Conformationally constrained butyrophenones with mixed dopaminergic (D2) and serotoninergic (5-HT2(A), 5-HT2(C)) affinities: Synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and - thienocycloa

2774

J . Med. Chem. 1999, 42, 2774-2797

Con for m a tion a lly Con str a in ed Bu tyr op h en on es w ith Mixed Dop a m in er gic (D₂)

a n d Ser oton in er gic (5-HT_2A, 5-HT_2C) Affin ities: Syn th esis, P h a r m a cology,

3D-QSAR, a n d Molecu la r Mod elin g of (Am in oa lk yl)ben zo- a n d

-th ien ocycloa lk a n on es a s P u ta tive Atyp ica l An tip sych otics^∇

Enrique Ravin˜a,*^,†J esu´s Negreira,^†J ose´ Cid,^†Christian F. Masaguer,^†Elizabeth Rosa,^‡M. Emilia Rivas,^‡

J ose´ A. Fontenla,^‡M. Isabel Loza,^‡Helena Trista´n,^‡M. Isabel Cadavid,^‡Ferran Sanz,^§Estrella Lozoya,^§

Angelo Carotti,^|and Antonio Carrieri^|

Departamento de Quı´mica Orga´nica, Laboratorio de Quı´mica Farmace´utica, and Departamento de Farmacologı´a, Facultad de

Farmacia, Universidad de Santiago, E-15706 Santiago de Compostela, Spain, Departamento d’Informa`tica Me`dica, Institut

Municipal d’Investigacio´ Me`dica, Universitat Pompeu Fabra, Dr. Aiguader 80, E-08003 Barcelona, Spain, and Dipartimento

Farmaco Chimico, Universita` di Bari, I-70126 Bari, Italy

Received October 11, 1998

A series of novel conformationally restricted butyrophenones (2-(aminoethyl)- and 3-(amino-

methyl)thieno- or benzocycloalkanones bearing (6-fluorobenzisoxazolyl)piperidine, (p-fluoroben-

zoyl)piperidine, (o-methoxyphenyl)piperazine, or linear butyrophenone fragments) were pre-

pared and evaluated as atypical antipsychotic agents by in vitro assays of affinity for dopamine

receptors (D₁, D₂) and serotonin receptors (5-HT_2A, 5-HT_2C) and by in vivo assays of antipsychotic

potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended

mainly on the amine fragment connected to the cycloalkanone structure. As a group, compounds

with a benzisoxazolyl fragment had the highest 5-HT_2Aactivities, followed by the benzoylpi-

peridine derivatives; in general, R-substituted cycloalkanone derivatives were more active than

the corresponding â-substituted congeners. CoMFA (comparative molecular field analysis) and

docking studies showed electrostatic, steric, and lipophilic determinants of 5-HT_2Aand D₂

affinities and 5-HT_2A/D₂selectivity. The in vitro and in vivo pharmacological profiles of N-[(4-

oxo-4H-5,6-dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine (23b,

QF 0510B), N-[(4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol-

3-yl)piperidine (24b, QF 0610B), and N-[(7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-6-yl)ethyl]-

4-(6-fluorobenzisoxazol-3-yl)piperidine (29b , QF 0902B) suggest that they may be effective

antipsychotic drugs with low propensity to induce extrapyramidal side effects.

In tr od u ction

D₄, appears to be involved in schizophrenia. The activity

of classical antipsychotics such as haloperidol (Chart 1)

and the intensity of their undesirable side effects

(prolactin release and extrapyramidal symptoms (EPS))

are closely correlated with their ability to block dopam-

ine receptor D₂.^2-4It has also been suggested that

Schizophrenia is a complex psychological disorder of

unclear aetiology which to some degree affects 0.5-1.5%

of the world’s population.¹It is widely accepted that the

dopaminergic system plays a key role in schizophrenic

illness. Affected individuals may exhibit a wide spec-

trum of behavioral and other symptoms, ranging from

social withdrawal, catatonia, and affective flattening of

the personality (“negative” symptoms thought to be

associated with dopaminergic hypoactivity in the pre-

frontal cortex) to hallucinations, paranoia, and disor-

ganized behavior (“positive” symptoms thought to be

associated with hyperactive dopaminergic transmission

in the mesolimbic region of the brain).^1,2

5

receptors D₃and D₄may be involved in antipsychotic

activity (the atypical antipsychotic clozapine has high

affinity for D₄), but clinical assays have shown selective

D₄blockers to be ineffective as antipsychotics.⁶

Haloperidol and other classical butyrophenone-based

antipsychotics, such as spiperone and fluanisone, not

only have the side effects mentioned above but are also

ineffective against negative symptoms. Clozapine (Chart

1) was the prototype of a new group of “atypical” (non-

classical) antipsychotics that cause no EPS and are ef-

fective against negative as well as positive symptoms.^7-9

This superior activity profile of clozapine and other

atypical antipsychotics, such as risperidone, olanzapine,

and quetiapine (Chart 1),¹⁰may be due to their blocking

The cell-borne receptors with which dopamine inter-

acts are broadly classified as D₁-like or D₂-like. Only

the D₂-like family, which includes receptors D₂, D₃, and

^∇Presented, in part, at the XIVth International Symposium on

Medicinal Chemistry, Maastricht, The Netherlands, September 1996

(Book of Abstracts, P-6.51). 20th paper in the series “Synthesis and

CNS Activity of Conformationally Restricted Butyrophenones”; for

preceding papers, see ref 47.

not only dopamine receptors but also serotonin receptor

11-13

5-HT_2A

,

and Meltzer and co-workers^14,15have ac-

* For correspondence and reprints: Prof. Enrique Ravin˜a. Phone:

+ 34-981-594628. Fax: + 34-981-594912. E-mail: qofara@usc.es.

^†Departamento de Qu´ımica Orga´nica.

cordingly suggested that it is reflected by the ratio

between the pK_i’s of these agents at receptors 5-HT_2A

and D₂, which appears to be >1.12 for atypical anti-

psychotics and <1.09 for classical antipsychotics.

^‡Departamento de Farmacolog´ıa.

^§Departamento d’Informa`tica Me`dica.

^|Dipartimento Farmaco Chimico.

Published on Web 07/13/1999

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2775

Ch a r t 1

Ch a r t 2

Currently there are two main hypotheses as to the

mechanism by which serotonin receptor blockage may

prevent the EPS that are otherwise induced by dopam-

ine receptor blockage. According to one, 5-HT receptor

blockage may lead to disinhibition of the nigrostriatal

dopaminergic pathway and hence to enhancement of

striatal dopaminergic release and competitive displace-

ment of the drug from postsynaptic striatal dopamine

receptors, i.e., to partial deblockage of this pathway.

According to the other, 5-HT₂blockage may raise the

threshold for EPS by modulating cholinergic or GABA-

ergic mechanisms. These two possibilities are not neces-

sarily mutually exclusive. In either case, the improve-

ment in negative symptoms caused by 5-HT₂blockers

is thought to be due to disinhibition of dopaminergic

transmission in the frontal cortex.¹⁶

Ch a r t 3. NRR of Structures in Chart 2

clozapine block both 5-HT_2Aand D₂, has been prompted

in part by the finding that clozapine increases the risk

of agranulocytosis.³⁶However, since none of these drugs

has proved to be as broadly effective as clozapine, the

discovery of effective antipsychotics with no side effects

is still a major research goal.

Recent experimental and clinical studies appear to

confirm the importance of 5-HT_2Afor the activity profile

of atypical antipsychotics.^17-21Indeed, even the 5-HT_2A

-

In previous papers^37,38we have reported the synthesis

of the 3-(aminomethyl)tetralones Ia ,d -f (Charts 2 and

3) and their affinities for D₁, D₂, and 5-HT_2A. Com-

pounds Ia ,e showed high affinity for 5-HT_2Aand D₂(pK_i-

(5-HT_2A, Ia ) ) 8.80, pK_i(5-HT_2A, Ie) ) 7.75, pK_i(D₂, Ia )

) 7.68, pK_i(D₂, Ie) ) 7.60) and in conventional behav-

ioral tests on laboratory animals exhibited antipsychotic

potential similar to that of haloperidol but much lower

cataleptogenicity. Both Ia ,e have two butyrophenone

pharmacophores: the common semirigid 3-(aminometh-

yl)tetralone fragment and either a flexible linear buty-

rophenone moiety linked to the cycloalkanone by a

piperazine bridge (Ie) or a 4-(p-fluorobenzoyl)piperidine

selective serotonin antagonist MDL 100907 (Chart 1),

which has no activity at dopamine receptors, has shown

antipsychotic potential in experiments with neuro-

chemical, electrophysiological, and behavioral models.^22-24

Atypical antipsychotics also bind to 5-HT_2C, 5-HT₆, and

5-HT₇serotonin receptors.^25-29In the case of the last

two recombinant receptors, new supplementary studies

are necessary in order to clarify their role as pharma-

cological receptors and their pathophysiological involve-

ments.³⁰In any case, 5-HT₇receptors are thought not

to be involved in schizophrenia.³¹

The development of drugs such as cinuperone,³²

risperidone,³³ocaperidone,³⁴or sertindol,³⁵which like

2776 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

Sch em e 1^a

a

Reagents: (i) MeOH, H⁺; (ii) CH(OCH₃)₃, (CH₂OH)₂/p-TsOH; (iii) LiAlH₄; (iv) CBr₄, Ph₃P; (v) HNRR, KI, Na₂CO₃, MeⁱBuCO.

moiety in which carbons 2-4 of the butyrophenone form

part of a six-membered ring (Ia ). As early as 1970, this

latter structure was described as an antipsychotic

pharmacophore of similar potency to linear butyrophe-

nones,³⁹and a SAR study of ketanserin analogues has

suggested that the benzoyl carbonyl (present in both

Ia ,e) may play a prominent role in anchoring or orient-

ing these compounds at receptor 5-HT₂.⁴⁰

We subsequently extended our SAR study to the

2-(aminoethyl)benzocycloalkanones IIa ,d -f, IIIa ,d -f,

and IVa ,^41-43the 5-(aminoethyl)-4,5,6,7-tetrahydroin-

dol-4-ones Vd ,f,⁴⁴(butyrophenone homologues of the

antipsychotic molindone), the 6-aminomethyl analogues

VIa -f,^45,46and the 2-(aminomethyl)-1,2,3,9-tetrahydro-

4H-carbazol-4-ones VIIa ,b,f.⁴⁷In all these series, the

conformation of the butyl chain is restricted by its

partial incorporation in a cycloalkanone ring fused to a

benzene ring or a heterocycle (Chart 2).

In continuation of our previous work, we have now

synthesized and pharmacologically evaluated a number

of members of the indanone series 10 and the ap-

proximately isosteric thiophene series 23, 24, 29, and

35, whose activity at receptors D₂and 5-HT_2Awas

suggested by the similarity of their structures to those

of previously synthesized active compounds such as Ia ,e;

we have used these structures and the pharmacological

results in a 3D-QSAR study. Like compounds I-VII,

most of the new target compounds (all except 24f and

35f) have two butyrophenone pharmacophores, one

being the common semirigid (aminoalkyl)cycloalkanone

moiety and the other either a flexible, linear butyrophe-

none fragment (e in Chart 3), a 4-(p-fluorobenzoyl)-

piperidine moiety (a ), or a 4-(6-fluoro-1,2-benzisoxazol-

3-yl)piperidine moiety (b). The NRR fragment b was

included because 1,2-benzisoxazole is bioisosteric to

benzoyl⁴⁸and in view of recent results on 3-(4-piper-

azinyl)-6-hydroxybenzisoxazoles as potential atypical

antipsychotics.⁴⁹

sulfonic acid, pyridinium tosylate, or acid ion-exchange

resins) failed to afford significant yields of the ethylene

ketal, but Delepine’s method (acid-catalyzed reaction of

the ketone with ethylene glycol and trimethyl orthofor-

mate) furnished ketal 3 in virtually quantitative yield

(80% from 1). Reduction of the ester with lithium alumi-

num hydride then gave alcohol 4, which was brominated

with carbon tetrabromide/triphenylphosphine to obtain

a 70% yield of the bromo derivative 5. However, all

attempts to replace the bromine atom of 5 with the

substituted piperidines or piperazines required by the

target compounds were unsuccessful (although it was

found possible to obtain 45-50% yields of compounds 6

and 7 by this method; see Experimental Section).

Target compounds 10, 23, 24, and 29 containing as

their NRR fragment either a , b, or f (Chart 3) were

eventually prepared by amide-linking the two moieties,

protecting non-amide carbonyls as ketals, reducing the

amide carbonyl, and deprotection (Schemes 2, 4, and 5).

For compound 10e and the previously reported⁴³com-

pounds 23e and 24e, the Chart 2 moiety was amide-

linked to piperazine-Boc (fragment c), Boc was removed,

and the rest of fragment e was added after reduction of

the amide carbonyl (Schemes 3 and 4). For compounds

35, the cycloalkanone ring was constructed after the

thiophene ring was linked as shown in Schemes 6 and

7 to a Chart 3 amine (a , b, or f for 35a ,b,f, respectively;

piperazine-Boc for 35e, in which the remainder of

fragment e was incorporated after construction of the

cycloalkanone ring). Details of the operations involved

in these strategies are given in what follows. The

melting points of all the target compounds are listed in

Tables 1-4 and 7 together with the yields of the final

step(s) of their synthesis.

Alkylation of the thienocycloalkanones 11, 12, and 25

with lithium diisopropylamide at -70 °C, followed by

quenching with ethyl bromoacetate, gave ethyl esters⁴²

that were then hydrolyzed to the thienocycloalkanone

acetic acids 17, 18, and 26, with yields of 50-55% from

the thienocycloalkanones. Compound 18 was also pre-

pared by condensation of thiatetralone with glyoxylic

acid in acidic medium to obtain 1-oxo-1,2,3,4-benzo[b]-

thiophene-5-ylideneacetic acid (14) and then subsequent

reduction of the alkene acid with zinc and acetic acid.

The amides listed in Table 5 were prepared in good

yields by direct acid-amine coupling, with carboxylate

Ch em istr y

We initially attempted to prepare target compounds

10a ,b,e,f via 3-(bromomethyl)-1-indanone (5; Scheme 1).

3-Carboxy-1-indanone (1) was prepared by Friedel-

Crafts cyclization of phenylsuccinic anhydride⁵⁰and

esterified to obtain the methyl ester 2. Reaction of 2 with

ethylene glycol in the presence of catalysts (p-toluene-

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2777

Ta ble 1. 3-(Aminomethyl)-1-indanone Hydrochlorides

Sch em e 2^a

compd

(code no.)

yield

(%)

mp (°C)

recryst solv

formula

6

174-175^aEtOH-Et₂O 45 (A) C₁₄H₁₉NO‚HCl

45 (B)

162-165^bEtOH-Et₂O 50 (A) C₁₄H₁₇NO₂‚HCl

45 (B)

7 (QF 0500B)

10a (QF 0501B) 229-231 i-PrOH

10e (QF 0502B) 216-217 i-PrOH

10f (QF 0503B) 220-222 i-PrOH

75

50

85

C

₂₂H₂₂FNO₂‚HCl

₂₄H₂₇N₂O₂‚2HCl

₂₁H₂₃N₂O₂‚2HCl

a

b

Base, mp 69-71 °C. Base, mp 72-73 °C (AcOEt); 2,4-

dinitrophenylhydrazone, mp 240-243 °C (EtOH). ^cBase, mp 99-

102 °C (AcOEt).

Ketalization of carbonyl groups with ethylene glycol

and p-toluenesulfonic acid or pyridinium tosylate (PPTS)

in anhydrous toluene, with azeotropic distillation of

water in a Dean-Stark apparatus, provided the ethyl-

ene ketals listed in Table 6 in yields of 80-95%.

Attempts to shorten the reaction times by using other

catalysts (amberlyst and boron trifluoride etherate) and/

or other conditions (e.g., by using 2,2-dimethyl-1,3-

propanediol⁵²instead of ethylene glycol or Noyori’s

conditions⁵³) were unsuccessful. The ethylene ketals

were isolated as colorless oils and used in the next step

without further purification.

Deketalization to restore carbonyl groups was initially

attempted by cautious dropwise addition of a saturated

solution of dry HCl in anhydrous ether to a solution of

aminoketone ketal. However, in the case of bis(ketals)

it was found that only one carbonyl was restored.

According to the results of NOE experiments showing

significant interaction between the protons of the phenyl

ring and ethylene ketal in the product obtained from

N-[(4-oxo-4H-5,6-dihydrocyclopenta[b]thiophene-5-yl)-

ethyl]-4-(p-fluorobenzoyl)piperidine bis(ethylene ketal)

(Figure 1), the nondeprotected carbonyl was that of the

benzoyl group.

a

Reagents: (i) HNRR, DCC/HOBt; (ii) (CH₂OH)₂/p-TsOH or

PPTS; (iii) (1) LiAlH₄, (2) HCl (dilute).

The piperazine-Boc derivatives 8c, 19c, and 20c were

transformed into the desired compounds 10e, 23e, and

24e by removal of Boc with trifluoroacetic acid, reduc-

tion of the amide carbonyl, alkylation of the piperazine

NH group with 4-chloro-1,1-(ethylenedioxy)-1-(4-fluo-

rophenyl)butane in methyl isobutyl ketone containing

catalytic amounts of potassium iodide,⁴³and cleavage

of the resulting bis(ethylene ketal) (overall yields of 35-

40% from 8d , 19d , and 20d ).

activation by dicyclohexylcarbodiimide (DCC) in the

presence of 1-hydroxybenzotriazole (HOBt) or by bis(2-

oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl)⁵¹(which

gave clean reactions with excellent yields). Direct

conversion of the keto ester to the amide with trimethyl-

aluminum amide (prepared in situ) was attempted for

20a ,c,f but only gave an acceptable yield in the case of

20f.

Sch em e 3^a

a

Reagents: (i) N-(tert-butyloxycarbonyl)piperazine, DCC/HOBt; (ii) CF₃CO₂H; (iii) (CH₂OH)₂/p-TsOH; (iv) LiAlH₄; (v) (1) 4-chloro-1,1-

(ethylenedioxy)-1-(4-fluorophenyl)butane, KI, Na₂CO₃, (2) HCl (dilute).

2778 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

Sch em e 4^a

a

Reagents: (i) HOOC-CHO; (ii) Zn/AcOH; (iii) (1) BrCH₂CO₂Et/LDA, (2) KOH/EtOH; (iv) HNRR, (CH₃)₃Al (only for benzo[b]thiophene

series); (v) HNRR, DCC/HOBt or BOP-Cl; (vi) TFA; (vii) (CH₂OH)₂/p-TsOH or PPTS; (viii) (1) LiAlH₄, (2) HCl (dilute); (ix) (1) LiAlH₄, (2)

4-chloro-1,1-(ethylenedioxy)-1-(4-fluorophenyl)butane, KI, Na₂CO₃, (3) HCl (dilute).

Sch em e 5^a

Ta ble 2. 5-(Aminoethyl)-4-oxo-5,6-dihydrocyclopenta[b]-

thiophenes

compd

(code no.)

recryst yield

solv (%)

mp (°C)

formula

23a (QF 0505B) 172-173^aAcOEt

70 C₂₁H₂₂FNO₂S‚C₂H₂O₄

23b (QF 0510B) 230-232^bi-PrOH 75 C₂₁H₂₁FN₂O₂S‚2HCl

23e (QF 0506B) 244-246^ci-PrOH 58 C₂₃H₂₇FN₂O₂S

a

Oxalate. ^bHydrochloride. ^cHydrochloride; base crystallized on

standing, mp 89-90 °C; 2,4-dinitrophenylhydrazone, mp 198-199

°C (MeOH).

Ta ble 3. 5-(Aminoethyl)-4-oxo-4,5,6,7-tetrahydrobenzo[b]-

thiophene Hydrochlorides

compd

(code no.)

mp (°C) recryst solv yield^a

formula

24a (QF 0601B) 278-280 MeOH-Et₂O 85 C₂₂H₂₄FNO₂S‚HCl

24b (QF 0610B) 248-249 AcOEt 75 ₂₂H₂₃FN₂O₂S‚HCl

C

24e (QF 0602B) 234-236 MeOH-Et₂O 50 C₂₄H₂₉FN₂O₂S‚2HCl

24f (QF 0603B) 233-235 MeOH-Et₂O 85 C₂₁H₂₆N₂O₂S‚2HCl

a

Overall yield for amide reduction + ketal cleavage.

a

Reagents: (i) (1) BrCH₂CO₂Et/LDA, (2) KOH/EtOH; (ii)

HNRR, DCC/HOBt or BOP-Cl; (iii) (CH₂OH)₂/PPTS; (iv) (1)

LiAlH₄, (2) HCl (dilute).

The general synthetic strategy used for the 6-(ami-

nomethyl)thiatetralone derivatives 35 (Schemes 6 and

7) parallels the approach used previously for the ben-

zene series.³⁷Thienylbutyrolactone 32 was prepared by

hydroxymethylation of â-thenoylpropionic acid 30 fol-

lowed by lactonization of thenoylbutyrolactone 31 and

subsequent Clemmensen reduction.⁵⁴Reaction of 32

with hydrogen bromide in acetic acid afforded unstable

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2779

Ta ble 4. 6-(Aminomethyl)-7-oxo-4,5,6,7-tetrahydrobenzo[b]-

thiophene Hydrochlorides

Experimental Section. In none of the binding assays did

the slope of the corresponding curve of specific radioli-

gand binding against competitor concentration differ

significantly from unity at the p ) 0.05 level, and in

none of the experiments on serotonin-induced contrac-

tion of rat aorta did the slope of the Schild plot differ

significantly from unity at the p ) 0.05 level. Table 9

lists affinities for D₁, D₂, 5-HT_2A, and 5-HT_2C, together

with pA₂values and the 5-HT_2A/D₂and 5-HT_2A/5-HT_2C

selectivity ratios.

compd

recryst yield^a

(code no.)

mp (°C)

solv

(%)

formula

29a (QF 0901B) 262-264 i-PrOH

29b (QF 0902B) 246-248 i-PrOH

65

80

C

₂₂H₂₄FNO₂S‚HCl

₂₂H₂₃FN₂O₂S‚2HCl

a

Overall yield for amide reduction + ketal cleavage.

(bromomethyl)-γ-(2-thenoyl)propionic acid, which was

immediately esterified to afford the bromo ester 33.

Subsequent nucleophilic substitution with amine a , b,

c, or f in basic methyl isobutyl ketone led to the â-amino

esters 34a -c,f in good to excellent yields (Table 8).

Finally, acid-catalyzed ring closure with polyphosphoric

acid⁵⁵gave the final thiatetralones in yields of up to

50%.⁵⁶

As a step toward currently incomplete studies of

receptor binding by the pure enantiomers of our com-

pounds, we obtained those of compound 35b. Attempts

to resolve racemic 35b using chiral columns failed, but

resolution of its â-amino ester precursor 34b was

successful, affording (+)34b and (-)34b with high

optical purity (ee > 95%).⁵⁷Subsequent ring closure of

each enantiomer (Scheme 8) gave (+)35b and (-)35b

with no loss of enantiomeric purity.⁵⁸

The new compounds all showed greater affinity for

D₂than for D₁. The most active at D₁were 23b, 24b,

29b, and 35b, which had pK_i’s ranging from 6.53 for

24b to 6.90 for 23b. For D₂, pK_i’s ranged from 5.98 for

10a to 7.70 for 23b. Figure 2 shows the radioligand-

binding curves recorded with 23b and 24b as competi-

tors at receptors D₁and D₂, respectively.

The affinities of the new compounds for 5-HT_2Ain rat

cerebral cortex, calculated as pK_iusing [³H]ketanserin

as the competing radioligand, ranged from <6 for 35f

to 8.84 for 24a (Figure 3A shows the radioligand-binding

curves recorded with 24b and risperidone as competi-

tors). The pK_iof the 5-HT_2A-specific agent ketanserin

(8.49 ( 0.11) was exceeded by 23b and 24a ,b, that of

the atypical antipsychotic clozapine (8.30) by 23b,

24a ,b, and 35b, and that of the classical antipsychotic

haloperidol (7.70) by 23a ,b, 24a ,b, 29a ,b, and 35b. The

pK_ivalues agree well with the pA₂values obtained

measuring inhibition of the 5-HT-induced contraction

Resu lts a n d Discu ssion

In Vitr o Stu d ies of New Com p ou n d s. Details of

the in vitro assays performed are described in the

Sch em e 6^a

a

Reagents: (i) (1) HCHO/NaOH, (2) HCl; (ii) Zn-Hg/HCl; (iii) (1) HBr-AcOH, (2) CH₂N₂; (iv) HNRR, KI, Na₂CO₃; (v) PPA.

Sch em e 7^a

a

Reagents: (i) N-(tert-butyloxycarbonyl)piperazine, KI, Na₂CO₃; (ii) HCl/CH₃OH; (iii) PPA; (iv) (1) 4-chloro-1,1-(ethylenedioxy)-1-(4-

fluorophenyl)butane, KI, Na₂CO₃, (2) HCl (dilute).

2780 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ta ble 5. Ketoamides

Ravin˜a et al.

compd

mp (°C)

recryst solv

coupling reagent

yield (%)

formula

C₂₂H₂₀FNO₃

C₁₉H₂₄N₂O₄

C₁₄H₁₆N₂O₂.HCl

8a

8c

146-149

146-147

142-143^b

165

AcOEt

i-PrOH

AcOEt

DCC/HOBt

80

85

80

78

75

85

90

78

85

15

90

15

80

65

70

90

75

90

8d ^a

8f

DCC/HOBt

BOP-Cl

C

₂₁H₂₂N₂O₃

19a

19b

c

C₂₁H₂₀FNO₃S

155-157

i-PrOH

C

₂₁H₁₉FN₂O₃S

₁₈H₂₄N₂O₄S

19c

116-118

264-266^b

143-145

i-PrOH

MeOH-Et₂O

i-PrOH

DCC/HOBt

19d ^a

20a

C₁₃H₁₆N₂O₂S‚HCl

DCC/HOBt

Me₃Al

DCC/HOBt

Me₃Al

C

₂₂H₂₂FNO₃S

20b

20c

161-163

113-115

i-PrOH

C

₂₂H₂₁FN₂O₃S

₁₉H₂₆N₂O₄S

20d ^a

20f

226-228^b

135-137

MeOH-Et₂O

AcOEt

C₁₄H₁₈N₂O₂S‚HCl

DCC/HOBt

Me₃Al

DCC/HOBt

BOP-Cl

DCC/HOBt

BOP-Cl

C

₂₁H₂₄N₂O₃S

₂₂H₂₂FNO₃S

₂₂H₂₁FN₂O₃S

27a

27b

163-165

148-150

cyclohexane

a

Obtained by BOC removal with TFA. ^bHydrochloride. ^cBis(2,4-dinitrophenylhydrazone), mp 223-225 °C (i-PrOH). Anal. (C₃₃H₂₈FN₉O₉S)

C, H, N. From the ester 16.

Ta ble 6. Ethylene Ketals

Ta ble 8. γ-Amino-â-(2-thenyl)butyric Acid Methyl Ester

Hydrochlorides

compd

catalyst

p-TsOH

pyridinium tosylate

p-TsOH

reaction time (h)

yield (%)

compd mp (°C)

recryst solv yield (%)

90

formula

9a ^a

9d

9f

96

144

96

120

168

96

48

120

90

93

82

93

87

90

95

90

94

95

90

34a

34b

34c

190-191 AcOEt

C

₂₂H₂₆FNO₃S‚HCl

₂₂H₂₅FN₂O₃S‚HCl

162-164 AcOEt

133-135 MeOH-Et₂O

85

90

95

90

21a ^b

21b

21d

22a ^b

22b

22d

22f

p-TsOH

pyridinium tosylate

p-TsOH

pyridinium tosylate

p-TsOH

pyridinium tosylate

C₂₃H₂₇FN₂O₂S‚HCl

34d ^a130-131 AcOEt

C₁₄H₂₂N₂O₂S‚2HCl

34f

191-192 AcOEt

C₂₁H₂₈N₂O₃S‚2HCl

a

From 34c by BOC removal (HCl/MeOH).

24

190

144

clozapine (7.00), and none of the new compounds had a

pK_iapproaching that of haloperidol (8.30).

28a ^b

28b

SAR Stu d ies. The pK_i’s listed in Table 9 for the

compounds synthesized in our laboratory show a fair

spread of values for 5-HT_2A(2.84 units if the lowest pK_i

is taken to be 6; n ) 25) and rather smaller spreads for

D₂(2.21; n ) 25), 5-HT_2C(2.09; n ) 14), and D₁(1.9; n

) 25). Highest affinities are shown for 5-HT_2A(range:

<6-8.84), followed by D₂(5.98-8.19), 5-HT_2C(<5-

7.09), and D₁(<5-6.90).

a

Bis(ethylene ketal), crystallized on standing, mp 138-139 °C.

b

Bis(ethylene ketals).

The highest 5-HT_2Aaffinities are those of the R-sub-

stituted cycloalkanones with a piperidine NRR fragment

(23a ,b, 24a ,b, 29a ,b, Ia , IIa , IIIa , all with pK_i> 7.9),

while most of the lowest affinities correspond to (o-

methoxyphenyl)piperazine derivatives (10f, 35f, If, all

with pK_i< 6.5). Isosteric substitution of thiophene for

the benzo ring fused to the cycloalkanone generally

reduces interaction with 5-HT_2Asomewhat (compare

compounds I with compounds 35, II with 23, III with

24 and 29; the exceptions are the pairs IIIa /24a and

IIe/23e). Moving the thiophene sulfur as close as

possible to the exocyclic oxygen of the cycloalkanone also

reduces 5-HT_2A-blocking activity slightly (compare 24a,b

with 29a ,b).

Among the â-substituted cycloalkanones, replacing

the six-membered cycloalkanone ring with a five-

membered ring dramatically reduces D₂-blocking activ-

ity (compare Ia ,e,f with 10a ,e,f). Replacement of the

fused benzo ring with thiophene generally gives rise to

a much more modest reduction in activity.

F igu r e 1. NOE interactions in N-[(4-oxo-4H-5,6-dihydro-

cyclopenta[b]thiophene-5-yl)ethyl]-4-(p-fluorobenzoyl)piperi-

dine monoethylene ketal.

Ta ble 7. 3-(Aminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene

Hydrochlorides

compd

(code no.)

yield

mp (°C) recryst solv (%)

formula

35a (QF 0605B) 243-244 i-PrOH

35b (QF 0609B) 258-260 AcOEt

25

40

C

₂₁H₂₂FNO₂S‚HCl

₂₁H₂₁FN₂O₂S‚2HCl

35e (QF 0606B) 236-237 MeOH-Et₂O 55 C₂₃H₂₇FN₂O₂S‚2HCl

35f (QF 0607B) 215-217 AcOEt

35

C₂₀H₂₄N₂O₂S‚2HCl

of rat aorta (Figure 3B shows dose-response curves for

35b), which supports the accuracy of both parameters

and attests to the similarity between cortical and

peripheral 5-HT receptors of type 2A.

The affinities of the new compounds for 5-HT_2C

,

calculated as pK_iusing [³H]mesulergine as the compet-

ing radioligand, ranged from <5 for 10e to 7.09 for 24f

(Figure 3C shows the radioligand-binding curves re-

corded with 24f and risperidone as competitors). Only

23b and 24b,f exhibited affinity similar to that of

There are no significant pairwise correlations among

the pK_i’s for the various receptors (r²e 0.35), presum-

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2781

Sch em e 8

Ta ble 9. In Vitro Assays

pK_i

pK_iratios

pA₂

compd

structure^a

D₁

D₂

5-HT_2A

5-HT_2C

5-HT_2A/D₂5-HT_2A/5-HT_2C

5-HT_2A

10a (QF 0501B)

10e (QF 0502B)

10f (QF 0503B)

23a (QF 0505B)

23b (QF 0510B)

23e (QF 0506B)

24a (QF 0601B)

24b (QF 0610B)

24e (QF 0602B)

24f (QF 0603B)

29a (QF 0901B)

29b (QF 0902B)

35a (QF 0605B)

35b (QF 0609B)

35e (QF 0606B)

35f (QF 0607B)

Ia (QF 0104B)^b

Ie (QF 0102B)^b

If (QF 0100B)^b

IIa (QF 0307B)^d

IIe (QF 0309B)^e

IIIa (QF 0303B)^d

IIIe (QF 0304B)^e

IIIf (QF 0301B)^c

IVa (QF 0311B)^d

haloperidol

VIII

IX

X

XII

XI

I

II

5.81 ( 0.06 5.98 ( 0.10 7.58 ( 0.14

5.15 ( 0.07 6.49 ( 0.13 7.34 ( 0.10

5.43 ( 0.09 6.19 ( 0.09 6.05 ( 0.21

5.60 ( 0.08 6.39 ( 0.14 8.15 ( 0.13

6.90 ( 0.14 7.70 ( 0.31 8.76 ( 0.20

6.49 ( 0.04 6.58 ( 0.19 7.37 ( 0.15

5.86 ( 0.03 6.68 ( 0.08 8.84 ( 0.17

6.53 ( 0.11 7.34 ( 0.20 8.56 ( 0.20

5.51 ( 0.07 6.65 ( 0.12 6.54 ( 0.13

5.27 ( 0.12 6.79 ( 0.16 6.84 ( 0.12

6.25 ( 0.20 6.76 ( 0.40 7.95 ( 0.09

6.87 ( 0.28 7.36 ( 0.33 8.17 ( 0.80

6.37 ( 0.03 6.50 ( 0.13 7.24 ( 0.12

6.89 ( 0.09 7.26 ( 0.10 8.33 ( 0.11

5.87 ( 0.10 6.57 ( 0.09 6.97 ( 0.13

5.96 ( 0.07

1.27

1.10

0.98

1.27

1.14

1.12

1.32

1.17

0.98

1.01

1.18

1.11

1.15

1.06

1.27

>1.47

0.94

1.28

1.24

1.25

1.36

1.24

1.02

0.96

8.13 ( 0.09

7.20 ( 0.20

6.21 ( 0.10

8.92 ( 0.04

<5

6.44 ( 0.07

6.38 ( 0.06

7.06 ( 0.06

5.90 ( 0.11

6.48 ( 0.06

6.90 ( 0.05

6.40 ( 0.70

7.09 ( 0.17

7.63 ( 0.08

9.02 ( 0.04

9.87 ( 0.40

6.83 ( 0.20

6.95 ( 0.02

6.03 ( 0.04

6.69 ( 0.12

5.40 ( 0.12

6.04 ( 0.06

1.20

1.24

1.29

7.82 ( 0.16

9.13 ( 0.70

7.79 ( 0.06

5.90 ( 0.01

7.86 ( 0.86

7.27 ( 0.70

6.48 ( 0.50

8.12 ( 0.11

7.30 ( 0.70

7.47 ( 0.81

7.35 ( 0.11

6.72 ( 0.06

6.75 ( 0.60

<5

6.49 ( 0.13 5.82 ( 0.06

6.49

6.42

5.87

5.55

5.88

5.81

5.87

5.83

5.89

7.68

7.60

8.19

7.15

7.17

7.32

7.04

7.64

7.33

8.80 ( 0.80

7.75 ( 0.60

6.29 ( 0.60

8.60 ( 0.80

6.91 ( 0.60

8.11 ( 0.80

7.14 ( 0.70

7.39 ( 0.70

7.88 ( 0.70

1.15

1.02

0.77

1.20

0.96

1.11

1.01

0.97

1.08

0.91

1.30

1.20

III

IV

6.80 ( 0.03 8.48 ( 0.25 7.70

6.77 ( 0.13 6.58 ( 0.10 8.30

8.09 ( 0.63 9.70

5.60

7.80

7.04 ( 0.7

1.37

1.10

1.29

clozapine

risperidone

SCH23390

9.16

9.27 ( 0.23

a

b

d

See Charts 2 and 3. See ref 36. ^cSee ref 40. See ref 41. ^eSee ref 42.

ably due to differences among the binding sites of the

3D-QSAR Stu d ies. Since its introduction in 1988,⁵⁹

receptors and the ways in which the compounds bind

to them. The best 5-HT_2A/D₂selectivity ratio, 1.32, is

that of 24a , which combines the highest pK_ifor 5-HT_2A

(8.84) with a moderate pK_ifor D₂(6.68); good ratios are

also shown by all the (p-fluorobenzoyl)piperidine deriva-

tives except 35a (1.11) and by the benzisoxazolyl deriva-

tives 23b (1.14), 24b (1.17), and 35b (1.15), despite their

high pK_i’s for D₂(7.26-7.70). Borderline selectivity

between Meltzer and co-workers’ limits of 1.09 and 1.12

is shown by the new compounds 10e (1.10), 29b (1.11),

and 35a (1.11). Selectivity for D₂versus 5-HT_2Awas

shown by the (o-methoxyphenyl)piperazine derivatives

10f, 35f, If, and IIIf and by the (p-fluorobenzoyl)-

propylpiperazine 24e.

comparative molecular field analysis (CoMFA) has

proved to be a useful tool in 3D-QSAR studies of

biologically active substances.⁶⁰Traditional CoMFA

correlates the biological activity of a series of molecules

with their steric and electrostatic fields sampled at grid

points in a 3D box around the aligned molecules.

Unfortunately, these two fields alone are not able to

describe all binding forces appropriately.⁶¹Moreover,

CoMFA describes only the enthalpy component of

ligand-receptor interactions. Introducing the molecular

lipophilicity potential (MLP)⁶²as an additional field

significantly improves the descriptive, predictive, and

interpretative powers of CoMFA in many cases. The

MLP encodes hydrogen-bonding and hydrophobic inter-

actions, which are not sufficiently described by the steric

and electrostatic fields, and also includes an entropy

component.⁶³The preferred regression method for analy-

sis of the dependence of biological activity on the large

24a also had the highest 5-HT_2A/5-HT_2Cselectivity

ratio, 1.36. In fact, all the new compounds had good

selectivity for 5-HT_2Aversus 5-HT_2Cexcept, once again,

the (o-methoxyphenyl)piperazines and 24e.

2782 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

F igu r e 2. Inhibition by reference drugs and selected new

compounds of [³H]SCH23390 binding by striatal D₁(A) and

[³H]spiperone binding by striatal D₂(B).

number of structure-related variables (steric, electro-

static, and lipophilic potentials at the grid points) is

partial least squares (PLS).⁶⁴The optimal number of

components (ONC) is determined by cross-validation,

and the predictive ability of the model is assessed as

the cross-validated r²(r²_cv, q²).⁶⁵Graphical representa-

tions of CoMFA results (coefficient isocontour maps)

indicate the regions where the variation in the steric,

electrostatic, and lipophilic properties of the molecules

in the data set is correlated with the variation in

biological activity.

In this work, the molecules synthesized in our labora-

tory that are listed in Table 9 were subjected to CoMFA

using steric, electrostatic, and/or lipophilic potentials

and the binding data for 5-HT_2Aand D₂(the only

receptors for which affinities were sufficiently high and

the number, spread, and distribution of the data ad-

equate).^66,67In accordance with Holtje and Folkers’

pharmacophore model for 5-HT_2Ablockers,⁶⁸molecular

alignment was carried out with reference to the cen-

troid(s) of the aromatic system(s), the oxygen atoms of

carbonyl and methoxy groups, and the charged amino

group; isoxazolyl nitrogens were treated as oxygens. The

compounds were initially considered in their most

extended conformations, which were optimized by en-

ergy minimization using the PM3 Hamiltonian of MO-

PAC.⁶⁹At this stage both enantiomers of chiral mol-

ecules were considered, but further analyses used only

the better-aligning enantiomer, which was the S form

for all the chiral compounds except 23a ,b,e. We note

that although the affinities of Table 9 refer to racemic

mixtures, preliminary data on some resolved enanti-

omers⁵⁸seem to indicate that their pK_ivalues are quite

F igu r e 3. (A) Inhibition by 24b (O) and risperidone (b) of

[³H]ketanserin binding by 5-HT_2Areceptors in murine frontal

cortex membrane preparations. (B) Inhibition by 35b of

serotonin-induced contractions of denuded rat aorta (curves

from a single representative of six replicate experiments;

vertical bars indicate SEM). (C) Inhibition by 24f (O) and

risperidone (b) of [³H]mesulergine binding by 5-HT_2Creceptors

in murine frontal cortex membrane preparations. Graphs A

and C show triplicate points from a single experiment; a total

of two replicate experiments were performed in each case.

similar, which justifies our exclusive use of the better-

aligning enantiomer.

To improve matching, the structures selected as

described above were rotated about single bonds and

replaced with the best-aligning resulting conformation

if the energy cost of the change was less than 8 kcal/

mol.⁷⁰The validity of this apparently high limit was

investigated by importing these conformers and the

minimum-energy structures from which they were

derived into Macromodel and reoptimizing (without

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2783

Ta ble 10. Statistical Results^aof CoMFA for Receptor Ligands^b

receptor(s)

5-HT_2A

model

field(s)

n

q²

nc

r²

s

F

S₁

S₂

E₁

E₂

L₁

L₂

ste

ele

25

24^c

25

24^c

25

24^c

25

24^c

25

24^c

25

24^c

25

24^c

25

0.505

0.617

0.486

0.624

0.493

0.619

0.519

0.615

0.504

0.637

0.530

0.642

0.521

0.630

0.714

0.604

0.721

0.688

0.743

0.720

0.583

0.640

0.601

0.626

0.606

0.613

0.625

4

5

4

3

lipo

SE₁

SE₂

SL₁

SL₂

EL₁

EL₂

SEL₁

SEL₂

S₃

E₃

L₃

SE₃

SL₃

EL₃

S₄

ste + ele

0.865

0.878

0.876

0.352

0.335

0.337

30.364

34.045

33.682

ste + lipo

ele + lipo

ste + ele + lipo

D₂

ste

ele

lipo

ste + ele

ste + lipo

ele + lipo

ste

0.928

0.914

0.161

0.177

64.601

52.849

d

5-HT_2A/D₂

E₄

L₄

SE₄

SL₄

EL₄

SEL₄

ele

lipo

ste + ele

ste + lipo

ele + lipo

ste + ele + lipo

0.823

0.836

0.380

0.381

0.366

32.650

32.492

35.700

a

n, q², nc, r², s, and F are the number of data points, the squared cross-validated correlation coefficient, the chosen number of components

b

(see text), the squared correlation coefficient, the standard deviation of regression equation, and the F ratio, respectively. See ref 65.

^cExcluding compound IIIf (QF 0301B). Selectivity expressed as pK_i(5-HT_2A) - pK_i(D₂).

d

changing torsion angles) using the solvent continuum

approximation;⁷¹the results suggest that the solvent

effect may substantially reduce the energy difference

between the two conformers.

affinity (SL₃and EL₃) are shown in Figure 4 together

with representations of the corresponding models for

5-HT_2A/D₂selectivity (SL₄and EL₄) and, to aid inter-

pretation, representations of both highly active or

selective ligands and poorly active or selective ligands.

These color maps (the color code is defined in Table 11)

show the regions of space in which variation of the field

considered has most effect on the dependent variable.

For the model of 5-HT_2Aaffinity SL₂, the map of

Figure 4 (which includes representations of the active

ligands 23b and 24a and the low-activity ligands 24e,f)

shows, in yellow, regions in which affinity is favored by

high MLPs and which chiefly correspond to those

associated with the cycloalkanone fragment, the alkyl

part of piperidine rings, and benzoyl-borne fluorine

atoms; in cyan, regions in which affinity is favored by

high hydrophilicity and which chiefly correspond to the

neighborhood of the carbonyl oxygens of R-substituted

cycloalkanone rings; in green, a sterically favorable

region around the aromatic systems opposite the benzo-

or thienocycloalkanone moiety; and in red, sterically

unfavorable regions associated with the methoxy groups

of (o-methoxyphenyl)piperazines and the carbonyl groups

of their butyrophenone congeners. The map for model

EL₂, which depicts the low-activity compound 10f as

well as those shown in the SL₂map, shows the same

lipophilic (yellow) and hydrophilic (cyan) regions as the

SL₂map (as expected); in magenta, regions in which

affinity is favored by high electron density, which

mainly correspond to the aromatic systems of the

piperidine compounds or the thieno sulfur; and in white,

a region in which affinity is disfavored by high electron

density and which corresponds to methoxy oxygen atoms

or the piperazine nitrogen farthest from the cycloal-

kanone (this unfavorable interaction in this region may

suffice by itself to explain the low affinities of the (o-

methoxyphenyl)piperazines).

For each combination of fields, the number of com-

ponents to be used in a final CoMFA model was

identified by leave-one-out cross-validation of models

with up to five components.⁷²Since in several cases the

model with the highest value of q²had a relatively large

number of components, the associated risk of overfit-

ting⁷³was avoided by taking, for the final model, the

number corresponding to the first maximum of a plot

of q²against the number of components. Final non-

cross-validated models were only actually calculated for

two-field combinations chosen on the basis of the q²

results.

CoMFA results for 5-HT_2Aand D₂affinities and

5-HT_2A/D₂selectivity are summarized in Table 10. Most

models had fairly high predictive power (q²> 0.5); no

significant improvements were achieved by changing

the standard CoMFA settings for grid size and mini-

mum σ. For 5-HT_2Aaffinity, all three single-field models

had similar predictive power, especially when the

flagrant outlier IIIf was excluded from the analyses

(models S₂, E₂, and L₂). Combining two or three fields

afforded, at most, moderate improvement in predictive

power. The good performance of the pure electrostatic

model E₂is in keeping with the excellent correlation

between electrostatic potential similarity and 5-HT_2A

affinity recently reported by some of us for a subset of

the compounds considered in the present study.⁷⁴For

D₂affinity, the best models are those in which the

lipophilic field is considered, either alone (model L₃) or

in combination with the electrostatic field (EL₃) or the

steric field (SL₃).

Graphical representations of the most significant two-

field models for 5-HT_2Aaffinity (SL₂and EL₂) and D₂

2784 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

F igu r e 4. STDEV×COEFF isocontour plots for models SL₂, EL₂, SL₃, EL₃, SL₄, and EL₄(for the color code, see Table 11). Model

SL₂levels: red, -0.039; green, 0.030; cyan, -0.023; yellow, 0.020. EL₂: magenta, -0.027; white, 0.034; cyan, -0.032; yellow,

0.020. SL₃: red, -0.018; green, 0.021; cyan, -0.027; yellow, 0.035. EL₃: magenta, -0.035; white, 0.022; cyan, -0.021; yellow,

0.035. SL₄: red, -0.028; green, 0.020; cyan, -0.020; yellow, 0.010. EL₄: magenta, -0.017; white, 0.030; cyan, -0.029; yellow,

0.018. Compounds shown: for SL₂, 23b, 24a ,e,f; for EL₂, 10f, 23b, 24a ,e,f; for SL₃, If, IIIf, 10a ,f, 29b; for EL₃, Ia ,f, 10f, 23b; for

SL₄and EL₄, If, 24a .

Ta ble 11. Color Code of CoMFA Isocontour Maps in Figure 4

means of a PLS analysis. Single-field and two-field

models had similar q²values (Table 10) and other

increased

affinity

decreased

affinity

field component

statistical parameters. The map of Figure 4 for SL₄,

which includes representations of the most and least

selective ligands (If and 24a , respectively), shows

regions in which selectivity is favored by high MLPs,

corresponding to the cycloalkyl part of piperidine rings;

a sterically favorable region around the fluorine atom

of piperidine compounds; and a sterically unfavorable

region associated with the methoxy groups of the D₂-

selective (methoxyphenyl)piperazines. The importance

of the electrostatic field for 5-HT_2A/D₂selectivity is

shown by the map for model EL₄, which shows the

p-fluorophenyl groups of 5-HT_2A-selective compounds in

regions in which high electron density favors selectivity

steric field

green

red

electrostatic field (positive charge)

electrostatic field (negative charge)

lipophilic field (lipophilic component)

lipophilic field (hydrophilic component)

white

magenta

yellow

cyan

magenta

white

cyan

yellow

For the model of D₂affinity SL₃, the map of Figure 4

(which includes representations of the active ligands If,

IIIf, and 29b and the low-affinity ligands 10a ,f) shows

sterically favorable regions associated with the thieno

moiety and the aromatic ring opposite the cycloalkanone

of some active ligands; sterically unfavorable regions

associated with the benzo ring of benzocycloalkanones

and benzoyl moieties; regions in which affinity is favored

by high MLPs (which appear to be most fully occupied

by the high-MLP zones around the most active ligands);

and hard-to-interpret regions in which affinity is dis-

favored by high MLP. The map for model EL₃, which

depicts compounds Ia ,f, 10f, and 23b, shows the same

lipophilic and lipophobic regions as the SL₃map (as

expected); the regions in which affinity is favored or

disfavored by high electron density are not easy to

interpret, but the former seem to correspond to the

aromatic systems of the most active compounds and the

latter to the benzo ring of benzocycloalkanones and the

fluorine atoms of compounds with low affinity.

and the phenyl group of compounds with low 5-HT_2A

-

selectivity in the region in which high electron density

discourages selectivity.

Dock in g of 24a ,b in to Recep tor 5-HT_2A. The

docking of two of the most active 5-HT_2Aligands, 24a ,b,

was simulated using a receptor model with the same

seven-transmembrane R-helices and topology as were

deduced by Baldwin⁷⁵for bovine rhodopsin from electron

density projection maps (Figure 5). The model was

geometrically optimized using the program AMBER

4.1⁷⁶and successfully passed the PROCHECK⁷⁷and

WHATCHECK⁷⁸quality tests. It has a possible binding

site that includes all the residues that have been

described as critical for receptor-ligand interactions in

site-directed mutagenesis experiments (Asp155 and

Ser159 in helix III, Ser239 in helix V, and Phe340 in

helix VI).^79,80Furthermore, it has the hydrogen bond

Even though careful visual comparison of the maps

for SL₂, EL₂, SL₃, and EL₃might suggest structural

elements favoring selectivity for 5-HT_2Arather than D₂,

we preferred to model 5-HT_2A/D₂selectivity directly by

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2785

Ta ble 12. In Vivo Assays

ED₅₀(mg/kg)

compd

climbing (CL 95%)

catalepsy

10a (QF 0501B)

10e (QF 0502B)

10f (QF 0503B)

23a (QF 0505B)

23b (QF 0510B)

23e (QF 0506B)

24a (QF 0601B)

24b (QF 0610B)

24e (QF 0602B)

24f (QF 0603B)

29a (QF 0901B)

29b (QF 0902B)

35a (QF 0605B)

35b (QF 0609B)

35e (QF 0606B)

35f (QF 0607B)

haloperidol

>7.0

>4.0

>8.0

>16.0

>20

>15.0

>4.0

>2.0

>10.0

>8.0

>4.0

>2.0

>16.0

>8.0

>2.0

>8.0

0.67

>8.0

2.65 (2.30-3.06)

0.47 (0.31-0.70)

3.34 (2.04-5.46)

2.03 (1.19-3.46)

0.79 (0.62-0.99)

>15.0

>8.0

1.98 (0.98-4.00)

0.50 (0.38-0.66)

1.25 (0.48-3.3)

1.46 (0.91-2.32)

>8.0

F igu r e 5. Model of the 5-HT_2Ashowing important amino acids

in the binding site and the hydrogen bond between Asp120 in

helix II and Asn376 in helix VII.

>8.0

between Asp120 in helix II and Asn376 in helix VII that

has been reported to be crucial for maintenance of the

functional receptor structure.⁸¹Ligand binding was

automatically explored using the Affinity module of

BIOSYM,⁸²which takes into account the conformational

flexibility of both ligand and receptor. Molecular dy-

namics simulations supported the stability of the most

interesting complexes obtained. Two of the most sig-

nificant and stable complexes are shown in Figure 6.

Both are stabilized by two hydrogen bonds, one of which

involves the amino group of the ligand and Asp155 in

helix III. The other hydrogen bond of the 24b complex

involves Asn343 in helix VI, while that of the 24a

complex involves Ser239 in helix V. Lipophilic or π-π

aromatic-aromatic interactions also contribute to sta-

bilization of the complexes; they include the interactions

between Trp336 in helix VI and the 6-fluorobenzisox-

azole moiety of 24b or the aromatic ring fused to the

cycloalkanone of 24a . Note that lipophilic interactions

involving the same fragments are clearly suggested by

the CoMFA results (Figure 4).

0.14 (0.13-0.15)

2.21 (2.03-2.41)

0.09 (0.08-0.09)

clozapine

risperidone

>50.0

>2.0

helix III and the protonated amino group, the cyclo-

alkanone moiety appears to one side of Asp155 in some

complexes and to the other side in others (Figure 6

shows an example of each orientation). This is coher-

ent with the presence of the same pharmacophore on

both sides of the protonated amino group (aryl-CO-

CH₂-CH₂-CH₂-NRH⁺-CH₂-CH₂-CH₂-CO-aryl′)

and hints at the possibility of multiple binding modes.

In Vivo Stu d ies. Potential for antipsychotic activity

was quantified in terms of inhibition of apomorphine-

induced climbing by mice and potential for causing EPS

in terms of induction of catalepsy in mice (Table 12).

Apomorphine-induced climbing by mice was strongly

inhibited by haloperidol and risperidone (ED₅₀< 0.2 mg/

kg), closely followed by the R-ethylbenzisoxazolyl de-

rivatives 23b (0.47), 24b (0.79), and 29b (0.50): see

Figure 7. Changing the size of the cycloalkanone ring

had relatively little effect on climbing inhibition among

the more active thiophene derivatives (compare 23a ,b

It must be pointed out that although all the complexes

obtained share the hydrogen bond between Asp155 in

F igu r e 6. Feasible complexes of 24b (a) and 24a (b) with the binding site of rat 5-HT_2A, showing hydrogen bonds and the interaction

with Trp336.

2786 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

F igu r e 8. Spontaneous locomotor activity in mice treated with

vehicle, haloperidol (2 mg/kg), clozapine (5 mg/kg), risperidone

(5 mg/kg), 23b (2 mg/kg), or reserpine (5 mg/kg).

F igu r e 7. Dose-effect curves for inhibition of induced climb-

ing by mice by reference drugs and selected new compounds.

with 24a ,b), and moving the position of the thiophene

sulfur also had little effect, although such change as

there was paralleled the slight changes in 5-HT_2A

-

blocking activity observed in the binding experiments

(compare 24a ,b with 29a ,b). The three R-ethylbenzisox-

azolyl derivatives were all more active than the â-me-

thylbenzisoxazolyl 35b (ED₅₀) 1.46 mg/kg), but the

reverse was true among the (p-fluorobenzoyl)piperidinyl

compounds (23a , 2.65; 24a , 2.03; 29a , 1.98; 35a , 1.25),

although none of these latter exhibited marked activity.

The difference in activity between the benzisoxazolyl

and (p-fluorobenzoyl)piperidinyl compounds was greater

in the R-ethyl than in the â-methyl series (compare the

difference between 35a and 35b with those between 23a

and 23b, 24a and 24b, and 29a and 29b). All the (o-

methoxyphenyl)piperazine derivatives were completely

devoid of activity (ED₅₀> 8 mg/kg), as were all the

compounds with the linear butyrophenone moiety e

(except 23e did have very slight activity: ED₅₀) 3.34

mg/kg).

None of the new compounds induced catalepsy at the

doses assayed. In particular, the compound showing

most activity in the climbing test, 23b, failed to induce

catalepsy at a dose of 20 mg/kg, more than 40 times its

ED₅₀for climbing inhibition (among the new com-

pounds, 23b also had the highest or near-highest

activity at all the receptors considered). The fact that

10f, 24e,f, and 35e were not cataleptogenic despite their

pK_i(5-HT_2A)/pK_i(D₂) ratios being similar to those of

classical antipsychotics (<1.09) may be due to their

affinities for both 5-HT_2Aand D₂being low (which is in

keeping with the climbing test results), to insufficient

dosage in the catalepsy trials, or to unevaluated factors

such as anticholinergic activity or R₁blockage. Halo-

peridol was markedly cataleptogenic, as expected (ED₅₀

) 0.67 mg/kg).

F igu r e 9. Inhibition of d-amphetamine-induced hypermotility

in mice treated with haloperidol (2 mg/kg), clozapine (5 mg/

kg), risperidone (5 mg/kg), 23b (2 mg/kg), or reserpine (5 mg/

kg).

kg haloperidol or 5 mg/kg clozapine (Figure 8). In

addition, 2 mg/kg 23b, like 2 mg/kg haloperidol, 5 mg/

kg clozapine, or 5 mg/kg risperidone, completely inhib-

ited d-amphetamine-induced hyperlocomotion, which

was not inhibited by reserpine (Figure 9). Hence 23b

seems likely to inhibit d-amphetamine-induced hyper-

locomotion by the same specific mechanism as haloperi-

dol, clozapine, and risperidone, which are assumed to

act by blocking dopaminergic receptors in the nucleus

accumbens.

Con clu sion

Several conformationally restricted butyrophenones

(R- and â-(aminoalkyl)cycloalkanones bearing (p-fluo-

robenzoyl)piperidine, (6-fluorobenzisoxazolyl)piperidine,

(o-methoxyphenyl)piperazine, or linear butyrophenone

fragments) were synthesized and evaluated in vitro for

affinity for dopamine receptors (D₁, D₂) and serotonin

receptors (5-HT_2A, 5-HT_2C). Most had good D₂and

5-HT_2Aaffinities and a high 5-HT_2A/D₂pK_iratio, thus

showing potential for atypical antipsychotic activity. 3D-

QSAR (CoMFA) analyses identified the most significant

steric, lipophilic, and electrostatic interactions involved

in 5-HT_2Aand D₂binding and 5-HT_2A/D₂selectivity. A

study of docking into a 5-HT_2Amodel constructed by

computer-assisted modeling techniques gave results

consistent with the CoMFA and furnished further

information on hydrogen bonds and π-π or hydrophobic

interactions involved in 5-HT_2Abinding. The newly

synthesized compounds were also subjected to in vivo

behavioral tests of antipsychotic potential and risk of

EPS. The pharmacological profiles of thiaindanone 23b

(QF 0510B) and thiatetralones 24b (QF 0610B) and 29b

(QF 0902B), all of which bear a benzisoxazolylpiperidine

Statistical analysis of pairwise correlations between

in vivo and in vitro test results found best Pearson

correlation between climbing inhibition (ED₅₀) and pK_i

at 5-HT_2A(r ) -0.640, p < 0.001 for n ) 22).

In view of its good performance in all the in vitro and

in vivo tests described above, compound 23b was

subjected to supplementary in vivo trials. At a dosage

of 2 mg/kg, its marked inhibition of spontaneous loco-

motor activity in mice was similar to that exerted by 5

mg/kg risperidone or 5 mg/kg reserpine (the latter

administered, as usual, 24 h prior to observation of the

response) and rather greater than that exerted by 2 mg/

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2787

2.86-3.12 (m, 4H, -HCH-COOH, H₄, H_4′, H₆); 6.96 (d, J ) 4.9,

H₃); 7.61 (d, J ) 4.9, H₂). ¹³C NMR (CDCl₃): δ 26.2, 30.9, 34.9

(C₄, C₅, -CH₂-COOH); 44.2 (C₆); 128.5, 135.0 (C₂, C₃); 136.2

(C_3a); 152.9 (C_7a); 178.1 (-COOH); 192.6 (C₇). MS (FAB, m/z):

211 (MH⁺). Anal. (C₁₀H₁₀O₃S) C, H.

fragment, suggest that they may be effective atypical

antipsychotic drugs with little propensity to produce

EPS.

Exp er im en ta l Section

3-Ca r boxy-1-in d a n on e Meth yl Ester (2). A solution of 1

(10 g, 0.057 mol) in methanol (40 mL) with a few crystals of

p-TsOH was refluxed with stirring for 5 h. After cooling, the

solvent was distilled off under reduced pressure. The residue

was dissolved in CH₂Cl₂, and the resulting solution was

washed with 10% NaHCO₃and water and then dried (Na₂-

SO₄). After removal of the solvent in vacuo the resulting orange

oil was ball-to-ball distilled (130-133 °C/0.4 mmHg) to give 2

(9.90 g, 92%) as a colorless oil which on standing soon

crystallized as white crystals of mp 119-120 °C (i-PrOH). IR:

Ch em istr y. Melting points were determined with a Kofler

hot stage instrument or a Gallenkamp capillary melting point

apparatus and are uncorrected. Infrared spectra were recorded

with a Perkin-Elmer 1600 FTIR spectrophotometer; the main

bands are given, in cm^-^{1 1}H and ¹³C NMR spectra were

.

recorded with a Bruker WM AMX spectrometer (300 MHz);

chemical shifts are recorded in parts per million (δ) downfield

from tetramethylsilane (TMS), and J values are given in hertz

(Hz). Mass spectra were performed on Kratos MS-50 or Varian

Mat-711 mass spectrometers in fast atom bombardment (FAB)

mode (with 2-hydroxyethyl disulfide as matrix) or by electron

impact (EI). Optical rotations at the sodium ^D-line were

determined in MeOH solutions of the indicated concentrations

using a Perkin-Elmer 241 polarimeter. Flash column chroma-

tography was performed using Kieselgel 60 (60-200 mesh, E.

Merck AG, Darmstadt, Germany). Reactions were monitored

by thin-layer chromatography (TLC) on Merck 60 GF₂₅₄

chromatogram sheets using iodine vapor and/or UV light for

detection; unless otherwise stated the purified compounds each

showed a single spot. Elemental combustion analyses were

performed on a Perkin-Elmer 240B apparatus at the Mi-

croanalysis Service of the University of Santiago de Compos-

tela; unless otherwise stated all reported values are within

(0.4% of the theoretical compositions. Solvents were purified

as per Vogel⁸³by distillation over the drying agent under an

argon atmosphere and were used immediately. The drying

agents used were Na/benzophenone for THF, ether, and

toluene; P₂O₅for CH₂Cl₂; K₂CO₃for acetone and ethyl acetate;

KOH for pyridine and TEA; and CaSO₄/4 Å molecular sieves

for DMF. Unless otherwise stated salts were prepared by the

following general procedures: (a) oxalates, by dropwise addi-

tion of a 1 mol equiv solution of oxalic acid in anhydrous ether

to a solution of the amine in anhydrous ether; (b) hydrochlo-

rides, by dropwise addition, with cooling, of a saturated

solution of HCl in anhydrous ether to a solution of the amine

in anhydrous ether or absolute ethanol/ether. 2,4-Dinitro-

phenylhydrazones were obtained by dropwise addition of a

solution 2,4-dinitrophenylhydrazine sulfate in absolute

MeOH to a 1 M solution of carbonyl derivative in absolute

MeOH.

3-Ca r boxy-1-in d a n on e (1) was prepared by Friedel-

Crafts cyclization of phenylsuccinic anhydride as per Hash-

imoto and Takatsuka.⁵⁰

4-Oxo-4,5-d ih yd r o-6H-cyclop en ta [b]th iop h en e (11, thi-

aindanone) was synthesized by ring closure of â-(2-thienyl)-

acrylic acid as per Sam and Thompson.⁸⁴2,4-Dinitrophenyl-

hydrazone: mp 152-154 °C (EtOH).

4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e (12) was

synthesized by ring closure of γ-(R-thienyl)butyric acid as per

Nishimura et al.⁸⁵2,4-Dinitrophenylhydrazone: mp 252-255

°C (AcOEt).

7-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e (25) was

prepared by Wolf-Kishner reduction of the 4-oxo derivative

12 and subsequent cerium ammonium nitrate (CAN) oxidation

of the resulting thiatetraline, as per Cagniant⁸⁶and Conjat et

al.⁸⁷

3200, 1737, 1713. ¹H NMR (CDCl₃): δ 2.83 (dd, 1H, J _gem

)

19.1, J _vic) 8, H₂); 3.10 (dd, 1H, J _gem) 19.1, J _vic) 3.6, H₂);

3.74 (s, 3H, CO₂CH₃); 4.26 (m, 1H, J _3-2) 8, J _3-2) 3.6, H₃);

7.41 (t, 1H, J ) 7.3, H₆); 7.56-7.62 (dt, 1H, J _5-4) 7.7, H₅);

7.67 (d, 1H, J _4-5) 7.7, H₄); 7.71 (d, 1H, J _7-6) 7.6, H₇). Anal.

(C₁₁H₁₀O₃) C, H.

3-Ca r boxy-1-in d a n on e Meth yl Ester , Eth ylen e Keta l

(3). Ketal 3 was prepared in a flask fitted with a Liebig

condenser and a water aspiration pump. The reaction was

monitored by TLC (ethyl acetate/benzene, 4:1). A vigorously

stirred mixture of keto ester 2 (5 g, 0.056 mol), trimethyl

orthoformate (5 mL, 0.26 mol), and p-TsOH (20 mg) in dry

benzene (25 mL) was held at 50 °C (bath temperature), and

methyl formate was distilled off under moderately low pres-

sure. Two 40-mg portions of p-TsOH were added at 1-h

intervals. After a total of 4 h, keto ester 2 had disappeared.

The bath temperature was raised to 70-80 °C, and volatile

components, including benzene, were distilled off in vacuo. The

resulting residue was dissolved in ether, the solution was

washed with 10% NaHCO₃(3×) and water (3×) and dried (Na₂-

SO₄), and the ether was distilled off. The residue, a pale-yellow

oil, was purified by ball-to-ball distillation (140-145 °C/0.4

mmHg) to give 3 (5.37 g, 87%) as a colorless oil which was

used in the next step without further purification. IR: 2800,

1

1739. H NMR (CDCl₃): 2.55 (dd, 1H, J _gem) 13.7, J _vic) 8.1,

H₂); 2.70 (dd, 1H, J _gem) 13.7, J _vic) 6.5, H₂); 3.76 (s, 3H,

-CO₂CH₃); 4.06-4.25 (m, 5H, H₃, -O-CH₂CH₂-O-); 7.32-7.42

(m, 4H, aromatic H).

3-(Hyd r oxym eth yl)-1-in d a n on e Eth ylen e Keta l (4). A

stirred solution of ester 3 (2 g, 8 mmol) in anhydrous 1:1 ether/

benzene was added dropwise to a vigorously stirred suspension

of LiAlH₄(0.9 g, 24 mmol) in anhydrous ether (75 mL) under

argon. The reaction mixture was heated under reflux for 8 h,

cooled to 0 °C in an ice bath, and quenched by the sequential

dropwise addition of H₂O (2 mL), NaOH (2 mL), and H₂O (2

mL). The coarse precipitate formed was filtered off and

thoroughly washed with ether. The organic extracts were

washed with water several times and dried (Na₂SO₄), and the

solvent was distilled off in vacuo. The crude brown oily residue

was purified by ball-to-ball distillation to give 4 (1.2 g, 85%)

as a colorless oil of bp 160-165 °C/0.5 mmHg. IR: 3300-3400.

¹H NMR (CDCl₃): δ 1.8 (s, 1H, -CH₂OH); 2.17 (dd, 1H, J _gem

)

13.8, J _vic) 4.3, H₂); 2.49 (dd, 1H, J _gem) 13.8, J _vic) 8.1, H₂);

3.4 (m, 1H, J _3-2) 4.5, J _3-2) 8, H₃); 3.85 (m, 2H, -CH₂OH);

4.06-4.21 (m, 4H, -O-CH₂CH₂-O-); 7.30-7.40 (m, 4H, aromatic

H). Anal. (C₁₂H₁₄O₃) C, H. 2,4-Dinitrophenylhydrazone: red

crystals, mp 230-231 °C (AcOEt). ¹H NMR (CDCl₃): δ 2.9 (dd,

4-Oxo-4H-5,6-d ih yd r ocyclop en ta [b]th iop h en e-5-ylid e-

n ea cetic a cid (13), 4-oxo-4,5,6,7-tetr a h yd r oben zo[b]th io-

p h en e-5-ylid en ea cetic a cid (14), 4-oxo-4H-5,6-d ih yd r o-

cyclop en ta [b]th iop h en e-5-yla cetic a cid (17), a n d 4-oxo-

4,5,6,7-tetr a h yd r oben zo[b]th iop h en e-5-yla cetic a cid (18)

were prepared as previously described.⁴³

1H, J _gem) 18, J _vic) 3.2, H₂); 3.12 (dd, 1H, J _gem) 18, J _vic

)

8.05, H₂); 3.72-3.75 (m, 1H, H₃); 3.94 (t, 2H, J ) 5.3, -CH₂-

OH); 7.40-7.49 (m, 3H, H₄, H₅, H₆); 7.90 (d, 1H, J ) 7.1, H₇);

8.13 (d, 1H, J _6′-5′) 9.6, H_6′); 8.36 (dd, 1H, J _5′-6′) 9.6, J _5′-3′

)

2.6, H_5′); 9.16 (d, 1H, J _3′-5′) 2.6, H_3′); 11.27 (s, 1H, -NH-). MS

(EI, m/z): 342 (M⁺). Anal. (C₁₆H₁₄O₅N₄) C, H, N.

7-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-5-yla ce-

tic a cid (26) was obtained similarly to its regioisomer 18 by

alkylation of the enolate of thiatetralone 25 with ethyl bro-

moacetate (50% yield) and subsequent ester hydrolysis

(95%): white crystalline solid of mp 70-72 °C (H₂O). IR: 1710,

3-(Br om om et h yl)-1-in d a n on e (5). A stirred solution of

alcohol 4 (2.06 g, 10 mmol), carbon tetrabromide (15 g, 12.5

mmol), and triphenylphosphine (3.93 g, 15 mmol) in CH₂Cl₂

(50 mL) was refluxed for 20 h under argon. After cooling, the

reaction mixture was washed with 5% NaHCO₃and water,

the organic phase was dried (Na₂SO₄), and the solvent was

1

1659. H NMR (CDCl₃): δ 1.98-2.12 (m, 1H, H₅); 2.27-2.35

(m, 1H, H_5′); 2.47 (dd, J _gem) 18.1, J _vic) 8.5, HCH-COOH);

2788 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

distilled off. Purification of the residue by flash chromatogra-

phy (AcOEt/hexane, 3:1) gave 5 (1.84 g, 82%) as a pale-brown

The amides 8c,f were obtained similarly from 1, 19a -c from

17,⁴²20a -c,f from 18,⁴²and 27a -b from 26, as white

crystalline solids (Table 5); their data follow.

oil which on standing gave white crystals of mp 224-225 °C

1

N¹-[(1-Oxoin d a n -3-yl)ca r bon yl]-N⁴-(ter t-bu toxyca r bo-

n yl)p ip er a zin e (8c): yield 85%, mp 146-147 °C (i-PrOH).

(i-PrOH). IR: 1715. H NMR (CDCl₃): δ 2.65 (dd, 1H, J _gem

)

19.2, J _vic) 3.1, H₂); 2.93 (dd, 1H, J _gem) 19.2, J _vic) 7.1, H₂);

3.84 (c, 1H, J ) 8.5, H₃); 3.81-3.87 (m, 2H, -CH₂Br); 7.46 (t,

1H, J ) 7.6, H₆); 7.57 (d, 1H, J ) 7.5, H₄); 7.66 (t, 1H, J ) 7.7,

H₅); 7.77 (d, J ) 7.6, H₇). MS (FAB, m/z): 226 (MH⁺). Anal.

(C₁₀H₉BrO) C, H.

1

IR: 2930, 1716, 1696, 1641. H NMR (CDCl₃): δ 1.49 (s, 9H,

-C(CH₃)₃); 2.89 (dd, 1H, J _gem) 18.5, J _vic) 7.6, H₂); 2.99 (dd,

1H, J _gem) 18.5, J _vic) 4.2, H₂); 3.63-3.74 (m, 8H, piperazine);

4.54 (m, 1H, J _3-2) 7.6, J _3-2) 4.2, H₃); 7.40-7.47 (m, 2H, H₄,

H₅); 7.62 (dt, 1H, J ) 7.5-1.2, H₆); 7.78 (d, 1H, J ) 7.6, H₇).

MS (FAB, m/z): 345 (MH⁺). Anal. (C₁₉H₂₄O₄N₂) C, H, N.

3-(N-Mor p h olin om eth yl)-1-in d a n on e (6). Meth od A. A

solution of (bromomethyl)indanone 5 (1 g, 4.45 mmol) in 20

mL of methyl isobutyl ketone (MIK) was added dropwise under

argon to a stirred suspension of morpholine (0.77 g, 8.9 mmol),

Na₂CO₃(0.94 g, 8.9 mmol), and KI (50 mg) in MIK (50 mL).

After refluxing with vigorous stirring for 12 h, the mixture

was allowed to stand at room temperature overnight and then

filtered. The filtrate was condensed under reduced pressure

to give a brown oil which was purified by flash chromatography

(AcOEt). The resulting colorless oil crystallized on standing.

Recrystallization from ethyl acetate gave 6 (0.51 g, 50%) as

white crystals of mp 72-73 °C (AcOEt). IR: 1708. ¹H NMR

(CDCl₃): δ 2.44-2.53 (m, 4H, -N(CH₂CH₂)₂O); 2.45 (dd, 1H,

J _gem) 12.4, J _vic) 8.5, -HCH-NRR); 2.57 (dd, 1H, J _gem) 19.25,

J _vic) 3.1, H₂); 2.68 (dd, 1H, J _gem) 12.4, J _vic) 6.4, -HCH-

NRR); 2.82 (dd, 1H, J _gem) 19.25, J _vic) 7.4, H₂); 3.55 (m, 1H,

J _3-2) 3.1, J _3-2) 7.2, J ) 8.5); 3.73 (t, 4H, -N-(CH₂CH₂)O, J

) 4.66); 7.4 (t, 1H, J ) 7.7, H₆); 7.58 (dd, 1H, J _4-5) 7.8, J _4-6

) 1.1, H₄); 7.61-7.66 (m, 1H, H₅); 7.74 (d, 1H, J ) 7.6, H₇):

¹³C NMR (CDCl₃) δ 35.93; 42.12; 54.17; 64.65; 67.24 (O(CH₂-

CH₂)₂N-); 123.85 (C₄); 126.59 (C₇); 128.10 (C₆); 134.79 (C₅);

137.24 (C_7a); 157.32 (C_3a); 206.42 (C₁). MS (FAB, m/z): 232

(MH⁺). Anal. (C₁₄H₁₇NO₂) C, H, N. 2,4-Dinitrophenylhydra-

zone: red needles, mp 240-243 °C (AcOEt).

Meth od B. A solution of (bromomethyl)indanone 5 (0.5 g,

2.2 mmol) and morpholine (0.39 g, 4.4 mmol) in absolute

ethanol (30 mL) was heated in a Parr reactor for 2 h. After

cooling, the mixture was vacuum-filtered to recover morpho-

linium bromide, and the filtrate was condensed under reduced

pressure. The oily residue was purified by flash chromatog-

raphy (AcOEt) to give 6 (0.21 g, 47%) as a colorless oil which

soon crystallized on standing: mp 72-73 °C (AcOEt).

3-(N,N-Dieth yla m in om eth yl)in d a n -1-on e (7) was pre-

pared by method B. Hydrochloride: mp 162-165 °C (EtOH).

Anal. (C₁₄H₁₉NO‚ClH) C, H, N. 2,4-Dinitrophenylhydrazone:

red crystalline powder, mp 240-243 °C (AcOEt).

N¹-[(1-Oxoin d a n -3-yl)ca r bon yl]-N⁴-(o-m eth oxyp h en yl)-

p ip er a zin e (8f): yield 81%, mp 165 °C (AcOEt). IR: 1706,

1638. ¹H NMR (CDCl₃): δ 3.07 (dd, 1H, J _gem) 18.5, J _vic) 7.5,

H₂); 3.21 (dd, 1H, J _gem) 18.5, J _vic) 4.1, H₂); 3.26-3.45 (m,

4H, CO-N(CH₂CH₂)₂N-); 4.03-4.23 (m, 4H, CO-N(CH₂CH₂)₂-

N-); 4.12 (s, 3H, -OCH₃); 7.02-7.3 (m, 4H, H_3′, H_4′, H_5′, H_6′);

7.57-7.79 (m, 3H, H₄, H_5,H₆); 7.95 (d, 1H, J ) 5.3, H₇). Anal.

(C₂₁H₂₂N₂O₃) C, H, N.

N-[(4-Oxo-4H -5,6-d ih yd r ocyclop en t a [b]t h iop h en e-5-

yl)a cetyl]-4-(p-flu or oben zoyl)p ip er id in e (19a ): yield 78%.

1

IR: 1701, 1680, 1643. H NMR (CDCl₃): δ 1.88-1.93 (m, 4H,

-N(CH₂CH₂)₂-CH); 2.51-2.68 (m, 1H, H₅); 2.77-2.89 (m, 2H,

-N(HCHCH₂)₂-CH); 3.07 (dd, 1H, J _gem) 16.6, J _vic) 3.1, H₆);

3.15-3.26 (m, 1H, -N(CH₂CH₂)₂-CH); 3.33-3.49 (m, 2H, -N(H-

CHCH₂)₂-CH); 3.55 (dd, 1H, J _gem) 16.6, J _vic) 4.4, H₆); 3.94

(dd, 1H, J _gem) 13.5, J _vic) 3.9, HCH-CON<); 4.54 (dd, 1H,

J _gem) 13.5, J _vic) 4.4, HCH-CON<); 7.11-7.17 (m, 3H, 1H₂,

2H: o-F-Ph); 7.31 (d, 1H, J ) 5.2, H₃); 7.97 (dd, 2H, J ) 8.9,

5.4, o-CO-Ph). Anal. (C₂₁H₂₀FNO₃S) C, H, N. 2,4-Dinitrophe-

nylhydrazone: mp 223-225 °C (i-PrOH). Anal. (C₃₃H₂₈

FN₉O₉S) C, H, N.

-

N-[(4-Oxo-4H -5,6-d ih yd r ocyclop en t a [b]t h iop h en e-5-

yl)a cetyl]-4-(6-flu or oben zisoxa zol-3-yl)p ip er id in e (19b):

yield 85%, mp 155-157 °C. IR: 1698, 1640, 1616. ¹H NMR

(CDCl₃): δ 1.89-2.16 (m, 4H, -N(CH₂-CH₂)₂C-); 2.60-2.68 (m,

1H, H₅); 2.91-3.00 (m, 2H, -N(HCH-CH₂)₂-); 3.10 (dd, 1H, J _gem

) 16.6, J _vic) 2.9, H₆); 3.23-3.46 (m, 3H, -N(HCH-CH₂)₂CH-,

-N(HCH-CH₂)₂-, HCH-CONRR); 3.57 (dd, 1H, J _gem) 17.4, J _vic

) 7.0, H_6′); 4.05 (dd, 1H, J _gem) 13.6, J _vic) 7.1, -HCH-CONRR);

4.57-4.66 (m, 1H, -N(HCH-CH₂)₂-); 7.08-7.11 (m, 1H, H_5′′);

7.16 (d, 1H, J ) 5.1, H₂); 7.25 (dd, 1H, J _7′-F) 8.2, J _7′-5′) 2.1,

H_7′); 7.32 (d, 1H, J ) 5.3, H₃); 7.63 (dd, 1H, J _4′-5′) 8.7, J _4′-F

) 4.3, H_4′). ¹³C NMR (CDCl₃): δ 30.7, 32.4, 35.0, 41.9, 45.6,

50.3 (C₅, C₆, -CH₂-CONRR, -N(CH₂-CH₂)₂C-); 97.9 (d, J _C-F

)

26.8, C_7′); 113.1 (d, J _C-F) 25.3, C_5′); 117.4 (C_3′a); 120.0, 131.1

(C₂, C₃); 122.5 (d, J _C-F) 11.0, C_4′); 145.4 (C_6a); 160.5 (C_3′); 164.2

(d, J _C-F) 13.5, C_7′a); 164.6 (d, J _C-F) 251, C_6′); 167.5 (C_3a);

169.5 (-CONRR); 199.7 (C₄). MS (FAB, m/z): 398.7 (MH⁺).

Anal. (C₂₁H₁₉FN₂O₃S) C, H, N.

N¹-[(1-Oxo-4H -5,6-d ih yd r ocyclop en t a [b]t h iop h en e-5-

yl)a cetyl]-N⁴-(ter t-bu toxyca r bon yl)p ip er a zin e (19c): yield

91%, mp 116-118 °C (i-PrOH). IR: 1697, 1645. ¹H NMR

(CDCl₃): δ 1.46 (s, 9H, -C(CH₃)₃); 2.59 (dd, 1H, J _gem) 16.7,

J _vic) 9.6, H₆); 2.94 (dd, 1H, J _gem) 17.4, J _vic) 3.0, -HCH-

CON<); 3.05 (dd, 1H, J _gem) 16.7, J _vic) 3.2, H₆); 3.36-3.49

(m, 8H, -N(CH₂-CH₂)₂N-); 3.56 (dd, 1H, J _gem) 17.4, J _vic) 7.1,

-HCH-CON<); 3.52-3.60 (m, 1H, H₅); 7.16 (d, 1H, J ) 5.1,

H₂); 7.33 (d, 1H, J ) 5.4, H₃). MS (FAB, m/z): 365 (MH⁺). Anal.

(C₁₈H₂₄N₂O₄S) C, H, N.

N-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-5-yl)-

a cetyl]-4-(p-flu or oben zoyl)p ip er id in e (20a ): yield 85%, mp

143-145 °C (i-PrOH). IR:1677, 1663, 1635, 1594. ¹H NMR

(CDCl₃): δ 1.74-1.91 (m, 4H, -N(CH₂-CH₂)₂CH-); 2.00-2.17

(m, 1H, H₆);2.23-2.33 (m, 1H, H₆); 2.41 (dd, 1H, J _gem) 16.3,

J _vic) 9.8, H-CH-CONRR); 2.81-2.94 (m, 1H, -CO-N(H-CH-

CH₂)₂CH-); 3.02-3.31 (m, 5H, H₅, H₇, H₇, H-CH-CONRR, -CO-

N(H-CH-CH₂)₂CH-); 3.43-3.52 (m, 1H, RRCH-CO-Phe); 4.04-

4.15 (m, 1H, -CON(H-CH-CH₂)₂CH-); 4.57-4.61 (m, 1H,

-CON(H-CH-CH₂)₂CH-); 7.06 (d, J ) 5.2, 1H, H₂); 7.16 (t, 2H,

J ) 8.4, o-F-Ph); 7.37 (d, 1H, J ) 5.2, H₃); 7.98 (dd, 2H, J )

8.4, 5.7, m-F-Ph). ¹³C NMR (CDCl₃): δ 25.6, 28.7, 41.5, 43.5,

(C-5, C-6, C-7, -CH₂-CONRR); 31.1 (-CH₂)₂CH-CO-); 44.0, 45.1

(-N(CH₂-CH₂)₂CH-); 116.15 (d, 2C, J _C-F) 22.6, o-F-Ph); 123.6,

Gen er al P r ocedu r e for Syn th esis of Ketoam ides (Table

5) Usin g DCC a n d HOBt a s Cou p lin g Rea gen ts. N-[(1-

Oxoin d a n -3-y l)c a r b on yl]-4-(p -flu o r o b e n zo yl)p ip e r i-

d in e (8a ). A solution of (p-fluorobenzoyl)piperidine (2.35 g,

11.36 mmol), 1-hydroxybenzotriazole (HOBt) (1.54 g, 11.36

mmol), and 3-carboxy-1-indanone (2) in anhydrous CH₂Cl₂(30

mL) was stirred under argon at room temperature for 15 min

and then cooled to 0 °C. At this temperature, dicyclohexylcar-

bodiimide (DCC) (2.34 g, 11.36 mmol) was added, and the

reaction mixture was kept at 0-5 °C for 1 h and then allowed

to reach room temperature and left overnight. The precipitated

dicyclohexylurea was filtered off, and the filtrate was washed

several times with 5% NaHCO₃and water, dried (Na₂SO₄),

and condensed to dryness. The oily residue was purified by

flash chromatography (AcOEt/hexane, 1:1) to give the amide

8a (3.32 g, 80%) as a white crystalline solid of mp 146-149

1

°C (AcOEt). IR: 2933, 1716, 1678, 1628. H NMR (CDCl₃): δ

1.97-2.03 (m, 4H, -N(CH₂CH₂)₂-CH-); 2.89 (dd, 1H, J _gem

)

13.6, J _vic) 7.1, H₂); 2.98 (dd, 1H, J _gem) 13.6, J _vic) 3.7, H₂);

2.96-3.01 (m, 1H, H₃); 3.45-3.59 (m, 2H, -N(HCHCH₂)₂-CH-

); 4.27-4.31 (m, 1H, -N(CH₂CH₂)₂-CH-); 4.55-4.59 (m, 2H,

-N(HCHCH₂)₂-CH-); 7.17 (t, 2H, J ) 8.4, o-F-Ph); 7.43 (t, 1H,

J ) 7.3, H₆); 7.59-7.61 (m, 1H, H₅); 1.17-1.78 (m, 1H, H₇);

1.98-8.01 (m, 2H, o-CO-Ph). ¹³C NMR (CDCl₃): δ 25.86; 28.98;

34.19; 43.46; 49.40; 116.32 (d, 2C, J _C-F) 21.8, o-F-Ph); 118.00

(C₄); 124.30 (C₇); 126.49 (C₆); 128.77 (C₅); 131.24 (d, 2C, J _C-F

) 9.1, m-F-Ph); 135.20; 137.08 (C_7a); 153.10 (C_3a); 164.47;

167.85; 170.55; 170.90; 200.27 (CO-Ph); 204.63 (C₁). MS (FAB,

m/z): 366 (MH⁺). Anal. (C₂₂H₂₀FNO₃) C, H, N.

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2789

125.2 (C₂, C₃); 131.2 (d, 2C, J _C-F) 9.8, m-F-Ph); 137.1, 155.6

(C_3a, C_7a); 132.7 (p-F-Ph); 165.0 (d, J _C-F) 251, F-C); 170.5

(-CONRR); 194.3 (C-4); 200.6 (-CO-Ph). MS (FAB, m/z): 400

(MH⁺). Anal. (C₂₂H₂₂FNO₃S) C, H, N.

1H, J ) 4.9, H₂); 7.81 (dd, 1H, J _4-5) 8.7, J _4-F) 5.1, H_4′). ¹³C

NMR (CDCl₃): δ 26.3 (C₅); 30.6 (-N(CH₂-CH₂)₂C-); 31.5 (C₄);

33.3 (-CH₂-CONRR); 42.2 (-N(CH₂-CH₂)₂CH-); 44.7 (C₆); 45.8

(-N(CH₂-CH₂)₂CH-); 97.9 (d, J _C-F) 27.0, C_7′); 113.0 (d, J ) 25.1,

C_5′); 117.3 (C_3a´); 123.1 (d, J _C-F) 11.1, C_4′); 128.5, 134.4 (C₂,

C₃); 136.5 (C_3a); 152.8 (C_7a); 160.7 (C_3′); 164.2 (d, J _C-F) 13.7,

C_7a´); 164.5 (d, J _C-F) 250.7, C_6′); 170.2 (-CONRR); 193.6 (C₇).

MS (FAB, m/z): 413.7 (MH⁺). Anal. (C₂₂H₂₁FN₂O₃S) C, H, N.

N-[(4-Oxo-4,5,6,7-t et r a h yd r oben zo[b]t h iop h en e-5-yl)-

acetyl]-4-(6-flu or oben zisoxazol-3-yl)piper idin e (20b): yield

85%, mp 161-163 °C (i-PrOH). IR: 1665, 1643. ¹H NMR

(CDCl₃): δ 1.93-2.15 (m, 5H, H6, -N(CH₂-CH₂)₂C-); 2.33 (dd,

1H, J _gem) 15.5, J _vic) 7.2, HCH-CONRR); 2.32-2.46 (m, 1H,

H₆); 2.89-2.98 (m, 1H, -CON(HCH-CH₂)₂-); 3.01-3.39 (m, 6H,

H₅, H₇, H₇, HCH-CONRR, -CON(HCH-CH₂)₂-, -CH₂)CH-);

4.06-4.13 (m, 1H, -N(HCH-CH₂)₂-); 4.62-4.75 (m, 1H, -N(HCH-

CH₂)₂-); 7.08-7.11 (m, 2H, H₂, H_5′); 7.26 (dd, 1H, J _7′-F) 8.3,

J _7′′-5′) 2.0, H7′); 7.38 (d, 1H, J ) 5.3, H₃); 7.68 (2dd, 1H, J _{4′′-5′′}

) 8.7, J _4′′-F) 5.1, H4′). ¹³C NMR (CDCl₃): δ 25.8, 30.8, 31.5,

34.6, 34.9, 44.2 (C₅, C₆, C₇, -CH₂CONRR, -N(CH₂-CH₂)₂C-); 97.8

(d, J _C-F) 26.7, C_7′); 112.7 (d, J _C-F) 25.3, C_5′); 117.7 (C_3a´);

Gen er a l P r oced u r e for Syn th esis of Ketoa m id es 19b

a n d 27a ,b (Ta ble 5) Usin g BOP -Cl a s Cou p lin g Rea gen t.

N-[(4-Oxo-4H-5,6-d ih yd r ocyclop en ta [b]th iop h en e-5-yl)-

a cetyl]-4-(6-flu or oben zisoxa zol-3-yl)p ip er id in e (19b). A

solution of carboxylic acid 17 (0.45 g, 2.27 mmol) and 4-(6-

fluorobenzisoxazol-3-yl)piperidine (0.5 g, 2.27 mmol) in CH₂-

Cl₂(15 mL) was stirred under argon until dissolution was

complete (10 min at 25 °C). TEA (0.61 mL, 4.5 mmol) and N,N-

bis(2-oxo-3-oxazolidinyl)phosphoroamidic chloride (0.57 g, 2.27

mmol) were added, followed after 2 h by H₂O (15 mL), and

the solution was then acidified to pH 1 with 6 N HCl. The

organic phase was washed with H₂O (2 × 20 mL) and NaHCO₃,

decantated, and dried with Na₂SO₄, and the solvent was

removed under reduced pressure. The residue was purified by

flash chromatography (AcOEt-hexane, 1:1) to give 16 (0.70

g, 85%) as a white solid of mp 154-156 °C (i-PrOH). IR: 1698,

1640. ¹H NMR (CDCl₃): δ 1.89-2.16 (m, 4H, -N(CH₂-CH₂)₂C);

2.60-2.68 (m, 1H, H₅); 2.91-3.00 (m, 2H, -N(HCH-CH₂)₂-);

3.10 (dd, 1H, J _gem) 16.6, J _vic) 2.9, H₆); 3.23-3.46 (m, 3H,

-N(HCH-CH₂)₂CH-, -N(HCH-CH₂)₂-, HCH-CONRR); 3.57 (dd,

1H, J _gem) 17.4, J _vic) 7.0, H₆); 4.05 (dd, 1H, J _gem) 13.6, J _vic

) 7.1, -HCH-CONRR); 4.57-4.66 (m, 1H, -N(HCH-CH₂)₂-);

7.08-7.11 (m, 1H, H_5′); 7.16 (d, 1H, J ) 5.1, H₂); 7.25 (dd, 1H,

J _7′-F) 8.2, J _7′-5′) 2.1, H_7′); 7.32 (d, 1H, J ) 5.3, H₃); 7.63 (dd,

1H, J _4′-5′) 8.7, J _4′-F) 4.3, H_4′). ¹³C NMR (CDCl₃): δ 30.7,

32.4, 35.0, 41.9, 45.6, 50.3 (C₅, C₆, -CH₂-CONRR, -N(CH₂-

CH₂)₂C-); 97.9 (d, J _C-F) 26.8, C_7′); 113.1 (d, J _C-F) 25.3, C_5′);

117.4 (C_3′a); 120.0, 131.1 (C₂, C₃); 122.5 (d, J _C-F) 11.0, C_4′);

145.4 (C_6a); 160.5 (C_3′); 164.2 (d, J _C-F) 13.5, C_7a´); 164.6 (d,

J _C-F) 251, C_6′); 167.5 (C_3a); 169.5 (-CON<); 199.7 (C₄). MS

(FAB, m/z): 398.7 (MH⁺). Anal. (C₂₁H₁₉FN₂O₃S) C, H, N.

123.1 (d, J ) 11.1, C_4′); 123.7, 125.4 (C₂, C₃); 137.1, 155.6 (C_3a

,

C

_7a); 160.6 (C_3′); 164.2 (d, J _C-F) 13.5, C_7a´); 164.4 (d, J _C-F)

251, C_6′); 170.5 (-CONRR); 194.5 (C₄). MS (FAB, m/z): 413

(MH⁺). Anal. (C₂₂H₂₁FN₂O₃S) C, H, N.

N¹-[(4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e-5-yl)-

a cetyl]-N⁴-(ter t-bu toxyca r bon yl)p ip er a zin e (20c): yield

90%, mp 114-116 °C (i-PrOH). IR: 1693, 1673 (CO); 1638.

¹H NMR (CDCl₃): δ 1.47 (s, 9H, -C(CH₃)₃); 2.03-2.10 (m, 1H,

H₆); 2.36 (dd, J _gem) 16.0, J _vic) 7.9, 1H, HCH-CONRR); 2.28-

2.44 (m, 1H, H_6′); 3.12 (dd, J _gem) 16.0, J _vic) 4.0, 1H, H-CH-

CONRR); 3.11-3.21 (m, 3H, H₇, H_7′, H₅); 3.44-3.71 (m, 8H,

-N(CH₂-CH₂)₂N-); 7.06 (d, J ) 5.4, 1H, H₂); 7.37 (d, J ) 5.4,

1H, H₃). ¹³C NMR (CDCl₃): δ 25.7, 31.5, 33.2, 42.0, 44.2, 45.7

(C₅, C₆, C₇, -CH₂-CONRR, -N(CH₂-CH₂)₂N-); 28.7 (-COO-

C(CH₃)₃); 80.6 -COO-C(CH₃)₃); 123.7, 125.4 (C₂, C₃); 137.1,

155.6 (C_3a, C_7a); 156.4 (N-CO-O-); 170.5 (-CONRR); 194.3 (C₄).

MS (FAB, m/z): 379 (MH⁺). Anal. (C₁₉H₂₆N₂O₄S) C, H, N.

N¹-[(4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e-5-yl)-

a cetyl]-N⁴-(o-m eth oxyp h en yl)p ip er a zin e (20f): yield 80%,

mp 135-138 °C (AcOEt). IR: 1668, 1644. ¹H NMR (CDCl₃): δ

2.02-2.08 (m, 1H, H₆); 2.34 (dd, 1H, J _gem) 16.1, J _vic) 8.04,

HCH-CONRR); 2.41-2.49 (m, 1H, J ) 12.8, 8.0, 4.1, H₆); 3.02-

3.17 (m, 7H, H₇, H₇, H₅, -CON(CH₂-CH₂)₂N-); 3.25 (dd, 1H, J _gem

) 16.1, J _vic) 3.8, HCH-CONRR); 3.67-4.12 (m, 4H, -CON-

(CH₂-CH₂)₂N-); 3.88 (s, 3H, -OCH₃); 6.87-6.94 (m, 3H, H_4′, H_5′,

H_6′); 7.03 (dd, 1H, J _o) 5.6, J _m) 3.6, H_3′); 7.06 (d, 1H, J ) 5.3,

H₂); 7.38 (d, 1H, J ) 5.3, H₃). ¹³C NMR (CDCl₃): δ 26.1, 33.1,

34.3, 43.8, 44.8, 52.4 (C₅, C₆, C₇, -CH₂-CON(CH₂-CH₂)₂N-); 56.5

(-OCH₃); 113.8 (C_6′); 118.6 (C_3′); 120.6 (C_5′); 122.6, 124.3, 125.3

(C₂, C₃, C_4′); 153.1 (C_2′); 156.4 (C_3a); 171.0 (-CONRR); 195.4

(C₄). Anal. (C₂₁H₂₄N₂O₃S) C, H, N.

Compounds 27a (yield 90%) and 27b (yield 90%) were

prepared similarly.

BOC Rem ova l. N¹-[(1-Oxoin d a n -3-yl)ca r bon yl]p ip er -

a zin e (8d ). A solution of amide 8c (4 g, 11.63 mmol) in

trifluoroacetic acid (TFA; 27 mL) was stirred under argon at

room temperature for 20 min. Evaporation of the solvent under

N₂gave an oil which was dissolved in CH₂Cl₂. The resulting

solution was washed several times with 0.1 N NaOH and water

and dried (Na₂SO₄), and the solvent was distilled off. The oily

residue was purified by flash chromatography (AcOEt) to give

8d (86%) as a colorless oil. IR: 2925, 1712, 1640. ¹H NMR

(CDCl₃): δ 2.88 (dd, 1H, J _gem) 18.5, J _vic) 7.8, H₂); 3.00 (dd,

1H, J _gem) 18.5, J _vic) 4.1, H₂); 2.83-3.04 (m, 4H, -N(CH₂-

CH₂)₂NH); 3.61-3.75 (m, 4H, -N(CH₂CH₂)₂NH); 4.52 (m, 1H,

J _3-2) 7.7, J _3-2) 4.1, H₃); 7.42-7.46 (m, 2H, H₄, H₅); 7.62 (t,

1H, J ) 7.5, H₆); 7.78 (d, 1H, J ) 7.6, H₇). Hydrochloride: mp

142-143 °C (i-PrOH). Anal. (C₁₄H₁₆N₂O₂‚HCl) C, H, N.

N-[(7-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

a cetyl]-4-(p-flu or oben zoyl)p ip er id in e (27a ): yield 70%, mp

1

162-164 °C (cyclohexane). IR: 1682, 1646. H NMR (CDCl₃):

δ 1.62-2.16 (m, 5H, -N(CH₂-CH₂)₂CH-, H₅); 2.27-2.44 (m, 2H,

-HCH-CONRR, H₅); 2.80-2.98 (m, 3H, -CON(HCH-CH₂)₂CH-,

H₄, H₄); 3.08-3.31 (m, 3H, HCH-CONRR, -CON(HCH-CH₂)₂-

CH-, H₆); 3.45-3.52 (m, 1H, CH-CO-Ph); 4.03-4.12 (m, 1H,

-CON(HCH-CH₂)₂CH-); 4.56-4.63 (m, 1H, -CON(HCH-CH₂)₂-

CH-); 6.95 (d, 1H, J ) 4.9, H₃); 7.15 (t, 2H, J ) 8.4, o-F-Ph);

7.60 (d, 1H, J ) 4.9, H₂); 7.98 (dd, 2H, J ) 5.7, m-F-Ph). ¹³C

NMR (CDCl₃): δ 26.3 (C₅); 28.9 (-N(CH₂-CH₂)₂C-); 31.3 (C₄);

33.2 (-CH₂-CONRR); 43.6 (-N(CH₂-CH₂)₂CH-); 44.7 (C₆); 45.5

(-N(CH₂-CH₂)₂CH-); 116.30 (d, 2C, J _C-F) 21.8, o-F-Ph); 128.5,

134.4 (C₂, C₃); 131.2 (d, 2C, J ) 9.0, m-F-Ph); 132.5 (p-F-Ph);

136.5 (C_3a); 152.8 (C_7a); 165.9 (d, J ) 251, F-C); 170.1

(-CONRR); 193.7 (C₇); 200.4 (-CO-Phe-F). MS (FAB, m/z): 399

(MH⁺). Anal. (C₂₂H₂₂FNO₃S) C, H, N.

The following piperazines were prepared similarly.

N¹-[(4-Oxo-4H -5,6-d ih yd r ocyclop en t a [b ]t h iop h en e-5-

yl)a cetyl]p ip er a zin e (19d ): yield 78%. IR: 2923, 1694, 1633.

¹H NMR (CDCl₃): δ 2.50 (dd, 1H, J _gem) 16.7, J _vic) 9.6, H₆);

2.53 (s, 1H, NH); 2.73-2.79 (m, 4H, -N(CH₂-CH₂)₂NH); 2.86

(dd, 1H, J _gem) 17.5, J _vic) 3.0, HCH-CON<); 2.96 (m, 1H,

J _gem) 16.7, J _vic) 3.1, H_6′); 3.28-3.59 (m, 5H, -N(CH₂-CH₂)₂-

NH, H₅); 3.49 (dd, 1H, J _gem) 17.5, J _vic) 9.1, HCH-CONRR);

7.08 (d, 1H, J ) 5.1, H₂); 7.25 (d, 1H, J ) 5.3, H₃). MS (FAB,

m/z): 265 (MH⁺). Hydrochloride: mp 264-266 (MeOH/ether).

Anal. (C₁₃H₁₆N₂O₂S‚HCl) C, H, N.

N-[(7-Oxo-4,5,6,7-t et r a h yd r oben zo[b]t h iop h en e-6-yl)-

acetyl]-4-(6-flu or oben zisoxazol-3-yl)piper idin e (27b): yield

1

75%, mp 148-150 °C (cyclohexane). IR: 1678, 1642. H NMR

N¹-[(4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e-5-yl)-

a cetyl]p ip er a zin e (20d ): yield 80%. IR: 2947, 1667, 1633.

¹H NMR (CDCl₃): δ 1.97-2.04 (m, 1H, H₆); 2.27 (dd, 1H, J _gem

) 16.0, J _vic) 7.7, H-CH-CON<); 2.37-2.43 (m, 1H, H_6′); 2.82-

2.89 (m, 4H, -N(CH₂-CH₂)₂NH); 3.06-3.12 (m, 3H, H₇, H_7′, H₅);

3.16 (dd, 1H, J _gem) 16.0, J _vic) 3.8, H-CH-CONRR); 3.47-

3.68 (m, 4H, -N(CH₂-CH₂)₂NH); 7.04 (d, 1H, J ) 5.3, H₂); 7.36

(CDCl₃): δ 1.92-2.19 (m, 5H, -N(CH₂-CH₂)₂CH-, H₅); 2.30-

2.40 (m, 2H, -HCH-CON<, H₅); 2.95-3.03 (m, 3H, -N(HCH-

CH₂)₂CH-, H₄, H₄); 3.20-3.39 (m, 4H, HCH-CON<, -N(HCH-

CH₂)₂CH-, H₆, -CH₂)₂CH-); 4.08-4.15 (m, 1H, -N(HCH-CH₂)₂-

CH-); 4.62-4.76 (m, 1H, -N(HCH-CH₂)₂CH-); 6.95 (d, 1H, J )

4.9, H₃); 7.08 (t, 1H, J ) 8.7, H_5′); 7.24 (s, 1H, H_7′); 7.60 (d,

2790 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

(d, J ) 5.3, 1H, H₃). ¹³C NMR (CDCl₃): δ 25.7, 31.4, 33.0, 43.2,

44.1, 46.3 (C₅, C₆, C₇, -CH₂-CON(CH₂-CH₂)₂NH); 123.7, 125.4

(C₂, C₃); 137.1, 155.8 (C_3a, C_7a); 170.2 (-CON<); 194.5 (C₄). MS

(FAB, m/z): 279 (MH⁺). Hydrochloride: mp 226.5-228.5 °C

(MeOH/ether). Anal. (C₁₄H₁₈N₂O₂S‚HCl) C, H, N.

N¹-(o-Meth oxyp h en yl)-N⁴-[(1-oxoin d a n -3-yl)m eth yl]p i-

p er a zin e (10f): yield 85%, mp 100-102 °C (AcOEt). IR: 2936,

2813, 1716. ¹H NMR (CDCl₃): δ 2.50 (dd, 1H, J _gem) 12.4, J _vic

) 8.4, HCH-NRR); 2.65 (dd, 1H, J _gem) 19.2, J _vic) 3.1, H₂);

2.61-2.77 (m, 4H, -CH₂-N(CH₂CH₂)₂-N-); 2.74 (dd, 1H, J _gem

12.4, J _vic) 6.6, -HCH-NRR); 2.82 (dd, 1H, J _gem) 19.2, J _vic

)

Syn th esis of Am id es 20a ,c,f fr om Ester 16 Usin g Tr i-

m eth yla lu m in u m . N-[(4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]-

th ioph en e-5-yl)acetyl]-4-(p-flu or oben zoyl)piper idin e (20a).

A 2 M solution of trimethylaluminum in hexane (3 mL, 6

mmol) was added at 0 °C under argon to a solution of N-(tert-

butoxycarbonyl)piperazine in anhydrous CH₂Cl₂(3 mL). After

stirring at room temperature for 15 min, a solution of ester

16 (0.7 g, 3 mmol) in anhydrous CH₂Cl₂(5 mL) was added

dropwise, and the resulting mixture was refluxed for 48 h.

After cooling, 10% HCl was added until cessation of gas

release. The organic layer was separated and dried (Na₂SO₄),

and the solvent was distilled off. The oily residue was purified

by flash chromatography (hexane/AcOEt, 1:1) to give 20a

(15%): mp 143-145 °C (i-PrOH).

7.4, H₂); 3.02-3.19 (m, 4H, -CH₂-N(CH₂CH₂)₂-N-); 3.49-3.62

(m, 1H, H₃); 3.83 (s, 3H, -OCH₃); 6.81-7.01 (m, 4H, H_3′, H_4′,

H_5′, H_6′); 7.38 (t, 1H, J ) 7.2, H₆); 7.59 (t, 1H, J ) 7.5, H₅);

7.67 (d, 1H, J ) 7.6, H₄); 7.72 (d, 1H, J ) 7.6, H₇). ¹³C NMR

(CDCl₃): δ 36.37; 42.50; 51.12; 54.09; 55.76; 64.56; 111.53 (C_6′);

118.61 (C_3′); 121.38 (C_5′); 123.94 (C₅); 137.41 (C_7a); 141.67 (C_1′);

152.65 (C_2′); 157.75 (C_3a); 206.77 (C₁). MS (FAB, m/z): 337

(MH⁺). Hydrochloride: mp 220-222 °C (i-PrOH). Anal.

(C₂₁H₂₃N₂O₂‚2HCl) C, H, N.

N-[(4-Oxo-4H -5,6-d ih yd r ocyclop en t a [b]t h iop h en e-5-

yl)eth yl]-4-(p-flu or oben zoyl)p ip er id in e (23a ): yield 70%.

1

IR: 1712, 1685. H NMR (CDCl₃): δ 1.75-1.85 (m, 6H, -CH₂-

CH₂-NRR, -CH₂)₂CH-); 1.88-2.19 (m, 4H, -N(CH₂-CH₂)₂CH-);

2.21-2.23 (m, 1H, H₅); 2.52 (t, 2H, J ) 7.3, -CH₂-NRR); 2.93

(dd, 1H, J _gem) 17.4, J _vic) 2.7, H₆); 3.06-3.11 (m, 1H, -CH₂)₂-

CH-CO-); 3.40 dd, 1H, J _gem) 17.3, J _vic) 6.9, H₆); 7.12-7.18

(m, 3H, J ) 5.3, H₂, o-F-Ph); 7.34 (d, 1H, J ) 5.2, H₃); 7.97

(dd, 2H, J ) 8.9, 5.4, m-F-Ph). ¹³C NMR (CDCl₃): δ 28.9(2C,

-N(CH₂CH₂)₂CH); 30.1 (C₆); 31.3, 43.9, 52.0, 53.4 (2C, -N(CH₂-

CH₂)₂CH-); 53.5, 56.4, 116.1 (d, 2C, J _C-F) 21.8, o-F-Ph); 120.0

(C₂); 131.0 (C₃); 131.2 (d, 2C, J _C-F) 9.4, m-F-Ph); 132.8 (d,

J _C-F) 3.0, p-F-Ph); 145.8 (C_6a); 166.02 (d, J _C-F) 251, C-F);

169.3 (C_3a); 200.5 (C₄); 201.4 (-CO-Ph). MS (FAB, m/z): 372

Compounds 20c,f (Table 5) were prepared similarly.

Gen er a l P r oced u r e for Syn th esis of Eth ylen e Keta ls

9a ,d ,f, 21d , 22a ,b,f, a n d 28a ,b (Ta ble 6). N-[(1-Oxoin d a n -

3-yl)ca r bon yl]-4-(p-flu or oben zoyl)p ip er id in e Bis(eth yl-

en e k eta l) (9a ). A stirred solution of amide 8a (3 g, 8.2 mmol),

ethylene glycol (50.84 g, 0.82 mol), and p-TsOH (50 mg) in

anhydrous toluene (75 mL) was refluxed in a Dean-Stark

apparatus for 96 h with azeotropic distillation of water. After

cooling, the toluene solution was washed several times with

10% Na₂CO₃and water and dried (Na₂SO₄), and the solvent

was removed under reduced pressure. The resulting crude

dioxolane (3.46 g, 93%), an orange oil with only one carbonyl

band in its IR spectrum (at 1641 cm^-1), was used in the next

step without further purification. A sample crystallized slowly

on standing: mp 138-139 °C. MS (FAB, m/z): 454 (MH⁺).

(MH⁺). Oxalate: mp 172-173 °C (AcOEt). Anal. (C₂₁H₂₂

FNO₂S‚C₂O₄H₂) C, H, N.

-

N-[(4-Oxo-4H -5,6-d ih yd r ocyclop en t a [b]t h iop h en e-5-

yl)eth yl]-4-(6-flu or oben zisoxa zol-3-yl)p ip er id in e (23b):

1

yield 75%. IR: 2924, 1698, 1615. H NMR (CDCl₃): δ 1.77-

2.25 (m, 9H, H₅, -N(HCH-CH₂)₂-, -CH₂-CH₂N<); 2.54 (t, 2H, J

) 7.3, -CH₂N<); 2.93 (dd, 1H, J _gem) 17.3, J _vic) 2.8, H₆); 3.02-

3.13 (m, 3H, -N(HCH-CH₂)₂CH-); 3.39 (dd, 1H, J _gem) 17.3,

J _vic) 6.9, H_6′); 7.04 (dt, 1H, J ) 8.8, 2.1, H_5′′); 7.15 (d, 1H, J

) 5.1, H₂); 7.22 (dd, 1H, J _7′′-F) 8.5, J _{7′′-5′′}) 2.1, H_7′′); 7.32 (d,

1H, J ) 5.1, H₃); 7.67 (dd, 1H, J _{4′′-5′′}) 8.7, J _4′′-F) 5.1, H_4′′).

¹³C NMR (CDCl₃): δ 29.0, 30.7, 31.2, 34.9 (C₅, C₆, -CH₂-CH₂-

NRR, -CH₂)₂-); 51.9 (-CH₂)₂CH-); 53.8 (-CH₂N<); 56.4 (-N(CH₂-

CH₂)₂-); 97.8 (d, J _C-F) 26.7, C_7′); 112.7 (d, J _C-F) 25.2, C_5′);

117.6 (C_3a′); 123.0 (d, J _C-F) 11.0, C_4′); 120.0, 131.1 (C₂, C₃);

161.4 (C_3′); 164.2 (d, J _C-F) 13.7, C_7a′); 165.0 (d, J _C-F) 250,

C_6′); 200.4 (C₄). MS (FAB, m/z): 385 (MH⁺). Hydrochloride:

mp 230-232 °C (i-PrOH). Anal. (C₂₁H₂₁FN₂O₂S‚HCl) C, H, N.

All the other ethylene ketals listed in Table 6 were prepared

similarly as crude oils, checked by IR and ¹H NMR spectros-

copy, and used in the following step without further purifica-

tion.

Gen er a l P r oced u r e for Syn th esis of Am in ok eton es

10a ,f (Ta ble 1), 23a ,b (Ta ble 2), 24a ,b,f (Ta ble 3), a n d

29a ,b (Ta ble 4). N¹-[(1-Oxoin d a n -3-yl)m eth yl]-4-(p-flu o-

r oben zoyl)p ip er id in e (10a ). A solution of amide bis(ethylene

ketal) 9a (2.08 g, 4.6 mmol) in anhydrous ether (20 mL) was

added dropwise under argon to a stirred suspension of LiAlH₄

(0.70 g, 18.5 mmol) in anhydrous ether (40 mL). The reaction

mixture was heated under reflux for 8 h, cooled to 0 °C in an

ice bath, and then quenched by sequential dropwise addition

of H₂O (1 mL), NaOH 10% (2 mL), and H₂O (4 mL). The coarse

precipitate formed was filtered out and thoroughly washed

with ether. The combined filtrates were treated with 10% HCl

and heated under reflux for 1-2 h. On cooling, the aqueous

phase was made alkaline with 10% NaOH and extracted with

CH₂Cl₂three times, the combined organic extracts were dried

(Na₂SO₄), and the solvent was removed in vacuo. The residue

was dissolved in anhydrous ether, and ether-saturated HCl

gas was cautiously added to the resulting solution. The white

precipitate formed was recovered and kept overnight in a

vacuum desiccator. Recrystallized from isopropyl alcohol, the

hydrochloride melted at 229-231 °C. Anal. (C₂₂H₂₂FNO₂‚HCl)

C, H, N. Data for free base: ¹H NMR (CDCl₃): δ 1.83-1.90

(4H, -N(CH₂CH₂)₂-CH-); 2.14-2.25 (m, 2H, -N(HCHCH₂)-CH-);

2.47 (dd, 1H, J _gem) 12.2, J _vic) 8.2, -HCH-NRR); 2.50 (dd,

1H, J _gem) 19.3, J _vic) 3.1, H₂); 2.65 (dd, 1H, J _gem) 12.3, -HCH-

NRR); 2.82 (dd, 1H, J _gem) 19.3, J _vic) 7.5, H₂); 2.99-3.05 (m,

2H, -N(HCHCH₂)₂-CH-); 3.22 (m, 1H, H₃); 3.55 (m, 1H, -N(CH₂-

CH₂)₂-CH-); 7.13 (t, 2H, J ) 8.6, o-F-Ph); 7.38 (t, 1H, J ) 7.3,

H₆); 7.55-7.60 (m, 1H, H₅); 7.69 (d, 1H, J ) 7.5, H₄); 7.73 (d,

1H, J ) 7.6, H₇); 7.97 (dd, 2H, J ) 8.8, 5.5, o-CO-Ph). ¹³C NMR

(CDCl₃): δ 29.04; 36.28; 42.22; 43.89; 53.75; 64.51; 116.05 (d,

2C, J _C-F) 21.89, o-F-Ph); 123.74 (C₄); 126.91 (C₇); 128.03 (C₆);

131.14 (d, 2C, J _C-F) 9.8, m-F-Ph); 132.63 (CO-C_aromatic); 134.77

(C₅); 137.17 (C_7a); 157.65 (C_3a); 164.21; 167.58; 201.40 (CO-

Ph); 206.58 (C₁). MS (FAB, m/z): 352 (MH⁺).

N-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-5-yl)-

et h yl]-4-(p -flu or ob en zoyl)p ip er id in e (24a ): yield 85%.

1

IR: 1678, 1680. H NMR (CDCl₃): δ 1.59-1.85 (m, 6H, -CH₂-

CH₂-NRR, -CH₂)₂CH-); 1.91-2.36 (m, 5H, H₆, -N(CH₂-CH₂)₂-

CH-); 2.49 (t, 2H, J ) 8.0, -CH₂-NRR); 2.45-2.58 (m, 1H, H₆);

2.96-3.10 (m, 3H, H₇, H_7′, -CH₂)₂-CH-CO-); 3.14-3.20 (m, 1H,

H₅); 7.05 (d, 1H, J ) 5.3, H₂); 7.13 (t, 2H, J ) 8.7, o-F-Phe);

7.32 (d, 1H, J ) 5.2, H₃); 7.95 (dd, 2H, J ) 8.7, 5.5, m-F-Ph).

¹³C NMR (CDCl₃): δ 24, 26, 29, 30 (C₆, C₇, -CH₂-CH₂NRR,

-CH₂)₂CH-); 43, 44 (C₅, -CH₂)₂CH-); 53, 56 (-CH₂-N(CH₂-CH₂)₂-

CH-); 116.0 (d, 2C, J _C-F) 21.8, o-F-Ph); 123.4, 125.3 (C₂, C₃);

131.1 (d, 2C, J _C-F) 9.0, m-F-Ph); 132.6 (d, J _C-F) 3.0, p-F-

Ph); 137, 155 (C_3a, C_7a); 167.3 (d, J _C-F) 254, C-F); 195.3 (C₄);

201.3 (-CO-Ph). MS (FAB, m/z): 386 (MH⁺). Hydrochloride:

white crystals, mp 278-280 °C (MeOH/ether). Anal. (C₂₂H₂₄

FNO₂S‚HCl) C, H, N.

-

N-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-5-yl)-

eth yl]-4-(6-flu or oben zisoxa zol-3-yl)p ip er id in e (24b): yield

75%. IR: 2922, 1668, 1615. ¹H NMR (CDCl₃): δ 1.59-1.85 (m,

6H, -CH₂-CH₂-NRR, -CH₂)₂CH-); 1.91-2.36 (m, 5H, H₆, -N(CH₂-

CH₂)₂CH-); 2.49 (t, 2H, J ) 8.0, -CH₂-NRR); 2.45-2.58 (m, 1H,

H₆); 2.96-3.10 (m, 3H, H₇, H₇, -CH₂)₂-CH-CO-); 3.14-3.20 (m,

1H, H₅); 7.05 (d, 1H, J ) 5.3, H₂); 7.13 (t, 2H, J ) 8.7, o-F-

Ph); 7.32 (d, 1H, J ) 5.2, H₃); 7.95 (dd, 2H, J ) 8.7, 5.5, m-F-

Ph). ¹³C NMR (CDCl₃): δ 24, 26, 29, 30 (C₆, C₇, -CH₂-CH₂NRR,

-CH₂)₂CH-); 43, 44 (C-₅, -CH₂)₂CH-); 53, 56 (-CH₂-N(CH₂-CH₂)₂-

CH-); 116.0 (d, 2C, J _C-F) 21.8, o-F-Ph); 123.4, 125.3 (C₂, C₃);

The following amines were prepared similarly.

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2791

131.1 (d, 2C, J _C-F) 9.0, m-F-Ph); 132.6 (d, J _C-F) 3.0, p-F-

Ph); 137, 155 (C_3a, C_7a); 167.3 (d, J _C-F) 254, C-F); 195.3 (C₄);

201.3 (-CO-Ph). MS (FAB, m/z): 399 (MH⁺). Hydrochloride:

mp 248-249 °C (AcOEt). Anal. (C₂₂H₂₃FN₂O₂S‚HCl) C, H, N.

7.1, >N-CH₂CH₂CH₂-CO-); 2.23-2.52 (m, 12H, RRN-CH₂CH₂-

CH₂-CO-, -N(CH₂CH₂)₂-N-, -HCH-NRR, 1H₂); 2.58 (dd, 1H, J _gem

) 12.2, J _vic) 6.6, -HCH-NRR); 2.74 (dd, 1H, J _gem) 19.3, J _vic

) 7.4, H₂); 2.91 (t, 2H, J ) 7.1, -N-CH₂CH₂CH₂-CO-); 3.42-

3.49 (m, 1H, H₃); 7.06 (t, J ) 8.6, 2H, o-F-Ph); 7.31 (t, 1H, J )

7.2, H₆); 7.49-7.58 (m, 2H, H₄, H₅); 7.66 (d, 1H, J ) 7.6, H₇);

7.93 (dd, 2H, J ) 5.4-8.8, o-CO-Ph). ¹³C NMR (CDCl₃): δ

21.79; 36.21; 36.44; 42.27; 53.35; 53.56; 57.91; 64.26; 115.71;

115.86 (d, 2C, J _C-F) 21.9, o-F-Ph); 123.78 (C₄); 126.70 (C₇);

128.02 (C₆); 130 (d, 2C, J _C-F) 9.8, m-F-Ph); 134.75 (C₅); 137.21

(C_7a); 157.56; 198.67 (CO-Ph); 206.61 (C₁). MS (FAB, m/z): 395

(MH⁺).

N¹-[(4-Oxo-4H -5,6-d ih yd r ocyclop en t a [b]t h iop h en e-5-

yl)eth yl]-N⁴-[3-(p-flu or oben zoyl)p r op yl]p ip er a zin e (23e)

[yield 58%, mp 89-90 °C (cyclohexane); hydrochloride, mp

244-246 °C (i-PrOH); 2,4-dinitrophenylhydrazone, mp 198-

199 °C (MeOH)] and N⁴-[3-(p-flu or oben zoyl)p r op yl]-N¹-[(4-

oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-5-yl)et h yl]p i-

per azin e (24e) [yield 50%; hydrochloride, 234-236 °C (MeOH/

ether)] were prepared as previously reported.⁴²

N¹-[(4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e-5-yl)-

eth yl]-N⁴-(o-m eth oxyp h en yl)p ip er a zin e (24f): yield 85%.

1

IR: 1670. H NMR (CDCl₃): δ 1.65-1.78 (m, 2H, -CH₂-CH₂-

NRR); 1.96-2.18 (m, 2H, H₆, H₆); 2.50-2.71 (m, 7H, -CH₂-

N(CH₂-CH₂)₂N-, H₇); 3.03-3.17 (m, 6H, H₅, H₇, -CH₂-CH₂)₂N-);

3.86 (s, 3H, -OCH₃); 6.84-7.02 (m, 4H, Ph); 7.05 (d, 1H, J )

5.2, H₂); 7.38 (d, 1H, J ) 5.2, H₃). ¹³C NMR (CDCl₃): δ 24.9,

26.7, 30.3 (C₆, C₇, -CH₂-CH₂N<); 45.0 (C₅); 50.9, 53.8 (-N(CH₂-

CH₂)₂N-); 55.7 (-OCH₃); 61.7 (-CH₂-NRR); 111.5 (C_6′); 118.6

(C_3′); 121.3 (C_5′); 123.3, 123.7, 125.0 (C₂, C₃, C_4′); 137.6 (C_7a);

141.6 (C_1′); 152.6 (C_2′); 155.6 (C_3a); 195.4 (C₄). MS (FAB, m/z):

371 (MH⁺). Hydrochloride: mp 233.5-235.5 °C (MeOH-

ether). Anal. (C₂₁H₂₆N₂O₂S‚2HCl) C, H, N.

N-[(7-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

et h yl]-4-(p -flu or ob en zoyl)p ip er id in e (29a ): yield 65%.

1

IR: 1678, 1653, 1596. H NMR (CDCl₃): δ 1.59-2.03 (m, 7H,

-CH₂-CH₂NRR, -N(CH₂-CH₂)₂CH-, H₅); 2.08-2.32 (m, 4H,

-N(CH₂-CH₂)₂CH-); 2.52 (t, 2H, J ) 7.9, -CH₂NRR); 2.47-2.67

(m, 1H, H₅); 2.79-3.04 (m, 3H, H₄, H₄, -CH₂)₂CH-); 3.14-3.24

(m, 1H, H₆); 6.94 (d, 1H, J ) 4.9, H₃); 7.13 (t, 2H, J ) 8.7,

o-F-Ph); 7.58 (d, 1H, J ) 4.9, H₂); 7.96 (dd, 2H, J ) 8.8, 5.5,

m-F-Ph). ¹³C NMR (CDCl₃): δ 25.4 (-CH₂-CH₂NRR); 26.9 (C₅);

29.1 (-N(CH₂-CH₂)₂CH-); 30.2 (C₄); 44.0 (C₆); 45.5 (-CH₂)₂-

CH-); 53.5 (-CH₂NRR); 56.6 (-N(CH₂-CH₂)₂CH-); 116.15 (d, 2C,

J ) 21.8, o-F-Ph); 128.5, 134.1 (C₂, C₃); 131.2 (d, 2C, J ) 9.0,

m-F-Ph); 132.8 (p-F-Ph); 136.9 (C_3a); 152.1 (C_7a); 165.5 (d, J )

251, F-C); 194.6 (C₇); 201.4 (-CO-Ph-F). MS (FAB, m/z): 386

â-(2-Th en oyl)-γ-bu tyr ola cton e (31). To a stirred solution

of â-(R-thenoyl)propionic acid (30; 10 g, 54.3 mmol) in 0.5 N

NaOH (120 mL) was added 37% CH₂O (5.2 mL). After 1 h at

room temperature, the mixture was brought to pH 1 with 6 N

HCl, and stirring was continued for 24 h. The white precipitate

formed was recovered and washed with ether, and recrystal-

lization from i-PrOH afforded 31 (9.05 g, 85%) as white

crystals: mp 99-100 °C. IR: 1765 (COO), 1646 (CO). ¹H NMR

(CDCl₃): δ 2.78 (dd, 1H, J _gem) 17.8, J _vic) 9.4, -H-CH-COO-),

3.03 (dd, 1H, J _gem) 17.8, J _vic) 7.9, -H-CH-COO-); 4.23-4.31

(m, 1H, Ar-CO-CH-); 4.48 (dd, 1H, J ) 9.2, 7.0, HCH-OCO-);

4.61 (t, 1H, J ) 8.9, HCH-OCO-); 7.20 (dd, 1H, J ) 4.9, 3.9,

H-4); 7.74 (dd, 1H, J ) 3.9, 1.1, -CHdCH-); 7.76 (dd, 1H, J )

5.0, 1.0, -CHdCH-). ¹³C NMR (CDCl₃): δ 31.3 (-C-COO-); 43.6

(Ar-CO-C); 69.5 (-C-O-CO-); 128.9; 133.1; 135.9; 142.5 (-CHd

C-); 175.4 (-COO-); 189.4 (Ar-CO-C). Anal. (C₉H₈O₃S) C, H.

â-(2-Th ien yl)-γ-bu tyr ola cton e (32). A suspension of Zn

wool (21 g) and Hg₂Cl₂(2.1 g) in a mixture of 6 N HCl (1 mL)

and H₂O (31 mL) was stirred under argon for 5 min. After

decantation, H₂O (15.6 mL), 6 N HCl (34.6 mL), toluene (21

mL), ketone 31 (10.5 g, 533.5 mmol), and glacial acetic acid (1

mL) were added. The reaction mixture was heated under reflux

with continuous stirring for 48 h, during which time additional

6 N HCl (1 mL) and glacial acetic acid were added every 12 h.

After cooling, the organic phase was dried (Na₂SO₄), and the

solvent was removed under reduced pressure. The oily residue

was purified by flash chromatography (silica gel, AcOEt/

hexane, 1:3) to give 32 (4.7 g, 50%) as a colorless oil. IR: 1774.

¹H NMR (CDCl₃): δ 2.29 (dd, 1H, J _gem) 17.6, J _vic) 6.7, HCH-

COO-); 2.63 (dd, 1H, J _gem) 17.6, J _vic) 8.2, HCH-COO-); 2.82-

2.87 (m, 1H, Ar-CH₂-CH-); 2.97 (d, 2H, J ) 7.5, Ar-CH₂-); 4.03

(dd,1H, J _gem) 9.2, J _vic) 6.0, HCH-O-CO-); 4.36 (dd, 1H, J _gem

) 9.2, J _vic) 7.0, -H-CH-O-CO-); 6.80 (dd, 1H, J _3-4) 3.4, J _3-5

) 1.0, H₃); 6.92 (dd, 1H, J _4-5) 5.1, J _4-3) 5.1, H-4); 7.15 (dd,

1H, J _5-4) 5.1, J _5-3) 1.1, H-5). ¹³C NMR (CDCl₃): δ 33.4,

34.5, 37.7 (Ar-C-, Ar-C-C-, -C-COO-); 72.9 (-C-OCO-); 124.6;

126.1; 127.5; 140.9 (-CHdCH-CH₂-); 177.1 (-COO-). MS (EI,

m/z): 182 (M⁺). Anal. (C₉H₁₀O₂S) C, H.

(MH⁺). Hydrochloride: mp 262-264 °C (i-PrOH). Anal. (C₂₂H₂₄

FNO₂S‚HCl) C, H, N.

-

N-[(7-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

eth yl]-4-(6-flu or oben zisoxa zol-3-yl)p ip er id in e (29b): yield

80%. IR: 1636. ¹H NMR (CDCl₃): δ 1.57-2.00 (m, 7H, H₅,

-CH₂-CH₂NRR, -N(CH₂-CH₂)₂CH-); 2.04-2.32 (m, 4H, -N(CH₂-

CH₂)₂CH-); 2.47-2.69 (m, 3H, -CH₂NRR, H₅); 2.80-3.11 (m,

4H, H₄, H₄, H₆, -CH₂)₂CH-); 6.95 (d, 1H, J ) 4.9, H₃); 7.04 (dt,

1H, J ) 8.8, 2.1, H_5′); 7.21-7.25 (m, 1H, H_7′); 7.59 (d, 1H, J )

4.9, H₂); 7.68 (dd, 1H, J _4′-5′) 8.7, J _4′-F) 5.1, H_4′). ¹³C NMR

(CDCl₃): δ 25.4, 27.0, 28.3, 30.2 (C₄, C₅, -CH₂-CH₂NRR, -CH₂)₂-

CH-); 41.6, 45.5 (C₆, -CH₂)₂CH-); 53.8 (-CH₂NRR); 56.7 (-N(CH₂-);

97.8 (d, J _C-F) 26.6, C_7′); 112.7 (d, J _C-F) 25.5, C_5′); 117.7 (C_3a´);

123.0 (d, J _C-F) 11.0, C_4′); 128.5, 134.1 (C₂, C₃); 137.0 (C_3a);

152.1 (C_7a); 161.5 (C_3′); 164.2 (d, J _C-F) 13.4, C_7a′); 165.0 (d,

J _C-F) 250, C_6′); 194.5 (C₇). MS (FAB, m/z): 399 (MH⁺).

Hydrochloride: mp 246-248 °C (i-PrOH). Anal. (C₂₂H₂₃

FN₂O₂S‚HCl) C, H, N.

-

Gen er a l P r oced u r e for P r ep a r in g N¹-[(Oxocycloa lk a -

n yl)a lk yl]-N⁴-[3-(p-flu or oben zoyl)p r op yl]p ip er a zin es 10e

(Ta ble 1), 23e (Ta ble 2), a n d 24e (Ta ble 3). N¹-[(1-Oxo-

in d a n -3-yl)m eth yl]-N⁴-[3-(p-flu or oben zoyl)p r op yl]p ip er -

a zin e (10e). A solution of 4-chloro-1,1-(ethylenedioxy)-1-(4-

fluorophenyl)butane (0.52 g, 21 mmol) in MIK (15 mL) was

added under argon with stirring to a mixture of ethylene ketal

10d (0.62 g, 2 mmol), anhydrous Na₂CO₃(1.65 g, 56 mmol),

and a few crystals of KI (0.032 g, 0.2 mmol) in MIK (45 mL).

After refluxing with vigorous stirring for 20 h, the mixture

was allowed to stand at room temperature overnight before

filtration. The filtrate was condensed under reduced pressure

to give 0.25 g of a white oil. This product was treated with

10% HCl, and the resulting suspension was vigorously stirred

at 35-40 °C for 2 h. After cooling, the aqueous layer was made

alkaline with 10% NaOH and extracted several times with

ether. The combined ether extracts were dried (Na₂SO₄), and

the solvent was partially removed under reduced pressure. To

the resulting concentrated solution was cautiously added dry

ether-saturated HCl gas. The white precipitate formed was

recovered and kept overnight in a vacuum desiccator. Recrys-

tallization from MeOH/ether afforded 0.18 g (35%) of amine

10e hydrochoride as white crystals, mp 216-217 °C (i-PrOH).

Anal. (C₂₄H₂₇FN₂O₂‚2HCl) C, H, N. Data for the free base:

IR: 2813, 1715, 1680. ¹H NMR (CDCl₃): δ 1.88 (c, 2H, J )

γ-Br om o-â-(2-th en yl)bu tyr ic Acid Meth yl Ester (33).

HBr-AcOH (33%, 3.1 mL) was added dropwise under argon

to a stirred solution of â-(2-thienyl)-γ-butyrolactone (32; 2.64

g, 15.9 mmol) in glacial acetic acid (35 mL) at 0 °C. After 15

min at room temperature the solution was heated at 80 °C for

4 h. After cooling, the reaction mixture was poured into ice-

water and extracted with CH₂Cl₂(3 × 25 mL). The organic

phase was washed several times with water and dried (Na₂-

SO₄), and the solvent was distilled off to provide the γ-bromo-

â-(2-thenyl)butyric acid (3.35 g, 75%), which was immediately

esterified with CH₂N₂/ether as usual. IR: 1734. ¹H NMR

(CDCl₃): δ 2.46-2.56 (m, 3H, -CH₂-COO-, -CH-CH₂-Br); 2.95-

2.98 (m, 2H, Ar-CH₂-C); 3.45 (dd, 1H, J _gem) 10.4, J _vic) 4.3,

HCH-Br); 3.54 (dd, 1H, J _gem) 10.4, J _vic) 3.9, HCH-Br); 3.69

(s, 3H, -COO-CH₃); 6.86 (dd, 1H, J _3-4) 3.4, J _3-5) 0.9, H₃);

6.93 (dd, 1H, J _4-3) 3.4, J _4-5) 5.1, H₄); 7.16 (dd, 1H, J _5-4

)

2792 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

5.1, J _5-3) 1.2, H₅). ¹³C NMR (CDCl₃): δ 33.0, 36.9, 38.1, 38.9

(Ar-C-C-, -C-COO-, -C-Br); 52.2 (-COO-CH₃); 124.5, 126.6,

127.4 (-CHdCH-, -CHdC-); 141.1 (-CHdC-); 172.8 (-COO-). MS

(FAB, m/z): 277.9 (MH⁺). Anal. (C₁₀H₁₃BrO₂S) C, H.

(dd, 1H, J ) 14.8, 6.8, thienyl-H-CH-); 2.95 (dd, 1H, J ) 14.8,

5.6, thienyl-HCH-); 3.05 (s.a., 4H, -N(H-CH-CH₂)₂N-Ph); 3.65

(s, 3H, -COOCH₃); 3.85 (s, 3H, Ph-OCH₃); 6.81 (d, 1H, J )

3.4, H₃); 6.81-7.02 (m, 5H, H_3′, H₄, H_4′, H_5′, H_6′); 7.14 (dd, 1H,

J _5-3) 1.1, J _5-4) 5.2, H₅). ¹³C NMR (CDCl₃): δ 32.8, 35.1,

37.6 (thienyl-CH₂-CH-CH₂-COO-); 51.1 (2C, -N(CH₂-CH₂)₂N-

Ph); 51.9 (-COOCH₃); 54.0 (2C, -N(CH₂-CH₂)₂N-Ph); 55.7

(-OCH₃); 62.6 (-CH₂-NRR); 111.5 (C_6′); 118.5 (C_3′); 121.3 (C_5′);

123.2 (C_4′); 124.1; 126.2; 127.1; 141.8 (C_1′); 142.2 (C₂); 152.6

(C_2′); 173.9 (-COOCH₃).

BOC Rem ova l. γ-(P ip er a zin -1-yl)-â-(2-th en yl)bu tyr ic

Acid Meth yl Ester Hyd r och lor id e (34d ). A solution of BOC

derivative 34c base (1.25 g, 3.2 mmol) in MeOH (15 mL) was

brought to pH 1 by addition of dry MeOH-saturated HCl gas

under argon and then stirred at room temperature for 24 h.

The solvent was removed under reduced pressure, and the

residue was dissolved in 10% NaHCO₃and extracted with CH₂-

Cl₂. The organic layer was dried and the solvent removed in

vacuo to provide 34d (0.87 g, 95%) as a colorless oil which was

subjected to ring closure without further purification. IR:

1734. ¹H NMR (CDCl₃): δ 2.11-2.43 (m, 9H, -CH-CH₂-

COOCH₃, -CH₂NRR, -N(CH₂-CH₂)₂NH); 2.75-2.89 (m, 6H,

thienyl-CH₂-, -N(CH₂-CH₂)₂NH); 3.60 (s, 3H, -COOCH₃); 6.83

(dd, 1H, J _4-5) 5.1, J _4-3) 3.5, H₄); 7.07 (dd, 1H, J _5-4) 5.1,

J _5-3) 0.8, H₅). ¹³C NMR (CDCl₃): δ 32.6, 34.8, 37.5 (thienyl-

CH₂-CH-CH₂-COO-); 46.3 (-N(CH₂-CH₂)₂NH); 51.7 (-COOCH₃);

54.9 (2C, -N(CH₂-CH₂)₂NH); 63.0 (-CH₂NRR); 124.0; 126.1;

127.0; 142.1 (C₂); 173.7 (-COO-). MS (FAB, m/z ): 283 (MH⁺).

Hydrochloride: mp 130-131 °C (AcOEt). Anal. (C₁₄H₂₂N₂O₂S‚

2HCl) C, H, N.

Gen er a l P r oced u r e for Syn th esis of 6-(Am in om eth yl)-

4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en -4-on e H yd r och lo-

r id es 35a ,b,d ,f (Ta ble 7). To 110 g of polyphosphoric acid

(Fluka) stirring under argon at 90 °C was slowly added the

appropriate crude aminomethyl ester (9 mmol), after which

the temperature was increased to 130 °C. After 5 h the reaction

mixture was poured into ice-water, stirred, made alkaline

with 5 N NaOH, and extracted with CH₂Cl₂. The organic phase

was washed several times with water to neutral pH and dried

(Na₂SO₄), and the CH₂Cl₂was removed in vacuo to afford the

desired 6-(aminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-

4-one. The oily residue was dissolved in anhydrous ether to

obtain the hydrochloride salt as usual.

Gen er a l P r oced u r e for th e Syn th esis of γ-Am in o-â-(2-

th en yl)bu tyr ic Acid Meth yl Ester Hyd r och lor id es 34a -

c,f. To a solution of amine (9 mmol) and γ-bromo-â-thenylbu-

tyric acid methyl ester (9 mmol) in MIK (35 mL) were added

K₂CO₃(2.5 g) and KI (0.045 g). This mixture was refluxed for

12 h. Inorganic salts were then filtered out, and the solvent

was removed under reduced pressure. The resulting oil was

dissolved in CH₂Cl₂, washed several times with water, and

dried (Na₂SO₄). The CH₂Cl₂was removed under reduced

pressure to afford the desired aminomethyl ester in quantita-

tive yields. After dissolution in anhydrous ether, ether-

saturated HCl gas was cautiously added. The white precipi-

tates formed were recovered and kept overnight in a vacuum

desiccator; recrystallization from various solvents afforded

34a -c,f as white crystals.

4-[(p-F lu or oben zoyl)p ip er id in -1-yl]-â-(2-th en yl)bu tyr -

ic a cid m eth yl ester h yd r och lor id e (34a ): mp 190-191 °C

(AcOEt). Anal. (C₂₂H₂₆FNO₃S‚HCl) C, H, N. Spectral data for

the free base: IR: 1732, 1678. ¹H NMR (CDCl₃): δ 1.76-1.81

(m, 4H, -N(CH₂-CH₂)₂CH-); 1.96-2.30 (m 6H, -CH₂-COO-,

-N(H-CH-CH₂)₂CH-, -CH₂NRR); 2.42-2.49 (m, 1H, -CH-CH₂-

NRR); 2.84-2.95 (m, 4H, -N(H-CH-CH₂)₂-, thienyl-CH₂-C-);

3.13-3.18 (m, 1H, -CH₂)₂-CH-CO); 3.65 (s, 3H, -COOCH₃); 6.78

(d, 1H, J _3-4) 3.4, H₃); 6.91 (dd, 1H, J _4,3) 3.4, J _4,5) 5.1, H₄);

7.09-7.16 (m, 3H, H₅, -CHdCH)₂-CF); 7.94 (dd, 2H, J ) 8.7,

5.5, -CHdCH)₂CF). ¹³C NMR (CDCl₃): δ 29.1, 29.2 (-N(CH₂-

CH₂)₂C-); 32.8, 35.3, 37.7 (thienyl-CH₂-CH-CH₂-COO-); 44.0

(-N(CH₂-CH₂)₂C-); 51.9 (-COOCH₃); 53.5, 54.2 (-N(CH₂-CH₂)₂-

C-); 62.6 (-CH₂-NRR); 116.15 (d, 2C, J _C-F) 21.8, o-F-Ph);

124.1, 126.1, 127.3 (C-3, C-4, C-5); 131.25 (d, 2C, J _C-F) 9.44,

m-F-Ph); 123.8 (CO-C aromatic); 165.0 (d, J _C-F) 251, F-C);

173.9 (-COO-CH₃); 201.6 (-CO-Ph).

γ-[4-(6-Flu or oben zisoxazol-3-yl)piper idin -1-yl]-â-(2-th e-

n yl)bu tyr ic a cid m eth yl ester h yd r och lor id e (34b): mp

162-163 °C (AcOEt). Anal. (C₂₂H₂₅FN₂O₃S‚HCl) C, H, N.

1

Spectral data for the free base: IR: 1732. H NMR (CDCl₃):

δ 2.0-2.37 (m, 10H, -N(CH₂-CH₂)₂CH-, -CH₂-COO-, -N(H-CH-

CH₂)₂CH-, -CH₂NRR); 2.43-2.53 (m, 1H,-CH-CH₂-NRR); 2.84-

3.04 (m, 5H, thienyl-CH₂-, -N(H-CH-CH₂)₂CH-, -N(CH₂-

CH₂)₂CH-); 3.67 (s, 3H, -COOCH₃); 6.79 (d, 1H, J _3-4) 3.2, H₃);

1-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

m et h yl]-4-(p -flu or ob en zoyl)p ip er id in e h yd r och lor id e

6.92 (dd, 1H, J _4-5) 5.1, J _4-3) 3.4, H₄); 7.05 (dt, 1H, J _5′-4′

J _5′-F) 8.8, J _5′-7′) 2.1, H_5′); 7.14 (dd, 1H, J _5-4) 5.1, J _5-3

)

(35a ): yield 25%, mp 243-244 °C (i-PrOH). Anal. (C₂₁H₂₂

-

1.1, H₅); 7.23 (dd, 1H, J _7′-F) 8.6, J _7′-5′) 2.1, H_7′); 7.66 (dd,

1H, J _4′-5′) 8.7, J _4′-F) 5.1, H_4′). ¹³C NMR (CDCl₃): δ 31.02,

31.08 (-N(CH₂-CH₂)₂C-); 32.8; 35.3; 37.7; 34.9 (-N(CH₂-CH₂)₂-

C-); 51.8 (-COOCH₃); 53.9; 54.5; 62.5 (-CH₂NRR); 97.8 (d, J )

26.7, C_7′); 112.7 (d, J _CF) 25.3, C_5′); 117.7 (C_3′a); 129.9 (d, J _C-F

) 11, C_4′); 124.1; 126.2; 127.1; 142.2 (C₂); 161.6 (C_3′); 164.2 (d,

J _C-F) 3.5, C_7′a); 164.4 (d, J _C-F) 251, C_6′); 173.8 (-COOCH₃).

γ-[4-(ter t-Bu toxyca r bon yl)p ip er a zin -1-yl]-â-(2-th en yl)-

bu tyr ic a cid m eth yl ester h yd r och lor id e (34c): mp 133-

134 °C (MeOH/Ether). Anal. (C₁₉H₃₀N₂O₄S‚HCl) C, H, N.

Spectral data for the free base: IR: 1736, 1695. ¹H NMR

(CDCl₃): δ 1.44 (s, 9H, -OCO-C(CH₃)₃); 2.12-2.49 (m, 9H,

-CH₂-COO-, -CH-CH₂NRR, -N(CH₂-CH₂)₂N-COO-); 2.83 (dd,

1H, J _gem) 14.8, J _vic) 6.8, thienyl-HCH-); 2.89 (dd, 1H, J _gem

) 14.9, J _vic) 6.0, thienyl-HCH-); 3.36 (t, 4H, J ) 4.7, -N(CH₂-

CH₂)₂N-COO-); 3.63 (s, 3H, -OCH₃); 6.77 (d, 1H, J _3-4) 3.1,

H₃); 6.90 (dd, 1H, J _4-5) 5.1, J ₄₃) 3.4, H₄); 7.12 (dd, 1H, J _5-4

) 5.1, J _5-3) 0.7, H₅). ¹³C NMR (CDCl₃): δ 28.8 (3C, -OC-

(CH₃)₃); 32.7, 35.0, 37.6 (thienyl-CH₂-CH-CH₂-COO-); 44.2 (2C,

-N(CH₂-CH₂)₂N-COO-); 51.8 (-COOCH₃); 53.6 (2C, -N(CH₂-

CH₂)₂N-COO-); 62.4 (-CH₂NRR); 79.8 (-OC(CH₃)₃); 124.1; 126.2;

127.1; 142.0 (C₂); 155.1 (-COOC(CH₃)₃); 173.7 (-COOCH₃).

FNO₂S‚HCl) C, H, N. Spectral data for the free base: IR: 1681,

1674. ¹H NMR (CDCl₃): δ 1.80-1.87 (m, 4H, -N(CH₂-CH₂)₂C-);

2.04-2.42 (m, 4H, -CH₂NRR, -N(HCH-CH₂)₂-); 2.46-2.99 (m,

5H, H₅, H₅, H₇, -N(HCH-CH₂)₂C-); 3.17-3.30 (m, 2H, H₇,

-CH₂)₂-CH-CO-); 7.07 (d, 1H, J ) 5.3, H₂); 7.13 (t, 2H, J ) 8.6,

o-F-Ph); 7.37 (d, 1H, J ) 5.3, H₃); 7.96 (dd, 2H, J ) 8.8, 5.4,

m-F-Ph). ¹³C NMR (CDCl₃): δ 29.0, 29.1 (-N(CH₂-CH₂)₂C-);

30.4 (C₇); 35.3; 43.0; 44.0 (-N(CH₂-CH₂)₂C-); 53.5, 54.6 (-N(CH₂-

CH₂)₂C-); 63.4 (-CH₂NRR); 116.18 (d, 2C, J _C-F) 21.8, o-F-Phe);

123.7; 125.0; 131.27 (d, 2C, J _C-F) 9.13, m-F-Ph); 132.8 (-CO-

Caromatic); 137.5 (C-_7a); 155.7 (C_3a); 165.9 (d, J ) 251, F-C);

193.1 (C₄); 201.4 (-CO-Ph). MS (FAB, m/z): 372 (MH⁺).

1-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

m eth yl]-4-[3-(6-flu or oben zisoxa zolyl)]p ip er id in e h yd r o-

ch lor id e (35b): yield 40%, mp 258-260 °C. Anal. (C₂₁H₂₁

-

FN₂O₂S‚HCl) C, H, N. Spectra data for the free base: IR: 1682.

¹H NMR (CDCl₃): δ 2.02-2.37 (mc, 11H, H₆, -CH₂NRR,

-N(CH₂-CH₂)₂CH-); 2.76 (dd, 1H, J _gem) 16.6, J _vic) 9.8, H₇);

2.95-3.16 (m, 3H, H₅, H₅, -N(CH₂-CH₂)₂CH-); 3.28 (dd, 1H,

J _gem) 16.6, J _vic) 3.9, H₇); 7.01 (dt, 1H, J _5′-4′) J _5′-F) 8.8,

J _5′-7′) 2.5, H_6′); 7.02 (d, 1H, J ) 5.2, H₂); 7.16-7.23 (m, 1H,

H_7′); 7.39 (d, 1H, J ) 5.2, H₃); 7.69 (dd, 1H, J _4′-5′) 8.7, J _4′-F

) 5.1, H_4′). ¹³C NMR (CDCl₃): δ 30.5; 31.0; 34.9; 35.4; 43.0

(-CH₂)₂-CH-); 54.0, 54.8 (-N(CH₂-CH₂)₂-); 63.6 (-CH₂NRR); 97.8

(d, J _C-F) 26.7, C_7′); 112.7 (d, J _C-F) 25.2, C_5′); 117.6 (C_3a);

122.9 (d, J _C-F) 11.0, C_4′); 133.7; 125.0; 137.6; 155.6; 161.4

(C_3′); 164.2 (d, J _C-F) 13.4, C_7′a); 165.0 (d, J _C-F) 250, C_6′);

193.2 (C₄). MS (FAB, m/z): 385 (MH⁺).

γ-[4-(o-Meth oxyp h en yl)p ip er a zin yl]-â-(2-th en yl)bu tyr -

ic a cid m eth yl ester h yd r och lor id e (34f): mp 190-192 °C

(AcOEt). Anal. (C₂₁H₂₈N₂O₃S‚2HCl) C, H, N. Spectral data for

the free base: IR: 1732 (COO). ¹H NMR (CDCl₃): δ 2.21-

2.36 (m, 4H, -CH₂-NRR, -N(H-CH-CH₂)₂N-Ph); 2.38-2.68 (m,

5H, -N(H-CH-CH₂)₂N-Ph, -CH₂-COOCH₃, -CH-CH₂NRR); 2.85

Conformationally Constrained Butyrophenones

J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15 2793

1-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

m eth yl]p ip er a zin e (35d ): Acid-catalyzed ring closure of 34d

was carried out with PPA as previously described, yield 45%.

IR: 1670. ¹H NMR (CDCl₃): δ 2.23-2.67 (m, 10 H, H₅, H₅,

H₆, -CH₂NRR, -N(CH₂-CH₂)₂NH); 2.72 (dd, 1H, J _gem) 16.6,

J _vic) 9.8, H₇); 2.95 (t, 4H, J ) 4.9, -N(CH₂-CH₂)₂NH); 3.23

(dd, 1H, J _gem) 16.6, J _vic) 3.9, H₇); 7.06 (d, 1H, J ) 5.2, H₂);

7.36 (d, 1H, J ) 5.2, H₃). ¹³C NMR (CDCl₃): δ 30.5 (C₇); 35.1;

42.9; 45.8 (2C, -N(CH₂-CH₂)₂NH); 54.0 (2C, -N(CH₂-CH₂)₂NH);

63.7 (-CH₂NRR); 123.7; 125.0; 137.6 (C_7a); 155.6 (C_3a); 193.0

(C₄). Hydrochloride: mp 108-110.5 °C (MeOH-ether). Anal.

(C₁₃H₁₈N₂OS‚2HCl) C, H, N.

and the mean of this sum was calculated for each group. ED₅₀

values were calculated by nonlinear curve fitting.

Ca ta lep sy: Catalepsy was tested in 6-12 mice 30 min after

administration of vehicle, haloperidol, clozapine, or new

compounds. The mice were placed with their forepaws on one

horizontal wire and their hindpaws on another 6 cm away and

2 cm lower. The time during which the mouse maintained this

position was recorded, and more than 30 s was considered to

indicate catalepsy. ED₅₀values were calculated by Litchfield

and Wilcoxon’s method.⁸⁹

Locom otor a ctivity: Spontaneous locomotor activity and

d-amphetamine-induced hyperlocomotion were monitored us-

ing a motion analysis system (EthoVision v.1.90, Noldus

Information Technology, Wageningen, The Netherlands). Mice

(4 per treatment) were placed in individual 50- × 50- × 30-cm

test arenas, and their activity was recorded for 1 h by a

videocamera fixed to the ceiling above the arenas and con-

nected to a videomonitor and to the computer running the

motion analysis system, which were located in a separate

room. Activity was determined by the analysis system as total

distance traveled, in cm.

In spontaneous activity assays, the mice were placed in the

arenas immediately after administration of vehicle, haloperidol

(2 mg/kg), risperidone (2 mg/kg), clozapine (5 mg/kg), or 23b

(2 mg/kg) or 24 h after administration of reserpine (5 mg/kg).

In amphetamine-induced hyperlocomotion assays, the mice

were placed in the arenas immediately after administration

of d-amphetamine sulfate (5 mg/kg), which was effected 30 min

after administration of vehicle, haloperidol, risperidone, cloza-

pine, or 23b or 24 h after administration of reserpine (all at

the same dosage levels as in the spontaneous activity assays).

Bin d in g a ssa ys (sp ecia l r ea gen ts): [³H]Spiperone (95 Ci/

mmol), [³H]SCH23390 (81 Ci/mmol), and [³H]mesulergine (76

Ci/mmol) were obtained from Amersham International (En-

gland), and [³H]ketanserin (60.08 Ci/mmol) was from DuPont

NEN (Boston, MA). Unlabeled R(+)SCH23390‚HCl, ketan-

serin, mianserine, and methysergide were supplied by Re-

search Biochemicals Inc. (Natick, MA), and sulpiride‚HCl by

Sigma (St. Louis, MO). The new compounds and reference

drugs were stored in 1 mM solutions at -20 °C and diluted to

the required concentration on ice immediately before use in

binding assays.

D₁a n d D₂r ecep tor bin d in g a ssa ys: Male Sprague-

Dawley rats were killed by decapitation, and their brains were

rapidly removed and dissected on an ice-cold plate. Striatal

membrane preparations were obtained by homogenization

(Polytron homogenizer, setting 6, 10 s) in 50 mM Tris-HCl (pH

7.7 at 25 °C; about 100 µL/mg of tissue) containing 5 mM

EDTA; the homogenates were centrifuged (49 000g for 15 min

at 4 °C; Sorvall RC-26 plus), resuspended in 50 mM Tris-HCl

buffer (pH 7.4 at 25 °C), and centrifuged again (same condi-

tions), and the final pellets were stored at -80 °C pending

use. J ust before binding assays, the pellets were resuspended

(1.25 mg original wet weight/750 µL for D₂assays, 1.00 mg/

750 µL for D₁) in 50 mM Tris-HCl buffer (pH 7.4 at 25 °C)

containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, and 1 mM

MgCl₂. For D₂binding assays, 750-µL aliquots of striatal

membrane preparation were added to ice-cold tubes containing

(a) 100 µL of [³H]spiperone, (b) 50 µL of ketanserin (final

concentration 50 nM) to block 5-HT_2Areceptors, and either (c)

100 µL of buffer (for total binding assay) or (d) 100 µL of

sulpiride (final concentration 10 µM) to allow quantification

of unspecific binding by [³H]spiperone, or (e) 100 µL of the

compounds to be tested. For D₁binding assays, the same

procedure was followed except that [³H]spiperone was replaced

by [³H]SCH23390, ketanserin by buffer, and sulpiride by

nonradiolabeled SCH23390 (final concentration 1 µM) to allow

quantification of nonspecific binding by [³H]SCH23390. The

final assay volume was thus 1 mL in all cases. All assays were

performed in duplicate. Incubations (15 min at 37 °C) were

stopped by rapid vacuum filtration through GF-52 glass fiber

filters (Schleicher and Schuell) in a Brandel M-30 cell har-

vester. The filters were rinsed three times with 3 mL of ice-

cold 50 mM Tris-HCl buffer (pH 7.4), and radioactivity was

1-[(4-Oxo-4,5,6,7-t et r a h yd r ob en zo[b]t h iop h en e-6-yl)-

m eth yl]-4-(o-m eth oxyp h en yl)p ip er a zin e h yd r och lor id e

(35f): yield 35%, mp 215-217 °C (AcOEt). Anal. (C₂₀H₂₄N₂O₂S‚

1

2HCl) C, H, N. Spectra for the free base: IR: 1669. H NMR

(CDCl₃): δ 2.31 (dd, 1H, J ) 16.4, 11.0, H₅); 2.44-2.78 (m,

7H, H₆, -CH₂NRR, -N(CH₂-CH₂)₂N-Ph); 2.60 (dd, 1H, J ) 16.5,

4.0, H₅); 2.75 (dd, 1H, J ) 16.5, 9.4, H₇); 3.08 (s.a., 4H, -N(CH₂-

CH₂)₂N-Ph); 3.28 (dd, 1H, J ) 16.5, 3.8, H₇); 3.86 (s, 3H,

-OCH₃); 6.85-7.03 (m, 4H, H_3′, H_4′, H_5′, H_6′); 7.07 (d, 1H, J )

5.3, H₂); 7.39 (d, 1H, J ) 5.3, H₃). ¹³C NMR (CDCl₃): δ 30.5

(C₇); 35.1; 43.0; 51.0 (2C, -N(CH₂-CH₂)₂N-); 54.2 (2C, -N(CH₂-

CH₂)₂N-); 55.7 (-OCH₃); 63.5 (-CH₂NRR); 111.5 (C_6′); 118.6 (C_3′);

121.3 (C_5′); 123.3; 123.7; 125.0; 137.6 (C_7a); 141.6 (C_1′); 152.6

(C_2′); 155.6 (C_3a); 193.2 (C₄). MS (FAB, m/z): 357 (MH⁺).

N¹-[(4-Oxo-4,5,6,7-tetr a h yd r oben zo[b]th iop h en e-6-yl)-

m eth yl]-N⁴-[3-(p-flu or oben zoyl)p r op yl]p ip er a zin e (35e).

A solution of 4-chloro-1,1-(ethylenedioxy)-1-(4-fluorophenyl)-

butane (0.24 g, 1 mmol) in MIK (10 mL) was added with

stirring to a mixture of 35d (0.25 g, 1 mmol), anhydrous Na₂-

CO₃(0.25 g), and KI (0.025 g) in MIK (20 mL). After refluxing

with vigorous stirring for 10 h, the mixture was allowed to

stand at room temperature overnight. The precipitate formed

was filtered out, and the solvent was removed under reduced

pressure to give 35e (0.23 g, 55%) as a white oil which on

standing crystallized as white prisms of mp 110-112 °C (i-

1

PrOH). IR: 1682, 1669. H NMR (CDCl₃): δ 2.95 (q, 2H, J )

7.1, -CH₂-CH₂-CH₂-CO-); 2.23-2.65 (m, 15H, H₅, H₅, H₆, -CH₂-

NRR, -N(CH₂-CH₂)₂N-CH₂-); 2.71 (dd, 1H, J _gem) 16.6, J _vic

)

9.8, H₇); 2.97 (t, 2H, J ) 7.1, -CH₂-CH₂-CO-Ph); 3.23 (dd, 1H,

J _gem) 16.6, J _vic) 3.9, H₇); 7.07 (d, 1H, J ) 5.4, H₂); 7.12 (t,

2H, J ) 3.8, m-F-Ph); 7.37 (d, 1H, J ) 5.4, H₃); 7.99 (dd, 2H,

J ) 8.9, 5.3, m-F-Ph). ¹³C NMR (CDCl₃): δ 22.0 (-CH₂-CH₂-

CH₂-CO-); 30.4 (C₇); 35.1; 43.0; 36.6 (-CH₂-CO-Ph); 53.5, 53.8

(4C, -N(CH₂-CH₂)₂N-); 58.0 (RRNCH₂-); 63.3 (-CH₂NRR); 115.9

(d, 2C, J _C-F) 21.8, o-F-Ph); 1123.6; 125.0; 131.1 (d, 2C, J _C-F

) 9.2, m-F-Ph); 137.6 (C_7a); 155.5 (C_3a); 165.9 (d, J _C-F) 251,

F-C); 193.1 (C₄); 198.6 (-CO-Ph). Hydrochloride: mp 236-237.5

°C (MeOH-ether). Anal. (C₂₃H₂₇FN₂O₂S‚2HCl) C, H, N.

P h a r m a cologica l Test Meth od s. Beh a vior a l stu d ies

(gen er a l): Male Charles River CD1 albino mice weighing 27

( 3 g were kept in a quiet room thermostated at 22 ( 1 °C

with a 12/12-h light/dark cycle (08:00-20:00). Assays were

always carried out at the same time of day so as to avoid

variation due to circadian rhythms. Food and tap water were

freely available in the home cage. All compounds were

administered in 0.01 mL/g injections (apomorphine subcutane-

ously and all others intraperitoneally). Haloperidol (Sigma)

was dissolved in 1% lactic acid in water and apomorphine

hydrochloride (RBI) in 0.9% saline solution with 1% ascorbic

acid (w/v) to prevent oxidation.

Ap om or p h in e-in d u ced clim bin g: The method of Protais

et al.⁸⁸was used, with a minor modification. The climbing

behavior of mice was observed in individual cylindrical stain-

less steel wire cages (diameter, 12 cm; height, 14 cm). Mice (6

per compound and dosage except for the control group, for

which 12 animals were used) were treated with vehicle,

haloperidol, clozapine, or new compounds and 30 min later

with 2 mg/kg apomorphine. During the next 30 min, climbing

activity was recorded every 10 min using the following scale:

0, four paws on the floor; 1, one or two paws against the wall;

2, the mouse clung to the wall with three or four paws. The

scores recorded 20 and 30 min post-apomorphine were added,

2794 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 15

Ravin˜a et al.

determined by liquid scintillation counting in a Beckman LS-

6000LL apparatus (counting efficiency approximately 50%).

Competition analyses were carried out with the aid of the

Prism program (GraphPad); K_ivalues were calculated as K_i

) IC₅₀/(1 + D/K_d), where D is the concentration and K_dthe

apparent dissociation constant of the ligand.

the rings were sensitized by addition of 10 µM 5-HT for 8 min.

Equilibration periods (60 min)⁹⁵were then alternated with the

construction of cumulative 5-HT concentration-effect curves

(from 30 nM to 100 µM). Two control runs giving identical

curves were followed by test runs with ketanserin or the new

compounds, which were added to the bath solution 20 min

before the end of the preceding equilibration period. Antagonist

potency was measured, following Arunlaksana and Schild, in

terms of pA₂(-log concentration of antagonist required to

maintain a constant response when agonist concentration is

doubled).

5-Hydroxytryptamine‚HCl was supplied by Sigma and ket-

anserin by RBI. All other drugs and chemicals were reagent

grade products from Sigma. Aqueous solutions of all drugs as

their hydrochlorides were prepared daily using distilled water.

All drug concentrations mentioned above are final molar

concentrations in the tissue bath.

Molecu la r m od elin g a n d CoMF A: Molecular models of

the protonated ligands were constructed with standard bond

distances and angles using SYBYL (ver. 6.4) software (Tripos

Assoc., St. Louis, MO) running on a Silicon Graphics Indigo2

R4400 workstation. Full geometry optimization was performed

with the PM3 Hamiltonian using the parameter set included

in the MOPAC (ver. 6.0)⁶⁹suite of programs. The Mulliken

partial atomic charges given by PM3 calculations were used

in the CoMFA study. Molecular alignment for CoMFA was

performed with the RIGIDFIT option of SYBYL. The CoMFA

study was carried out using the QSAR module of SYBYL with

default settings, except that the “drop-electrostatic” option was

set to “NO”. Steric and electrostatic interaction energies were

calculated at the points of a regular 3D lattice using an sp³

carbon atom probe with a charge of +1 and a van der Waals

radius of 1.52 Å. The MLP was calculated by the method of

Gaillard et al.⁶²The grid had a resolution of 2 Å, and the region

dimensions were defined automatically using the “molecular

volume” mode. For each combination of fields, the number of

components to be used in a final model was determined on

the basis of calculations of q²for PLS models of five or fewer

components (q²) (SD - PRESS)/SD, where SD is the sum of

squares of deviations of the observed values from their mean

and PRESS is the prediction error sum of squares). PLS was

then carried out without cross-validation using the number

of components so determined. The results of this latter analysis

were used to produce the final 3D-QSAR models with which

the coefficient isocontour maps of Figure 4 were constructed.

The predictive and fitting capabilities of the models were

assessed by q²and by r²and s, respectively.

5-HT_2Ar ecep tor bin d in g a ssa ys: Male 200-250-g Spra-

gue-Dawley rats were asphyxiated with CO₂and decapitated.

The frontal cortex, containing 5-HT_2Areceptors,^90,91was dis-

sected free on ice, frozen on dry ice, and stored at -70 °C until

use (generally less than 1 week later). All membrane prepara-

tion procedures were carried out at 4 °C. The tissue was

thawed on ice and homogenized with 10 volumes of 0.32 M

sucrose in a Polytron homogenizer (Brinkmann Instruments,

Westbury, NY). The homogenate was centrifuged twice at 4

°C (900g for 10 min followed by 40 000g for 30 min). The

supernatant was discarded and the pellet resuspended in Tris-

HCl buffer (pH 8.07) in a Teflon/glass homogenizer (10 strokes

by hand). The homogenate was incubated at 37 °C for 15 min

to remove endogenous 5-HT and centrifuged for 30 min at

40 000g. The final pellet was resuspended in Tris-HCl buffer

of pH 8.07 containing 4 mM CaCl₂and 0.1% ascorbic acid.

Competition at [³H]ketanserin binding sites was assayed in

triplicate in assay mixtures consisting of 750 µL of membrane

homogenate, 50 µL of [³H]ketanserin, 50 µL of either buffer

or the compound under test, 50 µL of masking ligand solution

(1 µM methysergide) as required, and buffer to a final volume

of 1 mL. Mixtures were incubated for 30 min at 37 °C. The

assay was terminated by rapid filtration through Whatman

GF/C filter strips (presoaked in 3% poly(ethylenimine)) in a

Brandel cell harvester (Gaithersburg, MD) followed by wash-

ing with ice-cold Tris-HCl buffer (pH 6.6) to remove unbound

radioligand. The radioactivity retained on filters was deter-

mined by liquid scintillation counting in a beta counter

(Beckman, LS-1800).

The nonlinear curve-fitting program Kaleidagraph (Synergy

Software, Reading, PA) was used to fit the equation E ) E_max

- [E_max- E_min/(1 + (IC₅₀/C)ⁿ)], where E_maxand E_minare dpm

at the beginning and end of the competition experiment,

respectively, IC₅₀is the drug concentration required to inhibit

binding by 50%, C is the concentration of the inhibitor, and n

is the slope of the decay. Nonspecific binding was determined

independently in the presence of unlabeled methysergide. pK_i

values were estimated from IC₅₀values using the equation K_i

) IC₅₀/(1 + D/K_d), where K_dis the equilibrium dissociation

constant for [³H]radioligand determined by saturation binding

studies and D is the concentration of [³H]ligand used.

5-HT_2Cr ecep tor bin d in g a ssa ys: Bovine choroid plexus

containing 5-HT_2Creceptors⁹²was treated as described in the

previous assay. A suspension of the resulting pellet in the same

buffer was stored on ice while not being manipulated. Com-

petition at [³H]mesulergine binding sites was determined by

a protocol analogous to that described above for the 5-HT_2A

binding assay, using a final [³H]mesulergine concentration of

2 nM and 1 mM mianserine as a 5-HT_2Areceptor masking

ligand. The mixtures were incubated for 1 h at room temper-

ature. Membranes were harvested on Whatman GF/B filter.

Nonspecific binding was determined in the presence of unla-

beled mianserine. IC₅₀and pK_ivalues were calculated as for

5-HT_2Areceptors.

F u n ction a l exp er im en ts: Antagonism of serotonin at

5-HT_2Areceptors^30,90was assayed using thoracic aorta from

male 250-350-g Sprague-Dawley rats killed by cervical dis-

location. The descending aorta was removed, cleaned, stripped

of endothelium, and cut into rings 4 mm in length⁴¹that were

then mounted under a tension of 2 g in a CELASTER-IOS 1

computerized organ bath containing 20 mL of Krebs solution

of the following composition (mM): NaCl, 119; KCl, 4.7;

MgSO₄‚7H₂O, 1.2; CaCl₂‚2H₂O, 1.5; KH₂PO₄, 1.2; NaHCO₃, 25;

glucose, 11. Clorpheniramine (1 µM) was added to block uptake

of serotonin.^93,94The bath solution was maintained at 37 °C

and aerated with carbogen (95% O₂, 5% CO₂). Isometric

contraction force was monitored via a CPOL 0-25 g trans-

ducer. Following equilibration for 60 min under a load of 2 g,

Ack n ow led gm en t. This research was supported by

Spanish Comisio´n Interministerial de Ciencia y Tecno-

log´ıa (CICYT) under Grants SAF 92-0957-C02-01, SAF

94-0593-C04, and SAF 95-1081 and by the Xunta de Ga-

licia under Grants XUGA 20308 B93, XUGA 20308B94,

and XUGA 20308B96. Thanks are given to Prof. Alex-

andros Makriyannis (School of Pharmacy, University of

Connecticut) for generous assistance with enantiomer

separation during visits to his laboratory by J . Negreira.

We also thank J ose´ Gonza´lez Parga for his enthusiastic

technical assistance. J . Negreira, J . Cid, E. Rosa, and

M. E. Rivas were aided by predoctoral grants from

Xunta de Galicia, and E. Lozoya was aided by a

predoctoral grant from CIRIT. The molecular modeling

studies were supported by CESCA grants (TMR fellow-

ship for A. Carrieri and computational facilities). We

are grateful to Sandoz and J anssen Laboratories for

generous gifts of clozapine and risperidone, respectively.

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J M981094E

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Conformationally constrained butyrophenones with mixed dopaminergic (D2) and serotoninergic (5-HT2(A), 5-HT2(C)) affinities: Synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and - thienocycloa

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