared as described by E.J. Corey et al. in J American Chem Soc. 109:5551-53 (1987). The reaction mixture was heated at reflux temperature for 4 h under a nitrogen atmosphere using a Dean Stark trap filled with 4 A molecular sieves to remove water. The reaction was then cooled and concentrated in vacuo to afford the title compound as a colorless oil. The product was carried on to the next step without purification.
  • reaction mixture was stirred for 10 min at ambient temperature and then cooled to ⁇ 0°C in an ice bath and then the reaction was quenched by the careful addition of 3 mL of methanol. Diethyl ether saturated with hydrogen chloride (2 mL) was added and the solution was allowed to warm to ambient temperature. The solution was stirred at ambient temperature for 0.5 h and then it was poured into 100 mL of diethyl ether and 100 mL of water. The organic layer was washed with IV aqueous hydrochloric acid solution, aqueous saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 216 mg (96% yield) of the title compound as a white solid.
  • Step 4 [1S] 1-(1'-Adamantyl)-2-(spiro-[( 1,3-benzodioxole)-2,1-cyclohexane])-1-ethanol n-Butyl hthium (6.7 mL of a 1.48 M solution in hexane, 9.9 mmol) was added over a 10 min period to a solution of spiro[(1,3-benzodioxole)-2,l -cyclohexane] in 14 mL of THF at 0°C. The reaction mixture was allowed to warm to ambient temperature over a 0.5 h period and then it was stirred for 3.5 h at ambient temperature.
  • Trimethylsilyltriflate (73 ⁇ L, 0.38 mmol) was added to a mixture of 3.5 g (9.5 mmol) of [1S] 1-(l'-adamantyl)-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-1-ethanol, from
  • Step 4 N-formylacetaldehyde dimethyl acetal (2 g, 15.2 mmol) in 20 mL of acetonitrile.
  • the reaction mixture was heated at a gentie reflux for 2 h and an additional 50 ⁇ L (0.26 mmol) of trimethylsilyltriflate was added. A precipitate formed and after 4 h the reaction mixture was cooled to 0°C. The precipitate was collected by filtration, washed with cold acetonitrile and dried to afford 2.92 g (70% yield) of the tide compound as colorless crystals, m.p. 220-221°C;
  • the resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h.
  • the reaction mixture was cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a colorless oil.
  • the oil was purified by column chromatography on sihca gel eluted with 20% ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound, m.p. 109-110°C.
  • Step 4 N-Methoxy-N-methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalene-1- carboxamide
  • N-Methoxy-N-methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaph-thalene-1- carboxamide (3.3 g), from Step 4, was dissolved in 80 mL of dry THF and the solution was cooled to 0°C. An excess (3-4 equivalents) of 2,2,5, 5-tetramethyl-1-aza-2,5- disilacyclopentane-1-propyl magnesium bromide was added and stirred overnight.
  • Each diastereomer was converted to its hydrochloride salt as follows: the formate salt was dissolved in water and the aqueous solution was made basic with sodium hydroxide. The free base was extracted with methylene chloride and the organic layer was washed with brine, dried over anhydrous magnesium sulfate , filtered and concentrated under reduced pressure. The residue was dissolved in diethyl ether and a saturated solution of hydrogen chloride gas in methanol was added to precipitate the hydrochloride salt The first compound to elute from the column gave 274 mg (7% yield) of the [1R, 3S, 2'R] isomer, m.p. 105-106°C. The structure was confirmed by NMR and X-ray crystallographic analysis (after recrystallization from acetone by slow evaporation).
  • Step 6 [1,3-cis] 5,6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene hydrobromide
  • Step 1 1-(3'-(3'-Carbomethoxypropanoic acid)-5,6-dimethoxy-3-phenyl-3,4- dihydronaphthalene
  • the reaction was heated for an addition 60 minutes and then cooled and poured into 50 mL of ice cold 2 N aqueous hydrochloric acid solution.
  • the aqueous phase was extracted with 5 X100 mL of diethyl ether.
  • the combined organic layers were extracted with 5 X 100 mL of aqueous saturated sodium bicarbonate solution.
  • the combined aqueous layers were acidified to pH 3 with 6 N aqueous hydrochloric acid solution and the product was extracted with 2 X 200 mL of 1:1 diethyl ether/ethyl acetate.
  • the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo .
  • Step 3 1-Carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-terrahydrophenalene
  • Step 5 [1R*,8S*,9aR*] 5,6-Dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene-1- carboxylic acid
  • the aqueous phase was acidified to pH 2 with 6 M aqueous hydrochloric acid solution and extracted with 3 X 25 mL of 1:1 ethyl acetate/diethyl ether. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.74 g (100% yield) of the title compound as an oil; DCl MS: 253 (M+H) + .
  • reaction mixture was cooled and concentrated under reduced pressure.
  • the residue was dissolved in 25 mL of diethyl ether and the ether solution was washed with 10 mL of 1 N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.
  • Step 7 [1R*,8S*,9aR*] 1-Amino-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene
  • a solution of sodium methoxide was prepared by the addition of 3.28 g (0.143 mol) of sodium metal to 97 mL of methanol with cooling to 0°C. Thiophenol (14.6 mL, 0.143 mol) was added dropwise over 10 minutes and then stirred an additional 10 minutes at 0°C. A solution of the above crude oil in 60 mL of THF was added dropwise over 30 minutes and the reaction was then allowed to warm to ambient temperature for 4 h. The solvents were removed in vacuo and the residue was dissolved in a mixture of 150 mL each of methylene chloride and water. The organic phase was collected and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 2 -5,6-Dimethoxy-3-phenyl-2-sulfoxophenyl-3,4-dihydronaphthalene
  • the crude resultant alcohol was dehydrated by the addition of 700 mL of toluene and 3.6 g (18.9 mmol) of p-toluenesulfonic acid monohydrate and heating to reflux with azeotropic removal of water for 30 minutes. After coohng, the solution was washed with 3 X 100 mL of saturated aqueous sodium bicarbonate, 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo . The crude thio-enolether was carried on directly by first, dissolution in 360 mL of methylene chloride.
  • Step 4 N-Methoxymethyl-N-trimethylsilylmethyl benzylamine
  • N-Trimethylsilylmethyl benzylamine (125.4 g, 0.649 mol), from Step 3, was added dropwise over a 10 minute period to a solution of 69.5 mL of 37% aqueous formaldehyde at 0°C. After an additional 10 minutes, 75.2 mL of methanol was added. The solution was then saturated with solid potassium carbonate and stirred at 0°C for 1 h. The layers were separated and the organic phase was stirred over sohd potassium carbonate at ambient temperature for 18 h. The solution was filtered and fractionally distilled at 20 mm of Hg to give a 145-155°C. fraction as a viscous oil, identified as N-methoxymethyl-N-trimethylsilylmethyl benzylamine.
  • Step 7 6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole formic acid salt

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Abstract

Nouveaux composés représentés par la formule (I), ainsi que leurs sels, esters et amides acceptables pharmaceutiquement, où A représente -O-; R?1, R3, R4, R5, R6, R7, R9, R10¿, X et Y sont définis spécifiquement, de sorte que X et Y ne sont pas tous deux hydrogène; et une combinaison au plus de (a) R?2 et R5, (b) R5 et R6, (c) R5 et R7, (d) R6 et R7¿ et (e) R7 et Y, avec les atomes auxquels ils sont fixés, peut constituer un noyau. Ces composés sont utiles pour traiter les troubles neurologiques, psychologiques et cardio-vasculaires associés à la dopamine, ainsi que l'altération cognitive, le déficit de l'attention, la toxicomanie et d'autres troubles de comportement provoqués par la dépendance. L'invention concerne également des intermédiaires et des procédés utiles pour la préparation desdits composés.
PCT/US1996/007361 1995-05-30 1996-05-22 Agonistes de dopamine WO1996038435A1 (fr)

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