AU655898B2 - Dopamine agonists - Google Patents

Description

I ~II DOPAMINE AGONISTS Technical Field This invention relates to novel compounds which are selective dopamine agonists useful for treating dopamine-related neurological, psychological, cardiovascular, cognitive and behavioral disorders.

Backaround of the Invention 0of o @5 0 0 0. 0 s o a of

S

9O

S.

S*

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.

It is now widely accepted that dopamine receptors in the CNS can be divided into 15 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 1 is 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 20 receptor by dopamine or a dopamine D-1 receptor agonist causes an increases an increase in the production of 3',5'-cyclic adenosine monophoshate (cAMP).

The D-2 receptor, on the other hand, 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 [inlib]019OSEF 4681UjS.P3 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, including, 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 14...Of the mammalian brain. In the early 1960's, the loss of striatal dopamine was stablished 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.

The success of L-DOPA therapy has led to the testing of other compounds of mimicking the post-synaptic receptor actions of dopamine. Such direct- S* acting agents might offer the therapeutic advantages of greater potency, increased duration of action, or fewer side effects over L-DOPA. For example, 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 2* *.response and allows for a delay in the onset of L-DOPA therapy. However, the response to bromocryptine alone is not as great as that observed with L-DOPA.

Another disorder in which dopamine has been implicated is the psychosis, 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 psychosis and involves disturbance of thouht processes, hallucinations and loss of touch wii. eality. The theory of schizophrenia as a disease of the CNS was first formalized by Kraepelin and Bleuler in the early 1900's. It was not until chlorpromazine was discovered by Delay 4684.US.P3 and Daniker in the early 1950's, however, that drug management of this disease was possible.

The pioneering work of Carlsson and others led to the now widely-held dopamine theory of schizophrenia. According to this theory, schizophrenia is caused by an excess of dopamine in the brain. Several lines of evidence support this hypothesis.

For example, chronic abuse of stimulants such as amphetamines, known to enhance dopaminergic activity in the brain, can lead to a paranoid psychosis that is almost indistinguishable from classic paranoid schizophrenia. The mechanism-of-action '*proposed for drugs with anti-schizophrenic activity is the blockade by these ompounds of the dopamine receptors, and consequently, the prevention of excess *eceptor stimulation. In the mid 1970's it was observed that virtually all of the currently Sused antipsychotic agents could displace radiolabeled haloperidol (a dopamine ntagonist) from striatal dopamine receptors with a good correlation between average effective clinical dose and drug binding affinity.

Unfortunately, the currently-available antipsychotic agents frequently produce undesirable side-effects, the most common of which are the so-called extrapyramidal effects that include bizarre involuntary movements and Parkinson-like effects.

*Sedation and hypotension are also common side effects. Because of these often Severe side-effects and the high incidence of patients unresponsive to currentlydrugs, more potent and more selective agents are needed.

It is also recognized that depressive conditions and related affective disorders result from a reduction in the central nervous system of certain biogenic amine geurotransmitters such as dopamine noradrenaline (NA) and serotonin Affective disorders are characterized by changes in mood as the primary clinical *.r-anifestation. 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 by either inhibition of the neuronal uptake of the neurotransmitters or inhibition of the metabolic enzymes responsible for converting the biogenic amines to inactive metabolites. Unfortunately, there are major drawbacks to the use of currently-available agents for treating affective disorders. For example, no antidepressant drug to date has proven to be superior to electroconvulsive shock therapy in the treatment of severe, suicidal depression. Other problems with the use of available drugs are delayed onset of activity, poor efficacy, 4684.US.P3 anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the danger of taking a fatal overdose. There also exists a large number of untreated individuals and treatment-resistant patients in need of effective therapy. A role for direct-acting dopamine agonists in antidepressant therapy has been suggested based on the effects observed for several dopamine agonists in various animal models used for predicting antidepressant activity such as the "mouse behavioral despair test".

A role for dopamine has been established in several other neurological functions such as cognitive function and attention mechanisms. Animal studies implicate *'elopamine in attention-related behaviors involving search and exploratory activity, io....distractibility, response rate, discriminability and the switching of attention. A ,*therapeutic role in the treatment of cognitive impairment and attention deficit disorders has therefore bean 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 'ause vasoconstriction at higher concentrations, presumably due to its secondary Effects on adrenergic receptors and by its emetic effects due to peripheral D-2 Agents selective for the peripheral D-1 receptors may offer significant advantages over currently used treatments for these and other related disorders.

Published evidence suggests that dopamine also has a central role in the brain's r.eward system. For example, it has been reported that animals trained to self- "administer cocaine will increase their consumption of this drug after treatment with ither 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 aduictive 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

O

4684.US.P3 subtypes are needed in order to obtain the anticipated physiological responses discussed above, separate from other possibly less desirable effects.

Related 5-hydroxy dopaminergic conrmounds were reported in U.S. Patent 4,994,486, which is also a continuation-in-part of U.S. Application Serial Number 359,448, and compounds having somewhat related structures to the novel compounds of the instant invention have been disclosed in European Patent Applications 0321968 and 0325963 and in French Patent 2,407,212. However, the 1-aminomethyl tetrahydronaphthalene derivatives of EP 0321968 are unsubstituted at the 3-position 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 S..of EP 0325963 are substituted on the amino group with an aryl-substituted or heterocycle-substituted alkyl group, and in the 1-aminoalkyl-substituted isochoman S'**end 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.

Summary of the Invention The present invention is directed to dopaminergic compounds of the formula:

OR

1

A

R

3 Y RZ/CH.

R ^NR 5

R

6 or a pharmaceutically-acceptable salt, ester or amide thereof, wherein A is O, S, CHR 2 or CR 2 n is 1 or 2; the dotted lines represent optional double bonds; R1, R2, R 3

R

4

R

5

R

6

R

7 X and Y are specifically defined; and one combination of R 2 and R 5

R

5 and R 6

R

5 and R 7

R

6 and R 7 or R 7 and Y and the atoms to which they are attached may be taken together to form a ring.

4684.US.P3 These compounds have the ability to bind and activate dopamine receptors in the central and peripheral nervous systems. Therefore they are useful in the treatment of dopamine-related neurological, psychological and cardiovascular disorders as well as in the treatment of substance abuse and other addictive behavior disorders, cognitive impairment and attention deficit disorder.

Betailed Description of the Invention This invention relates to novel compounds which are selective dopamine o' agonists represented by structural formula

OR'

X 8

Y

CH

Sa R 7 Z NR 5

R

6 or a pharmaceutically-acceptable salt, ester or amide thereof, wherein A is O, S, CHR 2 or CR 2 S n is 1 or 2; the dotted lines represent optional double bonds; R! is selected from hydrogen and a readily-cleavable group, as defined below; or a catechol-protecting group, as defined below;

R

2 is selected from hydrogen, methyl, ethyl, hydroxymethyi, hydroxyethyl, halomethyl, haloethyl, aminomethyl, and aminoethyl, or taken together with and the atoms to which each is attached forms a 5- or 6-membered ring containing only one hetero atom, the nitrogen shown in Formula

R

3 is selected from: Ci-Clo-alkyl, as defined below, substituted C 1 -Cs-alkyl, as defined below, 4684.US.P3 02-012-alkenyl, as defined below, substituted 02-05-alkenyl, as defined bel~w, 02-012-alkynyl, as defined below, substituted 02-05-alkynyl, as defined below, CYClo-C3-C1o-alkyl, as defined below, substituted CYCIO-C3-Olo-alkyl, as defined below, carbocycliC-C 6

-C

1 o-aryl, as defined below, substituted carbocycliC-C 6 -Cj o-aryl, as defined below, carbocyclic-C 6

-C

1 o-aryloxy-Ci -C5-alkyl, as defined belo~w, susiue abcei-6CoayoyC-5akl sdfndblw sbttdcarbocyclic-C6-Clo-aryl ox-Cl-CS-alkyl, as defined below, sbttdcarbo -C 6 -C o-aryl-Oi -C5-alkyl, as defined below 940: substituted Het, as defined below, Het-C 1 -C~r-alkyl, as defined below, and substituted iMet-Cli-C5-alkyl, as defined below; or taken together with R 4 and the atom to which it is attached forms a :0,0 spirocyclo-C 3

-C

10 -allkyl ring, as defined below;

R

4 is selected from hydrogen and Cl-Clo-alkyl, or taken together with R 3 and the atom to which it is attached forms a spirocyclo-C 3 -0 10 -alkyl ring; gee.O 0 R5 is selected from hydrogen, Ci -03-alkyl, hydroXY-C 2

-C

3 -alkyl, amino-C 2

-C

3 -alkyl, Ci-C3-alkoXY-0 2

-C

3 -alkyl, as defined below, 02-03-alkenyl, C2-C 3 -alky nyl,

CYCIO-C

3 -0 5 -alky I, Ci-C8-akanoyl, as defined below, a readily-cleavable group, amino acid, as defin ed below, and dipeptide, as defined below; 4684.US.P3 or, when A is CHR 2 or CR 2 is taken together with R 2 and the atoms to which each is attached to form a 5- or 6-membered ring containing only one hetero atom, the nitrogen shown in Formula or is taken together with R 6 or R7 and the atoms to which R 6 or R 7 is attached to form a pyrrolidine ring;

R

6 is selected from hydrogen and CI-C-alkyl, or taken together with R 5 and the atoms to which it is attached, forms a pyrrolidine ring;

R

7 is hydrogen or C 1 -Cs-alkyl, or taken together with R5 and the atoms to which it is attached forms a pyrrolidine ring, or taken together with Y and the atoms to which it is attached forms a 6- or 7-membered carbocyclic ring; X is selected from hydrogen, halogen, methyl and ethyl; Y is selected from hydrogen, halogen, methyl and ethyl, or Y taken together with

R

7 and the atoms to which it is attached forms a 6- or 7-membered carbocyclic ring; with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, and 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 6 described above: R 2 and R 5

R

5 and R 6

R

5 and R 7

R

6 and R 7 or R 7 and Y.

@1 The compounds of Formula have the ability to bind and activate dopamine 'eceptors in the central and peripheral nervous systems, thus mimicing the activity of dopamine, and are therefore useful in the treatment of dopamine-related neurological, psychological and cardiovascular disorders, as well as in the treatment of substance I*'*buse and other addictive behavior disorders, cognitive impairment and attention .Jeficit disorder.

The present invention also relates to pharmaceutical compositions comprising a therapeutically-effective amount of the compound of Formula and a pharmaceutically-acceptable carrier or diluent.

4684US.P3 Preferred compounds according to this invention have the following formula:

OR

1 5 R3 R'O 6 3 R4 x 8 1

CH

R7Z NRSR6 ,or are a pharmaceutically-acceptable salt, ester or amide thereof, herein a A is O; S the optional double bonds are not present; R1, R 3

R

4

R

5

R

6

R

7 X and Y are as defined above; with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, R 3 must be adamantyl and R 4 must be hydrogen when Y is halogen, and 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: S* R 5 and R 6

R

5 and R 7

R

6 and R 7 or R 7 and Y.

wherein i3* AisS; the optional double bonds are not present; S R 1

R

3

R

4 X and Y are as described above;

R

5 is hydrogen, C 1 -C3-alkyl, or C1-C 8 -alkanoyl;

R

6 is hydrogen;

R

7 is hydrogen; and with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, R 3 must be adamantyl and R 4 must be hydrogen when Y is halogen, and only one of the following combinations of groups and the atoms to which they ar8 attached may be taken together to form a ring as described above:

R

5 and R 6

R

5 and R 7

R

6 and R 7 or R 7 and Y.

or wherein: A is CHR 2 or CR 2 4684.US.P3 the dotted lines represent optional double bonds; R1, R 2

R

3 X and Y are as defined above;

R

4 is selected from hydrogen and C 1 -Clo-alkyl, or taken together with R 3 and the atom to which it is attached forms a spirocyclo-C3-C1o-alkyl ring;

R

5 is selected from hydrogen, Ci-Cs-alkyl, hydroxy-C2-C 3 -alkyl, amino-C2-C3-alkyl, C1-C 3 -alkoxy-C 2

-C

3 -alkyl,

C

2

-C

3 -alkenyl,

C

2

-C

3 -alkynyl, cyclo-C 3 C1-C 8 -alkanoyl, a readily-cleavable group, amino acid, and dipeptide, or, is taken together with R 2 and the atoms to which it is attached to form a S* or 6-membered ring containing only one hetero atom, the nitrogen shown in Formula or is taken together with R 6 or R 7 and the atoms to which R6 or R 7 is attached to form a pyrrolidine ring; R6 is selected from hydrogen and C 1 -C3-alkyl, or taken together with R 5 and the atoms to which it is attached, forms a pyrrolidine ring; o R 7 is hydrogen or C1-Cs-alkyl, or taken together with R 5 and the atoms to which it is attached forms a pyrrolidine ring, or taken together with Y and the atoms to which it is attached forms a 6- or 7-membred carbocyclic ring; and with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, and 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: R 2 and R 5

R

5 and R 6

R

5 and R 7

R

6 and R 7 or R 7 and Y.

4684.US.P3 *The following compounds are representative of the preferred compounds of Formula 1 -Amnino methyl-5,6-bi s(trim ethylacetoxy)-3-p he nyl-3,4-di hydro naphth ale ne; [1 ,3-cis] 1 -Aminomethyl-3-n-butyl-5 ,6-dihydroxy-3, 4-di hydro-1 H-?-benzopyt'an; 3-cisl 1 -Ami nornethyl-3-cyclopentylmethyl-5 ,6-di hydroxy-3 ,4-dihydro-1 H-2benzopyran; [1 ,3-cis] 1 -Aminomethyl-3-cyclooctyl-5,6-di hydroxy-3 ,4-di hydro-1 H-2-benzopyran; ,3-cis] 3-n-Butyl-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 M-2-benzopyran; ,3-cis] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -methyiaminomethyl-3,4-dihydro-1 H-2- 6Bi (ac benoyran -(alanylI-alany1) amino met hy!-3-p he nyl-3,4-di hyd ro nap hthale ne; *.v,-DksaILoxy)- 1 I utanIyI) amI inuorn hy 1-3-ph e ny-32,'+-uiIyu ronaph hale n e; 5,6-Bis(acetoxy)-1 -(alanyl)aminomethyl-3-phenyi..3,4-dihydronaphthalene; 5,6-Bis(acetoxy)-1 -(meth,,onyl)aminomethyl-3-phenyI-3,4-dihydronaphthalene; 1 -(Alanyl-ala nyl)ami nomethyl-5.6-bis(be nzoyloxy)-3-phenyl-3,4-di hydro naphthalene; [1 R*,2S*,3S*I 1 -Aminomethyl-5,6-dihydroxy-2-(2-hydr/xy-1 -ethyl)-3-phenyl-1 p2,3,4- *tetrahydronaphthalene; j*i ,3-cis] 1 -Aminomrnethyr-5,6-di hyd roxy-3- (3.-hyd ro xyp he nyl)- 1, 2,3,4tetrahydronaphthalene; :1 -Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene; [1 ,3-cis] 1 -Amnino methyl-3-benzyloxymethyl-5,6-di hydroxy-3,4-di hydro- 1 H-2- .00benzopyran; j1 ,3-cIsj 1 -Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(dipheny)methyl- H-2- 2' benzopyran; (1 ,3-cis] 1 -Amnino methyi-3,4-dihydro-5,6-di hydroxy-3- (3'-methyl-2'-n-pentyl)-1 H-2benzopyran; [1 ,3-cis] 1 -Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(1 '-but-3'-ene)-1 H-2-benzopyran; [1 2 3-cis] 1 -Amnino methyl-3,4-di hydro-5,6-di hydroxy-3-(6'-m ethyl-2'-hep-5'-en 1H-2benzopyran; [1 ,3-cis] 1 -Amnino methyl-3-cyclooctyl-5,6-di hyd roxy-3,4-di hydro-1I H-2-be nzopyran; [1 R*,8S*,9aR*] 1 -Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene; [1 S*,8S*,9aR*] 1 -Amino-5,6-dihydroxy-2,3 ,7,8,9,9a-hexahydro-8-phenylphenalene; 6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1 H-benzo[e~isoindole; 4684.US.P3 El R,3S] 3-(1 -Adamantyl)-l -aminomethyl-3,4-dihydro-5,6-dihydroxy-1 H-2-benzopyran; 1 -Aminomethyl-5,6-bis(benzoyloxy)-3-phenyl-3,4-dihydronaphthalene; 5-AminomethyI-7-(2-naph-khyI)-7,8-dihydronaphthalene-l 1 2-dioi; 5-Aminomethyl-7-(l -nap hthyl) -7,8-di hydron ap htha le ne-l 1,2-dioI1; 1 -Ami nomethyl-5,6-bis (butoxy)-3-phenyi-3,4-di hydro naphthalene; 1 -Aminomethyl-5,6-bis(isobutoxy)-3-phenyl-3,4-dihydronaphthalene; 1 -Amino methyl -5,6-bis(m ethyl sucoinyloxy)-3-phenyl-3,4-dihydronaphthalene; 1 -Acety lam inom ethyl-5,6-bis (acety loxy)-3-ph enyl-3,4-di hyd ro nap hth ale ne; -Acetyl methylani no rnethyI-3-ph enyI1-7,8-di hyd ro naphth ale n e-1 ,2-dioI1; 1;..A-AminomethyI-5,6-bis(propionyloxy)-3-phenyI-3,4-dihydronaphth~lene; .1 -Aminomethyl-5,6-bis(phenylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthcilene; 1-Amnin omethyl-5,6-bis (m ethoxycarbo nylo xy)-3-ph enyl-3,4-di hydro nap ht hale ne; 0 1-Aminomethyl-5,6-bis(isopropyl succi nylo xy)-3-p he nyl-3,4-di hyd ro nap hthale ne; Go 1 -Amino methy 15,6-bis (di methylami nocarbo ny loxy)-3-ph eny 1-3,4-di hydronap hth ale ne; 1 -Amino methy 1-5,6-bis (beta-alanoyloxy)-3-p he nyl-3,4-d ihyd ro naphth aleno.; 1 -Aminomethyl-5,6-bis(ethoxycarbonyloxy)-3-phenyi-3,4-dihydronaphthalene; .1 -Aminomethyl-5,6-bis(benzylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene; *-Ami no methylk5,6-bis(methy lami nocarbo nyloxy)-3-p he nyl-3,4-di hyd ro nap hth ale ne; :',6-Bis(aoetyloxy)-l -t-butyloxycarbonylaminomethyl-3-pheny-3 1 4dihydronaphthalene; 5 -AminomethyI-5,6-bis(p-methoxybenzoyloxy)-3-phenyl-3,4-dihydronaphthalene; 1 -Aminomethyl-5,6-bis(methylaminooarbonylc-xy)-3-phenyl-3 1 4-dihydro naphthalene; u ,3-ois] 1 -AminomethyI-5,6-dihydroxy-3-phenyl-3,4-dihydro-l H-2-benzothiopyran; 1 -Ani no met hyl-5,6-di hyd roxy-3- (3-mnetho xyph enyi)-3,4-di hyd ro- 1H-2benzopyran; [1 ,3-cis] 5,6-Dihydroxy-l ,-methyaminomethyI-3-phenyl-3,4-dihydro.l [1-2benzothiopyran; [1 1 3-cis] 3- (1 -Adama ntylI)-5,6-di hyd roxy-l1 -methy lam ino methyk-3,4-di hyd ro-lI H -2benzopyran; El .;arns] 3-(1 -Adamantyl)-l1 -amino methyl-5,6-di hydroxy-3,4-di hyd ro-l1 H-2benzopy ran; El ,3-trans] 1 -Aminomethyl-5,6-dihydroxy-3'-(4-nithoxybenzyI)-3,4-dihydro-l H-2benzopyran; 4684,US.P3 [1 ,3-cis] 5,6-Dihydroxy-3-(4-methoxybenzyl)-l -methylaminomethyl-3,4-dihydro-l H-2benzopyran; El S ,3S] 3-(1 -Adamantyl)-1 -ami nomethyl-5 ,6-di hydroxy-3 ,4-di hydro-l H-2-be nzopyran; [1 R,3R] 3-(1 -Adamantyl)-l -amino methyl-5,6-dihydroxy-3,4-di hydro-l H-2-benzopyran; El R,2'R,3S] 5,6-Dihydroxy-3-.phenyI-l -(2'-pyrrolidinyl)-3,4-dihydro-l H-2-benzopyran; El ,3-cis] 1 -Aminomethyl-5,6-dihydroxy..3-(2-(1 -oxoisoindole)methyl)-3,4-dihydro-l H-2benzopyran; [1 R,2'S,3S) 5,6-Dihydroxy-3-phenyi-l -(2'-pyrrolidinyl)-3,4-dihydro-l H-2-benzopyran; *fl ,3-cis] 5,6-Dihydroxy-l -methylaminomethyl-3-phenyi-3,4-dihydro-1 H-2-benzopyran; .q -Phenyl-l ,2,3,4,5,6,-hexahydrobenzo~hisoquinoline-7,8-dioI; Methyl-5-ph enyl-l exahyd robe nzo [h]i soqu ino line -7,8-dio1; -El'S ,lR,3S] 3,4-Dihydro-5,6-dihydroxy-l -methylaminomethyl-3-phenyl-l H-2benzopyran; l,3-cis] 1 -Aminomethyl-3-cyclohexyimethyl-3,4-dihydro-5,6-dihydroxy-l H-2benzopyran; El ,3-cis] 1 -Aminomethyl-5,6-dihydroxy-3-isobutyi-3,4-dihydro-l H-2-benzopyran; ,3-cis] 3- (1 -Adamantylm ethyl) -1 -amino methyk-5,6-di hydroxy-3,4-di hydro-l H-2benzopyran; t,3-cis1 -Adamantylmethyl)-5,6-dihydroxy-l -methylaminomethyi-3,4-dihydro-l H- 2-benzopyran; ,3-cis] 3-CyclohexylmethyI-5,6-dihydroxy-l -methylaminomethyl-3 ,4-dihydro-1 H-2benzopyran; 11,3-0131 1 -Atlyl amino methyl -3-n-b utyl-5,6 -di hyd roxy-3,4-di hyd ro-l H-2-benzopyran; 1l,3-cisJ 1 -Aminomethyl-3-(2-cyclohexylethyl)-5,6-dihydroxy-3,4-dihydro-1 H-2- 2% benzopyran; El ,3-cis] 1 -Aminomethyl-5,6-dihydroxy-3-(ethylmalonamidomethyl)-3,4-dihydro-l H-2benzopyran; 1 '-Aminomethyl-5',6'-dihydroxyspiro~cycloheptane-l ,3'-(3',4'-dihydro-l benzopyran)]; 1 '-Aminomethyi-5',6'-dihydroxyspirojlcyclooctane-l ,3'-(3',4'-dihydro-l benzopy ran)]; 5',6'-Dihydroxy-l '-methylaminomethylspiro[cycloheptane-l ,3'-(3',4'-dihydro-l benzopyran)]; 4684.US.P3 El ,3-cis] 3-(1 -Adamantyl)-1 -ami nomethyl-8-bromo-5 ,6-dihydroky-3 ,4-di hydro-1 H-2benzopy ran; 5',6'-Di hydroxy- l'-mrnethylam ino met hylIspi ro~cyclooctan e-1 ihyd ro-1 VH-2'benzopyran)]; [1 ,3-cis] 1 -Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro- H-2-benzopyran; 1 '-Ami nomrnethyl-5',6'-di hyd roxyspi ro[tetrahydropyran-4,3'- hyd ro- 1 benzopyran)]; 5',6'-Di hyd roxy-1 '-mrnethy [am inornethylspi ro [tetrahyd ro pyran-4,3'- (3,4'-di hydro- 1'H-2'- ***benzopyran)]; 1 R,3S] 3-t-Butyl-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H-2-benzopyran; il,3-trans] 1 -Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 H-2-benzopyran; *ri S,3R] 5,6-dihydroxy-3-phenyl-1 -(2(R)-pyrrolidinyl)-3,4-dihydro-1 H-2-benzopyran; 0.411,3-cis] 3-(1 -Adamantyl)-1 -aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1 H-2- .:'benzopyran; [1 ,3-cisl 1 -Aminomethyi-5,6-dihydroxy-3-(4-ethoxy-2,3,5,6-tetrafluorophenyimethyl)- 3,4-dihydro-1 H-2-benzopyran; 5'-Aminomethylspiro[cyclohexane-1 ihydronaphthaiene)I-1 ',2'-diol; [1,3-cis] 1 -Aminomethyl-5,6-dihydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydro-1 H-2benzopyran; 00 'Aminomethyl spi ro~cycloh exane-1 ,7'-(5',6',7,8'-tetrahyd ronaphth ale ne)-1 ',2'-diol1; El R,3S] 1 -Aminomethyl-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; 8:1*,3-cis] 3-AIlyI-l -aminomethyl-5,6-dihydroxy-3,4-dihyiro-1 H-2-benzopyran; 2'-Methylspiro~cyclohexane-1 14',5',6'-hexahydro-benzo[h]isoquinoline)]oil 7',8'-diol; Spiro[cyclohexane-1 ',2',3',4',5',6'-hexahydro-benzo[hlisoquinoline)]-7',8'-dio; [1 R,3S] 3-t-Butyl-5,6-dihydroxy-1 -dimethylaminomethyl-3,4-dihydro-1 H-2-benzopyran; [1 ,3-ois] 5,6-Dihydroxy-1 -methylaminomethy-3-n-pentyl-3,4-dihydro-1 H-2benzopyran; (5R)-5-Phenyl-1 hexahydrobenzo[h]isoquinoline-7,8-diol; Spiro[cyclopentane-1 ',2',3',4',5',6'-hexahydro-benzorhisoquinioline)]-7',8'-diol; 2'-Methylspiro[cyclopentane-1 ',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]- 7',8'-diol; 4684.US.P3 methylspi ro[cyclopentan e- 1 (5,6,7',8'-tet rahyd ro-n apht hale 1 '2-dioI; [1 R,3S] 3-(1 -Adamantyl)-1 -ami nomethyl-5,6-di hydroxy-7-fluoro-3 ,4-dihyd ro-1 H-2benzopyran; [1 R,3S] 3-(1 -Adamantyl)-5,6-dihydroxy-7-fluoro-1 -m ethyl ami nomethyl-3,4-di hyd ro- 1 H- 2-benzopyran; [1 R,3S] 3-t-Butyl-5,6-dihydroxy-1 -ethyiaminomehyl-3,4-dihydro-1 H-2-benzopyran; (1 R,3S] 1 -Allylaminomethyl-3-t-butyl,-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 3-t-Buty'methyl-5,6-dihydroxy-l -methylaminomethyl-3,4-dihydro-1 H-2- **benzopyran; lo 5'-Ami nomethyIspi ro[cyclo heptane- (5,'6,7',8'-tetrahyd ro nap ht hale '2'-dioI1; ''-Ami nomethylspi ro[cycloh eptane-1 ,7'-(7',8'-dihydro naphth ale 1 '2'-dioI; 'tpiro[cycloheptane-1 1 5',6'-hexahydrobenzo[hisoquinoline)]-7',8'-diol; 11R,3S] 1 -Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 H-2-benzopyran; ,3-cis] 1 -Aminomethyl-3-t-butylmethyl-5,6-dihylroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -Ami nomethyl-5,6-di hydroxy-3-(3R-but-1 -e nyl))-3,4-di hyd ro-l1H-2benzopyran; no methyl-7,4-b utyl-7,8-di hydro naphth ale ne- 1 ,2-diol; a "15 ,7-cis]-5-Aminomethyi-7-t-butyl-5,6,7,8-tetrahycironaphthalene-1 ,2-dioi; 1R,3S] 3-t-Butyl-5.6-dihydroxy-1 -n-propylaminomethyl-3,4-dihydro-1 H-2-benzopyran; 5-tButyl- 1 exahyd robe nzo [h]isoqui no li ne-7,8-dio1; :-Cyclohexy-1 ,2,3,4,5,6 ,-hexahydrobenzojh]isoquinoline-7,8-dioI; 5-Cyclopentylmethyl-1 ,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-dio; [1 R,3S] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -dimethylaminomethyl-3,4-dihydro-1 H-2- Sbenzopyran; a Spro[cyclooctane<' robe zoh] isoquinoli 8'-dio1; [111,31 1 -Amino methyl-3-(2,2-dimethylpropyl)-3,4-di hydro-5,6-dihydroxy- 1H-2benzopyran; 11 ,3-ois) 1 -Aminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran; [1 R,3R] 1 -Ami no met hyI-3- (2-m ethyl propyI)- ,4-di hyd ro-5,6-di hyd roxy- 1H-2be nzopy ran; [1 R,3R] 1 -Methylaminomethyl-3-(2,2-dimethylpropy)-34-dihydro-5,6-dihydroxy-1 H-2benzopyran; 4684.US.P3 [1 ,3-cis] 1 -Met hylami nomethyl1-3-cycl ope ntyl methyl-3,4-dihyd r-5,6-di hydroxy- 1H-2benzopyran; [1 R,3R] 1 -Methylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran; [1 ,3-cisl 1 -(N,N-Dimethylamino)methyl-3-(2,2-dirnethylpropyl)-3,4-dihydro-5,6dihydroxy-1 H-2-benzopyran; 1 '-Aminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro~cyciononane-1 benzopyran)]; ,3-cis] 1 -Aminomethyl-3-(1 -methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1 H-2lobB benzopyran; 1-Aminomethyl-3-(1 -phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- 3',4'-Dihydro-5',6'-dihydroxy-1 '-methylaminomethyispiro [cyclorionane-1 benzopyran)]; [1 ,3-cis] 1 -(N,N-Dimethylamino)methy!-3-(1 -phenylcyclohexyl)-3,4-dihydro-5,6dihydroxy-1 H-2-benzopyran; [1 ,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -methyloyclohexyl)-3,4-dihlydro-5,6a4 dihydroxy-1 H-2-benzopyran; 1R,2S-1 -(N,N-Dimethylamino)methyI-3-pheny-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran; S, 11,3-cis] 1 N-Di methylani no)m ethyl -m ethy Icyclo he xy1) -3,4-di hyd ro-5,6dihydroxy-1 H-2-benzopyran; [1 ,3-cis] N- Dim et hylam! no) methyl-3-cyolo hexyl-3,4-di hydro-5,6-di hyd roxy- 1 H-2benzopyran; 2 1'.ai ,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -methylcyoiohexyl)-3,4-dihydro-5,6dihydroxy-l benzopyran; 1 -Aminomethyl-3-adamantyl-5,6-dihydroxy-3,4-dihydronaphthalene; 1 '-Aminomethyi-3',4'-dihydro-5',6'-dihydroxyspiro[cyolononane-1 ,3'-naphthalene]; 1 -Amino methyI-3-(2,2-dimethylpropyl)-5,6-di hyd roxy-3,4-di hydro naphthalene; 1 -Ami nomethyl-', 4'-dihydro-5',6'-di hydroxyspiro[cyclodecan e- 1,3'-nap hth ale ne]; 1 -Aminomethyl-3-adamantyl-5 ,6-dihydroxy-1 ,2,3,4-tetrahydronaphthalene,; 1 '-Aminrjm ethyl- 1',2',3',4'-tetrahydro-5,6'-di hydroxyspiro~cyclo nonan e-1 naphthalene]; 4684. US.P3 1 '-Ami no met hyl rahyd ro-5',6'-dihydroxyspi ro[cycl odeca ne-1 33'naphthalene]; 5-Adamantyl-1 ,2,3,4,5,6-he xahyd robe nzo [h]isoq uino li ne-7,8-di ol; (5R)-1 ,2,3,4,5,6-Hexahydro-5-phenylbenzo~hlisoquinoline-7,8-diol; 1 ',2',3,4',5',6'-Hexahydro- ',8'-dihyd roxyspi ro[cyclodecane- 1,5'-be nzo[h]isoquinoline]; 1 exahydro-7' ,8'-di hyd roxyspi rolcyclo nonane- 1 ,5'-be nzothlisoquinoline); ,,05-(2,2-Dimethylpropyl)-1 ,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol; r-ButyI-1 ,2,3,4,5,6-hexahydrobenzohlisoquinoline-7,8-diol; .Ia-(2,2-Dimethylpropyl)-1,2,3,4,5,6-hey ihydro-2-methylbenzo[h]isoquinoline-'7,8-diol; 14 5-(cyclopentylmethyl)-1 ,2,3,4,5,6-hexahydro-2-methylbenzo[h]isoquinoline-7,8-diol; -1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol; (5S)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol; 1 ',2',3',4',5',6'-Hexahydro-7,8O-dihydroxy-2'-methylspiro[cyclononane-1 benzo[hjisoquinoline]; 1 Hexahyd ro-7',8'-d ihyd roxy-2'- met hylspi ro [cyclo heptan e-1, 0 benzollh]isoquinoline]; *O %vl ',2',3',4',5,6-Hexahydro-7',8'-dihydroxy-2-methylspiro~cyclooctane-1 benzo[h]isoquinoline]; 2-Ethyl-i ',2',3',4',5,6'-hexahydro-7',8-dihydroxy-spirolcycloheptane-1 benzo[h]isoquino line]I; or 1 ',2',3',4',5',5a',6',8a'-Octahydro-7',8'-dihydroxy-2'-methylspiro[cycloheptane-1 See a' I benzo[hjisoqu ino line); 2 66, nd pharmaceutical ly-acceptab le salts thereof.

The following compounds are representative of the more preferred compounds of Formula [1 ,3-cis] 1 -Aminomethyl-3-n-butyl-5 ,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -Aminomethyl-3-cyclopentylmethyl-5,6-dihydroxy-3,4-dihiydro-1 H-2benzopyran; [1 .3-cis] 1 -Amino methyl-3-cyclooctyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 .3-cis] 3-n-Butyl-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H-2-benzopyran; 4684.US.P3 [1 ,3-cis] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H-2benzopyran; [1 ,3-cis] 5 ,6-Dihydroxy-3-phenyil- (2'R*-pyrro lidi nyI)- 1 ,2,3 ,4-tetrahyd ro-nap hth ale ne; (1 ,3-trans] 5,6-Dihydroxy-3-phenyl-1 -(2'R*-pyrrolidiny)-1 ,2,3,4-tetrahydronaphthalene; [1 ,3-cis] 5,6-Dihydroxy-1 -methylaminomethyl-3-phenyl-1 ,2,3,4-tetrahydronaphthalene; [1 ,3-cis) 1 -Aminomethyl-5 ,6-dihydroxy-3-(3-hydroxyphe nyl)-1 ,2,3 ,4-tetrahydronaphthalene; *..1-Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene; 11 ,3-cis] 1 -Amino methyl-3-benzyloxymethyl-5,6-di hydroxy-3,4-cli hydro-1 H-2benz~pyran;I ,8(L9a 1 -Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene; IIS*[I,8.,9aM- 1 -Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene; :&,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1 H-benzole]isoindole; [1R3. 3-(1 -Adamantyl)-1 -arninomethyI-3,4-dihydro-5 I6-dihydroxy-1 H-2-benzopyran; 1 -Amino met hyl-5,6-bis (be nzoyloxy)-3-p he nyl-3,4-di hydronap hth alerie; Spi ro[cyolope ntane- 1 (1 exahyd robe nzo isoqu in o I!ne)-7',8-di ol; V Spiroloyolo hexan e-1 ex,-hyd robe nzo [hisoq uinoli n e))-7,8'-dio 1; S pr~ylhpae15-l,','4,'6,h xhdob noS~sqioie]7,-il Epiro[cyclohetane-1 ',2',3',4',5',6',-hexahydro-benzo[h]isoquinoline)]-7',8'-dio; S :pironylooctne1,5'('3,',',6',-hxahydrobenzo[h]isoquinoie78d ol n)-'8-iI 2cMethyl55Pheny ,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-dio 2-Methcyl5-phe-1,5 9 293,6,exahdro rbenzo[h]isoquinoline )]7,8-diol;l ro.yclooctae- 1 xay rob3'4,','-exao hvdro-beino isoqu8-iolie'-il -Oc1heyI1 2 3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-dio Cyclopentylmethy-l23456,hxhdoez~hioun~n-,-iI [1,3-cisl 1 -Amin omethyl-5,6-clihydroxy-3-(3-methoxyphenyl)-34-di hydro- H-2benzopy ran; [1 ,3-cis] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -methylaminomethiyl-3,4-clihydro-1 H-2benzopy ran; [1 R,3S] 5,6-Dihydroxy-1 -methylaminomethy-3-pheny-3,4-lihydro-1 H-2-benzopyran; [1 ,3-ois] 1 -Aminomethyl-3-cyolohexylmethy-5,6-dihiydroxy-3,4-dihydro-1 H-2benzopyran; [1 ,3-cisI 1 -Aminomethyl-5,6-dihydroxy-3-isobutyl-3,4-dihydro-1 H-2-br%--opyran; [1 ,3-cis] 3-(1 -Adarnantylmethyl)-1 -amino methyi-5,6-di hydroxy-3,4-di hyd ro-1 H-2benzopyran; 4684.US.P3 ,1 ,3-cis] 3-(1 -Adainantylmethyl)-5,6-dihydroxy-1 -methylaminor-fiethyi-3 ,4-dihydro-1 H- 2-be nzopyran; [1 ,3-cis] 3-Cyclo hexylmethyl-5 ,6-dihydroxy- 1 -methy lam ino mnethyi-3 ,4-dihyd ro- 1H-2benzopyran; 1 '-Aminomethyl-5',6-dihydroxyspiro[cyctoheptane-1 hydro-1 benzopyran)]; 1 '-Aminomethyl-5',6'-dihydroxyspiro~cyolooctane-1 ,3'-(3',4'-dihyclro-1 IH-2!benzopyran)]; 005',6'-Dihydroxy-1 '-methylaminomethylspirolcycloheptane-1 ,3'-(3',4'-dihydro-1 'H-2 t ir:benzopyran)]; ::.'6-Dihydroxy-1 '-methylaminomethylspiro[cyclooctane-1 t ,4'-dihydro-1 'H-2- *Obenzopyran)]; 1 *,3-cis] 1 -Allylaminomethyi-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 H-2-benzopyran; [11,9, 3S] 3-t-Butyl-5,6-dihydroxy-1 -methylaminomethyi-3,4-dihydro-1 H-2-benzopyran; [1 ,3-trans] 1 -Amin omethyl-5,6-dihydroxy-3-pheny-3,4-dihydro;-1 H-2-benzopyran; [I ,3-cis] 1 -Aminoin ethyl-5,6-di hyd roxy-3-(4-ethoxy-2,3,5,6-tet raf Iuo roph enyl methyl)- :*3,4-dihydro-1 H-2-benzopyran; L1 ,3-cis] 1 -Aminomethl'1-5,6-dihydroxy-3-(4-trifluorornethylpheny)-3,4-dihydro-1 H-2benzopyran; 2< 1 ,3-cis] 1 -Amin omethyl-5,6-d ihydroxy-3- (3-trif luo ro methyl ph enyl)-3,4-di hydro-1I H-2be nzopy ran; ji ,3-cis] 3-Allyl-1 -aminomethyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; ~1 R,3S] 3-t-Butyl-5,6-dihydroxy-1 -dimethylaminomethyi-3,4-dihydro-1 H-2-benzopyran; 1 ,3-cis] 5,6i-Dihydroxy-1 -methylaminomethyl-3-rn-pentyl-3,4-dihydrc,,-1H-2benzopjyran; [1 R,3S) 1 -Aminomethyi-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 R,3S] 3-(1 -Adamantyl)-1 -aminomethyI-5,6-dihydroxy-7-fluoro-3,4-dihydro-1 H-2benzopyran; [1 R,3S) 3-(1 -Adamantyl)-5,6-dihydroxy-7-fluoro-1 -methyiaminomethyi-3 ,4-dihydro-1 H- 2-benzopyran;I [1 ,3-cis] 3-t-Butyl-5,6-dihydroxy-1 -ethylarminomethyi-3 ,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 3-t-Butylmethyl-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H-2be nzopyra n; [1 ,3-cis] 1 -Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihiydro-1 H-2-benzopyran; 4684.US.P3 (1 ,3-cis] 1 -Aminomethyl-3-t-butylmethy-5,6-dihydroxy-3,4-dihy ,y H-2-benzopyran; [1 ,3-cis] 1 -aminomethyl-5,6-dihydroxy-3-(3R-but-1 -enyl))-3,4-dlnydro-1 H-2benzopyran; [1 R,3S] 3-(l -Adamantyl)-5,6-dihydroxy-1 -dim ethylamninomethy-3,4-di hydro- 1 H-2benzopyran; [1 R,3 R] 1 -Amino methyl-3-(2,2-dimethyfpropyl)-3,4-dihydro-5,6-dihydroxy-1 '1-2benzopy ran; .41 ,3-cis] 1 -Aminomethyi-3-cyclopentylmethyi-3,4-dihydro-5 ,6-dihydroxy-1 H-2benzopyran; 1 R,3R] 1 -Aminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- *benzopyran; J R,3R] 1 -MethylaminomethyI-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- :~benzopyran; [1 ,3-cis] 1 -Methyiaminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran; [1 R,3R] 1 -Methylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran; 1 1 N-dimethylamino)methyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6dihydroxy-1 H-2-benzopyrasn; 29*: .'-Aminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro[cyclononane-1 benzopyran)]; [1 ,3-.cis] 1 -Aminomethyl-3-(1 -methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- :benzopyran; [i 1 3-cisl 1 -Aminomethyl-3-(1 -phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- 00* benzopyran; 1 '-Methylamino methyl-3',4 t -dihydro-5',6'-di hydroxyspi ro [cyclo nonan e- 1 (1 benzopyran)]; [1 ,3-cis) 1 ,N-Dimethylamino)methyl-3-(1 -phenylcyclohexyl)-3,4-dhydro-5,6dihydroxy-1 H-2-benzopyran; ,3-cisl I -(N,N-Dimethyiamino)methyl-3-(1 -cethyloyclohexyl)-3,4-dihydro-5,6dihydroxy-1 H-2-benzopyran; 1 R,2S-1 -(N,N-Dimethylamino)methyl-3-phenyl-3,4-dihyciro-5,6-dihydroxy-l H-2benzopyran; 4684. US.P3 ,3.-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -methylcyclohexyl)-8,4-dihydro-5a6dihydroxy-1 H-2-benzopyran; [1 ,3-cis] 1 ,N-D~methylamino)methyl-3-cyclohexy-3,4-dihydro-5,'6-dihydroxy-1 H-2benzopyran; 11,3-cis] 1 -(N,N-Dimethylamino)rnethyl-3-(1 -methylcyrclohexyl)-3,4-dihydro-5,6dihydroxy-1 H-2-benzopyran; (5R)-1 ,2,3,4,5,6-hexahydro-5-phenylbenzo~h]isoquinoline-7,8-diol; -ButyI-1 ,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol; ,P0(5R)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzohisoquinoline-7,8-diol; 60006 .5S)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[n]isoquinoline-7,8-diol; l',2',3',4',5',6'-Hexahydro-7',8-dihydroxy-2'-methylspiro[cycloheptane-1 :..benzo[h]isoquino line]; or 1,13,'5See a y r-'8-iy ro y2- eh lpr~ y lotn benzo[h~isoquinoline]; and pharmaceutical ly-acceptab le salts thereof.

.oo:,The following compounds are representative of the most preferred compounds of the present invenlon: El R,3S) 3-(1 -Adamantyl)-l -aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1 H-2benzopyran; S*-Methyl-5-phenyl-1 3 2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol; 2',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-'2'-methylspiro~cycloheptane-1 be nzo~h]isoqu ino line]; [1 R,3R] 1 -Aminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran; [1 R,3R] 1 -Aminornethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2-benzopyran: [1 R,3R] 1 -Methylaminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-S' ,6-dihydroxy-1 H-2benzopyran;I [1 IR,3R] 1 -Met hylam in om ethyl-3-(2- met hylp ropyl)-3,4-d ihyd ro-56-di hyd roxy- 1 H-2benzopyran; [1 ,3-cis) 1 -(N,N-fDimeth.ylamino)methyl-3-(1 -methylcyclohexyl)-3,4 Jhydro-5,6-dihydrory- 1 H-2-benzopyran; 4684. US. P3 I R,3S-1 -(N,N-Dimethylamino)methyl-3-phenyl-3,4-dihydro-5,6-dihydroxy- H-2benzopyran; or [1 ,3-c6s] 1 -(N,N-Dimethylamino)methyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran: and ph arm ace utical,!y-acceptab le salt,3 thereof.

This inventicni is related in part to intermediate products in the preparation of the ompounds of Formula 1, particularly in a novel process for preparing a compound of the jo rmu Ia:

OR'

RIO 6 43R 7 3

NHCHO

wherein A is 0 or S; 3P1 is a catechol-protecting group;

R

3 is selected from Cl-Clo-alkyl, substituted 0 1

-C

5 -alkyi, 0 2 -C12-alkenyl, 02-012-alkynyl, CYCIo-C3-Ci o-alkyl, carbocyclic-C 6 -CI O-aryl, carbOCYC'(icC6-Clio-aryl-O i-Os-alkyl, and H et; 4 is selected from hydri-gen and Cl-Cio-alkyl or, 4aken together with R 3 and the carbon atom to which boh are attached, forms a spiro-C 3 -Cl 0 -cycloalkyl ring; comprising reacting a co'npound having the formula:

OR'

R'R3

AH

with N-formylaminoacetaldehyde dimethyl acetal in the presence of an acid catalyst selected from boron trifluoride etherate, zinc trif late, trimethylsilyl trif late and methanesulfonic acid.

4684.US.P3 This invention is also related in part to chiral intermediate products in the preparation of the compounds of Formula 1, particularly in a novel process for preparing a chiral compound of the formula:

OR

1

R'O

S* OH *:**4herein R 1 is a catechol-protecting group and R 8 is substituted C 2 -Co1-alkyl, comprising eacting a compound having the formula:

OR

1

R'O

Cl

OH

ith treatment with a strong base to form a chiral epoxide of the formula a

OR'

R'O

which is then reacted with an organometallic compound in a non-polar organic solvent.

Certain compounds of this invention may possess oner 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 Iisomers, racemic mixtures of the isomers, and mixtures thereof are intended to be within the scope of this invention. In particular, the stereochemistry at the 1- and 3positions, as shown in Formula may independently be either or unless specifically noted otherwise. Chiral forms of certain compounds of this invention are contemplated and are specifically included within the scope of this invention.

4684.US.P3 specifically noted otherwise. Chiral forms of certain compounds of this invention are contemplated and are specifically included within the scope of this invention.

The term "aikanoyl", as used h:rein, means a carbonyl group linked to an alkyl group, as defined below, of the size indicated.

The term "a.lkanoylamino" means an alkanoyl group, as defined above, of the size indicated, connected to an amino group.

The term "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-propenyi, isopropenyl, n-butenyl, isobutenyl, 2- -4thylhexenyl, n-octenyl, 2,4-dimethylpentenyl, and the like.

The term "alkoxy" means an oxygen atom linked by an ether bond to an alkyl .'group, as defined below, of the size indicated. Examples of alkoxy groups are rethoxy, ethoxy, t-butoxy, and the like.

The term "alkyl" means a straight- (r branched-chain carbon radical of the size indicated. Representative of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-',utyl, isobutyl, t-butyl, 2-ethylhexyl, n-octyl, 2,4-dimethylpentyl, and the like.

The term "alkylamino" means an alkyl group, as defined above, of the size indicate attached to an amino group. This definition includes the dialkylamino group.

26 e: xamples include methylamino, ethylamino, dimethylamino, and the like.

The term "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.

**epresentative of such radicals are ethynyl, n-propynyl, butynyl, 3-ethylhexynyl, n- .*.dctynyl, 4-methylpentynyl, and the like.

The terms "amino acid" and "dipeptide", as used herein, refer, respectively, to a single a-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.

4684.US.P3 The term "carbocyclic-C6-C1o-aryl" as used herein 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.

The term "carbocyclic C 6 -Cio-aryloxy" means an oxygen atom linked by an ether bond to a carbocyclic-C6-Clo-aryl group, as defined above, and exemplified by phenoxy, benzyloxy, and the like.

The term "carbocyclic C 6 -C1o-aryloxyalkyl" means a carbocyclic C6-Clo-aryloxy group, as defined above, attached to an alkyl group, as defined above.

The term "carbocyclic arylalkyl" means an alkyl group, as defined above, of the "ize indicated substituted with a carbocyclic-C 6

-C

10 -aryl g-oup, as defined above.

.1 *Representative examples of carbocyclic-C6-Clo-arylalkyl groups are benzyl and pheny!ethyl groups.

The term "catechol-protecting groups" as used herein refers to groups used to derivatize catechol hydroxyl oxygen atoms in order to prevent undesired reactions or degradation during a synthesis. The term "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). These derivatizing groups may be selected from 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. Commonly used catechol-protecting groups :***ifjcluVde dimethyl ethers, dibenzyl ethers, cyclohexylidene ketals, methylene acetals, acetonide derivatives, diphenylmethylene ketals, cyclic borate esters, cyclic carbonate esters, cyclic carbamates and the like.

The term "cycloalkyl" as used herein refers to a C 3 -and-up monocyclic, C 4 -andup 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, cycloctadieno, bicycloheptane, bicyclooctane, adamantane, norbornane, norbornene, camphene, pinene, and the like.

The term "cycloalkyl-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 -Cjo-alkyl.

e 26 4684.US.P3 The term "fused" is used herein to mean t" cyclic groups having at least two atoms in common to both rings.

The term "haloalkyl" refers to a alkyl group of the size indicated, as defined below, bearing at least one halogen substituent, for example chloroethyl and trifluoromethyl.

The terms "halo" or "halogen" refer to bromo, chloro, fluoro and iodo.

The term "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. In the 3-or-4 membered rings, there S may be only one hetero-atom, selected from N, 0, and S. In the 5-or-6 membered i. 'ings there may be from 1-to-3 nitrogen atoms, one N and one S, or one N and one 0.

.Examples of Het include furan, tetrahydrofuran, thiophene, pyrrolidine, pyridine, *piperidine, isoxazole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, *:*benzofuran and the like.

The term "Het-alkyl" means a Het, as defined above, attached to an alkyl of the size indicated, for example, Het-C 1

-C

5 -alkyl.

The term "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 .:**:gompounds of Formula 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 .*..**uccinoyl, t-butyl succinoyl, ethoxycarbonyl, methoxycarbonyl, benzoyl, 3gminocyclohexylidenyl, and the like.

The term "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.

The term "substituted alkenyl" means an alkenyl group, as defined above, monosubstituted with cyclo-C--C 8 -alkyl, carbocyclic C 6 -Clo-aryl, amino, hydroxy, C1-C4alkoxy or with a pyrrolidine, piperidine, pyridine, quinoline, isoquinoline, thiophene or isoxazole heterocycle.

The term "substituted alkoxy" means an oxygen atom linked by an ether bond to a substituted alkyl group, as defined below, of the size indicated.

4684.US.P3 The term "substituted alkyl", as used herein, 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, C1-C4-alkoxy, amino, C1-C4alkyl amino, C 3 -C8-cycloalkyl and C1-C4-alkanoylamino.

The term "substituted alkylamino" means a substituted alkyl group, as defined above, of the size indicated, attached to an amine group.

The term "substituted alkynyl" means an alkynyl group mono-substituted with pyclo-C 3

-C

8 -alkyl, carbocyclic C6-Cio-aryl, or with a Het as defined below.

t The term "substituted carbocyciic-Cs-Clo-aryl" means a carbocyclic-C6-Co1-aryl 16 .*'roup, as defined above, substituted with 1-to-5 non-hydrogen substituents, for xample, halogen, hydroxy, C1-C 4 -alkyl, C1-C 4 -alkoxy, or one phenyl group or one S*.,rifluoromethyl group in conjunction with 0-to-4 of the said non-hydrogen substituents.

The term "substituted carbocyclic-C6-C 1 o-arylalkyl" means a substituted carbocyclic-C6-C 1 o-aryl, as defined above, attached to an alkyl group, as defined above, of the size indicated.

The term "substituted carbocyclic-C 6 -C0o-aryloxy" means an oxygen atom linked by an ether bond to a substituted carbocyclic C6-Clo-aryl group, as defined above.

The term "substituted carbocyclic C6-C 1 o-aryloxyalkyl" means a substituted carbocyclic C6-Clo-aryloxy group, as defined above, attached to an alkyl group, as efined above.

The term "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 :"~bialogen, hydroxy, C1-C4-alkoxy, amino, C1-C4-alkyl amino, and C1-C4lkanoylamino.

The term "substituted Het" refers to a Het, as defined above, that may possess 1to-3 substituents selected from halogen, hydroxy, C 1

-C

4 -alkoxy, amino, C1-C 4 -alkyl amino, and C1-C 4 -alkanoylamino.

The term "substituted Het-alkyl" means a Het-alkyl group, as defined above, that may possess 1- to-3 substituents selected from halogen, hydroxy, C1-Cio-alkoxy, amino, C1-C4-alkyl amino, and C 1

-C

4 -alkanoylamino.

The term "administration" of the dopaminergic agent or composition, as used herein, 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 4684.US.P3 containing conventional nontoxic pharmaceutically acceptable carriers, adjuvar.'s and vehicles as desired.

The term "parenteral" as used herein includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion techniques.

By "pharmaceutically acceptable" it is meant those salts, amides and esters which 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 SYesponse and the like, and are commensurate with a reasonable benefit/risk ratio, bl:'".ffective 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 J. Pharmaceutical Sciences, 66: 1 19, 1977. The salts can be prepared in situ during the final isolation and purification of the compounds of Formula or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include hydrochloride, hydrobromide, sulfate, :-'*tisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, m *...benzoate, lactate, phosphate, toluenesulfonate, methanesulfonate, citrate, maleate, Sfmarate, succinate, tartrate, ascorbate, glucoheptonate, lactobion te, lauryl sulfate 2Q:'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 fitom C1-C6-alkyl carboxylic acids wherein the alkyl groups are straight or branched ohain, aromatic carboxylic acids such as derivatives of benzoic acid and heterocyclic a oo carboxylic acids such as furan-2-carboxylic acid or nicotinic acid. Amides of the compounds of Fornmua 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.

As used herein, the term "pharmaceutically acceptable carriers" means a nontoxic, 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 suc*ose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose aretate; 4684.US.P3 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; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible .substances used in pharmaceutical formulations. Wetting agents, emulsifiers and 'Jubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring 16 '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. Examples of pharmaceutically acceptable *"'antioxidants 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; end the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid sorbitol, tartaric acid, phosphoric acid and the like.

to 0 By a "therapeutically effective amount" of the dopaminergic agent is meant a aq:gufficient 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 *;*~.yvill 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.

The term "affective disorder" as used herein refers to disorders that are characterized by changes in mood as the primary clinical manifestation, for example, depression.

4684.US.P3 The term "antipsychotic agent" as used herein 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.

The term "attention deficit disorder" refers to a recently classified pediatric neuropsychiatric disorder characterized by inattention, impulsivity, distractibility and sometimes hyperactivity, which replaces the less formal diagnoses of hyperactivity Ssyndrome, hyperkinetic syndrome, minimal brain dysfunction and specific learning ":"aisability. 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.

The term "cognitive impairment" refers to a deficiency in any of the aspects of the cognitive (information processing) functions of perceiving, thinking and remembering.

i he term "dopamine-related cardiovascular disorders" as used herein 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 qardiovascular agents. The usefulness of dopaminergic agents in cardiovascular diseases, for example in the treatment of shock and congestive heart failure, is based 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 eds. Also included are 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.

The term "dopamine-related neurological and psychological disorders" as used herein 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, Huntington'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. Also included are miscellaneous indications for which dopaminergic agents have been found to be clinically useful. Examples of such indications 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.

4684.US.P3 "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 3,4dihydroxyphenylacetic acid. Abnormal dopamine levels are those levels that are not within the range of dopamine levels found in the brains of control subjects.

The term "substan.e abuse" is used herein to mean periodic or continued selfadministration of psychoactive substances in the absence of medical indications and despite the presence of persistent or recurrent social, occupational, psychological or :physical problems that tht person knows are caused by or may be exacerbated by 1o: .'continued use of the substance.

*0.

o 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. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 Smg 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.

Injectable preparations, for example, 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. Among the 4684.US.P3 acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, 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.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of a drug from subcutaneous or intramuscular injection. The most common way to *:*accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility 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 :*.**absorption 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. Depending on the 'ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. The depot injectables can also be made by Sntrapping 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.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms 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, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets 4684.US.P3 .and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release-controlling coatings.

Solid 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 tne 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.

If desired, 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 bacteriaretaining filter, or by incorporating 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. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transderma; administration of a compound of this invention further include ointments, pastes, cr.ams, 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, 4684.US.P3 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 a compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be aQ .Used to increase the flux of the compound across the skin. The rate can be controlled either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

In general, the compounds of this invention are synthesized by reaction schemes I through XVI as illustrated below. It should be understood that R 1

R

7 as used herein correspond to the R groups identified by Formula The oxygens of the catechol groups can be derivatized with "protecting groups" or "leaving groups" which are **:-nown 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. Commonly used phenol derivatives are ethers, for example alkyl, alkenyl, and cycloalkyl ethers (such as methyl, isopropyl, t-butyl, cyclopropylmethyl, cyclohexyl, allyl ethers and the alkoxyalkyl ethers such as methoxymethyl or methoxyethoxymethyl ether and the 'ke; 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, benzyl and the like; carbamates such as methyl, isobutyl, phenyl, benzyl, dimethyl, and the like; and sulfonates such as methanesulfonate, trifluoromethanesulfonate, toluenesulfonate and the like. Commonly used catechol derivatives include cyclic acetals and ketals such as methylene acetal, acetonide derivatives, cyclohexylidene ketal, diphenylmethylene

I

4684.US.P3 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, N-hydroxysuccinic acid imide ester Smethod, cyanomethyl ester method and the like), the Woodward reagent K method, the S DCC-HOBT (1-hydroxy-benzotriazole) method and the like. Classical methods for i. .*amino acid condensation reactions are described in "Peptide Synthesis" Second *".•.Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).

As in conventional peptide synthesis, 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 o-chloro-benzyloxycarbonyl p- '.'".nitrobenzyloxycarbonyl p-methoxybenzyloxycarbonyl t- ,butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc), 9- "Vlfluorer- .Imethoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc), tifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl (Nps), diphenylphosphinothioyl (Ppt) and dimethylphosphinothioyl (Mpt).

The examples of 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.

In the course of the synthesis of ctertain of the compounds of the present invention, specific amino acids having functional groups other than amino and carboxyl groups in the branched chain such as arginine, cysteine, serine and the like may be protected, if necessary, with suitable protecting groups. It is preferable that, for example, the guanidino group (NG) in arginine may be protected with ritro, ptoluenesulfonyl (Tos), benzyloxycarbonyl adamantyloxycarbonyl (Adoc), pmethoxybenzenesulfonyl, 4-methoxy-2,6-dimethyl-benzenesulfonyl (Mts) and the like, and the thiol group in cysteine may be protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetomidomethyl, ethylcarbamyl, 4-methylbenzyl (4-MeBn, 2,4,6,- 4684.US.P3 trimethylbenzyl (Tmb) and the like, and the hydroxy group in serine may be protected with benzyl t-butyl, acetyl, tetrahydropyranyl (THP) and the like.

Scheme I A The compounds of Formula 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) and a substituted cetic derivative, such as phenyl acetic acid, are condensed in the presence of a io: .'ehydr :.ag agent, such as acetic anhydride, and a proton acceptdr such as ,..riethylamine (TEA) to give compound 2. The carboxylic acid (or acid derivative such 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). 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 sui-uxide (DMSO). 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 5) is prepared by intramolecular acylation of the protected catechoi ring using a *.**.ehydrating agent such as polyphosphoric acid or methanesuifonic acid/ trifluoroacetic acid. Compound 5 is converted to the corresponding cyanohydrin by treatment with a nucleophilic cyano derivative such as trimethylsilylcyanide and the cyano alcohol is reduced to the amine (compound 6) by treatment with a reducing agent such as LAH, preferably in a ether solvent such as diethyl ether. The 1-hydroxyl group is eliminated from compound 6 by heating it unde' acidic conditions, e.g. in isopropyl alcohol saturated with hydrochloric acid, to produce the dihydronaphthalene derivative (compound 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 ther deprotected with e.g. boron tribromide or boron trichloride to produce lB. In the 4GS4.US.P3 preferred embodiments of compounds I A and I B, R 3 is phenyl or cyclohexyl and X is bromo or chloro.

Schem I B 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 and S, *'condensed with an a!pha-beta unsaturated acid derivative such as ethyl cinnamate in presence of dimethyi-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 IA. Compound 5 is further converted to IA and IB as described in Scheme IA.

Scheme li The compounds of Formulas II A and II B are prepared by the method illustrated Scheme II. 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. Compounds of ****.oFormula 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 aid. Compounds of Formula 11 are reduced using a suitable reagent such as LAH followed by elimination with an acid such as hydrogen chloride in isopropano! to afford compounds of Formula' 12. Compounds of Formula 12 are treated with a suitable reagent for removal of the catechol protecting groups, for example boron tribromide, to yield the compounds of Formula II A.

Alternately, 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 4684.US.P3 removal of the catechol protecting groups, for example boron tribromide to afford the compounds of Formula 11 B.

Scheme III Compounds of Formulas III A III E are synthesized by the methods illustrated in Scheme IIl. Naphthalenones of Formula 5 are alkylated to afford the compounds of S'Formula 15 by treatment with a suitable base(for example lithium is(trimethylylsiyl)amide and a suitable alkylating agent such as allyl bromide. The l!),;:.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 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 III A are prepared by reduction of compounds of Formula ''17 with a suitable reagent (for example by hydrogenation using a suitable catalyst uch as palladium on carbon), followed by treatment with a suitable reagent for rO emovai of the catechol protecting groups such as boron tribromide resulting in :"simultaneous elimination of carbon dioxide to afford the desired amines.

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 1.y treatment with a suitable reagent for removal of the catechol protecting groups such as boron tribromide.

Compounds of Formuki- Ill C, III D and III E are prepared from compounds of Formula 20. Compounds of Formula 17 are con.erted to compounds of Formula 20 by hydroboration/oxidation under standard conditions. Compounds of Formula 20 are converted to compounds of Formula III C by treatment with 3 equivalents of boron tribrom ie. Compounds of Formula 20 are converted to compounds of Formula Ill D by treatment with 4.5 equivalents of boron tribromide Compounds of Formula 20 are c, -erted to compounds of Formula E by.reductive opening of the oxazolidinone ring followed by treatment with a suitable reagent for remo.1al of the catechol protecting groups such as boron tribromide.

39 4684.US.P3 Scheme IV The compounds of Formula IV A, IV B and IV C are synthesized by the method di mussed herein. A catechol (compound 22 wherein R1 is selected from alkyl groups such as methyl or both R1 groups together form a spiro cycloalkyl group such as cyclohexyl) is reacted in the presence of a base, such as n-butyl lithium, with ar :....,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, IQ .'benzyl, phenylethyl, n-octyl, n-hexyl, 1-hex-5-enyl, n-decyl, t-butyl or benzyloxymethyl;

R

3 and R 4 together form a spirocycloalkyl group,such as cyclohexyl), to produce *compound 24.

Compound 24 can oxidized to the corresponding ketone with an oxidizing agent such as pyridinium chlorochromate (PCC) and the resultant ketone can be stereoselectively reduced with, for example, B-chlorodiisopinocampheylborane (as i'".described in Example 46) to give the optically active isomers of compound 24.

Compound 24 is condensed with a bromoaldehyde such as bromoacetaldehyde dimethyl acetal or 3-bromopropionaldehyde dimethyl acetal to form the substituted *:'pbenzopyran derivative 26. Compound 26 is converted to compound 27 by treatment with a nucleophilic azide such as Ilhium azide in a polar solvent such as dimethyl formamide, followed by reduction of the azido compound for example with LAH.

*.*pompound 27 is converted to IV A by generation of the amine salt in acidic solution nd deprotection of the catechol hydroxyl groups in acid solution. Compound 27 is converted to compound IV 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 ir acidic solution. Compound 26 is converted to IV C by treatment with an amine such as allyl amine, cyclopropylamine or pyrrolidine, followed by deprotection of the catechol hydroxyl groups and generation of the amine salt in acidic solution. In the case wherein the epoxide 23 is substituted with a benzyloxymet',l group R 3 benzyloxymethyl), R 3 is further elaborated as shown in Scheme V.

4684.US.P3 Scheme V The compounds of Formula V A, V B, V C, V D and V E are synthesized by the methods illustrated in Scheme V. R1 is defined in Scheme IV. Compound of Formula 28 are aikylated with an epoxide of Formula 29 (wherein Bn is benzyl, z is an integer from 0 to 6, and R 12 is a substituent selected from the group R 3 to afford compounds of Formula 30. Compounds of Formula 30 are condensed with N-formylaminoacetaldehyde dimethyl a'etal in the presence of a catalyst selected from boron ""*trifluoride etherate, zinc triflate, trimethylsilyl triflate, methanesulfonic acid, p- Q: .'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 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 !s hydrochloric acid in alcohol.

Compounds of Formula V C are prepared from the compourds of Formula 33 by cylation of the free amino group followed by simultaneous rem 'val of the amine and catechol protecting groups in acidic solution.

Alternately, 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.

4684.US.P3 Alternately, compounds of Formula 32 are converted to V 'F by activation of the 3hydroxymethyl group, for example by reaction with methanesulfonyl chloride followed" by displacement with a nucleophilic amine, NHR9R10, in which R9 and R10 are independently selected from H and lower alkyl or R 9 and R10 together form a ring containing a nitrogen atom such as pyrrolinyl or piperidinyl or morpholino, followed by deprotection of the amino group and the catechol hydroxyls in acidic solution.

Scheme VI Q: According to reaction Scheme VI A, compounds of Formula 35, wherein R1 is as defined in Scheme IV, are converted to compounds of Formula 36 by treatment with *i;oxalyl chloride followed by treatment with O-methyl N-methyl hydroxylamine.

Compounds of Formula 36 reacted with furan in the presence of a suitable base such as n-butyl lithium to afford the compounds of Formula 37. The furan ring and the ketone are then reduced, for example by hydrogenation using a suitable catalyst such palladium on carbon to afford the compounds of Formula 24. Compounds of Formula 24 are valuable intermediates and can be converted to the isochroman and isothiochroman compounds of the present invention by any of the methods shown in .**:".Schemes IV, V, VII and VIII.

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 38A 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 acetylide, 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 forrnyl group to give chiral compounds of formula 39. Compounds of Formula 39 can be either hydrolyzed or reduced followed by conversion to the HCI salt to give certain chiral compounds of Formula VIB directly. Alternately, the formyl group I 3-~c 4684.US.p3 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 above.

Scheme VIIA Compounds of Formulas 43 or 44, where either X or Y is Br or Cl, are synthesized the method illustrated in in Scheme VIIA. Compounds of Formula IVA are protected qt the amino position with a suitable N-protecting group, such as BOC, AOC, or ADOC, *f6r example, by reaction with the appropriate reagent, to give the compounds of 1(J *'ormula 42. These compounds are then reacted with a brominating or chlorinating Spragent, such as free bromine or chlorine, HOCI, HOBr, N-bromosuccinimide, or N- "tfhlorosuccinimide, for example, and the protecting group is removed by hydrolysis with the appropriate reagent. A mixture of compounds 43 and 44 is obtained, which may be separated by standard procedures in the art.

a o Scheme VIIB 0* Compounds of Formula 46, where either X or Y is fluoro, methyl or ethyl are synthesized by the procedure outlined in Scheme VIIB. The compounds ealogous to the compounds of formula 22 of Scheme IV, are reacted according to the .**'pocedures given in Scheme IV, in order to prepare the desired compounds of *6 Formula 46, where X or Y is fluoro, methyl, or ethyl. These compounds may be taken further to prepare the compounds where the nitrogen is substituted, as illustrated in Schemes IV or IX.

Scheme VIII The compounds of Formula VIII are s,nthesized by the methods illustrated in Scheme VIII. Intermediates of Formula 24 are converted to the corresponding thio compounds of Formula 40 by treatment with triphenylphosphine and diisopropylazodicarboxylate, followed by treatment with thioacetic acid to afford an intermediate thiolacetate which was treated with a suitable reagent such as LAH. The compounds of Formula 40 are valuable intermediates and are converted to the 4684.US.P3 compounds of Formula VIII and the thio equivalents of compounds IV, V, V! and VII by the methods illustrated in Schemes IV VII.

Scheme IX The compounds of Formula IX A and IX B are synthesized by the method discussed herein. R1, R 2 and R 3 are defined in Scheme I. Compound 5 is converted to the cyanohydrin by treatment with a nucleophilic cyano derivative such as "::trimethylsilyl cyanide in the presence of a catalyst such as aluminum trichloride. The I ,'.cyanohydrin is dehydrated to the a,~-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 so** 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 chloride, and N-methoxyrethylamine. Compound 48 is converted to a mixture of diastereomeric pyrrolidinyl derivatives 49 and 50 by treatment with 2,2,5,5tetramethyl-1-aza-2,5-disilacyclopentane-1-propyl magnesium bromide (by the .:::*procedure given in Tetrahedron Letters 25:5271-5274 (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 and IX B, respectively, by treatment with boron trihalide, preferably boron tribromide.

Scheme X The compounds X A and X B are synthesized by the method discussed herein.

R1 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 tbutoxide. Compound 51 is reduced to the corresponding 1,2,3,4-tetrahydronaphthalene and the tricyclic ring system is formed by treating compound 51, with 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 4684.US.p3 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.

Scheme XI The compounds of Formula XI are synthesized by the method described herein.

R1 R3 are defined in Scheme I. Compound 5 is converted to the a-bromoketone by *e *:treatment with a brominating agent such as phenyltrimethylammonium tribromide. The bromide undergoes nucleophilic displacement, for example, with the anion of thiophenol to give the a-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 thioo.,,: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 chloromethyltrimethylsilane 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 dded 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 he azomethine ylid in situ which traps the activated double bond of the a, 3unsaturated 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 1-chloroethylchloroformate followed by acyl group removal with a nucleophile, such as methanol to give compound 62. The catechol is deprotected by treatment with a boron trihalide, preferably boron tribromide to give XI.

4684.US.P3 Scheme XII The compounds of Formulas 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 ip: .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.

Alternately, 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 The compounds of Formula 65 are, in turn, cyclized by treatment with a suitable 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 ihydroxyl 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.

4684.US.p3 Scheme XIII The compounds of Formulas XIII 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 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 .o*xazolidinone ring with the elimination of carbon dioxide. The resultant amino o°lcohols 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 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 XIII A.

The compounds of Formula 21 are treated with a suitable reagent for protecting S.'*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. 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 XIII B.

,Scheme XIV The compounds of Formulas XIV A and XIV 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 tbutoxide. 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.

Compounds of Formula 74 are treated with diphenylphosphoryl azide and benzyl alcohol in the presence of a base such as triethylamine to give the carbobenzyloxy 4684.US.P3 protected amino derivatives, which are deprotected along with'the catechol hydroxyl groups using, for example, hydrogen bromide in acetic acid to give XIV A.

Alternately 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.

Scheme XV compounds of Formulas XV A arid XV B are synthesized by the methods "described herein. R 1 and R 3 are defined in Scheme I. The compounds of Formula 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 t'ie corresponding 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 tricyclic 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 rifluoroacetic acid, followed by hydrolysis of the ester group in basic solution affords compounds of Formula 81. Compounds of Formula 81 are treated with diphen'viospsphoryl 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 XV A.

Alternately 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 X!V A.

e 48 4684.US.P3 Scheme XVIA The process illustrated in 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 Nformylamino-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 S ether solvent such as diethyl ether or THF, or a polar aprotic solvent such as 1i, *acetonitrile. The reaction is carried out in the temperature range of'from about 0°C to '..about 100°C. The preferred reaction temperature is determined by the choice of ,j 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

S

**°from about 1 tc about 4 equivalents, preferably from about 1.5 to about Y"V'equivalents. The catalyst is preferably selected from boron trifluoride etherate, trimethylsilyl triflate, zinc triflate, polyphosphoric acid, methanesulfonic acid and ptoluene oulfonic 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 reaction is carried with either 1 mole trimethyisily! tifiate in refluxing acetonitrile br with 5 mole boron trifluoride etherate in refiuxing 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 XVIA 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. Alternately, 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 XVIA can be either hydrolyzed or reduced to give certain compounds of Formula I directly.

4684.US.P3 Scheme XVIB The process illustrated in Scheme XVIB is a practical method for preparing isochroman or thioisochroman compounds substituted with pyrrolidine at the 1position. The compounds of Formula 24 are condensed with the dimethyl acetal of S,*.,prolinaldehyde in the presence of an acid catalyst to afford the compounds of Formula .XVIB. 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 1,2i* dichloroethane, an ether solvent such as diethyl ether or THF, or a polar aprotic S",.,solvent such as acetonitrile. The reaction is carried out in the temperature range of ,:'"from about 0°C to about 1000C. The preferred 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 4catalyst is present in the range of from about 1 mole to about 3 equivalents. Most jpreferably 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 XVIB 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).

4684.US.P3 Scheme XVII Compounds of Formula I, as represented by the compounds of formula XVIIA-D, are alternately synthesized by the methods described herein. An ester compound of formula 86, wherein R 3 and R 4 are as described in Scheme IV, is treated with a strong base, preferrably LDA, and reacted with a bromomethyl catechol derivative of :*.*'ompound 87, wherein R 1 is as described in Scheme I. The intermediate is reduced 0 with a reducing agent such as LAH to produce the compound 88.

Compound 88 is selectively oxidized to the aldehyde 89, preferrably by reaction le" "with sulfur trioxide-pyridine, triethylamine and DMSO. Compound 89 is reacted with Os S.'osiTMS-dithiane to form the thiane derivative of the aldehyde. This intermediate is ,'°made to undergo an incernal ring closure by reacting it with HgCl2, 5% aqueous methyl cyanide to produce compound The tetralone compound 90 is then converted to the aminomethyl compou,,u 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 XVIIA as '*"'described in Scheme 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 rAduction to give the amino-disubstituted compounds similar to compounds IVC as described in Scheme IV.

Compound 93 is obtained by catalytic reduction as described in Scheme I.

Compounds XVIIB, C, and D are obtained by the appropriate deprotection as *'*-,escribed previously.

Scheme XVIII Compounds XVIIIA-D are synthesized by the methods illustrated in Scheme XVIII.

R

1

R

3

R

4 and R 6 are as described in Scheme XVII. Compounds of formula 90 are converted into compound 95 by the reactions described for converting compound into compound 11 in Scheme II. The lactone. 95 is reduced with LAH in THF to produce the amino diol compound 96, which by reac.ion with PBr 3 in methylene chloride undergoes ring closure to form compound 97. Deprotection of compound 97, by methods described earlier, produces compound XVIIIA.

8 51 4684,US.P3 Alternately, compound 97 may be alkylated at the ring-nitrogen position, by the amino alkylation procedures referred to above, to produce compound 98, which upon deprotection is converted into compound XVIIIB.

Also, alternately compound 97 is converted into compound 100 by catalytic hydrogenation over a catalyst as described earlier, which may then be deprotected to give compound XVIIID.

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 XVIIIC.

0 4684.US.P3 Scheme I A R'0 CHO Rio!

R

3

CHCO

2

H

R

1 0 R'O 2 C0 2

H

O* *S o 0 0 ogoeR 0 0 00 0 000 00 0 000 o Se.

0 0000

R

1 0 R'O 4

ON

I2 steps 2 steps 0* 50 0 0 0 0 2 steps R' 0 0 00000e 0 00 0 0 0 05 2 steps,-

NH

2

HCI

'IHa HX IA ~HH 53 Scheme I B EtO 2

C

4684.US.P3 0*

S

S

S

5.

S S

S

SOS

S 555

S

I 3 steps

R

1 0 R'O R 3 7

NH

2

HOI

3 steps

R'O

R

1 0R 0 5555* S

S

S. S 5 5 S 55 2 steps IB -NH 2

HX

054 4684.USP Scheme 11 R OR' 1 R

OR

1 2' R2steps R'01 R C0 2

R

OR

1 /1 2tpsN 0*9 x1 2sstpsps 0000 R' 11OR 1 HO O R 3 R 0

R

*OH

12 ~NH 2 HX 1 NC 2 00H A

OR

1 OHO 0 R 3 N OH

NH

2

HX

4684.US.P3 Scheme III

OR'

R'O v R 0

OR'

2 steps_ 2 steps 0

B

B

o oB S B

B

B

0S*

B..

S

OBBB

2 steps B. *S B B 0 B B 0* S 0*SB S B *0 B IIA

'NH

2

HX

OH

OHH

IIC NH 2

HX

OR'

R'O

R

N O H

HN,

0

OH

OH

HO R 3 III B

NH

2

HX

NH

2

HX

1110

NH

2 HX III E 4684.US.P3 Scheme IV R4 23 0 0 0 0 0 0 000 0 00 0 *00 S 0 0000 MeO yOMe

OH

2 Br

RIO

RIO,

RIO.

0S 00 0 0 0909 Oe 00 5 9000 o 09 00 0

NH

2 26 CH 2 Br 3 steps 009*** 0 OS 0 00 0 2 steps

OH

2 IB

I

NHR

5

HX

IVA

NH

2

HX

OVC H 2 N -9 6

HX

4684.USo-.P3 Scheme V OBn 29 OBn OR' -Rl RIO Z-o

(CH

2 )z NJ OH 4. 04 4 4 4

S

4 4 4 04 .4.

S See

C

OBn LI' 1 3 steps

'NH

2

HX

31 NHCHO *4 4.

S C o .4.9 44 4* 4 44 44 4 4 444444 4 4S 0 44 04 /3steps

NH

2 RO OR' -J R1

(CH

2 )z

R

1 0 0 33 NHBoc 1 4 steps

NR

9

R'

0 HX 3 steps

-NH

2

HX

V F 2 st 7 34 eNH 2

HX

R 12V 2 steps 4 steps NHAc .ACH2)zR 1 di

NHCH

3

HY.

v c 4684.US. P3 Scheme VI A

OR'

OH

OMe

C.

*0 C

C

OCC*CC

0 C *0 C 0 GeC C

C.

C*C

C

*0 C C* CC

CO

0@ 0 e.g.

CC

00 C Scheme VIB 0 0 CC C C C 1. n-BuLi 2.

OR'

R

1 0 ~I OH R' C)

CI

OR

1 38A

OR

1 Z OH

NH

2 HOI 39NHHI 38B NH2 HCI 4684.US.P3 Scheme VIIA Y Br or CI) IVA NH 2 eq *0 0 e 0

C

*OVeOe C C *0 C e

C

0*

B

Bee

S

e.g.

42,

NH-BOC

NH

2

NH

2 s. VIP *.so B 0:

S

asC 0000* Scheme VIIB Y Me, or Et)

OR'

NH

2 9i 40'84.US.P3 Scheme VIlI

R

1 0 0 0 0 00

S

S..

0@SS 0 GS #5 0 o 0 5009 00 9S 0 1' 7

NR

6

R

7

HX

0 0@S@0 S 5 00 0 0 S 0 S @0 4684.US.P3 Scheme IX R'0

RIO

46

CN

3 steps 0 a 0 "0 *s 0 00 C 4.

*aS so0 0 0 #1 00

R

1 0 48 1 ~H

OCH

3

RIO

47 COOH R R 3

HX

IX A

HXI

IXA XIIX B HX 4684.US.P3 Scheme X

RIO

R'O 19 R 3 0

R

1

Q

RIO

R'.

51 C0 2

CH

3 C0 2

H

0* IS SO 0 0 a OeO*09 0 a.

ft 0 *00 S aft

S.

a..

*005 0 5000 2 steps 4 0 oi 0 *000 9a. 0- 2

CH

3 52 I 2 steps

R

1 0

H

54 H I 3 steps

RIO

R'O

RP

H

-H

0 C0 2

CH

3 53 I 2 steps RI0 13 steps

'NH

2

HX

NH

2

HX

X A X B 4684 US.P3 Scheme XI

R

1 0 R'O 6 0 R -NH 2 58 +Mc 2 steps I3 steps 6 00 0 '0 R'0 R'O

R

57 oa. S.

S S a Ba.,

B

U. a. a

R

HN

K TMS 59

R

N

N \-TMS O0H 3 .Rl 61 1--N\ NH HX 91 4684.US.P3 Scheme' XII

R

0O ae a f~l 4 a 9*

S

0 a.

V 0

B*S

a

OR'

R

1 0 R3 H m 64 S NH CBZ 1 2 steps XII B

"NJ

H H-X R 3 2 steps *%%OMs -NH CBZ XH A H H-X OR' Oa 1* S 0&S* a a.

a. V4OV ad.

4* 0OR' R' 0< H, NH 2

HFX

66

OR'

R'O

R

3 '4

O

67 O H

S

*Se#wq 9 S4 S a ea a, 2 Steps Ri' xii c H HX NH CBZ H FIX 68

'-NH

2

HFX

100 4684.US.P3 Scheme X",I I

OR'

R

1 3 3 steps R Ob

R

3 0OH

IM

n2 OOn 0NA 70

NHCBZ

2 steps 0 0 a

:*OH

HO R3

HXHN~

a. aa soe t OR'

OR'

*o R 1 0 R 3 2 steps R'O R 3 '21 71

NH

2 NHC8Z OH 2 steps HO HX HN) XIII B e1 4684.US.P3 Scheme XIV

R'O

RIO

0 ges S *o 0

R

1 0 RIO R 3

CH

3 000 COpCH 3 72 I 2 steps

R

1 0 73 C0 2

CH

3

R

1 0

I-

CH

3 00C CC) 2

CH

3 I 2 steps

RIO

76 00 2

CH

3 0 600.5 S

S

S. S S S

S*

RIO

74 C0 2

H

3 steps

R

1 0 R'O NR' 77 C0 2

H

I3 steps XIV A

NH

2

HX

NH

2

HX

XIV B 4684.US.P3 Scheme XV

R

1 0 0 79.. C0CH

NC

R

1 0 51 C0 2 0H 3

HOOC

R

1

Q

R

1 0

R

3 78 CO 2

CH

3

HO

R

1

Q

CO

2

CH

3 84

R

1 0

R

1 O R3 82 CO 2

CH

3

HO

2 steps

R

1 0 83 CO 2

CH

3

NC

es Ce CO0~ C 0 C. C e.g.

00 S. C

C

CCC...

C

Ce C 5 0

CS

2 steps 12 steps

R

1 0

R

1 0 R'O R 3 C0 2

H

3 steps i 3 steps XV B

OH

HO N R 3 XV A INH 2

HX

4684.US.P3 Scheme XVIA ,OMe

NHCHO

A is 0 or S

C.

C

C

C.

C

C..

Co C. CC C C

C

C. CC C C

CCCO

C C CC C

NHCHO

(XVIA), ,Ais 0or S Scheme XVIB

C

CCC CCC C C

CC

OMe 86B A is 0 or S

XVIB

I1 4684.US.P3 Scheme XVII R3%>'C02Et 86

OR'

RoN Br 8 7b C0 0 0

C

asS.

RIO I R 3R ~~0 89

OR'

HO

HO R 3 HO 4 XVIIA NH 2 XVIIC

MID

4684.US.P3 Scheme XV1II OR' I OR 1 I OR' W MeO R'O RNoR I C O 2 E t 0 049 N 0 96: H ORH S. 96 OH O N N

NH

XVIIIA H H~r HNH OR' OR' *RIO R R 4 RIO R4 R'O R N N N 98 699 100 HO R 3 HO

R

4

H

N N XV1IIB a6 xviIic R 6 XII0 H 71 4684.US.P3 The foregoing may be better understood by reference to the following examples which are provided for the illustration and not the limitation of the invention.

Example 1 5.6-Dimethoxy-3-phenyl-1.2.3.4-tetrahydronaphthalen-1 -one Method A 1< Step 1: (E.Z)-3-(2,3''-Dimethoxyphenyl)-2-phenylprooenoic acid e o A solution of 202 g (1.21 mol) of 2,3-dimethoxybenzaldehyde (commercially S available from Aldrich Chemical 200 g (1.47 mol) of phenyl acetic acid (commercially available from Aldrich Chemical 600 mL of acetic anhydride 'f 5 and 204 mL (1.46 mol) of triethylamine (TEA) was heated at reflux temperature for 24 h. The reaction mixture was allowed to cool to ambient temperature and 1 L of water was added, followed by the addition of 2 L of ethyl acetate and another 4 L of water. The layers were separated and the organic layer was extracted with saturated aqueous sodium bicarbonate solution. The combined aqueous layers 0 were acidified with concentrated hydrochloric acid and extracted with 4 L of ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 250 g (72% yield) of the title compound as a 30/70 mixture of the E and Z isomers, m.p. 115-160°C; DCI MS: 285 .302 (M+NH4)+.

.Step 2: 3-(2'.3'-Dimethoxyphenyl)-2-phenylpropanol A solution of 15 g (395 mmol) of lithium aluminum hydride (LAH) in 500 mL of tetrahydrofuran (THF) was cooled to 0°C. A solution of 3 0 dimethoxyphenyl)-2-phenylpropenoic acid (50 g, 176 mmol), from step 1, in 100 mL of THF was added to the LAH solution dropwise over a 30 min period. The reaction mixture was heated at reflux temperature for 2 hand then cooled to 0°C The reaction was quenched by the sequential addition of 15 mL of water, 15 nm of aqueous sodium hydroxide solution and 45 mL of water. The precipitate was 3 5 filtered and the filtrate concentrated in vacuo to give 46.6 g (97% yield) of the title compound as an oil; 1 H NMR (CDCI3) 8: 1.8-.19 1H), 2.1-2.2 1H), 2.7-2.95 i 8 72 4684.US.P3 1H), 3.0-3.15 2H), 3.7-3.8 1H), 3.8 3H), 3.83 3H), 6.63 1H), 6.75 1 6.9 1 7.15-7.4 Step 3: 3-(2'.3'-Dimethoxyphenyl)-2-phenylpropane 1-methanesulfonate 3-(2',3'-Dimethoxyphenyl)-2-phenylpropanol (41.5 g, 15' ol), from step 2, and 30.5 g (301 mmol) of TEA were dissolved in 300 mL of Methanesulfonyl chloride (34.5 g, 301 mmol) was added slowly to this solution at 0°C. The reaction mixture was allowed to warm to ambient temperature. After stirring the reaction :1 mixture for 1 h at ambient temperature, it was diluted with 300 mL of diethyl ether and washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give 40.8 g (76% yield) of 3-(2',3'-dimethoxyph'enyl)-2pheiylpropane 1-methanesulfonate as an oil; 1H NMR (CDCI 3 6: 2.7 3H), 2.96 (dd, 1H), 3.1 (dd, 1H), 3.35-3.45 1H), 3.78 3H), 3.82 3H), 4.35 2H), 5 6.62 (dd, 1H), 6.77 (dd, 1H), 6.9 1H), 7.2-7.35 Step 4: 4-(2'.3'-Dimethoxyphenyl)-3-phenylbutanenitrile 3-(2',3'-Dimethoxyphenyl)2-phenylpropane 1-methanesulfonate 2 00 (40.5 g, 116 mmol), from step 3, and 17 g (347 mmol) of sodium cyanide were dissolved in 100 mL of dimethyl sulfoxide (DMSO) and the resultant solution was heated to 800C. After being stirred at 800C for 18 h, the reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate and washed sequentially with water and brine. The solvents were removed in vacuo to give 25 g 2 5: (77% yield) of the title compound as an oil; 1H NMR (CDC13) 2.56 2H), 3.02 8 1H), 3.05 1H), 3.25-3.35 1H), 3.72 3H), 3.75 3H), 6.65 (dd, 1H), 6.8 (dd, 1 6.93 1 7.2-7.4 Step 5: 4-(2'.3'-Dimethoxyphenyl)-3-phenylbutyric acid 4-(2',3'-Dimethoxyphenyl)-3-phenylbutanenitrile (20 g, 71 mmol), from Step 4, was dissolved in 1.5 L of ethanol. Sodium hydroxide (20 g, 0.5 mol) and 200 mL of water were added and the reaction mixture was heated at reflux temperature for 24 h. The solvent was removed in vacuo and 1L of water plus 1 L of methylene 3 5 chloride were added to the residue. The layers were separated and the organic layer discarded. The aqueous layer was acidified with concentrated hydrochloric 8 73 4684.US.P3 acid and extracted with 3 L of ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 21 g (98% yield) of the title compound as an oil; 1H NMR (CDCI3) 5: 2.6-2.7 2H), 2.9 2H), 3.4-3.5 1 3.72 3H), 3.82 3H), 6.6 (dd, 1H), 6.73 (dd, 1 6.88 1H), 7.1-7.3 Step 6: 5.6-Dimethoxy-3-phenyl-1.2.3.4-tetrahydron.phthalen-1-one 4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (37 g, 123 mmol), from Step 10 was added dropwise to 200 g of polyphosphoric acid heated to 1000C. The resultant mixture was stirred and heated at 100°C for 0.25 h. A mixture of 100 g of ice and 200 mL of water was added to the reaction mixture. Th6 precipitate which S formed was filtered, washed with 3 X 75 mL of water and dissolved in 300 mL of methylene chloride. The methylene chloride solution was dried over anhydrous 5 magnesium sulfate, filtered and concentrated to give 28 g (81% yield) of 5,6dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen- 1-one, m.p; 127-128C; 1 H NMR (CDCl3) 8: 2.75-3.0 3H), 3.3-3.5 2H), 3.8 3H), 3.95 3H), 6.93 1 H), 7.25-7.4 5H), 7.9 1 H).

*2Q Method B Step 1: 2-(2',3'-Dimethoxvphenyl)-1,3-dithiane A solution of 49.5 g (298 mmol) of 2,3-dimethoxybenzaldehyde and 48.4 g (447 S mmol) of propane-1,3-dithiol in 800 mL of methylene chloride was cooled to 0°C.

Boron trifluoride etherate (7.5 mL, 61 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at OOC for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was wGshed with 2 X 200 mL of 10% aqueous sodium hyaroxide solution, 200 mL of water and 100 mL of 3 0 brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 75 g (98% yield) of 2-(2',3'-dimethoxyphenyl)-1,3-dithiane, m.p. 119-120°C; 1 H NMR (CDCI3) 6: 1.8-2.0 1H), 2.1-2.25 1H), 2.86 1H), 2.91 1H), 3.05-3.2 (m, 2H), 3.83 3H), 3.91 3H), 5.68 1H), 6.86 (dd, 1H), 7.07 1H), 7.19 (dd, 1H).

74 4684.US.P3 Step 2: Ethyl 4-(2',3'-dimethoxyphenyl)-4-(1".3"-dithiane)-3-phenylbutyrate A solution of 2-(2',3'-dimethoxyphenyl)-1,3-dithiane (57 g, 222 mmol), from Step 1, in 273 mL of dry THF was cooled to -780C in a dry ice/acetone bath. To this solution was added 92.2 mL of a 2.5 M solution of n-butyl lithium in hexane. After the addition was complete the reaction mixture was stirred for 0.75 h at -780C. 1,3-Dimethyl-2-imidazolidinone (75 mL, 686 mmol), commercially available from Aldrich Chemical Company, was added to the reaction mixture in one portion, S followed by 39 g (221 mmol) of ethyl cinnamate (commercially available from 10 Aldrich Chemical Company) added dropwise. The reaction mixture was stirred for 1 h at -78 0 C then quenched with 50 mL of 10% aqueous acetic acid and allowed to warm to 0°C. The reaction mixture was diluted with 150 mL of diethyl ether and the layers separated. The organic layer was washed with 2 X 100 mL of saturated aqueous sodium bicarbonate solution, 100 mL of water and 100 mL of brine, dried 1 5 over anhydrous magnesium sulfate, filtered and concentrated to give a crude oily product. The crude product was crystalli.rd from ethyl acetate/hexane to give 32 g (48% yield) of the title compound, m.p. 1 5-1260C. A second crop of crystals yielded an additional 11 g (total yield 59%) of ethyl 4-(2',3'-dimethoxyphenyl)-4-(1",3"-dithiane)-3phenylbutyrate, m.p. 124.5-1250C; 1H NMR (CDC13) 5: 0.8 3H), 1.75-1.9 2H), 2.5-2.85 4H), 3.05-3.25 2H), 3.7-3.95 2H), 3.88 3H), 4.0 3H), 4.45- 1H), 6.8-6.9 2H), 7.0-7.4 6H).

Step 3: Ethyl 4-(2'.3'-dimethoxyphenyl)-3-phenylbutvrate D Ethyl 4-(2',3'-dimethoxyphenyl)-4-(1 ",3"-dithiane)-3-phenylbutyrate (14.5 g, 39 mmol), from Step 2, and 145 g Raney nickel and 300 mL of absolute ethanol were mixed together and heated at reflux temperature under 1 atmosphere of hydrogen for 3.25 h. The stirring was stopped and the mixture was allowed to cool slightly 3 0 before the solvent was decanted from the catalyst. An additional 300 mL of absolute ethanol was added to the catalyst and the mixture stirred and heated to reflux. The stirring was again stopped and the reaction mixture was allowed to cool slightly before the solvent was decanted from the catalyst. The combined supernatants were filtered through Celite® filter aid and concentrated in vacuo to 3 5 give 10.8 g (97% yield) of ethyl 4-(2',3'-dimethoxyphenyl)-3-phenylbutyrate as a clear oil; 1 H NMR (CDCl3) 5: 1.11 3H), 3.07 (dd, 1 3.35 (dd, 1H), 3.81 3H), 4684.US.P3 3.84 3H), 3.9-4.1 3H), 6.65 (dd, 1 6.77 (dd, 1 6.88 1 7.2-7.4 (m, Step 4: 4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid Ethyl 4-(2',3'-dimethoxyphenyl)-3-phenylbutyrate (40.3 g. 123 mmol), from Step 3, was dissolved in 400 mL of methanol and 62 mL of 3 M aqueous sodium hydroxide solution was added in one portion. The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated and the 1 residue was partitioned between 300 mL of diethyl ether and 200 mL. of water. The layers were separated and the aqueous layer was adjusted to pH 6 with 6 M aqueous hydrochloric acid solution and extracted with 3 X 200 mL of diethyl ether.

The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 37 g (100% yield) of the title compound as a colorless oil. The 1H NMR spectrum was identical to the spectrum reported for the product of Step 5 of Method A, Example 1.

Step 5: 5.6-Dimethoxv-3-phenyl-1.2.3.4-tetrahydronaphthalen-1-one *2 O0 4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (13.3 g, 44.3 mmol), from Step 4, was treated with 14 mL (216 mmol) of methanesulfonic acid and 200 mL of trifluoroacetic acid at 60°C for 1.5 h. After cooling the reaction mixture, the trifluoroacetic acid was removed in vacuo and ice water was added to the residue.

Methylene chloride was added and the layers were separated. The organic layer .2 5. was washed with 1N aqueous sodium hydroxide solution, water and brine, dried S over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized three times from methanol to give 9.6 g (77% yield) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, m.p.

126-128°C; 1 H NMR spectrum was identical to the spectrum reported for the 3 C0 product of Step 6 of Method A, Example 1.

76 4684.US.P3 Example 2 1-Aminomethyl-5.6-dihydroxv-3-phenyl-3.4-dihydronaphthalene Step: 1 1-Aminomethyl-5.6-dimethoxy-1-hydroxy-3-phenl-1 .2,3.4tetrahydronaphthalene 5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one (14.6 g, 51.7 mmol), from Example 1, 24 mL of acetonitrile, 10.3 g (104 mmol) of S1 0 trimethylsilylcyanide, commercialiy available from Aldrich Chemical Company, and 100 mg of aluminum chloride were mixed together and heated at reflux o* temperature for 2.5 h. The reaction mixture was cooled and concentrated. The S residue was added dropwise to a solution of 4.3 g (113 mmol) of lithium aluminum hydride in 101 mL of diethyl ether. After the reaction mixture was heated at reflux temperature for 2.5 h, 4.3 mL of water was added dropwise, followed by 4.3 mL of aqueous sodium hydroxide solution, followed by a second 4.3 mL of water.

The reaction mixture was stirred until a granular precipitate formed. The solid was filtered and washed with 3 X 80 mL of methylene chloride. The filtrate was concentrated and the resultant solid was triturated with ethyl acetate/hexane to give 120 11.9 g (73% yield) of the title compound, m.p. 175-176 0 C; 1 H NMR (d 6 -DMSO) 8: 2.03 1H), 2.28 (dt, 1H), 2.65 (dd, 1H), 2.83 (dd, 1H), 2.95-3.1 2H), 3.28 (dd, 1 3.75 3H), 3.86 3H), 6.87 1H), 7.2-7.4 6H).

Step 2: 1 -Aminomethyl-5.6-dimethoxy-3-phenyl-3.4-dihydronaphthalene .235: hydrochloride o 1 -Aminomethyl-5,6-dimethoxy-1 -hydroxy-3-phenyl- ,2,3,4tetrahydronaphthalene (11.5 g, 37 mmol), from Step 1, was heated at reflux temperature in 300 mL of isopropyl alcohol saturated with hydrochloric acid for 2 h.

3 0 The resultant solution was concentrated and the solid residue was triturated with hot toluene to give 10.6 g (98% yield) of 1-aminomethyl-5,6-dimethoxy-3-phenyl- 3,4-dihydronaphthalene hydrochloride, m.p. 189.5-190 0 C; 1 H NMR (d 6 -DMSO) 2.78 (dd, 1H), 3.11 (dd, 1H), 3.2-3.4 2H H 2 3.6 3H), 3.81 3H), 3.93 1H), 6.1 1H), 6.93 1H), 7.12 1H), 7.2-7.4 4684.US,P3 Step 3: 1 -Aminomethyl-5.6-dihydroxy-3-phenyl-3.4-dihydronaphthalene hydrobromide (Example 2A) 1-Aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (6.0 g, 20.2 mmol), from Step 2, was suspended in 200 mL of methylene chloride and boron tribromide (90.5 mL of 1 M solution of BBr 3 in methylene chloride) was added dropwise while the reaction mixture was being cooled (to -780C) in a dry ice/acetone bath. The reaction mixture was warmed to 0°C and stirred for 0.5 h, then again cooled to -780C in a dry ice/acetone bath. Methanol (50 mL) was added dropwise to the reaction mixture, which was allowed to warm to ambient temperature then concentrated in vacuo. Methanol was added to the residue and the solution was reconcentrated. This residue was dissolved in'a small amount of S methanol and the methanol solution was added to 700 mL of diethyl ether. The precipitate which formed was filtered, washed with diethyl ether and recrystallized 1 5 from methanol/ether to give 2.5 g (45% yield) of the title compound, m.p. 223- 2250C, 1 H NMR (d 6 -DMSO) 6: 2.68 (dd, 1H), 3.09 (dd, 1H), 3.6-3.7 1H), 3.9 (s, 2H), 5.97 1 6.69 2H), 7.2-7.35 5H), 8.1 (br s, 3H), 8.4 1H), 9.5 (s, 1H).

"2 0 Step 4: 1-Aminomethyl-5.6-dihydroxy-3-phenyl-3.4-dihydronaphthalene hydrochloride (Example 2B) A slurry of 10 g (25 mmol) of 1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4dihydronaphthalene hydrochloride, from Step 2, in 150 mL of 1,2-dichloroethane was cooled to 100C under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then-cooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambisnt temperature 3 0 and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and mL of heptane. Off-white crystals of 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4dihydronaphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, 3 5 m.p. 204-2050C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.

78 4684.US.P3 Example 3 5.6-Bis(acetoxy)-1-aminomethyl-3-phenyl-3.4-dihydronaphfhalene hydrochloride A suspension of 7.6 g (25 mmol) of 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4dihydronaphthalene hydrochloride (Example 2B) in 400 mL of acetic anhydride saturated with anhydrous hydrogen chloride was stirred at ambient temperature for 48 h. Approximately 2 L of diethyl ether was added and a solid was collected by filtration and washed with diethyl ether. Crystallization of the crude material (6.7 g) °16 was achieved by dissolving the powder in 400 mL of hot ethanol, adding 100 mL of water, filtering the solution hot and allowing it to cool. The white crystals which formed were filtered and dried to give 2.8 g (29% yield) of 5,6-bis(acetoxy)-1 aminomethyl-3-phenyl-3,4-dihydronaphthalene hydrochloride, m.p. 207-208°C. 1H NMR (d 6 -DMSO) 8: 2.28 6H), 2.62 (dd, 1H), 2.95 (dd, 1H), 3.7-3.8 1H), 3.97 "i 5 2H), 6.25 1 7.19 1 7.2-7.4 6H), 8.41 (br s, 3H).

Example 4 0 5.6-Bis(acetoxy)-l -(alany-alanyl)aminomethyl-3-phenyI-3.4-dihydronaphthalene hydrochloride (general procedure for preparation of arino prodruas) 0 ObO Step 1: 5,6-Bis(acetoxy)- -(N-t-butoxycarbonyl-alanvl-alanvlaminomethyl-3phen'y -3.4-dihydronaphthalene 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-3,4dihydronaphthalene hydrochloride (3 g, 7.74 mmol), the product of Example 3, in mL of DMF. The resultant solution was cooled to 0°C. To the cold solution was added 1.56 g (8.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 3 0 hydrochloride (EDCI), followed approximately 10 minutes later by 1.1 g (8.13 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) and, after allowing the HOBT to dissolve, by 1.8 g (16 mmol) of 4-methylmorpholine (NMM). The resultant solution was stirred for 3 h at 0°C and then stirred overnight at ambient temperature. The reaction mixture was then diluted with 100 mL of water and the resultant milky 3 5 mixture was extracted with 3 X 75 mL of ethyl acetate. The combined organic layers were washed successively with 50 mL of 1 M aqueous phosphoric acid solution, 4684.US.P3 Table 2: Examples 38 43 HO

O

N OH

NH

2

HCI

Aldehyde rn.P.

0 C0 MS* 0

OCH

3 210 284 Elemental Analysis C H -N calc 54.05 5.20 3.71 +3/4

H

2 0 .738 Found: 53.95 49738 calc: 55.78 5.01 3.83

H

2 0 Found: 55.64 5.25 3.74 39 a 0*0 09 41 0S *0 S OH OH

H.

NH

2

HCI

OH-

HO.

NH

2

HCI

OH

HO~.

N'

NH

2

HCI

OH

HO

NH

2

HO!

223-6 284 0 0 0 H >22 H-II1 192-8 318 C H N calc: Found: na calc: Found: na** 0:.

*5 9 50 ft 90 0 H

-I

OCH

3 2500C 286 HN cabc: 53.13 5.77 3.65 +1 HP0 Found: 52.97 5.53 4.03 0 190-6 320 C H N calc: Found: na*** all compounds 1-3 cis unless indicated otherwise DCI MS structure confirmed by NMR data 4684.US.P3 Example 44 1-Aminomethyl-5.6-dihydroxy-2-(2'-hydroxy-1'-ethvl)-3-phenyl-3.4dihydronaphthalene hydrobromide Step 1: 2-(Carboethoxy)methyl-5.6-dimethoxy-3-phenyl-1.2.3.4-tetrahydronaphthalen-1-one To a solution of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one 1.O0 (5 g, 17.7 mmol, 1.0 equivalents), the product of Example 1, in 150 rr of dry THF S cooled to -780C, was added 19.5 mL of lithium bis(trimethylsilyl)amide (1M solution in THF, 19.5 mmol, 1.1 equivalent). The resultant solution was stirred at -78°C for 1 h and then ethyl bromoacetate (2.2 mL, 19.5 mmol, 1.1 equivalent) was added in one portion. The reaction solution was then allowed to warm to ambient temperature and was stirred for 3 h. The reaction was quenched by the addition of mL of saturated ammonium chloride solution. The resultant light yellow colored THF layer was separated and evaporated to an oil. The oil was taken up into 200 mL of methylene chloride and the methylene chloride solution was washed with 2 X 50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate/hexane to give 5.4 g (83% yield) of the title compound as a white solid; IH NMR (CDCI 3 6: 1.2 3H, J=7.5 Hz), 2.45 2H), 3.03 1H), 3.30 2H), 3.43 1H), 3.78 3H), 3.93 3H), 4.07 2H), 6.92 1H, J=9.0 Hz), 7.32 5H), 7.89 1 H, J=9.0 Hz). Analysis calculated for 2.5: C 22

H

24 0 5 C, 71.72; H, 6.57. Found: C, 71.39; H, 6.63.

Step 2: 9b-Cyano-6.7-dimethoxy-2-oxo-4-phenyl-2,3.3a.4.5.9bhexahydronaphtho[1,2b]furan 3 0 To a solution of 2-(carboethoxy)methyl-5,6-dimethoxy-3-phenyl-1,2,3,4tetrahydronaphthalen-1-one (1.0 g, 2.7 mmol, 1.0 equivalent) from Step 1, in 10 mL of anhydrous toluene at ambient temperature was added 5.4 mL of diethylaluminum cyanide (1M solution in toluene, 5.4 mmol, 2.0 equivalents). The resultant solution was stirred at ambient temperature for 1 h and then poured with 3 5 vigorous stirring into a mixture of 15 mL of concentrated hydrochloric acid and mL of ice water. The organic layer was diluted with 75 mL of methylene chloride 3 91 4684.US.P3 and then separated from the aqueous layer. The organic layer was washed with mL of 2 M anhydrous hydrochloric acid solution, 25 mL of water and 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 1 g (105% crude yield) of the title compound as an oily residue. The crude product was carried on to the next step without purification; 1 H NMR (CDCI 3 8: 2.45 1H, J=18.0 Hz), 2.72 2H), 3.05 1 3.23 1H), 3.37 1H), 3.79 3H), 3.94 3H), 7.0 1 7.30 5H), 7.52 1 H, J=9.0 Hz).

Step 3: 1-Aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-3.4- 1 Q. dihydronaphthalene hydrochloride To a stirred solution of 9b-cyano-6,7-dimethoxy-2-oxo-4-phenyl-2,3,3a,4,5,9bhexahydronaphtho[1,2b]furan (1.0 g, 2.86 mmol, 1.0 equivalent), from Step 2, in mL of anhydrous THF, was added lithium aluminum hydride (0.22 g, 5.7 mmol, equivalents) from a solid addition funnel. After the addition was complete, the reaction mixture was heated at reflux for 3 h. The reaction mixture was then cooled, poured into a 250 mL Erlenmeyer flask and was diluted with 50 mL of anhydrous THF. The reaction was quenched by the addition of excess sodium sulfate decahydrate. The resultant suspension was filtered through Celite® filter aid and 20. 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 hydrochloric acid in isopropanol and the resultant solution was heated at reflux for 18 h. The solution was then concentrated in vacuo. The residue was triturated with methylene chloride/diethyl ether to give 250 mg (25% yield) of the title compound; 1H NMR (CDCI 3 8: 2.03 1H), 2.63 1H), 3.12 2H), 3.37 (s, V 3H), 3.52 3H), 3.71 3H), 3.80 1H), 4.18 2H), 5.28 (br s, 1 6.23 (d, S 1 H, J=8 Hz), 6.95-7.4 6H). Analysis calculated for C21 H 26 CIN0 3 +1.5 H20: C, 54.16; H, 6.40; N, 2.87. Found: C, 54.15; H, 6.01; N, 3.01.

Step 4: 1-Aminomethyl-5.6-dihydroxy-2-(2'-hydroxy-l'-ethyl)-3-phenyl-3,4dihydronaphthalene hydrobromide To a solution of 1-aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)-3phenyl-3,4-dihydronaphthalene hydrochloride (60 mg, 0.177 mmol, 3 5 equivalent), from Step 3, in 2 mL of anhydrous methylene chloride cooled to 4684.US.P3 -780C was added 350 glL of boron tribromide (1.0 IA solution in methylene chloride, 0.35 mmol, 2.0 equivalents). The resultant solution was allowed to warm to ambient temperature gradually over a period of 2 h and then it was aigain cooled to -780C and quenched by the addition of 20 mL of anhydrous methanol. The solid was filtered and recrystallized from a mixture of methanol, methylene chloride and diethyl ether to give 50 mg (80% yield) of the title compound as a white powder, m.p. 252-255oO; DCI MS MIZ: 312 I.R. (KBr): 3400,1600,1490, 1280, 1200, 700 cm- 1 1 H NMVR (CD 3 OD) 6: 2.22 (in, 1 2.75 (in, 1 2.93 (in, 1 H), 3.30 (in, 1 3.70 (in, 3H), 4.13 1 H, J=1 2 Hz), 4.28 1 H, J=1 3.5 Hz), 6.70 (d, 0A. 1 H, J=7.5 Hz), 6.85 I1H, J=7.5 Hz), 7.10 (in, 5H). Analysis calculated for

.C

1 9

H

22 BrNO 3 +0.5 CH2CI2: C, 53.87; H, 5.33; N, 3.22. Found: 0, 53.54; H, 5.24; N,3.21.

Example [1 -2-trans] 1 I-Aminomcthyl-5.6-dihydroxy-2-(2'-hydroxy-1 '-ethyl)Y3-phenvl-1 .2.3.4tetrahydronaphthalene formic acid salt a tep 1: [1-2-trans] 2-(Carboet hoxy) methyl- 1-cyano-5.6-di met hoxy-3-ph eny 1-3.4- "42tV. dihydronaphthglene 9b-Cyano-6,7-dimethoxy-2-oxo-4-phenyl-2,3,3a,4,5,9b-hexahydronaphtho[1,2b]furan (5.0 g, 14.31 minol, 1.0 equivalents), the product of Step 2 of Example 44, was dissolved in 120 mL of a solution of 2 M anhydrous hydrochloric 2? 5: acid in ethanol and the resultant solution was heated at ref lux for 2 h. The solvent **:was evaporated in vacuo and the residue was dissolved in 120 mL of methylene chloride. The methylene chloride solution was washed with 2 X 25 mL of saturated aqueous sodium bicarbonate solution, 25 mL of water and 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5 g 3 0 (93% yield) of the title compound as a colorless oil; 1 HNMR (CDCI 3 5: 1 .22 3H, Hz), 3.24 (in, 3H), 3.54 3.70 1 H, J=1 5 Hz), 3.58 3.90 (in, 1 4.08 (in, 2H), 6.82 1 H, J=7.0 Hz), 7.03 (in, 2H), 7.20 (in, 3H), 7.30 1 H, Hz).

3 5 Step 2: 11 -2-transl 1 -Aininome-thyl-5.6-dimethoxy-2-(2'-hydroxv-l -ethyl)-3-phenyl- 1 .2.3.4-tetrahydronaphthalen e 93 4684.US.P3 To a stirred solution of 2-(carboethoxy)methyl-1-cyano-5,6-dimethoxy-3phenyl-3,4-dihydronaphthalene (2 g, 5.3 mmol, 1.0 equivalent), from Step 1, in mL of anhydrous methanol at ambient temperature, was added 5.13 g (212 mmol, 40 equivalents) of magnesium powder. The resultant mixture was stirred at ambient temperature for 2 h and then it was cooled to 0°C. The reaction was quenched by the slow addition of 150 mL of 2 N aqueous hydrochloric acid solution. The aqueous solution was extracted with 4 X 50 mL of methylene chloride. The combined organic layers were washed with 50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a colorless oil. The oil was dissolved in 75 mL of anhydrous THF. To this solution at 0°C was S added 0.4 g (10.5 mmol, 2.0 equivalents) of lithium aluminum hydride. The resultant mixture was heated at reflux for 4 h and then diluted with 100 mL of anhydrous THF. The reaction was quenched by the addition of sodium sulfate decahydrate. The reaction mixture was then filtered through Celite® filter aid and the filter cake washed thoroughly with hot THF. The filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluted with methylene chloride/methanol/ ammonium hydroxide (89:9;1) to give 1.15 g (63% yield) of the title compound as a 1:1 mixture of diastereomers; 1H NMR (CDCI 3 5: 1.15-1.5 (m, 2 3 0: 4H), 1.67 1 1.90 1 2.20 1 2.35 1 2.45 1 2.55-3.05 6H), 3.18 4H), 3.50 4H), 3.73 3H), 3.75 1H), 3.83 3H), 3.87 (s, 6H), 6.80 2H), 6.92 2H), 7.2-7.4 Step 3: [l-2-trans] 1-Aminomethyl-5.6-dihydroxy-2-(2'-hydroxy-l'-ethyl)-3-phenyl- 1.2.3.4-tetrahydronaphthalene formic acid salt o To a stirred solution of 1-aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)- 3-phenyl-1,2,3,4-tetrahydronaphthalene (0.6 g, 1.76 mmol, 1.0 equivalents), from Step 2, in 18 mL of anhydrous methylone chloride cooled to 3 0 -780C, was added 3.52 mL of boron tribromide (1M solution in methylene chloride, 3.52 mmol, 2.0 equivalents). The resultant reaction mixture was stirred at -780C for 1 h and then it was allowed to warm to ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h and cooled again to -78°C. The reaction was quenched by the addition of 50 mL of anhydrous methanol. The resultant 3 5 solution was stirred at ambient temperature for 1 h and then concentrated in vacuo.

The residue was chromatographed on silica gel eluted with ethyl acetate/formic I 94 4684.US.P3 acid/water (18:1:1) to give the title compound as a light tan colored powder, m.p.

19000 (dec); DCI MS M/Z: i 2 1. R. (KBr): 3400, 3240, 1600, 1490, 1290, 1050, 700 cm- 1 1 H NMR (CD 3 OD) 5: 1 .21 (in, 1 1.50 (in, 2H), 1.67 (in, 1 H), 2.15 (in, 1 2.22 (in, 1 2.53 (in, 1 2.63 (in, 1 3.10 (in, 8H), 3.43 (in, 2H), 3.50 (in, 2H), 7.6 (in, 2H), 7.72 (in, 2H), 7.23 (in, 4H), 7.35 (in, 6H), 8.51 2H).

Ana',-sis calculated for C1 9

H

23 N0 3 +2.5 HCO2H: 0, 56.96; H, 6.37; N, 2.45.

Found: C, 56.72; H, 6.08; N, 3.30.

Example 46 1 -Aininoinethyl-5,6-dihydroxy-3-phenylnaphthalene hydroghloride, .0 Step 1: 1 -(N-t-Butgxycarbonyl)aininomethvl-5.6-bis(acetoxy)-3-phenyl-3.4- 0 so* dihydronaphthalene hydrochloride Triefthylamine (0.33 mL, 2 *37 minol) was added to a cold solution of 1 g (2.58 mni~ol) of 1 -aminoinethyl-5,6-bis(acetoxy)-3-phenyl-3,4-dihydronaphthalene hydrochlride, 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 Chemical Co.) in 2 mL- of DMF. The solution was allowed to stir at 0 0 C for approximately 0.5 h and then at ambient :temperature for 3 h. Water (25 i) was added and the resultant mixture was extracted with ethyl acetate. The combined organic layers were washed successively with 2 X 15 mL of 1 N aqueous hydrochloric acid solution, 2 X 15 mL 0: 25: of water and 15 mL of brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluted with hexane/ethyl acetate to give 0.84 g (72% yield) of the title compound; DCI MS MIZ: 469 1 H NMR (CDCI3) 5:1.45 9H), 2.25 (s, 3H), 2.28 3H), 2.63-2.78 (in, 1 2.91-3.03 (mn, 1 3.63-3.74 (in, 1 4.08- 3 0 4.34 (in, 2H), 4.65 (br s, 1 6.02 1 7.05 1 7.22-7.37 (in, 6H).

Step 2: 5,6-Bis(acetoxy)-1 -(N-t-butoxycarbonyl)aminoinethyl-3-pheniylnapl ,,tia',ne To a solution of 1 .59 g (3.52 minol) of 5,6-bis(acetoxy)-1 3 5 butoxycarbo nyl)aiino methyl1-3-ph enyl1-3,4-di hydro nap ht hale ne, from Step 1, in mL of toluene was added 0.80 g (3.52 minol) of 2,3-dichloro-5,6-dicyano-1 ,4- 4684.US.P3 benzoquinone as a solid. The reaction mixture was heated to 70°C under a nitrogen atmosphere and allowed to stir overnight. After cooling the reaction mixture to ambient temperature, the orange colored mixture was filtered through a bed of Celite® filter aid. The filtrate was concentrated in vacuo. The residue was taken up in 50 mL of methylene chloride and the methylene chloride solution was washed with 2 X 25 mL of 1 M aqueous phosphoric acid solution, 2 X 25 mL of aqueous sodium bicarbonate solution, 25 mL of water and 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column eluted with 3:1 hexane/ethyl acetate to give 0.77 g (49% yield) of the title compound as a white solid; 1H NMR (CDCI3) 6: 1.47 9H), 2.35 3H), 2.47 3H), 4.81 2H), 4.89 (br s, 1 7.36-7.43 7.64-7.71 2H), 7.94 1H), 8.01 1H).

Step 3: 5.6-Bis(acetoxy)-1-aminomethyl-3-phenylnaphthalene hvdrochloride 0O55 5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl)aminomethyl-3-phenylnaphthalene (300 mg, 0.67 mmol) from Step 2 was dissolved in 10 mL of dioxane saturated with anhydrous hydrogen chloride. The resultant solution was stirred for 2 h at ambient temperature and concentrated in vacuo. The solid residue was recrystallized from ethanol/hexane to give 130 mg (50% yield) of the title compound as a white solid; DCI MS M/Z: 350 (M+H) 367 1 H NMR (d6-DMSO) 6: 2.36 3H), 2.51 3H DMSO), 4.65 2H). 7.44-7.51 1H), 7.54-7.61 3H), 7.78 2H), 8.07 1H), 8.13-8.19 2H), 8.39 (brs, 3H).

Step 4: 1-Aminomethyl-5.6-dihydroxy-3-phenylnaphthalene hydrochloride 5,6-Bis(acetoxy)-l-aminomethyl-3-phenylnaphthalene hydrochloride (130 mg, 0.34 mmol) from Step 3 was dissolved in 10 mL of methanol saturated with hydrogen chloride. The resultant solution was stirred at ambient temperature for 3 h 3 0 and then concentrated in vacuo. The solid residue was dissolved in a minimal amount of ethanol. The ethanol solution was added slowly to 30 mL of dry diethyl ether and the precipitate was collected by filtration. The solid wa dried at 60°C in vacuo to give 77 irg (76% yield) of the title compound as a white s m.p. 205- 2120C (dec); DCI MS M/Z: 266 283 1 H NMR (d6-DMSO) 3 5 4.50 2H), 7.28 1 7.36-7.60 4H), 7.77 1 7.83 2H), 8.35 1H), 8.49 (br s, 3H), 9.22 (br s, 1 9.60 (br s, 1H).

4684.US.P3 Example 47 [1.3-cis]-1 -Bromomethyl-3-t-butyl-5.6-cyclohexylidenedioxy-3.4-dihydro-1 H-2benzopyran Step 1: Epoxide Synthesis t-Butyl ethylene oxide, the epoxide used in the'synthesis of [1,3-cis] 1i1}' bromomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1 H-2-benzopyran, is commercially available. Epoxides necessary for the synthesis of other benzopyran derivatives of the present invention which are not commercially' available were synthesized by either Method A, Method B or Method C described below.

a..

*o5 Method A: 1-Cyclohexyl ethylene oxide 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 *.2C 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 550C and stirred at 550C 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 S.I ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was distilled (440C, 0.1 mm) to give 14 g (62% yield) of 1-cyclohexyl ethylene oxide as a clear colorless liquid.

Method B: 1-Benzyl ethylene oxide A solution of m-chloroperbenzoic acid (mCPBA; 17 g, 0.1 mol) in 120 mL of methylene chloride was added (at ambient temperature) dropwise to a solution of 3 5 allyl benzene (10 g, 85 mmol) in 200 mL of methylene chloride. After the reaction mixture was stirred for 5 h with a mechanical stirrer, 5 additional grams of m-CPBA 97 4684.US.P3 were added and the reaction mixture stirred for another 2 h. The reaction mixture was then diluted with 200 mL of ether, washed with 2 X 100 mL of aqueous sodium bisulfite solution, 1 X 100 mL of aqueous sodium bicarbonate solution and 1 X 100 mL of brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by bulb-to-bulb distillation (600C, 0.1 mm) to give 8.5 g (77% yield) of 1-benzyl ethylene oxide as a clear colorless liquid.

Method C: R] 1-(1-Adamantyl)ethylene oxide The title compound was prepared as described in Example 179, Steps 1-3, below.

Step 2: 3.3-Dimethyl-l-(spiro-[(l.3-benzodioxole)-2.1 '-cclohexanel)-2-butanol e 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 0 C. After 4 h, 3,3-dimethyl- ,2-epoxybutane (2.5 g, 25 mmol), S* commercially available from Aldrich Chemical Company, was added dropwise and t the reaction mixture was warmed to 25°C. After 3 h at 250C, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted 2: with 3 X 75 mL of diethyl ether. The combined ether extracts were washed with mL of aqueous ammonium chloride solution and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. to an oil. The oil was purified on silica gel eluted with 10% ethyl acetate in hexane to give 3.5 g (48% yield) of the title compound as a viscous oil. DCI MS: 308 1H NMR (d6-DMSO) 8: 0.89 9H), 1.4-1.9 10H), 2.27 (dd, 1H, J=14.4, 9.3 Hz), 2.75 (dd, 1 H, J=14.4, 3.0 Hz), 3.3 1 4.38 1 H, J=6.3 Hz), 6.18 3H).

Step 3A: [1.3-cis]-1-Bromomethyl-3-t-butyl-5.6-cyclohexvlidenedioxv-3.4-dihydro- 1 H-2-benzopyran Boron trifluoride etherate (2.88 mL, 23.5 mmol) waF added dropwise to a stirred solution of the product of Step 2 (3.4 g, 11.7 mmol) and bromoacetaldehyde 3 5 dimethyl acetal (1.4 mL, 11.7 mmol) in 15 mL of methylene chloride at -250C. The reaction mixture was allowed to warm to 0°C. After 1 h at 0°C, the reaction mixture 98 4684.US.P3 was diluted with 20 mL of diethyl ether and poured into 50 mL of aqueous sodium carbonate solution. The resultant mixture was extracted with 3 X 50 mL of diethyl ether. The combined ether extracts were washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressLue. The residue was purified by column chromatography on silica gel eluted with 2.5% ethyl acetate in hexane to give 2.85 g (61% yield) of the title compound as a colorless solid, m.p. 113-1140C. DCI MS: 414 1 H NMR (CDC13) 1.0 9H), 1.4-1.95 10H), 2.6 2H), 3.28 (dd, 1 H, J=9.3, 5.4 Hz), 3.52 (dd, 1 H, J=1.25, 7.5 Hz), 3.85 (dd, 1 H, J=11.25, Hz), 4.87 1H), 6.5 1H, J=9.0 Hz), 6.6 1H, J=9.0 Hz).

Alternate Step 3B: [1.3-cis-1 -(2-Bromoethvl)-3-t-butvl-5.6-cvcl6hexvlidenedioxv- 3.4-dihvdro-1 H-2-benzopyran 5 The title compound was prepared following the procedure described in Step 3 above and using 3-bromopropionaldehyde dimethyl acetal instead of bromoacetaldehyde dimethyl acetal.

Example 48 [1,3-cis] 1-Aminomethyl 3-t-butyl-5.6-dihydroxy-3,4-dihvdro-1 H-2-benzopvran hydrochloride Step 1: [1.3-cis] 1-Azidomethyl-3-t-butyl-5.6-cyclohexylidenedioxv-3.4-dihydro-lH- 2-benzopyran 4« b 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 250C. The reaction mixture was heated at 75°C for 2h then cooled and poured into 50 mL of 3 0 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 concentrated in vacuo. The residue was purified by column chromatography on silica gel el',ted with ethyl acetate in hexane to give 1.56 g (69% yield) of the title compound as a 3 5 colorless syrup; MS DCI: 358 375 1H NMR (CDCl3) 5: 1.1 (s, 9H), 1.4-1.95 10H), 2.6 2H), 3.3 (dd, 1H, J=8.7, 6.0 Hz), 3.42 (dd, 1H,

S

99 4684.US.P3 J=13.5, 7.5 Hz), 3.52 (dd, 1H, J=13.5, 3.0 Hz), 4.9 1H), 6.42 1H, J=9.0 Hz), 6.59 1H, J=9.0 Hz).

Step 2: [1.3-cis] 1-Aminomethyl-3-t-butyl-5.6-cyclohexvlidenedioxv-3.4-dihydro-l

H-

2-benzopyran hydrochloride Lithium aluminum hydride (LAH) solution (4.2 mL of 1 M solution in ether, 4.2 mmol) was added dropwise to a solution of [1,3-cis] 1-azidomethyl-3-t-butyl-5,6cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran (1.5 g, 4.2 mmol) in 25 mL of dry diethyl ether at 0°C. After 15 min, the reaction mixture was allowed to warm to 250C and was stirred at 250C for 1 h. The reaction mixture was cooled to 0°C and Sthe reaction was quenched by the sequential addition of.0.16 mL of water, 0.16 mL of 15% aqueous sodium hydroxide solution and 0.48 mL of water. The precipitate was removed by filtration and washed with ether. The filtrate was concentrated in vacuo. The crude amine product was dissolved in 15 mL of diethyl ether and diothyl ether saturated with hydrogen chloride was added in excess. The solid was collected by vacuum filtration washed with diethyl ether and dried to give 1.48 g (96% yield) of the title compound as a colorless solid, m.p. 164-1670C; DCI MS: 332 1 H NMR (d 6 -DMSO) 8:1.0 9H), 1.4-1.9 10H), 2.6 2H), 2.9 (dd, 1 H, J=14.7,10.5 Hz), 3.2 2H), 3.5 (dd, 1 H, J=14.7, 3.0 Hz), 4.82 (br d, 1 H, S J=8 Hz), 6.7 2H), 7.9 (br s, 2H).

Step 3: [1.3-cis] 1-Aminomethyl-3-t-butyl-5,6-dihydroxv-3.4-dihydro-1 H-2benzopyran hydrochloride S2 A solution of [1,3-cis] 1-aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4dihydro-1H-2-benzopyran hydrochloride, from Step 1, (1 g, 2.72 mmol) in 15 mL of ethanol was saturated with anhydrous hydrogen chloride. The solution was heated to reflux temperature. After 2 h at reflux temperature, the solution was concentrated 3 0 to approximately 2 mL. A solid was precipitated with diethyl ether, filtered, washed with diethyl ether and dried in a vacuum oven at 800C to give 630 mg (81% yield) of the title compound as a colorless powder, m.p. 2580C; IR 3200, 1620, 1490, 1300, 1060 cm- 1 DCI MS: 252 1 H NMR (d 6 -DMSO) 8: 1.0 9H), 2.38 (dd, 1H, J=16.5, 12 Hz), 2.63 (dd, 1H, J=16.5, 2.8 Hz), 2.85 1H), 3.22 (dd, 1H, 3 5 J=1 2.0, 4.2 Hz), 3.45 1H), 4.8 (br d, 1 H, J=7.5 Hz), 6.5 1 H, J=7.8 Hz), 6.65 (d, 1100 4684.US.P3 1 H, J=7.8 Hz), 7.9 (br s, 2H), 8.46 (br s, 1 9.22 (br s, 1 Analysis calculated for

C

1 4

H

22 01N0 3 0, 58.43; H, 7.70; N, 4.9. Found: 0, 58.37; H, 7.69; N, 4.77.

Examples 49 106, Following the synthesis outlined in Examples 47 and 48, using the appropriate epoxide and the appropriate aldehyde diacetal, Examples 49 106 were made as disclosed in Table 3. The structure of each was confirmed by melting point elemental analysis and mass spectra as designated.

S1 4684.US.P3 Table 3: Examples 49 106 Ex. No. Compoufld* Epoxide*" rnn2Q MS...

Elemegntal Analysis C H N 60.60 6.05 4.42 60.63 6.27 '4.20 0P 0 146 272 -0 0900,53 0 000 000:5 0 0 0 225 278

HO

NH

2 204-6 224 234 264 02 CI %OMe 220-1 332 61.24 61.23 .55.50 55.85 60.10 60.20 58.78 58.39 60.60 60.63 60.45 60.34 66.74 66.54 64.03 63.90 7.71 7.83 6.99 7.15 7.40 7.53 6.03.

6.20 6,05 6.27 5.97 6.04 5.85 5.88 7.16 7.18 4.46 4.34 5.39 5.31 4.67 4.63 3.81 3.71 4.42 4.20 4.15 4.02 3.38 3.37 3.56 3.51 0 158 272 1 [alpha),)= -11 6.50 (c=0.405, IN HOI) 230 205 217 302 378 358 -3 *As the HCOI salt unless indicated otherwise (F8= free base); all compounds 1-3 cis unless indicated otherwise 1= commercially available, 2=synthesized by method A of Example 47, 3=synthesized by Method B of Example 47; 4=synthesized by Method C of Example 47.

DCl MS (Ml+H)+ Prepared by the procedure described in Examples 47, 48 and old 130 using (-)B-chlorcodiidoci,.,ampi'.rylborane 102 Table 3: continued 4684.US.P3 Ex. No. Compound* mp 0 12!C M. Elemegntal Analysis -0 H N 049.00 4.60 3.36 f: 49.03 4.65 '3.33 58 HO Ho~ Br Br

NH

2 3 225 380 330 59 0:00 0* 00.

*.4 0e 0 HO Adam

HO

HO

HO 0

*NH,

HO r--

HO&

0 HO

NH-

2

FB

NH 2

HO

HO decyl f' NH- 2 250 ,Adam 0 3 0 3 242 215 241 286 300 350 65.65 65.59 653.45 63.32 64.38 64.33 49.70 49.77 73.90 73.82 7.71 7.83 6.26 6.30 6.60 6.65 4.43 4.44 8.74 8.74 3.83 3.73 4.35 4.27 4.17 4.06 3.62 3.58 3.92 3.67 4.07 4.03 3.77 3.69 4.37 4.34 162-3 358 200 308 octyl 4 decyl 0c: 62.87 8.79 f: 62.80 8.69 336 64.58 64.74 9.21 9.13 7.77 7.77 66 H N 1 2 203 278 c: 60.08 +13H 2 0 f: 60.34 *As the HBr salt unless indicated otherwise (FB= free base); all compounds 1-3 cis unless indicated otherwise 1= commercially available, 2=synthesized by method A of Example 47, 3=synthesized by Method B of Example 47; 4=synthesized by Method C of Example 47.

-DOI MS ***Prepared by the procedure described in Examples 47, 48 and old13O using (-)B-chlorodiidopinocamphorylborane 103 Table 3: continued 4684.US.P3 Ex. No. Compound*

HO

67

HO.

NH

2 Epoxide rnn~ Elemental Analysis H N 240 224 68 *.9 06

HO

HO I hexyl tl J

NH

2 0<_ ,hexyl o 205 280 c: 55.49 f: 55.16 c: 59.71 +1/31- 2 0 f: 59.41 c: 49.70 f: 50.19 c: 58.53 +1/41- 2 0 f: 58.72 6.99 6.86 8.34 8.14 4.43 4.49 5.68 5.57

HO.

Br 0 2 0 2~2 0& 222 265 250 259 212 350 324 362 280 250 5.39 '5.29 4.35 4.25 3.62 3.60 4.26 4.15 3.52 3.41 4.43 4.29 4.75 4, S2 c: 69.43 6.08 f: 69.17 6.22 HO

HO

HO NH-1 2

HO

-0

NH,

c: 60.84 f: 59.80 c: 5 7.0 4 +1/21- 2 0 f: 57.,' 8.30 8.14 7.18 '0.98 723 4000:.

0 HO 74 HO o- 2 HO

NH-

2 HO 0 N H 2 306 f: na 227 316 c: 59.91 6.42 3.88 +1/21- 2 0 f: 59.94 6.05 3.89 *As the HBr salt unless Indicated otherwise (FB= free base); all compounds 1-3 cis un'ess indicated c~herwise commercially available, 2=synthesized by method A of Example 47, 3=synthesized by Method B of Example 47; 4=synthesized by Met;hod C of Example 47.

OCt MS the banzyl protecting group was remoyed by hydrogenolysis prior to removal of the cyclohexylidene group from the catechol, 8 104 Table 3: continued 4684.US.P3 Ex. No. Compound*

HO

76 HO 0 H Epoxid'** mrn M-S* Elemental Analysis C H N O 2 >250 306 77 *4.

3 4.

82

S

83 0

NH

2

HO

Ho ZN

NH

2 o'

O

o 3

CO-

o* 3 222 316 >230 278 c: 63.23 f: 62.99 c: 60.88 +1/2H 2 0 f: 60.64 c: 61.23 f: 61.26 c: 58.43 f: 58.38 c: 43.86 +1/2H 2 0 f: 43.73 6.72 6.52 7.71 7.71 7.71 7.58 4.03 3.93 8.25 4.10 8.16 4.00 215 252 butyl 1 257-9 398 0 2 o 2 2 0 2 SAdam o 3 3.74 3.85 4.46 4.44 4.87 4.77 3.20 3.15 3.57 3.51 4.15 6.01 3.98 3.91 3.32 3.15 233 250-1 (dec) 257 (dec) 357 302 316 c: 48.93 5.90 f: 49.18 5.86 c: 60.44 f: 60.23 c: 61.45 f: 61.20 5.97 6.01 6.30 6.30 8.38 8.02

HO

84 HO-< Adam

~NH

2 267-9 330 c: 62.77 +1/2Et20+1H 2 0 f: 62.56 As the HBr salt unless indicated otherwise (FB= free base); all compounds 1-3 cis unless indicated otherwise 1= commercially available, 2=synthesized by method A of Example 47, 3=synthesized by Method B of Evample 47; 4=synthesized by Method C of Example 47.

*"DCI MS Prepared by the procedure described in Examples 47, 48 and old130 using (-)B-chlorodiidopinocamphorylborane

S

105 Table 3: continued 6684.US.P3 Ex. No. C-mpound*

HO

HO,( Adam I Epoxide** rn2iQ M Elemental Analysis QC H N c: 63.06 7.85 3.68 +0.8H0 N:63.25 7.73 -3.35 Adain 44 86 *9 9

C

9 0

C

S.C

CCC

HOHO

H

HO 1i adarantyl -adamantyl

NI-

2 o0 4 HO 0 HO Nlo

N

2 145 (dec) 210 254 (dec) 330 330 341 c: 63.06 f: 63.16 c: 56.46 +O.76HCI f: 56.70 7.85 7.70 5.42 5.44 7.99 7.83 7.71 7.71 3.68 3.58 6.93 6.75 4.27 4.21 4.87 4.66

HO

HO

0NI1

HO

HO 0 0 HO

NH-

2 HO N Adam NH 2 251-2 292 03 62.28 62.75 58.43 58.48 235-6 252 0C 99990 4 9 C 4 S

S

CC 9 a o S* 92 na 344 ~-Adam OK 2 244-6 (dec) >260 (dec) 306 62.42 62.71 50.07 49.95 8.29 8.20 6.30 6.10 339 4.04 4.08 7.30 7.30 4.46 4.38

HO

93 HON 1 0 NH0 9 2 239 278 c: 61.24 7.71 f: 61.51 7.87 *As the HBr salt unless indicated otherwise (FB= free base); all compounds 1-3 cis unless indicated otherwise I= cmmercially available, 2=synthesized by method A of Example 47, 3=synthesize-d by Method 8 of Example 47;, 4=synthesized by Method C of Example 47.

DCI MS Prepared by the procedure described in Examples 47, 48 and oldl3O using (-)B-chlorodiidopinocamphorylborane S1 106 Table 3: continued 4684.US.P3 Ex. No. Compound* Epoxide rnf-Q Elemental Analysis C H N 94 HO.

HO

.96.

HO

b7 HO a8 HO 1 1 HC HO 0 N H2

HO

0 0

HO

0PETTF

ICPETF

NH

2 3 HO CF 3 0

CF

3 HO

NH-

2 0 3 0 CF 3

I

HO I-1 0O

CF

3 NH 4 228 f: na >260 266 171-4 272 c: 55.72 6.68 f: 56.06 6.78 c: 61.54 5.97 +1/41- 2 0 f: 61 .74 6.23 c: 50.85 4.56 +O.3HCI f: 50.74 4.22 4.64 4.63 4.48 4.15 3.12 3.50 na >225 (dec) >220 (dec) 255 402 340 340 252 c: 52.01 4.32, 3.47 +0.4HCI f: 52.31 4.49 3.59 c: 340.1 167**** f: 340.1161 c: 58.43 7.71 4.87 f: 58.20 7.58 4.67 c: 57.46 6.68 5.15 f: 56.18 5.93 4.92 HO-0 Ni-..

NH

2 03 204 (dec) 268 (dec) 272 252.1601 252.1600 *As the H~r salt unless indicated othe~iw.se (FB= free base); all compounds 1-3 cis unless indicated otherwise 1 commercially availablo, 2=synthesized by method A of Examaple 47, 3=synthesized by Method B of Example 47;, 4=synthesized by Method C of Example 47.

DCI MS Prepared by the procedure described in Examples 47, 48 and oldl3O using (-)B-chlorodiidopinocamphorylborane; *-High resolution mass spectrometry.

S1 107 Table 3: continued 4684. US. P3 Ex. No. -Compound* Epoxide*

W*

HO H 103 HO IAa

NH

2

HO

104 HO i,

NH

2

HO

NH

2 211-4 348 Adam Elemental Analysis Q H N c: 59.77 7.27 3.49 +HCI0+H 2 0 f: 59.77 6.89 '3.54 c: 59.70 8.02 4.64 59.85 8.06 4.57 266 0C o 3 Adam OK 3 249-51 250 206-10 348

C:

c: 58.46 7.36 3.41 +HCI+1 .SH 2 0 f: 58.32 7.20 3.22 54

S

S

455.

4.

6s S *5*55*

S

5 0

S.

*As the HBr salt unless indicated otherwise (F8= free base); all compounds 1-3 cis unless indicated otherwise i= commercially available, 2=synthesized by method A of Example 47, 3=synthesized by Method B of Example 47; 4=synthesized by Method C of Example 47.

DCI MS 108 4684.US.P3 Example 107 1 -Amino methbyl-8-bro mo-adamantyl-5,6-di hyd rxy-3.4-di hi~dro- 1 H-2-benzopyran hydrobromide- Starting with the compound of Example 59, protecting the amino group with BOO and reacting 2.00 g (4.66 mmol) of the BOO-protected compound with 0.746 g (4.66 mmol) of bromine in methylene chloride at 000 for 3 hours, followed by *quenching with sodium bisulfite, extraction with methylene chloride and purification 160. by chromatography on silica gel, the title compound was prepared. mp 21 0OG anal. calc. for C 20

H

26 BrNO 3 *0.8H-Br'O.5EtOH: 0, 50.83; H, 5.99: N, 2.85; fon:C,5.3 H, 6.22; N, 2.76.

OVO Example 108 1 5 (1 .3-cis] 1 S-(1 -Amino)ethyl)-5.6-dihydroxy-3-phenvl-3,4-dihydrQ-1 H-2benzopyran Following the synthesis outtined in Example 47, replacing the bromoacetaldehyde dimethyl ketal with N-Cbz-alaninal, the compound of Example .108 was piwpared. mp, 272-40C. MS: 286. anal. calc.+HOI+H20: C, 60.09; H, 6.50: N, 4.12; found: 0, 60.34; H, 6.32; N, 4.01.

Example 109 1 .3-cis] 1 Amin om ethyl-5 .6-di hydroxy-3-(2'-tet rahydrof uran yl)-3.4-di hyd ro-11-H-2benzopyran hydrobromide Step 1: 1 -(2'.3'-D'methoxyphenyl)-N-methoxy-N-methyl-acetamide Oxalyl chloride (0.45, 5.1 mmol) and 2 3 drops of N,N-dimethylformamide 3 0 (DMF) were added to a chilled (000) solution of 2,3-dimethoxyphenylacetic acid in 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 -m ethoxy-N -mnethyl -hyd roxylamin e hydrochloride (0.55 g, 5.61 mmol) was added and the resultant solution was chilled 3 5 to 0O. Pyridine (0.91 mL, 11 .23 mmol) was added and the solution was stirred for 2 h at 000. The solution was then washed twice with brine, dried over anhydrous S109 4684.US.P3 magnesium sulfate, filtered and concentrated in vacuo to an oil. The oil was purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 0.65 g (53% yield) of the title compound as an oil; MS DCI: 240 257 1 H NMR (CDCI3) 5: 3.21 3H), 3.68 3H), 3.80-3.84 5H), 3.87 3H), 6.80-6.87 2H), 6.98-7.4 1 H).

Step 2: 2-(2'.3'-Dimethoxyphenyl)-1-furanylethanone n-Butyl lithium (1.87 mL, 3.76 mmol of a 1.75 M solution in hexanes) was 1 6. added to a chilled 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 1 5 period and was then quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the extracts were washed once each with saturated aqueous ammonium chloride and brine. The extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.5 g (75% yield) of the title compound as an oil; MS DCI: 247 264 1 H NMR (CDCI3) 8: 3.80 3H), 3.85 3H), 4.15 2H), 6.51-6.53 1H), 6.82-6.88 3H), 6.99-7.05 1H), 7.25-7.28 1H).

Step 3: 2-(2'.3'-Dimethoxyphenyl)-1-tetrahydrofuranyl ethanol A solution of 450 mp (1.8 mmol) of 2-(2',3'-dimethoxyphenyl)-1furanylethanone, from Step 2, and 20% palladium on carbon (225 mg) in 75 mL of methanol was shaken under 4 atmospheres of hydrogen until hydrogen uptake ceased. The .Jtion was filtered and concentrated in vacuo to give 320 mg (69% yield) of the title compound as an oily solid. This product was carried on without 3 0 purification to the next step.

Step 4: 1 -Aminomethyl-3-(2'-tetrahydrofuranyl)-5 6-dihydroxy-3.4-dihydro-1 H-2benzopyran hydrobromide 3 5 2-(2',3'-Dimethoxyphenyl)-1-tetrahydrofuranyi ethanol, from Step 3, was converted to the title compound using the procedures described in Step 3 of 8 110 4684.US.P3 Example 47 and Steps 1 and 2 of Example 48. The dimethoxy protecting groups were removed with boron tribromide by the procedures described in Step 3 of Example 2 to afford the title compound, m.p. >250°C; FAB MS 266 1 H NMR (d6-DMSO) 8: 1.75-1.93 4H), 2.37-2:47 1H), 2.50-2.60 1H), 2.60-2.68 1H), 2.71-2.79 1H), 3.65-3.72 1H), 3.76-3.84 2H), 3.90- 4.00 1H), 4.84-4.91 1H), 6.48 1H), 6.68 1H), 7.72-7.84 2H); 8.41- 8.49 1H), 9.20-9.28 1H). High resolution mass spectral analysis calculated for C 1 4

H

2 0 N0 4 266.132. Found: 266.1391 Example 110 *C [1 .3-cis] 1 -Aminomethyl-5.6-dihvdroyv-3-(3'-prop-1'-ynvl-3,4-dihydro-1 H-2benzopyran hydrochloride 1 5 Step 1: 3-(Spiro-[(1,3-benzodioxole)-2.1'-cyclohexane])-propene oxide 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)-2,1'-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 650C 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 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 3 0 hexane to give 6.81 g (53% yield) of the title compound as a clear oil.

Step 2: 1-(Spiro-[(1 ,3-benzodioxole)-21 '.-cyclohexane])-4-pentyn-2-ol Crude 3-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-propene oxide (8.29 g, 33.7 3 5 mmol), from Step 1, was added to a chilled suspension of lithium acetylideethylenediamine complex (4.65 g, 45.5 mmol of a 90% solid) in 50 mL of methyl

I

I Il1114USP sulfoxide. The mixture was allowed to warm to ambient temperature over a 3 h period during which the mixture became a homogeneous solution. The reaction was quenched with 50 mL of water and the aqueous layer were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to an oil. The oil was purified by column chromatography on silica gel eluted with 15% ethyl acetate in hexane to give 2.08 g (23% yield) of the title compound as an oil; MS DCl: 273 290 (M+NqH4)+;l H NMR (CDCI3) 8: 1.45-1 .55 (in, 2H), 1 .67-1 .77 (in, 4H), 1 .85-1 .95 (in, 4H), 2.09 1 2.28 1 H), 2.32-2.50 (in, 2H), 2.80-2.93 (in, 2H), 4.00-4.15 (in, 1 6.62-6.77 (in, 3H).

*:~Step 3: 1 -Arnino methyl-5.6-dihydroxy-3-(3'-prop-1 '-ynyl)-3.4-di hydro-1 H-2- .Qpyran hydrpchlorid 1 -(Spiro-[(1 ,3-benzodioxole)-2,1 '-cyctohexanel)-4-pentyn-2-ol, from Step 2, was converted to the title compound using the procedures described in Step 3 of Example 47 and Steps 1 3 of Example 48 to afford the title compound, m.p.

>25000; DCl MS (MIZ): 234 1 H NMR (d6-DMSO) 5: 2.34-2.47 (in, 1 H), 2.52-2.57 (in, 1 2.57-2.68 (in, 1 2.84-2.92 (in, 2H), 2.95 1 3.39-3.47 (in, 1 3.71-3.81 (in, 1 4.87-4.91 (in, 1 HI 6.2 1 6.69 1 7.88 2H), -2 8.53 1 9.31 1 Analysis calculated for Cl A 6 CIN0 3 C, 57.89; H, 00 5.98; N, 5.19. Found: C, 57.73; H, 6.15; N, 5.09.

Example 111 0 [1 .3-cis] 3-Cyclohexyl-5,6-dihydroxy-1 -iethylaininomethyl-3,4-dihydro-1 H-2benzopyran hydrochloride [1 ,3-cis]-1 -Aininomethyl-3-cyclohexyl-5,6-cyclohexyiidenedioxy-3,4-dihydro-1 H- 3 0 2-benzopyran hydrochloride (synthesized( as described in Steps 1 and 2 of Example 48 for [1 ,3-cisl- aiinomethyl-3-P-butyl-5,6-cyclohexylidenedioxy-3,4dihydro-1 H-2-benzopyran hydrochloride). (0.82 g, 2.3 inmol) was partitioned between methylene chloride and saturafed aqueous sodiumn bicarbonate solution.

The inethylene chloride layer was concentrated under reduced and the 3 5 residue was dissolved in 25 mL of ethyl forinate. The ethyl formate solution was heated to reflux temperature. After 1 h at ref lux temperature, the reaction mixture 112 4684.US.P3 was concentrated to a white solid. The solid was dissolved in 15 mL of THF and 175 mg (4.6 mmol) of lithium aluminum hydride (LAH) was added. The reaction mixture was heatedi at ref lux temperature for 3 h then cooled to 0 0 C. The reaction was quenched by the sequential addition of 0.175 mL of water, 0.175 mL of 1 aqueous sodium hydroxide solution and 0.525 mL of watqr. The reaction mixture was filtered and the filter cake v:ashed with diethyl ether. The filtrate was concentrated in vacuc. The residue was dissolved in 20 mL of ethanol and the alcohol solution was saturated with anhydrous hydrogen chloride then heated at .reflux temperature for 2 h. The ethanol was evaporated down to approximately 2 16 mL-and ether was added until a solid precipitate was formed. The solid was filtered, *washed with diethyl ether and dried to give 504 mg (67% yield) of the title compound as a colorless powder, m.p. 24400; DCI MS: 292 Analysis ::calculated for C 1 7

H

2 6 CIN0 3 C, 62.28; H, 7.99; N, 4.27. Found: C, 62.24; H, 7.90; N, 4.21.

Example 112 1 1i RI3SI 3-t-Butyl-5.6-dibydroxy-1 -methylaminomgthvl-3,.,-dihydro-1 H-2benzopyran hydrochloride, Following the synthesis outlined in Example 111 and starting with [1 R,33J 1 aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,-dihydro-1 H-2-benzopyran hydrochloride from S.-ep 2 of Example 48, [1 R,3.5] 3-t-butyl-5,6-dihydroxy-1 methylaminomethyl-3,4-dihydro-1 H-2-benzopyran hydrochloride was prepared, m.p. 24600; DCI MS: 266 Analysis calculated for 0 15

H

2 3 C1N0 3 0,59.70; H, 8.00;N~, 4.64. Found: C, 59.64; H, 8.10; N, 4.45.

Example 113 3 0 fi .3-cis] 1-(N-Allyl)aminomethyl-3-cyclohexyl-5,6-ih droxy-3.4-dihvdro-1 H-2benzopyran hydrochlor-d Step 1: [1 .3-cis] 1 -(N-Allyl)amingmethyl-3-cyclohexyl-5,6-cyclohexylidenedioxy- 3.4-dihydro-1 H-2-benzopyran S113 4684.US.P3 [1,3-cis] 1-Bromomethyl-3-cyclohexyl .3,4-dihydro-5,6-dihydroxy-1 H-2benzopyran (1.1 g, 2.6 mmol) (prepared as described in Example 47, using cyclohexyl ethylene oxide) and dissolved in 10 mL of allyl arrjd'i. The reaction mixture was heated at reflux temperature for 5 h-then concentrated in vacuo. The residue was dissolved in 50 mL of ethyl acetate. The solution was washed with 2 X mL of aqueous sodium bicarbonate solution and 1 X 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with 30% ethyl acetate in hexane to give 928 mg (90% yield) of the title compound as a colorless oil; DCI S1 0 MS: 398 1H NMR (CDCI 3 1.0 20H), 2.05 (br d, 1 H, J=11.0 Hz), 2.4 (br s, 1 2.5 (dd, 1H, J=13.5, 9.0 Hz), 2.7 (dd, 1 H, J=13.5, 2.8 Hz), 2.82 (dd, 1H, J=10.0, 7.5 Hz), 3.18 (dd, 1H, J=10.0, 3.0 Hz), 3.48 3H), 4.7'(br d, 1H, J=7.5 Hz), 5.2 2H), 5.95 1H), 6.5 1H, J=6.3 Hz), 6.58 1H, J=6.3 Hz).

1 5 Step 2: [1,3-cis] 1-(N-Allyl)aminomethyl--cyclohexyl-3.4-dihydro-5.6-dihydroxy- 1 H-2-benzopyran hydrochloride [1,3-cis] 1-(N-Allyl)aminomethyl-3-cyclohexyl-3,4-dihydro-5,6-cyclohexylidenedioxy-1H-2-benzopyran (920 mg, 2.3 mmol), from Step 1, was dissolved in 26 mL of ethanol saturated with anhydrous hydrogen chloride. The acidic solution was heated at reflux temperature for 2 h then concentrated to 2 mL. Diethyl ether was added and the precipitat, was filtered, washed with diethyl ether and dried to give 590 mg (72% yield) of the title compound as an off-white powder, m.p. 217-219C; DCI MS: 318 Analysis calculated for C 1 9

H

2 8

CINO

3 C, 64.49; H, 7.98; N, 3.96. Found: C, 64.34; H, 8.02; N, 3.82.

Examples 114 148 Following the syntheses described in Examples 47 and 113, using the 3 0 appropriate epoxide and the appropriate amine, 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 Zprotected prolinal dimethyl acetal as indicated, followed by deprotection. The 3 5 chiral prolinals were prepared from the chiral amino acid alcohols following the S 114 4684.US.P3 prcedures given in Chem. Pharm. Bull (1982), 3Q, 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.

S

b•S S S oo S

S

115 Table 4: Examples 114 148 4684.US.P3 Ex. No. Compound* Amine mp.. MS**

HO

HCI

Elemental Analysis C H N c: 64.49 7.97 3.96 f: 64.43 8.02 -%.88

N

7 200

NH

2 318 1 I 0

S.

S

4 ft 9.

4* 6• 4 a 0

S

15 HO

NZI

HO

1.6

HO

SNH OH

HO

117 HO Adam NH 4

HO

18 HO

HO

119 HO- NMec

HO

120 HO N NMs^

HO

121 HO. hexyl o 0 b NMe

HO

122 HO hexyl NMe 240-2 332 NH2

OH

NH

2

NH

2 116 225 336 370 211-2 316 lNH

NH,

c: 65.29 f: 65.26 c: 59.91 +1/2H 2 0 f: 60.13 c: 68.05 f: 68.00 c: 64.86 f: 64.58 c: 64.85 f: 65.13 c: 65.29 f: 65.35 c: 64.94 f: 64.68 c: 65.29 f: 65.22 8.22 8.26 8.20 8.02 7.95 7.91 7.45.

7.59 7.75 7.68 8.22 8.36 8.72 8.70 8.22 8.17 3.81 3.73 3.67 3.61 3.45 3.36 3.98 3.82 3.78 3.72 3.81 3.77 3.79 3.73 3.81 3.79

NH

4.

216-8 330 172-3 332

NH

NH

144-6 334 141-2 332 As the HCI salt unless indicated otherwise (FB= free base); Adam=adamantyl; all compounds 1-3 cis unless indicated otherwise DCI MS I_

H

116 Table 4: continued 4684.US.P3 Ex. No. Compound* Amine mp MS** Elemental Analysis C H N c: 63.15 6.56 3.88 f: 63.29 6.16 3.87 123 124 *9

C.

o

B

'*126 fe* 248-50 (dec) 312 242-4 312 152-5 292

I,

NH

2

HO

HOH

NH

HO HO HO O H H

NH

HO

oO NH-

HO

HO

NH

215-222 (dec) 220 (dec) 312 312 280 292 c: 65.61 6.38 +1 HCI f: 65.21 6.48 c: 62.47 7.71 f: 62.43 8.04 c: 60.53 6.10 +0.8 HCI f: 60.43 5.89 c: 62.97 6.23 +0.4 HCI f: 62.89 6.10 c: 60.85 8.30 f: 60.85 8.31 c: 61.94 8.01 +0.1 f: 61.78 8.05 c: 64.93 6.34 +0.1 HCI f: 64.68 6.33 c: 61.90 8.56 f: 62.24 8.34 4.03 3.95 4.29 4.24 3.72 3.66 3.87 3.85 4.44 4.36 4.25 4.20 3.98 3.98 4.27 4.24 128 ,20 130 131

NH

2 II

NH

2

NH

2

NH

2 180-83 312

HO

HO

o

NH

374 As the HCI salt unless indicated otherwise (FB= free base); Adam=adamantyl; all compounds 1-3 cis unless indicated otherwise DCI MS I II 4684.US.P3 Table 4: continued Ex. N9. _flr~flQUgd* 132 HO rnP2!Q MS** Elemental Analysis 0 H N c: 59.03 7.46 4.59 +0.3 H 2 0 f: 59.20 7.32 -7.49 2 r,4 133 Olt *a 46 .o..3 .138 :*139

HO

1-100:

NH

2

NH-OH

2 HO HO Adam

HO

HO butyl

NH-OH

3

HO

HO NF ~0 HO NH-OH3

NH-OH

3

HO

HO~~

HO

N-H

N adamantyl -0

NH-OH

3 >260 239 264 344 194-6 266 46.31 46.04 ,66. 39 66.31 59.69 59.24 57.07 56.79 59.45 59.25 63.40 63.00 >260 304 6.48 6.03 7.96 7.94 8.02 7.94 5.92.

5.73 6.83 6.43 6.30 6.30 8.46 8.39 8.25 8.17 9.00 8.08 3.69 3.57 4.64 4.46 3.92 3.61 3.65 3.56 4.40 4.30 3.36 3.36 4.10 4.02 >260 (dec) 330 250-2 286 na 358 209-10 306 c: 66.25 +0.5 EIOH f: 66.30 c: 638. 2 f: 62.97 0

NH-OH

3 As the HOI salt unless indicated otherwise (FB= free base): Adam=adamantyl; all compounds 1-3 cis unless indicated otherwise **DCI MS 8 118 Table 4: continued 4684.US.P3 Ex. No. Compound* Rp° MS** Elemental Analysis C H N c: 62.28 7.99 4.27 f: 62.16 7.84 -4.26

HO

oNH- NH-CH3 145 292 142 o 0 a aw *"144 a a a t~ 194 247

NH-CH

HO

HO o 0

O

NH-CHa 306 280 280 c: 306.2069*** f: 306.2076 c: 57.05 7.02 f: 56.72 6.84 c: 60.85 8.30 f: 60.74 8.13 4.44 4.30 4.44 4.43

HO

HO 3 pentyl

NH-CH,

HO

HO

0 H adamantyl F H ^-NH-CH 3 >250 362

HO

HO

o HO NH-CH 3

HO

147 HO BO e 'HO N(CH 3 2 148 HO Adam

HO

148A HO SN(CH3)

N(CH

3 2 185 223 280 280 c: 58.07 6.96. 3.22 +2 HCI f: 5/.71 7.18 2.92 c: 60.85 8.30 4.44 f: 61.14 8.14 4.24 c: 60.85 8.30 4.44 f: 60.65 8.21 4.33 c: f: na c: 64.12 8.50 3.94 f: 63.95 8.48 3.84 dec 358 215 320 As the HCI salt unless indicated otherwise (FB= free base); Adam=adamantyl; all compounds 1-3 cis unless indicated otherw!ra DCI MS "'High Resolution mass spectrometry S119 4684.US.P3 Example 149 5.6-Dihydroxy-1-(N-methyl)aminomethyl-3-phenyl-3.4-dihydronaphthalene 1-Aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, the product of Step 2 of Example 2, was N-methylated as described in Example'111 and deprotected as described in Step 4 of Example 2 to give the title compound as its hydrochloride salt, m.p. 131-133oC; DCI MS: 282 Analysis calculated for C 1 8

H

2 0

CINO

2 C, 68.03; H, 6.34; N, 4.41. Found: C, 67.64; H, 6.54; N, 4.31.

*0000 °0 Example 150 0OSO 11.3-cis] 5.6-Dihydroxy-1-(N-methyl)aminomethyl-3-phenyl-1,2,3.4-tetrahydro- 0rO*" naphthalene [1,3-cis] 1-Aminomethyl-5,6-dimethoxy-3-phenyl-1,2,3,4tetrahydronaphthalene, the product of Step 1 of Example 35, was N-methylated as l *OoO described in Example 111 and deprotected as described in Step 4 of Example 2 to give the title compound as its hydrochloride salt, m.p. 211-213oC; DCI MS: 284 °2 6 Analysis calculated for C 18

H

2 2 CIN0 2 C, 65.75; H, 7.05; N, 4.26. Found: *0 :0 C, 65.54; H, 6.89; N, 4.04.

Examples 151 153 Following the synthesis described in Examples 1A and 2, the 1-aminomethyl precursors to 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 3 0 lithium aluminum hydride (LAH) as the reducing agent to give Examples 151 -153 as their hydrochloride salts unless otherwise noted. In the case of 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 elemental analysis and mass spectra, as designated.

120 Table 5: Examples 151 153 4684.US.P3 Ex. No. Compound* Acyl chloride mp! MS** High Resolution Mass Spectrum 152 0* C. S S *5 S S .0S S 0O l~ S 55

HO

HO

NH

MeSO 4 salt HO HO -0

NH

C1 198 310 C: Ci 309.1 725 309.1722 na 352 351.2196 351.2203 295.1572 295.1 571 122 296 S. 55 S S 5555 S S 55 OS S

S

SSSSSS

S

*5 S S

S.

*As the HCI salt unless indicated otherwise (FB= free base); all compounds 1-3 cis unless indicated otherwise **DCI MS -High Resolution mass spectrometry ~VP- -saC 121 4684.US.P3 Example 154 [1.3-cis] 1.3-Bis(aminomethyl)-3.4-dihydro-5.6-dihydroxy-1H-2-benzopyran dihydrochloride Step 1 1-Benzyloxy-3-(soiro-[(1.3-benzodioxole)-2,1'-cyclohexane])-2-propanol Glycidol (3.1 g, 42 mmol) was added drop;vise to a suspension of sodium hydride (1.0 g, 42 mmol) in 25 mL of dry dimethyl formamide (DMF) at 0°C. After :'i'0O stirring the suspension for 30 min at 0°C, 7.1 g (42 mmol) of benzyl bromide was added dropwise and the reaction mixture was stirred at 0°C for 40 min. The S reaction mixture was then diluted with 75 mL of diethyl ether, transferred to a separatory funnel and washed with 2 X 30 mL of 2 N aqueous sulfuric acid solution, 2 X 30 mL of water and saturated aqueous sodium bicarbonate solution.

The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to ryve 5.3 g of the protected epoxy alcohol as an oil.

N-Butyl lithium (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. The combined ether extracts were washed with ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica pel eluted with 20% ethyl acetate in hexane to give 4.4 g (38% yield) of the title compound as a colorless oil. DCI MS: 372 (M+NH 4 355 1 H NMR (CDCI 3 8: 1.4-1.9 10H), 2.46 1H, J=3.9 Hz), 2.79 2H, J=7.0 Hz), 3.4 (dd, 1H, J=9.9, 7,2 Hz), 3.52 (dd, 1H, J=9.9, 3 0 3.0 Hz), 4.12 1 4.54 2H), 6.6-6.73 3H), 7.34 122 4684.US.P3 Step 2: [13-cis] 3-Benzoxymethyl-l-bromomethvl-5.6-cyclohexylidenedioxy-3.4dihvdro-1 H-2-benzopyran A solution of 1-benzyloxy-3-(spira-[(1,3-benzodioxole)-2,1'-cyclohexane])-2propanol (4.3 g, 12 mmol), from Step 1, and bromoacetaldehyde dimethyl acetal (1.7 mL, 14 mmol) in 25 mL of methylene chloride was cooled to 0°C. Boron' trifluoride etherate (3.6 mL, 29 mmol) was added dropwise and the reaction mixture was stirred for 1.5 h. The resultant dark brown solution was poured into 50 mL of aqueous sodium carbonate solution and the aqueous solution was extracted with 3 X 50 mL of diethyl ether. The combined ether extracts were washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with 20% ethyl acetate a" in hexane to give 4.2 g of the title compound as a colorless syrup; DCI MS: 476 1H NMR (CDC3) 8: 1.45-1.95 10H), 2.57 (dd, 1H, J=16.5, 11.4 Hz), 2.71 (dd, 1H, J=16.5, 3 Hz), 3.59 (dd, 1H, J=11.4, 6 Hz), 3.63 (dd, 1H, J=10.8, 4.2 Hz), 3.73 (dd, 1H, J=10.8, 6 Hz), 3.87 (dd, 1H, J=11.4, 4.65 1H, J=12 Hz), 4.72 1H, J=12 Hz), 5.0 1H), 6.52 1H, J=8.4 Hz), 6.62 1H, J=8.4 S* Hz), 7.42-7.25 Step 3: [1,3-cis 1 -Bromomethyl-3-hydroxymethyl-5.6-cyclohexylidenedioxy-3,4dihydro-1 H-2-benzopyran Platinum on carbon (1.0 g) was added to a solution of [1,3-cis] 3benzyloxymethyl1 -bromomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1 H-2benzopyran (4.0 g, 8.7 mmol), from Step 2, in 150 mL of methanol and 5 mL of ethyl acetate. The reaction mixture was sealed under 4 atmospheres of hydrogen and shaken overnight. The reaction mixture was filtered to remove the catalyst and concentrated to a light brown oil. The oil was purified by column chromatography 3 0 on silica gel eluted with 30% ethyl acetate in hexane to give 2.2 g (68% yield) of the title compound as a white foam. 1 H NMR (CDC3) 8: 1.4-1.95 10H), 2.25 (dd, 1 H, J=8.4, 4.5 Hz), 2.62 2H, J=7.5 Hz), 3.57 (dd, 1 H, J=11.4, 6.9 Hz), 3.65- 3.9 4H), 4.98 1H), 6.52 1 H, J=8.4 Hz), 6.63 1 H, J=8.4 Hz).

3 5 Step 4: 1-Azidomethyl-5.6-cyclohexylidenedioxv-3-hydroxymethyl-3,4-dihydro-1 H- 2-benzopyran 4684.US.P3 Lithium azide (1.0 g, 20 mmol) was added to a solution of [1,3-cis] 1bromomethyl-5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4-dihydro-1 H-2benzopyran (2.17 g, 5.87 mmol), from Step 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. The combined ether layers were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The r residue was purified by column chromatography on silica gel eluted with 25% ethyl acetate in hexane to give 1.38 g (70% yield) of the title compound as a colorless glass. 1 H NMR (CDCI 3 5: 1.45-1.95 10H), 2.14 (dd, 1H, J=9.0, 4.8 Hz), 2.63 (d, 2H, 7.5 Hz), 3.5 (dd, 1H, J=13.5, 7.0 Hz), 3.62 (dd, 1H, J=13.5, 2.7 Hz), 3.65-3.9 (m, 3H), 5.02 1H), 6.45 1H, J=8.4 Hz), 6.61 iH, J=8.4 Hz).

Step 5: [1.3-cis] 1 3-Bis(azidomethyl)-5.6-cyclohexylidenedioxy-3.4-dihydro-1 H-2benzopyran Methanesulfonyl chloride (0.128 mL, 1.65 mmol) was added dropwise to a T solution of 1,3-cis 1-azidomethyl-5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4dihydro-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 00C. After stirring for min at 0°C, the reaction mixture was transferred to a separatory funnel and diluted with diethyl ether. The layers were separated and the organic layer was 2 5 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 lithium 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. The 3 0 aqueous solution was extracted with 3 X 30 mL of diethyl ether and the combined ether extracts were washed with 30 mL of water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica gel eluted with diethyl ether to give 450 mg (84% yield) of the title compound as a pale yellow oil; DCI MS: 374 (M+NH 4 1H NMR (CDCI3) 6: 1.45- 1.95 1OH), 2.67 2H), 3.38 (dd, 1H, J=13.5, 3.9 Hz), 3.5 2H), 3.7 (dd, 1H, 4684.US.P3 J=13.5, 2.7 Hz), 3.9 1H), 5.0 1H), 6.47 1 H, J=8.7 Hz), 6.62 1H, J=8.7 Hz).

Step 6: [1.3-cis] 1.3-Bis(aminomethyl)-5.6-cyclohexylidenedioxy-3.4-dihydro-1 H-2benzopyran 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)-5,6cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran (430 mg, 1.2 mmol), from Step .TO 5, in 10 mL of anhydrous diethyl ether at 00C. 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 p.L of water, 91 pL of 15% aqueous sodium hydroxide solution and 273 pL of water. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 212 mg (85% yield) of the title compound as a colorless glass; 1 H NMR (CDCI3) 5: 1.4-1.95 14H), 2.5 (dd, 1H, J=17.1 Hz), 2.65 (dd, 1H, J=17.1, 3 Hz), 2.9 2H), 3.0 (dd, 1H, J=13.8, 6 Hz), 3.21 (dd, 1H, J=13.8, 2.4 Hz), 3.66 1H), 4.7 1H), 6.51 (d, 1 H, J=8.4 Hz), 6.61 1 H, J=8.4 Hz).

Step 7: f[13-cis) 1.3-Bis(aminomethyl)-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- .2*S cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran from Step 6. The solution was ,i 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 3 0 oven at 80°C overnight to give 280 mg (96% yield) of the title compound as a fine white powder, m.p. >260°C; IR 3320, 3040, 1590, 1500, 1290 cm- 1 DCI MS: 225 1 H NMR (d 6 -DMSO) 5: 2.38 (dd, 1H, J=16.5, 12 Hz), 2.76 2H), 2.97 (m, 1 3.52 2H), 3.9 1H), 4.83 1H), 6.54 1 H, 8.1 Hz), 6.7 1 H, J=8.1 Hz), 8.25 (br s, 6H), 8.6 1 9.4 1 Analysis calculated for C11 H 1 8 C1 2

N

2 0 3 C, 44.46; H, 6,11; N, 9.43. Found: C, 44.70; H, 6.04; N, 9.22.

125 4684.US.P3 Example [1.3-cis] 1-Aminomethyl-3.4-dihydro-5.6-dihydroxy-3-hydroxymethyl-1 H-2benzopyran hydrochloride Step 1: [1.3-cis] 1-Aminomethyl-5.6-cyclohexylidenedioxy-3.4-dihydro-3hydroxymethyl-1 H-2-benzopyran 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-5,6cyclohexylidenedioxy-3,4-dihydro-3-hydroxymethyl-1H-2-benzopyran, the product Sof 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 Sreaction mixture was cooled to 0°C and quenched by the sequential addition of 42 I5 p.L of water, 42 gL of 15% aqueous sodium hydroxide solution and 126 p.L of water.

The solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 263 mg (77% yield) of the title compound as a white powder; DCI MS: 306 1 H NMR (CDC13) 8:1.4-1.95 13H), 2.6 (m, S" 2H), 3.03 (dd, 1H, J=13.5, 5.7 Hz), 3.23 (dd, 1H, J=13.5, 2.7 Hz), 3.7 (dd, 1H, J=11.7, 7.5 Hz), 3.77-3.9 2H), 6.52 1H, J=8.4 Hz), 6.62 1H, J=8.4 Hz).

Step 2: [1,3-cis] 1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-hydroxymethl-1 H-2benzopyran hydrochloride 1 Absolute ethyl alcohol was saturated with anhydrous hydrogen chloride and 0. added to a suspension of 256 mg (0.83 mmol) of [1,3-cis] 1-aminomethyl-5,6cyclohexylidenedioxy-3,4-dihydro-3-hydroxymethyl- H-2-benzopyran from Step 1 in 2 mL of ethanol. The reaction mixture was heated to reflux temperature. After h at reflux temperature, a precipitate had formed. The solvents were evaporated 3 0 down under reduced pressure to approximately 5 mL. Diethyl ether was added until the precipitation was complete and the solid was collected by vacuum filtration, washed with diethyl ether and dried in a vacuum oven at 800C overnight to give 160 mg (73% yield) of the title compound as an off-white powder, m.p.

235°C; DCI MS: 226 IR: 3200, 1590,1500, 1295, 1050 cm- 1 1 H NMR 3 5 (d 6 -DMSO) 6: 2.28 (dd, 1 H, J=16.8, 11.4 Hz), 2.66 (dd, 1 H, J=16.8, 3.0 Hz), 2.83 (dd, 1 H, J=12.3, 9.3 Hz), 3.45-3.7 4H), 4.8 2H), 6.51 1 H, J=8.4 Hz), 6.67 126 4684.US.P3 1 H, J=8.4 Hz), 8.05 (br s, 3H), 8.48 (br s, 1 9.3 (br s, 1 Analysis calculated for C11H1 6

CINO

4 C, 50.48; H, 6.16; N, 5.35. Found: C, 50.64; H, 6.24; N, 5.20.

Example 156 [1.3-cis]1 -Aminomethyl-3.4-dihydro-5.6-dihydroxy-3-pyrrolidinylmethyl- H-2benzopyran dihydrochloride Step 1: [1R. 3S] 1-Azidomethyl-5.6-cyclohexvlidenedioxy-3.4-dihydro-3- 0 pyrrolidinylmethyl-1 H-2-benzopyran S. Methanesulfonyl chloride (0.146 mL, 1.89 mmol) was added dropwise to a S solution of 0.57 g (1.72 mmol) of [1B, 3.8]1-azidomethyl-5,6-cyclohexylidene-dioxy- 3,4-dihydro-3-hydroxymethyl-1H-2-benzopyran, the product of Step 4 of Example 5 154, and 0.36 mL (2.58 mmol) of triethylamine in 15 mL of methylene chloride at 0°C. The reaction mixture was stirred for 30 min at 0°C then transferred to a separatory funnel and diluted with 45 mL of diethyl ether. 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 950C for 2.5 h then poured into 75 mL of water. The aqueous solution was extracted with 3 X 40 mL of diethyl ether. The combined ether extracts were washed with 2 X 30 mL of water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with 10% methanol in methylene chloride to give 210 mg (55% yield) of the title compound as a white foam; DCI MS: 385 1 H NMR (CDC13) 8: 1.4-1.9 14H), 2.5-2.9 8H), 3.45 (dd, 1H, J=13.2, 6.6 Hz), 3.68 (dd, 1H, J=13.2, 2.4 Hz), 3.9 1H), 4.97 1H), 6.45 1H, J=8.1 Hz), 6.6 1H, J=8.1 Hz).

Step 2: [1.3-cis] 1-Aminomethyl-5.6-cyclohexylidenedioxy-3.4-dihydro-3- Dvrrolidinvlmethvl-1 H-2-benzooyran 127 4684.US.P3 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-5,6cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl-!H-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 andit was stirred at ambient temperature for 40 min. The reaction mixture was then cooled to 0°C and quenched by the sequential addition of 20 U.L of water, 20 pIL 6f 15% aqueous sodium hydroxide solution and 60 .L of water. The resultant solution was dried over anhydrous magnesium sulfate and the precipitate filtered. Diethyl ether saturated with :.OQ anhydrous hydrogen chloride was then added dropwise to the filtrate to precipitate the hydrochloride salt of [1,3-cis] 1-aminomethyl-5,6-cyclohexylidenedioxy-3,4dihydro-3-pyrrolidinylmethyl-1H-2-benzopyran which was collected by vacuum S filtration yielding 220 mg (98% yield) of the title compound as its hydrochloride salt, a white solid; DCI MS: 359 Step 3: [1,3-cis] 1-Aminomethyl-5,6-dihydroxy-3-pyrrolidinylmethyl1 H-2bnzopyran dihydrochloride Absolute ethanol (10 mL) was saturated with anhydrous hydrogen chloride and 213 added to 187 mg (0.44 mmol) of the product of Step 2, [1,3-cis] 1-aminomethyl-5,6cyclohexylidenedioxy-3,4-dihydro-,-pyrrolidinylmethyl-1H-2-benzopyran. The reaction mixture was heated to reflux temperature. After 2 h at reflux temperature, a precipitate formed and the reaction mixture was cooled to ambient temperature.

The volume of the reaction mixture was reduced under reduced pressure to approximately 5 mL. Diethyl ether was added to the concentrate to precipitate the product which we collected by vacuum filtration and washed with diethyl ether.

The solid was dried in a vacuum oven at 80°C overnight to give 146 mg (96% yield) of the title compound as a fine white powder, m.p. 280°C; IR 3400, 3200, 2960, 1510, 1295 cm-1; DCI MS: 279 1 H NMR (D 6 -DMSO) 5: 2.0 4H), 3 0 2.33 (dd, 1H, J=16.2, 10.8 Hz), 3.1 2H), 3.4 2H), 3.6 3H), 4.05 1H), 4.93 1H), 6.54 1H, J=8.7 Hz), 6.7 1H, J=8.7 Hz), 8.4 (br s, 3H), 8.6 1H), 9.4 1H), 10.6 (br s, 1H).

Analysis calculated for C15H24CI2N203: C, 51.29; H, 6.89; N, 7.97.

Found: C, 50.94; H, 6.82; N, 7.76.

128 4684.US.P3 Examples 157 160 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 Following the synthesis illustrated in Scheme V using the appropriate acylating agent Examples 161- 172 were prepared as disclosed in Table 7, as their 1:5 hydrochloride salts. The structure of each was confirmed by melting point, mass spectra and elemental analysis as designated, Examples 173- 175 'o Following the synthesis described in Examples 154 and 155, using 4- (be .zyloxy)butylene oxide and the procedure for N-methylation described in Example 111, Examples 173- 175 were prepared as disclosed in Table 8, as their hydrochloride salts. The structure of each was confirmed by melting point, mass spectra and elemental analysis as designated.

0 4684.US.P3 Table 6: Examples 157 160 Ex. No.. d* Amine rn!! Ms-*

HO

157

H

0 K"6 0

ONH

NH

2 255 295 158 H~( .06. NH 2 265 293 G NH Elemental Analysis H N c: 49.06 6.59 7.63 f: 49.05 6.68 7.42 c: 52.61 7.17 7.67 f: 52.8 7.21 7.53 c: 46.52 6.72 8.68 +1/4 EtOH f: 46,45 6.59 8.40 C: 51.93 6.61 5.05 +0.1 H 2 0 f: 51.79 6.52 4.75 9 V i NO 1 -'.NH 2

NH

2

HO

HO t~ OH

NH

2 >250 239 224 240 all compounds 1-3 cis unless incicated %fipwise .DCI MS

C

*9

C

OC

130 Table 7: Examples 161 169 468A.,IS.P3 Ex. No. CQmound"', Apyl chloride n22-Q M Elemental Analysis C H N o.

0 0 0 006

I

*4 16 OHO 0 Ho 01 CH

NH

2 0 HO N A, 162 HO,( 0 0 pentyl CI CH 3 *0 NH O HO N&.

H FOt 0 0 -tyl ClJ CH 3

NH

2 T64 HONHO 0 0 N N Jb C A

NH

2

O

HO N IL-CI 165 HO pyl 0 HO NH 2 -066 HO YN 0 I NI1

NH

2 f: na 337 183-4 337 h 188 >260 267 329 371 165 c: 57.65 +1/2 EtOH f: 58.05 c: 55.30 +1 H 2 0 f: 55.17 c: 55.82 +1,25 H 2 0 f: 56.00 c: 53.08 f: 52.71 C: 1.38 40.8 HO!V f: 51.48 c: 4 8.23 +1A4 iH 2 0 f: 48.09 c: 53.49 +1/4 H 2 0 f: 53.43 c: 53.73 +1/4 H 2 0 f: 53.69 8.14 7.82 7.98 7.61 6.12 6.00 6.93.

6.86 6.95 6.88 4.61 4.59 5.47 5.52 7.06 6.90 7.07 6.78 7.17 7.13 7.23 7.01 6.88 6.70 7.49 7.37 6.25 6.12 7.80 7.59 8.35 8.06 >250 309

HO

001

NH,

235 408

*O

00 HO 8 HO NH 2 HO N H N I-120

NH

2 >250 319 >250 295 i. compounds 1.3 cis unless mcdicated otherwise; *DCI MS (M+H)4- 131 Table 7:continued 4684.US.P3 Ex. No. QgmlPQv-ud* Acyl chloride HO 0 170 HO

N

HO H0 171

H

0

NH-

2 HO 0 goo~ :toNH 2

CI

0 Co

MS**

>250 330 >250 295 Elemental Analysis .0 H -N c: 48.58 5.52 10.00 +0.1 H 2 0 f: 48 .98 5.66 9.70 c: 54.18 7,76 7.43 +1 MRQ f: 54.07 7.70 7.28 c: 49.06 6.50 7.43 f: 49.03 6.35 7.48 234 281 all compounds 1-3 c~s unless indicated otherwise; DCI MS 45

S

S

@5 5S S S 0* S

S

S

05 4 S5 x S1 4684. US .P3 Table 8:173-175 Ex. No.. Comound* Mac~

MS**

173 174 S. 55 S S

C

S

~S4S.e S S S

S

:..175 .555

S

Seed HO

NH

2

NHCH

3

HO

HO

OH

NHCH

2

HO

HO.( NHCH 3

NHCV-

>246 253 >243 254 >260 253 Elemfental Analysis 'C H N p: 47.61 7.04 8.29 +0.4 MeOH f: 47.93 6.83 *7.69 c: 53.88 6.96 4.83 f: 53.62 6.99 4.90 c: 45.55 6.50 7.99 +i0.3 0H 2

C

2 f: 45.55 6.29 8.37 all compounds 1-3 cis unless indicated otherwise; S. .'5 ti~I MS

S

5.59 C S 55 55** 55 dO C 0 SSS OS S

S

4* 50 ~d 8133 48.SP Example 176 [1.3-isl 1Aminomethyl-3-cyclohexyl-6.7-dihydroxy-1 .3.4.S-tetrahydro-2benzoepin hydrochloride Step 1: Spiro[(4-methyl-1 .3-benzoQdioxole)-2.1 '-cyclohexane] 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 Sreflux temperature and the water produced in the condensation reaction was removed using a Dean Stark trap. After 6 h, the solution was concentrated to approximately 50 mL and purified on a silica gel column (10 cm X 6 cm) eluted with hexan e to give 14 g of the title compound as a colorless liquid; 1 H NMR (ODC1 3 53: -151. 5 (in, 2 1. 7 (in, 4 1. 9 (mn, 4 2.2 3 6.6 (in, 3 H).

Step 2: 1 -Cyclohexyl-2-(2'.3'-cyclohexylidenedioxy-4'-methylphenyl)ethanoI L~ 1- Cyclohexyl-3-(2'.3'-cyclohexylidenedioxyphenyl)-1 -propanol vit N-Butyl lithium (23 mL of a 2.1 M solution in hexane, 49 mmol) was added 6:.4 dropwise to a solution of spi ro[(4-m ethyl- 1 3-be nzodioxo le)-2,1'-cyclo he xan e] (9 g, 0e 44 mmol), from Step 1, in 60 mL of THF at 000. The reaction mixture was allowed to warm to 2500 and stirred at ambient temperature for 4 h. The reaction mixture was *then cooled to OO and 1 -cyclohexylethylene oxide was add.1( The reaction '2 5 mixture was stirred for 2 h at 2500C and 30 min at 500C ther! ,,'.ured into 100 mL of saturated aqueous ammonium chloride solution and extracted with 3 X 1QO mL of diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The title compounds were separated by column chromatography on silica gel eluted with 5% ethyl acetate in hexane to give 5.12 g (35% yield) of 1 -cyclohexyl-2-(2',3'cyclohexylidenedioxy-4'-methylphenyl)ethanol and 3.63 g (25% yield) of 1cyclohexyl-3-(2'?3'-cyclohexylidenedioxyphenyl)-1 -propanol.

Step 3: [1 .3-cis] 1 -Bromoinethyl-3-cyclohexvl-6,7-cyclohexylidenedioxy1 .3.4.5- 3 5 tetrahydro-2-benzoxepiri hydrochloride 134 4684.US.P3 Boron trifluoride ethevate (1.47 mL, 12 mmol) was added dropwise to a solution of 2 g (6.06 mmol) of 1-cyclohexyl-3-(2',3'-cyclohexylidenedioxy-phenyl)-1propanol from Step 2 and bromoacetaldehyde dimethyl acetal (0.716 mL, 6.06 mmol) in 30 mL of methylene chloride at -20°C. The temperature of the reaction mixture was maintained between -10°C and -50C for 1 h. The 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 silica gel eluted with 2% ethyl acetate in S'1d hexane to give 1.2 g (46% yield) of the title compound as a colorless foam.

9 0 o, .Step 4: [1.3-cis] 1-Aminomethyl-3-cyclohexyl-6.7-cyclohexylide'nedioxy-1.3.4,5- 8, tetrahydro-2-benzoxepin hydrochloride 5 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 S. mixture was heated to 650C, 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. The combined ether extracts were washed with mL of water and 75 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with 2% ethyl acetate in hexane to give 850 mg (89% yield) of [1,3-cis]-1-azidomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro- ,2 2-benzoxepin hydrochloride. This azide intermediate was dissolved in 25 mL of diethyl ether and lithium 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 JL. of water, 80 p.L of 3 0 15% aqueous sodium hydroxide solution and 240 g.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. The precipitate was collected by vacuum filtration and dried to give 770 mg (90% yield) of the title compound as a 3 5 colorless solid, m.p. 250°C; DCI MS: 372 1 H NMR (CDC13) 5: 0.9-1.9 (m, S135 48.SP 23H), 2.7 (in, 1 3.02 (in, 1 3.3 1 H, J=1 1.4 Hz), 3.52 (in, 2H), 4.97 (dd, 1 H, J=1 1.4, 2.9 Hz), 6.45 1 H, J=7.,E Hz), 6.5 1 H, J=7.5 Hz), 8.5 (br s, 2H).

Step 5: Hl .3-cis] -1 -Ain omethyl-3.-cyclohexyl-6 .7-dihydroxy-l .3.4 .5-tetrahydro-2benzoxepin hydrochloride [1 ,3-cis] 1 -Aminomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1 ,3,4,5tetrahydro-2-benzoxepin hydrochloride (200 mg, 0.49 inmol), from Step 4, was added to a 1 N solution of anhydrous hydrogen chloride in ethyl alcohol. The as I 1Q' reaction mixture was heated to 5000 and monitored by TLC analysis. 'After two ot-- hours the solution was concentrated to approximately 1 mL and the residue .triturated with diethyl ether. The solid was collected by vacuum filtration, washed ass0 with diethyl ether and dried to give 62 mg (40% yield) of the title compound as a 0*gcolorless powder, m.p. 21 6-21 900; DCI MS: 292 Analysis calculated for 17

H

26 01N0 3 C, 62.28; H, 7.99; N, 4.27. Found: C, 62.22; H, 8.05; N,*4.14.

Example 177 Z [1 .3-cis] 1 -Aminomethyl-3-cyclohexyl-3,4-dihydro-5.6-dihydroxv-7-methyl-1 H-2- .~:benzopyran hydrochloride 1 -Cyclohexyl-2-(2',3'-cyclohexylidenedioxy-4'-methylphienyl)ethanol, from Step 2 of Example 176, was converted to the title compound by the procedures described in Example 176 above, Steps 3 5, m.p. l68-170OC; DCI MS: 292 Analysis calculated for C 17

H

26 CIN0 3 +1/2H 2 0: C, 60.61; H, 8.077; N, a, e: 4.16. Found: C, 60.39; H, 7.92; N, 4.12.

136 4684.US.P3 Example 178 [1 S.3R1 1-Aminomethyl-3-phenyl-5.6-dihydroxy-1 H-2-benzopyran hydrochloride Step 1: 2-(2',3'-Cyclohexylidenedioxyphenyl)-1-phenylethanone A solution of 15.5 g (50 mmol) of 2-(2',3'-cyclohexylidenedioxyphenyl)-1phenylethanol prepared from styrene oxide (ccmmercially available from Aldrich Chemical Company) by the procedure described in Step 2 of Example 47, in 60 mL 1 i of methylene chloride was added dropwise to a mixture of 60 g (28 mmol) of pyridinium chlorochromate (PCC) and 35 g of Celite® filter aid in 300 mL of methylene chloride at ambient temperature. After 4 h, the reaction mixture was diluted with 200 mL of diethyl ether and filtered through silica gel. The chromiumcontaining residue was washed several times with diethyl ether. The filtrate was concentrated under reduced pressure to give 14 g (90% yield) of the title compound as a yellow syrup; DC MS: 326 309 1H NMR (CDCI3) 5: 1.4-1.9 10H), 4.2 2H), 6.7 3H), 7.42 2H), 7.53 1 H), 8.05 2H).

"2 0: Step 2: [1RI 2-(2'.3'-cyclohexylidenedioxyphenyl)-1 -phenylethanol A solution of 754 mg (2.45 mmol) of 2-(2',3'-cyclohexylidenedioxyphenyl)-1phenylethanone, from Step 1, in 1 mL of THF was added to a solution of 936 mg (2.9 mmol) of B-chlorodiisopinocampheylborane (commercially available from Aldrich Chemical Company) in 3 mL of THF at -20°C. After storing the resultant S solution for 12 h at -150C, the solvent was evaporated, the residue was dissolved in mL of diethyl ether and 565 mg of diethanolamine was added. The mixture was stirred for 30 min. The precipitate was removed by filtration through Celite® filter aid. The filtrate was concentrated and the residue purified by column 3 0 chromatography on siiica gel eluted with methylene chloride/hexane/diethyl ether (100:20:1) to give 546 mg (72% yield) of the title compound; DCI MS: 328

(M+NH

4 1H NMR (CDCI 3 1.4-1.9 10H), 2.3 (br s, 1H), 3.0 2H), 4.98 (dd, 1 H, J=7.5, 5.0 Hz), 6.62 3H), 7.3 137 4684.US.P3 Step 3: [1 S.3R1 1 -Aminomethyl-3.4-dihydro-5,6-dihydroxy-3-henv-l H-2benzopyran hydrochloride [1R] 2-(2',3'-Cyclohexylidenedioxyphenyl)-3-phenylethanol was converted to [1S,3R] 1-amino methyl-3,4-di hydro-5,6-di hydroxy-3-phe nyl-1 H-2-benzopyran by the procedures detailed in Step 3 of Example 47 and Steps 1 3 of Example 48, m.p. 158-16000; [alpha]D +1100 (c 0.52, 1N HCI); DCI MS: 272 Analysis calculated for C 16

H

18 CIN0 3 C, 60.60; H, 6.05; N, 4.42. Found: C, 60.71; H, 6.2; N, s 4.31.

ea Example 179 S [1 R,3S]1 3-Adamantyl-1 -aminomethyl-3.4-dihydro-5,.6-dihydroxy-1 H-2-benzopyran hydrochloride Step 1: 1-Aza-2-boro-3-oxa-1 .4.4-triphenyl-bicyclo[3.3.0]octane 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 G diphenyl-(2R-2'-pyrrolidinyl)methanol was prepared as described by E.J. Corey, et al. in J American Chem Soc, 109: 5551-3 (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.

Step 2 [1 R] 1-(1'-adamantyl)-2-bromo-1-hydroxvethane Diborane in THF (5.2 mL of 1.0 M THF solution 5.2 mmol) was added 3 0 dropwise over a period of 10 min to a solution of 2.22 g (8.63 mmol) of I adamantyl-bromomethyl ketone (commercially available from Aldrich Chemical Co.) and 2.1 mL of a 0.2 M solution in THF (0.43 mmol) of 1 -aza-2-boro-3-oxa- 1,4,4-triphenyl-bicyclo[3.3.0]octane, from Step 1, in 16 mL of anhydrous THF. The reaction mixture was stirred for 10 min at ambient temperature and then cooled to 3 5 -OoC 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 138 4684.US.P3 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 1 N 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 3: (1R 1 1-('-adamantyl)-ethylene oxide s. OS 1 0 A 15% aqueous solution of sodium hydroxide was added to a solution of 1.9 g (7.34 mmol) of [1R] 1-(1'-adamantyl)-2-bromo-1-hydroxyethane, from Step 2, in 50 mL of diethyl ether The mixture was stirred vigorously at ambient temperature for ~18 h. The mixture was then diluted with 100 mL of diethyl ether and 50 mL of water. The aqueous layer was extracted with 50 mL of diethyl ether. The combined 1 5 organic layers were washed with 2 X 50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 1.3 g of the title compound. The product was carried on to the next step without purification.

'2 0 Step 4: [1S] 1-(1'-Adamantyl)-2-(spiro-[(1.3-benzodioxole)-2.1'-cvclohexane]-1 ethanol n-Butyl lithium (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)-2,1'-cyclohexane] in .2 5: 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. The reaction mixture was cooled to -780C and a solution of 1.2 g (6.74 mmol) of [1R] 1-(1'-adamantyl)-ethylene oxide, from Step 3, in 5 mL of THF was added. Boron trifluoride etherate (1.15 mL, 9.44 mmol) was then added dropwise 3 0 over a 7 min period. After 30 minutes, 25 mL of aqueous saturated sodium bicarbonate solution was added, followed by 25 mL of ethyl acetate. The reaction mixture was allowed to warm to ambient .temperature and transferred to a separatory funnel. Ethyl acetate (50 mL and saturated aqueous sodium bicarbonate solution (25 mL) were added to the funnel and the layers were 3 5 separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 2 X 50 mL of aqueous sodium bicarbonate 4684.US.P3 mL of saturated aqueous sodium bicarbonate solution, 2 X 50 mL of water and mL of brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a light yellow colored 'foam. The foam (5.06 g) was purified by flash chromatography using C180DS (C18-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. 114-1160C; 1 H NMR (CDCI3) 8: 1.23 3H), 1.35 3H), 1.42 9H), 2.23 3H), 2.28 3H), 2.70 1 2.95 (dd, 1H), 3.68 1H), 4.05 1H), 4.2-4.47 3H), 6.01 1H), 7.04 1H), 7.17 1H), l' 7.26

S

Step 2: 5.6-Bis(acetoxy)-1-(alanyl-alanyl)aminomethyl-3-phenyl-3.4dihydronaphthalene hydrochloride *0 5 5,6-Bis(acetoxy)-1 -(N-t-butoxycarbonyl-alanyl-alanyl)aminomethyl-3-phenyl- 3,4-dihydronaphthalene hydrochloride (2.00 g, 3.36 mmol) from Step 1 was dissolved in 25 mL of diethyl ether. The resultant solution was cooled and saturated with hydrogen chloride. The solution was stirred at ambient temperature for 3 h. The precipitate was filtered and washed thoroughly with dry diethyl ether.

*120 The solid was dried overnight at 60°C in vacuo to give 1.69 g (95% yield) of the title compound as an off-white solid, m.p. 145-161°C (dec); 1 H NMR (CDC13) 6:1.35 (dd, 3H), 1.41 3H), 2.23 3H), 2.26 3H), 2.70 (dt, 1 2.95 (dd, 1 3.69 (br s, 1 3.89 (dq, 1H), 4.17-4.45 3H), 6.11 1H), 7.07 1 7.25 6H), 8.27 1 Analysis calculated for C27H33N306+1.3HCI: C, 59.73; H, 6.37; N, 32 5 7.74. Found: C, 59.94; H, 6.08; N, 7.64.

6" Example 1-Aminomethyl-5.6-bis(trimethvlacetoxy)-3-phenyl-3.4-dihydronaphthalene hydrochloride Step 1: N-t-Butyloxycarbonyl-1-aminomethyl-5,6-dihydroxy-3-phenyl-3.4dihydronaphthalene Triethylamine (7 mL) was added to a solution of 15 g (56 mmol) of 1- 3 5 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 8 80 4684.US.P3 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. The combined organic layers from the extraction were washed with 1 N hydrochloric acid solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The brown residue was triturated with boiling hexanes to give 16.7 g'(99% yield) of the title compound as an off-white solid, m.p. 175-177°C, 1 H NMR 5: 1.45 9H), 2.74 (dd, 1H), 3.19 (dd, 1H), 3.6-3.7 1H), 4.1-4.25 2H), 4.71 (br s, 1 5.4 (br s, 1 5.88 1 6.0 (br s, 1 6.68 2H), 7.2-7.35 1 0 Step 2: N-t-Butyloxycarbonyl-1-aminomethyl-5.6-bis(trimethylacetoxy)-3-phenyl- 4-dihydronaphthalene a@* N-t-Butyloxycarbonyl-1-aminomiethyl-5,6-dihydroxy-3-phenyl-3,4- 1 5 dihydronaphthalene (3 g, 8.16 mmo!), 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 0 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 "2 C the pH was adjusted to 4 with concentrated phosphoric acid. The reaction mixture was extracted with diethyl ether. The combined ether extracts were washed with aqueous saturated sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 4.26 g (89% yield) of N-t-butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3je* phenyl-3,4-dihydronaphthalene as an off-white solid, m.p. 64-69°C; 1H NMR S" (CDCI3) 8: 1.3 9H), 1.34 9H), 1.45 9H), 2.68 (dd, 1 2.93 (dd, 1 3.6- 3.76 1H), 4.1-4.3 2H), 4.63 (brs, 1H), 6.03 e.98 1H), 7.15-7.35 6H).

3 0 Step 3: 1-Aminomethyl-5.6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalene hydrochloride N-t-Butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4dihydronaphthalene (14 g, 26 mmol), from Step 2, was dissolved in 75 mL of 3 5 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 8 81 4684.US.P3 minimum amount of methanol and the methanol solution was added dropwise to an excess amount (500 mL) of diethyl ether. The precipitate was filtered, washed with diethyl ether and dried to give 9.1 g (90% yield) of 1-aminomethyl-5,6bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthaiene hydrochloride as a white powder, m.p. 210-212°C; 1 H NMR (d 6 -DMSO) 8: 1.25 9H), 1.28 9H), 2.61 (dd, 1 2.89 (dd, 1 3.75-3.85 1H), 3.99 2H), 6.28 2H), 7.15 1H), 7.2-7.35 5H), 7.37 1 8.37 (br s, 3H).

Examples 6

C

Following the procedures described in Example 4 using th'e appropriate aminomethyl compound of Formula I with both catechol hydroxyl group protected as shown in the table and the appropriate or amino acid or peptide having l5 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 in Table 1.

Examples 16- 34 Following the procedures described in Example 15, replacing the trimethylacetyl chloride with R1-CI, where R1 is as shown in the fable, Examples 16 34 were prepared as disclosed in Table 1.

*0 o•

V

0* e

S

S

SS

e 0

S.

S

S..

S 555

S

S. *S Table 1 :Examoles 6 6 acetyl 7 acetyl 8 acetyl 9 acetyl 10 acetyl 11 aceityl 1 S. OS S 0 *50* S S *5* 00 2 0H(0H 3

OCCJCH

3 y-L-glutamyl L-Ieucyl a-L-aspartyl L-alanyl D-alanyl L-norvalyl L-prolyl L-methlonyl L-alanyl-L-alanyl

H

H

ME) N M S a(M+H) I :12 acetyl 13 acetyl oil 499

(M+NH

4 142-177 481 (dec) 187-192 451 (dec) 150 (dec) 467 150-158 423 (dec) 150-157 423 (dec) 136 (dec) 451 150-152 449 (dec) 135-142 483 (dec) 184-185 618 (dec) 173-1 82 145-150 408 (dec) a 14 calc: 64.85 5.65 2.91 found: 64.68 5.99 2.74 calc: 481.1975 b found: 481.1696 calc: 62.01 '6.30 5.48 found: 62.39 6.54 5.60 calc: 57.32 5.33 5.33 found: 57.44 5.63' 5.36 calc: 61.28 5.93 6.15 found: 61.60 6.03 5.99 caic: t6i .06 5.89 6.09 found: 61.13 6.07 5.94 calc: 62.95 6.47 5.79 found: 62.96 6.50 5.65 calc: 60.31 5.82 5.41 found: 60.19 5.79 5.51 calc: 59,19 6.00 5.40 found: 59.14 6.11 5.30 calc: 63.55 5.00 5.76 found: 63.54 4.96 5.72 calc: d found: calc: (66.29 6.90 3.09 +0.5 H 2 0 :14 acetyl benzoyl 1 6 benzoyl 17 butanoyl 18 isobutanoyl H 1 9 methyl succinoyl H na 408 116-118 496 found1: calc: +0.2 H 2 0 found: calc: found: 65.98 6.80 2.96 67.09 6.85 3. 13 67.04 60.96 60.87 6.79 5.68 5.66 3.11 2.63 2.72 91 4tjb4.U 3 lable continued E&A~ B1 propionyl H 21 -CO-NH-phenyl H 111-112 380 na na 22 acetyl 23 methoxycarbonyl o 0 24 **2 25 66*6 6666 isobutyl succinoyl 135-138 384 112-114 552 100-103 410 128-130 532 dimethylamino- carbonyl 26 trifluormethyl- H sulfonyl calc:+ 62.20 1.7 HA 2 0 found: 62.20 calc: found: na calc: 64.69

H

2 0 found: 63.36 calc: 58.81 +0.5 H 2 0 found: 58.64 calc: 63.12 +0,1 H 2 0 found: 62.74 calc:+1.1 61.95

H

2 0 +0.3 EtOAc found: 58.83 catc:+0.1 40.18 G6H14 found: 41.07 calc: found: na calc: 65.56 +0.1 found: 65.08 calc: 61.06 found: 61.21 calc: 69.53 +0.5 found: 68.11 calc: 60.36 found: 59.08 calc: 69.16 found: 68.93 calc: 61.84 found: 61.55 calc: 67.17 +1 H 2 0 found: 67.16 h 2L 6.74 2.57 6.74 2.26 6.20 3,59 6.10 3.48 5.40 3.27 5.25 3.25 6.53 2.37 6.50 2.30 6.33 9.42 6.2b 8.19 2.84 2.47 2.93 2.50 4.89 4.25 4.91 4.17 5.90 3.10 5.97 3.05 5.66 7.37 5.57 7.18 5.79 10.06 5.93 9.23 6,47 3.10 6.45 3.10 4.01 6.98 4.04 6.86 5.47 2.37 **6 27 *0 66 beta-alanyl *966 6 0 of 6 28 (1,2-carbonyl) H 29 ethoxycarbonyl H 30 -CO-NH-benzyl H 31 -CO-NH-methyl H 66 6 6 66 245 (dec) 294 130-132 412 214-215 534 205-206 382 161-162 469 150 (dec) 566 159-161 536 32 acetyl CO-O-t-butyl 33 p-nitrobenzoyl H 34 p-methoxybenzoyl 5.24 2.35 i

I

a. Mass spectral M/Z (DCI/NH3) b. High Resolution mass spectral analysis c. starting from compound of Example 35 instead of Example d. structure confirmed by NMR data S1 4684.US.P0t a.

a a *t a a..

Exam le-16 1 -Amin omethyl-5.6-mbis (bpnzyloxy)-3-phe nyl-3.4-d~iydro napht hale no hydrlorbidei Following the procedures described in Example 5, replacing trimetilylacetyl chloride with benzoyl chloride and 1 -aminomethyl-5,6-dihydroxy-3-phenyl-3,4dihydronaphthalene hydroc:.,oride with the compound of Example 15, the title compound was prepared. mn.p. 173-i82aC; I H NMR (CD3OD) 5: 2.88 1 3.05 (dd, 1 3.65-3.8 (in, 2H), 4.0-4.1 (br s, 1 H+CH3OH), 6.35 1 7.05-7.35 (in, 1 OH), 7.35-7.55 (mn, 3H), 7.9-8.0 (in, 4H), 8.5-8.65 (br s, 3H).

Example r..-cs -Aiimty-6-ihro-3pel1.2,3,4-tetrahydronaphhLene hyd rob ro mide Step 1: .3-cis] 1 -Aminomethvl-5.6-dimethoxy-3-phenyl-1 .2.3A.4 tetrahydronaphthalene hydrochloride *a a a a To 0.2 g (0.67 inmol) of 1-aminomiethyl-5,6-dimethoxy-3-phenyl-3,4- .:di hydro naphthalene hydrochloride, from Step 2, of Example 2, was added 0.05 g of palladium supported on carbon. The reaction mixture was sealed under hydrogen and stirred overnight at ambient temperature.The reaction mixture was flushed with nitrogen before it was filtered through Celite@ filter aid and washed with 15 mL of absolute ethanol and 15 inL of mnethylene chloride. The filtrate was concentrated to give 0.2 g (100% yield) of [1,3-cis] 1 -aminomethyl-5,6-dimethoxy-3pheryl-1 ,2,3,4-tetrahydronaphthalene hydrochloride, in.p. 230-231 0 C; 1 H NMR (d 6 -DMSO) 5: 2.15-2.25 (in, 1 2.5-2.65 (in, 1 2.8-2.95 (in, 2H), 3.0-3.1 (in, 1 3.1-3.4 (in, 1 3.45-3.5 (in, 1 3.66 3H), 3.78 3H), 6.95 I1H), 7.12 1 7.2-7.3 (in, 1 7.35-7.45 (in, 4H), 8.0 (br s, 3H).

Step 2: [1 .3-cis] 1 -Aminomenthyka5 jhydroxy-3-phenyl-1.2,3.4terahyrdronaph halene hydrobroinide 4684.US.P3 [1 ,3-cis] 1-Aminomethy.-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride (0.2 g, 0.67 mmol), from Step 1, was suspended in 13 mL of methyiene chloride and the suspension was cooled to -780C in a dry ice/acetone bath. bcron tribromide (3 mL of a 1 M solution in methylene chloride, 3 mmol) was added and trie reaction mixture was allowed to warm to ambient temperature, kept at ambient temperature for 1.5 h then cooled to -780C. Methanol (3 mL) was-added to the reaction mixture and it was again aiiowed to warm to ambient temperature then concentrated in vacuo. The residue was redissolved in methanol and reconcentrated. The residue was again redissolved in methanol and the methanol %i'0 solution was added to a large excess of diethyl ether. The resultant precipitate was a 0 filtered and recrystallized from ethanol/diethyl ether to give 0.14 (34% yield) of S the title compound as a white powder, m.p. 256-259oC; 1H NMR (d 6 -DMSO) 8: 1.63 1H), 2.1-2.25 1H), 2.4-2.5 1H), 2.75-2.95 2H), 3.02 (dd, 1H), 3.15-3.3 1H), 3.4-3.5 1H), 6.68 2H), 7.2-7.3 1H), 7.3-7.4 4H), 7.8 :5 (brs, 3H), 8.2 (brs, 1H), 9.1 (brs, 1H).

Example 36 1-Aminomethyl-3-cycloihexyl-56-dilydroxy.3.4-dihydronaphthalene hydrobromide Step 1: Ethyl 3-cyclohexylpropenate Sodium hydride (2.6 g, 108 rnmol) was added to 100 mL of THF and 19.8 mL (98.9 mmol) of tr:ethylphosphonoacetate, commercially available from Aldrich Chemical Company, was added dropwise at 0°C. The reaction mixture was stirred for h at ambient temperatui. and 12.1 mL (99.9 mmol) of cyclohexanecarboxaldehyde, commercially available from Aldrich Chemical Company, was added. The reaction mixture was heated at reflux temperature for min then cooled and filtered. The filtrate was concentrated under reduced 3 0 pressure and the product was distilled at 1400C (15 Torr) to give 15.2 g (84% yield) of ethyl 3-cyclohexylpropenoate as a clear liquid; 1H NMR (CDCl3) 8:1.1-1.4 (m, 6H), 1.3 3H), 1.6-1.8 5H), 2.05-2.2 1 4.2 2H), 5.75 1H), 6.92 (d, 1H).

86 4684.US.P3 Step 2: 1-Aminomethyl-3-cyclohexyl-5.6-dimethoxy-3.4-dihydronaphthalene bydrochloride 2-(2',3'-Dimethoxyphenyl)-1,3-dithiane, from Step 1 of Example 1, Method B, and ethyl 3-cyclohexylpropenoate, from Step 1 of this Example, were condensed as described in Step 2 of Example 1, Method B. The adduct was treated with Raney nickel and sodium hydroxide to give the corresponding acid. The acid was cyclized with polyphosphoric acid as described in Step 6 of Example 1, Method A, to give 3cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one. 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- S tetrahydronaphthalene. The hydroxy group was eliminated by treatment with anhydrous hydrogen chloride in isopropyl alcohol as described in Step 2 of 1S Example 2 to give 1-aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4dihydronaphthalene hydrochloride, m.p. 178-179OC; 1 H NMR (d6-DMSO) 8: 1.4 7H), 1.5-1.9 6H), 2.0-2.2 1H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.6 3H), 3.81 3H), 5.8 1 6.6 2H).

9 Step 3: 1-Aminomethyl-3-cyclohexyl-5.6-dihydroxy-3.4-dihydronaphthalene hvdrobromide 1-Aminomethyi-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride (2.7 g, 8.9 mmol), from Step 2, was dissolved in 72 mL of methylene chloride and cooled to -780C. Boron tribromide (36 mL of a 1 M solution in methylene chloride) was added and the reaction mixture was warmed to 0°C for 1 h. The reaction mixture was cooled again to -780C and 30 mL of methanol was added. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated, diluted with methanol and reconcentrated. The residue was 3 0 dissolved in methanol and the methanol solution was added dropwise to an excess amount of diethyl ether. The precipitate was filtered and recrystallized from ethanol/ether to give 2.2 g 79% yield) of'the title compound, m.p. 212-2130C; 1

H

NMR (d 6 -DMSO) 6: 1.0-1.4 7H), 1.55-1.9 6H), 2.05-2.15 1H), 2.47 (dd, 1 2.74 (dd, 1H), 5.83 1H), 6.60 2H).

*1 87 4684.US.P3 Example 37 3S] 1-Aminomethyl-5.6-dihydroxy-1.2.3,4-tetrahydronaphthalene hydrobromide Step 1: [1R. 3S] 1-Aminomethyl-3-cyclohexyl-5.6-dimethoxy-1,2.3.4tetrahydronaphthalene hydrochloride 1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene T hydrochloride (1 g, 3.3 mmol), from Step 2 of Example 36, was dissolved in 20 mL of ethanol and 0.25 g of 10% palladium on carbon was addad to the ethanol solution. The reaction mixture was sealed under one atmosphe're of hydrogen and S shaken at ambient temperature for 24 h. The reaction mixture was filtered to remove the catalyst and concentrated to give 1 g (100% yield) of the title compound, m.p. 282-2830C; 1 H NMR (d 6 -DMSO) 1.0-1.5 8H), 1.5-1.9 (m, 2.0-2.2 2H), 2.7-3.1 3H), 3.3-3.4 1H), 3.8 3H), 3.9 3H), 6.4-6.8 2H).

Step 2: [1R. 3S 1 -Aminomethvl-3-cyclohexvl-5.6-dihydroxv-1.2,3.4- .tB tetrahydronaphthalene hydrobromide [1R, 3S] 1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-1,2,3,4tetrahydronaphthalene hydrochloride (0.7 g, 2.3 mmol), from Step 1, was suspended in 20 mL of methylene chloride at -780C. Boron tribromide (9.7 mL of a 1 M solution in methylene chloride, 9.7 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After stirring at ambient temperature for 1 h, the reaction mixture was cooled to -780C and 10 mL of methanol was added. The reaction mixture was again allowed to warm to ambient temperature and stirred at ambient temperature for 1 h. The solvent was removed in vacuo and 3 0 methanol was added to the residue. The methanol solution was concentrated and the residue dissolved in a minimal amount of methanol and added dropwise to a large excess of diethyl ether. The precipitate was filtered and recrystallized from ethanol/diethyl ether to give 0.48 g (65% yield) of [1R, 3S] 1-aminomethyl-3cyclohexyl-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, m.p. 203- 2040C; 1 H NMR (d 6 -DMSO) 6: 0.9-1.5 8H), 1.6-1.9 5H), 2.0-2.1 2H), 2.7- 3H), 3.3-3.4 1H), 6.5-6.7 2H).

8 88 4684.US.P3 Examples 38 43 Following the synthesis outlined in Example 36, using the appropriate aldehyde, Examples 38 43 were maoe, as their hydrochloride salts, as disclosed in Table 2. The structure of each was confirmed by melting point 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 elemental analysis and mass spectra as designated.

S *9*

S

0 *C 139 4684.US.P3 solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to an oil. The crude product was dissolved in 20 mL of methanol and the solution was cooled to 0°C. The precipitate was collected by filtration and washed with cold methanol to give 2.21 g (89% yield) of the desired product. The title compound was recrystallized from methanol to give 1.6 g of the title compound, m.p. 72-73OC; [alpha]D -27.750 (c 1.63, CHCl3); DCI MS: 386 1H NMR (CDC13) 6: 0.9 0.25 H, J=6 Hz, MeOH solvate), 1.5-2.1 (m, 2.5 (dd, 1H, J=13.5, 10.5 Hz), 2.87 (dd, 1H, J=13.5, 2.0 Hz), 3.3 1H), 0.75H, J=6 Hz, MeOH solvate). Analysis calculated for C 2 4

H

3 2 0 3 +0.25MeOH: 1 @6 C, 77.35; H, 8.83. Found: C, 77.09; H, 8.77.

Step 5: [1 R.3S] 3-(1 '-Adamantyl)-5.6-cvclohexylidenedioxy-3.4-dihydro-1-(Nformyl)aminomethyl-1 H-2-benzopyran Trimethylsilyltriflate (73 p.L, 0.38 mmol) was added to a mixture of 3.5 g mmol) of 1-(1'-adamantyl)-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-lethanol, from Step 4, and N-formyiacetaldehyde dimethyl acetal (2 g, 15.2 mmol) in 20 mL of acetonitrile. The reaction mixture was heated at a gentle reflux for 2 h and an additional 50 U.L (0.26 mmol) of trimethylsilyltriflate was added. A precipitate '2 0' 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 yield) of the title compound as colorless crystals, m.p. 220-221OC; [alpha]D 33.150 (c 1.63, CHCI3); DCI MS: 438 1 H NMR (d6-DMSO) 6: 140°C 2.05 25H), 2.5 2H), 2.8 1H), 3.1 (dd, 1H, J=7.5, 3.0 Hz), 3.32 1H) .2 5: 3.71 (br s, 1 4.65 (br s, 1H), 6.6 2H), 8.05 (br s, 1H).

Step 6: [1 R.3S] 3-(1'-Adamantyl)-1 -aminomethyl-5.6-cyclohexvlidenedioxy-3.4dihydro-1 H-2-benzopyran [1 R,3S] 3-(1 '-Adamantyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1 formyl)aminomethyl-1 H-2-benzopyran (2.8 g, 6.41 mmol) was mixed together with mL of 15% aqueous sodium hydroxide solution, 30 mL of methanol and 20 mL of THF. The mixture was heated at ~500C for 3 h and then it was concentrated in vacuo to -30 mL. The concentrated mixture was diluted with 150 mL of ethyl 3 5 acetate/methylene chloride and 50 mL of water. The organic layer was washed with 2 X 50 mL of water and 50 mL of brine. The combined aqu jus layers 140 4684.US.P3 were extracted with ethyl acetate/methylene chloride and discarded. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.64 g of the title compound as a light tan colored foam. The product was carried on to the hext step without purification.

Step 7: [1 R.3S] 3-(1'-Adamantyl-1 -aminomethyl-3.4-dihydro-5.6-dihydrxy-1 H-2benzopyran hydrochloride SA solution of hydrochloric acid in 10:1 THF/water (20 mL of a 4 N solution) 1 0 was added to [1 R,3S] 3-(1'-adamantyl)-1-aminomethyl-5,6-cyclohexylidenedioxy- *of: 3,4-dihydro- H-2-benzopyran (1.1 g, 2.7 mmol) from Step 6, and the reaction mixture was heated at reflux temperature for 3 h. The reaction rixture was cooled to 0°C and 10 mL of diethyl ether was added. At the onset of crystallization an additional 10 mL of diethyl ether was added. After 30 min the precipitate was removed by filtration, washed with diethyl ether and dried to give 0.81 g (82% yield) of the title compound as a colorless solid; DCI 330 1H NMR 5:1.65-2.05 15H), 2.6 (dd, 1H, J=16.5, 12.0 Hz), 2.72 (dd, 1H, J=16.5, 3.0 Hz), 3.08 (dd,'lH, J=12.6, 7.5 Hz), 3.15 (dd, 1H, J=12.0, 3.0) 3.54 (dd, 1H, J=12.6, 3.2 Hz), 4.85 1H), 6.5 1H, J=8.4 Hz), 6.69 1H, J=8.4 Hz).

2 0' 9 Example 180 [1 3-cis] 5.6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinvl)-1 2.3.4-tetrahydronaphthalene .2 5 hydrobrormide Step 1:1-Cyano-5.6-dimethoxy-3-phenyl-3.4-dihydronaphthalene To a suspension of 10 g (35 mmol) of 5,6-dimethoxy-3-phenyl-1,2,3,4- 3 0 tetrahydronaphthalen-1-one, the product of Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AICI3). The reaction mixture was heated at 60°C for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture was 3 5 reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of triflucroacetic acid and 100 mg of p- S 141 4684.US.P3 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 silica 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 2: 1-Cyano-5.6-dimethoxy-3-phenyl-1,2,3.4-tetrahydronaphthalene Sodium borohydride (6.8 g) was added to a suspension of 6.8 g (23.3 mmol) of 1-cyano-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, from Step 1, in 100 mL of absolute ethanol and the reaction mixture was heated at reflux temperature for 1.5 h. The solvent was evaporated under reduced pressure and the residue was 1'5 dissolved in ethyl acetate. The ethyl acetate solution was washed with 1 N aqueous hydrochloric acid solution, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil.

The oil was triturated with heptane to give 5.63 g (82% yield) of the title compound as a white crystalline solid, m.p. 118-121°C.

Step 3: 5,6-Dimethoxy-3-phenvl-1.2,3,4-tetrahydronaphthalene-l-carboxvlic acid A mixture of 5.6 g (19.1 mmol) of 1-cyano-5,6-dimethoxy-3-phenyl-1,2,3,4tetrahydronaphthalene, from Step 2, 40 mL of 5% aqueous potassium hydroxide 2 5. solution and 90 mL of ethylene glycol was heated at reflux temperature for 8 h. The S reaction mixture was then cooled to -200C and made acidic by the addition of cold concentrated aqueous hydrochloric acid solution. The acidic solution was extracted with methylene chloride and the organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 5 g (84% yield) 3 0 of the title compound which was used in the next step without purification.

Step 4: N-Methoxy-N-methyl-5,6-dimethoxy-3-phenyl-1,2.3.4-tetrahydronaphthalene-1 -carboxamide 3 5 5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene-l-carboxylic acid (5 g, 16 mmol), from Step 3, was suspended in 100 mL of toluene and 5 mL of oxalyl 142 4684.US.P3 chloride was added. The reaction mixture was heated at reflux temperature for h under a nitrogen atmosphere. The solvent was evaporated and excess reagents removed from the residue as an azeotrope with toluene (2 X 40 mL). The acid chloride and 2g (20 mmol) of N,O-dimethylhydroxylamine hydrochloride was dissolved in 80 mL of ethanol-free chloroform. The solution was cooled to 0°C and 3.3 mL of pyridine was added slowly. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for approximately 4 h then evaporated to dryness. The residue was dissolved in a 1:1 mixture of diethyl ether and methylene chloride and washed with brine. The layers were separated and the 1 0 organic layer dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil in 98% yield. The product of Step 4 was used in the next step without purification.

Step 5: 5.6-Dimethoxy-3-phenyl-1 -(2'-yrrolidinyl)-1.2.3.4-tetrahydronaphthalene 1 5 hydrochloride N-Methoxy-N-methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaph-thalene-1carboxamide (3.3 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-1aza-2,5-disilacyclopentane-1-propyl magnesium bromide was added and stirred overnight. The 2,2,5,5-tetramethyl-1-aza-2,5-disilacyclo-pentane-1-propyl magnesium bromide was prepared as described by Basha and DeBernardis in Tetrahedron Letter5, 25, 5271-5274 (1984). The reaction mixture was cooled to 00C, 10% hydrochloric acid solution in ethanol was added slowly, and it was allowed to warm to ambient temperature again. The reaction mixture was stirred at ambient temperature for 3 h and the solvent was evaporated. The residue was dissolved in 50 mL of methanol, cooled to 0°C and treated with an excess of sodium cyanoborohydride. The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 2 h. The solvent was removed 3 0 in vacuo and the residue was redissolved in diethyl ether and washed with water.

The layers were separated and the acidic aqueous layer was made basic and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with ethyl acetate/formic 3 5 acid/water (18:1:1) to give a total yield, after concentration in vacuo, of 2.42 g (42% yield) of the title compound as individual diastereomers as their formate salts. Each 143 4684.US.P3 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 yield) of the [18, 3S, 2'R] isomer, m.p. 105-1060C. The structure was confirmed by NMR and X-ray crystallographic analysis (after recrystallization from S1 acetone by slow evaporation).

The final product to elute from the column gave 400 mg (11% yield) of the 3B, 2'8] isomer, m.p. 150-152°C. The structure was confirmed by NMR and Xray crystallographic analysis after recrystallization from acetone by slow evaporation.

Step 6: [1.3-cis] 5,6.Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl)-1.2,3,4tetrahydronaphthalene hydrobromide 0 5,6-Dimethoxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene hydrochloride (200 mg, m.p. 105-106°C), from Step 5, was dissolved in 10 mL of methylene chloride and the solution was cooled to ,780C under a nitrogen atmosphere. Boron tribromide (0.25 mL of a 1 M solution in methylene chloride) was added and the reaction mixture was stirred for 3 h at -780C. The reaction mixture was then allowed to warm to -200C for 1 h, cooled to -780C and quenched with 10 mL of methanol. The solution was evaporated to dryness and distilled with methanol three times to azeotrope methyl borate from the residue. The solid residue was crystallized from methanol/ethyl acetate to give 130 mg (67% yield) of the title compound, m.p. 265°C (with decomposition). Analysis calculated for C20H24BrNO2+1/2H20: C, 60.16; H, 6.31; N, 3.51. Found: C, 60.06; H, 6.17; N, 3.42.

Example 181 [1,3-cis] 5,6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl-1.2,3,4-tetrahydronaoh-thalene hydrobromide

S

144 4684.US.P3 According to the procedures described in Step 6 of Example 180, [1B, 3BJ 5,6dimethoxy-3-phenyl-1 -(2'-pyrrolidinyl)-1 ,2,3,4-tetrahydronaphthalene hydrochloride (350 mg), from Step 5 of Example 180, in 10 mL of methy!ene chloride at -780C, was treated with 472 of a 1M solution of boron tribromide in methylene chloride. The title compound was obtained (213 mg) in 61% yield after crystallization from methanol/ethyl acetate, m.p. 250°C (with decomposition).

Analysis calculated for C20H24BrNO2+1/2H20: C, 60.16; H, 6.31; N, 3.51. Found: C, 60.23; H, 6.24; N, 3.38.

Example 182 [1 R*.8S*.9aR*] 1 -Amino-5.6-dihvdroxv-8-phenvl-2.?,7.8.9.9a-hexahvdrophenalene hydrobromide 0 Step 1: 1-(3'.."3'-Carbomethoxypropanoic acid)-5.6-dimethoxy-3-phenyl-3.4dihydronaphthalene To a suspension of 4.0 g. (14.2 mmol) of 5,6-dimethoxy-3-phenyl-1,2,3,4tetrahydronaphthalen-1-one, the product of Example 1, in 5 mL of t-butyl alcohol was added dropwise a mixture of 13 mL (99.4 mmol) of dimethyl succinate, 9.6 g i (86 mmol) of potassium t-butoxide, and 65 mL of t-butyl alcohol. After 10 mL of the mixture was added, the reaction was heated to 55°C and maintained at this temperature for the duration of the reaction. When the addition was complete, 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 *2 5. 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 3 0 sulfate, filtered, and concentrated in vacuo. The title compound (5.0 g, 86% yield) was obtained as an oil; MS DCI: 397 1H NMR (CDCI3) 5: 2.6-2.8 (m, 4H), 3.1-3.3 1H), 3.69 3H), 3.71 3H), 3.87 3H), 4.1-4.25 1H), 5.9- 6.7-6.8 1H), 7.0-7.5 6H).

S

145 4684.US.P3 Step 2: 1 -(3'-(3'-Carbomethoxypropnanoic acid)-5.6-dimethoxy-3-phenyl-1.2.3.4tetrahvdronahthalene To a solution of 15.8 g (39.9 mmol) of 1-(3'-(3'-carbomethoxypropanoic acid)-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, from step 1,in 200 mL of ethyl acetate was added 3.16 g. of 10% palladium supported on carbon. The reaction mixture was shaken under 4 atmospheres of hydrogen until hydrogen uptake ceased. The reaction mixture was filtered and concentrated under reduced pressure to give 12.2 g (74% yield) of the title compound as an oil. The product 1 (G was carried on without further purification to the next step.

*0 Step 3: 1-Carbomethoxy-5,.6-dimethoxy-3-hydroxy-8-phenyl-7.8.9.9atetrahydrophenalene -Carbomethoxypropanoic acid)-5,6-dimethoxy-3-phenyl-1,2,3,4tetrahydronaphthalene (3.5 g, 8.5 mmol), from Step 2, was added to 11 g of polyphosphoric acid at 0 0 C. The ice bath was removed and the mixture was stirred at ambient temperature for 3 hours. The aqueous solution was extracted with 3 X 50 mL of 1:1 ethyl acetate/diethyl ether. The combined organic layers were *z0 washed with 50 mL of saturated aqueous sodium bicarbonate solution, dried over ,:anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

The product was purified by chromatography on silica gel, eluted with 20% ethyl acetate in hexanes. Four diastereomeric products were obtained of which two were characterized.

The first diastereomer, [1R*,8S*,9aR*]-1 -carbomethoxy-5,6-dimethoxy-3- S hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene (182-3A), was obtained in 18% yield (0.59 g) as a solid, m.p 170-172OC; DCI MS: 381 398 (M+NH 4 1

H

NMR (CDC1 3 6: 1.6-1.7 1H), 2.1-2.2 1H), 2.6-2.7 1H), 2.9-3.1 4H), 3.2-3.4 2H), 3.71 3H), 3.87 3H), 3.91 3H), 7.2-7.4 5H), 7.53 (s, 1 H).

The second diastereomer, [1S*,8S*,9aR*]-1 -carbomethoxy-5,6-dimethoxy-3hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene (182-3B) was obtained in 18% yield (0.60 g) as a solid, m.p 160-161OC; DCI MS: 381 398 (M+NH 4 )f; 1 H NMR (CDC 3 6: 2.0-2.1 1H), 2.15-2.25 1H), 2.6-2.8 2H), 3.0-3.1 (m, 146 4684.US.P3 2H), 3.2-3.3 (in, 2H), 3.4-3.5 (in, 1 3.7 3H), 3.83 3H),,3.91 3H), 7.2-7.4 (in, 5H), 7.54 1 H).

S9tep 4: [1 R*.8S*,9aR*I 1I -Carbo methoxy-5jQ-di met hoxy-8-ph enyl-2.3,7.8,9.9ahexahydrophenalene To a solution of 0.5 g (1.3 mmol) of [1.B,8.3,9aa-1 -carbomethoxy-5,6dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene (1 82-3A) in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL of concentrated aqueous 0* hydrochloric acid was solution was added 0.2 g of 5% palladium supported on :::carbon and the mixture was shaken under 4 atmospheres of hydrogen until the gas ::'uptake had ceased. The palladium catalyst was removed by filt iration through Celite® filter aid and the filtrate concentrated to give a white solid, which was carried on to the next step without purification.

Step 5: [1 R*.8S*.9aR 5,6--D imet hoxy-8- ph enyl-2.3,7.8.9 .9a-h exa hydro phe nale ne- Crude [1 R*,8S*,9aR*] 1 -Carbomethoxy-5,6-dimethoxy-8-phenyl- 210: 2,3,7,8,9,9a-hexahydrophenalene (0.8 2.1 minol), from Step 4, was dissolved in 100 mL of methanol and 8 mL of 1 N aqueous sodium hydroxide solution was added. After stirring for 3 days at ambient temperature, the methanol was removed under reduced pressure. The residue was partitioned between 50 mL of diethyl :ether and 75 mL of water. The aqueous phase v ,as acidified to pH 2 with 6 IA aquecus hydrochloric acid solution and extracted with 3 X 25 mL of 1:1 ethyl Sacetate/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; OCI MS: 253 1 H NMR (0D013) 8: 2.0-2.3 (in, 2H), 2.65-2.85 (in, 2H), 2.9-3.1 (in, 6H), 3.2-3.3 (in, 1 3.73 3 0 3H), 3.83 3H), 6.56 1 7.2-7.4 (in, Step 6:11l *.8S*.9aRI] 1 -Carbobe nzyloxyami no-5,6-di met hoxy-8-phe nyl- 2.3.7.8.9 .9a-hexahydrophenalene 3 5 [1 R*,8S*,9aR*] 5,6-Dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene- 1 -carboxylic acid (0.8 g, 2.3 mmol), from Step 5, and triethylamnine (0.32 mL, 2.3 147 4684.US.P3 mmol) were dissolved in 16 mL of toluene and 0.55 mL (2.5 mmol) of diphenylphosphoryl azide was added. The reaction mixture was heated at 800C for 2.5 h then 0.5 mL (4.8 mmol) of benzyl alcohol was added and heating was continued at 800C for an additional 3 h and at 65°C for 15 h. The 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. The product was purified by chromatography on silica gel eluted with 20% ethyl acetate in hexanes to give 0.4 1 g (39% yield) of the title compound as a white solid; DCI MS: 475 (M+NH 4 458 367 (M-benzyl+H) 324 (M-benzyloxy-carbonyl+2H)+. 1 H NMR (CDC3) 8: 1.6-1.7 3H), 2.2-2.35 2H), 2.6-2.75 2H), 2.9-3.0 3H), 3.2- 3.3 1H), 3.73 3H), 3.82 3H), 4.65-4.7 1H), 5.08 2H), 6.54 1 H), 7.2-7.4 1 OH).

Step 7: [1R*.8S*.9aR*1 1-Amino-5.6-dimethoxy-8-phenyl-2,3.7.8.9.9ahexahydrophenalene A suspension of 0.65 g 1.4 mmol) of [1 R*,8S*,9aR*] 1-carbobenzyloxyamino-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene, from Step 6, in 50 mL of methanol and 0.1 g of 10% palladium supported on carbon was stirred under 1 atmosphere of hydrogen for 1 hour. The solid dissolved as the reaction proceeded. The catalyst was removed by filtration and the solution was concentrated under reduced pressure to give 0.4 g 87% yield) of crude title .2 5 compound which was carried on to the next step without further purification.

Step 8: 1 R*.8S*.9aR*] 1 -Amino-5.6-dihydroxy-8-phenyl-2.3.7,8.9,9ahexahydrophenalene hydrobromide 3 0 To a solution of 0.4 g (1.2 mmol) of [1R*,8S*,9aR*] 1-amino-5,6-dimethoxy- 8-phenyl-2,3,7,8,9,9a-hexahydrophenalene in 9 mL of methylene chloride at 780C, was added dropwise 4.4 mL (4.4 mmol) of a M solution of boron tribromide in methylene chloride The reaction mixture was warmed to ambient temperature for 1 hour and cooled to -780C and the rm;vtion was quenched by the addition of 3 5 mL of methanol. The reaction was allowed to warm to ambient temperature and 148 4684.US.P3 stirred for 1 hour. The solvent was removed in vacuo. Methanol (5 mL) was added and the solution was concentrated to remove methyl borate by azeotropic distillation. The title compound was obtained (0.32%g 69% yield) after recrystallization fromn ethanol/diethyl ether as a white solid; DCI MS: 279 296 (M-INH 4 1 H NMFR (d6-DMSO) 8: 1.4-1.6 (in, 1 1.7-1.9 (in, 1 2.1-2..2 (in, 1 2.2-2.3 (mn, 1 2.4-2.5 (in, 2H), 2.7-3.2 (in, 5H), 6.41 1 7.2-7.4 (br s, 5H). Ana?.lysis calculated for C, 9

H

2 2BrNO 2 +0.5 H20: C, 59.23; H, 5.99;, NI 3.64. Found: C, 59. 26; H, 5.86; N, 3.59.

Example 183a 2 U~$.9aR* I 1-Amino-5.6-dihvidroxv,.-phenyl-2.378.9.9a-hexahydrophenalene ydrobromide 0o .5 [1 S*,8S*,9aR*] 1 -Amnino -5,6 -diineth oxy-8-p he ny-2,3,7,8,9,9 ahexahydrophenalene hydrobroinide was prepared from the second isomeric product of Step 3 of Example 1 82 (313) according to the procedures described in *foSteps 4 through 8 of Example 182; DCI MS 279 296 (M-NH 4 1 H NMR Se:(d6-DMSO) 5: 1.6-1.75 (in, 1 1.8-2.05 (in, 2H), 2.25-2.7 (in, 5H), 2.85-3.05 (in, 020- 3H), 6.37 1 7.1-7.4 (in, 511), 7.7 (br s, 5H). Analysis calculated for ,,coC 19 qH 22 BrNO 2 +1 H20: C, 57.88; H, 6.14; N, 3.55. Found: C, 57.82; H, 5.74; N, 3.56.

Example 184 6.7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1 H-benz~e]isoindole formic acid salt Etep 1: 5.6-Dimethoxy-3-phenyl-2-thiophenyl-1 .2.3.4-tetrahydronaphthalen-1 -one, To a solution of 28.9 g (0.102 mol) of 5,6-dimethoxy-3-phenyl-1 ,2,3,4tetrahydronaphthalen-1 -one, the product of Example 1, in 240 mL of THF was added 40.4 g (0.107 mol) of phenyltrimethylainmoniumn tribromide. After stirring at ambient temperature for 1 h, 960 mL of water was added. The solution was 3 5 extracted with 3 X 250 mL of ethyl acetate. The combined organic phase was 4684.US.P3 washed with 3 X 250 mL of water, 250 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give an oil which was carried on without further purification or characterization.

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 tha above crude oil in 60 mL of THF was added dropwise over 30 minutes and the reaction was then allowed to warm S1( to ambient temperature for 4 h. The solvents were removed in vacuo and the re!'due was dissolved in a mixture of 250 mL each of methylene chloride and S*«s water. The organic phase was collected and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated o.under reduced pressure. The product was recrystallized froii ethyl •It 5 acetate/hexanes to give 33.15 g (83% yield from the ketone) of 5,6-dimethoxy-3phenyl-2-thiophenyl-;,2,3,4-tetrahydro-naphthalen-1-one as a white solid; MS DCI: 391 1 H NMR (CDC13) 8: 3.35 (dd, 1H, J=6,18 Hz), 3.55 (dd, 1H, J=6,18 Hz), 3.71 1H, J=6 Hz), 3.52 3H), 3.93 3H), 4.19 1H, J=6 Hz), 6.91 (d, 1 H, J=9 Hz), 7.1-7.3 8H), 7.4-7.5 2H), 7.37 (d,1 H, J=9 Hz).

"2 0 Step 2: -5.6-Dimethoxy-3-phenyl-2-sulfoxophenyl-3.4-dihydronaphthalene A solution of 20.96 g (53.7 .nmol) of 5,6-dimethoxy-3-phenyl-2-thiophenyl- 1,2,3,4-tetrahydronaphthalen-l-one in 320 mL of ethanol was treated with 20.03 g.

2 5. (0.529 mol) of sodium borohydride. The reaction was heated to reflux temperature for 2 h, then cooled and 500 mL of water was added. The solvents were removed in vacuo and the residue was taken up in 500 mL of 1:1 diethyl ether/methylene chloride and 500 mL of water. The organic layer was removed and washed with 100 mL each of water and brine, dried over magnesium sulfate, filtered, and 3 0 concentrated under reduced pressure. The crude resultant alcohol was dehydrated by the addition of 700 mL of toluene and 3.6 g (18.9 mmol) of ptoluenesuifonic acid monohydrate and heating to reflux with azeotropic removal of water for 30 minutes. After cooling, the solution was washed with 3 X 100 mL of saturated aqueous sodium bicarbonate, 100 mL of water, dried over anhydrous 3 5 magnesium sulfate, filtered and concentrated in vacuo The crude thio-enolether S150 4684.US.P3 was carried on directly by first, dissolution in 360 mL of methylene chloride. This solution was cooled to -150C and a solution of 12.1 g of 3-chloroperoxybenzoic acid (mCPBA) in 160 mL of methylene chloride was added dropwise over 30 minutes. After the addition was complete, the meaction was quenched by the addition of 100 mL of aqueous saturated sodium thiosulfate. The organic layer was separated, and washed with 3 X 100 mL of saturated aqueous sodium bicarbonate, 100 mL of water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed on silica gel eluted with 25% ethyl acetate in 1 (T f hexanes to give 18.65 (89% yield) of 5,6-dimethoxy-3-phenyl-2-sulfoxophenyl-3,4dihydronaphthalene as a white solid as a mixture of diastereomers; MS DCI: 391 1 H NMR (CDCI3) 8: 2.9-3.1 1H), 3.1-3.3 1H), 3.46 and 3.51 (2 x s, S 3H total), 3.55 and 3.7 (2 x m, 1H total), 3.83 and 3.86 (2 x s,3H total), 6.75-7.15 (m, 7H), 7.3-7.6 6H).

Step 3: N-Trimethylsilylmethyl benzylamine y A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g. (0.796 mol) of chloromethyltrimethylsilane was heated to 200°C for 2.5 h then cooled to 10°C. A ,*270: 0.1 M sodium hydroxide solution (400 mL) was added and the product was extracted with 3 X 200 mL of diethyl ether. The combined organic phase was S' washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled at 115- .1250C. and 5 mm of Hg to give 125.4 g (81% yield) of N-trimethylsily'methyl '2 5 benzylamine as a clear liquid; 1 H NMR (CDC1 3 5: 0.0 9H), 1.1 (br s,1 2.01 2H), 3.76 2H), 7.1-7.3 Step 4: N-Methoxymethyl-N-trimethylsilylmethyl benzylamine 3 0 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 3 5 solid potassium carbonate at ambient temperature for 18 h. The solution was 6151 48.SP filtered and fractionally distilled at 20 mm of Hg to give a 145-1 5500. fraction as a viscous oil, identified as N-methoxymethyl-N-trimethylsilylmethyl benzylamine. 1 H NMVR (CDC1 3 8: 0.0 9H), 2.13 2H), 3.18 3H), 3.71 2H), 3.96 2H), 7.1 7.3 (in, Step 5: 2-Benzyl-6.7-dimethoxy-4-phenyl-2.3.4.5-tetrahydro-1 H-benz(ejisoindole To a solution of 1.22 g (3.13 inmol) of 5,6-dimethoxy-3-phenyl-2sulfoxophenyl-3,4-dihydronaphthalene in 10 mL of methylene chloride was added r 1 g (4.21 mmol) of N-methoxymethyl-N-trimethylsilylmethyI benzylamine, from SStep 4, and 0.1 mL of trifluoroacetic acid. At 12 h intervals, the amine and acid additions were repeated 7 more times. The solvent was then rdmoved under reduced pressure with heating to 10000C and the product was chromatographed on I a 0: silica gel, eluted with 25% ethyl acetate in hexanes to give 0. 14 g (11 yield) of 2- 01,105 benzyl-6,7-di meth oxy-4-ph enyl -2,3,4,5-tetrahyd robe nzo[e]i soi ndol e; MS DCI. 398 1 H NMR (ODC1 3 8: 3.0-3.15 (in, 1 3.25-3.35 (mn, 1 3.45-3.55 (mn, 3H), 3.62 3H), 3.65-3.7 (in, 2H), 3.8-3.9 (mn, 2H), 3.82 3H), 6.68 (in, 1 7.1 7.4 11 H).

Step 6: 6.7-Dimethoxy-4-phenyl-2.3.4.5-tetrahydro-1 H-benz~e]isoindole, bdrochloride To a solution of 1 .0 g (2.52 inmol) of 2-benzyl-6,7-dimethoxy-4-phenyl- :2,3,4,5-tetrahydro-1 H-benz~e]isoindole, from Step 5, in 22 mL of 1,2was added 0.11 g (0.05 minol) of 1 ,8-bis(diinethylamino)naphthalene and 0.33 mL (3.15 mmol) of 1-chloroethyl chioroformate at 0CC. The solution was heated to ref lux for 2 h and the solvent removed in vacuo. The residue was filtered through silica gel eluted with 25% ethyl acetate in hexanes.

After concentration under reduced pressure, methanol (20 mL) was added and the 3 0 solution was heated to reflux for 30 minutes, before the solvent was removed in vacuo. The product was crystallized from ethanol/ether to give 0.46 g. (75% yield) of 6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1 H-benz[e] isoi ndole hydrochloride as a white solid.; MS DCI: 308 1 NMR (d 6 -DMSO) 8: 3.05-3.25 (in, 2H), 3.55 3H), 3.80 3H), 3.88 (in, 1 4.0-4.15 (mn, 2H), 4.25-4.45 (in, 2H), 6.91 (mn, 3 5 1 7.15-7.3 (in, 3H), 7.4-7.6 (in, 3H).

152 4684.US.P3 Step 7: 6.7-Dihydroxy-4-phenyl-2.3.4.5-tetrahydro-1H-benz[elisoindole formic acid salt A suspension of 54.5 mg (0.159 mmol) of 6,7-dimethoxy-4-phenyl-2,3,4,5tetrahydro-1 H-benz[e]isoindole hydrochloride, from Step 6, in 2 mL of methylene chloride was cooled to -78°C and 0.64 mL of a 1 M solution of boron tribromide in methylene chloride was added. The reaction was warmed to ambient temperature for 1 h and cooled to -780C before 1 mL of methanol was added. After warming to ambient temperature for 1 h, the solvents were removed in vacuo. Additional 0 methanol (5 mL) was added and removed in vacuo. The product was S chromatographed on silica gel eluted with ethyl acetate/formic acid/ water (18:1:1) to give 29.8 mg (58% yield) of the title compound as an off-white powder, m.p.

144°C; MS DCI: 279 1 H NMR (d 6 -DMSO) 6: 2.95-3.15 2H), 3.6-3.9 1 5 3H), 4.1-4.3 2H), 6.43 1H, J=7.5 Hz), 6.62 1H, J=7.5 Hz), 7.1-7.3 (m, 8.3 1 H).

9* Example 185A [1.3-cis] 3-(1'-Adamantyl)-5.6-cyclohexylidenedioxv-3.4-dihydro-1-(N- ,formyl)aminomethyl-1 H-2-benzopyran Method A •A mixture of 185 mg (0.5 mmol) of 1-(1'-adamantyl)-2-(spiro-[(1,3-benzo- 2.5 dioxole)-2,1'-cyclohexane])-1-ethanol (from Example 179 Step 4 above), 110 mg (0.83 mmol) N-formyl-acetaldehyde dimethyl acetal and 46 mg (0.13 mmol) of zinc triflate in 3.0 rnL of dry 1,2-dichloroethane was heated at reflux under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to ambient temperature and the reaction was quenched with-30 mL ethyl acetate and 3 0 saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was triturated with methanol to give 191 mg (87% yield) of the title compound as a solid, m.p. 182-1840C.

S

153 4684.US.P3

S.

0e 0 10 0@ 0 9 e S SOS

S

5055 Example 185B F. .3-cis) 3-(1 '-Adamantyl)-5.6-cycloheoxylidenedioxy-3,4-dihvdrr il-{N.

formyl)amino methyl-i H-2-benzopyra~n Meho To a mixture of 94 mg (0.26 mmol) of 1-(l'-adamantyl)-2-(spiro-[(1 ,3benzodioxole)-2, 1'-cyclohexane)-1 -ethanol (from Example 59 Step 2 above), and 100 mg (0.75 mmol) of N-formylacetaldehyde dimethyl acetal in 2.0 mL of dry acetonitrile was added 3 RL equivalent) of methanesulfonic acid and the reaction mixture was heated at ref lux for 12 h. The mixture was cooled to 0CC. The solid was removed by filtration, washed with cold acetonitrilke and dried to give 79 mg (70% yield) of the title compound as a beige solid, m.p. 185-1 8700.

55 S S .21:) *5o* S S 55 5 0 555.55

S

S@

[1 .3-cisl 3-(1 '-Adamantyl)-5.6-cyclohexylidenedioxy-3.4-dihvdro-1 formyl)aminomethyl-I H-2-benzopyran Method C To a mixture of 50 mg (0.14 mmol) of 1-(1'-adamantyl)-2-(spiro-[(l ,3benzodioxole)-2,1'-cyclohexane])-1 -ethanol (from Example 59 Step 2 above), and 60 mg (0.45 mmol) of N-formylacetaldehyde dimethyl acetal was added a solution of 3 mg of polyphosphoric acid in -0.5 mL of acetonitrile. The reaction mixture was heated at ref lux for 48 h and then was cooled to 000 for 0.5 h and filtered. The solid was washed with cold acetonitrile and dried to give 10.9 mg (18% yield) ci the title compound as an off-white solid, m.p. 185-i 8700.

Example 185D (1 .3-cis] 3-(1 '-Adamantvl)-5,6-cyclohexylidenedioxy-3,4-dihydro- I-(Nformflaminomethyl-1 H-2-benzopyran Method D To a mixture of 181 mg (0.5 mmol) of 1-(1'-adamantyl)-2-(spiro-j(1,3benzodioxole)-2,1'-cyclohexane])-1-ethanol (from Example 59 Step 2 above), and 1 154 4684.US.P3 107 mg (0.83 mmol) of N-formylacetaldehyde dimethyl acetal was added 25 p.L of a M a solution of trimethylsilyl triflate in methylene chloride. The reaction mixture was heated at reflux for 4 h and then was cooled to 0°C for 0.5 h and filtered through a sintered glass funnel. The solid was washed with cold acetonitrile and dried to give 198 mg (92% yield) of the title compound as a white solid, m.p. 187- 1890C.

Example 186 [1.3-cis] 1 -Aminomethyl-3-phenyS-3.4-dihydro-5.6-dih"droxy-1 H-2-benzothiopyran 1 0 hydrochloride Step 1: 1-Phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]ethanol Following the procedure of Example 47, Step 2, replacing the 3,3-dimethyl- 1,2-epoxybutane with styrene oxide, the title compound was prepared and taken 1 5 directly to the next step.

Step 2. S-Acetyl-1-phenyl-2-[3-(1.2-cyclohexylidenedioxy)pheny]ethanethiol A solution of triphenylphosphine (1.86 g, 7.09 mmol) in 50 mL of dry THF was cooled to 0°C. Diisopropylazodicarboxylate (1.43 g, 7.09 mmol) was added "2 0O dropwise via syringe and the reaction mixture was stirred at 0°C for 30 min. A solution of 1.10 g (3.54 mmol) of 1-phenyl-2-[3-(1,2cyclohexylidenedioxy)pheny]ethanol, from Step 1, and thiolacetic acid (0.67 g, 8.86 mmol) in 5 mL of THF was then added dropwise to the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour, warmed to ambient temperature and stirred for 1 hour at ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluted with 3% ethyl acetate in hexane to give 0.82 g (63% yield) of the title product as a colorless oil. MS (DCI/NH 3 369 386 (M+NH 4 3 0 Step 3. 1-Phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]-ethanethiol The thiolacetate from step 2 was dissolved in 10 mL of anhydrous diethyl ether. The resultant solution was added dropwise to a solution of lithium aluminum hydride (2.2 mmol) in 15 mL of diethyl ether. After stirring for 15 min at ambien' temperature the reaction was quenched by the careful addition of 20 mL of 1 N 3 5 aqueous hydrochloric acid solution. The diethyl ether layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 155 4684.US.P3 680 mg of the title product as a colorless oil. MS (DCI/NH 3 327 344

(M+NH

4 Step 4. [1.3-cis] 3-Phenyl-5.6-cyclohexylidenedioxy-3,4-dihydro-1-(Nformyl)aminomethyl-1 H-2-benzothiopyran Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (6 0.28 mmo)! was added dropwise to a stirred solution of 0.600 g (1.84 mmol) oi 1-phenyl-2-[3-(1,2cyclohexylidenedioxy)pheny]ethanethiol, from step 3 above, and 0.388 g (2.94 mmol) of N-formylaminoacetaldehyde dimethyl acetal in 10 mL of anhydrous acetonitrile. The reaction was heated at reflux for 1 hour, then cooled and diluted with 50 mL of ethyl acetate. This solution was washed with 10% aqueous sodium .carbonate solution, saturated NaCI solution, dried over anhydrdus magnesium sulfate and concentrated in vacuo to a brown oil. The residue was purified by flash chromatography on silica gel eluted with 40% ethyl acetate/hexane to afford 357 1 5 mg of the title product as a white solid. MS (DCI/NH 3 396 413

(M+NH

4 Step 5 .3-cis] 1-Aminomethyl-3-phenyl-3.4-dihvdro-5.6-dihydrox-1 H-2benzothiopyran hydrochloride To a solution of 174 mg of the formamide compound from step 4 in 2 mL of THF and 2 mL of methanol was added 1 mL of 15% NaOH solution. The mixture was heated to reflux and stirred for 4 hours. The reaction was cooled, diluted with mL of ethyl acetate, and the layers separated. The aqueous layer was extracted with 10 mL of ethyl acetate. The organic layers were combined, washed with water and brine, dried over magnesioum sulfate and concentrated in vacuo to yield 145 mg of the free amine product as a colorless oil. The oil was dissolved in 3 mL of absolute ethanol, and 3 mL of 18%HCI in ethanol was added. The mixture was heated at reflux for 5 hours and cooled at 5°C for 64 hours. The precipitate was filtered, washed and dried in vacuo at 50°C to afford 30 mg of the title product as a 3 0 white solid. mp 23000 (dec). MS (FAB): 288 1 H NMR (CD 3 OD) 6: 2.98 (dd, 1 3.31-3.35 2H), 3.65 (dd, 1 4.14 (dd, 1 4.24 (dd, 1H), 6.67 1H), 7.2-7.5 5H). Anal calc'd. for C 16

H

18 CIN0 2 S: C, 59.34; H, 5.60; N, 4.33; found: C, 59.56; H, 5.73, N, 4.26.

156 4684.US.P3 Example 187 [1.3-cis] 1-(N-Methyl)aminomethyl-3-phenyl-3.4-dihydro-5.6-dihydroxy-1 H-2benzothiopyran hydrochloride To a solution of 139 mg (0.35 mmol) of 3-phenyl-5,6-cyclohexylidenedioxy- 3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzothiopyran, from Example 186 Step 4, in 4 mL of anhydrous THF was added 27 mg (0.70 mmol) of LAH (0.7 mL of 1N LAH in IF). The reaction was stirred and heated to reflux for 1.5 hours. The reaction was cooled to 00C, diluted with 10 mL of ether and quenched by the ,1A careful addition ol water (0.028 mL), 15% NaOH solution (0.028 mL), and water S (0.084 mL). To this mixture was added a small amount of magnesium sulfate, and the mixture was filtered to give an ether solution of the product. The solvent was removed in vacuo to afford 125 mg of the free base as a colorless oil. The oil was dissolved in 2 mL of absolute ethanol, and 3 mL of 18% HCI in ethanol was added.

1 5 The reaction was heated to reflux for 2 hours, cooled, concentrated to 2 mL, and diluted with ether. A white precipitate which formed upon standing was collected by filtration, washed with ether and dried in vacuo to afford 75 mg of the titi; product. mp 2300C (dec). MS (FAB): 302 1 H NMR (CD 3 OD) 8: 2.65 (s, 3H) 2.9 (dd, 1H), 3.25 (dd, 1H), 3.38 (dd, 1H), 3.64 (dd, 1H), 4.12 (dd, 1H), 4.26 (dd, 1H), 6.65 1 6.7 1H), 7.2-7.5 5H). Anal calc'd. for C 17

H

20 CIN0 2 S: C, 60.44; H, 5.97; N, 4.15; found: C, 60.17; H, 5.97, N, 4.10.

Example 188 1'-Aminomethyl-5'.6'-dimethoxyspiro[cycloheptane-1 3'-(3'.4'-dihydro-2'Hnaphthalene)] hydrobromide Step A. 2.3-Dimethoxybenzylbrmide To a stirred solution of 2,3-dimethoxybenzyl bromide (25 g, 148 mmol, Aldrich) 3 0 in 500 mL anhydrous ether was added PBr 3 (7 mL, 74 mmol), via syringe. The resulting solution was stirred at room temperature for 2 hours. The reaction was quenched by the addition of cold water. The layers were separated and the ether layer was washed with water, Na 2

CO

3 solution, water and brine. The ether layer was then dried over MgSO 4 filtered, and evaporated to give 34 g (100% yield) of the title 3 5 product as a low melting white solid.

S

157 4684.US.P3 Step B. Ethyl 1-(2.3-dimethoxybenzyl)cyclohptane carboxylate To a stirred solution of ethyl cycloheptane carboxylate (14 g, 82.4 mmol, prepared by esterification of the acid, which was obtained from Aldrich, by refluxing in ethanol in the presence of an acid catalyst), in 6)0 mL anhydrous THF cooled to -780C was added 60 mL of 1.5M LDA (monotetrahydrofuran in hexane, Aldrich) via syringe.

The resulting light yellow reaction solution was stirred at -780C for 45 min and the benzyl bromide (from step A above) was added (19 g dissolved in 75 mL of THF, 82.4 mmol). The reaction was stirred at -780C for 4hours, then it was quenched by addition of sat'd. NH 4 CI, water and ether. The layers were separated, and the organic layer 1.0: was washed with M HCI, water, and brine. The organic layer was dried over MgSO 4 0 filtered, and evaporated to yield a light amber oil (28g) which was used without further purification.

Step C. [1-(2.3-dimethoxybenzyl)cycloheptyl]methanol 1 5 The crude ester (26 g, 82 mmol, from Step B above), was dissolved in 400 mL anhydrous THF to which was added solid LAIH4 (4.6 g, 123 mmol) in small portions at S room temperature. The reaction was stirred at room temperature until TLC indicated completion. The reaction was then quenched with 1M HCI and diluted with ether. The layers were separated, and the organic layer was washed with 1M HCI, water, and 220 brine. The organic layer was dried over MgSO 4 filtered and evaporated. The resulting oil was purified by silica gel chromatography to give 20 g of the title product as a colorless oil.

Step D. -(2.3-dimethoxybenzyl)cycloheptane carbaldehyde The alcohol from Step C above (25 g, 89 mmol) was dissolved in 500 mL of anhydrous DMSO. To this solution was added Et 3 N (50 mL, 358 mmol). Then SO3*Pyridine (57 g, 358 mmol), was dissolved in 400 mL of DMSO, and this solution was added to the reaction vessel. The solution was then stirred at room temperature for two hours. The reaction solutio'i was then poured over ice and the resulting 3 0 mixture was warmed to room temperature and extracted with CH 2

CI

2 The organic layer was washed with 1M HCI, water, and brine, then the organic layer was dried over MgSO 4 filtered and evaporated. The crude product was chromatographed on silica gel, eluting with 10:1 hexane:EtOAc to give the title product as a colorless oil (20 g, 81% yield).

w 158 4684.US.P3 Step E. 2-[1-(2.3-dimethoxvbenzyl)cycloheptymethylene-[1.31-dithiane To a solution of TMS-dithiane (18 mL, 94 mmol, Aldrich) in 500 mL of anhydrous THF cooled to -780C was added nBuLi (37.5 mLof a 2.5M soln in hexane, 94 mmol), slowly via syringe. The resulting solution was stirred at -78 0 C for 30 min.

and the aldehyde from Step D above (20 g, 72 mmol) was added as a solution in mL of anhydrous THF. The reaction solution was then stirred for 1h at -780C. The reaction was quenched with sat'd. NH4CI at room temperature and diluted with ether.

The resulting layers were separated, and the organic layer was washed with 1M HCI, water and brine. The organic layer was then dried over MgSO 4 filtered and 1 0. evaporated to give 27 g (100% yield) of the title product, which was used without further purification.

Step F. 5'.6'-Dimethoxyspiro[cvcloheptane-1.3'-(3'.4'-dihvdro-2 l-naphthalene)]-1'- 1 5 The crude product from Step E above (27 g, 72 mmol) was dissolved in 500 mL of 5% aq. MeCN. To this solution was added HgCI2 (39 g, 144 mmol) in one portion.

The resulting suspension was refluxed for 1 hour, cooled to room temperature, filtered and the filtrate evaporated to a solid. The solid was dissolved in 500 mL CH 2

CI

2 which was washed with 1M HCI, water, dried over MgSO 4 filtered, evaporated and chromatographed (silica gel, 6:1 hexane/ EtOAc) to give the spirotetralone title product (15 g).

Step G- 1'-Aminomethyl-5'.6'-dimethoxyspiro[cycloheotane-1.3'-(3'.4'-dihydro-2'Hnaphthalhne)] hydrochloride Following the procedure of Example 2, Steps 1 and 2, the compound from Step F above was reacted and the title product was isolated.

Step H. 1'-Aminomethyl-5'.6'-dihydroxyspiro[cycloheotane-1,3'-(3'.4'-dihydro-2'Hnaphthalene)] hydrobromide 3 0 Following the procedure described in Example 2, Step 3, the title compound was prepared. mp 157-80C. MS (DCI) M/Z: 274. anal. calc. for C 17

H

24 BrNO 2

C,

57.63; H, 6.82; N, 3.95; found: C, 57.70; H, 6.80; N, 3.97.

Examples 189-198 3 5 Following the synthesis outlined in Example 188, using the appropriate ester as indicated, Examples 189 to 192 were made, as their H5r salts, as disclosed in Table 9 159 4684.US.P3 The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

Examples 193 to 198 were prepared, using the appropriate ester, as described in Example 188, hydrogenated and deprotected as described in Example 35 as their HBr salts, as disclosed in Table 9. The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

0*

S

*0 f S S o

H

4684.US.P3 Table 9: Examples 189 198 Ex, No. Compound* Ester

S

S

4 *5

S.

S

S

I

SO

SE

SE

*SE

S

HO

189 HO

NH

2

HO

190 HO, a

NH

2

HO

191 HO

NH

2 OHO HO :192 HOH NH2 .193 Ho

NH

O

NH

2

HO

195

HO

HO

NH

2

HO

195 HO

HO

197 HO H O Q 198 HO

NH

2 0 COOEt COOEt O COOEt COOEt coo- COOEt COOEt COOEt COOEt mp°Q MS** 140-2 260 263-4 248 285-6 288 174-5 276 240-1 276 176-8 262 242-3 250 210-1 248 182-3 290 242-4 278 c: 54.89 6.76 f: 55.02 6.83 c: 59.82 7.23 f: 59.85 7.27 c: 57.02 7.37 +0.1 H20 f: 56.64 7.38 c: 57.02 7.37 +0.1 H20 f: 56.86 7.07 c: 55.27 7.13 f: 55.18 6.87 c: 54.55 7.32 f: 54.75 7.43 c: 52.86 6.92 f: 52.72 6.77 c: 58.38 7.62 f: 57.92 7.70 c: 55.05 7.62 +0.2 CH 2

CI

2 f: 55.18 7.46 Elemental Analysis C H

N

c: 57.62 7.04 3.65 f: 57.52 7.15 3.47 4.27 4.38 3.48 3.54 3.91 2.87 3.91 3.87 4.03 3. 9 4.24 4.25 4.11 3.95 3.78 4.02 3.73 3.64 As the HBr salt unless indicated otherwise (FB= free base); all compounds 1-3 cis unless indicated otherwise *'DCI MS i 161 4684.US.P3 Example 199 Spiro[cycloheptane-1,5'-(1'. 6'-hexahydrobenzo[h]isouinoline)-7'.8'-dioI hydrobromide Step A. 5'.6'-Dimethoxyspiro[cycloheptane-1.3'-(3'.4'-dihydro-2'H-naphthalene)] acetic acid ethyl ester A stirred solution of 5',6'-dimethoxyspiro[cycloheptane-1,3'-(3'.4'-dihydro-2'Hnaphthalen))-1'-one, from Step F of Example 188 above, (15.75 g, 54.5 mmol) in 500 mL of anhydrous THF was cooled to -78°C. To this solution was added 1M LDA in THF via cannula (60 mL, 60 mmol). The reaction was stirred at -780C for 45 min and ethylbromoacetate (6.34 mL, 57.2 mmol) was added via syringe. The resulting S reaction solution was slowly warmed to room temperature and stirred for an additional 24 hours. The reaction was quenched by the addition of sat'd. NH 4 CI, then water, and diluted with ether. The organic layer was separated and washed with 1M HCI, water 1 5 and brine, dried over MgSO 4 filtered, evaporated and chromatographed on silica gel eluting with 7:1 hexane:EtOAc to furnish the title product as a light amber oil (7.6 g).

Step B. 9b'-Cyano-5'.6'-dimethoxyspiro[cycloheptane-1 4, 5, 9b-tetrhydro-3Hnaphtho[1'.2'-b]furan)]-2- one To a stirred solution of the ester from Step A above (16 g, 42.8 mmol) in 500 mL of anhydrous toluene was added 1M Et 2 AICN in toluene (86 mL, 86 mmol) quickly via syringe. The resulting reaction solution was stirred for 2 hours. The reaction was poured into 400 mL of ice cold 2M HCI, diluted with ether, and the organic layer separated and washed with 1M HCI, water and brine. The organic layer was then dried over MgSO4, filtered and evaporated to yield t'j tricyclic lactone title product as a light yellow solid (15 g, 100% yield).

Step C. 1'-Aminomethvl-5'.6'-dimethoxv-l'-hydroxvspiroTcvcloheotane-1,3'-(1'. 3'.

4'-tetrahydronaphthalene)]-2-ethanol To a stirred solution of the tricyclic lactone (15 g, 42.3 mmol, from Step B above) in 500 mL of anhydrous THF was added LiAIH4 (6.4 g, 169 mmol) in portions, causing the THF to reflux. The THF was refluxed for 2 hours then cooled to room temperature, transferred to a 2L Erlenmeyer flask, diluted with 200 mL of THF and quenched with solid Na 2

SO

4 10H 2 0. After the quench was completed, celite filter aid was added to 3 5 the slurry, and the slurry was filtered over celite, the filter cake was washed with warm THF, and the filtrate was evaporated under reduced pressure to yield 12 g of crude 4684.US.P3 product as an off-white solid. The crude product was triturated with a minimal amount of CH 2 C1 2 and filtered to yield 6.3g of the title product as a fluffy white solid. The filtrate was concentrated and purified by column chromatography eluting with 89:9:1

CH

2

CI

2 :MeOH:NH 4 0H diluted to 150% of its volume with CH 2 CI2) to yield another 3.6 g. (Total yield: Step D. 7'.8'-Dimethoxyspiro[cycloheptane-1.5'-(1'. 6'hexahydrobenzo[hisoquoinoline)] To a stirred solution of the product from Step C above (6.3 g, 17.36 mmol) in S1 170 mL of anhydrous CH2C1 2 cooled to -780C was added PBr 3 (4.9 mL, 52.1 mmol) slowly via syringe. The cooling bath was removed and the reaction was stirred at room temperature for 48 hours, and the CH2CI2 was then evaporated. The resulting oil was Spartitioned between 200 mL of ethyl acetate and 200 mL of 50% ammonium hydroxide/water. The layers were separated, and the aqueous layer was washed with 1 5 EtOAc. The organic layers were combined and washed with wter, dried over MgSO 4 filtered and evaporated to furnish 3 g of crude title product. The product was purified by column chromatography on silica gel, eluting with 89:9:1 CH 2

CI

2 :MeOH:NH 4 0H diluted with CH2CI2 60:40), to yield pure title product (2.4 g, 42% yield).

*0 Step E. Spiro[cycloheptane-1.5'-(1'. 6'-hexahydrobenzo(h]isoquinoline)]- 7',8'-diol hydrobromide To a stirred solution of the compound from Step D (1.5 g, 4.59 mmol) in anhydrous CH 2

CI

2 cooled to -78 0 C was added 1 M BBr 3 in CH 2

CI

2 (9.2 mL, 9.2 mmol) slowly via syringe. The cooling bath was removed and the reaction solution was 2.5: warmed to room temperature. The reaction solution was again cooled to -780C and quenched with 100mL of absolute methanol. The reaction solution was evaporated to a residue which was re-dissolved with 100 mL of absolute methanol and heated to reflux on a steam bath. The solution was then cooled to room temperature by bubbling nitrogen into the solution. The solvent was removed under reduced pressure to 3 0 provide a residue which was triturated with CH 2

CI

2 to precipitate the product. The product was filtered and dried in a vacuum oven at 550 over night to furnish the title product as a white solid (1.3 g, 76% yield). mp 288-290. MS (DCI) M/Z: 300. anal.

calc. for C 19

H

25

NO

2 *HBr.0.5 H 2 0: C, 58.35; H, 7.00; N, 3.58; found: C, 58.55; H, 7.07; N, 3.46.

S163 4684.US.P3 Examples 200 209 Following the synthesis outlined in Example 199, using the appropriate tetralone, Examples 200 209 were made as their HBr salts, as disclosed in Table The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

@0 0 e to 0 *a Ip -C In 4684.US.P3 Table 10: Examples 200 209 Ex, o. ompgund* 200 201 0 04 00 0 206 0 204 205 0 2 -'COOEt 0-'-'COEt %COOEt OQ--.COEt

MS**

268-70 294 229-231 294 236-7 300 na 274 Elemental Analysis 0 H N c: 60.97 5.39 3.74 f: 60.84 5.39 3.77 c: 60.97 f: 60.81 c: 60.00 f: .60.08 f: na c: 56.52 f: 56.48 5.39 3.74 5.35 3.74 6.89 3.68 6.95 3.72 c0- COOEt 279-281 272 6.72 3.88 6.18 3.73

HO

HO%

N

HO

H CI

N

HO

HO N HO

N

N

0- COO Et O& COEt COQEt C COOEt 274-5 286 279-280 300 184-6 314 248-9 302 229-230 300 c: 56.26 6.82 3.65 f: 56.27 6.86 3.43 c: 60.00 6.89 3.68 f: 59.87 6.72 3.50 c: 58.70 7.11 3.80 f: 59.03 7.23 3.61 c: 57.26 7.13 3.51 +0.2 HBr f: 57.42 7.00 3.41 c: 60.00 6.89 3.68 f: 60.09 6.93 3.56 As the HBr salt unless indicated otherwise (FB= free base) **DCI MS

H

165 4684.US.P3 Example 210 2-M~lethyl-5-phenyl-1. 2. 3. 4. 5. 6-hexahydrobenzothlisog!jr.8-i Step A. 7. 8-Dimethoxy-2-formyl-5-phenyl-1. 2. 3, 4. 5, 6hexahydrobenzorh]isoquinoline To a solution of the free base 7,8-dimethoxy-5-phenyl-1, 2, 3, 4, 5, 6hexahydrobenzo[h]isoquinoline, (390 mg, 1.2 mmol, from Example 200) in THF 96 mL) was added ethyl formate (40 mL). The resulting solution was heated at reflux .Q for 17 hours, concentrated, and the concentrate was chased with THF. The crude product was used directly in the next step.

CC

o C

I

CCC I c C

CCC

CC

C.r

CCC

C9CC *0 C C C

CCC

Step B. 7.8-Dimethoxy-2-methyl-5-phenyl-1, 2. 3. 4, 5. 6hexahydrobenzo[h]isoquinoline To a solution of the compound from Step A (1.2 mmol) in THF (25 mL) was added LAH (60 mg, 1.6 mmol). The reaction was refluxed for 3 hours, diluted to 300 mL with THF, quenched with excess sodium sulfate decahydrate, and filtered over celite. The filtrate was concentrated then subjected to flash chromatography on silica gel with NH40H/MeOH/EtOAc/CH2Cl2 (1:4:50:50) as the eluting solvent to give the title product (270 mg, 67% yield).

Step C. 2-Methyl-5-phenyl-1, 2. 3, 4, 5. 6-hexahydrobenzo[hlisoauinoline-7,8-diol hydrobromide To a solution of the free base from Step B above (270 mg, 81 mmol) in acetic acid (30 mL) was added 48% HBr (28 mL). The resulting solution was heated at reflux for 6 hours, cooled and concentrated in vacuo to 5 mL. This concentrate was chased with ethanol, methanol and heptane until dry. The product was dried under vacuum overnight and then crystallized from MeOH/Et20 to afford 230 mg (73% yield) of the title product as a tan powder.

3 0 Analysis calculated for C20H22BrNO2 (0.2 H20): C, 61.30; H, 5.76; N,3.57. Found: C, 61.30; H, 5.67; N, 3.44. MS DCI/NH3 M/Z: 308 Melting point: 259 2610.

Following the synthesis outlined in Example 210, using the appropriate spiro 3 5 aldehyde, Examples 211 and 212 were made as their HBr salts, as disclosed in Table

I

166 4684.US.P3 11. The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

Table 11: Examples 211 212 a. a a S 9 a.

S

o 555 a~r Ex. No. Compound* Ho 211 H

N

I

212 H

O

N

mp°C MS** 163-5 286 289-290 300 Elemental Analysis C H N c: 59.02 6.60 3.82 f: 59.11 6.58 3.79 c: 58.08 7.03 3.57 f: 57.81 6.73 3.43 o a 5* SW a a a. S 5 5**5

S

As the HBr salt unless indicated othervise (FB= free base) DCI MS Example 213 1-Acetylaminomethyl-3-phenyl-5.6-dihydroxy-3.4-dihydronaohthalene Approximately 1 mmol of 1-aminomethyl-3-phenyl-5,6-dihydroxy-3,4dihydronaphthalene, from Example 2, was reacted with 1.2 mmol of acetic anhydride in the presence of 1.2 mmol of triethylamine in an excess of methylene chloride. The mixture was washed with 0.1 N HCI, and dried. The product was precipitated by addition of ether, collected, and dried. mp 2380C. MS M/Z: 310. Anal. calc. for

C

19

H

19

NO

3 HBr C: 65.03; H, 5.72; N, 3.61; found: C, 73.46; H, 6.13; N, 4.49.

1 67 4684.US.P3 Example 214 A85545 1 -Aminomethyl-3-(2,2-dimethvlpropyl)-3.4-dihydro-5.6-dihydroxv-1 -2benzopyran hydrochloride Ste, 1. Diphenvlmethylenedioxybenzene Catechol (14.7 g, 0.134 mol, Aldrich Chemical Co.) was placed in a 3-neck flask flushed with Argon. The flask was immersed in a 1800C oil bath, the catechol allowed to melt, and neat dichlorophenylmethane (24.6 mL, 0.134 mol) was carefully added in small portions, with resulting vigorous gas evolution. Heating S was continued for an additional 10 min, the flask was cooled, and the crude &0 product was dissolved in 300 mL of ether. The organic layer was separated and t washed with 1N NaOH and brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. The crude product was triturated with 5% ethyl acetate in hexane, which was filtered to yield 13.1 of an off-white solid. A second crop was obtaired, and the total yield wea 24.8 g (68% yield) of the title compound. MS (fOA/NH 3 M/Z: 275 1 H NMR (CDC13, 300 MHz) 6: 6.8-6.9 4H), 7.3- 7.45 6H), 7.5-7.65 4H).

Step 2. (2S)-3-chloro-l-(2.3-diphenylmethylenedioxyphenyl}-2-propanol n-Butyl lithium (2.3 mL of a 9.5 M solution in hexane, 22 mmol) was added dropwise to a solution of 5.47 g of diphenylmethylenedioxybenzene (from step 1) in mL of THF at 0°C. After 5 hr the solution was cooled to -780C, and a solution of 1.85 g (20 mmol) of (S)-(+)-epichlorohydrin (Aldrich Chemical Co.) in 10 mL of THF was added. Boron trifluoride etherate (2.4 mL, 20 mmol) was then added dropwise, and the reaction was stirred for 1.5 hr. The reaction was quenched by addition of 50 mL of saturated NaHCO 3 and the mixture was warmed to ambient temperature and partitioned between 100 mL of ether and 100 mL of water. The aqueous phase was extracted with ether (2 x 40 mL), and the ether extracts were combined and washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown oil, which was purified by flash chromatography over silica gel, eluting with 15% ethyl acetate in hexane, to afford after removal of the solvent 4.23 g of the title compound as a light yellow oil (58% yield). MS (DCI/NH 3 M/Z: 367 384 (M+NH 4 1 H NMR (CDCI3, 300 MHz) 2.3 1H), 2.9-3.0 2H), (dd, 1H), 3.6 (dd, 1H), 4.1-4.23 1H), 6.65-6.85 3H), 7.37 6H), 7.55 4H).

168 4684.US.P3 Step 3, (2S)-3-(2,.3-uiphenylmethylenedioxyphenvyl)-1 .2-eoxyoronane A 15% aqueous NaOH solution (60 mL) was added to a solution of 9.51 g (25.9 mmol) of (2S)-3-chloro-1 -(2,3-diphenylmethylenedioxypheny)-2-propanol (from step 2 above) in 180 mL of 2:1: ether:methanol. The mixture was stirred vigorously and heated to reflux for 3 hr. The reaction was poured into 100 mL of water, and the aqueous phase was extracted with ether 2 x 75 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 8.35 g of the title compound as a light brown oil. This o*i* material was taken directly to the next step. MvS (DC/NH 3 M/Z: 331 348 ip (M+NH 4 Step 4. (2R)-4.4-Dimethyl-1 -(2,3-diphenylmethylenedioxvyphenvyl)-2-pentanol t-Butyl lithium (21.4 mL of a 1.7 M solution in pentane, 36.4 mmol) was added dropwise to a suspension of CuCN (1.63 g, 18.2 mmol) in 120 mL of THF at -780C. The mixture was stirred for 30 min and allowed to warm to -100C. A soultion of 8.01 g (2S)-3-(2,3-diphenylmethylenedioxyphenyl)-1,2-epoxypropane (24.2 mmol) of (from step 3 above) in 20 mL of THF was added dropwise. The reactions was stirred for 18 hr, then quenched by addition of 100 mL of 9:1 V a. saturated NH 4 CI: conc. NH 4 0H. The mixture was stirred vigorously for 30 min and partitioned between 50 mL of water and 150 mL of ether. The aqueous phase was extracted twice with 50 mL of ether and the combined layers were washed with water and saturated NH 4 CI and dried over MgSO 4 The solvents were removed under vacuum to give an amber oil. The oil was purified by flash chromatography over silica gel, eluting with 20% ethyl acetate:hexane to afford 5.95 g (63% yield) of the title compound as a yellow oil. MS (DC/NH 3 M/Z: 389 406

(M+NH

4 1 H NMR (CDC1 3 300 MHz) 6: 0.95 9H), 1.45 2H), 2.73 (dd, 1H), Se 2.85 (dd, 1H), 4.08 1H), 6.65-6.8 3H), 7.37 6H), 7.57 4H).

Step 5. 1-aminomethyl-3-(2.2-dimethylpropyl)-5.6-diohenylmethylenedioxy-3.4dihydro-1 H-2-benzopyran hydrochloride Following the procedures of steps 5 and 6 of Example 179, the (2R)-4,4- Dimethyl-1 -(2,3-diphenylmethylenedioxyphenyl)-2-pentanol compound from step 4 above was converted into the title product.

Step 6. 1-aminomethyl-3-(2.,2-dimethylpropyl)-34-dihdro-5,6-dihydroxy-1 H-2benzovpyran hvrojrclorid To as solution of 1 -aminomethyl-3-(2,2-dimethylpropyl)-5,6diphenylmethylenedioxy-3,4-dihydro-1 H-2-benzopyran hydrochloride, from step above, in 50 ml of methanol, was added 210 mg of 10%Pd/C. The mixture was wq 169 4684.US.P3 purged and hydrogenated at 1 atm for 18 hr. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo, dissolved in 10 mL of 1N HCI, washed with ether, and taken to dryness. The residue was crystallized from ethanol/ether to afford 300mg of the title compound. mp 220°C. MS (DCI/NH 3 M/Z: 266 283 1 H NMR (DMSO-d 6 300 MHz) 0.97 9H), 1.45 (dd, 1H), 1.65 (dd, 1H), 2.32 (dd, 1H), 2.65 (dd, 1H), 2.87 (dd, 1H), 3.38 (dd, 1H), 3.65 1H), 4.85 1H), 6.52 1H), 6.67 1H), 7.8 (bs, 3H), 8.45 (bs, 1H), 9.28 (bs, 1H).

S16, Examples 215-220 o 0 Following the synthesis outlined in Example 214, using the appropriate organocuprate reagent, Examples 215 and 216 were prepared. Following the the procedures described in Examples 214 and 111, Examples 217-219.

Example 220 was prepared by the procedures described in Examples 214 and 111, repeating the procedure of Example 111 in order to place the second methyl group on the amino function. The structures of Examples 215-220 were confirmed by melting point, mass spectra and elemental analysis as designated. The data for examples 215-220 are shown in Table 12.

."oO Examples 221-230 Following the synthesis outlined in Examples 47 and 48, using the appropriate epoxide and the appropriate aldehyde diacetal, Examples 221-223 5: were made as disclosed in Table 13. The structure of each was confirmed by 0** melting point elemental analysis and mass spectra as designated.

Following the synthesis outlined in Examples 47, 48 and 111 using the appropriate epoxide and the appropriate aldehyde diacetal, Examples 224-226 were made as disclosed in Table 13. The structure of each was confirmed by melting point elemental analysis and mass spectra as designated.

Following the synthesis outlined in Examples 47, 48 and 111, and repeating the procedure of Example 111, using the appropriate epoxide and the appropriate aldehyde diacetal, Examples 227-230 were made as disclosed in Table 13. The structure of each was confirmed by melting point elemental analysis and mass spectra as designated.

170 4684.US.P3 Examples 231-237 Following the synthesis outlined in Example 188, using the appropriate ester as indicated, Examples 231 to 234 were made, as their HBr salts, as disclosed in Table 9 The structure of each was confirmed by melting point, mass spectruin and elemental analysis as designated.

Examples 235 to 237 were prepared, using the appropriate ester, as described in Example 188, hydrogenated and deprotected as described in 1 Example 35, as their HBr salts, as disclosed in Table 14. The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

S 0*

C

Examples 238-243 Following the synthesis outlined in Example 199, using the appropriate tetralone, Examples 238 243 were made as their HBr salts, as disclosed in Table 10. The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

Examples 244-250 Following the synthesis outlined in Examples 199 and 210, using the appropriate tetralone, Examples 244 250 were made as their HBr salts, as disclosed in Table 10. The structure of each was confirmed by melting point, mass spectrum and elemental analysis as designated.

Example 251 Following the synthesis outlined in Examples 199 and 210, using the appropriate tetralone, and substituting acetic anhydridp for the ethyl formate of Example 210 followed by reduction with LAH, E;amp'. 251 was made as the HBr salt, as disclosed in Table 16. The structure was confirmed by melting point, mass spectrum and elemental analysis as designated.

S

171 4684.US.P3 Example 252 Following the procedure of Example 35, the compound of Example 206 was hydrogenated, and the compound of Example 252 was isolated as the HBr salt, as disclosed in Table 16. The structure was confirmed by melting point, mass spectrum and elemental analysis as designated.

0 e 0 0 *0 ft *0 0* 0* *0 0 0 i"

S

1 72 4684.US.P3 Table 12: Examples 215 220 Ex. No. £rnp1und~* rnpicl .MS* Elemental Analysisi 0 H N 215

HO

HO,,0

NH

2

HO

HOt 0

NH

2 na 278 o 0 0000** 0 00 0 0 *0*S 00 0 0

SO

0@ 0 *000 0 0S 0 216 189 252

HO

217 HO, l 0 N4HCH 3 218 HO HO 0

NHCH

3

HO

219 HOt

LNHCH,

230 dec 280 187 292 c: .56.65 7.81 f: 56.87 7.42 +0.51- 2 0 c: 5 9.16 8.3 4 f: 59.15 8.01 +0.5H 2 0 c: 61.27 8.05 f: 61.00 7.66 O.3H 2 0 c: 56.94 7.77 f: 57.13 7.70 +0.4HCI c: 6 0.9 0 8.6 0 f: 60.79 8.34 +0.31- 2

O

4.72 4.65 4.31 4.19 4.20 4.06 00*00 0 0 0 90 170 215 266 294 4.34 4.64 4.18 4.19 220

HO

1,N(CH 3 2 *As th-e HCI salt unless indcated otherwise (FB= free base) **DCl MS

S

173 4684.US.P3 Table 13: Examples 221-230 m..Q 9 0* 0 C. C 0 C Ex No. Compound* HOHO D

H

221 HO

NH

2

HO

222 HO Z 0

NH

2 HO Ph 223 HO I HO NI-H2

HO

224

HO

NHCH,

HO Ph 225

HO

NHCH

3

HO

226 HO 0 HO NHCH 3 227 HO Phenyl

N(CH

3 2

HO

228 Ho

N(CH

3 2 229 HO Phenyl

HO

S0

N(CH

3 2 230 Ho H

HO

0 0

N(CH

3

S\

2 2 Op Ph9 2 Ph 0 2 o 2 Phenyl 2 0 Op 2 Ph 2 0 92 0 292 >240 306 na 354 >215 dec 320 na 368 Element c: 62.26 f: 61.88 +0.3H 2 0 c: 62.2.8 f: 62.29 c: 65.35 f: 65.43 O.8HO c: 63.16 f: 63.00 +0.3H 2 0 c: 66.90 f: 66.80 c: 63.24 f: 62.92 c: na f: na c: 61.62 f: 61.59 +0.5H 2 0 c: 66.95 f: 66.75 +0.7HO 2 0 c: 63.80 f: 63.70 +0.1H 2 0 na 305 222(dec) 300 239(d) 306 na 382 7.99 8.05 7.38 7.33 8.54 8.53 7.57 7.88 8.25 8.27 8.33 8.22 7.82 7.57 8.51 8.32 tal A alysis H N 8.30 4.03 8.17 4.31 4.27 4.09 3.46 3.11 3.88 3.92 3.39 3.02 4.10 3.91 3.99 4.33 3.25 3.27 3.92 3.85 na 320 As the HCI salt unless indicated otherwise (FB= free base); compounds 1-3 dcis unless indicated otherwise 1= commercially available, 2=synthesized by method Art Example 47, 3=synthesized by Method B of Example 47; 4=synthesized by Mthod C of Example 47.

DCI MS Prepared by the procedure described in Examples 47, 48 and old130 using (-)B-chlorodiidopinocamphorylborane

S

174 4684.US.P3 Table 14: Examples 231 237 Fx. No. Compound* Ester

HO

231 HO 900t 231 H I Adam-CH 2 -COOEt HO /Wt 232 HOj

NH

HO

233 HO "rt-butyl t-bu-(CH 2 2 -COOEt

NH

2 irnp MS* 240(dec) 326 210-1 302 140-3 262 204-5 316 a a a

C

*ss

C

o*

S

C S. a S 234 235 236 237

HO

HO HO 10 I-N1 unNH 2 COOEt Adam-CH 2 -COOEt COOEt COOEt Elemental Analysis C H N c: 61.53 6.98 3.42 f: 61.22 7.29 3.09 +0.2H 2

O

c: 58.69 7.28 3.60 f: 58.72 7.19 3.71 ,O.08HBr c: 54.97 7.00 3.95 f: 55.34 6.78 3.57 +0.1MeOH +0.10H 2 0 2 c: 59.39 7.50 3.46 f: 59.41 7.46 3.39 +0.1 He, c: 44.87 5.72 2.49 f: 44.73 5.81 3.58 +1.8 HBr c: 56.97 7.60 3.50 f: 57.01 7.51 3.69 +0.2 HBr c: 52.72 7.80 3.37 f: 57.77 7.73 3.39 +0.22 HBr 254 328 Ho 9

NH

2

HO

10 HO

NH

NH

2 184-6 304 146-8 318 As the HBr salt unless indicated otherwise (FB= free base); all compounds 1? dcis unless indicated otherwise DCI MS 175 4684.US.F3 Table 15: Examples 238-243 Ex. No. -Qro unQ d* Ester rnpiQ Ma" 0 0 0 0.

000 000 0 0 00 0 0000 6 00 0 238 239 240 241

HO

HO~t, Adar

N

HOc HOd

N

Elemental Analysis C H N c: 61.96 6.94 3.14 f: 61.83 6.82 3.09 +0.2 HBr Adarrt- COQEt 0D-COOEI: G-cOQOEt G9>- COQOt t-bu--% 0H 2 -COOEt n-bu- CH 2 -COOEt 226 na 294 281-4 342 294-6 328 c: 59.94 5.52 f: 59.48 5.30 iO.5H 2 0 c: 59.32 7.63 f: 59.09 7.40 +0.25HBr+0.25EtOH c: 60.00 7.78 f: 59.97 7.49 +o,5H20+0.5EtOH 3.65 3.75 3.01 3.01 3.18 3.16 352

HO

242 HO t-bu

N

HO

243 HOC bu

N

229-31 288 c: na f: na c: na f: na 125-30 274 000000 0 0 00 0 0 00 0 00 *As the HBr salt unless indicated otherwise (FB- free base) ***DCI MS 176 176 4684.US. P3 Table 1 6: Examples 244-252 Ex. No. Compound* Ester mp 0 C ms** 9

S

S

S.

S

*05 SO S.

5955

S

Sb OS S S S. 5555 S S S5 S 244 245 246 247 248 t-butyl COOEt 0-1- oOEt 150-3 276 288 314 308 308 c: 44.19 5.60 f: 44.22 5.30 +0.8HBr+0.5H 2 0 2.58 2.63 3.47 3.45 Elemental Analysis QC H N c: 58.41 7.14 3.78 f: 58.09 7.03 3.77 +0.1 HP0 0 -COEI: -COOEt C>COOEt COOEt c: 59.52 f: 59.60 +0.2HBr 5.72 5.57 c: na f: na 249 170-180d 342 155-7 314 167-70d 328 C: 58.10 f: 58.24 +0.4HBr c: 59.29 f. 59.09 40.6 H 2 0 7.18 7.21 7.26 6.96 3.08 2.94 3.46 3.31 555555 a *5 5

IS

250 HO8

N

Me c: na f: na 251 252 a7 COOEt a7- OOEt 119-21 328 165-7 302 c: 54.26 f: 54.48 +0.9CH 2 01 2 c: 51.41 f: 51.63 1.OCH 2

CI

2 6.61 2.89 6.51 3.28 6.A7 3.00 6.49 3.01 *As the HBr salt Unless indicated otherise (FB= free base) *DOI MVS VIP 177 4684.US.P3 Competitive Binding D-1 and D-2 Receptor Binding Assays Homogenized rat caudate was incubated in the presence of 1 2 5 1]SCH- 23982 (a selective antagonist of the dopamine D-1 receptor) and the compounds of this invention, according to procedures described by A. Sidhu, et al. in European Pharmacology, 113: 437 (1985) and in European J S Pharmacology, 128: 213 (1986). The compounds compete with the radiolabeled ligand for occupancy of the receptors and the molar potency of each compound was quantified. The affinity of the compound for the receptor (Ki) was calculated as described by Y.C. Cheng and W.H. Prus6ff in Biochemical Pharmacology, 22: 3099 (1973) from the relationship Ki IC50(1+[L]/KD) where IC50 is the concentration of test compound which produces a 50% inhibition in the specific binding of the radioligand, L; is the concentration of radioligand; and KD is the affinity of the radioligand for the receptor.

The procedure for the dopamine D-2 receptor binding assay was similar to that used for the D-1 receptor assay. Homogenized rat caudate was the source of the D-2 recepFors. The tissue homogenate was incubated in the presence of 1 25 11-p-aminophenylethyl spiroperidol (a selective antagonist of the dopamine D-2 receptor) and the compounds being evaluated, according to the protocol described by T. Agui, N. Amlaiky, M.G. Caron and J.W. Kebabian in Molecular Pharmacology, 33: 163 (1988). The.molar affinity of the compound for the receptor binding site was calculated by the same method used for the D-1 receptor assay, assuming a competitive interaction between the compound and the radiolabeled ligand.

The competitive binding data (Ki values) from the D-1 and D-2 receptor binding assays are shown in Table 17. The Ki values are inversely proportional to the affinity of the compound for the receptor.

Sl 178 4684.US.P3 Table 17 Como~titive Bindina for D-1 and D-Z Recebtors omo titive Binding fQr D-1 and D-2 BecebtQrs 6S 44 4e 4 4 4 4.4 4 a 44 4 4 4 .4 4 44w is

S

Example dopamine 2A 17 18 19 20 23 24 27 29 36 37 38 39 41 42 43 46 48 49 51 52 53 54 56 8.0 0.15 0.8 1.3 0.6 1.9 0.5 0.9 >10 6.0 >10 0.03 0.20 0.057 0.12 1.4 5.0 0.7 0.06 1 2.4 4.6 1.7 0.036 0.002 0.007 0.235 0.90 0.25 0.004 0.38 2.2 6.3 6.6 32 0.76 27 3.9 12 13.

1.2 3.9 6.2 0.65 0.91 1.3 do S1 79 48.SP SS 99 0 9 9 a 9 *9 99 0 9 be a 9.

0 9.6 00 09 9 0 0 Id 40 *9 Ja 9 *099 S 09 9 57 58 59 61 62 63 64 65 66 67 68 69 71 72 73 74 76 77 78 79 80 81 82 83 84 86 87 88 89 91 D-1 KI() 1.1 0.26 0.037 0.53 0.29 0.21 71 0.64 14 0.48 1.9 0.10 0.087 0.005 15 0.015 0.064 0.10 0.48 0.098 2.3 0.049 0.73 0.014 0.21 0.011 2.8 1.3 8.1 1.5 11.

0.13 0.02 1 0.076 0.29 0.73 1.2 1.4 2.2 1.3 3.7 0.54 16 0.64 2.7 0.65 2.8 8.2 34 4.6 0.44 0.50 0.81 0.92 1.1 4.6 0.82 1.3 0.7 1.4 0.9 0 0&.*90 4 S S. 0

SO

S.

SNN

1 4684.US.P3 so 0 92 93 94 96 97 98 99 100 101 102 103 104 105 106 107 108 110 111 112 113 114 115 117 118 119 120 123 124 125 126 127 128 129 130 D-1 Ki (UtM) 1.5 0.47 0.084 0.52 0.027 0.071 0.22 0.022 0.019 0.012 0.24 0.036 0.037 0.017 0.35 2.5 4.1 0.55 0.014 0.038 0.22 0.42 12 1.2 2.5 3 3.5 8.2 1.9 2.7 0.16 1.3 0.57 2.1 0.051 D-2 KiM 5.4 0.87 1.9 8.9 54 0.91 1.1 0.72 1.4 0.90 6.7 0.47 6.6 23 3.1 0.19 CC 0 181 4684.US.P3 0 as 0 0 00000 0 0 0 0a 131 132 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 1 48A 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 Q-1 iL(11M) 0.52 0.086 0.035 0.18 0.10 2.9 0.003 0.45 0.06 0.12 0.19 1.2 0.10 0.067 0.049 0.40 0.064 0.71 0.46 0.025 5.8 59 0.85 1.4 2.6 6.3 1.3 2.3 3.1 1.3 1.3 0.67 0.79 3.6 1.8

D-KLIM)

2.7 0.64 1.6 0.55 2.2 3.2 2.6 0.09 1 12 1.4 4.6 2.6 19 12 12 17 8.2 16 16 3.7 1.7 0.17 0.71 0.83 0.25 17 s1 82 4684.US.P3 *0*S* *o

S

*5S S. S.

0* 55 S S

S

50 Exmple 166 167 168 169 170 171 172 173 174 176 177 178 179 180 181 182 183 184 186 187 188 189 190 191 192 193 195 196 197 198 199 200 201 202 D- i (4M) 4.8 0.31 17 8.0 0.57 0.53 1.1 3.6 1.2 0.65 0.13 7.3 0.063 1.1 0.39 0.28 6.5 0.07 1.9 2.5 2.0 3.3 0.33 1.1 3.2 0.65 4 0.25 6.0 0.88 3.7 0.054 0.038 0.045 0.20 2.4 0.0021 0.111 0.81 14 2.6 6.6 1.3 4.7 4.6 2.2 34 6.4 6.3 >1 0 3.2 3.3 1.4 3.3 1.6 550 0 S. S S S s 183 1 83 4684.US.P3 .9 9.

S 9 9 900999 9 *0 9 S 990 0

S

9@9 9999 0 9990 9* 90 9 9 9 9.99 9, *0 9 9099 00 *9 9 9091)90 0 99 9 .9 0 99 203 204 205 206 207 208 209 210 211 212 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 D-1Ku.

1.0 0.16 0.21 0.026 0.07 0.53 0.149 0.047 0.58 0.63 0.02 0.02 0.003 0.03 0.02 4.0 0.41 0.09 0.01 0.04 0.23 0.09 0.02 0.02 0.03 0.26 0.026 0.30 3.8 3.2 3. 9 0.55 4.4 6.5 5.1 D-2 LI~MA 4.3 1.6 1.2 3.1 2.8 1.3 0.70 5.2 0.80 3.7 0.41 1.6 3.1 3.2 2.7 2.3 1.7 3.6 A? 0 S 184 4684.US.P3 Example 239 240 241 242 243 244 245 246 247 "0 248 249 250 251 252 D-1 Ki (L.M) 0.04 0.75 0.40 1.50 0.07 0.24 0.35 0.19 0.02 0.58 0.05 0.15 0.53 1.0 D-2 Ki (IM) 5.2 2.9 1.2 0.18 3.2 1.8 0.88 0.60' 1.6 1.2 oo0 @0 0 0 *eo o 0 06 Intrinsic Activity 4 *1 The interaction of dopamine or a dopamine D-1 receptor agonist with the D-1 receptor causes a dose-dependent increase in the adenylate cyclasecatalyzed conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The functional activity of the compounds of the invention was determined by assaying, in vitro, their ability to either stimulate the enzyme adenylate cyclase to produce more cAMP (agonist activity) or to antagonize a dopamine-induced increase in cAMP levels.The protocol for the adenylate cyclase assays was described by K.J. Watling and J.E.Dowling in J Neurochemistry, 36: 559 (1981) and by J.W. Kebabian, et al. in Proc Nat! Acad Sci USA, 69: 2145 (1972). In order to determine agonist activity, cell-free tissue homogenates are incubated in an ionic buffer solution containing ATP and the compound being evaluated. The tissue was obtained from either goldfish retina or rat striatum.

Table 18 shows the intrinsic activity in an adenylate cycle, assay indicating that the compounds of the present invention are dopamine agonists 185 1 4684.US.P3 Table 18 Anonist Activity in Adenviate Ovolase Assav 99 99 9 9 9 *999* 9 99 0 9 999 9 99 9 9** 0 99 99 9 9 9.9, 99 9 Example dopamine 2A 17 18 20 23 24 27 29 36 37 38 39 41 42 43 45 46 48 49 51 52 53 54 56 57 58 2.5 0.043 2.8 1.5 0.5 1.1 0.5 0.2 1.0 0.010 0.079 0.031 0.033 0.05 1.1 1.8 0.006 0.15 0.06 0.22 0.019 0.0024 0.005 0.18 0.071 0.023 0.002 0.024 0.43 0.030 0.019 100 56 42 46 71 54 66 57 56 91 84 86 81 98 62 69 112 66 71 88 67 71 51 46 56 63 099999 .9 9 9 9 9.

186 464USP 4684.US.P3

S.

5* 0

S

05 0 0 to. 0 0O

S

4** 0S 00 0 0**S *0 0 0 000* 0S 0S 0 59 61 62 63 64 66 67 68 69 70 71 72 73 74 75 76 77 78 79 67 81 82 83 84 86 87 88 89 91 92 93

MY

0.006 0.037 0.006 0.17 0.71 0.39 0.32 0.013 0.23 0.014 0.072 0.004 0.71 0.17 0.16 0.84 0.29 0.0058 0.093 0.015 0.007 0.008 0.067 0.007 0.30 0.11 0.65 0.08 1 0.05 0.012 0.Q07 0.022 0.67 0.60 0.11 92 93 76 111 43 91 84 92 108 110 66 138 105 122 107 147 151 161 61 107 64 72 68 87 54 133 130 'i28 135 69 113 0 0 00 5 0 0 0 50 1 87 4684.US.P3 0

S.

U 0

S

00 0 *5* S. 50

S

*SUS

SO 0 0 0* *0 0

S

*0

S

Seq...

*0 0 I S

S.

94 96 97 98 99 100 101 102 103 104 105 106 107 110 ill 112 113 114 117 118 119 120 121 123 125 126 127 128 129 130 131 132 134 0.071 0.10 0.25 0.055 0.018 0.005 0.019 0.032 0.054 0.013 0.054 0.009 0.004 0.24 0.088 0.0013 0.008 0.058 0.06 2.2 0.08 0.056 0.060 1.1 21 0.77 1.0 0.04u 0.52 0.087 1.0 0.17 0.27 0.87 0.004 Intrinsic Activity 110 104 99 187 108 134 112 1 113 88 110 110 135 106 124 6 8 87 66 64 51 61 63 94 108 97 82 42 81 188 188 4684.US.P3 e S4 0

S.

S

S..

0940 S. S.

S

S

I.'

55 *5 5 S S S. S

S

S

o 4 5 Example 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 153 154 155IS 156 157 i58 159 160 1 61 162 163 164 165 166 167 168 169 170 EC0.007 0.007 1.0 0.051 0.0097 0.0084 0.080 0.087 1.1 0.032 0.038 0.12 0.066 0.022 0.036 0.006 7.0 3.1 0.10 0.15 9.5 0.52 0.33 0.15 0.14 0.45 0.69 1.45 0.20 0.031 0.18 0.12 0.27 0.20 0.13 Intinsic Activt 136 133 93 157 129 113 97 71 94 107 49 89 79 78 102 58 53 127 i1l 100 129 136 58 107 140 96 105 97 125 103 150 151 189 1 89 4684.US. P3 9* a a 0 Ba 0 0 Oa* B *0 as.

Ba %g a B *a a.

B

5* a. B 171 '172 173 174 176 177 178 179 180 181 182 183 184 186 187 189 190 191 193 194 195 196 197 199 200 201 202 203 204 205 206 207 209 210 211 0.18 0.22 0.39 (1065 0.32 0.17 8.6 0.01 0.08 0.017 0.021 0.60 0.022 1.3 1 .2 1.5 0.11 1.5 0.68 0.058 0.40 1.1 0.18 0.033 0.033 0.0036 0.078 >10 0.048 0.068 0.068 0.027 0.052 0.063 Intrinsic Activity 124 116 63 62 99 107 71 56 47 92 58 63 82 73 56 83 120 110 84 0 110 100 79 64 98 38 a00 a a. B a 0* a 0.

190 190 4684.US. P3 0* 4 4 0*

S

4** S S 0 e C. S Example 212 21 3 214 2 115 216 21/ 218 220 221 222 223 224 225 226 227 228 229 230 231 232 234 235 236 237 239 240 241 243 246 2-47 249 251 252 0.48 0.02 0.02 0.005 0.02 0.01i 0.40 0.08 0.04 0.07 0.24 0.1 3 0.04 0.37 0.28 0:.33 0.12 0.09 1.7 2,7 0.30 0.70 1.9 0.04 0.13 0.40 0.95 0.22 0.03 0.20 0.47 1.7 intdnsicActvit 43 106 114 114 108 116 72 84 87 52 64 76 89 94 71 34 59 49 53 83 36 34 103 48 78 32 41 49

S

50455*

S

S. S I S 55 191 4684.US.P3 Rotation Behavior The behavioral assay used was based on the rat rotational model.

Striatal dopamine was depleted by the intracranial injection of 6hydroxydopamine, a neurotoxin which specifically destroys catecholaminergic neurons. The intracranial injection was conducted on anesthetized animals using standard stereotaxic techniques Ungerstedt and G.W. Arbuthnott, Brain Research, 24: 485, 1970, and U. Ungerstedt, Acta Physiol. Scand. Suppl.

367, 69: 1973). This unilateral lesioning of dopamine-containing neurons 0 causes the post synaptic dopamine receptors to become supersensitive to dopaminergic stimulation in behavioral assays. When these striatal dopamine receptors are stimulated by the test compounds, the rats rotate or physically turn, in a direction that is away from the side of their body that receives the greater dopaminergic activation due to the receptor supersensitivity. Agonist activity was measured by the ability of the test compound to induce rotation.

Tables 19 and 20 show the rotation behavior of selected compounds of the present invention.

00 0 0 192 192 4684.US.P3 Table 19 R~taton jyior Example No. ED50 (u.mollka) s.c.- ED50 (iimol/kcff oral I ED50 (Ltmol/ka) 9* 99 9 6 9 Q S.

p @9 966 999 9 9999 @9 99 ~9 9 9 .999 6b 99 9 8 9 *9 9

S

9 9 9 S 99 2A 3 35 36 48 49 50 5 5 59 51 64 86 88 89 90 93 100 103 104 105 ill 112 126 130 138 139 145 146 147 148 1.2 0.91 0.5 0.12 0.39 0.35 13.6 1.02 7 58 0.45 0.61 0.12 0.6 0.9 0.12 0.05 0.13 0.17 0.25 0.10 0.16 0.13 0.15 0.4 0.31 0.12 0.05 0.12 27 21.4 170 19.5 10.9 29.5 >37 32 7 8 8 6.25 1 .0 28 8 23 7 11 193 193 4684.US.P3 -F mple NQ 199 200 201 204 205 210 214 215 216 217 218 219 see$ 220 221 222 223 225 226 227 as 228 231 239 240 6 00: 241 244 246 247 249 250 ED50 (Wmol/ka) S.C.

1.5 0.7 0.34 1.1 3.4 0.005 0.085 0.55 0.07 0.12 0.93 0.09 0.52 >3 0.3 >3 >3 >1 0.045 0.1 >3 >3 >3 >3 >3 0.54 0.014 0.12 0.51 ED50 (limol/Ro') oral 31 19 18 1.6 injected subcutaneously 194 4684.US.P3 Table Rotation Behavior Example Number mean rotations over 360 minutes* 4 3329 6 2564 1516 14 3653 15 1760 16 4844 dose =143 micromoles/kg p.o. mean rotations over 20 hours o: CARDIOVASCULAR PHARMACOLOGY Hemodynamic Studies in Anesthetizrd Dogs: S1q' Male Beagle dogs were anesthetized with pentobarbital (30 mg/kg. i.v.) :and maintained with i.v. infusion (Abbott/Shaw Life Care Pump, Model II/D) to maintain stable cardiovascular function. The dogs were incubated with a cuffed endotracheal tube and ventilated with room air by means of a positive pressure respiratory pump. Expired respiratory C02 was monitored with a Beckman LB-2 gas analyzer and maintained at 5% by appropriate pump adjustments. The dogs were maintained at a body temperature of 37.5 1.0 0 C with a thermostatically controlled animal table. Polyethylene catheters were placed in the abdominal aorta via the femoral and carotid arteries for blood pressure and left ventricular pressure recordings. A Swan-Ganz thermodilution catheter with a 15 cm proximal port was placed in the jugular vein for central venous and pulmonary arterial recordings and for determination of cardiac output (American Edwards Cardiac Output Computer, Model COM-1). Heart rate and electrocardiogram (ECG) recordings were made from a Lead II ECG connection. With the dog on its right side-the abdominal cavity was surgically entered laterally, immediate inferior to the rib cage, to expose the left rena! artery. A calibrated electromagnetic flow probe (Carolina Medical Electronics) was positioned around the renal artery. The abdominal cavity is closed with wound clips. Recordings were made on a Grass polygraph.

O

195 4684.US.P3 An additional small polyethylene catheter was inserted into a branch of the left femoral artery and the tip positioned in the aorta above the renal arteries.

Compounds were continuously infused intrarterially (Harvard Infusion Pump, Model 975) for approximately 5 minutes per dose. A thirty-fold dose-responsecurve was administered by varying flow rate from 0.01 to 0.30 mL/minute.

Table 21 shows the effects of selected compounds of the present invention on cardiovascular pharmacology.

a. 4 9 a *r a 90 4 000 Table 21 EFFECTS OF SELECTED DOPAMINERGIC AGONISTS ON THE RENAL BLOOD FLOW (RBF) AND MEAN ARTERIAL BLOOD PRESSURE (MAP) IN ANESTHETIZED DOGS Dose range Max Increase RBF Max Decrease MAP Example g/kg/min flf fAA 2A 3-10 27 32 3 1-10 83 8 1-3 35 26 36 1 -10 94 13 37 1-30 48 39 Cumulative intraaortic (above renal) infusion DIURETIC EFFECTS OF EXAMPLE 2A IN SPONTANEOUSLY '1 HYPERTENSIVE RATS Male, spontaneously hypertensive rats (SHR), weighing 285-350 grams were used. Following an overnight fasting period with free access to drinking water, the rats received an intragastric fluid load of 0.9 saiine at 5% of their body weight. Simultaneously with the load, the rats were dosed with a test compound or vehicle and placed individually in stainless steel metabolic cages where they had access to drinking water throughout the duration of the experiment. For intravenous administration, the rats were instrumented with indwelling cannulas placed into the jugular vein at least one week prior to the experiment.

Urine was collected at 2 and 4 hours following drug administration. The volume of excreted urine at each collection interval was measured accurately and the samples were analyzed for sodium, potassium and chloride ions.

196 4684.US.P3 Sodium and potassium were measured using a Digital Readout Flame Photometer (Instrumentation Labs). Chloride was measured by the method of Shales and Shales, J Biol Chem, 140:879 (1941). The statistical analysis of the data was computed by an off-line comput-r program. In this program, a comparison test is made between the vehicle (control) group and each treatment group for all variables at each time interval of the experiment. The test of statistical significance is based on the Student's t-test, where the calculated t is a measure of the probability density function.

The compound of Example 2A was administered to six rats intravenously at a dose of 0.3, 1.0 and 3.0 mg/kg. A control group of six rats received 0.1

S

mg/kg of saline solution acidified by ascorbic acid (0.3 mL). This solution was also the vehicle for the test compound.

Table 22 shows the diuretic and saliuretic effects of the compound of too: Example 2A.

TABLE 22 DIURETIC EFFECTS OF THE COMPOUND OF EXAMPLE 2A GIVEN INTRAVENOUSLY AT THE DOSE OF 3.0 mg/kg TO HYDRATED SPONTANEOUSLY HYPERTENSIVE RATS URINE ANALYSIS AT 2 HOUR INTERVAL FOLLOWING

ADMINISTRATION

Volume Sodium Potassium Chloride Na/K (mL/kg) (meq/ka) (meq/kg) (meq/kg) Ratio Control Group 13.02 1.60 0.29 1.87 9.99 Example 2A Group 22.57 2.35 0.55 2.71 5.06 Control Group SD 4.29 0.59 0.17 0.83 10.27 Example 2A Group SD 8.30 0.84 0.22 0.75 2.85 p<=0.05 0.0313* 0.1043 0.0423* 0.0950 0.28134 Sstatistically significant n=6

Claims (6)

1. A compound having the formula ORI (C)n#A x 8 1 YCH R/ NRSR6 or a pharmaceutically-acceptable salt, ester or amide thereof, wherein A is 0, S, C HR 2 or CR 2 n is 1 or 2; the dotted lines represent optional double bonds; RI is selected from hydrogen and a readily-cleavable group, or a catechol-protect'ng group; R 2 is selected from hydrogen, methyl, ethyl, hydroxmethyl, hydroxyethyl, halomethyl, haloethyl, aminomethyl, and aminoethyl, or taken together with R 5 and the atoms to which each is attached forms a 5- or 6-membered ring containing only one Rishetero atom, the nitrogen shown in Formula R isselected from: C 1 -Cl 0 -alkyl, 9::substituted CI-C 5 -alkyl, C 2 -C 12 -alkenyl, substituted C 2 -C 5 -alkenyl, C 2 -C 12 -alkynyl, substituted C 2 -C 5 -alkynyl, CYCIO-C 3 -Cl 0 -alkyl, substituted cycIO-C 3 -C 10 -alkyl, carbocYclic-C 6 -Cl 0 -aryl, substituted carboryclic-C 6 -Cl 0 -aryl, carbocyclic-C 6 -C 10 -aryloxy-C 1 -C 5 -alkyl, substituted carbocyclic-C 6 -Cl 0 -aryloxy-Cl-C 5 -alkyl, carbocyclic-C 6 -Cl 0 -aryl-C 1 -C 5 -alkyl, substituted carbocyclic-C 6 -C 10 -aryl-Cl-C 5 -alkyl, Het, substituted Het, Het-Cl-C 5 -alkyl, and substituted Het-C 1 -C-alkyl, n [N:\118XX100229;KEH-/SEP 'T or taken together with R 4 and the atom to which it is attached forms a spirocyclo-C 3 -C 1 0 -alkyl ring, R 4 is selected from hydrogen and C 1 -Clo-alkyl, or taken together with R 3 and the atom to which it is attached forms a spirocyclo-C 3 -Clo-alkyl ring; R 5 is selected from hydrogen, C 1 -C 3 -ilkyl, hydroxy-C 2 -C 3 -alkyl, amino-C 2 -C 3 -alkyl, C 1 -C 3 -alkoxy-C 2 -C 3 -alkyl, C 2 -C 3 -alkenyl, C 2 -C 3 -alkynyl, cyclo-C 3 -C 5 -alkyl, C 1 -Cs-alkanoyl, a readily-cleavable group, amino acid, and dipeptide, or, when A is CHR 2 or CR 2 is taken together with R 2 and the atoms to which each is attached to form a 5- or 6-membered ring containing only one hetero atom, the nitrogen shown in Formula or is taken together with R 6 or R 7 and the atoms to which R 6 or R 7 is attached to form a pyrrolidine ring; R 6 is selected from hydrogen and C 1 -C 3 -alkyl, or taken together with R 5 and the atoms Sto which it is attached, forms a pyrrolidine ring; R 7 is hydrogen or C 1 -C 5 -alkyl, or taken together with R 5 and the atoms to which it is attached forms a pyrrolidine ring, or taken together with Y and the atoms to which it is attached forms a 6- or 7-membered carbocyclic ring; X is selected from hydrogen, halogen, methyl and ethyl; Y is selected from hydrogen, halogen, methyl and ethyl, or Y taken together with R 7 and the atoms to which it is attached forms a 6- or 7-membered carbocyclic ring; with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, and 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: R 2 and R 5 R 5 and R 6 R 5 and R 7 R 6 and R 7 or R 7 and Y. IN:\LIBXXI00220:KEHISEF 199

2. A compound of claim 1 having the following formula: e *o*ot *0° *e or are a pharmaceutically-acceptable salt, ester or amide thereof, wherein A is O; the optional double bonds are not present; R 1 R 3 R 4 R 5 R 6 R 7 X and Y are as defined in claim 1; with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, R 3 must be adamantyl and R 4 must be hydrogen when Y is halogen, and 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 defined in claim 1: R 5 and R 6 R 5 and R 7 R 6 and R 7 or R 7 and Y.

3. A compound of claim 1 having the following formula: OR RIO 5 R3 R4 7A X 8 1 Y CH R/ NRSR6 15 or are a pharmaceutically-acceptable salt, ester, or amide thereof, wherein A is S; the optional double bonds are not present; R 1 R 3 R 4 X and Y are as defined in claim 1; R 5 is hydrogen, C 1 -C 3 -alkyl, or Ci-Cg-alkanoyl; R 6 is hydrogen R 7 is hydrogen; and with the provisos that at least one of X and Y must be hydrogen when Y is not combined in a ring, R 3 must be adamantyl and R 4 must be hydrogen when Y is halogen, and only one of the following combinations of groups and the atoms to which the are attached may be taken together to form a ring as defined in claim 1: 1' R 5 and R 6 R 5 and R 7 R 6 and R 7 or R 7 and Y. A'- \-cz~ -1 S." [N:\LIBXX00229:KEH/SEF 200

4. A compound of claim 1 having the following formula: or are a pharmaceutically-acceptable salt, ester or amide thereof, wherein A is CHR 2 or CR 2 the dotted lines represent optional douole bonds; R 1 R 2 R 3 X and Y are as defined in claim 1; R 4 is selected from hydrogen and C 1 -C 1 0 -alkyl, or taken together with R 3 and the atom to which it is attached forms a spirocyclo-C 3 -Clo-alkyl ring; R 5 is selected from hydrogen, C 1 -C 3 -alkyl, hydroxy-C 2 -C 3 -alkyl, amino-C 2 -C 3 -alkyl, C 1 -C 3 -alkoxy-C 2 -C 3 -alkyl, 15 C 2 -C 3 -alkenyl, .C 2 -C 3 -alkynyl, cyclo-C 3 -C 5 -alkyl, Ci-Cg-alkanoyl, a readily-cleavable group, 20 amino acid, and So dipeptide, or, is taken together with R 2 and the atoms to which it is attached to form a

6-membered ring containing only one hetero atom, the nitrogen shown in Formula or is taken together with R 6 or R 7 and the atoms to which R 6 or R 7 is attached to form a pyrrolidine ring; R 6 is selected from hydrogen and C 1 -C 3 -alkyl, or taken together with R 5 and the atoms to which it is attached, forms a pyrrolidine ring; R 7 is hydrogen or C 1 -C 5 -alkyl, or taken together with R 5 and the atoms to which it is attached forms a pyrrolidine ring, or taken together with Y and the atoms to which it is attached forms a 6- or 7- membered carbocyclic ring; srd with the provisos that at least one of X and Y must be hydrogen when Y is not combined S in a ring, S IN:\LIBXX)OO229:KEHISEF T Z' 201 and 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 defined above: R 2 and R 5 R 5 and R 6 R 5 and R 7 R 6 and R 7 or R 7 and Y. The compound of claim 1 wherein R 5 and R 6 are hydrogen. i -'1 A'r (NA~LIOXXIO02MUMEHSEF 202 a. a. a. S a e.G C *5* C a CC,. 0* S. *SS* a, C S a CCC.*C a CCC a C *CCC 6. A compound which is: 1 -Amino methyl-5,6-bis (trim ethylacetoxy)-3-phe ny!-3 ,4-dihydro naphth ale ne; [1 ,3-cis] 1 -Aminomethyl-3-n-butyU-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 1 3-cis] 1 -Aminomethyl-3-cyclopentylmethyl-5,6-dihydroxy-3A-dihydro-1 H-2- benzopyran; [1 ,3-cis] 1 -Aminomethyl-3-cycloocty!-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; ,1 ,3-cis] 3-n-Butyl-5,6-dihydroxy-1 -m ethyliami no methyl-3,4-di hydro- 1 H-2-benzopyran; [1 ,3-ois] 3-(1 -Adam antylI)- 5,6-dihyd roxy- 1-methylaminomethy-3,4-dihydro-1 H-2- benzopyran; 5,6-Bis(acetoxy)-1 -(alany I-alanyl)ami nomrethyl-3-ph enyl-3,4-dihydronaphth ale ne; ,6-Bis (acetoxy)-1 -(garnma-glutarnyl)aminomethyl -3 -phenyl-3 ,4-d ihydronaphthlalene; 5,6-Bis(acetoxy)-1 -(alanyl)aminomethyl-3-phenyl-3 4-dihydronaphthalene; 5,6-Bis(acetoxy)-1 -(methionyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene; 1 -(AlanyI-aianyl)ami nom ethyl-5,6-bis (be nzoyloxy) -3-p he nyl-3,4-di hydro nap htliale ne; [1 R*,2S*,3S*l i-A iiinomethyl-5,6-dihydroxy-2-(2-hydroxy-1 -ethyl)-3-phenyl-1 ,2,3 ,4- tetrahydronaphthalene; [1 ,3-cis) 1 -Amin omethyI-5,6-dihydroxy-3-(3-hydroxypheny)-1 2,3,4- 20 tetrahydronaphthalene; 1 -AminomethyI-5,6-dihydroxy-3-ph enylnaphthalene; [1 ,3-ois] 1 -Aminomethyl-3-benzyloxymethyl-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; [1 3 3-cis] 1 -AminomethyI-3,4-dihydro-5,6-dihydroxy-3-(diphe nyl)methyl-1 H-2- 25 benzopyran; [1 ,3-cis] 1 -Aminomothyl-3 ,4-dihydro-5,6-dihydroxy-3-(3'-methyl-2'-n-pentyl)-1 H-2- benzopyran; [1 ,3-ois] 1 -Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(1 '-but-3'-ene)-1 H-2-benzopyran; [1 1 3,cis] 1 mnm ty-34dhdo5,-iyrx--('m ty e-H-2- benzopyrar; [1 ,3-dsJ 1 om ethyl-3-cycoocty -5,6-di hydroxy,-3,4-di hydro- 1 H -2-be nzopy ran; [1 R*,8S*,9aR*] 1 -Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene; [1 S*,8S',9aR*I 1 -Amino-5,6-dihydroxy-2,3,7,89,9a-hexahydro-8-phenylphenalene; 6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1 H-benzo~e]isoindole; L~, 203 [113,3S] 3-(1 -Adamanty 1)-i -aminomethyl-3 ,4-dihydro-5,6-dihydroxy-1 H-2-benzopyran; 1 -Aminomethyl-5,6-bis(benzoy!oxy)-3-phenyf-3,4-d.ihydronaphthalene; 5-Arinomethyl-7-(2-naphthyl)-7,8-dihycironaphthalene-1 ,2-diol; 5-Aminomethyl-7-(1 -naphthyl)-7,8-dihydronaphthalene-1 ,2-diol; 1 -Aminomethyl-5,6-bis(butoxy)-3-phenyl-3,4-dihydroniaphthalene; 1 -AminomethyI-5,6-bis(isobutoxy)-3-phenyl-3,4-dihydronaphthalene; 1 -Aminomethyl-5,6-bis(methyi sucoi nyloxy)-3-ph enyI-3,4-dih ydro naphth alene; 1 -Acetylam in omethyl-5,6-bis(acetyloxy) -3-ph enyl-3,4-dihydro naphth ale ne; 5-N-Acetylmethylam-inomethyl-3-phenyi-7,8-dihydronaphthalene-1,2-dioI; 1 -AminometnyJ1-5,6-bis(propionyloxy)-3-phenyl-3,4-dihydronaphth~Iene; 1 -Amino methyl-5,6-bis (phenylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene; 1 -Ami nom ethyl-5,6-bis (mneth oxycarbonylcxy)-3-phe nyl-3,4-di hydrcn apht hale ne; 1 -Aminomethyl-5,6-bis(isopropyl succi nylo xy)-3-ph enyl-3,4-dihyd ro nap hth ale ne; *1 -Amino methyl-5,6-bis (di methylani n ocarbo nyloxy)-3-ph enyl-3,4-di hydro nap hth alene; 1 -Amino methy 1-5,6-bis(beta-alanoyloxy)-3-p he nyl-3,.-dihydronaphth ale ne; 1 -Aminomethyl-5,6-bis(ethoxycarbonyloxy)- 3-phenyl-3,4-dihycdronaphthalene; 0 0 60 401 -Aminomethyl-5,6-bis (benzylamfnocarbonyoxy)-3-phenyr-3,4-dihydronaphth alene; 1-Amino met hyl-5,6-bis(methylami nocarbo nyloxy)-3-ph enyl-3,4-di hydro napht hale no;

56-Bis(acetyloxy)-1 -t-butyloxycarbonylaminomethyl-3-phenyl-3,4- 20 dihydronaphthalene; 1 -Aminomethyl-5,6-bis(p-methoxybenzoyloxy)-3-phenyl-3,4-dihydronaphthalene; 1 -Amin om ethyl-5,6-bis (mnethyla min ocarbo nyloxy)-3-ph enyl-3,4-di hydro naphth ale ne; [1 ,3-cis] 1 -Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 H-2-benzothiopyran;, 25[1 ,3-cis] 1 -Amin omethyl-5,6-dihydroxy-3-(3-rnethoxyphenyl)-3,4-dihydro-1 H-2- benzopyran; [1 ,3-cis] 5,6-Dihydroxy-1 -methylaminomethy-3-phgny-3,4-dihydro-1 H-2- a ~benzothlopyran;, [1 ,3-cis] 3-(1 -Adamantyl)-5,6-dihydrox"-1-methyfaminomethy-3,4-dihydro-1 H-2- benzopyran; (1 ,3-trans] 3-(1 -Aclamantyl)-1 -aminomethyl-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; [1 ,3-trans) 1 -A minom methyl-5,6-di hydroxy-3-(4 -met hoxybe nzyf -3,4-dihydro-1 H-2- ben zo pyran; XA 204 (1 ,3-cis] 5,6-Dihydroxy-3-(4-Irmethoxybenzyl)-1 -methylamnino methyl -3,4-dihydro- 1 H-2- ben zopy ran; [1 S,3S] 3-(1 -Adamanty)-1 -aminomethyl-5,6-dihydroxy-3,4-dihydro-1 H..2-benzopyran; [1 R,3R] 3-(1 -Adamantyl)-l -amino methyl-5,6-dihydroxy-3 ,4-di hydro- 1 H-2-benzopyran; [1 R 1 2'R,3S] 5,6-Dihydroxy-3-pheny-1 rrolidinyl)-3,4-dihydro-1 H-2-bEnzopyran; [1 ,3-cis) 1 -Aminomethyl-5,6-dihydr',xy-3-(2-(1 -oxoisoindole)methyl)-3,4-dihydro-1 H-2- benzopyran; [1 R,2'S,30-] 5,6-Dihydroxy-3-phenyl-1 2-proidnl-34dhyr H-2-benzopyran; [1 ,3-cis] 5,C--Dihyciroxy-1 -methylaminomethyf-3-phenyl-3,4-dihydro-1 H-2-benzopyran; 5-P he ny!-1 exahydro be nzo[h]isoqui noi ne-7,8-diol; 2- Methyl-5-ph enyl- 1 ,2,3,4,5,6,-hexahydrobe nzo [h]isoqui no I!n e-7,8-dio [1 'S,1 R,3S] 3,4-Dihydro-5,6-dihydroxy-1 -methylaminornethyl-3-phenyl-1 H-2- benzopyran; (1 ,j-cis] 1 -Aminiomethyi-3-cyclohexylmethyf -3 ,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; ,0-cis] 1 -Amino methyl-5,6- di hydroxy-3-isobutyl-3 ,4-dihydro-1 H -2-be nzopyrari; jfi .3-cis] 3-(1 -Adamnaniylm ethyl)-1 -aminomethyl-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; [,3-cis] 3-(,I-Adama, ntylmethyl)-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H- '0 2-benzopyran; (1 ,3-cis] 3-Cycloh'erxy~mejhyl-5,6-dilhydroxy-1 -rnethylaminomethy!-3,4-dihydro-1 H-2- benzopyran; (1 ,3-cisl 1 -Allylam-inomethyl-3-n-butyI-5,6-dihydroxy-3,-di ,ydf-o-1H-2"-benzopyran; 25 1 T3-cis] 1 -Aminomethyl-3-(2-oyclohe~tyfethyl)-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; Ti ,3-cIsj 1 -Aminomethyl-5,6-dihydroxy-3O-(ethylmalonamidomethyl)-3 ,4-dihydro-1 H-2- *.:benzopyran; 1 mnmtyl5,'dhdrxsiocr-oetn-,3'-(3'A4'-dihydro-1 'H-2 benzopyran"J; 1 '-Aminomethyl-5',6' dihydroxyspiro[cycloootan6,-1 1 3'-(3',4'-dihydro-1 benzopyran)I; ,6'-Dihvidroxy-1 '-methylaminomethylspiro[cycloheptane-1 ,3'-(3',4'-cihydro-1 H-2'- benzopyran)J; 205 [1 ,3-cis] 3-(1 -Adamantyl)-1 -amino methyl-8-bromo-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; 5',6'-Dihydroxy-1 '-methylaminomethylspiro[cyclooctane-1 ,3'-(3',4'-dihydro-1 benzopyran)]; [1 ,3-cis] 1 -Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro- H-2-benzopyran; 1 '-Aminomethyl-5',6'-dihydroxyspiro[tetrahydropyran-4,3'-(3',4-dihydro- benzopyran)]; 5',6'-Dihydroxy-1 '-methylaminomethylspiro[fetrahydropyran-4,3'-(3',4'-dihydro-1 'H-2 t benzopyran)]; (1 R,3S] 3-t-Butyl-5,6-dihydroxy-1-4methylaminomethy-3,4-dihydro-1 H-2-benizopyran; [1 ,3-trans) 1 -Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 f--2-benzopyran; (1 S,3R1 5,6-dihydroxy-3-phenyl-1 -(2(R)-pyrrolidirny!)-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 3-(1 -A amanty)-1 mirnomethyl-5,6-dihy-droxy-7-fluoro-3,4-dihydro-1 H-2- benzopyran; [1 ,3-ois] 1 -Aminom ethyl-5,6-dihydroxy-3-(4-ethoxy-2,3,5,6-tetraf luo roph enylm ethyl)- 3,4-dihydro-1 H-2-benzopyran; 5'-Aminomethylspiro[cyciohexane-1 1 7'-(7',8-dihydronaphthalene)]-1 ',2'-dioI; **too: [1 ,3-cis 1 -Amin omethyI-5,6-dihydro xy-3-(4-tri f uo romethylph en y)-34-di hydro- 1H-2- benzopyran; 20 (1 ,3-cis] 1 -Amin omethyl-5,6-dihydroxy-3- (3-trif Iuoro methylph enyI)-3,4-di hydro -1 H-2 benzopyran; ino methylspiro[cyolo hexan e-1 rahydro nap hthale V, 2'-dio 1; [1 R,3S] 1 -Aminomethyl-3-t-butyl-5,6-dihydroxy-3,-dihydro-1 H-2-benzopyran; *fee ,1 3-cis) 3-A!Jy!-1 -aminomethyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; 25 2'-Methylspiro~cyciohexane-1 ',2',3',4',5',6'-hexahydro-benzo~hjisoquinoline)]- 7t 8'.,diol to** Spiro~cyclohexane-1 ',2',3',4',5',6'-hexahydro-benzo~hlisoquinoine)]-7',8'-dio; [1 RI3S] 3-t-Butyl-5,6-dihydroxy-1 -dimethylaminomethyl-3,4-dihydro-1 H-2-henzopyran; *to(1 ,3-cis]J 5,6-Dihydroxy-1 -methylarnir~omethyl-3-n-pentyl-3,4-dihydro-1 H-2- benzopyran; (5R)-5-Phenyl-1 ,2,3,4,5,6,-hExahyirobenzo~h]isoquinoine-7,8-dio; Spiro[cyciopentane-1 ,5'-(1l',2',3',4',5',6'-hexahydro-benzo[hisoquinoline)]-7',8'-diol; 2'-Methylspiro[cyclopentane-1 ',2',3',4',5',6'-hexahydrobenzo[h]isoquinoine)]- 7',8'-diol; 206 in o methylspi ro (yclop entan e-1, T7- (5,6,7',8'-tet ra hyd ro-nap ht hale ne)]-1 V, 2 t -di o [1 R,3S] 3-(l -Adamantyl)-1 -aminomethyl-5,6-dihydroxy-7-fiuoro-3,4-dihydro-1 H-2- benzopy,-n; [1 R,3S] 3-(1 -Adamantyl)-5,6-dihydroxy-7-fluoro-1 -methylaminomethyl-3,4-dihydro-1 H- 2-benzopyran; (119R,3S] 3-t-Butyl-5,6-dihydroxy-1 -ethylaminomethyl-3,4-dihydro-1 H-2-benzopyran; [1 R,3S] 1 -Allylaminomethyl-3-t-butyl-5,6-clihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 3-t-Butylmethy!-5,6-dihydroxy-1 -methyfaminomethyl-3 ,4-dihiydro-1 H-2- benzopyran; lo 5'-Aminomethylspiro[cycloheptane-1 ,7'-(5',6',7',8'-tetrahydronaphthalene)>1 ',2'-diol; nom ethylspiro[cyctoh eptan e-1 hyd ro nap hth ale 1 ',2'-dioi; Spiro[cycloheptane-1 ',2',3',4',5',6'-hexahydrobenzo(]isoquinoine]-7 1 ,8'-diol; [1 R,3SJ 1 -All ylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro- H-2-benzopyran; [1 ,3-cisl 1 -Aminomethyl-3-t-butylmethyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -Aminomethyl-5,6-ciihydroxy-3-(3R-but-1 -enyl))-3,4-dihydro-1 H-2- :seat,,benzopyran; 5-Ami no methyl-7-t-butyl-7,8-dihydro naphth ale ne-1, ,2-diol; [5,7-cis]-5-Aminomethyl-7-t-butyl-5,6,7,8-tetrahydronaphthalene-1 2-diol; [1 R,3S] 3-t-Butyl-5,6-dihydroxy-1 -n-propylaminomethyl-3,4-dihydro-1 H-2-benzopyran; ease 20 5,t-Butyl-1 ,2,3,4,5,6,-hexahv drobenzo[h]isoquinoline-7,8-diol; 5-Cycloh exyl-1 2,3,4,5,6,-h exahyd robe nzo [h]isoq ui nofi ne-7,8-diol; 5-Cyclopentylmethyl-1 ,2,3,4,5,6,-hexahydrobenzo[V-, ,,juinoline-7,8-diol; [1 R,3S] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -dimethylaminomethyl-3,4-dihydro-1 H-2- ben zopy ran;, 25 Sioccotne1 hexah yd robe nzo~h]isoquno n e)]-7'8'-dolI [1 R,3R] 1 -Ami no methyl-3-(2,2-di methyl propy)-3,4-dih yd ro-5,6-dihyroxy- 1H-2- eae* benzopyran; [1,3-cis) 1 -Aminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; [1 R,3R] 1 -Aminomethyl-3-(2-methylpropyl)-3 ,4-dihydro-5,6-dihydroxy- 1H-2- ben zopy ran; [119I319] 1 -Methylaminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy- H-2- benzopyran; L- j. 207 [1 ,3-cis] 1- Met hylami no methy-3-cycI opelty I m ethyI-3,4-di hyd ro5,6dihyd roxy- 1H-2- benzopyran; [I R,3 8] 1 -Methylaminornethy-3-(2-nmethylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; [1 ,3-cis] 1 -(N,N-Dimethylamino)methyI-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6- dihydroxy-1 H-2-benzopyran; 1 '-Aminomethyl-3',4'-iihydr-5',6'-dihydroxyspir[cycIloflnafe-1,3'-(1 be nzopyran)]; [1 ,3-cis] 1 -Arinomethyl-3-(1 -methylcyclohexyl)-3,4-ciihydro-5,6-dihydroxy-1 H-2- benzopyran; [1 ,3-cis] 1 -Aminomethyl-3-(1 -phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- ben zopy ran; 3',4'-Dihydro-5',6'-dihydroxy-1 '-methylaminomethylspiro [cyclononane-1 benzopyran)1; [i ,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -phenylcyclohexyl)-3,4-dihydro-5,6- dihydroxy-1 H-2-benzopyran; [1 ,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -methylcyclohexyl)-3A4-dihydro-5,6- dihydroxy-1 H-2-benzopyran; 1 R,2S-1 -(N,N-Dimethylamino)methyl-3-phenyA-3,4-dihydro-5,6-dihydroxyl1 H-2- benzopyran; [1,3-cis] 1 N-Dimethylamino)methyl-3-(1 -methylcyclohexyl)-3,4-dihydro-5.6- dihydroxy-1 H-2-benzopyran; [1 ,3-cis] 1 ,N-Dimethylamino)methyl-3-cycIohexyI-3,-dihYdro-5,6-dihydrox\/l H-2- 25 1 ben zo pyran; 1-Aminomethyl-3-adamantyl-5,6-dihydroxy-3,4-dihydronaphtLhalene; 1 '-Ami nomrnethyl-3',4'-di hydro-5',6'-di hyd roxyspi ro[cyclo no nan e-1 nap hLh ale ne]; *see*: 1 -A minomrnethyI-3-(2,2-dimrnethylpropyl) -5,6-di hyd roxy-3,4-di hyd ro nap ht hale ne; :1 -Ami nomnethyl-3',4'-di hydro-5'6'-di hydroxyspiro[cyclodecan e- 1 ,3'-naphth ale ne]; 1 -Am inomrnethyl-3-adamantyl-5,6-di hyd ro xy- 1 ,2,3,4-tet rahyd ro nap ht haler. e; or 1 min omrethyl- 3',4'-tetrahyd 'o-5',6-di hydroxyspi ro[cycfo non an e- 13'- naphthalene]. ,AJ T~f 208 7. A compound which is: 1 '-Ami nom ethyl-l trahydro-5', 6-dihydroxyspiroicyclodecan e- 1 23 naphthalene]j; anty1-1 ,2,3,4,5,6-h exahyd robe nzo [hli soqui no li ne-7,8-dio1; (5R)-1 ,2,3,4,5,6-Hexahydro-5-phenylbenzo(h]isoquinoline-7,8-diol; 11,21 ,3',4',5',6'-Hexahydro-7',8'-dihydroxyspiro[cyclodecane-1 iso quin olin e]; 1 ',2',3',4',5',6'-Hexahydro-7' ,8'-rlihydroxyspiro[cyclononane-1 iso qu ino line]; 5-(2,2-Dimethylpropyl)-1 ,2 ,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol; 5-Butyl-1 ,2,3,4,5,6-hexahydrobenzo[hisoquinoline-7,8-diol; 5-(2,2-Dimethylpropyl)-1 ,2,3,4,5,6-hexahyclro-2-methylbenzo[hisoquinoline-7,8-diol; entylmethyl)-1 ,2,3,4,5,6-h exahydro-2-m ethyl be nzo [hisoqu in olin e-7,8-di o (5R)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[hisoquinoline-7,8-diol; (5S)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[hisoquinoline-7,8-diol; 1,2,32,42 ,5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cyclononane-1,52.. benzo[hisoquinoline]; 1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cycloheptane-1 benzo~h]isoquinoline1; 1 ',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cyclooctane-1 benzo[h]isoquinoline]; 2-Ethyl-l ,2',3',4',5',6'-hexahydro-7',8'-dihydroxy-spiro[cycloheptane-1 benzo[h]isoquinoline]; or 1 6',8 a'-Octah yd ro-7',8'-di h yroxy-2'-m ethyl spi ro[cyclo heptan e- 1 benzo[h]isoquinoline]; a nd pharmaceutically-acceptable salts thereof. 8. A compound which is: [1 ,3-cis] 1 -Aminomethyl-3-n-butyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -Aminomethyl-3-cyclopentylmethyl-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; [1 ,3-cis] 1 -Amino methyl-3-cyclooctyl-5,6-di hyd roxy-3,4-di hydro- 1 H-2-be nzopy ran; [1 ,3-cis) 3-n-Butyl-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H-2-benzopyran; 209 [1 ,3-cis] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H-2- benzopyran; Ii ,3-cis] 5,6-Dihydroxy-3-pheny-1 -(2IR*-pyrrolidiny)-1 ,2,3,4-tetrahydro-naphthalene; [1 ,3-trans) 5,6-Dihyciroxy-3-phenyl-1 -(2IR*-pyrrolidinyl)-1 ,2 ,3,4-tetrahydronaphthalene; [1 ,3-cis] 5,6-Dihydroxy-1 -methylaminomethyl-3-phenyl-1 1 23,4-tetrahydronaphthalene; [1 ,3-cis] 1 -Aminomethyl-5,6-dihydroxy-3-(3-hydroxypheny)-1 ,2 ,3,4-tetrahydro- naphthalene; 1 -Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene; [1 ,3-cis] 1 -Aminomethyl-3-benzyloxymethyl-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; [1 R*.,8!,9aaR] 1 -Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenyfphenalene; [1S$Z8Zj9aR2 1 -Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexa~iydro-8-phenylphenalene; 6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1 H-be nzojje]isoindole; [1 3-(1 -Aciamantyl)-1 -aminomethyl-3,4-ciihydro-5,6-dihydroxy-1 H-2-benzopyran; 1 -Amino methyl-5,6-bis(benzoyloxy)-3-phenyl-3,4-dihydronaphih-alene; Spiro[cyclopentane-1 ',2',3',4',5',6',-hexahydrobe nzo[h~isoquinoline)]-7',8'-diol; Spiro[cyclohexane-1 ,5a-(1 ',2',3',4',5',6',-hexahydrobenzo[bi]isoquinoline))-7',8'-diol; 0 Spiro[cyoioheptane-1 ,5'-(1',2',3',4',5',6',-hexahydro-benzo[h]isoquinoline)]-7',8-diol; Spiro[cyclooctarie-1 ',2',3',4',5',6',-hexahydro-benzo[h)isoquinoine)]-7',8'-diol; 20 5-Phenyl-1 ,2,3,4,5,6,-hexahydrobenzo(hjisoquinoline-7,8-diof; 2-Methyi1-5-phenyl-1 ,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol; Spiro[cyclooctane-1 1 5',6',-hexahydro-benzohlisoquinoline)]-7',8'-diol; 0005- CycIo h e xy1-1 he xa h ydrob e nzo(h is oq u in o ine-7,8-d io 1; pe ntyl meth y-1 exah ydro b enzo[h]i soqui no li ne-7,8 -dio 1; 25 [1 ,3-cis] 1 -Aminomethylk5,6-dihydroxy-3-(3-methoxyphenyl)-3,4-dihydro-1 H-2- ben zopy ran; [1 ,3-cis] 3-(1 -Aclamantyl)-5,6-dihydroxy-1 -methylaminomethyl-3 1 4-dihydro-1 H-2- [1benzopyran; [R,3S] 5,6-Dihydroxy-1 -methylaminomethyl-3-phenyl-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -Am in om ethyl-3-cyclo hexyf me thyl1-5, 6-dihydroxy-3,4-dihydro-1 H -2- benzopyran; [1 ,3-cis] 1 -Aminomethyl-5,6-difiydroxy-3-isobutyl-3,4-dihydro-1 H-2-benzopyran; (1 ,3-cis] 3-(1 -Adamantylmethyl)-1 -aminomethyl-5,6-dihydroxy-3,4-dihydro-1 H-2- benzopyran; 210 [1 ,3-cisl 3-(1 -Adamantylmethyl)-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1 H- 2-benzopyran; [1 ,3-cis] 3-Gyclohexylmethyl-5,6-dihydroxy-1 -methylaminomethyl-3 ,4-dihydro.1 H-2- benzopyran; I '..Aminomethyl-5',6'-dihydroxyspiro[cycloheptane-1 ,3'-(3',4'-dihydro-1 be nzopyran)]; 1 '-Aminomethyl-5',6'-dihydroxyspiro[cyclooctane-1 ,3'-(3',4'-ciihyciro- 1'H-2'- be nzopyran)I; 5',6'-Dihydroxy-1 '-methylaminomethylspiro~cycloheptane-1 ,3'-(3',4'-dihydro-l benzopyran)]; 5',6'-Dihydroxy-1 '-methylaminomethylspiro[cycloootane-1 ,3'-(3',4'-dihydro-1 'H benzopyran)]; [1 ,3-cis) 1 -Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 H-2-benzopyran; (1 R, 3S] 3-t- Buty 1-5,6-d ih ydroxy-1I -mnethyliamino met hyl-3,4-di hyd ro- 1 H -2-be nzc'pyran; [1 ,3-trans] 1 -Aminomethyl-5,6-dihydroxy-3-phenyl-3 ,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -AminometLhyl-5,6-dihydroxy-3-(4-ethoxy-2 ,3,5,6-tetrafluoroph enylm ethyl)- 3,4-dihydro-1 H-2-benzopyran; 1,3-cis] 1 -Aminomethyi-5,6-dihydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydro-1 H-2- benzopyran; 20 (1 ,3-cis] 1-Aminomethyl5,6-dihydroxy3(3-trifluoromethylphenyl)3,4-dihydro-lH-2- 000* benzopyran; sos[1 ,3-cis] 3- Aliyl-i-arninomethyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; 0 [1 R,3S] 3-t-ButyJ-5,6-dihydroxy-1 -dimethylaminomethyl-3,4-dihydro-1 H-2-benzopyran; 090:09[1 ,3-cis] 5,6-Dihydroxy-1 -methylamiiiomethyl-3-n-pentyl-3,4-dihydro-1 H-2- benzopyran; see 5 [119,8'8 1 -Aminomethyl-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 R,3S] 3-(1 -Adarnantyl)-1 -aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1 H-2- C benzopyran; [1 R,3SI 3-(1 -Adamantyl)-5,6-di hyd roxy-7-flIuoro- I -m ethyl amino meth yl-3,4-dihydro- 1 H- 2-benzopyran; [1 ,3-cis] 3-t-Butyl-5,6-dihydroxy-1 -ethylaminomethyf -3 ,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 3-t-Butylmethyl-5,6-dihydroxy-1 -methylaminomethyl-3,4-dihydro-1-H-2- benzopyran; [1 ,3-cis] 1 -Ally! aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1 H-2-benzopyran; 211 [1 ,3-cis] 1 -Aminomethyl-3-t-butylmethyi1-5,6-dihydroxy-3,4-dihydro-1 H-2-benzopyran; [1 ,3-cis] 1 -aminomethyi-5,6-dihydroxy-3-(3R-but-1 -enyl))-3,4-dihydro-1 H-2- benzopyran; [1 R,3S] 3-(1 -Adamantyl)-5,6-dihydroxy-1 -dim ethylaminomrnethyl-3,4-di hydro-1 H-2- benzopyran; [1 R,3R] 1 -Ai ninomeihyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; [1 ,3-cis) 1 -Aminomethyl-3-cyclopentylmethy 7 l-3,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; [1 R,3R] 1 -Aminomethyi-3-(2-methyipropyi)-3,4-dihydro-5,6-dihydroxy-! H-2- benzopyran; [1 R,3R] 1 -Methylaminomethyl-3-(2 ,2-dimethylpropyl)-3,4-dihydro-5 ,6-dihydroxy-1 H-2- benzopyran; [1 ,3-cis] 1 -Methylarninomethyl-3-cyclopentylmethyl-3,4-dihydro-5 ,6-ciihydroxy-1 H-2- benzopyran; [1 R,3R] 1 -Methylaminomethyi-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy- H-2- benzopyran; [1 ,3-cis] 1 N-di methyl amino) methyl-3-(2,2-di methylpropy)-34-Ji hydro-5,6- dihydroxy-1 H-2-benzopyran; 1 r.Am n om ethy I3' 4'-di hyd ro-5', di hyd roxyspi ro [cycfo n ona ne 1 benzopyran)]; (1 ,3-cis] 1 -Aminomethyl-3-(1 -methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; (,3-cis] 1 -Aminomethyl-3-(1 -phenylcyclohexyl)-3,4-dihydro-5 6-dihydroxy-1 H-2- benzopyran; 1 Met hylam ino methyl-3' 1 4'-di hydro-5',6'-di hydroxyspiro[cyclo nona 21e- 1 (1 [1benzopyran)]; [,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -pheriylcyclohexyl)-3,4-dihydro-5,6- d~hydroxy-1 H-2-benzopyran; [1 ,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -methyfcyclohexyf)-3,4-dihydro-5,6- dihydroxy-1H-2-benzopyran; or 1 R,2S-1 -(N,N-Dimethylamino)methyI-3-phenyl-3,4-dihydro-5,6-dihydroxy-I H-2- benzopyran. 212 9. A compound which is: [1 ,3-cis] 1 -(N,N-Dimethylamino)methyl-3-(1 -methylcyclohexyl)-3,4-dihydro-5,6- dihyclroxy-1 H-2-benzopyran; [1 ,3-cis) 1 N-D m ethy lam ino) methyl-3-cyclo hexyl-3,4-di hydro -5,-dibhyd roxy-1I H -2- benzopyran; [1 ,3-cls] 1 -(N,N-Dimethylamino)methyl-3-(1 -methylcyclohexyl)-3,4-dihydro-5,6- dihyciroxy-1 H-2-benzopyran; (5R)-1 ,2,3,4,5,6-hexahyidro-5-ph enylbenzo(h]isoquinolne-7,8-diol; Butyl-1 ,2,3,4,5,6-h exahydrobe nzo[hisoqu in ol ne-7,8-diol; (5R)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[hisoquinoline-7,8-diol; lo (5S)-1 ,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol; 1 exahyd ro-7',8'-dihyd roxy-2'- met hylspi ro[cycloh eptan e- benzo[h~isoquinoline]; or 1 ',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methyspiro[cyclooctane-1 benzo[h~isoquinoline]; and pharmaceutical ly-acceptable salts thereof. 00 10. A compound which is: [1 R,3S] 3-(1 -Adamantyl)-1 -aminomethyl-5,6-dihydroxy-7-fluoro-3A4-dihydro-1 H-2- benzopyran; enyl-1 he xahydrobe nzo [hjisoqu ino line -7,8 -dio 1; 1 ',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2,-methylspiro[cycloheptane-1 25 be nzo[hjisoquino line]; (1 R,3R] 1 -Aminorrethyl-3- (2,2-dim ethylpropyl)-3,4-di hydro-5,6-dihydroxy- 1 H-2- benzopyran; [1 R,3R] 1 -Aminomethyl-3-(2-methylpropyl)-3,-dihydro-5,6-dihydroxy-1 H-2-benzopyran; 0001 rR,31R] 1 -Methylaminomethyl-3-(2,2-dimethypropyl)-3,4-dihydro-5,6-dihydroxy-1 H-2- benzopyran; [119,319] 1 -Mvethylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihvdroxy-1 H-2- benzopyran; or [1 ,3-cis] 1- (N,N-Dimethy lamino)m ethyl -methylcyclohexyl)-3,4-dihydro-5 1 6-dih.droxy- 1 H-2-benzopyran, 11. A compound which is: 1R,3S-l-(N,N-Dimethylamino)methyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-lH-2- benzopyran; or [1,3-cis] 1-(N,N-Dimethylamino)methyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2- s benzcpyran; and pharmaceutically-acceptable salts thereof. 12. A pharmaceutical composition for selectively binding and activating dopaminergic receptors comprising a pharmaceutically-acceptable carrier and an amount of a compound according to anyone of claims 1 to 11 effective to selectively binded activate dopaminergic receptors. 13. A pharmaceutical composition for treating dopamine-related neurological, psychological, cardiovascular, substance abuse or addictive behaviour, or cognitive or attention disorders comprising a pharmaceutically-acceptable carrier and an amount of a compound of anyone of claims 1 to 11 effective for treating dopamine-related neurological, psychological cardiovascular, substance abuse or addictive behaviour, or cognitive or attention disorders. 14. A method for selectively acting on dopaminergic receptors comprising administering to a patient in need, an amount of a compound according to anyone of claims 1 to 11 or a composition of claim 12 effective to selectively bind and activate 20 dopaminergic receptors. i 15. A method for treating dopamine-related neurological, psychological, cardiovascular, substance abuse and addictive behaviour, and cognitive and attention disorders characterised by abnormal dopaminergic activity comprising administering to a patient in need an amount of a compound of anyone of claims 1 to 11 or a 25 composition of claim 13, effective for treating dopamine-related neurological, psychological, cardiovascular, substance abuse or addictive behaviour, or cognitive or a attention disorders. 16. A process for preparing a compound of the formula: ORI O 5 4 R3 7 A 8 12 NHCHO wherein A is 0 or S; R 1 is a catechol-protecting group; IN:\LIBXXI00229:KEH/SEF lrrl*r~CI__ 214 R 3 is selected from C 1 -Co-alkyl, substituted C 1 -C 5 -alkyl, C 2 -C 12 -alkenyl, C 2 -C 12 alkynyl, cyclo-C 3 -Clo-alkyl, carbocyclic-C 6 -Clo-aryl, carbocyclicC 6 -Clo-aryl-C 1 -C 5 alkyl, and Het; and R 4 is selected from hydrogen and C 1 -Clo-alkyl or, taken together with R 3 and the carbon atom to which both are attached, forms a spiro-C 3 -Co 1 -cycloalkyl ring; comprising reacting a compound having the formula: with N-formylaminoacetaldehyde dimethyl acetal in the presence of an acid catalyst selected from boron trifluoride etherate, zinc triflate, trimethylsilyl triflate and methanesulfonic acid. 17, A compound as defined in claim 1 and substantially as herein described with reference to any one the Examples. 18. A pharmaceutical composition for selectively binding and activating dopaminergic receptors, comprising a compound of claim 17 in an amount effective to selecively bind and activate dopaminergic receptors together with a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. 19. A pharmaceutical composition for treating dopamine-related neurological, psychological, cardiovascular, substance abuse or addictive behaviour, or cognitive or Sattention disorders comprising a pharmaceutically-acceptable carrier and an amount of a 20 compound of claim 17 effective for treating dopamine-related neurological, psychological, cardiovascular substance abuse or addictive behaviour, or cognitive or attention disorders. 20. A method for selectively acting on dopaminergic receptors comprising administering to a patient in need, an amount of a compound according to claim 17 or a composition of claim 18, effective to selectively bind and activate dopaminergic receptors. 21. A method for treating dopamine-related neurological, psychological, cardiovascular, substance abuse and addictive behaviour, and cognitive and attention disorders characterised by abnormal dopaminergic activity comprising administering to a patient in need an amount of a compound of claim 17 or a composition of claim 19, effective for treating dopamine-related neurological, psychological cardiovascular, substance abuse or addictive behaviour, or cognitive or attention disorders. 22. A process for preparing a compound of claim 1 which process is substantially as herein described with reference to any of the Examples. 23. The compound of claim 1 wherein n is 1. IN:\LIBXXO00229:vgs/SEF 215 Dated 28 October, 1994 Abbott Laboratories Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 0* T -4 -v c 4 LN:ALIBXXIO229tvUs/SEF