New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans

J . Med. Chem. 1997, 40, 4235-4256

4235

New Gen er a tion Dop a m in er gic Agen ts. 1. Discover y of a Novel Sca ffold Wh ich

Em br a ces th e D₂Agon ist P h a r m a cop h or e. Str u ctu r e-Activity Rela tion sh ip s of

a Ser ies of 2-(Am in om eth yl)ch r om a n s

Richard E. Mewshaw,*^,†J oseph Kavanagh,^†Gary Stack,^†Karen L. Marquis,^‡Xiaojie Shi,^‡Michael Z. Kagan,^†

Michael B. Webb,^†Alan H. Katz,^§Anna Park,^†Young H. Kang,^†Magid Abou-Gharbia,^†Rosemary Scerni,^‡

Theodore Wasik,^‡Luz Cortes-Burgos,^‡Taylor Spangler,^‡J ulie A. Brennan,^‡Michael Piesla,^‡

Hossein Mazandarani,^‡Mark I. Cockett,^‡Rafal Ochalski,^‡J oseph Coupet,^‡and Terrance H. Andree^‡

Global Chemical Sciences and CNS Disorders Departments, Wyeth-Ayerst Research Laboratories, CN 8000,

Princeton, New J ersey 08543-8000

Received J une 2, 1997^X

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity

High

and selectivity for both the high- and low-affinity agonist states (D₂

and D₂^Low, respectively)

of the dopamine (DA) D₂receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed

to be the primary D₂agonist pharmacophore. The 2-methylchroman moiety was discovered to

be an entirely novel scaffold which could be used to access the D₂agonist pharmacophore.

Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had

High

significant effects on selectivity for the D₂

receptor vs the 5HT_1Aand R₁receptors. A novel

DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as

having the highest affinity and best selectivity for the D₂

High

receptor vs the R₁and 5HT_1A

receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential

sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-

2-AMC moiety was identified as fulfilling the McDermed model D₂agonist pharmacophoric

criteria and was proposed as the D₂receptor-bound conformation. Structure-activity relation-

ships gained from these studies have aided in the synthesis of D₂partial agonists of varying

intrinsic activity levels. These agents should be of therapeutic value in treating disorders

resulting from hypo- and hyperdopaminergic activity, without the side effects associated with

complete D₂agonism or antagonism.

In tr od u ction

available on DA neurons while far fewer spare DA

receptors are available on postsynaptic cells.⁶In a

hyperactive dopaminergic system, a D₂partial agonist

should reduce the overstimulation of the D₂postsynaptic

receptors by competing with dopamine and in principle

normalize dopaminergic transmission. In a hypoactive

situation, commonly associated with both a dysfunc-

tional prefrontal cortex and the negative symptoms, the

supersensitive D₂postsynaptic receptors may be suf-

ficiently stimulated by a D₂partial agonist. As such, a

D₂partial agonist may provide a viable approach toward

influencing dopaminergic activity both pre- and postsyn-

aptically and therefore be a successful means of treating

the positive and negative symptoms of schizophrenia

with low liability for producing EPS.⁷D₂partial ago-

nists could also be of value in hyperprolactinemia,

Parkinson’s disease, Tourette’s syndrome, and poten-

tially any disorder in which DA function is abnormal.

The discovery of more effective side effect free therapy

for the treatment of both the positive and negative

symptoms of schizophrenia remains a challenging re-

search problem. The positive symptoms are believed

to be associated with hyperactive dopaminergic trans-

mission in the mesolimbic brain region, whereas the

negative symptoms are associated with a hypoactive

prefrontal cortex.^1,2Although traditional D₂antagonist

antipsychotics are efficacious for the positive symptoms,

they are also responsible for extrapyramidal side effects

(EPS) which occur as a result of excessive attenuation

of brain dopamine (DA) neuronal activity due to the

blockade of postsynaptic DA receptors. One theory

which has gained renewed attention in recent years is

based on the potential normalization of dopaminergic

activity using a DA D₂partial agonist.³A successful

D₂partial agonist would be effective in treating the

positive symptoms by selectively activating the inhibi-

tory presynaptic D₂autoreceptors located on the cell

bodies and terminals of DA neurons to inhibit DA

neuronal firing, synthesis, and release of DA via a

feedback mechanism which decreases neuronal activity.⁴

Though there is no evidence for a structural difference

between the DA D₂pre- and postsynaptic receptors,⁵it

has been postulated that the autoreceptors are much

more sensitive due to a large DA receptor reserve

Numerous DA agonists with various levels of intrinsic

activity have been prepared and concomitantly used to

explore the pharmacophoric and topographical require-

ments of the DA D₂receptor.⁸As a result of this

research, the discovery of several D₂agonists have

emerged which can be categorized into two general

classes (Chart 1). The first class has a close resem-

blance with respect to the pharmacophoric elements of

DA [i.e. (S)-3-PPP (1),⁹talipexole (2),¹⁰U-68553 (3),¹¹

pramipexole (4),¹²PD 128483 (5),¹³SDZ-208-911 (6),¹⁴

SDZ-208-912 (7)¹⁴] and a second class whose structural

elements do not mimic DA and whose pharmacophore

is less well understood [i.e. roxindole (8),¹⁵PD 120700

^†Medicinal Chemistry.

^‡CNS Disorders.

^§Structural Biology.

^XAbstract published in Advance ACS Abstracts, December 1, 1997.

4236 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Ch a r t 1. Several Dopamine D₂Partial Agonists

Mewshaw et al.

Ch a r t 2. WAY 124486 and Its 2-Aminomethyl Chroman Analogue Variations

(9),¹⁶PD 119819 (10),¹⁷and CI-1007 (11)¹⁸]. Recently

it has been suggested that there may be alternative

modes of agonist binding other than those represented

by the McDermed DA D₂concept.¹⁹

were systematically carried out to evaluate (a) the

importance of the dioxan ring of 12, (b) the importance

of the anilino moiety, (c) the optimal length of the side

chain spacer, (d) the D₂primary pharmacophoric ele-

ments, and (e) how intrinsic activity may be influenced

through molecular modifications. Our ultimate goal

was to establish SAR directed at identifying a highly

selective and potent D₂partial agonist with low intrinsic

activity. Although 5-HT_1Aagonism has been shown to

reverse D₂antagonist-induced catalepsy in rodent,²⁶it

was felt that a suitable D₂partial agonist candidate

would not need this additional property to be of thera-

peutic value.

As a consequence of our study, we identified that the

2-AMC and 2-AMB moieties were found to be entirely

novel scaffolds which could be used to access the D₂

agonist pharmacophore. A conformational analysis and

proposed receptor-bound conformation will also be

discussed.

Clinically, compounds such as talipexole (2) and

pramipexole (4) appear to possess too much intrinsic

activity, as evidenced by the appearance of hallucina-

tions in some patients.²⁰Pramipexole (4) is currently

being marketed for Parkinson’s disease.²¹Compounds

such as SDZ-208-911(6) and SDZ-208-912 (7) have

shown efficacy with respect to the positive symptoms;

however, due to their low intrinsic activity, they can

produce an unacceptable level of EPS.²²Other agents

either lack specificity, have a pharmacokinetic profile

that hinders therapeutic ability, or are currently being

evaluated.

Our interests in the discovery of a D₂partial agonist

emerged with the recent identification of the 2-(ami-

nomethyl)benzodioxan (2-AMB) WAY 124486 (12, Chart

2).²³Previously reported structure-activity relation-

ship (SAR) studies of the AMB derivatives revealed the

7-hydroxyl group and S configuration were essential

requirements to achieve high affinity for the D₂receptor

[K_i(D₂^High) ) 0.3 nM vs [³H]quinpirole, Table 1].

Despite the poor bioavailability and rather low selectiv-

ity vs the 5-HT_1Aand R₁receptors, 12 provided an

opportunistic chemical lead to evolve toward other more

selective compounds with improved pharmacokinetic

properties.

Resu lts

Ch em ica l Syn th esis. The general synthetic routes

for the syntheses of the 2-AMCs (22-60) are shown in

Schemes 1-3 For detailed transformations, see the

Experimental Section. In all cases, the chromones

(15a ,b,e) were synthesized from their respective known

2-hydroxyacetophenones (14) using the method of Ko-

stanecki (Scheme 1).²⁷Hydrogenation in acetic acid

afforded the chromans (16a ,b, R ) OMe or OBn).

Benzyl-protected chroman (15b) was prepared as previ-

ous described from 14b.²⁸Reduction of esters 16a ,b,e

using LiBH₄furnished the alcohols (17a ,b,e). Alcohols

17a ,b,e were converted in a straightforward manner to

In this report will be discussed several potential

avenues for D₂, 5HT_1A, and R₁receptor profile modula-

tion within a related series of 2-(aminomethyl)chromans

(2-AMCs; i.e., 13, Chart 2).^24,25Structural modifications

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4237

Ta ble 1. Affinity of Benzo-Fused Ring Variations Derivatives

a

K_ivalues are the means of at least two experiments ( SEM (performed in triplicate determined from nine concentrations). Values

without SEM are for a single determination only. The radioligands used were [³H] quinpirole (D₂^High),[³H]spiperone + GTP (D₂^Low), [³H]

b

8-OH-DPAT (5-HT_1A), and [³H]prazosin (R₁). ^cAll compounds were prepared in racemic form unless otherwise noted. Reference 23.

d

*Not determined.

Sch em e 1^a

a

Reagents and conditions: (a) H₂, Pd/C; (b) LiBH₄, THF; (c) CBr₄, PPh₃, CH₂Cl₂; (d) MsCl, NEt₃; (e) TsCl, pyridine; (f) NH₂R₁, method

A or B; (g) DIAD, PPh₃, HOAr; (h) 40% HBr; (i) Ph₂PH, n-BuLi, THF; (j) NCS, THF, rt; (k) (CO₂Et)₂, NaOEt.

Sch em e 2^a

a

Reagents and conditions: (a) H₂, Pd/C; (b) LiBH₄, THF; (c) CBr₄, PPh₃, CH₂Cl₂; (d) MsCl, NEt₃; (e) TsCl, pyridine; (f) NR₁R₂, method

A or B; (g) DIAD, PPh₃, HOAr; (h) 40% HBr; (i) Ph₂PH, n-BuLi, THF; (j) NCS, THF, rt; (k) (CO₂Et)₂, NaOEt.

their corresponding bromides, mesylates or tosylates

(18-20) using standard protocol. Chlorination of 20

with NCS led exclusively to 21. Treatment of 18-21

with an excess of the appropriately substituted amines

provided the 2-AMCs (22-48) (method A or B). The

amino alcohols (22a ,b) were coupled to a variety of

phenol derivatives using the Mitsunobu protocol (method

C).²⁹The formation of azetidine 61a b was observed as

a byproduct in cases when the intermediate phenoxide

anion was relatively nonnucleophilic. The phenol moi-

4238 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

Sch em e 3^a

a

Reagents and conditions: (a) H₂, Pd/C; (b) LiBH₄, THF; (c) CBr₄, PPh₃, CH₂Cl₂; (d) MsCl, NEt₃; (e) TsCl, pyridine; (f) NH₂R₁, method

A or B; (g) DIAD, PPh₃, HOAr; (h) 40% HBr; (i) Ph₂PH, n-BuLi, THF; (j) NCS, THF, rt; (k) (CO₂Et)₂, NaOEt.

Sch em e 4^a

a

Reagents and conditions: (a) NaH, EtOCOOEt, THF; (b) Et₃SiH, TFA, CH₂Cl₂; (c) LiBH₄, THF; (d) CBr₄, PPh₃, CH₂Cl₂; (e) NH₂(CH₂)OH;

(f) DEAD, PPh₃, 3-nitrophenol; (g) H₂, Pd/C; (h) HBr.

eties were liberated by using either 48% HBr (method

D) for the methoxy derivatives or hydrogenolysis (method

F) of the benzoxy derivatives to afford compounds 22c-

tion of the nitro group of 68, followed by treatment with

48% HBr, furnished tetralin (70).

The 2-AMB (78) was prepared in six steps as depicted

in Scheme 5. Commercially available 72 was reacted

with (2R)-(-)-gylcidyl 3-nitrobenzenesulfonate to afford

epoxide 73. Treatment with m-chloroperbenzoic acid

followed by base hydrolysis and cyclization gave ben-

zodioxan 75. Tosylation followed by reaction with

excess benzylamine provided 77, which was subse-

quently demethylated with 48% HBr to afford 78.

30

60c. Reduction of quinoline 50c using NaBH₄-NiCl₂

afforded the tetrahydroquinoline 51c (method E). Meth-

anesulfonamides (22f, 35f, 47f, 49f) were prepared

using a similar route beginning with 14g³¹(Scheme 3).

Synthesis of the tetralin 70 began with commercially

available 7-methoxy-1-tetralone (62) (Scheme 4). The

â-keto ester 63 was prepared from 62 using diethyl

carbonate and sodium hydride. Subsequent treatment

with triethylsilane afforded ester 64.³²Conversion to

the corresponding bromide (66) followed by treatment

with 1-aminopropanol afforded the 2-(aminomethyl)-

tetralin (67). Coupling of 3-nitrophenol to 67 using

Mitsunobu methodology provided the bis(arylalkyl)-

amine (68). A significant amount of azetidine (71) was

isolated during the Mitsunobu reaction. Presumably

the increased nucleophilicity of the nitrogen of 67 (next

to a tetralin ring vs a chroman ring) allows for the

intramolecular reaction to compete effectively. Reduc-

Resolu tion a n d Deter m in a tion of Absolu te Con -

figu r a tion . Racemic 35c, 41c, and 48c were resolved

using a Diacel Chiralcel OJ 1 in. × 25 cm (10 mkm)

preparative column. The optical purities of (-)-35c and

(+)-35c was determined to be 99.0% ee and 99.8% ee,

respectively, using a Chiralcel OD-R (0.46 × 25 cm,

acetonitrile-1 M sodium perchlorate, 1:1, 0.5 mL/min,

280 nM). The optical purities of (-)-41c, (+)-41c, (-)-

48c, and (+)-48c were determined to be 100% ee, 99.5%

ee, 100% ee, and 96.6% ee, respectively. The absolute

stereochemistry of the eutomers [(-)-35c and (-)-41c]

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4239

Sch em e 5^a

a

Reagents and conditions: (a) NaH, (2R)-(-)-glycidyl 3-nitrobenzenesulfonate; (b) mCBPA; (c) K₂CO₃/MeOH; (d) TsCl, pyridine; (e)

BnNH₂, DMSO, 80 °C; (f) HBr.

Sch em e 6^a

a

Reagents and conditions: (a) Lipase PS-30, (b) LiBH₄; (c) TsCl, pyr; (d) NCS; (e) RNH₂, DMSO.

was determined to be of the R configuration when both

were prepared from a known intermediate [i.e. R-(-)-

16c³³] through an alternative route depicted in Scheme

6. The corresponding phenylbutyl derivative [i.e.

R-(-)-32c] was similarly prepared from R-(-)-16c.

the antagonist ligand [³H]spiperone. The affinities were

expressed as K_ivalues using the Cheng-Prussoff equa-

tion.³⁶The compound’s intrinsic activity was predicted

upon the preferential antagonism of agonist vs antago-

nist radioligand binding, based upon a similar method

previously reported by Lahti et al.³⁷The displacement

of the antagonist, [³H]spiperone, in the presence of high

P h a r m a cology

concentrations of GTP measures the ability of the ligand

All compounds were evaluated for their in vitro

binding affinity to rat striatal DA D₂receptors using

the agonist [³H]quinpirole to label the high affinity state

(D₂^High) and the antagonist [³H]spiperone plus GTP to

label the low-affinity state (D₂^Low). Ketanserin (30 nM)

was present in all assays with [³H]spiperone to preclude

binding of spiperone to 5-HT₂receptors. Although [³H]-

quinpirole possesses high affinity for D₃receptors, it

appears to be labeling predominantly the D₂high-

affinity state in striatal tissue, and may be the ligand

of choice for assessing D₂agonist binding.^34,35Addition-

ally, the majority of quinipirole binding (>80%) appears

to be very sensitive to inhibition by guanylylimido-

diphosphate (unpublished results). Compounds were

also evaluated for their affinity for the 5-HT_1Aand R₁

receptors using [³H]-8-OH-DPAT and [³H]prazosin,

respectively. Selected compounds were further evalu-

ated for their binding affinity for the human D_2s, D₃,

and D_4.4receptors, each expressed in CHO cells using

Low

to bind to the D₂

receptor, while displacement of an

agonist, [³H]quinpirole, in the absence of GTP measures

High

the ligand’s ability to bind to the D₂

receptor [K_i^L

)

K_i(D₂^Low); K_i^H) K_i(D₂^High)]. The ratio [i.e. (K_i^L/K_i^H)] was

shown to be a reliable estimate with the ligand’s

intrinsic activity as determined by other assays. Se-

lected compounds which displayed impressive affinity,

selectivity, and a ratio predictive of intrinsic activity

between talipexole (2) [(K_i^L/K_i^H) ) 466, Table 1] and

SDZ-208-911 (6) [(K_i^L/K_i^H) ) 1.1, Table 1] were subse-

quently evaluated in vivo by utilizing the well-estab-

lished phenomenon of receptor-mediated feedback in-

hibition of the presynaptic neuron.³⁸Activity at DA

autoreceptors was established by their ability to

reverse γ-butyrolactone (GBL)-induced increase in DA

synthesis as measured by the rate of dihydroxypheny-

lalanine (DOPA) formation in the rat corpus striatum.

Effects in mouse exploratory locomotor activity (LMA)

4240 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

Ta ble 2. Affinities of Bis(arylalkyl)Amines: Side Chain Variations of 7-Hydroxy-2-AMCs

were used as a behavioral index of DA autoreceptor

activation/postsynaptic DA agonism; selective activation

of DA autoreceptors results in the inhibition of LMA,

while postsynaptic DA stimulation increases LMA. The

pharmacological test models are described in detail in

the Experimental Section.

[K_i(5-HT_1A)/K_i^H) 154; K_i(R₁)/K_i^H) 70]. The SAR

suggests that the flexible arylalkyl side chain moiety

may be playing an auxiliary role in the ligand’s ability

to bind to the D₂receptor. In fact, as shown in Table 3,

when the aryl moiety was completely removed (i.e. 22c),

High

high affinity for the D₂

receptor was retained (K_i^H

) 3.4 nM), indicating that the primary pharmacophore

was the 7-OH-2-AMC nucleus. Apparently the D₂

receptor can withstand the complete removal of the side

chain aryl group with only a slight loss in affinity (22c;

K_i^H) 3.4 nM vs 49c; K_i^H) 0.90 nM). However, a more

significant loss in affinity was observed for 5HT_1Aand

R₁receptors (49c-60c vs 22c), which suggests these

receptors may be more dependent on hydrophobic

interactions than on complementary receptor-ligand

interactions. Further investigation of the simple alkyl

side chains (Table 4) revealed that elongation of the

alkyl group to a hexyl group (i.e. 26c) resulted in

maximum affinity for D₂and 5HT_1Areceptors. The

Resu lts a n d Discu ssion

Str u ctu r e-Affin ity Rela tion sh ip s (SAR). Bind-

ing affinities for the D₂^High, D₂^Low, 5HT_1A, and R₁

receptors are reported in Tables 1-8 along with relevant

reference compounds. As indicated in Table 1, ring

variations of 2-AMB (()-12 revealed that the D₂

receptor was very sensitive to structural modification

High

in this region of the molecule. The 7-OH-2-AMB (()-

12 (K_i^H) 1.0 nM) and 7-OH-AMC (49c, K_i^H) 0.90 nM)

High

had almost identical affinities for the D₂

receptor,

whereas, in the case of the tetralin (70), replacement of

both oxygens led to a 25-fold loss in affinity (K_i^H) 22.3

nM).

butyl derivative (24c) had the best selectivity for the

High

Our initial focus was the modification or replacement

of the anilino moiety of 49c to attempt to control affinity

and selectivity (Table 2). Surprisingly, the bis(aryla-

lkyl)amines (49c-60c) all had affinities of <3 nM for

D₂

receptor vs the 5-HT_1A[K_i(5HT_1A)/K_i^H) 112]

receptor when compared to the simple alkyl derivatives.

Branched alkyl group side chains (i.e. 27c-31c) had

High

lower affinity for the D₂

receptor than their corre-

the D₂^High, indicating a large tolerance of the D₂

sponding isomeric straight chain analogues. However,

when these branched alkyl derivatives were compared

to their respective alkyl groups of the same length, little

difference in affinity was observed (23c vs 28c; 25c vs

High

receptor toward structural variation in this region of

the molecule. Interestingly, every molecule in Table 2,

with the exception of 60c, had affinities of similar

magnitude (<7 nM) at the 5HT_1Areceptor. The ami-

nopyrimidine (60c) was identified as the most selective

compound of the bis(arylalkyl)amine shown in Table 2

29c). In general, the arylalkylamines shown in Table

High

4 retained excellent selectivity for the D₂

receptor

vs the R₁receptor, and were overall superior in selectiv-

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4241

Ta ble 3. 7-Position Substitutent Effects of Simple Alkyl Side Chains vs Arylalkyl Side Chain Derivatives

K_i(nM)^a,b

5-HT_1A

ratio

compd^c

X

series

D₂

1132

R₁

(D₂^Low/D₂

)

High

Low

High

49a

49c

49d

49f

22a

22c

22d

22f

OMe

I

II

222 35

*

5

18

14

6

16

52

9

OH

H

0.9 ( 0.2

34 ( 19

16 ( 1

1300 ( 93

3.4 ( 0.5

294 ( 70

102 ( 36

15.9 ( 6.7

472 ( 197

102 ( 58

20,861

177 ( 62

2763 ( 493

662 ( 93

2.6 ( 1.4

2.8

3

*

86

*

38 ( 10

11

35

*

NHSO₂Me

OMe

OH

H

307 ( 20

*

NHSO₂Me

56

500

6

^a-cSee footnotes of Table 1. *Not determined.

Ta ble 4. Simple Alkyl-Substituted 2-(Aminomethyl)chroman Analogues

K_i(nM)^a,b

ratio

compd^c

R₁

D₂

5-HT_1A

R₁

(D₂^Low/D₂

)

High

Low

High

22c

23c

24c

25c

26c

27c

28c

29c

30c

31c

(CH₂)₃OH

(CH₂)₂CH₃

(CH₂)₃CH₃

(CH₂)₄CH₃

(CH₂)₅CH₃

CH(CH₃)₂

CH₂CH(CH₃)₂

CH₂CH₂CH(CH₃)₂

CH(CH₂CH₃)₂

cyclohexyl

3.4 ( 0.5

6.9 ( 1.5

2.4 ( 0.6

1.2 ( 0.2

0.7 ( 0.05

58 ( 7

156 ( 67

96 ( 4

62 ( 30

44 ( 14

17 ( 1

515 ( 112

372 ( 212

36 ( 1.5

413 ( 183

230 ( 132

86

177 ( 24

307 ( 20

582

177

160

111

*

452

375

*

46

14

26

37

24

9

47

22

10

268

13

2.9

*

308

67

*

7.9

1.6 ( 0.1

40 ( 16

22 ( 2

330

1268

^a-cSee footnotes of Table 1. *Not determined.

Ta ble 5. Phenyl Group Tether Study of 7-Hydroxy-2-AMCs (32c-35c)

K_i(nM)^a,b

ratio

compd^c

n

D₂

5-HT_1A

R₁

(D₂^Low/D₂

)

High

Low

High

RS-(()-32c

R-(-)-32c

33c

34c

35c

4

3

2

1

0.6 ( 0.1

0.2 ( 0.1

0.4 ( 0.1

0.8 ( 0.2

0.2 ( 0.1

4.0 ( 0.8

2.8 ( 0.7

13.5 ( 2.7

26.4 ( 6.7

8.4 ( 1.2

1.4

0.40

3.60

7.0

40.0

9.5

63.5

43.0

572.5

7

14

34

33

42

52.0

^a-cSee footnotes of Table 1.

ity when compared to the bis(aryl)alkylamine deriva-

tives shown in Table 2. The anomalous selective

bis(arylalkyl) amine (i.e. 60c) suggests that an aryl

group side chain having hydrophilic properties may not

be complementary to the 5-HT_1Aand R₁receptor binding

sites. Instead, 60c may be recognized by 5-HT_1Aand

R₁receptors as having hydrophobic properties not unlike

the simple alkyl-substituted 2-AMCs (22c-31c).

The significance of having a hydrogen bond donating

group in the 7 position is nicely unveiled in Table 3. A

38-fold loss in affinity was manifested when the 7-hy-

droxyl group was replaced by a hydrogen (i.e. 49c vs

49d ), while incorporation of a methoxy group (i.e. 49a )

resulted in a 247-fold loss in affinity vs 49c. An attempt

to identify a hydroxy group replacement proved disap-

pointing with the methanesulfonamido group (i.e. 49f),

which led to a 18-fold loss in affinity when compared to

49c. Though the methanesulfonamide moiety is known

to be a popular bioisosteric replacement for phenol,³⁹

High

its decreased D₂

affinity may arise from differences

in both steric effects and their preferred hydrogen-bond

directionality capabilities. While the deshydroxy AMC

(22d ) resulted in a 86-fold loss in affinity, the meth-

anesulfonamide (22f) lost only 30-fold affinity when

compared to the 7-hydroxy analogue (22c), again ex-

emplifying the inefficient hydrogen bonding interaction

High

of the sulfonamido group with the D₂

receptor.

Table 5 depicts an investigation of the spacer unit

utilized between a phenyl group and the 7-OH-AMC

nucleus. Interestingly, when the oxygen of the four-

atom linkage of 54c (Table 2) was replaced with a

methylene (i.e. 32c), improved selectivity was discovered

High

for the D₂

receptor over the R₁receptor [32c, K_i(R₁)/

K_i^H) 67 vs 54c, K_i(R₁)/K_i^H) 18], as was also observed

for the 2- and 3-atom linkages (i.e. 33c and 34c).

However, rather low selectivity was observed with

4242 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Ta ble 6. Ring Variation Analogues of AMC 35c

Mewshaw et al.

K_i(nM)^a,b

Low

ratio

compd^c

R₁

D₂

5-HT_1A

R₁

(D₂^Low/D₂

)

High

35c

36c

37c

38c

39c

40c

Ph

2-thienyl

2-furanyl

cyclohexyl

1-naphthyl

4-pyridinyl

0.2 ( 0.1

0.6 ( 0.1

1.1 ( 0.4

0.9 ( 0.3

1.1 ( 0.4

1.1 ( 0.2

8.4 ( 1.2

2.8 ( 0.7

42 ( 29

7.2 ( 1.6

3.8 ( 1.7

115 ( 18

52.0

42.5

208

26.5

6.0

572

514

1710

414

36

1002

42

5

38

8

3

104

57.5

^a-cSee footnotes of Table 1.

Ta ble 7. Analogues of AMC 35c: Substituent Effects

K_i(nM)^a,b

ratio

compd^c

Y

X

R₂

R₆

R₇

D₂

5-HT_1A

R₁

(D₂^Low/D₂

)

High

Low

High

35c

35d

35f

41c

42c

43d

44c

45c

46c

47f

48c

H

Cl

H

OH

H

NHSO₂Me

OH

H

OH

H

Me

H

F

Cl

OH

Me

H

0.2 ( 0.1

51 ( 19

8.4 ( 1.2

*

52.0

59.5

52.0

387

192

46.0

71.5

43.5

31.5

10.5

*

572

315

1136

69

811

641

1442

624

504

579

160

42

*

5

7

13

*

86

108

27

4

8.8 ( 0.01

1.0 ( 0.3

4.8 ( 0.3

73.7 ( 3.5

0.8 ( 0.1

0.3 ( 0.02

0.6 ( 0.2

7.1 ( 1.7

0.6 ( 0.2

46.3 ( 17.0

7.1 ( 1

61.1 ( 3.6

*

68.9 ( 4.7

32.4 ( 10.3

16.2 ( 1.6

25.4 ( 7.1

3.2 ( 1.3

NHSO₂Me

OH

(CH₂)₂

5

^a-cSee footnotes of Table 1. *Not determined.

respect to the 5-HT_1Areceptor when the tethering unit

was a two-, three-, or four-atom linkage. Remarkably,

the benzyl-substituted 2-AMC (35c) was observed to

methanesulfonamides (22f, 35f, and 49f) were all

observed to have near parallel losses in affinity (20-

40-fold) when compared to their respective hydroxy

analogues (i.e. 22c, 35c, and 49c), suggesting that the

7-methanesulfonamido and 7-OH-AMCs were aligning

themselves in a similar orientation in the D₂^Highreceptor

cavity.

have excellent affinity (K_i^High) 0.2 nM) and impressive

High

selectivity for the D₂

receptor [K_i(5-HT_1A)/K_i^H) 260;

K_i(R₁)/K_i^H) 2862)]. Maintaining the one atom spacer,

a limited study of ring variation analogues of 35c (Table

6) afforded several compounds (36c-40c) having high

Substituting a chlorine atom for hydrogen in the 6

High

affinity and impressive selectivity for the D₂

receptor

position of 35c (i.e. 41c) led to a 5- and 7-fold loss in

High

vs the R₁receptor and the 5HT_1Areceptor. A π electron

affinity for D₂

and 5HT_1Areceptors, respectively.

High

Low

interaction with the D₂

receptor does not appear to

However, 41c increased affinity for D₂

and R₁recep-

be operative for the aryl side chain of 35c when

considering the cyclohexyl derivative (38c) had similar

affinity to that of 35c, suggesting lipophilicity may be

playing a role in affinity.

tors vs 35c. A limited study on the substituent effects

at the 4-position of the benzyl side chain of 35c and 35f

(i.e. 44c-46c, 47f) revealed little change in affinity for

High

the D₂

receptor occurred when replacing a hydrogen

with either a fluorine, chlorine, or a hydroxyl group.

Unexpectedly, when the hydroxyl group of 35c was

Interestingly, converting the secondary amine (35c) to

removed (i.e. 35d ), a 255-fold loss in affinity was

High

its methylamino analogue (i.e. 42c) led to a 24-fold loss

observed for the D₂

receptor (Table 7). Previous

High

in affinity for the D₂

receptor. However, incorporat-

examples of hydroxyl removal revealed only a 38-fold

(49c vs 49d ) and a 86-fold (22c vs 22d ) loss in affinity.

To make valid arguments with respect to receptor

topography and SAR, knowledge of whether a class of

ligands is consistently binding with a common align-

ment rule needs to be assessed. In the case of the

deshydroxy and hydroxy analogues, parallel modifica-

ing the methyl group of 42c within a six-membered ring

High

(i.e. 48c) led to a 8-fold increase in affinity for the D₂

receptor (42c; K_i^H) 4.8 nM vs 48c; K_i^H) 0.6 nM).

En a n tioselectivity. Upon resolution of (()-35c, it

was determined that R-(-)-35c had 60-fold higher

High

affinity for the D₂

receptor than S-(+)-35c (Table 8).

tions led to nonparallel effects on affinity, suggesting a

All three receptors recognized R-(-)-35c as the eutomer;

High

common orientation at the D₂

receptor was not being

however, R-(-)-35c was much more enantioselective for

High

maintained. The observation that the anilino analogue

the D₂

receptor, having eudismic ratios of 60, 44, and

High

(49d ) decreased affinity by 38-fold for the D₂

receptor

8 for the D₂^High, 5HT_1A, and R₁receptors, respectively.

vs its 7-hydroxy analogue (49c) and the benzyl analogue

(35d ) decreased affinity 255-fold vs its 7-hydroxy ana-

logue (35c) implies that 49d has a different mode of

binding not available to 35d . In the same light, the

Interestingly, although 60 times less potent, the dis-

tomer [S-(+)-35c] maintained significant affinity (K_i^H

High

) 12 nM) and selectivity for the D₂

receptor. Reso-

lution of (()-41c again revealed the eutomer to have

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4243

Ta ble 8. Affinities of 35c, 41c, S-78, and 48c

K_i(nM)^a,b

ratio

compd^c

Y

V

R₂

R₆

D₂

5-HT_1A

R₁

(D₂^Low/D₂

)

High

Low

High

RS-(()-35c

R-(-)-35c

S-(+)-35c

RS-(()-41c

R-(-)-41c

S-(+)-41c

S-(-)-78

(()-48c

H

Cl

H

CH₂

O

CH₂

H

0.2 ( 0.1

12 ( 2.4

1.0 ( 0.3

0.6 ( 0.1

32 ( 10

0.4 ( 0.2

0.6 ( 0.1

0.6 ( 0.2

40 ( 2

8.4 ( 1.2

3.3 ( 0.8

110 ( 21

7.1 ( 1

2.2 ( 0.5

28.1 ( 17.7

5.7 ( 3.7

3.2 ( 1.3

3.8 ( 0.1

110 ( 33

52.0

22.5

990

387

214

4961 ( 1109

156

110

35.5

635 ( 164

572

212

1624

69

487

285

254

160

120

98

42

16

9

7

4

0.9

14

5

6

3

(CH₂)₂

(-)-48c

(+)-48c

H

^a-cSee footnotes of Table 1.

Ta ble 9. Affinities of 35c, 41c, S-78, and 48c

K_i(nM)^a

DOPA

compd^c

hD₂

hD₃

hD₄

LMA (ED₅₀, mg/kg, sc)

(% inhib at 10 mg/kg, sc)

RS-(()-35c

R-(-)-35c

S-(+)-35c

RS-(+)-41c

R-(-)-41c

S-(+)-41c

RS-(()-48c

(-)-48c

9.7 ( 2.4

10.4 ( 0.2

228 ( 4.5

5.2 ( 0.2

7.0 ( 0.6

77 ( 5

4.3 ( 0.9

2.5 ( 0.6

73.9 ( 6.5

7.2 ( 0.5

8.4 ( 1.3

2.4 ( 0.1

27.6 ( 1.2

5.0 ( 0.1

3.4 ( 0.0

19.7 ( 1.9

0.5 ( 0.1

0.2 ( 0.1

1.0 ( 0.4

1.1 ( 0.02

192 ( 7.5

0.01 (0.006-0.018)

0.0014 (0.0006-0.0032)

0.22 (0.11-0.45)

0.18 (0.08-0.43)

0.20 (0.08-0.60)

NSE

0.04 (0.02-0.07)

0.02 (0.01-0.03)

NSE

*

66%

43%

*

116 ( 15

256 ( 4

4.9 ( 1.0

8.7 ( 0.5

73.0 ( 1.0

396 ( 102

529 ( 136

292 ( 44

16.6 ( 0.2

(+)-48c

S-(-)-78

*

a,b

See footnotes of Table 1. *Not determined. NSE ) no significant effect.

the R configuration with an eudismic ratio of 53 for the

compound’s affinity ratio {i.e. [K_i(D₂^Low)/K_i(D₂^High)]}.

Conversion of the AMB 12 (WAY 124486) to its chroman

analogue (49c) resulted in very similar ratios. As

indicated in Table 2, the bis(arylalkyl)amine derivative

52c had the highest ratio (54) predicting high intrinsic

activity. Compounds 54c and 55c had the lowest ratios

(13 and 12, respectively) of the bis(arylalkyl)amine

derivatives shown in Table 2. By replacing the phenyl

group of 49c by a hydrogen (i.e. 22c) resulted in a high

ratio again (52, Table 3).

As indicated in Table 5, tethering the phenyl ring

from the basic nitrogen resulted in ratios of 42, 33, and

34 for the benzyl, phenylethyl, and phenylpropyl side

chain derivatives, suggesting similar intrinsic activities.

Interestingly, incorporating a four carbon spacer be-

tween the phenyl ring and nitrogen (i.e. RS-(()-32c)

resulted in one of the lower ratios [i.e. (K_i^L/K_i^H) ) 7]

observed in this study and parallels a similar observa-

tion made in Table 2 for compound 54c [i.e. (K_i^L/K_i^H) )

13]; both compounds have four-atom tethers and an

unsubstituted phenyl ring. R-(-)-32c was prepared to

again verify that the active component in this class of

2-(aminomethyl)chromans resided in the R enantiomer,

which was observed to have a ratio of 14. Restricting

the benzyl side chain, exemplified by (()-48c, resulted

in another means for lowering the ratio [i.e. (K_i^L/K_i^H) )

5]. (-)-48c was predicted to have slightly higher

intrinsic activity [i.e. (K_i^L/K_i^H) ) 6] than its distomer,

(+)-48c [i.e. (K_i^L/K_i^H) ) 3] (Table 8). By substituting

other ring systems for the phenyl ring of 35c (Table 6),

the ratio was observed to vary from as low as 3 (39c) to

High

D₂

receptor. The absolute configuration of R-(-)-

35c and R-(-)-41c corresponded to the previously

observed S configuration of (-)-12 (benzodioxan), indi-

High

cating that the D₂

receptor recognized the analogous

levorotary enantiomer as the eutomer in both series.

Resolution of (()-48c revealed that the levorotary

isomer [i.e. (-)-48c] was again found to be the eutomer

(K^H) 0.6 nM), with an eudismic ratio of 67. The

i

corresponding benzodioxan analogue of R-(-)-35c [i.e.

S-(-)-78)] was observed to have similar affinity for

High

D₂

and R₁receptors.

The affinities of 35c, 41c, 48c, and 78 for the human

D_2s, D₃, and D_4.4receptors are disclosed in Table 9.

R-(-)-35c, R-(-)-41c, and (-)-48c were recognized as

the eutomers at all three receptors, with the hD_2s

receptor demonstrating the highest enantioselectivity.

Although R-(-)-35c was observed to be selective for the

hD_2sand hD₃vs the hD_4.4receptor, R-(-)-41c demon-

strated virtually no selectivity for D₂-like receptors. The

only noticeable difference between R-(-)-35c and S-(-

)-78 for D₂-like receptors was the 7-fold increase in

affinity for the hD_4.4receptor observed for S-(-)-78.

Interestingly, (-)-48c and (+)-48c were both found to

have high affinity and selectivity for the hD₃receptor

vs hD_2sand D_4.4receptors.

In tr in sic Activity a n d in Vivo Stu d ies. An initial

assessment of intrinsic activity was estimated based on

the ability of the compounds of this study to bind to the

High

Low

D₂

and D₂

affinity states of the D₂receptor. A

comparison of the results obtained with the six stan-

dards using the current methodology⁴⁰agrees well with

that reported by Lahti et al.³⁷According to this method,

a reliable prediction of intrinsic activity between the

range of 100% and 10% can be made based on a

as high as 104 (40c). Though the thiophene analogue

High

(36c) had similar affinity for the for the D₂

receptor

as 35c, their ratios were quite different 35c [i.e. (K_i^L/

K_i^H) ) 42 vs (K_i^L/K_i^H) ) 5], which suggests 36c to have

4244 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

F igu r e 3. Dose-response curves for inhibition of spontaneous

locomotor activity for RS-48c, (+)-48c, and (-)-48c.

F igu r e 1. Dose-response curves for inhibition of spontaneous

locomotor activity for RS-35c, R-35c, and S-35c.

Evidence for postsynaptic receptor stimulation was

seen in the locomotor studies as the dose-response

curves for RS-(()-35c, R-(-)-35c, and S-(-)-78 are

U-shaped with low doses, presumably stimulating pr-

esynaptic receptors, thereby reducing locomotor activity,

and at higher doses, presumably stimulating postsyn-

aptic receptors, having less of an effect. Since these

three agents are also known to possess D₃affinity (Table

9), and since the D₃agonist PD 128907 has been

reported to produce hypolocomotor activity at low doses

and hyperlocomotor activity at high doses,^42,43a poten-

tial role for D₃receptors in this response cannot be

excluded. The decreased locomotor activity at the

highest doses is not clearly understood but could be due

to factors such as excessive autoreceptor agonism,

postsynaptic dopamine receptor antagonism and/or

potential sedative properties of these agents. RS-(()-

41c, R-(-)-41c, (()-48c, and (-)-48c did not produce

U-shaped dose-response curves, suggesting that these

compounds do not have sufficient intrinsic activity to

stimulate postsynaptic dopamine D₂receptors. These

data confirm the low estimated intrinsic activity ratios

(K_i^L/K_i^H) of RS-(()-41c, R-(-)-41c, (()-48c, and (-)-48c

from in vitro studies compared with the higher ratios

of RS-(()-35c, R-(-)-35c, and S-(-)-78 (Table 8). More-

over, R-(-)-35c (Figure 1) and S-(-)-78 (Figure 2) had

similar LMA profiles as was estimated by their intrinsic

activity ratios. As no compound produced sufficient

postsynaptic agonism to result in hyperactivity, these

compounds are presumably partial agonists at dopam-

ine D₂receptors. RS-(()-35c and R-(-)-35c functioned

as partial agonists at postsynaptic dopamine D₂recep-

tors in vivo showing both postsynaptic agonist and

antagonist effects. RS-(()-35c and R-(-)-35c reversed

apomorphine-induced stereotypy and climbing behavior.

RS-(()-35c produced significant antagonism of apomor-

phine-induced stereotypy at 3 and 10 mg/kg sc and the

ED₅₀vs apomorphine-induced climbing was 1.8 mg/kg

sc. R-(-)-35c antagonized apomorphine-induced stereo-

typy with an ED₅₀of 1.5 mg/kg sc and apomorphine-

induced climbing with an ED₅₀of 0.4 mg/kg sc. RS-(()-

35c and R-(-)-35c also stimulated postsynaptic dopamine

D₂receptors. RS-(()-35c produced apomorphine-like

stereotypy (0.3-10 mg/kg sc) in reserpinized mice

F igu r e 2. Dose-response curves for inhibition of spontaneous

locomotor activity for RS-41c, R-41c, S-41c, and S-78.

a lower intrinsic activity. As indicated in Table 7,

substituent effects on the benzyl side chain only played

a minor role in varying the ratio (i.e. 44c-46c vs 35c).

Replacement of the hydroxy group of 35c with a meth-

anesulfonamide (i.e. 35f) achieved a very low intrinsic

activity [i.e. (K_i^L/K_i^H) ) 5], verifying a similar trend

observed in Table 3 (i.e. 49c and 22c vs 49f and 22f).

Interestingly, when a chlorine was attached to the 6

position [i.e. RS-(()-41c], a significant decrease in the

predicted intrinsic activity ratio was observed when

compared to 35c [i.e. (K_i^L/K_i^H) ) 42 vs (K_i^L/K_i^H) ) 7].

As depicted in Table 8, the ratios of the enantiomers of

RS-(()-35c predicted that the eutomer [R-(-)-35c] to

have slightly greater intrinsic activity than the distomer

[S-(+)-35c] [i.e. (K_i^L/K_i^H) ) 16 vs (K_i^L/K_i^H) ) 9].

Further in vivo neurochemical and behavioral evalu-

ations were performed on RS-(()-35c, R-(-)-35c, S-(+)-

35c, RS-(()-41c, R-(-)-41c, S-(+)-41c (()-48c, (-)-48c,

(+)-48c, and S-(-)-78. R-(-)-35c inhibited dopamine

synthesis (Table 9), indicating in vivo presynaptic

dopamine D₂agonism. All compounds, except S-(+)-

41c and (+)-48c, produced significant reductions in

locomotor activity (LMA) (Figures 1-3; Table 9). These

actions are most readily explained by either a presyn-

aptic agonist or postsynaptic antagonist effect of each

active compound on dopamine D₂receptors in vivo.⁴¹

With respect to their racemates, potencies for the

hypolocomotor effects of R-(-)-35c, R-(-)-41c, and (-)-

48c were shifted to the left or remained the same. No

significant effects were observed over the same dose

range for S-(+)-35c, S-(+)-41c, and (+)-48c. These

results confirm that R-(-)-35c, R-(-)-41c, and (-)-48c

are recognized as the eutomers in vivo.

whereas R-(-)-35c produced both stereotypy (ED₅₀

)

0.3 mg/kg sc) and climbing (ED₅₀) 5.7 mg/kg sc) in

reserpinized mice. RS-(()-35c produced no significant

effects in mice treated with a D₁agonist, whereas

R-(-)-35c induced significant stereotypy only (0.3-10

mg/kg sc). These results suggest that RS-(()-35c and

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4245

Ch a r t 3. Molecules Discussed in Molecular Modeling

Studies

conformations which adhered to the D₂pharmacophore

as represented by the McDermed model,⁴⁴an initial

simplified conformational analysis was performed on the

methyl analogue of R-35c (i.e. R-79, Chart 3). A random

search was performed using Sybyl on the unprotonated

amine R-79, which led to the identification of thirty

conformations of which 20 conformers were within 4

kcal of the global minimum. Eight of these conforma-

tions had a basic nitrogen to oxygen distance ranging

between 6.4 and 7.8 Å, a criteria abided by potent D₂

agonists. However, only one of the eight conformers

adhered to the nitrogen lone pair directionality require-

ments represented by the McDermed model. This

conformation, depicted in Figure 4, was also observed

to be the global minimum and was discerned as the most

plausible D₂receptor-bound conformation. A Grid

Search in Sybyl about the aminomethyl side chain of

R-79 again identified this exact conformation. The

aminomethyl side chain is in a pseudoequatorial posi-

tion with the nitrogen atom located syn to the oxygen

of the pyran ring. The N-O distance of 7.3 Å and the

lone pair electrons of the nitrogen are nearly orthogonal

to the plane of the phenyl ring, as stipulated by the

McDermed D₂model. Using the known D₂agonist

(4aR,10bR)-81 as a template, with its N-propyl group

oriented as previously rationalized and directed toward

the large N-alkyl binding site in the D₂receptor,^50ban

overlay of R-79 is shown in Figure 4. A root-mean-

square value of 0.3 was observed when the hydroxyl

groups, basic nitrogens, and centroids were used as

fitting points, and as revealed in Figure 4 the crucial

pharmacophoric groups (7-OH and nitrogen) could be

fitted over each other in extremely close proximity, with

the lone pair electrons directed at a similar region of

space. A random search performed on the correspond-

ing benzodioxan S-80 identified an analogous low-

energy conformer to that found for the global minimum

of R-79, which again fulfilled the McDermed model

criteria very closely (Figure 5).

R-(-)-35c stimulate presynaptic dopamine D₂receptors

at low doses and stimulate supersensitive postsynaptic

dopamine D₂receptors at high doses.

Molecu la r Mod elin g Stu d ies

The immense amount of interest in the D₂receptor

has led to a prolific amount of SAR directed at discern-

ing the D₂receptor pharmacophore and topography. The

D₂dopamine agonists which have been most helpful at

formulating the D₂receptor topography have been the

dopamine-like and ergot-like structures.^44-50To discern

whether the 7-OH-AMCs had access to low energy

F igu r e 4. (4aR,10bR)-81 (green) and R-79 (blue) in their D₂agonist “Pharm” conformations and superimposed.

4246 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

F igu r e 5. Superimposition of S-80 (green) and R-79 (blue) in their D₂agonist “Pharm” conformations and superimposed.

F igu r e 6. Superimposition of R-48c (green) and R-35c (blue) in their low-energy D₂agonist “Pharm” conformations and

superimposed.

A systematic search was performed on the benzyl side

chain of R-(-)-35c and revealed no apparent conforma-

tional preference in terms of energy. Although confor-

mational ambiguities appear to exist for the benzyl side

be the eutomers in the AMC class. In light of this

observation, modeling studies performed on (-)-48c,

assumed, by analogy, the (-)-eutomer to be of the

putative “R” configuration. Shown in Figure 6 is a low-

energy pharmacophore conformer (“pharm”) of R-(-)-

35c, identified from a random search, overlayed onto a

minimized “pharm” conformer of “R”-(-)-48c. This

superimposition suggests that the benzylamine of

R-(-)-35c and the dihydroisoquinoline group of

“R”-(-)-48c may access similar spacial requirements in

their receptor-bound conformations. Also worthmen-

tioning, are the orientation of the side chains of R-79,

High

chain, comparison of the high affinities for the D₂

receptor of R-(-)-35c with that of (-)-48c (i.e. K_i) 0.2

nM vs 0.6 nM) strongly suggests that the phenyl ring

of the benzyl and dihydroisoquinoline groups, as well

as the chroman rings, can access similar spacial regions

in the D₂receptor cavity. Although the stereochemistry

of (-)-48c was not unambiguously established, the

R/levorotary enantiomers were consistently observed to

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4247

S-80, and “R”-48c, of which all are pointed toward the

large N-alkyl binding site and not interfering with the

sterically encumbered “propyl cleft” known to exist in

the D₂receptor.^50a

affinities for the 5-HT_1Areceptor. Also, Kuipers et al.⁵⁴

recently reported a series of N⁴-substituted N¹-arylpip-

erazines which prefer apolar aromatic rings tethered to

the N¹-arylpiperazine nucleus in order to bind with high

affinity to both D₂and 5-HT_1Areceptors. Taken to-

gether, these observations strongly suggest that N⁴-

substituted N¹-arylpiperazines, as well as their respec-

tive side chains, may be capable of aligning and

interacting in a similar fashion to AMCs and AMBs

within both the D₂and 5HT_1Areceptor cavities.

To rationalize the 24-fold loss in affinity when the

pyranyl oxygen was replaced by a methylene (i.e. 49c

vs 70), the oxygen atom of the proposed receptor bound

conformer of R-79 was replaced by a methylene and

subsequently minimized. Consequently two major dif-

ferences between the chroman ring system and the

tetralin ring system were revealed: (1) the critical

nitrogen to oxygen distance increased from 7.3 to 7.8 Å

and (2) this particular conformer was approximately 1

kcal/mol higher in energy than the global minimum. The

Con clu sion

We have identified a series of 7-OH-AMCs which have

High

high affinity for the D₂

receptor. Both the AMC and

combination of these two differences may be playing a

High

AMB moieties represent entirely novel scaffolds which

have access to the D₂agonist pharmacophore as repre-

sented by the McDermed D₂model. Side chains at-

tached to the 7-OH-2-AMC moiety had a secondary

binding interaction which could influence affinity and

selectivity at other receptors (5HT_1A, R₁, and D₂^Low). As

revealed in this study, the bis(arylalkyl)amines were

significant role in D₂

receptor affinity. Interestingly,

Seeman reports the highest potencies for D₂agonists

were those compounds wherein the distance between

the hydroxyl group and nitrogen atom was 7.3 Å or

less.⁴⁵

One of the major differences with the receptor-bound

conformation of R-79 and the postulated D₂pharma-

cophore based on the McDermed model was the obser-

vation that the nitrogen was 0.92 Å below the plane of

the phenyl ring. In general, all known rigid D₂agonists

were observed to have their nitrogen atoms nearly

coplanar with the phenyl ring (approximately 0.2-0.6

Å from the plane of the aromatic ring).⁴⁵Though the

side chain of R-79 containing the basic nitrogen is

flexible, any conformations involving the nitrogen ad-

justing to a position closer to the plane of the phenyl

ring also required a large amount of energy. Since it is

known that the D₂receptor can tolerate a range of N-O

distances (preferably 7.3 Å or less), it is not unreason-

able to assume that it may also tolerate a range of

distances from the plane of the aromatic ring as well.

Our results suggests that the previously proposed

positional criteria of the phenyl ring with respect to the

basic nitrogen may simply be a consequence of having

the D₂pharmacophoric elements deduced based on rigid

dopamine-like structure which utilized the phenethy-

lamine scaffold. As such, certain topographical criteria

of the currently known D₂models may need to be

expanded to incorporate structures which no longer

embrace the phenethylamine backbone. Apparently,

structures exploiting the 7-OH-AMC and 7-OH-AMB

moieties exemplify that this particular characteristic

does not need to be adhered to for the pharmacophoric

groups to be recognized by the D₂receptor.

among some of the largest dopamine agonists reported

High

to date to bind to the D₂

receptor as depicted in the

McDermed D₂pharmacophore model. However, they

were also found to be, in general, the least selective

derivatives of this class of D₂ligands. The most

selective derivatives contained side chains with a one

atom tether between the 7-OH-AMC moiety and another

ring system. The most potent and selective member of

High

this series for the D₂

receptor was observed to be

the benzyl derivative RS-(()-35c. The R isomer [i.e.

R-(-)-35c] was identified as the eutomer, having a 60-

fold higher affinity than its distomer. Modeling studies

identified low-energy conformations of the 7-OH-AMC

and 7-OH-AMB moieties which closely adhered to the

McDermed D₂model. The combination of modeling

studies and SAR studies strongly suggested a low

energy conformation of R-(-)-35c which was at least

High

topographically complementary to the D₂

receptor.

A conformationally restricted analogue of R-(-)-35c [i.e.

(-)-48c] suggested that in both structures the aryl rings

may exist in a similar spacial environment in their

receptor-bound conformations. In vivo studies of RS-

(()-35c and R-(-)-35c are indicative of a highly potent

agonist in the LMA and DOPA accumulation assay.

Lower intrinsic activity could be achieved by replacing

the benzyl side chain with other types of side chains

with the caveat of attaining less selectivity. However,

lower intrinsic activity could also be achieved with little

loss in selectivity by either maintaining the benzyl side

chain and attaching a chlorine atom at the 6 position

of the AMC ring (i.e. 41c) or by conformationally

restricting the benzyl group as in 48c.

The 7-OH-2-AMC and 7-OH-2-AMB moieties repre-

sent prototypic reference templates for the future design

of a new generation of dopaminergic agents currently

being investigated in our laboratories. These two novel

templates no longer use the phenethyl scaffold (based

on dopamine) but instead exploit the 2-methylchroman

and 2-methylbenzodioxan moieties as scaffolds which

can be used to access the D₂agonist pharmacophore.

Interestingly, our proposed D₂receptor-bound con-

formation of the 7-OH-AMC and 7-OH-AMB moieties

are related to Hibert’s putative 5HT_1Apharmacophore

model,⁵¹with respect to the phenyl rings and basic

nitrogens. The 7-OH-AMC and 7-OH-AMB moieties

High

access the D₂

and 5-HT_1Apharmacophoric elements

simultaneously through the global minimum of the

AMC and AMB moieties. In fact, recently 2-(aminom-

ethyl)chroman derivatives have been reported in the

patent literature to have 5-HT_1Aand D₂activity.⁵²

Worth mentioning is the observation that the AMCs in

this study appear to have remarkably parallel SAR for

the 5HT_1Areceptor as another series of heterobicylic

phenylpiperazines published by van Steen et al.⁵³In

both series the simple alkyl side chain affinities were

observed to be maximum for the n-hexyl derivatives,

with the benzyl side chain derivatives having the lowest

Exp er im en ta l Section

Ch em istr y. Melting points were determined on a Thomas-

Hoover melting point apparatus and are uncorrected. ¹H NMR

spectra were recorded on a Varian Unity Plus 400, Varian

4248 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

VXR-300, or Varian XL-200 instrument. Chemical shifts are

reported in δ values (parts per million, ppm) relative to an

internal standard of tetramethylsilane in CDCl₃or DMSO-

d₆. Infrared (IR) spectra were recorded on a Mattson Galaxy

Series FT-IR 3000 spectrophotometer and are reported in

reciprocal centimeters (cm^-1). Microanalyses were obtained

on a Perkin-Elmer 2400 elemental analyzer. The mass spectra

were determined on a LKB-9000S, Kratos MS 50, or Finnigan

8230 mass spectrometer. Optical rotation were performed on

a Perkin-Elmer 241MC polarimeter. Analytical thin-layer

chromatography (TLC) was carried out on precoated plates

(silica gel, 60 F-254), and spots were visualized with UV light

and stained either with an alcohol solution of phosphomolybdic

acid or in an iodine chamber. Where analyses in the tables

are indicated by symbols of the elements, analytical results

obtained for those elements were (0.4% of the theoretical

values. Solvents and reagents were used as purchased.

7-Meth oxych r om an -2-car boxylic Acid Eth yl Ester (16a).

A solution of 15a ²⁸in AcOH (200 mL) was hydrogenated over

10% palladium on carbon at room temperature at 50 psi for 5

days. The reaction mixture was filtered through Celite, and

the solvent was removed under vacuum. The product was

crystallized and washed with 1:1 EtOAc-hexane to afford 20

g (72% yield) of product: mp 63-64 °C; MS (EI) m/e 236 (M⁺).

Anal. (C₁₃H₁₆O₄) C, H.

m), 3.66 (3H, s), 4.16 (1H, m), 4.26 (1H, m), 6.18 (1H, d, J )

2.42 Hz), 6.38 (1H, dd, J ) 8.35, 2.64 Hz), 6.90 (1H, d, J )

8.35 Hz), 7.48 (2H, d, J ) 8.57 Hz), 7.82 (2H, d, J ) 8.35 Hz).

Anal. (C₁₈H₂₀O₅S).

Tolu en e-4-su lfon ic Acid, (6-Ch lor o-7-m eth oxych r om an -

2-yl)m eth yl Ester (21a ). A solution of 20a (1.32 g, 3.79

mmol) and N-chlorosuccinimide (607 mg, 4.54 mmol) in

anhydrous THF (12 mL) was allowed to stir at room temper-

ature for 40 h and then poured into ether (200 mL). The

organic layer was washed with water (100 mL), dried over

MgSO₄, and filtered, and the solvent was removed under

vacuum. Purification by chromatography (10% EtOAc-hex-

anes) afforded 1.37 g (94%) of a white solid. Recrystallization

from EtOAc provided an analytical sample: mp 114-115 °C;

¹H NMR (CDCl₃) δ 1.76 (m, 1H), 1.93-1.99 (1H, m), 2.45 (3H,

s), 2.64-2.73 (2H, m), 3.81 (3H, s), 4.15-4.21 (3H, m), 6.31

(1H, s), 6.99 (1H, s), 7.35 (2H, d, J ) 8.06 Hz), 7.82 (2H, d, J

) 8.35 Hz); MS (EI) m/e 382/384 (M⁺). Anal. (C₁₈H₁₉ClO₅S)

C, H.

Meth od A. 3-[[(7-Meth oxych r om a n -2-yl)m eth yl]a m i-

n o]p r op a n -1-ol (22a ). A mixture of 18a (12.8 g, 49 mmol)

and 1-amino-3-propanol (10 equiv) was heated to 100 °C for 2

h. The reaction mixture was poured into water (750 mL) and

extracted with CH₂Cl₂(3 × 500 mL). The organic layer was

dried over MgSO₄and filtered and the solvent evaporated to

afford 11.3 g (92%) of desired product: ¹H NMR (CDCl₃) δ

1.80-1.96 (3H, m), 2.69-2.79 (2H, m), 2.89-3.00 (2H, m), 3.05

(2H, t, J ) 5.60 Hz), 3.76 (3H, s), 4.22 (1H, m), 6.40 (1H, d, J

) 2.42 Hz), 6.45 (1H, d, J ) 8.24, 2.42 Hz), 6.92 (1H, d, J )

8.34 Hz): MS (EI) m/e 251 (M⁺). The oxalate salt was

(7-Meth oxych r om a n -2-yl)m eth a n ol (17a ). To a solution

of 16a (20.0 g, 84.7 mmol) in THF (215 mL) was added a 2.0

M solution of LiBH₄(100 mL, 0.20 mol) over 0.5 h. After 2 h

the reaction was complete and the excess LiBH₄was destroyed

by the cautious addition of MeOH. The reaction mixture was

then diluted with EtOAc and washed with water. The organic

layer was separated and dried over MgSO₄and the solvent

removed under vacuum to afford 16 g (97% yield) of a clear

prepared from MeOH, mp 180-190 °C. Anal. (C₁₄H₂₁

NO₃‚C₂H₂O₄) C, H, N.

-

Using the above procedure, compounds 23a , 24a , 25a , 28a ,

29a , 32a , 33a , 34a , and 35a were prepared in yields ranging

from 90 to 99%, by replacing 1-amino-3-propanol with the

appropriate amine. 22d was prepared by replacing 18a with

2-(bromomethyl)chroman.⁵⁶

oil: IR (CDCl₃) 3600, 3450, 2920, 1620, 1585, and 1510 cm^-1

;

MS (EI) m/e 194 (M⁺); ¹H NMR (CDCl₃) δ 1.75-1.94 (2H, m),

2.08 (1H, bs), 2.67-2.84 (2H, m), 3.74-3.86 (2H, m), 3.76 (3H,

s), 4.09 (1H, m), 6.40 (1H, d, J ) 2.6 Hz), 6.46 (1H, dd, J )8.35,

2.64 Hz), 6.94 (1H, d, J ) 8.35 Hz).

N-[(7-Met h oxych r om a n -2-yl)m et h yl]-N-p r op yla m in e

(23a ): yield 98%; MS (EI) m/e 235 (M⁺).

(7-(Ben zyloxy)ch r om a n -2-yl)m eth a n ol (17b). This com-

pound was prepared from 16b ²⁸by the procedure described to

prepare 17a in 98% yield as a clear oil: MS (EI) m/e 270 (M⁺);

¹H NMR (DMSO-d₆) δ 1.57-1.67 (1H, m), 1.92-1.98 (1H, m),

2.48-2.73 (2H, m), 3.51-3.61 (2H, m), 4.74 (1H, t, J ) 5.71

Hz), 5.02 (2H, s), 6.36 (1H, d, J ) 2.64 Hz), 6.46 (1H, dd, J )

8.35, 2.64 Hz), 6.92 (1H, d, J ) 8.35 Hz), 7.28-7.41 (5H, m).

2-(Br om om eth yl)-7-m eth oxych r om a n (18a ). To a solu-

tion of 17a (3.14 g, 16.2 mmol) and CBr₄(9.13 g, 28 mmol) in

of CH₂Cl₂(50 mL) was slowly added a solution of triph-

enylphosphine (7.21 g, 27.5 mmol) in CH₂Cl₂(50 mL) at 0 °C.

The reaction was allowed to warm to room temperature,

stirred for 12 h, then poured into water (150 mL), extracted

with CH₂Cl₂(300 mL), dried over MgSO₄, and filtered and the

solvent evaporated. Purification by chromatography (15%

EtOAc-hexanes) afforded 3.2 g (75% yield) of a clear oil: IR

(film) 2920, 1620, 1580, 1505, 1440, and 1160 cm^-1; MS (EI)

m/e 256/258 (M⁺); ¹H NMR (CDCl₃) δ 1.84-1.93 (1H, m), 2.11-

2.18 (1H, m), 2.72-2.80 (2H, m), 3.52 (1H, dd, J ) 10.54, 5.93

Hz), 3.59 (1H, dd, J ) 10.54, 5.49 Hz), 3.75 (3H, s), 4.18-4.24

(1H, m), 6.40 (1H, d, J ) 2.42 Hz), 6.45 (1H, dd, J ) 8.35, 2.64

Hz), 6.94 (1H, d, J ) 8.35 Hz).

N-Bu tyl-N-[(7-m eth oxych r om a n -2-yl)m eth yl]a m in e ox-

a la te (24a ): yield 99%; mp 210-212 °C; MS (EI) m/e 249 (M⁺).

Anal. (C₁₅H₂₃NO₂‚C₂H₂O₄) C, H, N.

N-[(7-Met h oxych r om a n -2-yl)m et h yl]-N-p en t yla m in e

(25a ): yield 90%; MS (EI) m/e 263 (M⁺).

N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-(2-m eth ylp r o-

p yl)a m in e (28a ): yield 91%; MS (EI) m/e 235 (M⁺).

N -[(7-Me t h ox yc h r om a n -2-y l)m e t h yl]-N -(3-m e t h y l-

bu tyl)a m in e oxa la te (29a ): yield 97%; mp 221-222 °C; MS

(EI) m/e 263 (M⁺). Anal. (C₁₆H₂₅NO₂‚C₂H₂O₄‚0.25H₂O) C, H,

N.

N -[(7-Me t h o x y c h r o m a n -2-y l)m e t h y l]-N -(4-p h e n y l-

bu tyl)a m in e oxa la te (32a ): yield 90%; mp 217-218 °C.

Anal. (C₂₁H₂₇NO₂‚C₂H₂O₄) C, H, N.

N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-(3-p h en ylp r o-

p yl)a m in e oxa la te (33a ): yield 99%; mp 219-220 °C; MS

(EI) m/e 311 (M⁺). Anal. (C₂₀H₂₅NO₂‚C₂H₂O₄‚0.25H₂O) C, H,

N.

N -[(7-Me t h oxych r om a n -2-yl)m e t h yl]-N -p h e n e t h yl-

a m in e oxa la te (34a ): yield 93%; mp 223-224 °C; MS (EI)

m/e 297 (M⁺). Anal. (C₁₉H₂₃NO₂‚C₂H₂O₄) C, H, N.

N-Ben zyl-N-[(7-m eth oxych r om a n -2-yl)m eth yl]a m in e -

oxa la te (35a ): yield 95%; mp 223-224 °C; MS (EI) m/e 283

(M⁺). Anal. (C₁₈H₂₁NO₂‚C₂H₂O₄‚0.25H₂O) C, H, N.

3-[(Ch r om an -2-ylm eth yl)am in o]pr opan -1-ol (22d): yield

37%; mp 173-174 °C. Anal. (C₁₃H₁₉NO₂‚HCl‚0.25H₂O) C, H,

N.

7-(Ben zyloxy)-2-(br om om eth yl)ch r om a n (18b). This

compound was prepared similarly to 18a starting with 17b in

60% yield as a white solid, mp 76-78 °C. Anal. (C₁₇H₁₇BrO₂)

C, H.

Tolu en e-4-su lfon ic Acid , (7-Met h oxych r om a n -2-yl)-

m eth yl Ester (20a ). To a solution of 17a (23.0 g, 0.12 mol)

in anhydrous pyridine (500 mL) was added p-toluenesulfonyl

chloride (33.9 g, 0.78 mol). The reaction mixture was allowed

to stir for 2 days under nitrogen at room temperature, and

then the solution was concentrated under vacuum. The crude

product was diluted with CH₂Cl₂(1 L) and washed with 1 M

H₂SO₄(2 × 500 mL). The organic layer was washed with

saturated aqueous NaHCO₃(1 L) and brine (500 mL). The

organic layer dried over MgSO₄, filtered, and concentrated

under vacuum to afford 34 g (92% yield) of a white solid: mp

67-69 °C; MS (EI) m/e 348 (M⁺); ¹H NMR (DMSO-d₆) δ 1.51-

1.65 (1H, m), 1.84-1.90 (1H, m), 2.41 (3H, s), 2.53-2.70 (2H,

3-[[[7-(Ben zyloxy)ch r om an -2-yl]m eth yl]am in o]pr opan -

1-ol (22b). This compound was prepared from 18b and

1-amino-3-propanol according to method A in 98% yield as a

pale yellow solid, mp 54-55 °C; MS (EI) m/e 327 (M⁺). Anal.

(C₂₀H₂₅NO₃) C, H, N.

Using method A and replacing 3-amino-1-propanol with the

appropriate amines afforded compounds 26b, 27b, 30b, 31b,

37b, 38b, and 39b.

N -[[7-(B e n zy lo x y )c h r o m a n -2-y l]m e t h y l]-N -h e x y l-

1

a m in e (26b): yield 100%; H NMR (DMSO-d₆) δ 0.86 (3H, t,

J ) 3.4 Hz), 1.16-1.30 (6H, m), 1.42 (2H, m), 1.61 (1H, m),

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4249

1.98 (1H, m), 2.58-2.84 (6H, m), 3.34 (1H, bs, NH), 4.04 (1H,

m), 5.75 (2H, s), 6.37 (1H, d, J ) 2.64 Hz), 6.47 (1H, dd, J )

8.46, 2.42 Hz), 6.93 (1H, d, J ) 8.35 Hz), 7.28-7.41 (5H, m);

MS (EI) m/e 353 (M⁺).

triphenylphosphine (3.67 g, 14 mmol) in anhydrous THF (50

mL) was slowly added a solution of DEAD (2.44 g, 14 mmol)

in THF (10 mL). The reaction was allowed to stir for 3 h and

then quenched with water, extracted with CH₂Cl₂(150 mL),

dried over MgSO₄, and filtered and the solvent removed under

vacuum. Chromatography (2.5% MeOH-CH₂Cl₂) afforded

2.72 g of product (55% yield): MS (EI) m/e 378 (M⁺). The

maleate salt was prepared from THF, mp 132-134 °C. Anal.

(C₂₃H₂₆N₂O₃‚2.0C₄H₄O₄‚1.0H₂O) C, H, N. The more polar

azetidine byproduct (61a ) was isolated and converted to its

N-[[7-(Ben zyloxy)ch r om a n -2-yl]m et h yl]-N-isop r op yl-

a m in e (27b): yield 77%; MS (EI) m/e 311 (M⁺).

N-[[7-(Ben zyloxy)ch r om a n -2-yl]m eth yl]-N-(2-p en tyl)-

a m in e (30b): yield 60%; MS (EI) m/e 339 (M⁺).

N -[[7-(B e n zy lo x y )c h r o m a n -2-y l]m e t h y l]-N -c y c lo -

h exyla m in e (31b): yield 87%; MS (EI) 351 m/e (M⁺).

N-[[7-(Ben zyloxy)ch r om a n -2-yl]m eth yl]-N-(fu r a n -2-yl-

oxalate salt in THF: mp 176-177 °C. Anal. (C₁₄H₁₉

-

1

NO₂‚C₂H₂O₄) C, H, N.

m eth yl)a m in e (37b): yield 97%; H NMR (CDCl₃) δ 1.74-

Using method C and replacing 7-hydroxyquinoline with

3-nitrophenol, 4-chloro-3-nitrophenol, 2-methyl-3-nitrophenol,

phenol, 4-methyl-3-nitrophenol, and 4-hydroxyindole afforded

the corresponding bis(arylalkyl)amine derivatives.

1.98 (4H, m), 2.69-2.94 (2H, m), 3.86 (2H, s), 4.13 (1H, m),

5.01 (2H, s), 6.21 (1H, d, J ) 3.2 Hz), 6.33 (1H, dd, J ) 3.2,

1.9 Hz), 6.47-6.53 (2H, m), 6.93 (1H, d, J ) 8.35 Hz), 7.31-

7.44 (6H, m); MS (EI) m/e 349 (M⁺).

N -[(7-Me t h oxych r om a n -2-yl)m e t h yl]-N -[3-(3-n it r o-

p h en oxy)p r op yl]a m in e oxa la te (49a -n itr o): yield 52%; MS

(EI) m/e 372 (M⁺).

N-[3-(4-Ch lor o-3-n itr op h en oxy)p r op yl]-N-[(7-m eth oxy-

ch r om a n -2-yl)m eth yl]a m in e oxa la te (52a -n itr o): yield

18%; mp 215-216 °C; MS (EI) m/e 406/408 (M⁺). Anal.

(C₂₀H₂₃ClN₂O₅‚C₂H₂O₄) C, H, N.

N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-[3-(2-m eth yl-3-

n itr op h en oxy)p r op yl]a m in e oxa la te (53a -n itr o): yield

40%; mp 221-223 °C; MS (EI) m/e 386 (M⁺). Anal.

(C₂₁H₂₆N₂O₅‚C₂H₂O₄‚0.25H₂O) C, H, N.

N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-(3-p h en oxyp r o-

p yl)a m in e oxa la te (54a ): yield 63%; mp 204-205 °C; MS

(EI) m/e 327 (M⁺). Anal. (C₂₀H₂₅NO₃‚C₄H₄O₄) C, H, N.

N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-[3-(4-m eth yl-3-

n itr op h en oxy)p r op yl]a m in e oxa la te (55a -n itr o): yield

49%; MS (EI) m/e 386 (M⁺).

N-[3-(1H-In dol-4-yloxy)pr opyl]-N-[(7-m eth oxych r om an -

2-yl)m eth yl]a m in e oxa la te (56a ): yield 67%; mp 206-207.5

°C. Anal. (C₂₂H₂₆N₂O₃‚C₄H₄O₄‚0.33H₂O) C, H, N.

N-[3-(Ben zoxa zol-6-yloxy)p r op yl]-N-[[(7-(b en zyloxy)-

ch r om a n -2-yl]m eth yl]a m in e (57b). This compound was

prepared from 22b and 6-hydroxybenzoxazole using method

C in 95% yield and converted to the hydrogen oxalate salt,

mp 127-128 °C. Anal. (C₂₇H₂₈N₂O₄‚1.5C₂H₂O₄‚0.75H₂O) C,

H, N.

In an analogous fashion replacing 6-hydroxybenzoxazole

with 5-hydroxybenzoxazole, 3-methyl-6-hydroxybenzisoxazole

and isocytosine afforded compounds 58b (78%), 59b (77%), and

60b (51%), respectively.

Meth od D. Gen er a l P r oced u r e for Dem eth yla tion .

2-[[[3-Qu in olin -7-yloxy)p r op yl]a m in o]m eth yl]ch r om a n -

7-ol (50c). A solution of 50a (2.19 g, 5.7 mmol) in 48% aqueous

HBr (30 mL) was heated to reflux for 3 h. The reaction

mixture was then allowed to cool to room temperature and

basified with 1 N NaOH until pH 12. The basic reaction

mixture was extracted with EtOAc (2 × 100 mL), dried over

MgSO₄, and filtered and the solvent removed under vacuum.

Chromatography (7% MeOH-CH₂Cl₂containing 1% NH₄OH)

afforded 1.34 g (63%) of product. The corresponding hydrogen

oxalate salt was prepared in ethanol, mp 195.5-196.5 °C. Anal.

(C₂₂H₂₄N₂O₃‚2C₂H₂O₄) C, H, N.

Using this general procedure, phenols 23c-25c, 28c, 29c,

32c, R-32c, 33c-36c, 40c-42c, 44c-46c, 48c-50c, 52c-55c,

70, and 78 were prepared. See Table 10 for physical data.

Met h od E .³⁰2-[[[3-(1,2,3,4-Tet r a h yd r oq u in olin -5-yl-

oxy)p r op yl]a m in o]m eth yl]ch r om a n -7-ol (51c). A mixture

of 50c (1.1 g, 3.0 mmol) and NiCl₂‚6H₂O (6 mmol) was

dissolved in MeOH (30 mL), and NaBH₄(0.14 mol) was added

in portions with stirring under cooling for 30 min and then

allowed to warm to room temperature for 0.5 h. After removal

of MeOH, the black precipitate was dissolved in 1 N HCl, and

the acidic solution was basified by the addition of concentrated

NH₄OH and extracted with ether. The organic layer was dried

over MgSO₄and filtered, and the solvent was removed under

vacuum. Chromatography (10% MeOH-CH₂Cl₂) afforded 350

mg (29%) of a brown oil: MS (EI) m/e 368 (M⁺). The oxalate

salt was prepared from MeOH, mp 136-139 °C. Anal.

(C₂₂H₂₈N₂O₃‚2.0 C₂H₂O₄‚0.5H₂O) C, H, N.

N-[[7-(Ben zyloxych r om a n -2-yl]m eth yl]-N-cycloh exyl-

m eth yla m in e (38b): yield 98%; ¹H NMR (CDCl₃) δ 1.51 (1H,

m), 1.64-1.99 (10H, m), 2.48-2.57 (2H, m), 4.14 (1H, m), 5.01

(2H, s), 6.47 (1H, s), 6.51 (1H, d, J ) 8.35, 2.64 Hz), 6.93 (1H,

d, J ) 8.35 Hz), 7.29-7.43 (5H, m). MS (FAB) m/e 366 (M +

H⁺).

N-[[7-(Ben zyloxy)ch r om a n -2-yl]m eth yl]-N-(n a p h th yl-

1-ylm eth yl)a m in e (39a ): yield 67%; MS (EI) m/e 409 (M⁺).

Meth od B. N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-(4-

p yr id in yl)a m in e (40a ). A solution of 20a (2.0 g, 6.4 mmol)

and 4-(aminomethyl)pyridine (1.29 g, 11.9 mmol) in anhydrous

DMSO (30 mL) was heated at 100 °C for 6 h and then poured

into water (200 mL) and extracted with CH₂Cl₂(2 × 150 mL).

The combined organic layers were dried over MgSO₄and

filtered and the solvent removed under vacuum. Purification

by flash chromatography (5% MeOH-CH₂Cl₂) afforded 1.2 g

(69% yield) of a thick oil: ¹H NMR (DMSO) δ 1.71-1.97 (2H,

m), 2.70-2.89 (4H, m), 3.75 (3H, s), 3.92 (2H, s), 4.19 (1H, m),

6.38 (1H, d, J ) 2.42 Hz), 6.44 (1H, dd, J ) 8.35, 2.63 Hz),

6.93 (1H, d, J ) 8.35 Hz), 7.34 (2H, d, J ) 5.47 Hz), 8.56 (2H,

d, J ) 0.88 Hz); MS (EI) m/e 284 (M⁺).

Replacing 4-(aminomethyl)pyridine with the appropriate

amines afforded compounds 36a , 42a , 44a , 45a , 46a , and 48a .

N-[(7-Meth oxych r om a n -2-yl)m eth yl]-N-(th iop h en d -2-

ylm eth yl)a m in e (36a ): yield 71%; MS (EI) m/e 289 (M⁺).

N -B e n zy l-N -[(7-m e t h o x y c h r o m a n -2-y l)m e t h y l]-N -

m eth yla m in e (42a ): yield 34%; MS (EI) m/e 297 (M⁺).

N-(4-Fluorobenzyl)-N-[(7-methoxychroman-2-yl)methyl]-

a m in e (44a ): yield 41%; MS (EI) m/e 301 (M⁺).

N-(4-Chlorobenzyl)-N-[(7-methoxychroman-2-yl)methyl]-

1

a m in e (45a ): yield 59%; H NMR (CDCl₃) δ 1.75-1.83 (1H,

m), 1.91-1.97 (1H, m), 2.61 (1H, s, NH), 2.65-2.91 (4H, m),

3.75 (3H, s), 3.85 (2H, s), 6.37 (1H, d, J ) 2.64 Hz), 6.44 (1H,

dd, J ) 8.35, 2.64 Hz), 6.92 (1H, d, J ) 8.35 Hz), 7.30 (4H, s);

MS (EI) m/e 317/319 (M⁺).

N -(4-Me t h oxyb e n zyl)-N -[(7-m e t h oxych r om a n -2-yl)-

m eth yl]a m in e (46a ): yield 88%; mp 68-70 °C; MS (EI) m/e

313 (M⁺). Anal. (C₁₉H₂₃NO₃) C, H, N.

(3,4-Dih yd r o-1H-isoqu in olin yl)[(7-m eth oxych r om a n -2-

yl)m eth yl]a m in e (48a ): yield 89%; MS (EI) m/e 385 (M⁺).

N -B e n z y l-N -[(6-c h lo r o -7-m e t h o x y c h r o m a n -2-y l)-

m eth yl]a m in e (41a ). A solution of 21a (1.97 g, 5.15 mmol)

in dry DMSO (12 mL) containing benzylamine (3 equiv) was

reacted according to method B to afford 1.48 g (90%) of a clear

oil: ¹H NMR (CDCl₃) δ 1.72-1.80 (3H, m), 1.92-1.98 (1H, m),

2.62-2.92 (4H, m), 3.82 (3H, s), 3.87 (2H, s), 4.14 (1H, m), 6.41

(1H, s), 7.01 (1H, s), 7.25-7.38 (5H, m); MS (EI) m/e 317 (M⁺);

HRMS calcd for C₁₈H₂₀NO₂Cl 317.118 26, observed 317.1101.

2-[(Ben zyla m in o)m eth yl]-6-ch lor och r om a n -7-ol (41c).

Treatment of 41a (1.41 g, 4.43 mmol) with HBr according to

method D afforded 1.20 g (89%) of yellow solid: mp 151-152

°C. Anal. (C₁₇H₁₈NO₂Cl) C, H, N. The fumarate salt was

prepared in 2-propanol: mp 216-217 °C; MS (EI) m/e 303/

305 (M⁺); ¹H NMR (DMSO-d₆) δ 1.60 (1H, m), 1.94-1.97 (1H,

m), 2.58-2.65 (2H, m), 2.84-2.86 (2H, m), 3.91 (2H, s), 4.11

(1H, m), 6.38 (1H, s), 6.55 (2H, d, J ) 2.42 Hz), 6.98 (1H, s),

7.26-7.41 (5H, m). Anal. (C₁₇H18NO₂Cl‚C₄H₄O₄) C, H, N.

Meth od C. Gen er a l P r oced u r e for Mitsu n obu Cou -

p lin g. N-[(7-Meth oxy-ch r om a n -2-yl)m eth yl]-N-[3-(qu in o-

lin -7-yloxy)p r op yl]a m in e (50a ). To a solution of 22a (3.07

g, 13 mmol), 7-hydroxyquinoline (1.88 g, 13 mmol), and

Meth od F . 2-[[[3-[(3-Meth ylben zo[d ]isoxa zol-6-yl)oxy]-

p r op yl]a m in o]m eth yl]ch r om a n -7-ol (59c). A solution of

4250 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Ta ble 10. Physical Data

Mewshaw et al.

compd

formula^a

mp, °C

recyr solvent

method

% yield^b

22a

22c

22d

22f

23c

24c

25c

26c

27c

28c

29c

30c

31c

32c

R-32c

33c

34c

35c

R-35c

S-35c

35d

35f

36c

37c

38c

39c

C₁₄H₂₁NO₃‚C₂H₂O₄

180-190

163-165

173-174

164-165

216-219

175-178

169-170

171-173

195-196

158-160

185-186

165-166

190-191

227-228

148-149

270-290 dec

194-195

176-177

212-213

231.5-232.5

247-248.5

203-205

169-170

160-161

113-114

210-211

216-217

214-215

211-212.5

179-180

231-232

165-166

179-180

188-189

247-248.5

177-178.5

198-199

195-196

214-216

163-170

136-137

183-185

195.5-196.5

136-139

219-220

153-154

196-198

165-166

186-187

199-201

193-195

162-175

233-235

193-196

176-177

211-212

209-219

MeOH

Et₂O/EtOH

IPA

THF

IPA

THF

IPA

THF

IPA

A

F

92

71

37

63

25

55

39

81

63

48

66

67

81

47

32

61

46

33

52

87

31

34

47

50

41

42

89

87

86

29

54

34

35

33

83

87

85

75

66

91

70

63

29

87

72

46

52

38

39

66

48

69

63

26

62

95

C

₁₃H₁₉NO₃‚C₂H₂O₄

₁₃H₁₉NO₂‚HCl^e

A

D

F

₁₄H₂₂N₂O₄S‚C₂H₂O₄

₁₃H₁₉NO₂‚0.5C₂H₂O₄

c

₁₄H₂₁NO₂‚C₂H₂O₄

₁₅H₂₃NO₂‚C₂H₂O₄

₁₆H₂₅NO₂‚C₂H₂O₄

₁₃H₁₉NO₂‚C₂H₂O₄

₁₄H₂₁NO₂‚C₂H₂O₄

F

D

F

e

₁₅H₂₃NO₂‚C₂H₂O₄

d

₁₅H₂₃NO₂‚0.5C₂H₂O₄

₁₆H₂₂NO₂‚C₂H₂O₄

F

₂₀H₂₅NO₂‚0.5C₂H₂O₄

₂₀H₂₅NO₂‚C₄H₄O₄

D

K

J

B

D

F

D

K

D

J

D

B

D

K

F

₁₉H₂₃NO₂‚0.5C₂H₂O₄

e

₁₈H₂₁NO₂‚C₂H₂O₄

c

₁₇H₁₉NO₂‚C₂H₂O₄

₁₇H₁₉NO‚C₂H₂O₄

₁₉H₂₄N₂O₃S‚C₂H₂O₄

h

₁₅H₁₅NO₄S‚C₂H₂O₄

g

₁₅H₁₇NO₃‚C₂H₂O₄

₁₇H₂₅NO₂‚C₂H₂O₄

₂₁H₂₁NO₂‚C₂H₂O₄

e

40c

41c

₁₆H₁₈N₂O₆‚C₂H₂O₄

₁₇H₁₈NO₂Cl‚C₄H₄O₄

₁₈H₂₁NO₂‚C₂H₂O₄

₁₇H₁₈NOF‚C₂H₂O₄

₁₇H₁₈NF‚C₂H₂O₄

R-41c

S-41c

42c

43d

44c

45c

46c

47f

48c

(-)-48c

(+)-48c

49a

49c

49d

49f

50c

51c

52a

52c

53c

54c

55c

56c

57c

58c

59c

60c

₁₇H₁₈NO₂Cl‚C₂H₂O₄

IPA

e

₁₈H₂₁NO₃‚C₂H₂O₄

₁₉H₂₄N₂O₃S‚C₂H₂O₄

₁₉H₂₁NO₂‚C₂H₂O₄

THF

EtOH

IPA

THF

EtOH

MeOH

THF

MeOH

THF

IPA

e

₁₉H₂₁NO₂‚C₂H₂O₄

e

₁₉H₂₁NO₂‚C₂H₂O₄

₂₀H₂₆N₂O₃‚2HCl

₁₉H₂₄N₂O₃‚2.0HCl

D

F

e

₁₉H₂₄N₂O₂‚C₄H₄O₄

c

₂₀H₂₇N₃O₄S‚2.0C₂H₂O₄

₂₂H₂₄N₂O₃‚2.0C₂H₂O₄

G

D

E

G

D

H

F

C

D

c

₂₂H₂₈N₂O₃‚2.0C₂H₂O₄

₁₉H₂₃N₂O₃Cl‚C₄H₄O₄

f

₂₀H₂₅N₂O₃Cl‚C₄H₄O₄

c

₂₀H₂₆N₂O₃‚C₂H₂O₄

c

₁₉H₂₃NO₃‚C₂H₂O₄

f

₂₀H₂₃N₂O₃‚2.0C₂H₂O₄

f

₂₁H₂₄N₂O₃‚C₂H₂O₄

c

₂₀H₂₂N₂O₄‚C₂H₂O₄

e

₂₀H₂₂N₂O₄‚C₂H₂O₄

IPA

₂₁H₂₄N₂O₄‚C₂H₂O₄

MeOH

THF

MeOH

IPA

c

₁₇H₂₂N₄O₃‚1.5C₂H₂O₄

61a

70

S-78

₁₄H₁₉NO₂‚C₂H₂O₄

₂₀H₂₆N₂O₂‚C₂H₂O₄

₁₆H₁₇NO₃‚C₂H₂O₄

a

C₂H₂O₄and C₄H₄O₄represent oxalic acid and fumaric acid, respectively. All new compounds analyzed correctly ((0.4%) for C, H, N.

See the Experimental Section. ^cHemihydrate. Hydrate. ^eQuarterhydrate. ^f0.33H₂O. 0.75H₂O. 0.3C₄H₈O.

b

d

g

h

59b (2.72 g, 5.9 mmol) in MeOH (120 mL) containing 10%

palladium on carbon (530 mg) was hydrogenated at 50 psi for

12 h. The mixture was filtered through Celite and washed

with MeOH, and the solvent was evaporated. Chromatogra-

phy (3% MeOH/CH₂Cl₂) afforded 1.5 g (69%) of a tan foam.

The oxalate was prepared from MeOH to afford 1.23 g of an

off-white solid: mp 233-235 °C. Anal. (C₂₁H₂₄N₂O₄‚C₂H₂O₄)

C, H, N.

Using this procedure phenols 22c, 26c, 27c, 30c, 31c, 37c-

39c, 49a , 49d , and 57c-60c were prepared. See Table 10 for

physical data.

Meth od G. 2-Ch lor o-5-[3-[(7-m eth oxych r om a n -2-yl)-

m eth yl]a m in o]p r op oxy]p h en yla m in e (52a ). To a mixture

of [3-(4-chloro-3-nitro-phenoxy)propyl](7-methoxychroman-2-

yl)methyl]amine (52a -nitro) (990 mg, 2.43 mmol) and hydra-

zine (156 mg, 4.87 mmol) in EtOH at 5 °C was added Raney

nickel (400 mg). After 0.5 h another portion of Raney nickel

(300 mg) was added, and the reaction was heated to reflux for

1 h. The catalyst was filtered and the solvent removed to

afford 800 mg (87%) of the title compound. The oxalate salt

was prepared in THF, mp 219-220 °C. Anal. (C₂₀H₂₅N₂O₃-

Cl‚C₂H₂O₄) C, H, N.

Compounds 49a , 53a , and 55a were prepared in a similar

fashion from their respective nitro derivatives.

5-[3-[[(7-Meth oxych r om an -2-yl)m eth yl]am in o]pr opoxy]-

p h en yla m in e oxa la te (49a ): yield 71%; mp 214-216 °C.

Anal. (C₂₀H₂₆N₂O₃‚2.0HCl) C, H, N.

5-[3-[[(7-Meth oxych r om an -2-yl)m eth yl]am in o]pr opoxy]-

2-m eth ylp h en yla m in e (53a ): yield 75%.

5-[3-[[(7-Meth oxych r om an -2-yl)m eth yl]am in o]pr opoxy]-

4-m eth ylp h en yla m in e oxa la te (55a ): yield 65%; mp 209-

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4251

213 °C; MS (EI) m/e 356 (M⁺). Anal. (C₂₁H₂₈N₂O₃‚

C₂H₂O₄‚0.25H₂O) C, H, N.

N-[2-(Hyd r oxym eth yl)ch r om a n -7-yl]m eth a n esu lfon a -

m id e (17f). To a solution of 16f (3.2 g, 10.7 mmol) in

anhydrous THF (30 mL) was added 2.0 M LiBH₄(10.1 mL).

The reaction mixture was allowed to stir at room temperature

for 18 h then quenched by the slow addition of MeOH. After

2 h water was slowly added (100 mL) and the reaction mixture

extracted with ether (2 × 100 mL). The organic layer was

separated, dried over MgSO₄, and filtered and the solvent

removed under vacuum to afford a clear oil: MS (EI) m/e 257

Met h od H . 2-[[[3-(1H -In d ol-4-yloxy)p r op yl]a m in o]-

m eth yl]ch r om a n -7-ol (56c). To a solution of diphenylphos-

phine in anhydrous THF (25 mL) at 5 °C was added n-

butyllithium (3.5 mL, 2.5 M). After 10 min a solution of 56a

in THF (10 mL) was added, and the mixture was allowed to

stir for 2.5 days. The reaction was quenched with water and

poured into ether (100 mL). The organic layer was separated

and dried over MgSO₄and the solvent evaporated under

vacuum. Chromatography (5% MeOH-CH₂Cl₂containing 1%

NH₄OH) afforded 280 mg (39.1%) a white foam. The oxalate

salt was prepared from THF, mp 199-201 °C. Anal.

(C₂₁H₂₄N₂O₃‚C₂H₂O₄‚0.33H₂O) C, H, N.

7-Am in o-4-oxo-4H-1-ch r om en e-2-ca r boxylic Acid Eth yl

Ester (15e). A mixture of 14g³¹(24.1 g, 0.125 mol) and diethyl

oxalate (47.5 g, 0.33 mol) in absolute EtOH (200 mL) was

added to a solution of sodium ethoxide (14 g sodium in 300

mL absolute EtOH). The reaction was heated to reflux for 2

h, allowed to cool to room temperature, and then poured into

water (500 mL) and CH₂Cl₂(1500 mL). The aqueous layer

was made slightly acidic using 6 N HCl, the organic layer was

separated, and the aqueous layer was washed again using CH₂-

Cl₂(500 mL). The combined organic layers were dried, and

the solvent was removed under vacuum. The solid material

(35.8 g) was dissolved in EtOH (350 mL), and concentrated

HCl (6 mL) was added. The solution was heated to reflux for

1 day, removed from heat, and allowed to stand for 2 days.

The orange solid was filtered to afford 17 g of product. The

mother liquor was concentrated to afford another 4.94 g (76%)

of desired product: ¹H NMR (DMSO-d₆) δ 1.32 (3H, t, J ) 7.25

Hz), 4.34 (2H, q, J ) 7.03 Hz), 6.50 (2H, bs), 6.53 (1H, d, J )

1.98 Hz), 6.69 (1H, dd, J ) 8.78, 1.98 Hz), 6.71 (1H, s), 7.68

(1H, d, J ) 8.78 Hz); MS (EI) m/e 233 (M⁺).

1

(M⁺); H NMR (CDCl₃) δ 1.77-1.99 (2H, m), 2.71-2.85 (2H,

m), 3.00 (3H, s), 3.73-3.87 (2H, m), 4.10 (1H, m), 6.62-6.74

(2H, m), 7.00 (1H, J ) 7.91 Hz).

Tolu en e-4-su lfon ic Acid , [7-[(m eth ylsu lfon yl)a m in o]-

ch r om a n -2-yl]m eth yl Ester (20f). A solution of 17f (2.1 g,

8.16 mmol) and p-toluenesulfonyl chloride (2.33 g, 12.2 mmol)

in anhydrous pyridine (20 mL) was allowed to stir for 24 h

and then poured into 1 N aqueous HCl (100 mL). The reaction

was then extracted with CH₂Cl₂(350 mL) and the organic layer

washed with 1N HCl (100 mL) followed by water (100 mL).

The organic layer was dried over MgSO₄and filtered, and the

solvent removed under vacuum to afford a solid. Trituration

with ether (30 mL) afforded 2.87 g (85.5%) of a white solid:

mp 170-171 °C; MS (EI) m/e 411 (M⁺); ¹H NMR (DMSO-d₆) δ

1.60 (1H, m), 1.86 (1H, m), 2.42 (3H, s), 2.55-2.72 (2H, m),

2.92 (3H, s), 4.13-4.28 (3H, m), 6.60 (1H, d, J ) 2.05 Hz),

6.68 (1H, dd, J ) 8.20, 2.05 Hz), 6.97 (1H, d, J ) 8.20 Hz),

7.48 (2H, d, J ) 8.06 Hz), 7.81 (2H, d, J ) 8.35 Hz), 9.58 (1H,

s).

Met h a n esu lfon ic Acid , [7-[(m et h ylsu lfon yl)a m in o]-

ch r om a n -2-yl]m eth yl Ester (19f). To a solution of 17e (810

mg, 4.96 mmol) in dry CH₂Cl₂(20 mL) containing pyridine (4

equiv) at 0 °C was added methanesulfonyl chloride (1.42 g,

12.4 mmol), and the mixture was allowed to stir for 1.5 h while

gradually warming to room temperature. The reaction mix-

ture was poured into 1 N HCl (100 mL) and extracted with

CH₂Cl₂(2 × 100 mL). The organic layer was washed with 1

N HCl (50 mL) and water (50 mL), dried over MgSO₄, and

filtered, and the solvent was removed under vacuum. Puri-

fication by chromatography (50% EtOAc-hexanes) afforded

1.48 g (90%) of desired product as a white foam: IR (film) 3290,

7-Am in o-4-ch r om an -2-car boxylic Acid Eth yl Ester (16e).

To a solution of 15e (2.4 g, 10.3 mmol) in acetic acid (40 mL)

was added 10% palladium on carbon, and the mixture was

hydrogenated on a Parr hydrogenator at 50 psi for 5 days. The

catalyst was filtered through Celite and the acetic acid

removed under high vacuum. The crude product was chro-

matographed (30% EtOAc-hexanes) to afford 1.27 g (56%) of

desired product as a yellow oil: ¹H NMR (CDCl₃) δ 1.28 (3H,

3H, t, J ) 7.14 Hz), 2.07-2.26 (2H, m), 2.59-2.74 (2H, m),

3.50 (2H, bs), 4.23 (1H, q, J ) 7.03 Hz), 4.66 (1H, m), 6.25

(1H, dd, J ) 8.02, 2.42 Hz), 6.28 (1H, d, J ) 2.42 Hz), 6.79

1

3050, 2950, 1630, and 1600 cm^-1; MS (EI) m/e 335 (M⁺); H

NMR (CDCl₃) δ 1.82-1.94 (2H, m), 2.03-2.08 (2H, m), 2.79-

2.86 (2H, m), 3.00 (3H, s), 3.12 (3H, s), 4.29-4.45 (3H, m), 6.64

(1H, bs), 6.72-6.75 (3H, m), 7.02 (1H, d, J ) 8.56 Hz).

Meth od I. N-[2-[[[3-(3-Am in op h en oxy)p r op yl]a m in o]-

m eth yl]ch r om a n -7-yl]m eth a n esu lfon a m id e (49f). A mix-

ture of 19f (128 mg, 0.38 mmol), 3-(3-nitrophenoxy)-1-

aminopropane (374 mg, 1.91 mmol), K₂CO₃(132 mg, 2.5 mmol),

and 20 mg of NaI in dry DMF (20 mL) was heated to 80 °C for

16 h. The reaction mixture was poured into ether (150 mL),

extracted with water (2 × 100 mL), washed with brine, dried

over MgSO₄, and filtered, and the solvent was removed under

vacuum. Chromatography (3% MeOH-CH₂Cl₂) afforded 68

mg of desired product [i.e. N-[2-[[[3-(3-nitrophenoxy)propyl]-

amino]methyl]chroman-7-yl]methanesulfonamide] (41%): MS

(EI) m/e 436 (M⁺).

To a mixture of the above product (250 mg, 0.618 mmol)

and Raney nickel (1 g) in EtOH (40 mL) was added hydrazine

(1.5 g). The reaction mixture was heated to reflux for 1 h and

allowed to cool to room temperature. The catalyst was filtered

through Celite and the solvent removed under vacuum.

Purification by chromatography (10% MeOH-CH₂Cl₂contain-

ing 1% NH₄OH) afforded 175 mg (70%) of a foam. The oxalate

salt was prepared from THF and triturated with MeOH: mp

183-185 °C; MS (EI) m/e 405 (M⁺). Anal. (C₂₀H₂₇N₃O₄S‚-

2C₂H₂O₄‚0.5H₂O) C, H, N.

N-[2-[[(3-Hydr oxypr opyl)am in o]m eth yl]ch r om an -7-yl]-

m eth a n esu lfon a m id e (22f). This compound was prepared

according to method A by reacting 19f with 3-aminopropanol

to afford the product in 62.8% yield. The oxalate salt was

prepared from 2-propanol: mp 164-165 °C. Anal.

(C₁₄H₂₂N₂O₄S‚C₂H₂O₄) C, H, N.

N-[2-[(Ben zyla m in o)m et h yl]ch r om a n -7-yl]m et h a n e-

su lfon a m id e (35f). A mixture of 20f (900 mg, 2.19 mmol),

benzylamine (469 mg, 4.37 mmol), and triethylamine (221 mg,

2.19 mmol) was reacted according to method B to afford 496

mg (65%) of a clear thick oil. The oxalate salt was prepared

(1H, d, J ) 7.91 Hz); IR (film) 3400, 2930, 1750, and 1630 cm^-1

;

MS (EI) m/e 221 (M⁺).

7-[(Meth ylsu lfon yl)a m in o]ch r om a n -2-ca r boxylic Acid

Eth yl Ester (16f). To a solution of 16e (2.5 g, 11.2 mmol) in

CH₂Cl₂(20 mL) containing pyridine (6 mL) at 5 °C was added

methanesulfonyl chloride (1.3 g, 13.6 mmol). The reaction

mixture was allowed to stir for 20 min then poured in water

(80 mL) and washed with 1 N aqueous HCl (2 × 100 mL),

followed by water (100 mL). The organic layer was dried over

MgSO₄and filtered, and the solvent was removed under

vacuum. Purification by chromatography (30% EtOAc-hex-

anes) afforded 3.21 g (95%) of a clear oil: MS (EI) m/e 299

(M⁺); IR (film) 1730 cm^-1; ¹H NMR (CDCl₃) δ 1.29 (3H, t, J )

7.24 Hz), 2.15-2.27 (2H, m), 2.68-2.79 (2H, m), 2.96 (3H, s),

4.26 (2H, q, J ) 7.25 Hz), 4.72 (1H, dd, J ) 7.14, 3.52 Hz),

6.77-6.82 (2H, m), 6.98 (1H, d, J ) 8.57 Hz).

(7-Am in och r om a n -2-yl)m eth a n ol (17e). To a solution of

16e (1.47 g, 6.64 mmol) in THF (25 mL) at 0 °C was added 2.0

M LiBH₄(7 mL), and the mixture was allowed to warm to room

temperature. The reaction was quenched after 1.5 h by the

cautious addition of MeOH (5 mL), and the reaction mixture

was stirred for another 2 h. The reaction mixture was diluted

with EtOAc (300 mL) and washed with water (2 × 60 mL).

The aqueous layer was washed again with EtOAc (100 mL),

the combined layers were dried over MgSO₄and filtered, and

the solvent was removed under vacuum. Purification by

chromatography (50% EtOAc-hexane) afforded 892 mg (82%)

1

of desired product as a white solid: mp 89-90 °C; H NMR

(CDCl₃) δ 1.73-1.95 (2H, m), 2.61-2.83 (3H, m), 3.72-3.84

(2H, m), 4.04-4.12 (1H, m), 6.18 (1H, d, J ) 2.34 Hz), 6.24

(1H, dd, J ) 8.06, 2.34), 6.83 (1H,d, J ) 7.91). Anal. (C₁₀H₁₃

NO₂) C, H, N.

-

4252 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

in THF: mp 232-233 °C; ¹H NMR (DMSO-d₆) δ 1.62-1.67

(1H, m), 1.97-2.01 (1H, m), 2.62-2.76 (2H, m), 2.92 (3H, s),

3.07-3.19 (2H, m), 4.19 (2H, s), 4.32 (1H, m), 6.68 (1H, dd, J

) 8.13, 1.98 Hz), 6.74 (1H, d, J ) 1.98 Hz), 7.01 (1H, d, J )

8.13 Hz), 7.37-7.47 (3H, m), 7.51-7.53 (2H, m). Anal.

(C₁₈H₂₂N₂SO₃‚C₂H₂O₄) C, H, N..

N-[2-[[(4-Meth ylben zyl)a m in o]m eth yl]ch r om a n -7-yl]-

m eth a n esu lfon a m id e (47f). Utilizing 20f and 4-methylben-

zylamine according to method B afforded 47f. The oxalate salt

was prepared in THF: mp 247-248.5 °C. Anal.

(C₁₉H₂₄N₂O₃S‚C₂H₂O₄) C, H, N.

7-Meth oxy-1-oxo-1,2,3,4-tetr a h yd r on a p h th a len e-2-ca r -

boxylic Acid Eth yl Ester (63). To a solution of 62 (25 g,

0.142 mol) in anhydrous THF (300 mL) was added NaH (60%

oil dispersion, 21 g, 0.525 mol), and the mixture was heated

to reflux for 2.5 h. The reaction was quenched with AcOH

(35 mL) and allowed to stir overnight at room temperature.

The solvent was removed, and benzene was added and

evaporated to remove any remaining AcOH. The residue was

partitioned between EtOAc (300 mL) and water (300 mL). The

aqueous layer was washed with EtOAc (3 × 400 mL), and the

combined organic layers were washed with brine, dried over

MgSO₄, and filtered, and the solvent was evaporated. Puri-

fication by chromatography (5% EtOAc-hexanes) afforded 33.3

g (94%) of product: mp 47-48 °C; MS (EI) m/e 248 (M⁺); IR

(KBr) 1750, 1740 cm^-1. Anal. (C₁₄H₁₆O₄) C, H.

7-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len e-2-ca r boxy-

lic Acid Eth yl Ester (64). To a solution of 63 (10.0 g, 40

mmol) and triethylsilane (9.4 g, 80 mmol) in CH₂Cl₂(50 mL)

at 0 °C was slowly added trifluoroacetic acid (30 mL) over 0.5

h. The reaction mixture was allowed to stir for 16 h and then

quenched with aqueous NaHCO₃(200 mL). The mixture was

extracted with EtOAc (3 × 100 mL), dried over MgSO₄, and

filtered and the solvent removed under vacuum. Chromatog-

raphy (2% EtOAc-hexanes) afforded 5.5 g (59%) of 64⁵⁵as a

clear oil: IR (film) 2900, 1730, 1610, and 1500 cm^-1; MS (EI)

m/e 234 (M⁺).

(7-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -2-yl)m eth a -

n ol (65). According to the procedure used to prepare 17, ester

64 (5.92 g, 25.3 mmol) was reacted with 2 M LiBH₄in THF

(50 mL) to afford 4.6 g (95%) of the title compound as a clear

oil: ¹H NMR (CDCl₃) δ 1.36-1.48 (1H, m), 1.90-2.04 (2H, m),

2.50 (1H, dd, J ) 16.48, 10.54 Hz), 2.69-2.89 (3H, m), 3.63

(2H, dd, J ) 6.37, 1.32 Hz), 3.77 (3H, s), 6.63 (1H, d, J ) 8.35,

2.63 Hz), 6.99 (1H, d, J ) 8.35 Hz); IR (film) 3300, 2910, 1610,

1502, and 1400 cm^-1; MS (EI) m/e 192 (M⁺).

2-(Br om om et h yl)-7-m et h oxy-1,2,3,4-t et r a h yd r on a p h -

th a len e (66). The title compound was prepared from 64

according to the procedure used to prepared 18 and isolated

in 95% yield as a yellow oil: ¹H NMR (CDCl₃) δ 1.48-1.58

(1H, m), 2.01-2.18 (2H, m), 2.57 (1H, dd, J ) 16.47, 10.54

Hz), 2.75-2.80 (2H, m), 2.96 (1H, dd, J ) 16.36, 4.39 Hz), 3.44

(2H, d, J ) 6.37, 2.20 Hz), 3.77 (3H, s), 6.63 (1H, d, J ) 2.64

Hz), 6.70 (1H, dd, J ) 8.46, 2.64 Hz), 7.00 (1H, d, J ) 8.35

Hz) MS (EI) m/e 254, 256 (M⁺).

3-[[(7-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len yl-2-yl)-

m eth yl]a m in o]p r op a n -1-ol (67). This compound was pre-

pared from 66 and 1-amino-3-propanol according to method

A to afford 3.3 g (49%) of the title compound as an orange solid.

The oxalate salt was prepared in MeOH: mp 165-170 °C.

Anal. (C₁₅H₂₃NO₂‚0.5C₂H₂O₄‚0.33H₂O) C, H, N.

7-[[[3-(3-Am in op h en oxy)p r op yl]a m in o]m eth yl]-5,6,7,8-

tetr a h yd r on a p h th a len -2-ol (69). Alcohol 67 (2.9 g, 11.6

mmol) was coupled to 3-nitrophenol according to method C to

afford 2.35 g (55%) of [(7-methoxy-1,2,3,4-tetrahydronaphtha-

len-2-yl)methyl]-[3-(3-nitrophenoxy)propyl]amine (68) as a

yellow semisolid: MS (EI) m/e 370 (M⁺). The more polar

azetidine 71 (1.29 g, 48%) was also isolated; MS (EI) m/e 231

(M⁺). The corresponding oxalate salt of 71 was prepared in

MeOH as a white crystalline solid: mp 165-166 °C. Anal.

(C₁₅H₂₁NO‚C₂H₂O₄) C, H, N.

with HBr according to method D to afford 1.1 g (62%) of 70 as

an oil. The oxalate salt was prepared in MeOH, mp 211-212

°C. Anal. (C₂₀H₂₆N₂O₂‚C₂H₂O₄) C, H, N.

(2R)-5-Meth oxy-2-(oxir an ylm eth oxy)ben zaldeh yde (73).

To a suspension of 60% NaH (2.4 g, 60.3 mmol) in anhydrous

DMF (60 mL) at room temperature was slowly added a solution

of 72 (7.34 g, 48.2 mmol) in DMF (5 mL). After 1 h

(2R)-(-)-glycidyl 3-nitrobenzenesulfonate (10.0 g, 38.6 mmol)

was added, and the solids were rinsed into the flask with

another 5 mL of DMF. The reaction was heated to 70 °C and

allowed to stir for 6 h. Upon cooling to ambient temperature,

the reaction was poured into CH₂Cl₂(400 mL) and washed

consecutively with 2 N HCl (2 × 150 mL), saturated Na₂CO₃

(80 mL), and brine (80 mL). The solution was dried over

MgSO₄and filtered, and the solvent was removed under

vacuum. Purification by chromatography (20-50% EtOAc-

hexanes) afforded 3.18 g (32%) of a yellow oil: ¹H NMR (CDCl₃)

δ 2.76 (1H, dd, J ) 4.83, 2.64 Hz), 2.91 (1H, app t, J ) 4.47

Hz), 3.34-3.39 (1H, m), 3.78 (3H, s), 3.98 (1H, dd, J ) 11.20,

5.78 Hz), 4.32 (1H, dd, J ) 11.13, 2.78 Hz), 6.94 (1H, dd, J )

8.93, 5.86 Hz), 7.10 (1H, dd, J ) 9.00, 3.00 Hz), 7.28 (1H, d, J

) 3.37 Hz), 10.46 (1H, s); MS (EI) m/e 208 (M⁺); HRMS calcd

for C₁₁H₁₂O₄208.073 560, observed 208.065 12.

((S)-7-Meth oxy-2,3-d ih yd r oben zo[1,4]d ioxin -2-yl)m eth -

a n ol (75). To a solution of 73 (3.2 g, 15.4 mmol) in CH₂Cl₂

(50 mL) at room temperature was added mCPBA (2.91 g, 16.9

mmol). After 1 h the solids were filtered, and the solvent was

removed and dissolved in ether (80 mL). The solution was

washed with sodium thiosulfite, followed by 50% aqueous Na₂-

CO₃(2 × 100 mL), followed by brine (80 mL), dried over

MgSO₄, and filtered. Evaporation of the solvent afforded 3 g

of the formate ester (74) which was dissolved in methanol (80

mL), and 4 g of Na₂CO₃was added. After 0.5 h the mixture

was filtered and partitioned between CH₂Cl₂(100 mL) and

water (50 mL). The organic layer was dried over MgSO₄and

filtered, and the solvent was evaporated. Chromatography

(20% EtOAc-hexanes) afforded 2.3 g (76%) of desired product

as a clear oil: [R]²⁵_D-31.4° (c ) 1.0, CHCl₃); ¹H NMR (CDCl₃)

δ 2.13 (1H, bt, OH), 3.74 (3H, s), 3.78-3.95 (2H, m), 4.10-

4.11 (1H, m), 4.21-4.31 (2H, m), 6.42 (1H, dd, J ) 8.79. 2.93

Hz)), 6.48 (1H, d, J ) 2.93 Hz), 6.78 (1H, d, J ) 8.79 Hz); MS

(EI) m/e 196 (M⁺); HRMS calcd for C₁₀H₁₂O₄196.0356,

observed 196.0650.

Tolu en e-4-su lfon ic Acid, (7-Meth oxy-2,3-dih ydr oben zo-

[1,4]d ioxin -2(S)-yl)m eth yl Ester (76). A solution of 75 (2.27

g, 11.6 mmol) and tosyl chloride (4.59, 24.1 mmol) in dry

pyridine (40 mL) at room temperature was allowed to stir for

4 h. The reaction was poured into 3 N aqueous HCl (250 mL)

and extracted with CH₂Cl₂(2 × 150 mL). The organic layer

was washed with 3 N HCl (80 mL), followed by saturated

aqueous NaHCO₃(100 mL), dried over MgSO₄, and filtered

and the solvent evaporated to afford a solid. Trituration with

ether (70 mL) afforded 2.78 g (69%) of a white solid: mp 102-

103 °C; [R]²⁵_D-3.98° (c ) 1.0, CHCl₃); ¹H NMR (CDCl₃) δ 2.46

(3H, s), 3.72 (3H, s), 4.00 (1H, m), 4.15-4.23 (3H, m), 4.38 (1H,

m), 6.35-6.42 (2H, m), 6.74 (1H, d, J ) 8.79 Hz), 7.36 (2H, d,

J ) 8.06 Hz), 7.80 (2H, d, J ) 8.20 Hz); MS (EI) m/e 301 (M⁺);

HRMS calcd for C₁₇H₁₈O₆S 350.082 413, observed 350.078 93.

Anal. (C₁₇H₁₈O₆S).

N -(S )-Be n zyl-N -[(7-m e t h oxy-2,3-d ih yd r ob e n zo[1,4]-

d ioxin -2-yl)m eth yl]a m in e (77). A solution of 76 (2.76 g, 7.85

mmol) and benzylamine (3.36 g, 31.4 mmol) in dry DMSO (10

mL) was heated to 80 °C for 15 h. The reaction mixture was

poured into a dilute solution of 10% NaHCO₃(200 mL) and

extracted with CH₂Cl₂(2 × 200 mL). The organic layer was

dried over MgSO₄and filtered, and the solvent was removed

under vacuum. Purification by chromatography (40% EtOAc/

hexanes) afforded 2.05 g (92%) of a clear oil: [R]²⁵-36.92 °

D

(c ) 1.01, CHCl₃); ¹H NMR (CDCl₃) δ 2.86-2.95 (2H, m), 3.74

(3H, s), 3.86 (2H, m), 4.00 (1H, m), 4.22 (1H, d, J ) 11.31,

2.20 Hz), 4.29 (1H, m), 6.42 (1H, d, J ) 8.79, 2.86 Hz), 6.47

(1H, d, J ) 2.86 Hz), 6.78 (1H, d, J ) 8.79 Hz), 7.28 (1H, m),

Hydrogenation of 68 according to method F afforded the title

compound in 78% yield, which was analyzed as its bisoxalate

salt: mp 185-186 °C; MS (EI) m/e 340 (M⁺). Anal.

(C₂₁H₂₈N₂O₂‚2C₂H₂O₄) C, H, N.

7-[[[3-(3-Am in op h en oxy)p r op yl]a m in o]m eth yl]-5,6,7,8-

t et r a h yd r on a p h t h a len -2-ol (70). Aniline 69 was treated

7.34 (3H, app s); MS (EI) m/e 285 (M⁺); HRMS calcd for C₁₇H₁₉

-

NO₃285.136 494, observed 285.1328.

(S)-3-[(Ben zyla m in o)m et h yl]-2,3-d ih yd r ob en zo[1,4]-

d ioxin -7-ol (78). A mixture of 77 (1.90 g, 6.66 mmol) and

aqueous HBr (35 mL) was reacted according to method D to

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4253

give a light yellow oil: [R]²⁵_D-47.5° (c ) 1.00, CHCl₃); ¹H NMR

(CDCl₃) δ 2.79-2.87 (2H, m), 3.81-3.86 (2H, m), 3.94 (1H, d,

J ) 12.96 Hz), 4.13 (1H, dd, J ) 11.20, 2.20 Hz), 4.25 (1H, m),

6.32 (1H, dd, J ) 8.79, 2.86 Hz), 6.40 (1H, d, J ) 2.86 Hz),

6.66 (1H, d, J ) 8.79 Hz), 7.28-7.38 (5H, m), (3H, s); MS (EI)

m/e 271 (M⁺). The oxalate salt was prepared in 2-propanol:

evaporated. Purification by chromatography (5% MeOH-CH₂-

Cl₂) afforded 119 mg (31%) of product as a clear oil. The

oxalate was prepared from THF: mp 231.5-232.5 °C. Anal.

(C₁₇H₁₉NO‚C₂H₂O₄) C, H, N.

N -(4-F lu or ob e n zyl)-N -(ch r om a n -2-ylm e t h yl)a m in e

(43d ). Compound 43d was prepared according to the above

procedure (method J ) using 4-fluorobenzyl chloride in 29%

yield. The oxalate salt was prepared in THF: mp 231-232

°C. Anal. (C₁₇H₁₈FNO‚C₂H₂O₄) C, H, N.

3-[3-[(Ch r om a n -2-ylm et h yl)a m in o]p r op oxy]p h en yl-

a m in e (49d ). Treatment of chroman-2-ylmethylamine hy-

drochloride⁵⁶with 3-(nitrophenoxy)propyl bromide according

to the above procedure (method J ) gave [3-(3-nitrophenoxy)-

propyl](chroman-2-ylmethyl)amine, followed by hydrogenation

according to method F afforded the title compound (Table 10).

The fumarate salt was prepared in 2-propanol: mp 136-137

°C. Anal. (C₁₉H₂₄N₂O₂‚C₄H₄O₄‚0.25H₂O) C, H, N.

mp 209-210 °C; [R]²⁵_D-39.4° (c 1.00, DMSO). Anal. (C₁₆H₁₇

NO₃‚C₂H₂O₄).

-

(R)-2-(Hyd r oxym eth yl)ch r om a n -7-ol (R-17c). A solution

of 16c^29a(1.5 g, 6.8 mmol) in THF (100 mL) was reacted with

2.0 M LiBH₄as described above for 17a . After 2 h the reaction

was diluted with ether (50 mL), poured into a 1:1 solution of

water/brine (100 mL), acidified to pH 2 with 2 N HCl, and

then extracted with ether (2 × 150 mL). The organic layer

was dried over MgSO₄and the solvent removed under vacuum.

Purification by chromotagraphy (50% EtOAc-hexanes) af-

forded 1.1 g (91%) of a white crystalline solid: mp 88-90 °C;

MS(EI) m/e 180 (M⁺); [R]²⁵-114.3° (c ) 1.01, DMSO); ¹H

D

Meth od K. Resolu tion of (+)-2-[(Ben zyla m in o)m eth yl]-

ch r om a n -7-ol (35c). (()-2-[(Benzylamino)methyl]chroman-

7-ol (35c) (400 mg) was submitted to semipreparative HPLC

containing a Chiralcel OJ column and eluted (10 mL/min,

pressure 430 psi, detection at 280 nm) with a hexane/EtOH

(1:1) mixture. The first peak at 8.7 min was collected to afford

R-(-)-35c (103 mg) as a clear thick oil (99.0% ee): [R]²⁵_D-107°

(c ) 1.01, CHCl₃). The (-)-free base was treated with excess

oxalic acid in THF to afford 118 mg of oxalate salt: mp 212-

NMR (DMSO-d₆) δ 1.53-1.63 (1H, m), 1.88-1.95 (1H, m),

2.63-2.69 (2H, m), 3.47-3.56 (2H, m), 3.86-3.92 (1H, m), 4.82

(1H, t, J ) 5.7 Hz), 6.12 (1H, d, J ) 2.42 Hz), 6.22 (1H, dd, J

) 8.24, 2.42 Hz), 6.79 (1H, d, J ) 8.13 Hz), 9.07 (1H, s). Anal.

(C₁₀H₁₂O₃).

(R)-(-)-2-[(Ben zyla m in o)m eth yl]ch r om a n -7-ol [R-(-)-

35c]. To a solution of R-(-)-17c (400 mg, 2.22 mmol) in

anhydrous pyridine was added p-toluenesulfonyl chloride (444

mg, 2.33 mmol). The reaction mixture was stirred for 4 h at

5 °C then poured into 2 N HCl (50 mL) and extracted with

CH₂Cl₂(2 × 100 mL). The organic layer was dried over MgSO₄

and filtered, and the solvent was removed under vacuum. The

product mixture was purified by flash chromatography (30%

EtOAc-hexanes) to afford 697 mg of R-20c as a clear oil which

¹H NMR and mass spectroscopy [(EI) m/e 344 (M⁺) and (EI)

m/e 488 (M⁺)] identified a 85:15 mixture of the desired tosylate

and the ditosylate. The mixture was dissolved in anhydrous

DMSO (10 mL) containing benzylamine (703 mg, 6.56 mmol).

The reaction mixture was heated to 100 °C for 10 h whereby

the reaction mixture was poured into water (50 mL) and

extracted with EtOAc (2 × 150 mL). The organic layer dried

over MgSO₄and filtered, and the solvent was removed under

vacuum. Purification by flash chromatography (3% MeOH-

213 °C; [R]²⁵-76° (c ) 1.03, DMSO). Anal. (C₁₇H₁₉

-

D

NO₂‚C₂H₂O₄) C, H, N. Optical purity observed to be 99.0% ee

by HPLC (acetonitrile-1 M sodium perchlorate, 1:1, 0.5 mL/

min, 280 nM). The second peak isolated with a retention time

of 10.15 min was collected to afford the S-(+)-35c (174 mg) as

a clear thick oil: [R]²⁵_D+104 ° (c ) 1.15, CHCl₃). Optical purity

observed to be 100% ee (acetonitrile-1 M NaClO₄, 1:1, 0.5 mL/

min, 280 nM). The (+)-free base was treated with excess oxalic

acid in THF to afford 175 mg of oxalate salt: mp 212-213 °C;

[R]²⁵+82° (c ) 1.0, DMSO). Anal. (C₁₇H₁₉NO₂‚C₂H₂O₄) C,

D

H, N.

Resolu tion of (+)-2-[(Ben zyla m in o)m eth yl]-6-ch lor o-

ch r om a n -7-ol. RS-(()-41c (731 mg) was resolved on

a

Chiralcel OJ column (10 mL/min, pressure 430 psi, detection

at 290 nm) in a similar fashion as described for 35c (method

K) by collecting fractions from 40 separate runs using ap-

proximately 18 mg per injection to initially afford R-(-)-41c

(322 mg, 8.9 min) as a light tan solid (optical purity determined

CH₂Cl₂) afforded 311 mg (52%) of a thick clear oil: [R]²⁵

D

-110.0° (c ) 1.04, CHCl₃). The free base was converted to

the oxalate salt in THF: mp 213-214 °C; [R]²⁵-77.5° (c )

D

to be 100% ee): mp 118-119 °C; [R]²⁵-124.0° (c ) 1.0,

1.1, DMSO). The optical purity determined to be 99% ee using

the chiral method described below in method K.

D

CHCl₃). The (-)-free base was converted to its fumarate salt

in 2-propanol to afford a white crystalline solid: mp 214-215

(R)-(-)-2-[[(4-P h en ylbu tyl)a m in o]m eth yl]ch r om a n -7-

ol [R-(-)-32c]. The title compound was prepared in 32% yield

in a similar fashion as that described above for R-(-)-35c by

°C; [R]²⁵-69.0° (c ) 1.0, DMSO). Chemical purity deter-

D

mined to be 97.6% pure by HPLC, and optical purity was

determined to be 99.6% ee. Anal. (C₁₇H₁₈ClNO₂‚C₄H₄O₄) C,

H, N.

replacing benzylamine with phenylbutylamine; [R]²⁵-98.0°

D

(c ) 1.4, CHCl₃, free base); MS (EI) m/e 311 (M⁺). The

fumarate salt was prepared from 2-propanol: mp 148-149 °C;

The second peak isolated having a retention time of 10.9

min was collected to afford S-(+)-41c (321 mg) as a light

pinkish solid (optical purity determined to be 99.4% ee): mp

[R]²⁵-62.5° (c ) 1.0, DMSO). Anal. (C₂₀H₂₅NO₂‚C₄H₄O₄) C,

D

H, N.

116-118 °C; [R]²⁵+120.0° (c ) 1.0, CHCl₃). The fumarate

(R)-(-)-2-[(Ben zyla m in o)m eth yl]ch r om a n -6-ch lor o-7-

ol [R-(-)-41c]. To a solution of R-20c (930 mg) in THF (30

mL) was added N-chlorosuccinimide (375 mg) and the reaction

allowed to stir at room temperature for 18 h. The reaction

mixture was poured into water (100 mL) and extracted with

CH₂Cl₂(2 × 150 mL). The combined organic layers were dried

over MgSO₄and filtered, and the solvent was removed.

Purification by chromatography (25% EtOAc-hexanes) af-

forded 677 mg of R-(-)-21c (contaminated with a small amount

D

salt was prepared in 2-propanol to afford white crystalline

solid: mp 211-212.5 °C; [R]²⁵+68.1 (c ) 1.0, DMSO).

D

Chemical purity was determined to be 100.0% and optical

purity found to be 99.0% ee. Anal. (C₁₇H₁₈ClNO₂‚C₄H₄O₄) C,

H, N.

Resolu tion of (+)-2-(3,4-Dih yd r o-1H-isoqu in olin -2-yl-

m eth yl)ch r om a n -7-ol [RS-(+)-48c]. (()-2-(3,4-Dihydro-1H-

isoquinolin-2-ylmethyl)chroman-7-ol [(()-48c] (610 mg) was

resolved in a similar fashion as described in method K by

dissolving in EtOH and submitting to semipreparative HPLC

containing a Chiralcel OJ column and eluted (0.8 mL/min,

pressure 430 psi, detection at 254 nm) with a hexane/2-

propanol (4:1) mixture. The first peak at 8.1 min was collected

of dichlorinated product): MS (EI) m/e 368/370 (M⁺); [R]²⁵

-54.2° (c ) 1.0, CHCl₃).

D

A solution of R-(-)-21c (638 mg, 1.73 mmol) and benzy-

lamine (740 mg, 6.92 mmol) in dry DMSO (7 mL) was reacted

according to method B to afford 363 mg (62%) of title product:

mp 117.5-118.5 °C; [R]²⁵-123.4 (c ) 1.0, CHCl₃).

to afford (-)-48c (265 mg) as a yellow glass (100% ee), [R]²⁵

D

Meth od J . N-Ben zyl-N-(ch r om a n -2-ylm eth yl)a m in e

(35d ). To a suspension of chroman-2-ylmethylamine hydro-

chloride⁵⁶(300 mg, 1.5 mmol) and K₂CO₃(519 mg, 4.5 mmol)

in dry DMF (5 mL) was added benzyl chloride (190 mg, 1.5

mmol), and the mixture was allowed to stir at 55 °C for 2 h.

The reaction mixture was poured into water (25 mL) and

extracted with ether (2 × 40 mL). The organic layer was

separated, dried over MgSO₄, and filtered, and the solvent was

-105° (c ) 1.1, CHCl₃). The (-)-free base (240 mg) was treated

with excess oxalic acid in EtOH to afford 160 mg of oxalate

salt: mp 198-199 °C; [R]²⁵-75°, (c ) 1.0, DMSO). Anal.

D

(C₁₉H₂₁NO₂‚C₂H₂O₄‚0.25H₂O) C, H, N. The second peak

isolated with a retention time of 11.1 min was collected to

afford the (+)-48c (260 mg) as a yellow glass: [R]²⁵+103° (c

D

) 1.0, CHCl₃). Optical purity observed to be 96.6% ee

(acetonitrile-1 M NaClO₄, 1:1, 0.5 mL/min, 280 nM). The (+)-

4254 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26

Mewshaw et al.

free base (240 mg) was treated with excess oxalic acid in EtOH

mately 0.3 mg of protein). Incubation buffer was 50 mM Tris,

pH 7.4, containing 1 mM EDTA, 5 mM KCl, 1.5 mM CaCl₂,

and 4 mM MgCl₂(NaCl was omitted to promote high-affinity

agonist binding). Incubation was at 25 °C for 1 h. Sulpiride

(10 µM) was used to define specific binding. Affinity for the

low-affinity state of the D₂receptor was determined by

measuring the ability of various drugs to inhibit [³H]spiperone

(1 nM) binding to striatal membranes (approximately 0.3 mg

protein). Incubation buffer was 50 mM Tris, pH 7.4, contain-

ing 125 mM NaCl, 5 mM KCl, 1 mM CaCl₂, and 1 mM MgCl₂;

1 mM GppNHp was present in all tubes to shift binding to

the low-affinity state. and 30 nM ketanserin was present in

all tubes to exclude binding to 5-HT₂receptors. Incubation

was at 37 °C for 5 min. All incubations were terminated by

adding cold buffer followed by rapid filtration using a TomTec

96 cell harvester. Bound radioactivity was counted using a

Wallac 1205 BetaPlate Counter. K_ivalues were calculated

from IC₅₀values by the method of Cheng and Prusoff,³⁶using

nine concentrations of the drug, in triplicate.

to afford 223 mg of oxalate salt: mp 195-196 °C, [R]²⁵+74°

D

(c ) 1.1, DMSO). Anal. (C₁₉H₂₁NO₂‚C₂H₂O₄‚0.25H₂O) C, H,

N.

Molecu la r Mod elin g. All computation were performed

using Sybyl software package version 6.3 (Tripos Associates,

St. Louis, MO) and a Silicon Graphic workstation. For

Maximin calculations (Tripos force field), the Powell method

was chosen (default values).

Cell Cu ltu r e a n d P r ep a r a tion of h D₂, h D₃, a n d h D₄

Recep tor Mem br a n es. Chinese hamster ovary cells (CHO)

expressing the human dopamine D_2Sand D₃receptors were

cultured in suspension by expansion, in serum free media

(CHO-SFM) to which was added 5% fetal calf serum. The

culture was expanded in a 1:5 split every 3-4 days. NS-0 cells

semiattached from a cell line, expressing the human dopamine

D_4.4receptor, were cultured in roller bottles, in DMEM media

supplied with 10% dialyzed fetal calf serum, and split in the

same ratio ratio as the CHO. Upon reaching a density of

approximately 7.5 × 10⁵cells per mL of suspension, the cells

were harvested by low speed centrifugation (900g) for 10 min.

The pellet was resuspended in half volume of 1× Dulbecco

phosphate-buffered saline solution (PBS) without calcium

chloride or magnesium chloride, at pH 7.4. The suspension

was recentrifuged as to remove traces of the culture media.

The cell pellet was immediately resuspended in 50 mM of

Tris‚HCl buffer, pH 7.4, containing 1.5 mM CaCl₂, 5.0 mM

EDTA, 5.0 mM KCl, 120 mM NaCl, 1.0 mM PMSF, and 1.0

mg % leupeptin. The cells are homogenized in a glass/Teflon

homogenizer with zero clearance, with 20 up and down strokes.

The homogenate was centrifuged at 900g for 10 min and the

supernatant saved. The pellet was resuspended in fresh buffer

(approximately 10 mL), rehomogenized and recentrifuged as

before. The supernatant fluid was combined with the previous

one and centrifuged at 40000g for 30 min. This operation was

repeated once with the resulting pellet. The final pellet was

resuspended in a small volume of 50 mM Tris HCl, pH 7.4.

An aliquot (10-50 µL) of the final suspension was withdrawn

for protein determination, by the method of Lowry.⁵⁷The

suspension was then finally diluted with 50 mM Tris‚HCl to

give a protein concentration of 125 µg/mL of membrane

suspension and stored at -80 °C until used in receptor binding

assays.

Recep tor Bin d in g Assa ys: h D_2s, h D₃, a n d h D_4.4Dop a -

m in e Recep tor s. [³H]Spiperone (SA 80-100 Ci/mmol) was

used as a ligand for binding to all three human dopamine

receptor subtypes. Cell membrane preparation was incubated

with [³H]ligand in a final volume of 200 µL. Briefly, 100 µL

of incubation buffer was added to the wells of a 96-well

microtiter plate. Wells for nonspecific binding (NSB) assess-

ment or test compounds received 80 µL of incubation buffer.

[³H]Spiperone was added at 0.5 nM in 20 µL volume to all

wells, followed by the addition of displacer for NSB determi-

nation: ^D-butaclamol (1 µM) for D_2sreceptors, 7-OH-DPAT (1

µM) for D₃receptors, and clozapine (10 µM) for D_4.4receptors,

all in 20 µL volume. The reaction was initiated by the addition

of 80 µL of appropriate tissue membranes. The mixture was

incubated at room temperature for 120 min. Following

incubation, the wells were harvested onto Glass fiber filter

(GF/B), presoaked in 0.1% polyethylimine (PEI), using a

Brandell harvester. The filter disks were washed three times

with 5.0 mL of cold 50 mM Tris‚HCl buffer, pH 7.4. The filter

mat was dried in an oven and sealed in an envelope with

melted multilex, for scintillation counting in a Wallac 1205

BetaPlate Counter. The data obtained were analyzed with the

help of a computer-assisted software program by Lundon

Software Inc. (OH). In competition experiments, apparent K_i

values were calculated from IC₅₀values by the method of

Cheng and Prusoff,³⁶using nine concentrations of the drug,

in triplicate.

Recep tor Bin d in g Assa ys: 5-HT_1Aa n d r₁Recep tor s.

The 5-HT_1Aand R₁receptor binding assays are modifications

of those used by Hall et al.⁵⁸and Morrow et al.,⁵⁹respectively.

Compounds were evaluated for their affinity at 5-HT_1Arecep-

tors using rat hippocampal homogenates labeled with [³H]-8-

OH-DPAT (1.8 nM). Samples were incubated for 10 min at

37 °C and incubations terminated by adding cold buffer (50

mM Tris, pH 7.7). Affinity at the R₁receptors was determined

using rat cortical homogenates labeled with [³H]prazosin (0.2

nM). Samples were incubated at 25 °C for 30 min. Incuba-

tions were then terminated by the addition of cold buffer (50

mM Tris, pH 7.4) followed by rapid filtration using a TomTec

96-cell harvester. Bound radioactivity was counted as above.

Test compounds were run in triplicate, using at least eight

concentrations. All analyses were done using nonlinear

regression. In competition experiments, apparent K_ivalues

were calculated from IC₅₀values by the method of Cheng and

Prusoff.³⁶

Mou se Hyp olocom otion .⁴¹Spontaneous locomotor activ-

ity effects were tested in mice (25-30 g, Charles River CF-1).

Test compounds, dissolved in 0.25% Tween 80 were adminis-

tered at several dose levels (10-12 mice/dose) immediately

prior to testing. Horizontal activity counts were collected 10-

20 min after dosing using infrared monitors (Omnitech Digis-

can) surrounding an open field (8 × 8 in.) in a darkened room.

Data were analyzed by one-way ANOVA followed by Dunnett’s

comparison to control post-hoc analyses and by nonlinear

regression analysis followed by inverse prediction to obtain

potency estimates.

In d u ction or An ta gon ism of Ster eotyp y a n d Clim b-

in g.^60,61Induction of apomorphine-like stereotypy and climb-

ing behaviors were tested in mice (20-30 g, Charles River CF-

1) treated with the D₁agonist SKF-38393 (10 mg/kg ip)

immediately prior to drug or reserpine (5 mg/kg sc) 20-24 h

prior to drug. Tests for antagonism of apomorphine-induced

stereotypy and climbing behavior were conducted in mice

treated with apomorphine (1 mg/kg sc) 30 min after drug.

Drug, dissolved in 0.25% Tween 80, was administered subcu-

taneously at five dose levels (six mice/dose) for each test. After

the final injection, mice were scored for stereotypy (2-point

scale) and climbing (3-point scale) every 5 min for a total of

30 min. Accumulated scores were analyzed by one-way

ANOVA followed by Dunnett’s comparison to control test and

by nonlinear regression analysis followed by inverse prediction

to obtain potency estimates.

In h ibition of Dop a Accu m u la tion .⁶²Male Sprague-

Dawley rats (225-300 g, Charles River) were given test drugs

at a dose of 10 mg/kg, sc (t ) 0 min). Ten minutes later (t )

10) rats were administered γ-butyrolactone (GBL) (750 mg/

kg, ip) to inhibit neuronal impulse flow. Twenty minutes later

(t ) 20) rats were administered the dopa decarboxylase

inhibitor NSD-1015 (100 mg/kg, ip) to permit an accumulation

of dopa levels. Thirty minutes following NSD-1015 (t ) 50)

administration, animals were killed and striatal tissue was

removed, placed in perchloric acid, and frozen at -80 °C until

subsequent analysis of dopa levels using HPLC analysis with

Recep tor Bin d in g Assa ys: Dop a m in e D₂High - a n d

Low -Affin ity Sta tes. The affinity of dopaminergic agents for

the high- and low-affinity states of the D₂receptor was

determined using conventional in vitro receptor binding

methodology. Affinity for the high-affinity state was deter-

mined by measuring the ability of various drugs to inhibit [³H]-

quinpirole (4 nM) binding to striatal membranes (approxi-

New Generation Dopaminergic Agents

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 26 4255

Wise, L. D.; Wustrow, D. J . The Discovery and Structure-

Activity Relationships of 1,2,3,6-Tetrahydro-4-phenyl-1-[(aryl-

cyclohexenyl)alkyl]pyridines. Dopamine Autoreceptor Agonists

and Potential Antipsychotic Agents. J . Med. Chem. 1994, 37,

3523-3533.

electrochemical detection. Compounds possessing agonism at

D₂autoreceptors are known to inhibit dopa accumulation in

this model.

(19) Wustrow, D. J .; Wise, L. D.; Cody, D. M.; MacKenzie, R. G.;

Georgic, L. M.; Pugsley, T. A.; Heffner, T. G. Studies of the Active

Conformation of a Novel Series of Benzamide Dopamine D₂

Agonists. J . Med. Chem. 1994, 37, 4251-4257.

Ack n ow led gm en t. The authors thank Bruce Hoff-

man, J ames Mattes, William Letter, and Dr. Mei-Yi

Zhang for their analytical assistance and Dr. J ohn

Yardley for helpful discussions.

(20) Kasper, S.; Barnas, C.; Heiden, A.; Volz, H. P. Laakmann, G.;

Zeit, H, Pfolz, H. Pramipexole as Adjunct to Haloperidol in

Schizophrenia. Safety and Efficacy. Eur. J . Neuropsychophar-

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J M9703653

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New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans

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