Repaglinide and related hypoglycemic benzoic acid derivatives

J . Med. Chem. 1998, 41, 5219-5246

5219

Rep a glin id e a n d Rela ted Hyp oglycem ic Ben zoic Acid Der iva tives

Wolfgang Grell,*^,†Rudolf Hurnaus,^†Gerhart Griss,^†,|Robert Sauter,^†Eckhard Rupprecht,^‡,Michael Mark,^‡

Peter Luger,^§Herbert Nar,^†Helmut Wittneben,^†and Peter Mu¨ller^†,#

Departments of Chemical and Biological Research, Boehringer Ingelheim Pharma KG, Postfach 1755, D-88397 Biberach,

Germany, and Institute for Crystallography, Freie Universita¨t Berlin, Takustrasse 6, D-14195 Berlin, Germany

Received May 7, 1998

The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5,

6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced

by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethyl-

piperidino (5h ) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide

analogon 4 bearing an inversed amido function when the 2-methoxy, the 5-fluoro, and the

R-methyl residue were replaced by a 2-piperidino, a 5-hydrogen, and a larger R-alkyl residue,

respectively. An alkoxy residue ortho to the carboxy group further increased activity and

duration of action in the rat. The most active racemic compound, 6a l (R₄) isobutyl; R )

ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1).

Activity was found to reside predominantly in the (S)-enantiomers. Compared with the SUs

1 and 2 (glimepiride), the most active enantiomer, (S)-6a l (AG-EE 623 ZW; repaglinide; ED₅₀

) 10 µg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic

for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From

investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded

that in addition to the two already knownsthe acidic group (COOH; SO₂NH) and the amidic

spacer (CONH; NHCO)sthe ortho residue R₁(alkyleneimino; alkoxy; oxo) must be regarded

as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid

derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions

of low-energy conformations (LECs) of 1, 2, and (S)-6a l, it was concluded that a common binding

conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor

and in the mechanism of insulin release between repaglinide and the two SUs may be due to

specific hydrophobic differences.

Non-insulin-dependent diabetes mellitus (NIDDM)

represents a common heterogeneous metabolic disorder

with all its defects (e.g., impaired insulin secretion,

diminished peripheral insulin action, increased hepatic

glucose output) being present in variable proportions

in different individuals.¹Therapy includes diet and

exercise, as well as, upon failure, drug treatment.

Agents with different mechanisms of action are avail-

able: (i) stimulators/modulators of insulin secretion, (ii)

enhancers of insulin action, (iii) inhibitors of hepatic

glucose production, or (iv) inhibitors of glucose absorp-

tion.²Among the sulfonylurea (SU) compounds belong-

ing to group i, e.g., 1 (glibenclamide) and 2 (glimepiride)

(Figure 1), glibenclamide is one of the most frequently

prescribed agents. One of the thiazolidine-diones of

group ii, troglitazone, has recently reached the market.

Contrary to the monotherapy with the biguanide met-

formin of group iii, acarbose of group iv is mostly used

as adjunct to SU therapy. The main risks and limita-

tions of the currently available drugs are the following:

SU-induced hypoglycemia and weight gain; primary and

secondary failure of SUs; metformin-associated lactic

acidosis; and acarbose-associated gastrointestinal side

effects as well as limited efficacy.²

Having in mind the limitations (above all the risk of

hypoglycemia³) of the SU therapy, we looked for com-

pounds being orally active but structurally different

from the SUs which might avoid such risks. The

substituted benzoic acids 3 (meglitinide) and 4 (Figure

1), both exhibiting tolbutamide-like hypoglycemic activ-

ity, appeared to be useful lead compounds.^4,5The acidic

(COOH in 3 or 4, SO₂NH in the SUs) and amidic groups

(CONH and NHCO, respectively) were regarded as

being involved in binding to two putative binding sites

of the SU receptor.⁶Meglitinide was reported to

stimulate insulin secretion in vitro^7,8,9and in vivo^4,10by

blocking the K_ATPchannel of the pancreatic B-cell,^11,12

however less potently than glibenclamide.

Of the structural modifications investigated, replace-

ment of the ortho methoxy group in 3 and 4 by a

secondary amino (in contrast to an amino, methylamino,

or ethylamino¹³) group was found to lead to an increase

in hypoglycemic activity. The structure-activity rela-

tionships (SARs) observed in the resulting benzoic acid

derivatives of type 5 and 6, respectively (Figure 2), are

presented in this paper.

^†Department of Chemical Research, Boehringer Ingelheim Pharma

KG.

^‡Department of Biological Research, Boehringer Ingelheim Pharma

KG.

^§Freie Universita¨t Berlin.

^|Deceased.

Ch em istr y

Present address: Boehringer Ingelheim Pharma Wien, Postfach

73, A-1121 Wien, Austria.

The benzoic acid derivatives 5 were obtained by

condensation of a substituted benzoic acid 9 with a

#

Present address: Boehringer Ingelheim Pharm. Inc., Ridgefield,

CT 06877.

Published on Web 12/03/1998

5220 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

resulting amino group by a chlorine atom via diazotation

and Sandmeyer reaction. The educts 10 were synthe-

sized by catalytic hydrogenation from the corresponding

benzylcyanides.^15,16For the synthesis of the benzoic

acid derivatives 6, a substituted benzylamine 12 (either

racemic or enantiomeric) was acylated with a substi-

tuted phenylacetic acid 13 (Scheme 2); alternatively, a

ketimine 16 was acylated with a substituted phenylace-

tic acid 13, and the resulting enamide (E/Z)-17 was

hydrogenated (Scheme 3). The educts 13 were obtained,

analogously to literature procedures,¹⁹from the corre-

sponding benzylcyanides as described in the Experi-

mental Section. Racemic educts 12 were synthesized

according to routes A-D (Scheme 4). Route A was

preferred when the addition of a Grignard reagent to

nitrile 15 was feasible; otherwise, route B via alkylation

of the anion of aldimine 19a was followed. To introduce

R₃dCl, routes C and D were used. For the synthesis of

enantiomeric benzylamines 12, routes E-I were applied

(Scheme 5): resolution of the racemic amine 12q by

means of N-acetyl-glutamic acid (E); asymmetric hy-

drogenation of the N-(1-phenethyl)-ketimines (S′)-31

and (R′)-31, respectively (F); asymmetric hydrogenation

of the (Z)-N-acetyl-enamine (Z)-33 (G); diastereoselec-

tive addition of a Grignard reagent to the N-(1-phen-

ethyl)-aldimines (R′)-35 and (S′)-35 (H); chromato-

graphic resolution of the diastereomeric N-(4-tolyl-sulfi-

nyl)-amines (R,S′)-37 and (S,S′)-37 (I). The synthesis

of (S)-12q was accomplished best by resolution (E); of

the asymmetric routes investigated (F, G, H), route F

was the most favorable one. The enantiomers of 12o

were synthesized via routes F and H, respectively.

The absolute configuration of (+)-12q was determined

as (S) by X-ray structure analyses of the diastereomeric

salt (S,S′)-28 (Figure 3) and of the urea derivative

(S,S′)-38b (Figure 4, only structural formula shown).

The assignment of (S) to (+)-12o was based on the X-ray

structure analysis of the urea derivative (S,S′)-38a

(Figure 4, only structural formula shown) and on the

circular dichroism (CD) spectrum²⁵of (+)-12o being

complexed with [Rh(OAc)₂]₂in acetonitrile which re-

sembled those of (S)-1-phenethylamine,²⁶but not those

of (R)-1-phenethylamine.²⁷For (-)-12s and (+)-12s,

Horeau’s method²⁸was used to determine the corre-

sponding configurations (S) and (R), respectively.

Configurational stability of enantiomeric benzyl-

amines 12 and their N-acyl-derivatives was found to be

very high as exemplified for (S)-12q and (R)-34 (see

Experimental Section).

F igu r e 1. Structural formula of reference compounds 1, 2, 3,

3a , 4, 4a , and 4b.

P h a r m a cology

The novel compounds were administered orally to

adult fasted female rats. Blood glucose was monitored

hourly up to 4 h after administration in comparison with

a control group (N ) 7). Statistical significance was

checked with Student’s t-test (P e 0.05). The maximum

percentage decrease of blood sugar (∆BG) observed

within 4 h was taken as the measure for a compound’s

blood sugar lowering activity. For the most interesting

compounds, ED₅₀values were calculated.

F igu r e 2. Structural formula of compounds of type 5 and 6.

substituted 2-phenethylamine 10 (Scheme 1). The

educts 9 were obtained mostly from 2-chloro-5-nitro-

benzoic acid by reaction with a secondary amine HNR₁R₂,

reduction of the nitro group, and replacement of the

Str u ctu r e-Activity Rela tion sh ip s

With regard to the NR₁R₂residue in the substituted

benzoic acid derivatives of type 5 (Table 1), the activity

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5221

Sch em e 1.^aSynthesis of Benzoic Acid Derivatives 5

a

(a) HNR₁R₂; (b) H₂/Pd-C; (c) (i) HCl/NaNO₂, (ii) copper powder; (d) SOCl₂or CDI¹⁴; (e) KOH or NaOH.

Sch em e 2.^aSynthesis of Benzoic Acid Derivatives 6

a

17

(a) SOCl₂or CDI¹⁴or Ph₃P/CCl₄/NEt₃or N,N′-DCCD¹⁸; (b) NaOH; (c) H₂/Pd-C.

Sch em e 3.^aAn Alternative Route to Benzoic Acid Derivatives 6

a

15

(a) (i) R₄MgBr(Cl), toluene/THF, reflux; (ii) saturated aqueous NH₄Cl/concentrated ammonia; (b) CDI¹⁴or Ph₃P/CCl₄/NEt₃or N,N′-

DCCD¹⁸; (c) H₂/Pd-C, EtOH; (d) NaOH.

of the dimethylamino and diethylamino compounds 5a

and 5b, respectively, is not improved with larger di-

alkylamino groups (not shown here) but slightly in-

creased with N(Me)R₂groups in which R₂is changed to

a cyclohexyl, phenyl, or benzyl residue (not shown here).

However, activity is strongly increased with alkylene-

imino groups N(CH₂)_5-9(5d , 5j, 5k , 5l, 5p ) culminating

in the octamethyleneimino compound 5l which was

found to be almost equipotent with glibenclamide.

Dechlorination (5m ) or substituting RdH for methoxy

(5n ) or ethoxy (5o) results in decreased activity. Inter-

estingly, methyl groups on the piperidino ring (5d ) exert

quite different effects: unfavorable in 2-, 4-, and trans-

3,5- (5e, 5g, 5i), favorable in 3- (5f), and very favorable

in cis-3,5-position (5h ). The latter (5h ) and the octa-

methyleneimino compound (5l) are almost equipotent,

probably because their NR₁R₂residues are similar with

respect to conformation and space demand. What is not

shown here: Replacement of R₃dCl by other substitu-

ents (fluoro, bromo, iodo, methyl, ethyl, methoxy, cyano)

also results in active but not superior compounds, and

displacement of R₃dCl to other positions on the benzene

ring decreases the activity (5 > 4 ≈ 3 . 6).

With regard to substituted benzoic acid derivatives

of type 6.1 (Table 2) having R₄) Me and R_4a) H (6a -

6e, 6j-6t), highest activity resides in compound 6e

(NR₁R₂) piperidino, R₃) H; ED₅₀) 0.3 mg/kg).

Activity is strongly reduced if a (R₃) chloro (6d ) or a

(R_4a) methyl (6g) is added, if the (R₄) methyl (6i) is

omitted, or if the piperidino residue is substituted by

one or two methyl groups (6k , 6m , 6n , 6o). The fol-

lowing is not shown here: Compared with R₃) H (6e),

not only chloro but also further (R₃) substituents (bromo,

methyl, hydroxy, methoxy, benzyloxy, nitro, amino,

dimethylamino, acetylamino, benzoylamino) decrease or

abolish activity.

Starting from compound 6e, we examined the SARs

in the benzoic acid derivatives of type 6.2 (Table 3) with

respect to the substituents (R₄, R) and to chirality. The

activity of the racemic compounds with R ) H (6e, 6u -

6a d ) depends on R₄. Activity is low for an isopropyl

(6w ), cyclohexyl (6a a ), benzyl (6a c), or phenethyl (6a d )

group, moderate for a phenyl (6a b), methyl (6e), ethyl

(6n ), or n-butyl (6x) group, and good for the n-propyl

(6v) or isobutyl (6y) group. Activity is further increased

if R ) H is replaced for an ethoxy or methoxy group

5222 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

(6a e, 6a h -6a j, 6a l-6a n , 6a p , 6a v); interestingly, the

duration of action is prolonged simultaneously as il-

lustrated for compounds 6a h /6a i versus 6v (Table 4,

Figure 5). However, as already mentioned above, the

same R groups (ethoxy, methoxy) decreased activity in

compounds of type 5 (5n /5o versus 5l; Table 1). Com-

pound 6a l (R₄) isobutyl, R ) ethoxy; AG-EE 388 ZW)

turned out to exhibit maximum activity (ED₅₀) 22 µg/

kg) and a long duration of action (>4 h after 30 µg/kg).

The isobutyl group in 6a l can be mimicked to some

extent by cycloalkylmethyl groups (6a q-6a u ), best with

respect to potency by cyclopropylmethyl (6a q), and best

with respect to duration of action (not shown) by

cyclohexylmethyl (6a t).

As one could already suggest from the higher activity

of 6e in comparison to 6g (Table 2), chirality is highly

important for the hypoglycemic activity of compounds

of type 6.2 (Table 3). The enantioselectivity observed

(S . R) is in accordance with that reported for the lead

compound 4.⁵The most potent enantiomer, (S)-6a l (AG-

EE 623 ZW; repaglinide, ED₅₀) 10 µg/kg), is g100

times more active than the antipode, (R)-6a l (AG-EE

624 ZW). Compared with the SUs glibenclamide (1,

ED₅₀) 255 µg/kg) and glimepiride (2, ED₅₀) 182 µg/

kg), repaglinide is 25 and 18 times more active. The

blood sugar lowering effects of (S)-6a l in rats and dogs

are described in more detail elsewhere.³³Clinically,

repaglinide turned out to be an efficious and surpris-

ingly short acting therapeutic for type 2 diabetic pa-

tients;³⁴approval was granted recently by the FDA and

the EMEA. The enantiomer (S)-6a m was used to

synthesize [³H]-(S)-6a l (not described here).

(51) led to diminished activity; for the -NH-SO₂-

spacer (52), no activity was detected at 25 mg/kg.

(e) Modifications of the R₁residue and of the -NH-

CO- spacer in 6v (Table 10) were also examined. For

R₁residues differing in lipophilicity and space demand,

a potency ranking order was found: piperidino (6v) >

methoxy (56) > cyclohexene-1-yl (54) g cyclohexyl (53)

> phenyl (55) ≈ H (42). For the spacers -NH-CS-

(58), -NMe-CO- (57), and -CH₂-CO- (60), activity

was g10-fold lower; for the spacers -NH-CH₂- (59)

and -CH₂-CH₂- (61), no activity was detected at the

doses tested.

We conclude the following from the above investiga-

tions: (i) In addition to the two well-known pharma-

cophoric groups, the acidic group W (COOH; SO₂NH)

and the amidic spacer (CONH; NHCO), the residue R₁

(alkyleneimino; alkoxy; oxo) must be regarded as an

important third one. (ii) Within the amidic spacer, the

oxo part seems to be more important than the imino

part (60 > 59), possibly for enabling hydrogen bonding

to a distinct H-donor on the SU receptor site. (iii) The

residues R, R₂, and most strongly, R₃seem to modify

activity; a distinct R or R₂residue can exert opposite

effects in type 5 and type 6 compounds. (iv) In sum-

mary, a general pharmacophore model containing three

pharmacophoric groups is proposed (Figure 6).

In vestiga tion s on P oten tia l Bin d in g

Con for m a tion s of (S)-6a l (REP ), 1 (GLIB), a n d 2

(GLIM)^37,38

REP and the SUs GLIB and GLIM (Figures 1 and 7)

are binding to the SU receptor, yet differences in the

binding modi³⁹and the mechanisms of action,⁴⁰at least

between REP and GLIB, have been reported. On the

basis of the pharmacophore model (Figure 6) which we

suggest to be valid also as a model for receptor binding,

we sought to gain insight into the structural basis for

these differences. Therefore, we examined the X-ray

structures of REP (Figure 8), GLIB,⁴¹and GLIM (Figure

9) and analyzed conformational space and hydrophobic

and electrostatic potentials. Furthermore, and without

considering potential binding sites, we performed cal-

culations on conformational analysis and energy opti-

mizations of selected conformations in vacuo.

By conformational analysis, several low-energy con-

formations (LECs) were determined, three for REP (I,

II, III), two for GLIB (I, II), and two for GLIM (I, II).

The minimum conformations I (LECs I) were found to

be identical with the conformations observed in the

crystalline state. The LECs II and III differ from the

corresponding LECs I by less than 3 kcal/M (Table 11).

All LECs have to be considered as potential binding

conformations.

In contrast to prior analysis of conformational space

described for hypoglycemic agents (i.a. for repaglinide),⁴²

we were considering the common pharmacophoric groups

derived by SAR and have performed the superposition

of different LECs in order to optimally fit the central

phenylene rings and the highly important acidic groups

of each molecule. The LECs observed in the crystalline

state (REP-I, GLIB-I, GLIM-I) did not significantly

overlap (Figure 10A). The torsion angles æ1 to æ5

(Figures 1 and 7) of REP-II, GLIB-II, and GLIM-II were

found to be rather similar, whereas those of REP-III

In vestiga tion s on a Gen er a l P h a r m a cop h or e

Mod el for Hyp oglycem ic Ben zoic Acid

Der iva tives a n d Su lfon ylu r ea s^35,36

To gain information beyond that already pub-

lished^5,6,9,21about the pharmacophoric groups of hy-

poglycemic benzoic acid derivatives and SU compounds,

we have investigated how important specific residues,

positions, and spacers are. For this purpose, compounds

of type 5.1 (Table 5) and of type 6.3 to 6.7 (Tables 6-10)

were examined.

(a) Replacement of (R₁) alkyleneimino or (W) carboxy

in 5l (Table 5) and 6v (Table 6) for a hydrogen atom

resulted in loss or drastic decrease of activity (39, 40;

42, 43). Replacement of R₂) Cl in 5l (Table 5) or 41

(Table 6) for a hydrogen atom decreased (5m ) or

increased (6v) activity. Replacement of R₂) H in 5l or

6v for an ethoxy group decreased (5o) or increased (6a i)

activity. As already mentioned (Table 3), activity of type

6.3 compounds resides in the (S)-enantiomers.

(b) Displacement of compound 6e’s (Table 7) 2′-

piperidino group to the 3′-position (44) or of its 4-carboxy

group to the 3-position (46) led to 100-fold lower activity.

For the respective 4′-piperidino (45) and the 2-carboxy

(47), no activity was detected at 25 mg/kg.

(c) Replacement of the 4-carboxy group in 6e (Table

8) by residues which might serve as (bio)isosteric

substitutes resulted in a 10-fold lower activity for the

substituted SU residue (50) or in loss of activity for the

tetrazolo (48) and sulfonamido (49) residue at the doses

tested.

(d) Replacement of the amido spacer -NH-CO- in

6e (Table 9) by the inversed amido spacer -CO-NH-

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5223

Sch em e 4.^aSynthetic Routes A-D to Racemic Substituted Benzylamines 12

a

(a) HNR₁R₂/HC(O)NR₁R₂, 120-140 °C; (b) (i) R₄MgBr(Cl), toluene/THF, reflux; (ii) saturated aqueous NH₄Cl/concentrated ammonia;

(c) H₂/Raney-Ni, NH₃/MeOH, or NaBH₄/MeOH; (d) H₂/Raney-Ni, NH₃/MeOH; (e) Raney-Ni/HCOOH; (f) purum, Na₂SO₄; (g) (i) LiN(i-Pr)₂,

THF, -25 °C; (ii) R₄MgBr(Cl), -70 °C;²⁰(h) (i) evaporation in vacuo; (ii) aqueous HCl; (iii) concentrated NH₄OH, 0 °C; (iv) rapid extraction

(EtOAc) and chromatographic purification; (i) HNR₁R₂, EtOH, reflux; (j) H₂/Pd-C, EtOH or DMF; (k) (i) aqueous HCl/NaNO₂; (ii) CuCl₂;

(l) LiAlH₄, Et₂O²¹; (m) (i) HCONH₂/HCOONH₄, 150 °C; (ii) concentrated HCl;²¹or Na(CN)BH₃/NH₄OAc, MeOH; (n) H₂NOH‚HCl, EtOH;

(o) Zn, aqueous HCl; or H₂/Pd-C, NEt₃; or LiAlH₄, Et₂O.

differ largely from the others (Table 12). Therefore, it

seems reasonable to consider the LECs II as favorable

potential binding conformations. Their superposition

(Figure 10B) supports this view: the pharmacophoric

groups fit well; the amidic oxo groups are located to

enable hydrogen bonding to the same binding site of the

SU receptor; no counterpart to REP’s (S)-isobutyl is

found in GLIB and GLIM; and the ethoxy group of REP

and the (methyl)cyclohexyl groups of GLIB and GLIM,

respectively, marginally overlap.

To understand molecular features which are not

apparent from a structural superposition, hydrophobic

and electrostatic potential maps of REP-II, GLIB-II, and

GLIM-II were also calculated. The hydrophobic poten-

tials of REP-II differ from those of GLIB-II and GLIM-

II (Figure 11). The ethoxy group of REP and the

(methyl)cyclohexyl groups of GLIB and GLIM margin-

ally overlap. The (S)-isobutyl group of REP is found to

be unique; it obviously fitsslike other (S)-groups of

proper sizesinto an enantiospecific pocket of the SU

receptor and is, in this respect, behaving like a further

(enantiospecific) pharmacophoric group. A similar (S)-

enantiospecificity was already observed in chiral SUs

and sulfonamido-pyrimidines.⁴³The electrostatic po-

tentials of REP-II were found to be rather similar to

those of GLIB-II and GLIM-II (not shown here).

We conclude from these investigations that the LECs

II of REP, GLIB, and GLIM may represent a common

binding conformation and that differences in the binding

to the SU receptor (involved in K_ATPchannel closure)

and also differences in the mechanism of insulin release

may be due to hydrophobic differences.

Exp er im en ta l Section

Ch em istr y. Melting points were determined in open glass

capillaries in an electrothermal melting point apparatus and

5224 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

Sch em e 5.^aSynthetic Routes E-I to Enantiomeric Substituted 2-Piperidino-benzylamines 12

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5225

Sch em e 5 (Continued)

a

(a) (i) N-Acetyl-glutamic acid, acetone/MeOH; (ii) recrystallization; (b) aqueous ammonia or aqueous NaOH, CH₂Cl₂- or toluene-

extraction; (c) (i) evaporation of the (S,S′)-28 filtrate to dryness; (ii) digestion with hot acetone; (iii) evaporation of the filtrate to dryness;

(iv) liberation of the crude (R)-12q; (d) glutaric acid, acetone; (e) (i) i-BuMgBr, toluene/THF, reflux; (ii) aqueous HCl, 0 °C; (f) (S′)-1-

phenethylamine/TiCl₄/NEt₃, toluene, 0 °C; (g) H₂/Raney-Ni, EtOH; (h) H₂/Pd-C (10%), EtOH/1.1 equiv aqueous HCl; (i) (R′)-1-

phenethylamine/TiCl₄/NEt₃, toluene, 0 °C; (j) (i) Ac₂O, toluene, 0 °C; (ii) chromatographic separation of (E)- and (Z)-isomers; (k) H₂/

Ru(OAc)₂[(S)-BINAP/0.5% Ti(O-i-Pr)₄, MeOH/CH₂Cl₂(5:1); (l) aqueous HCl; (m) Raney-Ni, HCOOH; (n) (S′)-1-phenethylamine, purum,

Na₂SO₄; (o) R₄MgBr; (p) (R′)-1-phenethylamine, purum, Na₂SO₄; (q) (i) n-BuLi, THF, -15 °C; (ii) (-)(S′)-[(1R,2S,5R)-menthyl]-p-toluene-

sulfinate, THF, -10 °C, thereafter 20 °C; (iii) chromatographic separation of the diastereomers; (r) TFA, MeOH, +5 °C, thereafter 50 °C.

F igu r e 4. Structural formula of the urea derivatives (S,S′)-

38a and (S,S′)-38b.

For TLC analysis, precoated TLC plates (Silica Gel 60 F-254,

Merck, Germany) were used. For column chromatography,

silica gel (Silica Woelm 32-63 µm) was used. HPLC analyses

carried out mostly on a Gilson model 303 are described at the

respective experiments. Organic layers obtained after extrac-

tion of aqueous solutions were dried over Na₂SO₄and filtered

before evaporation in vacuo. Petrolether (30-60 °C) was used.

E d u ct s 9. 5-Ch lor o-2-d im et h yla m in o-b en zoic Acid

(9a ). A solution of chlorine (4.25 g, 60 mM) in glacial HOAc

(35 mL) was added dropwise to a stirred cooled (0 °C) solution

of N,N-dimethyl-anthranilic acid⁴⁴hydrochloride (12.6 g, 60

mM) in a mixture of CHCl₃(300 mL) and MeOH (40 mL). After

being stirred for 0.5 h, the reaction mixture was extracted 5

times with 2 N NaOH. The combined aqueous phases were

acidified to pH 3 with 2 N HCl and extracted with CHCl₃. The

organic layer was dried and evaporated in vacuo to give the

title compound (2.6 g, 22%); mp 122-125 °C (Et₂O).

F igu r e 3. ORTEP plot of the X-ray structure of (S,S′)-28.

are uncorrected. Infrared (IR) spectra were obtained on a

Perkin-Elmer model 299 spectrophotometer, KBr wafer (1 mg/

300 mg KBr) or in CH₂Cl₂(40 g/L), with a cell path length of

0.02 cm. Ultraviolet (UV) spectra were obtained on a Perkin-

Elmer model 554 spectrophotometer, with a cell path length

of 0.2 cm and in ethanol (0.05 g/L). Nuclear magnetic

resonance (¹H NMR) spectra were recorded on a Bruker WP80/

DS, AC 200, or AMX400, respectively, with tetramethylsilane

as internal standard. Mass spectra (MS) were obtained on a

Finnigan-MAT (Bremen) model 4023 or 8320, respectively.

Elemental analyses were carried out on a Heraeus Merz Mikro

Rapid CHN apparatus. Optical rotation was measured on a

Perkin-Elmer model 241 polarimeter (λ ) 589 nm, l ) 10 cm).

5-Ch lor o-2-d ieth yla m in o-ben zoic Acid (9b) was syn-

thesized from 2-chloro-5-nitro-benzonitrile via 5-amino-2-dieth-

ylamino-benzonitrile analogously to 9d ; mp not determined.

5-Ch lor o-2-p yr r olid in o-ben zoic Acid (9c). (a) A mixture

of 2-chloro-5-nitro-benzoic acid (Aldrich, 20.1 g, 100 mM),

pyrrolidine (21.3 g, 300 mM), and EtOH (200 mL) was refluxed

for 7 h and thereafter evaporated in vacuo. Water (400 mL),

aqueous HCl (ad pH 3), and EtOH were added, and the

mixture was stirred at room temperature for 20 min. The

resulting precipitate was filtered, washed successively with 2

N HCl, EtOH, and ether, and dried at 90 °C to afford 5-nitro-

2-pyrrolidino-benzoic acid (21 g, 89%); mp 226 °C. (b) The

5226 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Ta ble 1. Substituted Benzoic Acid Derivatives 5

Grell et al.

a

(Re)crystallization solvents: A ) water; B ) diethylether; C ) isopropanol; D ) ethylacetate; E ) acetone; F ) acetone/diethylether;

b

G ) diethylether/petrolether; H ) aqueous ethanol. Analyzed for C, H, and N; results were within (0.40% of the theoretical values.

^cMaximum % decrease of blood glucose (∆BG) observed within 4 h after administration to fasted female rats (N ) 7) versus a control

group (P ) 0.05). Minimum ED₅₀within 4 h at the time indicated. ^eNS ) not significant. ^fLit.¹³mp 170-172 °C. Lit.²⁹mp 115-117

d

g

°C. Lit.³⁰mp 172-174 °C.

h

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5227

Ta ble 2. Substituted Benzoic Acid Derivatives 6.1

a

(Re)crystallization solvents: A ) diethylether; B ) petrolether/acetone; C ) ethylacetate; D ) acetone; E ) trichloromethane; F )

b

toluene/trichloromethane; G ) petrolether/trichloromethane; H ) petrolether/ethylacetate; J ) ethanol; K ) aqueous ethanol. Analyzed

for C, H, and N; results were within (0.40% of the theoretical values. ^cMaximum % decrease of blood glucose (∆BG) observed within 4

d

h after administration to fasted female rats (N ) 7) versus a control group (P ) 0.05). Minimum ED₅₀within 4 h at the time indicated.

^eFor synthetic route see Experimental Section. ^fNS ) not significant. ^gSynthesized from 6f. Synthesized analogously to 4.^{5 i}Synthesized

h

from 4a .

5228 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Ta ble 3. 2′-Piperidino-Substituted Benzoic Acid Derivatives 6.2^a

Grell et al.

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5229

Ta ble 3 (Continued)

a

b

The compounds were synthesized according to Scheme 2 unless otherwise indicated. (Re)crystallization solvents: A ) diethylether;

B ) ethanol; C ) acetone; D ) aqueous ethanol; E ) acetonitrile; F ) ethylacetate; G ) diethylether/acetone; H ) petrolether/ethanol;

J ) petrolether/acetone; K ) petrolether/diethylether; L ) petrolether/methylenechloride; M ) petrolether/toluene; N ) aqueous methanol.

^cAnalyzed for C, H, and N; results were within (0.40% of the theoretical values unless otherwise indicated. Maximum % decrease of

d

blood glucose (∆BG) observed within 4 h after administration to fasted female rats (N ) 7) versus a control group (P ) 0.05). ^eMinimum

ED₅₀within 4 h at the time indicated. ^fSynthesized according to Scheme 3. NS ) not significant. Synthesized from 6a i with BBr₃(see

g

h

Experimental Section). C: calcd, 71.21; found, 71.92. Molpeak M⁺: calcd, 438; found, 438. C: calcd, 72.39; found, 71.90. ee ) 99.6%.

i

j

k

ee g 99.2%. ee not determined. ee g 99.98%. ^oee g 99.8%. For synthesis see Experimental Section. ee ) 100%. Lit.³⁰mp 172-

l

m

n

p

q

r

174 °C. Lit.³¹mp 207 °C; lit.³²mp 168-170 °C (aqueous acetone).

s

Ta ble 4. Time Course of the Hypoglycemic Activity of the Compounds 6v, 6a h , 6a i, (S)-6a l, 1, and 2

a

b

d

% Decrease of blood glucose (∆BG). ND ) not determined. ^cNS ) not significant. The analogous compound with R ) O-n-Pr was

found to be less active: 0.5 mg/kg; -34% (1 h), -36% (2 h), -24% (3 h), NS (4 h). Statistical significance (vs control): *P < 0.05, **P <

0.01, ***P < 0.001.

preceding nitro compound (21 g, 89 mM) was hydrogenatedin

DMF (500 mL) over 10% Pd/C (1 g) for 1 h at 20 °C and 1 bar.

After filtration and evaporation in vacuo, the residue was

crystallized from hot EtOH (50 mL) to give 5-amino-2-

pyrrolidino benzoic acid (14.5 g, 79%); mp not determined. (c)

A solution of NaNO₂(5.25 g, 75 mM) in water (21 mL) was

added dropwise during 1 h to a stirred cooled (0 °C) solution

of the preceding amino compouund (14 g, 68 mM) in concen-

trated HCl (29 mL) and water (29 mL). The resulting solution

was dropped slowly at 0 °C into a vigorously stirred slurry of

copper powder (6.5 g, 102 mM) and concentrated aqueous HCl

(5 mL). The reaction was warmed to 20-25 °C (nitrogen

escaped vigorously), kept overnight at room temperature,

diluted with water to double volume, and extracted with

5230 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

KOH (30 g, 535 mM), and water (12 mL) was reacted in an

open flask at 160 °C for 1.5 h. After cooling and addition of

concentrated HCl (ad pH 2), 1 N KOH was added (ad pH 7).

The precipitate, crude 5-chloro-2-piperidino-benzamide, was

filtered and refluxed for 7 h in 18% aqueous HCl. After evap-

oration in vacuo, addition of water, and filtration, the filtrate

was adjusted to pH 6-7 with solid Na₂CO₃and extracted with

ether. The organic layer was dried and evaporated in vacuo

to give 9d (2.9 g, 65%); mp 160 °C (Et₂O).

5-Ch lor o-2-(2-m eth yl-piper idin o)-ben zoic Acid (9e) was

obtained from 2-chloro-5-nitro-benzoic acid and 2-methyl-

piperidine analogously to 9c; mp < 20 °C.

5-Ch lor o-2-(3-m eth yl-p ip er id in o)-ben zoic Acid (9f) was

obtained from 2-chloro-5-nitro-benzoic acid and 3-methyl-

piperidine analogously to 9c; mp 165 °C.

5-Ch lor o-2-(4-m eth yl-piper idin o)-ben zoic Acid (9g) was

obtained from 2-chloro-5-nitro-benzoic acid and 4-methyl-

piperidine analogously to 9c; mp 107 °C.

5-Ch lor o-2-(cis-3,5-d im eth yl-p ip er id in o)-ben zoic Acid

(9h ) was obtained from 2-chloro-5-nitro-benzoic acid (1 equiv)

and cis-3,5-dimethyl-piperidine‚HCl⁴⁶(1 equiv) in the presence

of dry NEt₃(3 equiv) analogously to 9c; mp 166-167 °C

(EtOAc).

5-Ch lor o-2-(tr a n s-3,5-dim eth yl-piper idin o)-ben zoic Acid

(9i) was obtained from 2-chloro-5-nitro-benzoic acid (1 equiv)

and trans/cis (85:15) 3,5-dimethyl-piperidine‚HCl⁴⁶(1 equiv)

in the presence of dry NEt₃(3 equiv) analogously to 9c and

purified by column chromatography with CHCl₃/acetone (3:

1). 9i was eluted tightly after the cis isomer 9h ; mp 130-132

(EtOAc).

5-Ch lor o-2-h exa m eth ylen eim in o-ben zoic Acid (9j) was

synthesized from 2-chloro-5-nitro-benzonitrile via 5-amino-2-

hexamethyleneimino-benzonitrile analogously to 9d ; mp 105-

113 °C.

5-Ch lor o-2-h ep ta m eth ylen eim in o-ben zoic Acid (9k )

was obtained from 2-chloro-5-nitro-benzoic acid and 2-hep-

tamethyleneimine analogously to 9c; mp < 20 °C.

5-Ch lor o-2-octa m eth ylen eim in o-ben zoic Acid (9l). (a)

A mixture of 2-chloro-5-nitrobenzoic acid (36.4 g, 180 mM),

octamethyleneimine⁴⁷(23 g, 180 mM), and sodium carbonate

(38.7 g, 365 mM) was refluxed in EtOH (236 mL) for 4 h. After

evaporation in vacuo, the residue was dissolved in water (250

mL), acidified (pH 1), and extracted with CHCl₃. The organic

layer was dried and evaporated in vacuo to afford 5-nitro-2-

octamethyleneimino-benzoic acid (49.2 g, 93%); mp 129-131

°C. (b) The preceding nitro compound (9 g, 30.8 mM) was

hydrogenated in MeOH (90 mL) over 10% Pd/C (0.5 g) at 20

°C and 5 bar for 1 h to give 5-amino-2-octamethyleneimino-

benzoic acid (7.8 g, 96%); mp 191-192 °C. (c) The preceding

amino compound (5.2 g, 19.8 mM) in concentrated aqueous HCl

(20 mL) and water (20 mL) was diazotized with NaNO₂(1.54

g, 22.3 mM) in water (6 mL) at 0 °C. After being stirred for

20 min, the suspension was added at 5-10 °C during 10 min

to a stirred slurry of copper powder (2 g, 31.5 mM) in

concentrated aqueous HCl (50 mL). The reaction was stirred

at 5 °C for 10 min and at room temperature for 12 h, and then

diluted with water (100 mL) and extracted with CHCl₃(3 ×

200 mL). The organic layer was dried and evaporated in

vacuo. The residue was triturated with EtOAc (30 mL) to give

5-chloro-2-octamethyleneimino-benzoic acid‚HCl‚2H₂O (4.1 g,

58%); mp 174-176 °C (Et₂O). (d) The preceding hydrochloride

(4.1 g) was stirred in water (100 mL) at 35-40 °C. Solid

NaHCO₃(1 g, 11.9 mM) was added. After the mixture was

stirred for 2 h, CHCl₃(200 mL) and EtOH (20 mL) were added.

After the mixture was stirred for another hour, the reaction

was filtered. The aqueous layer was extracted with CHCl₃/

EtOH (20:2) (4 × 220 mL). The combined organic layers were

dried and evaporated in vacuo. The residue was triturated

with diethyl ether and filtrated. The filtrate was evaporated

in vacuo to afford 9l (3.3 g, 58%); mp 80-81 °C.

F igu r e 5. Time course of the hypoglycemic activity of the

compounds 6v, 6a h , 6a i, (S)-6a l (REP), 1 (GLIB), and 2

(GLIM).

CHCl₃/MeOH (100:5). The organic layer was dried and

evaporated in vacuo. The residue was boiled in 710 mL EtOAc/

EtOH (70:1); after decanting, the solution was evaporated in

vacuo. The residue was purified by column chromatography

(EtOAc/MeOH; 95:5) to give 9c (4.6 g, 30%); mp 164 °C.

5-Ch lor o-2-p ip er id in o-ben zoic Acid (9d ). (a) 5-Amino-

2-piperidino-benzonitrile (10 g, 50 mM; mp 146 °C, obtained

from 2-chloro-5-nitro-benzonitrile (Aldrich) according to lit-

erature⁴⁵) in concentrated HCl (20 mL) and water (20 mL) was

diazotized at 0-4 °C with NaNO₂(3.6 g, 51 mM) in water (15

mL). This solution was slowly dropped into a stirred mixture

of copper powder (4 g, 63 mM) and concentrated HCl (4 mL)

at 20 °C (nitrogen escaped vigorously). After stirring at 20

°C for 2 h, the reaction was extracted with CHCl₃. The organic

layer was dried and evaporated in vacuo. The residue was

purified by column chromatography (toluene) to give 5-chloro-

2-piperidino-benzonitrile (8.4 g, 76%); mp 41-43 °C. (b) A

mixture of the preceding benzonitrile (4.2 g, 19 mM), powdered

5-Ch lor o-2-n on a m eth ylen eim in o-ben zoic Acid (9m )

was obtained from 2-chloro-5-nitrobenzoic acid, nonameth-

yleneimine,⁴⁷and sodium carbonate analogously to 9l; mp

87 °C.

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5231

Ta ble 5. Substituted Benzoic Acid Derivatives 5.1

a

(Re)crystallization solvents: A ) ethylacetate; B ) acetone/diethylether; C ) diethylether; D ) water; E ) toluene/ethylacetate.

Analyzed for C, H, and N; results were within (0.40% of the theoretical values. ^cMaximum % decrease of blood glucose (∆BG) observed

b

d

within 4 h after administration to fasted female rats (N ) 7) versus a control group (P ) 0.05). Synthesized according to ref 13, example

1. ^eLit.¹³mp 202-202 °C. ^fSynthesized according to Scheme 1 with 2-phenethylamine. NS ) not significant.

g

Ta ble 6. Substituted Benzoic Acid Derivatives 6.3^a

Ta ble 7. Substituted Benzoic Acid Derivatives 6.4^a

a

The compounds were synthesized according to Scheme 2 unless

a

b

The compounds were synthesized analogously to Scheme 2 by

otherwise indicated. (Re)crystallization solvents: A ) ethanol;

reaction of a corresponding R-methyl-(1-piperidinyl)-benzylamine

B ) petrolether/ethanol; C ) aqueous ethanol; D ) acetone.

^cAnalyzed for C, H, and N; results were within (0.40% of the

with a corresponding [(ethoxy(or methoxy)carbonyl)phenyl]acetic

b

d

acid. (Re)crystallization solvents: A ) diethylether; B ) ethanol;

theoretical values unless otherwise indicated. Maximum

%

C ) aqueous ethanol. ^cAnalyzed for C, H, and N; results were

decrease of blood glucose (∆BG) observed within

4 h after

d

within (0.40% of the theoretical values. Maximum % decrease

administration to fasted female rats (N ) 7) versus a control group

(P ) 0.05). ^eC: calcd, 71.21; found, 71.92. Molpeak M⁺: calcd, 438;

of blood glucose (∆BG) observed within 4 h after administration

to fasted female rats (N ) 7) versus a control group (P ) 0.05).

^eNS ) not significant.

found, 438. ^fSynthesized with R-propyl-benzylamine. Synthe-

g

sized with phenylacetic acid.

[freshly prepared from the corresponding salt by dissolution

in iced water, alkalinization, rapid extraction with CHCl₃,

drying, and evaporation of the organic layer in vacuo] in dry

THF (5 mL) was added. After stirring overnight at room

temperature, the reaction was evaporated in vacuo. The

residue was purified by column chromatography with toluene/

EtOAc (8.5:1.5) to give 11.

5-Ch lor o-2-d eca m eth ylen eim in o-ben zoic Acid (9n ) was

obtained from 2-chloro-5-nitrobenzoic acid, decamethylene-

imine,⁴⁷and Na₂CO₃analogously to 9l; mp 70 °C.

E d u ct s 10. Met h yl 4-(2-a m in oet h yl)-ben zoa t e (10a )‚

HCl:^15amp 242 °C; lit.^15amp 209-216 °C.

Eth yl 4-(2-a m in oeth yl)-ben zoa te (10b)‚HCl: mp 255-

260 °C; lit.^15bmp 178-180 °C.

A2. A stirred mixture of educt 9 (10 mM) and SOCl₂(30

mM) in dry CHCl₃(20 mL) was refluxed for 4-5 h. After

evaporation in vacuo, the residue was dissolved in dry CHCl₃

(10 mL). This solution was added at room temperature during

15 min to the corresponding salt of 10 (10 mM) and dry NEt₃

(30 mM) in dry CHCl₃(14 mL). The reaction was refluxed for

30 min, cooled to room temperature, and washed successively

with water (2×), diluted aqueous HOAc, and aqueous NaHCO₃.

The organic layer was dried and evaporated in vacuo. The

Met h yl 4-(2-a m in oet h yl)-2-m et h oxy-b en zoa t e (10c)‚

H₂SO₄was prepared analogously to that in ref 16; mp 141-

145 °C.

Eth yl 4-(2-a m in oeth yl)-2-eth oxy-ben zoa te (10d )‚H₂SO₄:

mp not determined; lit.¹⁶(‚HCl) mp not reported.

Gen er a l P r oced u r es for Ester s 11. A1. N,N′-Carbonyl-

diimidazole¹⁴(6.3 mM) was added at room temperature to a

stirred solution of educt 9 (5.3 mM) in dry THF (5 mL). After

the mixture was stirred for 2 h, a solution of 10 (6.3 mM)

5232 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Ta ble 8. Substituted Phenylacetamides 6.5

Grell et al.

Ta ble 10. Substituted Benzoic Acid Derivatives 6.7

a

(Re)crystallization solvents: A ) diethylether; B ) acetone/

diethylether; C ) acetone. ^bAnalyzed for C, H, and N; results were

within (0.40% of the theoretical values. ^cMaximum % decrease

of blood glucose (∆BG) observed within 4 h after administration

to fasted female rats (N ) 7) versus a control group (P ) 0.05).

For synthesis see Experimental Section. ^eNS ) not significant.

d

^fSynthesized from 49.

Ta ble 9. Substituted Benzoic Acid Derivatives 6.6

a

(Re)crystallization solvents: A ) aqueous ethanol; B ) aceto-

nitrile; C ) diethylether/petrolether; D ) petrolether; E ) acetone/

b

petrolether; F ) neat (on standing). Analyzed for C, H, and N;

results were within (0.40% of the theoretical values unless

otherwise indicated. ^cMaximum % decrease of blood glucose (∆BG)

observed within 4 h after administration to fasted female rats (N

d

) 7) versus a control group (P ) 0.05). For synthesis see

Experimental Section. ^eNS ) not significant. ^fSynthesized ac-

g

cording to Scheme 2 with R-propyl-benzylamine. C, H, N not

determined. Molpeak M⁺: calcd, 379; found, 379.

a

(Re)crystallization solvents: A ) diethylether; B ) ethanol.

b

Analyzed for C, H, and N; results were within (0.40% of the

theoretical values unless otherwise indicated. ^cMaximum % de-

crease of blood glucose (∆BG) observed within 4 h after adminis-

tration to fasted female rats (N ) 7) versus a control group (P )

0.05). For synthesis see Experimental Section. ^eC: calcd, 72.10;

d

found, 72.59. ^fNS ) not significant.

residue was purified by column chromatography with CHCl₃/

acetone (9:1) to give 11.

Gen er a l P r oced u r es for Su bstitu ted Ben zoic Acid s 5.

B1. To a stirred solution of 11 (1.6 mM) in dioxane (6 mL)

and MeOH (6 mL) was added at room temperature a solution

of KOH (4.8 mM) in water (2 mL); thereafter, water (30 mL)

was added so slowly that the solution remained clear. After

the mixture was stirred at room temperature overnight, the

reaction was evaporated in vacuo. The residue was dissolved

in water. After extraction with CHCl₃(discarded), the aqueous

layer was adjusted to pH 4.5-5.5 with 2 N HCl to precipitate

5.

B2. A mixture of ester 11 (5 mM) in EtOH (50 mL) and 1

N NaOH (10 mL) was refluxed for 30 min. After evaporation

in vacuo to about one-third of the original volume, water (60

mL) and diluted aqueous HOAc (to pH 6) were added to

precipitate 5.

F igu r e 6. General pharmacophore model suitable for hy-

poglycemic benzoic acid derivatives, SUs, and sulfonamides

of type A and B.

Com p ou n d s Syn th esized Accor d in g to P r oced u r es B1/

A1. Note: The melting points of compounds 5 are reported in

Table 1. 4-(2-(5-Chloro-2-dimethylamino-benzoylamino)-ethyl)-

benzoic acid (5a ): 70%, via methyl 4-(2-(5-chloro-2-dimethyl-

amino-benzoylamino)-ethyl)-benzoate (11a ), 48%; mp 99 °C.

4-(2-(5-Chloro-2-diethylamino-benzoylamino)-ethyl)-benzoic acid

(5b): 60%, via methyl 4-(2-(5-chloro-2-diethylamino-benzoyl-

amino)-ethyl)-benzoate (11b), 51%; mp 92-93 °C. 4-(2-(5-

Chloro-2-pyrrolidino-benzoylamino)-ethyl)-benzoic acid (5c):

68%, via methyl 4-(2-(5-chloro-2-pyrrolidino-benzoylamino)-

ethyl)-benzoate (11c), 43%; mp 164 °C. 4-(2-(5-Chloro-2-

piperidino-benzoylamino)-ethyl)-benzoic acid (5d ): 82%, via

methyl 4-(2-(5-chloro-2-piperidino-benzoylamino)-ethyl)-ben-

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5233

Ta ble 11. Calculated Energy Differences (∆E, kcal/M) of the

Low-Energy Conformations (LECs) of Repaglinide (REP),

Glibenclamide (GLIB), and Glimepiride (GLIM) with Respect to

the Corresponding Minimum Conformations I

; r

F igu r e 7. Structural formula of (S)-6a l (REP).

Ta ble 12. Torsion Angles æ1 to æ5 of the Low-Energy

Conformations (LECs) of Repaglinide (REP), Glibenclamide

(GLIB), and Glimepiride (GLIM)

ethyl)-benzoate (11f): 51%; mp 93 °C. 4-(2-(5-Chloro-2-(4-

methyl-piperidino)-benzoylamino)-ethyl)-benzoic acid (5g): 83%,

via methyl 4-(2-(5-chloro-2-(4-methyl-piperidino)-benzoylamino)-

ethyl)-benzoate (11g): 45%; mp 55 °C. 4-(2-(5-Chloro-2-

hexamethyleneimino-benzoylamino)-ethyl)-benzoic acid (5j):

89%, via methyl 4-(2-(5-chloro-2-hexamethyleneimino-benzoyl-

amino)-ethyl)-benzoate (11j), 72%; mp 79-81 °C. 4-(2-(5-

Chloro-2-heptamethyleneimino-benzoylamino)-ethyl)-benzoic

acid (5k ): 47%, via ethyl 4-(2-(5-chloro-2-heptamethylene-

imino-benzoylamino)-ethyl)-benzoate (11k ), 24%; mp < 20 °C.

4-(2-(5-Chloro-2-octamethyleneimino-benzoylamino)-ethyl)-

benzoic acid (5l): 92%; mp 148 °C (H₂O); mp 165-167 °C

(recrystallized from EtOAc); via ethyl 4-(2-(5-chloro-2-octa-

methyleneimino-benzoylamino)-ethyl)-benzoate (11l), 41%; oil.

4-(2-(5-Chloro-2-octamethyleneimino-benzoylamino)-ethyl)-

benzoic acid (5l)‚0.8HCl: 90%; mp 205 °C, obtained from 5l

in hot acetone with HCl/i-PrOH. 4-(2-(5-Chloro-2-octameth-

yleneimino-benzoylamino)-ethyl)-2-methoxy-benzoic acid (5n )‚

HCl: 96%, from 5n in ether with HCl/i-PrOH, via methyl 4-(2-

(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl)-2-methoxy-

benzoate (11m ), 46%; oil (in dry pyridine, 48 h, 100 °C). 4-(2-

(5-Chloro-2-octamethyleneimino-benzoylamino)-ethyl)-2-ethoxy-

benzoic acid (5o)‚HCl: 62%, from 5o with HCl/i-PrOH, via

ethyl 4-(2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl)-

2-ethoxy-benzoate (11n ), 61%; oil (in dry pyridine, 48 h, 100

°C). 4-(2-(5-Chloro-2-nonamethyleneimino-benzoylamino)-

ethyl)-benzoic acid (5p ): 71%; via ethyl 4-(2-(5-chloro-2-

nonamethyleneimino-benzoylamino)-ethyl)-benzoate (11o), 67%;

oil (in dry pyridine, 24 h, 100 °C). 4-(2-(5-Chloro-2-decameth-

yleneimino-benzoylamino)-ethyl)-benzoic acid (5q): 58%; via

ethyl 4-(2-(5-chloro-2-decamethyleneimino-benzoylamino)-ethyl)-

benzoate (11p ), 65%; oil (in dry DMF, 12 h, 90 °C).

F igu r e 8. ORTEP plot of the X-ray structure of (S)-6a l (REP).

Com p ou n d s Syn t h esized Accor d in g t o P r oced u r es

B2/A2. 4-(2-(5-Chloro-2-(cis-3,5-dimethyl-piperidino)-benzoyl-

amino)-ethyl)-benzoic acid (5h ): 87%; via methyl 4-(2-(5-

chloro-(2-(cis-3,5-dimethyl-piperidino)-benzoylamino)-ethyl)-

benzoate (11h ), 77%; mp 94-95 °C (CH₂Cl₂/petrolether); mp

122-124 °C (MeOH). 4-(2-(5-Chloro-2-(trans-3,5-dimethyl-

piperidino)-benzoyl-amino)-ethyl)-benzoic acid (5i): 86%, via

methyl 4-(2-(5-chloro-(2-(trans-3,5-dimethyl-piperidino)-ben-

zoylamino)-ethyl)-benzoate (11i): 75%; mp 105-107 °C (MeOH).

Sp ecia l P r oced u r e: 4-(2-(2-Octa m eth ylen eim in o-ben -

zoyla m in o)-eth yl)-ben zoic Acid (5m ). 5l (2.15 g; 5 mM)

F igu r e 9. ORTEP plot of the X-ray structure of 2 (GLIM).

zoate (11d ): 72%, mp 98 °C. 4-(2-(5-Chloro-2-(2-methyl-

piperidino)-benzoylamino)-ethyl)-benzoic acid (5e): 57%, via

methyl 4-(2-(5-chloro-2-(2-methyl-piperidino)-benzoylamino)-

ethyl)-benzoate (11e), 23%; mp 82 °C. 4-(2-(5-Chloro-2-(3-

methyl-piperidino)-benzoylamino)-ethyl)-benzoic acid (5f): 83%,

via methyl 4-(2-(5-chloro-2-(3-methyl-piperidino)-benzoylamino)-

5234 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

F igu r e 10. Stereopicture of the superposition of low-energy conformations (LECs). (A, above) LECs I (X-ray structures): REP-I

(red), GLIB-I (green), and GLIM-I (blue). (B, bottom) LECs II (calculated): REP-II (red), GLIB-II (green), and GLIM-II (blue).

The superpositions were performed in order to optimally fit the central phenylene ring and the acidic pharmacophoric groups of

each molecule. As it turns out, the conformational differences as quantified in the list of main torsion angles (Table 12) led to

drastically different positions of the two other pharmacophoric groups when comparing REP-I to GLIB-I/GLIM-I. REP-I is in a

compactly folded conformation, whereas GLIB-I and GLIM-I have an extended shape. The two SU compounds differ in the

configuration of their ureido moieties (cis in GLIB-I, trans in GLIM-I), resulting in distinct orientations of the cyclohexyl

substituents; furthermore, a difference of 180° in the torsion angle æ3 changes the orientation of the amide carbonyl and of its

substituent.

was hydrogenated in MeOH (100 mL) for 5 h at room

temperature and 5 bar over 10% Pd/C (0.5 g). After filtration

and evaporation in vacuo, the residue was dissolved in aqueous

NaOH. After filtration, aqueous HCl was added (ad pH 5.5)

to precipitate 5m , 71%; mp 154-156 °C.

20-23 °C), and subsequent Bouveault reaction (aqueous

NaNO₂, 2 h, 35 °C).

(2-Met h oxy-4-m et h oxyca r b on yl-p h en yl)-a cet ic a cid

(13c), 49%, mp 50-52 °C, was prepared from methyl 4-cya-

nomethyl-2-methoxy-benzoate, mp 55-56 °C, via methyl 4-ami-

nocarbonylmethyl-2-methoxy-benzoate, 79%, mp 107-109 °C,

and subsequent Bouveault reaction.

Ed u cts 13. (4-Meth oxyca r bon yl-p h en yl)-a cetic Acid

(13a ). (a) Methyl 4-methyl-benzoate was reacted with N-

bromo-succinimide (NBS) (1 equiv) and a trace of dibenzoyl-

peroxide in CCl₄for 2.5 h under reflux to give methyl

4-bromomethyl-benzoate, 80%; bp_0.290-95 °C. (b) The result-

ing bromo ester was dropped within 1.5 h to a warm (40 °C)

solution of NaCN (1 equiv) in DMSO. After 2 h at 40 °C,

workup (iced water, extraction with Et₂O) gave methyl-4-

cyanomethyl-benzoate, 54%; bp_0.2110-112 °C. (c) The cya-

nomethyl compound was treated in MeOH with gaseous HCl

for 8 h under reflux. After 48 h at 20 °C, the reaction was

filtrated. The filtrate was evaporated in vacuo; the residue

was dissolved in Et₂O and washed (H₂O, aqueous NaHCO₃)

to yield methyl 4-methoxycarbonylmethyl-benzoate, 75%; bp_0.6

118-122 °C. (d) The diester was stirred with NaOH (1.0

equiv) in MeOH for 4 h at 50 °C and for 24 h at 20 °C. The

reaction was evaporated in vacuo; the residue was dissolved

in Et₂O and extracted with water. The aqueous phase was

acidified with concentrated HCl and extracted with Et₂O to

yield 13a , 74%; mp 104-106 °C (Et₂O/petrolether); mp 110-

113 °C (recrystallized from Et₂O).

(2-Eth oxy-4-eth oxyca r bon yl-p h en yl)-a cetic Acid (13d ).

(a) 2-Hydroxy-4-methyl-benzoic acid (Aldrich) in acetone was

stirred with K₂CO₃(2.3 equiv) at room temperature. Ethyl-

bromide (2.3 equiv) was added, and the reaction mixture was

heated for 30 h at 150 °C in an autoclave under stirring to

give ethyl 2-ethoxy-4-methyl-benzoate, 100% (crude). (b) The

obtained compound was reacted with NBS (0.9 equiv) and 2,2′-

azo-bis-(isobutyronitril) (0.082 equiv) in CCl₄to yield ethyl

4-bromomethyl-2-ethoxy-benzoate, 57%; mp 77-80 °C (petro-

lether). (c) To a solution of NaCN (1.2 equiv) and N-benzyl-

tri-n-butylammonium-chloride (0.046 equiv) in water (0.5 mL/

mM) was dropped a solution of the 4-bromomethyl ester in

CH₂Cl₂(1 mL/mM) at 15-20 °C. After the mixture was stirred

for 43 h at 20 °C, the organic phase was separated, washed

with water, and evaporated in vacuo. The residue was

triturated with petrolether to give ethyl 4-cyanomethyl-2-

ethoxy-benzoate, 97%; mp 57-63 °C. (d) The cyanomethyl

ester was treated with gaseous HCl in EtOH under reflux to

yield ethyl 2-ethoxy-4-ethoxycarbonylmethyl-benzoate, 91%,

crude; oil. (e) The crude diester was hydrolyzed with 2 N

NaOH (0.8 equiv) in EtOH (1.5 h, 23-25 °C). EtOH was

removed in vacuo at 40 °C. The aqueous phase was diluted

with water and extracted several times with toluene (dis-

carded), cooled in ice, and acidified with 2 N HCl (0.8 equiv).

Further workup included extraction with toluene, washing

(4-Eth oxyca r bon yl-p h en yl)-a cetic Acid (13b), 58%, mp

99-100 °C, was prepared from ethyl 4-ethoxycarbonylmeth-

yl-benzoate analogously to 13a . 13b (63%; mp 90-95 °C)

was also obtained from ethyl 4-cyanomethyl-benzoate in an

one-pot reaction via intermediary ethyl 4-aminocarbonyl-

methyl-benzoate, mp 135-140 °C (concentrated HCl, 1.5 h,

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5235

F igu r e 11. Stereopicture of the isocontour surfaces of the hydrophobic potential of the LECs II: REP-II (upper), GLIB-II (middle),

and GLIM-II (bottom). Contour levels: blue (-6), yellow (+4 kcal/M). The yellow and the blue surfaces represent lipophilic and

hydrophilic regions, respectively.

with water (to remove diacid), drying and treating of the

organic phase with charcoal for 10 min at 80-90 °C, filtration,

and evaporation in vacuo. The crude product (70%) was

dissolved in hot toluene, and an equal volume of cyclohexane

was added. On cooling, crystallization was induced to give

13d , 59%; mp 70-75 °C. In the case of 13d , a one-pot

conversion, analogous to 13b , starting from ethyl 4-cyano-

methyl-2-ethoxy-benzoate yielded only 39% of 13d ; mainly (4-

carboxy-2-ethoxy-phenyl)-acetic acid, mp 141-142 °C, was

obtained.

P r oced u r es for Ra cem ic Am in es 12. Rou te A. 3-Meth -

yl-1-(2-p ip er id in o-p h en yl)-bu tyla m in e (12q). (a ) 2-P ip -

er id in o-ben zon itr il (15a ). 2-Chloro-benzonitrile (0.5 M),

N-formyl-piperidine (1 M), and piperidine (1.5 M) were re-

fluxed at 160-170 °C for 64 h. The reaction was dissolved in

toluene (1 L), washed with water (3 × 200 mL), dried, filtrated,

and evaporated in vacuo. The residue was dissolved in toluene

(500 mL); the solution was stirred at room temperature with

silica gel (130 g) for 1 h and with additional silica gel (130 g)

for another hour. The silica gel was filtered off and washed

with toluene; the filtrate was evaporated in vacuo. On

distillation over a 5 cm Vigreux column, 15a was obtained

(84%; bp_0.6106-109 °C; mp 37-39 °C).

(b ) (3-Met h yl-b u t yl)-(2-p ip er id in o-p h en yl)-k et im in e

(16q). To a solution of i-BuMgBr (268 mM) in 135 mL of

toluene/THF (4:1) was added a solution of 15a (107 mM) in

135 mL of toluene/THF (4:1). After reflux for 3 h and standing

overnight, the reaction mixture was dropped into a cold (-15

°C) mixture of concentrated ammonia (300 mL) and saturated

aqueous NH₄Cl (300 mL). After the mixture was stirred for

10 min, the mixture was filtered through a layer of kieselguhr,

and the organic layer was separated, dried, and evapoarted

in vacuo to give 16q as a yellow oil (crude, 100%).

(c1) 3-Meth yl-1-(2-piper idin o-ph en yl)-bu tylam in e (12q).

Crude 16q (45 mM) in saturated methanolic ammonia (170

mL) was hydrogenated over Raney-Ni (5.5 g) at 80 °C and 5

bar for 6 h. After filtration, the filtrate was evaporated in

vacuo. The residue was dissolved in 1 N HCl and extracted

5236 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

with CH₂Cl₂(3 × 25 mL). The aqueous phase was alkalinized

with concentrated NaOH and extracted with CH₂Cl₂(2 × 25

mL); filtration through a layer of kieselguhr was needed to

afford separation of the phases. The organic layer was washed

with water, dried, filtrated, and evaporated in vacuo to give

the title compound (59%; oil). (c2) Alternatively, NaBH₄(161

mM) was added within 1 h to crude 16q (80.5 mM) in MeOH

(160 mL) at 0 °C; stirring was continued at 15 °C for 2 h. The

reaction was evaporated in vacuo, and 10% aqueous HCl (100

mL) was added cautiously under cooling with ice. After

extraction with CH₂Cl₂(4 × 40 mL, discarded), the aqueous

phase was alkalinized with 50% NaOH and extracted with

CH₂Cl₂(2 × 50 mL). The organic layer was washed with water

(40 mL), dried, and evaporated in vacuo. The residue was

dissolved in EtOH (25 mL) and cooled in ice. A solid product

was filtered off, and the filtrate was evaporated in vacuo to

give 12q as a yellow oil (65%) which was used for further

reaction. For purification and/or storage, the salt 29 ()12q‚

glutaric acid; mp 179-180 °C) was formed.

Com p ou n d s Obta in ed Accor d in g to Rou te A. (The

method involved catalytic hydrogenation of the corresponding

ketimine 16.) 1-(2-Piperidino-phenyl)-ethylamine (12d ): 69%;

bp₂110-115 °C. 1-(5-Chloro-2-(2-methyl-piperidino)-phenyl)-

ethylamine (12g): 44%; oil, and the more polar 1-(2-(2-methyl-

piperidino)-phenyl)-ethylamine, 32%; oil. 1-(2-(4-Methyl-piperi-

dino)-phenyl)-ethylamine (12i): 59%; oil. 1-(2-Hexamethyl-

eneimino-phenyl)-ethylamine (12l): 49%; bp_0.4103-107 °C.

1-(2-Piperidino-phenyl)-butylamine (12o): 68%; bp_1.5102-

103 °C. Phenyl-(2-piperidino-phenyl)-methylamine (12s):

100%, crude; oil. 1-(2-Piperidino-phenyl)-pentylamine (12u ):

100%, crude; oil. 1-(2-Piperidino-phenyl)-hexylamine (12x):

100%, crude; oil. 1-(2-Piperidino-phenyl)-heptylamine (12y):

54%; oil. 2-Cyclohexyl-1-(2-piperidino-phenyl)-ethylamine

(12a c): 45%; oil. 2-Phenyl-1-(2-piperidino-phenyl)-ethylamine

(12a e): 64%; oil.

elution with CHCl₃/MeOH/concentrated ammonia (10:1:0.01)

resulted in 12w as a brownish oil (46%). For storage, the salt

12w × glutaric acid, mp 138-140 °C, was formed.

Com p ou n d s Obta in ed Accor d in g to Rou te B. (The

method involved reaction of the Li salt of 19a with the

corresponding halide.) 1-(2-Piperidino-phenyl)-4-pentenylamine

(12v): 40%; oil. 2-Cyclopropyl-1-(2-piperidino-phenyl)-ethyl-

amine (12z): 50%; oil. 2-Cyclobutyl-1-(2-piperidino-phenyl)-

ethylamine (12a a ): 41%; oil. 2-Cyclopentyl-1-(2-piperidino-

phenyl)-ethylamine (12a b ): 31%; oil. 2-Cycloheptyl-1-(2-

piperidino-phenyl)-ethylamine (12a d ): 46%; oil.

Rou te C. 1-(5-Ch lor o-2-pyr r olidin o-ph en yl)-eth ylam in e

(12b). (a) 5-Nitr o-2-pyr r olidin o-ben zon itr ile (21a). 2-Chlo-

ro-5-nitro-benzonitrile (219 mM; Aldrich) and pyrrolidine (657

mM) in dry EtOH (400 mL) were refluxed for 2 h. The reaction

was evaporated in vacuo; the residue was dissolved in water

and acidified with 2 N HCl. Extraction with Et₂O and

crystallization from EtOH yielded 21a , 97%; mp 135-137 °C.

(b) 5-Am in o-2-p yr r olid in o-ben zon itr ile (22a ). A mix-

ture of 21a (212 mM), iron powder (747 mM), water (112

mL), and NH₄Cl (125 mM) was refluxed for 2 h. After cooling

to room temperature, the reaction was extracted with CHCl₃

to give, after crystallization from EtOH, 22a , 86%; mp

125-127 °C.

(c) 5-Ch lor o-2-p yr r olid in o-ben zon itr ile (23a ). A solu-

tion of NaNO₂(182 mM) in water (73 mL) was added dropwise

at 0 °C to a solution of 22a (182 mM) in semiconcentrated HCl

(109 mL). The obtained cold solution was added dropwise to

a mixture of Cu₂Cl₂(238 mM) in concentrated HCl (95 mL)

which was stirred in a bath of 40 °C. After 2 h at 40 °C, the

reaction was cooled and extracted with CHCl₃. The organic

phase was washed with water, dried, and evaporated in vacuo.

The residue was purified by column chromatography (toluene)

to yield 23a , 57%; mp 73-75 °C.

(d) 1-(5-Ch lor o-2-pyr r olidin o-ph en yl)-eth ylam in e (12b).

Analogous to ref 21, a solution of 23a (68 mM) in dry Et₂O

(40 mL) was added dropwise to a (freshly prepared) solution

of MeMgI (270 mM) in dry Et₂O (140 mL). The reaction was

refluxed for 94 h; TLC control indicated that 23a had disap-

peared almost completely. LiAlH₄(203 mM) was added, and

reflux was continued for 4 h. After cooling to 0 °C, 2 N NaOH

(135 mL) was added cautiously. The precipitate was filtered

and washed with Et₂O. The organic layer was washed with

water, dried, and evaporated in vacuo. The residue was

purified by column chromatography with CHCl₃/MeOH (10:1)

to give 12b, 58%; oil (containing ∼15% of 5-chloro-2-pyrroli-

dino-benzylamine).

Com p ou n d s Obta in ed Accor d in g to Rou te C. (The

method involved reaction of 23 with R₄MgX and subsequent

reduction of the intermediary MgX salt of ketimine 24 with

LiAlH₄.) 1-(5-Chloro-2-(3-methyl-piperidino)-phenyl)-ethylamine

(12h ): 63%; oil (containing ∼5% of 5-chloro-2-(3-methyl-

piperidino)-benzylamine). 1-(5-Chloro-2-(3,5-cis-dimethyl-pi-

peridino)-phenyl)-ethylamine (12j): 67%; oil (containing ∼10%

of 5-chloro-2-(3,5-cis-dimethyl-piperidino)-benzylamine. 1-(5-

Chloro-2-piperidino-phenyl)-2-methyl-propylamine (12p): 56%;

oil. 1-(5-Chloro-2-piperidino-phenyl)-propylamine (12t): 77%;

oil.

Rou te D1. 1-(5-Ch lor o-2-piper idin o-ph en yl)-eth ylam in e

(12c). (a) 5-Nitr o-2-piper idin o-acetoph en on (25a). 2-Chlo-

ro-5-nitro-acetophenon (mp 62 °C; lit.⁴⁸mp 62 °C) and piperi-

dine (3 equiv) in dry EtOH (10 mL/g) were refluxed for 1.5 h.

The reaction was evaporated in vacuo. The residue was

dissolved in water and extracted with ether. The organic

phase was washed with semiconcentrated HCl and H₂O, dried,

and evaporated in vacuo to leave 25a as a deep-red oil (100%,

crude).

(b) 5-Ch lor o-2-p ip er id in o-a cetop h en on (26a ). Crude

25a (62 g, 0.25 M) was hydrogenated over Pd/C (10%) (3.7 g)

in DMF (620 mL) for 2 h at room temperature and 1 bar to

yield 5-amino-2-piperidino-acetophenon (30 g, 55%, crude; mp

105-107 °C (EtOH)) which was dissolved in semiconcentrated

HCl (82 mL). To this solution was dropped a solution of

NaNO₂(9.5 g, 137 mM) in water (55 mL) at 0 to 5 °C ()

Rou te B. 3-Meth yl-1-(2-p ip er id in o-p h en yl)-3-bu ten yl-

a m in e (12w ) was obtained analogously to ref 20.

(a ) 2-P ip er id in o-ben za ld eh yd e (18a ). Nitrile 15a (536

mM) was dissolved in 98% formic acid at room temperature.

The solution was stirred in a bath of 80 °C, and (wet aqueous)

Raney-Ni (180 g) was added in 10-12 g portions in intervals

of 15 min. After filtration over kieselguhr, the filtrate was

evaporated in vacuo. The residue was dissolved in water (500

mL); solid Na₂CO₃was added for neutralization. Extraction

with CH₂Cl₂and distillation of the extract residue over a 5

cm Vigreux column gave 18a , 62%; bp_0.0597 °C.

(b) 2-P ip er id in o-ben zyla m in e (12a f). 15a (134 mM) in

saturated methanolic ammonia (250 mL) was hydrogenated

over Raney-Ni (10 g) for 4 h at 50 °C and 5 bar. Filtration

and evaporation in vacuo gave 12a f as an oil (100%).

(c) N-(2-P ip er id in o-ben zyl)-2-p ip er id in o-ben za ld im in e

(19a ). To cooled (+5 °C) amine 12a f (50 mM) was dropped

18a (50 mM). After standing for 48 h at room temperature,

the reaction was dissolved in Et₂O and dried over Na₂SO₄.

Evaporation in vacuo left 19a as an honey-like product (100%,

crude).

(d ) 3-Meth yl-1-(2-p ip er id in o-p h en yl)-3-bu ten yla m in e

(12w ). Under an atmosphere of dry nitrogen, a solution of

n-BuLi (15% in hexane; 21.6 mM) was dropped at 0 to -5 °C

to a solution of diisopropylamine (21.6 mM) in dry THF (10

mL). After the mixture was stirred for 15 min, the LDA

solution was cooled to -20 to -25 °C, and a solution of crude

19a (7.2 mM) was added dropwise (color changed to red-violet).

After the mixture was stirred for 30 min at -20 °C, the

reaction was cooled to -70 °C, and a solution of 2-methyl-

allylchloride (7.2 mM) in dry THF (4 mL) was added dropwise

(color changed to violet). After removal of the cooling bath,

stirring was continued overnight. The reaction was evapo-

rated in vacuo. Semiconcentrated HCl (30 mL) was added at

0 °C. After 30 min at 0 °C, the reaction was alkalinized at 0

°C with concentrated ammonia and extracted rapidly with

CHCl₃. The organic layer was dried and evaporated in vacuo.

The residue was purified immediately by column chromatog-

raphy. Elution with CHCl₃gave recovered 18a , thereafter,

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5237

solution A). Cu₂Cl₂[freshly prepared by dropwise addition of

a solution of NaHSO₃(11.5 g, 91 mM) in water (36 mL) to a

solution of CuSO₄‚5H₂O (45.4 g, 182 mM) and NaCl (16 g, 274

mM) in water (36 mL) at T_i) 35 °C, filtration, and washing

with water] was dissolved in concentrated HCl (72.6 mL)

()solution B). Cold (0 °C) solution A was dropped into solution

B at T_i) 0 °C (foaming!). Thereafter, the reaction was

warmed to 50 °C. After cessation of the nitrogen evolution,

the reaction was cooled to 20 °C and extracted with CHCl₃.

The organic extract was purified by column chromatography

(toluene) to yield 26a as an oil (18 g, 55%).

(c) 1-(5-Ch lor o-2-p ip er id in o-p h en yl)-eth yla m in e (12c).

Analogous the literature,²¹26a (18 g, 75.7 mM) was added to

ammonium formiate (19 g, 300 mM) heated at T_i) 130 °C.

The temperature was kept at 150 °C for 5 h while H₂O was

allowed to distill off. After cooling to room temperature,

concentrated HCl (61 mL) was added, and the mixture was

refluxed for 3.5 h. After standing overnight, the solution was

extracted with EtOAc. The aqueous phase was acidified with

concentrated NaOH and extracted with EtOAc. The organic

phase was washed with water, dried, and evaporated in vacuo.

The residue was purified by column chromatography (CHCl₃/

MeOH/concentrated ammonia (10:1:0.1)) to yield 12c (4.7 g,

26%; mp 68-70 °C); 12c‚1.7HCl, mp 258-262 °C.

1-Cyclohexyl-1-(2-piperidino-phenyl)-methylamine (12r ): In

this case, the corresponding oxime (mp 173-180 °C) was

reduced in glacial HOAc with Zn dust/concentrated HCl at 40

°C to yield 12r (100%, crude; oil).

Sp ecia l P r oced u r es. 2-(5-Ch lor o-2-p ip er id in o-p h en -

yl)-2-p r op yla m in e‚HCl (12e). (a) HCl was introduced for 8

h into a refluxed solution of 9d in EtOH (2.4 mL/mM). After

standing overnight at room temperature, the reaction was

evaporated in vacuo. The residue was neutralized with

aqueous NaHCO₃and extracted with ether. The organic layer

was washed with water and worked up as usual to give ethyl

5-chloro-2-piperidino-benzoate (60%; oil). (b) LiAlH₄(245 mM)

was stirred in dry ether (800 mL) at -60 to -70 °C, and a

solution of the aforementioned ester (205 mM) in dry ether

(170 mL) was added dropwise within 1.5 h at -60 to -70 °C.

After the mixture was stirred at T_i) -30 °C for 3 h, EtOAc

(8.9 mL) and, thereafter, saturated aqueous NH₄Cl (60 mL)

were added at 0 °C. The resulting precipitate was filtered,

and the filtrate was washed with H₂O. Workup of the etheral

layer gave 5-chloro-2-piperidino-benzylalcohol (91%; oil). (c)

A solution of the preceding benzylalcohol (191 mM) in CHCl₃

(35 mL) was added dropwise to SOCl₂(423 mM) at T_i) 10-

15 °C within 1 h. After the mixture was stirred at room

temperature for 2 h, the reaction was evaporated in vacuo.

Toluene was repeatedly added and distilled off in vacuo. The

resulting residue was triturated with ether to yield 5-chloro-

2-piperidino-benzylchloride‚HCl (93%; mp 160-162 °C). (d)

A solution of the preceding hydrochloride (10.7 mM) in dry

DMSO (12 mL) was stirred at 45 °C in a stream of dry N₂

with a trap containing aqueous FeSO₄at the outlet (for capture

of HCN). NaCN (21.4 mM) dissolved in DMSO (17 mL) was

added dropwise within 1 h. After the mixture was stirred for

5 h at 40-50 °C, the reaction was poured into iced water and

extracted with ether. Workup of the organic layer and

purification by column chromatography (toluene) gave 5-chloro-

2-piperidino-benzylcyanide (64%; oil). (e) Analogous to the

literature,⁴⁹a solution of the above benzylcyanide (4.26 mM)

in dry DMF (1.5 mL) was dropped slowly at room temperature

to NaH (8.52 mM) in dry DMF (5 mL). After stirring for 0.5

h at T_i) 40-50 °C, a solution of MeI (9.37 mM) in dry DMF

(1.5 mL) was added at room temperature. After the mixture

was stirred for 2 h at room temperature, the reaction was

poured into iced water and extracted with ether. Workup of

the organic layer and purification by column chromatography

with toluene/petrolether (1:1) gave 2-(5-chloro-2-piperidino-

phenyl)-2-propyl-cyanide (63%; mp 82-84 °C). (f) The afore-

mentioned cyanide (51.4 mM) was heated in 85% H₂SO₄(135

mL) at 50 °C for 3 h. After cooling to room temperature, the

reaction was dropped slowly into a mixture of excess concen-

trated ammonia and ice at T_i∼10 °C. The resulting precipitate

was filtered and triturated with H₂O and ether. The organic

layer was washed with H₂O and worked up as usual. Crystal-

lization from EtOH gave 2-(5-chloro-2-piperidino-phenyl)-2-

methyl-propanoyl-amine (68%; mp 176-178 °C). (g) Analo-

gous to the literature,⁵⁰the preceding amide (3.9 g, 13.9 mM)

was added at 0 °C to a solution of NaOBr [freshly prepared

by adding bromine (0.72 mL, 13.9 mM) at -2 to 0 °C to a

solution of NaOH (3.33 g, 83.3 mM) in water (25 mL)]. After

the mixture was stirred for 3 h at 0 °C, dioxane (15 mL) was

added, and stirring was continued (2 h, 0 °C and 2.5 h without

cooling). Some H₂O was added, and extraction was performed

with toluene (4 × 500 mL). The organic layer was washed

with water, and workup gave N,N′-bis-(2-(5-chloro-2-piperi-

dino-phenyl)-2-propyl)-urea (3.6 g, 97% crude: mp 215-217

°C; recrystallized from EtOAc: mp 224-226 °C). (h) The

preceding urea derivative (3.55 g, 6.68 mM) was heated with

semiconcentrated HCl (70 mL) for 6 h in a glass ampule at

150 °C. The reaction was evaporated in vacuo. The residue

was triturated in a mortar, suspended in water, acidified with

2 N HCl (ad pH < 3), and extracted with ether until no solid

material was left. The acidic aqueous phase was extracted

with CHCl₃. Workup of the CHCl₃extract (brown solid, 2.8

g) and crystallization from i-PrOH gave 12e‚HCl (1.65 g, 41%;

mp 229-234 °C).

Com p ou n d Obta in ed Accor d in g to Rou te D1. (The

method involved reaction of ketone 26 with ammoniumformi-

ate and subsequent hydrolysis with concentrated HCl.) 1-(5-

Ch lor o-2-d im eth yla m in o-p h en yl)-eth yla m in e (12a ): 31%;

oil; 12a ‚2HCl, mp 216-218 °C.

Rou te D2. 1-(5-Ch lor o-2-octa m eth ylen eim in o-p h en yl)-

eth yla m in e (12n ). (a ) 5-Nitr o-2-octa m eth ylen eim in o-

a cetop h en on (25b). Equimolar amounts of 2-chloro-5-nitro-

acetophenon, NaHCO₃, and octamethyleneimine⁴⁷were refluxed

in EtOH (250 mL/100 mM) for 1.5 h. The reaction was

filtrated and evaporated in vacuo. The residue was triturated

with H₂O and CH₂Cl₂. The organic phase was dried, filtered,

and evaporated in vacuo to give 25b (91%, crude; oil).

(b) 5-Ch lor o-2-octam eth ylen eim in o-acetoph en on (26b).

A solution of 4 equiv of Na₂S₂O₄in water (1 mL/mM) was

dropped within 2 h to crude 25b in EtOH (3 mL/mM) whereby

T_irose from 20 to 32 °C. After the mixture was stirred for

further 30 min, EtOH was distilled off in vacuo. H₂O was

added, and extraction was performed with CH₂Cl₂. The

organic phase was dried, filtered, and evaporated in vacuo to

yield 5-amino-2-octamethyleneimino-acetophenon (100%, crude;

oil) which was, analogously to 26a , diazotized, submitted to

Sandmeyer reaction with Cu₂Cl₂, and purified to give to 26b

(32%, crude; oil).

(c) 5-Ch lor o-2-octam eth ylen eim in o-acetoph en on -oxim e

(27a ). A mixture of crude 26b and NH₂OH‚HCl (1.1 equiv)

was refluxed in EtOH (3.3 mL/mM) for 3.5 h. The reaction

was evaporated in vacuo. H₂O was added, and extraction was

performed with ether. Usual workup of the organic phase,

purification by column chromatography with toluene/acetone

(10:1), and crystallization from petrolether/toluene yielded 27a

(38%; mp 125-127 °C).

(d ) 1-(5-Ch lor o-2-oct a m et h ylen eim in o-p h en yl)-et h -

yla m in e (12n ). LiAlH₄(42 mM) in dry Et₂O (50 mL) was

added cautiously at room temperature to 27a (10.5 mM) in

dry Et₂O (50 mL) whereby strong hydrogen evolution occurred.

Thereafter, the reaction was refluxed for 90 h. H₂O was

cautiously added, and extraction was performed with ether.

Usual workup of the organic phase and purification by column

chromatography with CHCl₃/MeOH/concentrated ammonia

(100:10:0.25) gave 12n (31%; mp 68-70 °C; R_f0.73) and, due

to Neber rearrangement and subsequent reduction, 5-chloro-

2-octamethyleneimino-N-ethyl-aniline (23%; oil; R_f0.52).

Com p ou n d s Obta in ed Accor d in g to Rou te D2. (The

method involved reduction of oxime 27 with LiAlH₄.) 1-(5-

Chloro-2-hexamethyleneimino-phenyl)-ethylamine (12k ): 29%,

oil; ‚2HCl; mp 216-220 °C; containing some 5-chloro-2-

hexamethyleneimino-N-ethyl-aniline. 1-(5-Chloro-2-hepta-

methyleneimino-phenyl)-ethylamine (12m ): 36%, oil; contain-

ing ∼20% of 5-chloro-2-heptamethyleneimino-N-ethyl-aniline.

5238 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

(5-Ch lor o-2-p ip er id in o-p h en yl)-m eth yla m in e (12f)‚1.5

HCl. (a) 5-Chloro-2-piperidino-benzyl chloride‚HCl (89 mM)

and potassium phthalimide (187 mM) were heated in dry DMF

(375 mL) for 2 h at 90 °C. The reaction was evaporated in

vacuo. H₂O was added to the residue. The solid material was

filtered, washed with EtOH and ether, and then digested in

CHCl₃. The remaining solid was filtered and dried to yield

N-(5-chloro-2-piperidino-benzyl)-phthalimide (74%; mp 190-

193 °C). (b) The preceding phthalimide (22 g, 62 mM) and

80% N₂H₄‚H₂O (4.7 g, 75 mM) in EtOH (380 mL) were refluxed

for 10 h. EtOH was partially (∼50%) distilled off in vacuo;

semiconcentrated HCl (ad pH < 3) and H₂O (500 mL) were

added. Precipitated material was filtered off. The filtrate was

evaporated in vacuo.To the residue was added concentrated

ammonia, and extraction was performed with ether. The

organic layer was washed with water, and usual workup gave

12f (11.2 g, 80%; oil) which was transformed in i-PrOH with

HCl/ether to 12f‚1.5HCl (11 g; mp 230-240 °C).

THF (4:1) (465 mL) was added a solution of nitrile 15a (268

mM) in toluene/THF (4:1) (330 mL). After reflux for 6.5 h,

the reaction was cooled to room temperature and dropped

slowly into 4 N HCl (1.2 L) under stirring and adding ice (to

keep T_iat 20 °C). The acidic aqueous phase was separated,

alkalinized with concentrated ammonia, and extracted with

EtOAc. The organic phase was washed with water; usual

workup and purification by column chromatography with

cyclohexane/EtOAc (10:1) gave 30q (56%) as a yellow oil. An

attempt to purify crude 30q via distillation (bp_0.8125 °C)

resulted mostly in decomposition.

(b) (Isobu tyl)-(2-p ip er id in o-p h en yl)-N-[(S′)-1-p h en eth -

yl]-k etim in e (S′)-(31q). To a stirred solution of 30q (31 g,

126 mM), (S′)-1-phenethylamine (30.5 g, 252 mM; Fluka, ee

g 98%), and triethylamine (57.3 mL, 413 mM) in dry toluene

(320 mL) was dropped a solution of TiCl₄(11.2 mL, 100 mM)

in dry toluene (38 mL) at -15 °C during 1 h. After stirring

overnight at room temperature, Et₂O was added. The pre-

cipitate was filtered and washed with Et₂O. The combined

filtrates were evaporated in vacuo. The tarry residue was

triturated heavily with Et₂O. The filtrate was evaporated in

vacuo, and the residue was triturated as before. This proce-

dure was repeated several times until the ethereal solution

remained clear. At last, the residue (red-brown oil) was

distilled over a 5 cm Vigreux column to give (S′)-31q as a

yellow-orange oil (27.9 g, 63%; bp_0.4155-165 °C). In vain was

attempted to react 30q with (S′)-1-phenethylamine in toluene

in a Dean-Stark apparatus with p-TsOH or/and molecular

sieves.

P r oced u r es for En a n tiom er ic Am in es 12. Note: Chiral

stationary phase (CSP)-HPLC analysis to determine enantio-

meric purity was carried out according to the following

procedures.

(a ) After Der iva tiza tion of th e En a n tiom er ic Am in e

12 w ith Aceta n h yd r id e (A) or in Situ w ith 1-Na p h th oyl-

ch lor id e (N). Bakerbond DNPG (covalent) column; chiral

phase: (R)-N-(3,5-dinitro-benzoyl)-2-phenyl-glycine covalently

bound to aminopropyl silica gel; particle size: 5 µm; pore

width: 60 Å; l ) 250 mm; L ) 4.6 mm; flow rate: 2 mL/min;

HPLC-apparatus: HP1090M with HP1040 (DAD); mobile

phase: n-hexane/EtOH p.a.: 98.5/1.5 (A), or 99.0/1.0 (N);

temperature: 20 °C (A) or 45 °C (N); UV detection: 254(10)

nm, ref 550(50) nm (A), or 280(10) nm, ref 550(50) nm (N); or

(b) F or th e En a n tiom er ic Am in e 12 or Sa lts Th er eof.

Chiralcel OD-R column [10 µm; l ) 250 mm; L ) 4.6 mm; flow

rate: 0.4 mL/min; mobile phase: 0.2 M aqueous NaClO₄

(adjusted with HClO₄to pH 5.3)/ MeOH/ MeCN (32:27:41);

temperature: 35 °C; UV detection: 254(10) nm, ref 450(50)

nm; HPLC apparatus: HP1090 with Laserjet 4 plus printer.

(c) N-{(S)-3-Meth yl-1-[2-(1-p ip er id in yl)p h en yl]bu tyl}-

N-[(S′)-1-p h en eth yl]-a m in e (S,S′)-(32q). (S′)-31q (17 g, 49

mM) was hydrogenated in EtOH (170 mL) in the presence of

Ti(O-i-Pr)₄(1.7 g, 6 mM) over Raney-Ni (8 g, +8 g after 20

h) for 72 h at 50 °C and 200 bar to yield (S,S′)-32q (13.2 g,

76%; bp_0.2152 °C; de 96.8%; [R]²⁰-55.3° (c 1.1, MeOH)).

D

HPLC analysis was performed on a Lichrosorb RP18 column

(Merck, Germany) [7 µm; l ) 250 mm; L ) 4 mm; mobile

phase: MeOH/dioxane/0.1% aqueous NaOAc (adjusted with

HOAc to pH 4.05) (135:60); temperature: 23 °C; UV detec-

tion: 254(10) nm; peak 1 (S,S′)/peak 2 (R,S′)-ratio: 98.4:1.4].

Without Ti(O-i-Pr)₄, the hydrogenation required higher

temperature and more time.

Rou te E. (S)-3-Meth yl-1-(2-(1-p ip er id in yl)p h en yl)-bu -

tyla m in e (S)-(12q) and (R)-3-m eth yl-1-(2-(1-p ip er id in yl)-

p h en yl)-bu tyla m in e (R)-(12q). (a) 3-Methyl-1-(2-piperidino-

phenyl)-butylamine 12q (122 g, 495 mM; optionally purified

via its glutarate of mp 179-180 °C) and (L)(-)-N-acetyl-

glutamic acid (93.7 g, 495 mM; Fluka) were refluxed in a

mixture of acetone (1000 mL) and MeOH (80 mL). After the

solution had become clear, stirring was continued overnight

at room temperature. By filtration and washing with cold

(-15 °C) acetone, a solid (98.9 g; mp 163-166 °C) was obtained

which was recrystallized from acetone (1000 mL)/MeOH (200

(d) (S)-3-Meth yl-1-(2-(1-piper idin yl)ph en yl)-bu tylam in e

(S)-(12q). (S,S′)-32q (12.5 g, 36 mM) was hydrogenated in

water (125 mL)/concentrated aqueous HCl (3.6 mL, 44 mM)

over Pd/C (10%) (1.3 g) for 10 h at 50 °C and 5 bar to give

(S)-12q (6.4 g, 72%; bp_0.4115-117 °C; ee 93.5%).

Com p ou n d s Obta in ed Accor d in g to Rou te F . (R)-3-

Methyl-1-(2-(1-piperidinyl)phenyl)-butylamine (R)-(12q) (57%;

bp_0.2100-105 °C; ee e 95.2%) via (isobutyl)-(2-piperidino-

phenyl)-N-[(R′)-1-phenethyl]-ketimine (R′)-(31q) (49%; bp_0.1

142-150 °C), hydrogenation (160 h, 50 °C, 200 bar) to

N-{(R)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl}-N-[(R′)-1-

phenethyl]-amine (R,R′)-(32q) (66%; bp_0.6155-160 °C), and

subsequent hydrogenolytic cleavage. (R)-1-(2-(1-Piperidinyl)-

phenyl)-butylamine (R)-(12o) (84%; bp_0.2108-115 °C; ee

97.4%), via (n-propyl)-(2-piperidino-phenyl)-ketone (30o) (72%;

bp_0.2110 °C), (n-propyl)-(2-piperidino-phenyl)-N-[(R′)-1-phen-

ethyl]-ketimine (R′)-(31o) (88%, crude), hydrogenation (22 h,

50 °C, 200 bar) to N-{(R)-1-[2-(1-piperidinyl)phenyl]butyl}-N-

[(R′)-1-phenethyl]-amine (R,R′)-(32o) (76%; bp_0.05145-153 °C;

mL) to yield (S,S′)-28 (65.1 g, 30.2%; mp 168-171 °C; [R]²⁰

D

+35.7° (c 1, MeOH); ee 98.0). For X-ray structure determi-

nation, crystals (mp 173.2 °C) were grown from a solution in

H₂O. (b) For synthesis, (S)-12q was liberated from an aqueous

solution of (S,S′)-28 with concentrated ammonia/toluene.

Workup of the toluene extract gave (S)-12q (bp_0.6112 °C; [R]²⁰

D

+6.9° (c 1, MeOH)). (c) For X-ray structure determination,

(S)-12q was reacted with (S′)-1-phenethyl-isocyanate (ee ∼

96%, Fluka) in ether to give N¹-[(S)-3-methyl-1-[2-(1-piperidi-

nyl)phenyl] butyl-N³-[(S′)-1-[phenyl]ethyl]-urea (S,S′)-38b (mp

183-184 °C; [R]²⁰-2.2° (c 1, MeOH)). Crystals were grown

D

from a solution in EtOH/H₂O (5:1). (d) The filtrate of the

preceding (a) 98.9 g crop of (S,S′)-28 was evaporated in vacuo

to dryness. The crude residue (R/S ) 72:28) was digested in

hot acetone (10 mL/g). After cooling to 20 °C, the solid

material (R/S ) 70:30) was filtered. The filtrate was evapo-

rated in vacuo; from this residue, (R)-12q (very crude, ∼40%

impurities) was liberated and purified via salt formation with

de 97.9%; [R]²⁰+55.6° (c 1.0, MeOH)), and subsequent

D

hydrogenolytic cleavage. (S)-1-(2-(1-Piperidinyl)phenyl)-bu-

tylamine (S)-(12o) (81%; bp_0.6115-117 °C; ee 91.2%; [R]²⁰

D

+18.5° (c 1, MeOH)), via (n-propyl)-(2-piperidino-phenyl)-N-

[(S′)-1-phenethyl]-ketimine (S′)-(31o) (96%, crude), hydroge-

nation (41 h, 50 °C, 5 bar) to N-{(S)-1-[2-(1-piperidinyl)phenyl]-

butyl}-N-[(S′)-1-phenethyl]-amine (S,S′)-(32o) (74%; bp_0.05

glutaric acid in acetone to yield (R)-29 (mp 152-155 °C; [R]²⁰

D

130-140 °C; de 91.2%; [R]²⁰-52.8° (c 1.2, MeOH)), and

-25.6° (c 1, MeOH); R/S ) 97:3). (e) For synthesis, (R)-12q

was liberated from an aqueous solution of (R)-29 with con-

centrated ammonia/toluene.

D

subsequent hydrogenolytic cleavage. For X-ray structure

determination, (S)-12o was reacted with (S′)-1-phenethyl-

isocyanate (ee ∼ 96%) in ether to give N¹-[(S)-1-[2-(1-piperidi-

nyl)phenyl]butyl-N³-[(S′)-1-[phenyl]ethyl]-urea (S,S′)-(38a) (mp

Rou te F . (S)-3-Meth yl-1-(2-(1-p ip er id in yl)p h en yl)-bu -

tyla m in e (S)-(12q). (a ) (Isobu tyl)-(2-p ip er id in o-p h en yl)-

k eton e (30q). To a solution of i-BuMgBr (805 mM) in toluene/

183-184 °C; [R]²⁰+2.1° (c 1, MeOH)); crystals were grown

D

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5239

from a solution in EtOH/water (3:1). A CD spectrum of a

complex of (S)-12o (1.24 mM/L in MeCN) with [Rh(OAc)₂]₂

showed a very high similarity to that of (S)-1-phenethylamine

with [Rh(OAc)₂]₂.²⁵

reaction was poured into a mixture of 2 N HCl and ice.

Concentrated ammonia (+ ice) was added, and extraction was

performed with Et₂O (3×). The organic extract was washed

with H₂O. Workup of the organic phase gave a crude residue

containingsdue to HPLC-analysiss(S,S′)-36o (peak 1, 23.6%)

and (R,S′)-36o (peak 2, 76.4%). Column chromatography with

(i) toluene/saturated with concentrated ammonia and (ii)

toluene/acetone/concentrated ammonia (10:1:0.01) gave (S,S′)-

Rou te G. (S)-3-Meth yl-1-(2-(1-p ip er id in yl)p h en yl)-bu -

tyla m in e (S)-(12q). (a ) N-Acetyl-N-[3-m eth yl-1-(2-(1-p i-

p er id in yl)p h en yl)-1-(Z)-bu ten -1-yl]-a m in e (Z)-(33). To a

solution of 16q (44 g, 180 mM) in toluene (440 mL) was

dropped acetanhydride (17 mL, 180 mM) at 0 °C. After the

mixture was stirred (3 h at 0 °C, 15 h at room temperature),

the reaction was evaporated in vacuo. The residue, dissolved

in EtOAc, was washed with aqueous Na₂CO₃. Workup of the

organic phase and purification by column chromatography

with toluene/EtOAc (5:1) gave (E)-33 (5.8%; mp 135-137 °C;

R_f0.47) and (Z)-33 (31 g, 34%; mp 139-141 °C; R_f0.40).

(b) N-Acetyl-N-[(S)-3-m eth yl-1-(2-(1-p ip er id in yl)p h en -

yl)-1-bu tyl]-a m in e (S)-(34). (Z)-(33) (0.57 g, 1.99 mM) was

dissolved in degassed MeOH/CH₂Cl₂(5:1) (10 mL) under argon.

The solution was added to a solution of the Noyori catalyst

Ru(OAc)₂[(S)-BINAP] (16.8 mg, 1 mol %) {prepared from [Ru-

(COD)Cl₂]_nwith (S)-2,2′-bis(diphenylphosphino)-1,1′-binaph-

thyl [(S)-BINAP], NEt₃, and NaOAc} and Ti(O-i-Pr)₄(3.4 mg,

0.5 mol %) in degassed MeOH/CH₂Cl₂(5:1) (10 mL) under

argon. The mixture was transferred to an evacuated (10^-2

mbar) autoclave. After repeated ventilation with hydrogen (4

bar), hydrogenation took place at 30 °C and 100 bar for 170 h

(end of H₂uptake). The reaction was evaporated in vacuo.

The residue was refluxed with n-hexane (30 mL). The hot

mixture was filtered, and the filtrate was cooled to give (S)-

34 (0.31 g, 54%; mp 127-131 °C; ee 82%). Further extraction

of the undissolved material with hot n-hexane gave r a c-34

(14%; mp 154-156 °C). For comparison, pure (S)-34 (mp 130-

36o (7.2%; oil; R_f0.60; [R]²⁰-53.5° (c 1, MeOH)) and (R,S′)-

D

36o (33.4%; oil; R_f0.47; de g 99%; [R]²⁰-35.5° (c 1, MeOH)).

D

(b) Hydrogenation of (R,S′)-36o (1.8 g, 5.3 mM; de g 99.0%)

in EtOH (20 mL) over Pd/C (10%) (0.5 g) for 5 h at 50 °C and

5 bar gave (R)-(12o) (1.1 g, 89%; oil; ee 79.8%). The surpris-

ingly low ee value (79.8%) can be probably referred to the use

of EtOH (instead of H₂O + 1.1 equiv HCl). A portion of the

base in Et₂O was transformed with HCl/Et₂O to (R)-(12o)‚

1.4HCl (mp 90-100 °C; [R]²⁰-20.0° (c 1, MeOH)).

D

R ou t e I. (R)-P h en yl-(2-(1-p ip er id in yl)p h en yl)-m et h -

yla m in e (R)-(12s) a n d (S)-P h en yl-(2-(1-p ip er id in yl)p h en -

yl)-m et h yla m in e (S)-(12s). (a ) N-[(R)-P h en yl-(2-(1-p i-

p er id in yl)p h en yl)-m et h yl]-N-[(S′)-p -t olu en e-su lfin yl]-

a m in e (R,S′)-(37) a n d N-[(S)-P h en yl-(2-(1-p ip er id in yl)-

p h en yl)-m eth yl]-N-[(S′)-p-tolu en e-su lfin yl]-a m in e (S,S′)-

(37). To a stirred solution of 12s (44.7 g, 167.8 mM) in dry

THF (400 mL) was dropped under N₂at -15 °C a solution of

n-BuLi (1.7 molar in n-hexane, 167.8 mM). After stirring for

5 min, a solution of (-)(S′)-[(1R,2S,5R)-menthyl]-p-toluene-

sulfinate (Aldrich, 24.7 g, 83.9 mM) was added dropwise at

-10 °C. The reaction mixture was stirred overnight at room

temperature and then evaporated in vacuo. The residue was

dissolved in water. Extraction with CH₂Cl₂, workup of the

organic phase, and repeated column chromatography with

cyclohexane/EtOAc (12:1) gave (S,S′)-37 (7.85 g, 23%; mp 97-

98 °C; R_f0.39; de 99.6%; [R]²⁰_D+166° (c 1, MeOH)) and (R,S′)-

132 °C; ee 99.4%; [R]²⁰+3.1° (c 1, MeOH)) was obtained by

D

reaction of (S)-12q with acetanhydride). Without Ti(O-i-

Pr)₄, no hydrogen uptake was observed over 96 h, but (Z)-33

(75%) was recovered.

37 (6.2 g, 18.3%; oil; R_f0.31; de g 98%; [R]²⁰+52° (c 1,

D

MeOH)), respectively.

(c) (S)-3-Meth yl-1-(2-(1-piper idin yl)ph en yl)-bu tylam in e

(S)-(12q). (S)-34 (ee 82%) was boiled in concentrated hydro-

chloric acid (10 mL/g) for 5.5 h to give (S)-12q (98%; oil; ee

82%).

Rou te H. (S)-3-Meth yl-1-(2-(1-p ip er id in yl)p h en yl)-bu -

tyla m in e (S)-(12q). (a ) [2-(1-P ip er id in yl)p h en yl]-N-[(R′)-

1-p h en eth yl]-a ld im in e (R′)-(35). 18a was dropped at +5

°C to (R′)-1-phenethylamine (1 equiv, ee g 98%, Fluka). After

stirring overnight at room temperature, ether was added. The

solution was dried over Na₂SO₄and evaporated in vacuo to

yield (R′)-35 (91.8%, crude; oil).

(b) (S)-P h en yl-(2-(1-p ip er id in yl)p h en yl)-m eth yla m in e

(S)-(12s). To a solution of (S,S′)-37 in dry MeOH (8 mL/mM)

was added TFA (4 equiv) at +5 °C. After the mixture was

stirred (1 h at 30 °C and 0.75 h at 40 °C), it was evaporated in

vacuo. The residue was dissolved in aqueous HCl. After

extraction with Et₂O (discarded), the aqueous phase was

alkalinized with 10 N NaOH under cooling and extracted with

CH₂Cl₂. The organic phase was worked up to yield (S)-12s

as a yellow oil (97%; [R]²⁰-60° (c 1; MeOH)). To determine

D

de, (S)-12s was reacted with (S)-1-phenethylisocyanate in

Et₂O. The resulting urea derivative (mp 191-192 °C; [R]²⁰

D

-8.4° (c 1, MeOH)) showed de ) 98.6%. To determine the

configuration, (-)-12s (1.6 mM) was reacted with 1-(rac-2-

phenyl-butanoyl)-imidazol (3.29 mM) in benzene (7.8 mL) for

18 h at room temperature. After dilution with benzene (30

mL), the reaction was extracted with 2 N NaOH (2 × 20 mL).

The alkaline aqueous phase was washed with benzene, acidi-

fied with 5 N HCl, and extracted with toluene. The toluene

phase was worked up to give recovered 2-phenyl-butanoic acid

(b) N-{(S)-3-Meth yl-1-[2-(1-p ip er id in yl)p h en yl]bu tyl}-

N-[(R′)-1-ph en eth yl]-am in e (S,R′)-(36q). A solution of crude

(R′)-35 (2 g, 6.84 mM) in dry THF (20 mL) was added to a

solution of i-BuMgBr (27.4 mM, 4 equiv) in dry THF (22 mL).

After each stirring period (18 h at 60 °C, 12 h at 80 °C),

i-BuMgBr/THF (2 equiv each) was added. Heating at 80 °C

was continued for further 60 h. After cooling to room tem-

perature, concentrated HCl was added and the mixture was

evaporated in vacuo. To the residue was given concentrated

ammonia, and extraction was performed with ether. Workup

of the organic extract and purification by column chromatog-

raphy with toluene/acetone (95:5) yielded (S,R′)-36q (0.2 g,

8.3%; oil; de 91.2%). Reaction of crude (R′)-35 with i-BuMgBr

(6 equiv) in toluene/THF (4:1) in the presence of Ti(O-i-Pr)₄

(0.05 equiv) for 60 h at 100 °C in a sealed glass vessel gave

(S,R′)-36q (5%; de 97.6%).

(c) (S)-3-Meth yl-1-(2-(1-piper idin yl)ph en yl)-bu tylam in e

(S)-(12q). (S,R′)-36q (de 91.2%) was hydrogenated in water

(+1.1 equiv HCl) over Pd/C (10%) (5 h, 50 °C, 5 bar) to yield

(S)-12q (63%; oil; ee 87.6%).

Com p ou n d s Obta in ed Accor d in g to Rou te H. (R)-1-

(2-(1-P ip er id in yl)p h en yl)-bu tyla m in e (R)-(12o). (a) To a

stirred and refluxed solution of aldimine (S′)-35 (50%; bp_0.02

155-157 °C; [R]²⁰_D-84.8° (c 1, MeOH)) in dry Et₂O was added

n-PrMgBr (2 equiv, in Et₂O); further n-PrMgBr (2 and 4 equiv)

was added after 0.5 and 4.5 h, respectively. After reflux

(overall 6 h) and standing overnight at room temperature, the

(0.67 mM; [R]²⁰-12.3° (c 4, benzene). According to the

D

literature²⁸teaching that a negative sign of the optical rotation

of the recovered acid correlates with (S), (-)-12s must be

considered as (S)-configurated.

(c) (R)-P h en yl-(2-(1-p ip er id in yl)p h en yl)-m eth yla m in e

(R)-(12s). (R,S′)-37 was cleaved as described above to give

(R)-12s as an oil (94%; [R]²⁰+52° (c 1, MeOH)). Reaction

D

with (S)-1-phenethylisocyanate in Et₂O afforded the corre-

sponding urea derivative (mp 198-200 °C; de 94.4%; [R]²⁰

D

-11.2° (c 1, MeOH)). Reaction with 1-(rac-2-phenyl-butanoyl)-

imidazol (2 equiv) led to recovered 2-phenyl-butanoic acid

(78%; [R]²⁰_D+6.6° (c 4, benzene)). According to the literature²⁸

(+)-12s must be considered as (R)-configurated.

Con figu r a tion a l Sta bility of (S)-Am in e (S)-12q a n d of

N-Acetyl-(R)-a m in e (R)-34. (a) (S)-12q (10 mM; containing

0.85% (R)-12q) was heated (i) with t-BuOK (1.5 mM) in DMSO

(4 mL) for 60 min at 90 °C or (ii) with p-TsOH‚H₂O (30 mM)

in water (12 mL) for 3 days at 100 °C in a sealed glass tube.

The recovery of (S)-12q was 85% (i) and 92% (ii), and the

5240 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

contents of (R)-12q were 0.88% (i) and 0.70% (ii), respectively.

Under conditions comparable to (i), (R)-1-phenethylamine was

reported to racemize completely.⁵¹

even to 0 °C), the precipitate was filtered, washed with H₂O,

and dried to yield the targeted acid 6. Mostly, enantiomeric

acids 6 were recrystallized to raise enantiomeric purity.

(b) (R)-34 (mp 125-130 °C; ee ) 65.2%) was heated: (i)

with solid NaOH (1% w/w) for 3 h at 160 °C; (ii) with solid

KOH (5% w/w) for 3 h at 210 °C; (iii) with glacial HOAc (5

parts) + Ac₂O (0.2 parts) for 3 h at 160 °C; (iv) with glacial

HOAc (10 parts) + NaOAc (1 equiv) for 3 h at 160 °C. (R)-34

was recovered by column chromatography with 50% (i, ii, iv)

and 67% (iii), respectively; ee was 59.0 ( 0.2% (each).

Gen er a l P r oced u r es A3-A7 for Ester s 14. Note: Enan-

tiomeric purity was determined by CSP-HPLC according to

the method described for (S)-14z.

A3. N,N′-Carbonyl-diimidazole (10.3 mM) was added at

room temperature to a stirred solution of educt 13 (10.3 mM)

in dry THF (14 mL). After refluxing for 1 h, a solution of

amine 12 (10.3 mM) in dry THF (7 mL) was added at room

temperature. After being stirred overnight at room temper-

ature, the reaction mixture was evaporated in vacuo. The

residue was purified by column chromatography on silica gel

with toluene/acetone (5:1) to afford the targeted ester 14.

A4. A mixture of educt 13 (11.9 mM), amine 12 (11.9 mM),

triphenylphosphin (14.3 mM), NEt₃(23.8 mM), and tetrachlo-

romethane (11.9 mM) in acetonitrile (29 mL) was stirred for

15 h at room temperature. After evaporation in vacuo, H₂O

and EtOAc were added to the residue for extraction. The

organic layer was dried, filtered, and evaporated in vaccuo.

The residue was purified by column chromatography on silica

gel with toluene/acetone (10:1) to afford ester 14.

A5. Phosphortrichloride (1.5 mol) was added to educt 13

(0.5 mol) at room temperature. After standing overnight at

room temperature, the reaction was heated for 30 min at 50

°C. The clear yellowish solution was decanted and evaporated

in vacuo at 50 °C to yield the corresponding phenylacetyl-

chloride (crude, 99%). A solution of the acid chloride (0.4 mol)

in CH₂Cl₂(490 mL) was dropped to a stirred solution of amine

12 (0.4 mol) and NEt₃(0.44 mol) in CH₂Cl₂(980 mL) at 20 °C

within 20 min. The reaction was extracted subsequently with

H₂O (3 × 500 mL), 10% aqueous HCl (2 × 500 mL), and H₂O

(3 × 500 mL). The organic phase was dried, filtered, and

evaporated in vacuo. The residue was crystallized from

toluene/petrolether and/or acetone to afford ester 14.

A6. To a dried and stirred solution of amine 12 (1 mM) in

toluene (30 mL) was added educt 13 (1.1 mM) at room

temperature. After the solution had become clear, N,N′-

dicyclohexyl-carbodiimide (1.16 mM) was added. After stirring

for 2 h at room temperature, the reaction was filtered, and

the filtrate was evaporated in vacuo. The residue was crystal-

lized from petrolether or toluene/petrolether; alternatively, it

was purified by column chromatography on silica gel with

petrolether/EtOAc (2:1) to afford ester 14.

B5. A solution of acid 6 (R₃) Cl) [or ester 14 (R₃) Cl)] in

EtOH (4 mL/mM) was hydrogenated over Pd/C (10%) (0.2

g/mM) for 3 h at 50 °C and 1 bar. The reaction was evaporated

in vacuo. H₂O and EtOAc were added; pH was adjusted to 6

with aqueous ammonia. The organic layer was separated,

washed with H₂O, dried, filtered, and evaporated in vacuo. The

residue was crystallized to afford the corresponding acid 6 (R₃

) H) [or ester 14 (R₃) H)].

Com p ou n d s Obta in ed Accor d in g to P r oced u r e A3.

Methyl 4-[2-[[1-[5-chloro-2-dimethylamino-phenyl]ethyl]amino]-

2-oxoethyl]-benzoate (14a ): 67%; mp 153-155 °C, from 12a .

Methyl 4-[2-[[1-[5-chloro-2-(1-pyrrolidinyl)phenyl]ethyl]amino]-

2-oxoethyl]-benzoate (14b): 58%; mp 132-135 °C, from 12b.

Methyl 4-[2-[[1-[5-chloro-2-(1-piperidinyl)phenyl]ethyl]amino]-

2-oxoethyl]-benzoate (14c): 69%; mp 146-148 °C, from 12c.

Methyl 4-[2-[[2-[5-chloro-2-(1-piperidinyl)phenyl]-2-propyl]-

amino]-2-oxoethyl]-benzoate (14d ): 84%; mp 229-234 °C,

from 12e. Methyl 4-[2-[[5-chloro-2-(1-piperidinyl)phenyl]-

methyl]amino]-2-oxoethyl]-benzoate (14e): 75%; mp 123-125

°C, from 12f. Ethyl 4-[2-[[1-[5-chloro-2-(2-methyl-1-piperidi-

nyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoate (14f): 71%; vis-

cous, from 12g. Methyl 4-[2-[[1-[5-chloro-2-(3-methyl-1-piperi-

dinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoate (14g): 54%;

mp 160-162 °C, from 12h . Methyl 4-[2-[[1-[5-chloro-2-(3,5

cis-dimethyl-1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-

benzoate (14i): 44%; mp 190-193 °C, from 12j. Methyl 4-[2-

[[1-[5-chloro-2-hexamethyleneimino-phenyl]ethyl]amino]-2-

oxoethyl]-benzoate (14j): 42%; mp 146-147 °C, from 12k .

Ethyl 4-[2-[[1-[2-hexamethyleneimino-phenyl]ethyl]amino]-2-

oxoethyl]-benzoate (14k ): 68%; mp 145-148 °C, from 12l.

Methyl

4-[2-[[1-[5-chloro-2-heptamethyleneimino-phenyl]-

ethyl]amino]-2-oxoethyl]-benzoate (14l): 30%; mp 152-156 °C,

from 12m . Methyl 4-[2-[[1-[5-chloro-2-octamethyleneimino-

phenyl]ethyl]amino]-2-oxoethyl]-benzoate (14m ): 38%; mp

184-185 °C, from 12n . Methyl 4-[2-[[1-[5-chloro-2-(1-piperidi-

nyl)phenyl]-2-methyl-propyl]amino]-2-oxoethyl]-benzoate

(14n ): 61%; mp 155-158 °C, from 12p .

Accor d in g to p r oced u r e A4 the following compounds

were obtained: Ethyl 4-[2-[[1-[2-(4-methyl-1-piperidinyl)phen-

yl]ethyl]amino]-2-oxoethyl]-benzoate (14h ): 56%; mp 125-

128 °C, from 12i. Ethyl 4-[2-[[3-methyl-1-[2-(1-piperidinyl)-

phenyl]butyl]amino]-2-oxoethyl]-benzoate (14o): 73%; mp 152-

155 °C, from 12q. Ethyl 4-[2-[[cyclohexyl-[2-(1-piperidinyl)-

phenyl]methyl]amino]-2-oxoethyl]-benzoate (14p ): 54%; mp

not determined, from 12r . Ethyl 4-[2-[[phenyl-[2-(1-piperidi-

nyl)phenyl]methyl]amino]-2-oxoethyl]-benzoate (14q): 74%;

mp 160-162 °C, from 12s. Ethyl 2-ethoxy-4-[2-[[1-[2-(1-

piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoate (14r ):

70%; mp 92-93 °C, from 12d . Ethyl 2-ethoxy-4-[2-[[1-[5-

chloro-2-(1-piperidinyl)phenyl]propyl]amino]-2-oxoethyl]-ben-

zoate (14s): 51%; mp 110-112 °C, from 12t. Methyl 2-meth-

oxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-

-benzoate (14u ): 66%; mp 128-131 °C, from 12o. Ethyl

2-ethoxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxo-

ethyl]-benzoate (14v): 81%; mp 110-115 °C, from 12o. Ethyl

2-ethoxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]pentyl]amino]-2-oxo-

ethyl]-benzoate (14w ): 64%; mp 113-115 °C, from 12u . Ethyl

2-ethoxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]-4-penten-1-yl]amino]-

2-oxoethyl]-benzoate (14x): 58%; mp 117-120 °C, from 12v.

Ethyl 2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]bu-

tyl]amino]-2-oxoethyl]-benzoate (14y): 85%; mp 143-145 °C,

from 12q. Ethyl 2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)-

phenyl]-3-buten-1-yl]amino]-2-oxoethyl]-benzoate (14z): 34%;

mp 126-128 °C, from 12w . Ethyl 2-ethoxy-4-[2-[[1-[2-(1-

piperidinyl)phenyl]hexyl]amino]-2-oxoethyl]-benzoate (14a a ),

43%; mp 100-105 °C, from 12x. Ethyl 2-ethoxy-4-[2-[[1-[2-

(1-piperidinyl)phenyl]heptyl]amino]-2-oxoethyl]-benzoate

(14a b): 80%; mp 100-104 °C, from 12y. Ethyl 2-ethoxy-4-

[2-[[phenyl-[2-(1-piperidinyl)phenyl]methyl]amino]-2-oxoethyl]-

benzoate (14a c): 77%; mp 149-151 °C, from 12s. Ethyl

2-ethoxy-4-[2-[[2-cyclopropyl-1-[2-(1-piperidinyl)phenyl]ethyl]-

A7. Analogous to general procedure A4, educt 13, ketimine

16, triphenylphosphin, NEt₃, and tetrachloromethane were

reacted to yield, after column chromatography, the enamido-

ester (E/Z)-17 [(E) predominant and more polar]. A mixture

of (E/Z)-17 or (E)-17 (11 mM) was hydrogenated over Pd/C

(10%) (1.2 g) in EtOH (45 mL) for 5 h at 20 °C and 5 bar to

yield ester 14.

Gen er a l P r oced u r es B3-B5 for Su bstitu ted Ben zoic

Acid s 6. Note: Enantiomeric purity was determined by CSP-

HPLC according to the method described for (S)-6a m .

B3. A solution of ester 14 (5 mM) in EtOH (23 mL) and

aqueous NaOH (8 mM/7 mL H₂O) was stirred for 2 h at 50

°C. The reaction was evaporated in vacuo (not completely),

poured into water, adjusted to pH 6 with 10% aqueous HCl,

and extracted with EtOAc (or CH₂Cl₂). The organic phase was

washed with H₂O, dried, filtered, and evaporated in vacuo. The

residue was crystallized to afford the targeted acid 6 (for

solvents used, see Tables 2 and 3).

B4. To a stirred warm (bath temperature 60 °C) solution

of ester 14 (370 mM) in EtOH (10 mL/g) was added 1 N NaOH

(480 mM; 1.3 equiv). After the mixture was stirred for 4 h at

60 °C, the heating bath was removed, and 1 N HCl (480 mM;

1.3 equiv) was added. After cooling to room temperature (or

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5241

amino]-2-oxoethyl]-benzoate (14a d ): 29%; mp 126-127 °C,

from 12z. Ethyl 2-ethoxy-4-[2-[[2-cyclobutyl-1-[2-(1-piperidi-

nyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoate (14a e): 14%; mp

116-118 °C, from 12a a . Ethyl 2-ethoxy-4-[2-[[2-cyclopentyl-

1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoate

(14a f): 37%; mp 120-121 °C, from 12a b. Ethyl 2-ethoxy-4-

[2-[[2-cyclohexyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxo-

ethyl]-benzoate (14a g): 68%; mp 94-97 °C, from 12a c. Ethyl

2-ethoxy-4-[2-[[2-cycloheptyl-1-[2-(1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoate (14a h ): 48%; mp 96-98 °C, from

12a d . Ethyl 2-ethoxy-4-[2-[[2-phenyl-1-[2-(1-piperidinyl)phen-

yl]ethyl]amino]-2-oxoethyl]-benzoate (14a i): 72%; mp 102-

105 °C, from 12a e. (R)(+)-Ethyl 4-[2-[[phenyl-[2-(1-piperidi-

nyl)phenyl]methyl]amino]-2-oxoethyl]-benzo-ate (R)-(14q): 71%;

mp 160-162 °C; ee 98.6%; [R]²⁰_D+2.6° (c 1, MeOH), from (R)-

12s. (S)(-)-Ethyl 4-[2-[[phenyl-[2-(1-piperidinyl)phenyl]m-

ethyl]amino]-2-oxoethyl]-benzoate (S)-(14q): 72%; mp 164-

Com p ou n d s Obta in ed Accor d in g to P r oced u r e B3.

Note: For melting points, look at Tables 2 and 3, respectively.

4-[2-[[1-[5-Chloro-2-dimethylamino-phenyl]ethyl]amino]-2-oxo-

ethyl]-benzoic acid (6a ): 88%, from 14a . 4-[2-[[1-[5-Chloro-

2-(1-pyrrolidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(6c): 81%, from 14b. 4-[2-[[1-[5-Chloro-2-(1-piperidinyl)phen-

yl]ethyl]amino]-2-oxoethyl]-benzoic acid (6d ): 85%, from 14c.

4-[2-[[2-[5-Chloro-2-(1-piperidinyl)phenyl]-2-propyl]amino]-2-

oxoethyl]-benzoic acid (6f): 83%, from 14d . 4-[2-[[[5-Chloro-

2-(1-piperidinyl)phenyl]methyl]amino]-2-oxoethyl]-benzoic acid

(6h ): 78%, from 14e. 4-[2-[[1-[5-Chloro-2-(2-methyl-1-piperi-

dinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid‚0.25H₂O

(6j): 64%, from 14f. 4-[2-[[1-[5-Chloro-2-(3-methyl-1-piperidi-

nyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid (6l): 69%,

from 14g. 4-[2-[[1-[2-(4-Methyl-1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoic acid (6n ): 67%, from 14h . 4-[2-

[[1-[5-Chloro-2-(3,5-cis-dimethyl-1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoic acid (6o): 82%, 14i. 4-[2-[[1-[5-

Chloro-2-hexamethyleneimino-phenyl]ethyl]amino]-2-oxo-

ethyl]-benzoic acid (6p ): 81%, from 14j. 4-[2-[[1-[2-Hexa-

methyleneimino-phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(6q): 68%, from 14k . 4-[2-[[1-[5-Chloro-2-heptamethylene-

imino-phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid (6r ): 44%,

from 14l. 4-[2-[[1-[5-Chloro-2-octamethyleneimino-phenyl]-

ethyl]amino]-2-oxoethyl]-benzoic acid (6s): 75%, from 14m .

4-[2-[[1-[2-Octamethyleneimino-phenyl]ethyl]amino]-2-oxo-

ethyl]-benzoic acid (6t): 80%, from 14a j. 4-[2-[[1-[2-(1-Pip-

eridinyl)phenyl]propyl]amino]-2-oxoethyl]-benzoic acid (6u ):

71%, from 14ak. 4-[2-[[1-[2-(1-Piperidinyl)phenyl]butyl]amino]-

2-oxoethyl]-benzoic acid (6v): 45%, from 14a l. 4-[2-[[1-[2-(1-

165 °C; eeg 99.0%; [R]²⁰-2.9° (c 1, MeOH), from (S)-12s.

D

(R)(-)-Ethyl 2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phen-

yl]butyl]amino]-2-oxoethyl]-benzoate (R)-(14y): 19%; mp

122-123 °C; ee g 99.6%; [R]²⁰-5.4° (c 1, MeOH), from (R)-

D

12q (ee e 95.2%). (S)(+)-Ethyl 2-ethoxy-4-[2-[[3-methyl-1-[2-

(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoate (S)-

(14y): 29%; mp 121-123 °C; ee 99.1%; [R]²⁰+7.8° (c 1,

D

MeOH), from (S)-12q (bp_0.196-97 °C). Ethyl 2-ethoxy-4-[2-

[[1-[5-chloro-2-(1-piperidinyl)phenyl]propyl]amino]-2-oxoethyl]-

benzoate (14a q): 80%; mp 110-112 °C, from 12e.

Com p ou n d s Obta in ed Accor d in g to P r oced u r e A5.

Ethyl 2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]bu-

tyl]amino]-2-oxoethyl]-benzoate (14y): 64%; mp 140-142 °C,

from 12q. (R)(-) Ethyl 4-[2-[[1-[2-(1-piperidinyl)phenyl]butyl]-

amino]-2-oxoethyl]-benzoate (R)-(14a l): 28%; mp 122-124 °C;

ee 98.7%; [R]²⁰_D-8.7° (c 1, MeOH), from (R)-12o. (S)(+) Ethyl

4-[2-[[1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-ben-

zoate (S)-(14a l): 58%; mp 124-125 °C; ee 95.4%; [R]²⁰_D+8.6°

(c 1, MeOH), from (S)-12o.

Piperidinyl)phenyl]pentyl]amino]-2-oxoethyl]-benzoic

acid

(6x): 70%, from 14am . 4-[2-[[1-[2-(1-Piperidinyl)phenyl]hexyl]-

amino]-2-oxoethyl]-benzoicacid (6z): 73%,from 14an . 2-Ethoxy-

4-[2-[[1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-

benzoic acid sodium salt‚1.5H₂O (6a e): 76%, from 14r . The

oily acid was transformed in EtOH with 1 N NaOH (1 equiv)

into the sodium salt. 2-Ethoxy-4-[2-[[1-[2-(1-piperidinyl)phen-

yl]butyl]amino]-2-oxoethyl]-benzoic acid (6a i): 69%, from

14v. 2-Ethoxy-4-[2-[[phenyl-[2-(1-piperidinyl)phenyl]methyl]-

amino]-2-oxoethyl]-benzoic acid (6a p ): 88%, from 14a c. (R)-

(+)-4-[2-[[Phenyl-[2-(1-piperidinyl)phenyl]methyl]amino]-2-

Com p ou n d s Obta in ed Accor d in g to P r oced u r e A6.

Ethyl 2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]-3-

buten-1-yl]amino]-2-oxoethyl]-benzoate (14z): 70%; mp 120-

124 °C, from 12w ‚glu ta r ic a cid . (R)(-)-Ethyl 2-ethoxy-4-[2-

[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-

oxoethyl]-benzoic acid (R)-(6a b): 79%; [R]²⁰+5.8° (c 1.04,

benzoate (R)-(14y): 69%; mp 120-123 °C; ee g 99.6%; [R]²⁰

D

MeOH), from (R)-14q (ee 98.6%). (S)(-)-4-[2-[[Phenyl-[2-

-9.9° (c 1, MeOH), from (R)-29 (ee 95.1%). (S)(+)-Ethyl

2-ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-

2-oxoethyl]-benzoate (S)-(14y): 59%; mp 122-123 °C; ee g

(1-piperidinyl)phenyl]methyl]amino]-2-oxoethyl]-benzoic acid

(S)-(6a b): 87%; [R]²⁰-6.3° (c 1, MeOH), from (S)-14q (ee g

D

99.8%; [R]²⁰+9.3° (c 1, MeOH), from (S,S′)-28 (ee 98.0%).

99.0%). 4-[2-[[1-[5-Chloro-2-(1-piperidinyl)phenyl]-2-methyl-

propyl]amino]-2-oxoethyl]-benzoic acid (6a w ): 82%; mp 235-

240 °C, from 14n .

D

Com p ou n d s Obta in ed Accor d in g to P r oced u r e A7.

Ethyl 4-[2-[[1-[2-octamethyleneimino-phenyl]ethyl]amino]-2-

oxoethyl]-benzoate (14a j): 38%; mp 170-173 °C via ethyl

4-[2-[[1-[2-octamethyleneimino-phenyl]-1-ethenyl]amino]-2-oxo-

ethyl]-benzoate (17a ), 33%; mp 114-116 °C. Ethyl 4-[2-[[1-

[2-(1-piperidinyl)phenyl]-1-propyl]amino]-2-oxoethyl]-ben-

zoate (14a k ): 71%; mp 132-134 °C via ethyl 4-[2-[[1-[2-(1-

piperidinyl)phenyl]-1-(E)-propenyl]amino]-2-oxoethyl]-ben-

zoate (17b), 56%; mp 82-84 °C. Ethyl 4-[2-[[1-[2-(1-piperi-

dinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoate (14a l): 52%;

mp 126-128 °C via ethyl 4-[2-[[1-[2-(1-piperidinyl)phenyl]-1-

(E)-butenyl]amino]-2-oxoethyl]-benzoate (17c), 35%; mp 115-

117 °C. Ethyl 4-[2-[[1-[2-(1-piperidinyl)phenyl]pentyl]amino]-

2-oxoethyl]-benzoate (14a m ): 45%; mp 115-120 °C via ethyl

4-[2-[[1-[2-(1-piperidinyl)phenyl]-1-(E)-pentenyl]amino]-2-oxo-

ethyl]-benzoate (17d ), 16%; mp 90-97 °C. Ethyl 4-[2-[[1-[2-

(1-piper idin yl)ph en yl]h exyl]a m in o]-2-oxoet h yl]-ben zoa t e

(14a n ): 50%; mp 105-110 °C via ethyl 4-[2-[[1-[2-(1-piperid-

inyl)phenyl]-1-(E)-hexenyl]amino]-2-oxoethyl]-benzoate (17e),

27%; mp 80-85 °C. Ethyl 4-[2-[[2-phenyl-1-[2-(1-piperidinyl)-

phenyl]ethyl]amino]-2-oxoethyl]-benzoate (14a o): 88%; mp

161-162 °C via ethyl 4-[2-[[2-phenyl-1-[2-(1-piperidinyl)-

phenyl]-1-(E)-ethenyl]amino]-2-oxoethyl]-benzoate (17f), 47%;

mp 157-159 °C. Ethyl 4-[2-[[3-phenyl-1-[2-(1-piperidinyl)-

phenyl]propyl]amino]-2-oxoethyl]-benzoate (14a p ): 57%; mp

118-119 °C via ethyl 4-[2-[[3-phenyl-1-[2-(1-piperidinyl)-

phenyl]-1-(E)-propenyl]amino]-2-oxoethyl]-benzoate (17g), 62%;

viscous.

Com p ou n d s Obta in ed Accor d in g to P r oced u r e B4.

Note: For melting points, look at Tables 2 and 3, respectively.

4-[2-[[3-Methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxo-

ethyl]-benzoic acid (6y): 85%, from 14y. 4-[2-[[Cyclohexyl-[2-

(1-piperidinyl)phenyl]methyl]amino]-2-oxoethyl]-benzoic acid

(6a a ): 58%, from 14p . 4-[2-[[Phenyl-[2-(1-piperidinyl)phenyl]-

methyl]amino]-2-oxoethyl]-benzoic acid (6a b): 64%, from 14q.

4-[2-[[2-Phenyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxo-

ethyl]-benzoic acid (6a c): 68%, from 14a o. 4-[2-[[3-Phenyl-

1-[2-(1-piperidinyl)phenyl]propyl]amino]-2-oxoethyl]-benzoic acid

(6a d ): 68%, from 14a p . 2-Ethoxy-4-[2-[[1-[2-(1-piperidinyl)-

phenyl]propyl]amino]-2-oxoethyl]-benzoic acid (6af): 73%, from

14t. 2-Methoxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]butyl]amino]-

2-oxoethyl]-benzoic acid (6a h ): 86%, from 14u . 2-Ethoxy-4-

[2-[[1-[2-(1-piperidinyl)phenyl]pentyl]amino]-2-oxoethyl]-ben-

zoic acid (6a j): 91%, from 14w . 2-Ethoxy-4-[2-[[1-[2-(1-

piperidinyl)phenyl]-4-penten-yl]amino]-2-oxoethyl]-benzoic acid

(6a k ): 61%, from 14x. 2-Ethoxy-4-[2-[[3-methyl-1-[2-(1-pi-

peridinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoic acid (6a l):

88%, from 14y. 2-Ethoxy-4-[2-[[3-methyl-1-[2-(1-piperidinyl)-

phenyl]-3-buten-yl]amino]-2-oxoethyl]-benzoic acid (6am ): 74%,

from 14z. 2-Ethoxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]hexyl]-

amino]-2-oxoethyl]-benzoic acid (6a n ): 77%, from 14a a .

2-Ethoxy-4-[2-[[1-[2-(1-piperidinyl)phenyl]heptyl]amino]-2-oxo-

ethyl]-benzoic acid (6a o): 88%, from 14a b. 2-Ethoxy-4-[2-[[2-

cyclopropyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-

5242 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

benzoic acid (6a q ): 88%, from 14a d . 2-Ethoxy-4-[2-[[2-

cyclobutyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-

benzoic acid (6a r ): 33%, from 14a e. 2-Ethoxy-4-[2-[[2-cy-

clopentyl-1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-ben-

zoic acid (6a s): 75%, from 14a f. 2-Ethoxy-4-[2-[[2-cyclohexyl-

1-[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic

acid (6a t): 82%, from 14a g. 2-Ethoxy-4-[2-[[2-cycloheptyl-1-

[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(6a u ): 83%, from 14a h . 2-Ethoxy-4-[2-[[2-phenyl-1-[2-(1-

10 µm; L ) 10 mm; l ) 250 mm; n-hexane/i-PrOH (90:10); 2.5

mL/min; 1.4 bar; 1 mL injections (a` ∼ 25 mg); peak 1 (4.9 min),

(R)-14z; peak 2 (6.3 min), (S)-14z; ee ) 100% each as proven

with an analytical column. Crude (S)-14z (440 mg) was

dissolved in petrolether (4.4 mL) + toluene (0.4 mL) by heating

on a steam bath. After cooling to 0 °C, the precipitate was

filtered and dried (45 °C/1 Torr) to yield (S)-14z (355 mg; mp

56-60 °C and 90-92 °C; ee 100%; [R]²⁰+18.5° (c 1.55,

D

MeOH).

piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic

acid

(b) (S)(+)-2-Eth oxy-4-[2-[[3-m eth yl-1-[2-(1-p ip er id in yl)-

p h en yl]-4-bu ten -yl]a m in o]-2-oxoeth yl]-ben zoic Acid (S)-

(6a m ). A solution of (S)-14z (320 mg, 0.6686 mM) in EtOH

(3 mL) was stirred in a bath of 60 °C. 1 N NaOH (0.85 mL,

0.85 mM) was added. After 4 h at 60 °C, 1 N HCl (0.85 mL)

was added, and the heating was removed. To initiate crystal-

lization of the viscous precipitate, H₂O (7 × 0.1 mL) was added.

After further addition of H₂O (0.8 mL) and standing overnight

at room temperature, the precipitate was filtered, washed with

H₂O, and dried (55 °C/1 Torr) to yield (S)-6a m (240 mg, 79.8%;

(6a v): 90%, from 14a i. (R)(-)-4-[2-[[1-[2-(1-Piperidinyl)-

phenyl]butyl]amino]-2-oxoethyl]-benzoic acid (R)-(6v): 74%;

ee 99.7%; [R]²⁰-7.1° (c 1, MeOH), from (R)-14a l. (S)(+)-4-

D

[2-[[1-[2-(1-Piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-ben-

zoic acid (S)-(6v): 46%; ee g 99.2%; [R]²⁰+7.7° (c 1.04;

D

MeOH), from (S)-14a l. (R)(-)-2-Ethoxy-4-[2-[[3-methyl-1-[2-

(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoic acid (R)-

(6a l): 92%; ee g 99.7%; [R]²⁰_D-7.9° (c 1.04, MeOH), from (R)-

14y (ee g 99.6%). (S)(+)-2-Ethoxy-4-[2-[[3-methyl-1-[2-(1-

piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoic acid (S)-

(6a l): 92%; ee g 99.8%; [R]²⁰_D+7.4° (c 1.07, MeOH), from (S)-

14y (ee g 99.8%).

mp 90-95 °C; ee g 99.9%; [R]²⁰+17.1° (c 1.05, MeOH). The

D

enantiomeric purity was examined on a Chiral AGP column

[5 µm; L ) 4 mm; l ) 100 mm; acetonitrile/buffer of sodium

phosphate pH 5.1 (30:70); 0.5 mL/min; 5.8 bar; temperature:

20 °C; UV detection at 240 nm; peak 3.2 min (S), peak 5.4

min (R)].

Com p ou n d s Obta in ed Accor d in g to P r oced u r e B5.

Note: For melting points, look at Tables 2 and 3, respectively.

4-[2-[[1-[2-Dimethylamino-phenyl]ethyl]amino]-2-oxoethyl]-

benzoic acid (6b): 53%, from 6a . 4-[2-[[1-[2-(1-Piperidinyl)-

phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid (6e): 67%, from

6d . 4-[2-[[2-[2-(1-Piperidinyl)phenyl]-2-propyl]amino]-2-oxo-

ethyl]-benzoic acid (6g): 68%, from 6f. 4-[2-[[[2-(1-Piperidi-

nyl)phenyl]methyl]amino]-2-oxoethyl]-benzoic acid (6i): 60%,

from 6h . 4-[2-[[1-[2-(2-Methyl-1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoic acid (6k ): 90%, from 6j. 4-[2-[[1-

[2-(3-Methyl-1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-

benzoic acid (6m ): 86%, from 6l. 4-[2-[[2-Methyl-1-[2-(1-pi-

Com p ou n d s of Ta bles 5-10. For melting points, look at

the respective table. 4-(2-(3-Chloro-benzoylamino)-ethyl)-ben-

zoic acid (39), 61%, from methyl 4-(2-(3-chloro-benzoylamino)-

ethyl)-benzoate, 43%; mp 94 °C. N-[5-Chloro-2-octameth-

yleneimino-benzoyl]-N-[2-phenyl-ethyl]-amine (40), 69%, from

the imidazolide of 9l and 2-phenethylamine. 4-[2-[[1-[5-Chloro-

2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-benzoic acid

(41), 82%, from ethyl 4-[2-[[1-[5-chloro-2-(1-piperidinyl)phenyl]-

butyl]amino]-2-oxoethyl]-benzoate, 40%; mp 135-140 °C. 4-[2-

[[1-(Phenyl)butyl]amino]-2-oxoethyl]-benzoic acid (42), 87%,

from ethyl 4-[2-[[1-(phenyl)butyl]amino]-2-oxoethyl]-benzoate,

70%; mp 105-108 °C [obtained from R-propyl-benzylamine

with 13b]. N-[Phenyl-acetyl]-N-[1-[2-(1-piperidinyl)phenyl]-

butyl]-amine (43), 80%, from 12o with phenylacetic acid. 4-[2-

[[1-[3-(1-Piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(44), 33%, from ethyl 4-[2-[[1-[3-(1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoate, 24%; mp 163-164 °C [obtained

from crude 1-(3-piperidino-phenyl)ethylamine with 13b]. 4-[2-

[[1-[4-(1-Piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(45), 51%, from ethyl 4-[2-[[1-[4-(1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoate, 39%; mp 118-120 °C [obtained

from crude 1-(4-piperidino-phenyl)ethylamine with 13b]. 3-[2-

[[1-[2-(1-Piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(46), 86%, from ethyl 3-[2-[[1-[2-(1-piperidinyl)phenyl]ethyl]-

amino]-2-oxoethyl]-benzoate, 47%; mp 155 °C [obtained from

12d with crude (3-ethoxycarbonyl-phenyl)-acetic acid]. 2-[2-

[[1-[2-(1-Piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoic acid

(47)‚0.3H₂O, 7%, from methyl 2-[2-[[1-[2-(1-piperidinyl)phenyl]-

ethyl]amino]-2-oxoethyl]-benzoate‚0.2H₂O, 82%; mp 107-108

°C [obtained from 12d with (2-methoxycarbonyl-phenyl)-acetic

acid, mp 145-147 °C].

N-[1-[2-(1-P ip er id in yl)p h en yl]eth yl]-N-[4-(1H-tetr a zol-

5-yl)-p h en yl-a cetyl]-a m in e (48)‚0.5H₂O. (a) The imida-

zolide of 6e in dry pyridine was reacted with excessive liquid

ammonia to give 4-[2-[[1-[2-(1-piperidinyl)phenyl]ethyl]amino]-

2-oxoethyl]-benzamide, 74%; mp 197-199 °C. (b) The above

benzamide (6 mM) in pyridine (13.5 mM) was reacted with

p-toluene-sulfonylchloride (6 mM) for 0.25 h at room temper-

ature and 1.5 h at 50 °C to give, after workup and purification

by column chromatography with CHCl₃/MeOH (4:1), 4-[2-[[1-

[2-(1-piperidinyl)phenyl]ethyl]amino]-2-oxoethyl]-benzoni-

trile, 55%; mp 155-157 °C. (c) A mixture of the above

benzonitrile (0.5 g, 1.44 mM), NaN₃(0.124 g, 1.9 mM), and

glacial acetic acid (0.191 mL, 3.34 mM) in n-BuOH (6 mL) was

refluxed for 91 h. H₂O was added, and the mixture was (not

completely) evaporated in vacuo. EtOAc was added, and the

organic phase was extracted several times with 10% aqueous

NaOH. The aqueous phase was extracted with Et₂O (dis-

peridinyl)phenyl]propyl]amino]-2-oxoethyl]-benzoic

acid

(6w ): 68%, from 6a w . Ethyl 2-ethoxy-4-[2-[[1-[2-(1-piperi-

dinyl)phenyl]propyl]amino]-2-oxoethyl]-benzoate (14t): 74%;

mp 115-117 °C, from 14a q.

Sp ecia l P r oced u r es. 2-Hyd r oxy-4-[2-[[1-[2-(1-p ip er id i-

n yl)p h en yl]bu tyl]a m in o]-2-oxoeth yl]-ben zoic a cid (6a g).

BBr₃(2.5 mM) was added slowly to a solution of 6ai (2.2 mM)

in 1,2-dichloro-ethylene (20 mL) at -30 °C. The cooling bath

was removed, stirring was continued for 2 h at room temper-

ature, and EtOH/H₂O (1:1) (15 mL) was dropped in cautiously.

The reaction was evaporated in vacuo. H₂O and CHCl₃were

added to the residue. The organic layer was washed with

water, dried, filtered, and evaporated in vacuo. The residue

was purified by column chromatography on silica gel with

CHCl₃/MeOH (10:1) to yield 6a g (20%; mp 136-138 °C).

(R)(-)-Eth yl 2-Eth oxy-4-[2-[[3-m eth yl-1-[2-(1-p ip er id i-

n yl)p h en yl]bu tyl]a m in o]-2-oxoeth yl]-ben zoa te (R)-(14y)

a n d (S)(+)-Eth yl 2-Eth oxy-4-[2-[[3-m eth yl-1-[2-(1-p ip er i-

din yl)ph en yl]bu tyl]am in o]-2-oxoeth yl]-ben zoate (S)-(14y).

14y (920 mg) was injected in 10 mg doses to a semipreparative

CSP-HPLC Baker column; chiral phase: (S)-N-3,5-dinitro-

benzoyl-leucine covalently bound to aminopropyl silica gel;

particle size: 40 µm; L ) 20 mm; l ) 250 mm; n-hexane/THF/

EtOH/CH₂Cl₂(180:20:3:2); 21.25 mL/min; temperature: 27 °C;

UV detection at 285 nm. (R)-14y was eluted first, thereafter

(S)-14y was eluted. The fractions containing peak 1 (crude,

423 mg) and peak 2 (crude, 325 mg) were purified by column

chromatography on silica gel with toluene/acetone (10:1) to

yield (R)-14y (234.5 mg, 51%; mp 122-124 °C; [R]²⁰-8.3° (c

D

1, MeOH) and (S)-14y (131.2 mg, 28.5%; mp 122-124 °C;

[R]²⁰+8.3° (c 1, MeOH). The separation can be performed

D

also on a Chiralcel OD column (Daicel) with EtOH/n-hexane

+ 0.2% diethylamine (5:95) at 40 °C and UV detection at 245

nm; peak 1: (R)-14y; peak 2: (S)-14y.

(S)(+)-2-E t h oxy-4-[2-[[3-m et h yl-1-[2-(1-p ip er id in yl)-

p h en yl]-4-bu ten -yl]a m in o]-2-oxoeth yl]-ben zoic Acid (S)-

(6a m ). (a ) (S)(+)-Eth yl 2-Eth oxy-4-[2-[[3-m eth yl-1-[2-(1-

p ip er id in yl)p h en yl]-3-b u t en -1-yl] a m in o]-2-oxoet h yl]-

ben zoa te (S)-(14z). Semipreparative CSP-HPLC of 14z was

performed on a Chiralcel OD column (Daicel); particle size:

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5243

carded), acidified with semiconcentrated HCl (ad pH 5.7), and

extracted with EtOAc to give, after workup of the organic

phase, 48‚0.5H₂O (0.055 g, 9.8%; mp 172-175 °C).

4-[2-[[1-[2-(1-P ip er id in yl)p h en yl]et h yl]a m in o]-2-oxo-

eth yl]-ben zen e-su lfon a m id e (49), 15%, was obtained from

12d with 4-(carboxy-methyl)-benzene-sulfonamide (mp 176-

180 °C; lit.⁵²mp 176-178 °C) and purification by column

chromatography with toluene/acetone (2:1).

N¹-{Cycloh exyl}-N³-{4-[[2-[[1-[2-(1-p ip er id in yl)p h en yl]-

eth yl]am in o]-2-oxoeth yl]-ph en yl]-su lfon yl}-u r ea (50), 55%,

was obtained from the sodium salt of 49 (3.5 mM) in dry DMF

(15 mL) with cyclohexyl-isocyanate (3.7 mM) at 5 °C, stirring

overnight at 5 °C, addition of H₂O (150 mL) and of 1 N HCl

(3.5 mL), extraction with CHCl₃, washing of the organic extract

with H₂O, workup of the organic phase, and crystallization

from hot acteone (+ some charcoal).

4-[2-[[2-[2-(1-P ip er id in yl)p h en yl]p r op a n oyl]a m in o]-

m eth yl]-ben zoic Acid (51). (a) 2-(2-Chloro-phenyl)-pro-

panoic acid (mp 88 °C) in concentrated H₂SO₄was nitrated

at -25 to -15 °C with a mixture (1:2) of fuming HNO₃/

concentrated H₂SO₄to give 2-(2-chloro-5-nitro-phenyl)-pro-

panoic acid (94%; mp 129-131 °C). (b) The aforementioned

compound was refluxed with excessive piperidine for 72 h to

give 2-(5-nitro-2-piperidino-phenyl)-propanoic acid (94%; mp

135-138 °C). (c) Hydrogenation of the preceding compound

(b) in DMF over Pd/C (10%) for 2 h at room temperature and

5 bar gave 2-(5-amino-2-piperidino-phenyl)-propanoic acid

(56%; mp 223 °C). (d) Diazotation of the preceding amino

compound and subsequent Sandmeyer reaction with Cu₂Cl₂

gave 2-(5-chloro-2-piperidino-phenyl)-propanoic acid (51%; mp

130-132 °C). (e) The preceding acid (d) was reacted, according

to procedure A4, with ethyl 4-(aminomethyl)-benzoate‚HCl (mp

247-249 °C; lit.⁵³mp 250-251 °C) to give ethyl 4-[2-[[2-[5-

chloro-2-(1-piperidinyl)phenyl]propa noyl]a mino]methyl]-

benzoate, 70%; viscous. (f) The preceding ester was hydrolyzed

with NaOH in EtOH to give 4-[2-[[2-[5-chloro-2-(1-piperidinyl)-

phenyl]propanoyl]amino]methyl]benzoic acid, 74%; mp 168-

170 °C. (g) The preceding chloro compound was hydrogenated

over Pd/C (10%) in MeOH to give 51, 47%; mp 125 °C.

4-[2-[[1-[2-(1-Cycloh exen -1-yl)p h en yl]bu tyl]a m in o]-2-

oxoeth yl]-ben zoic Acid (54). (a) 1-(2-(1-Cyclohexen-1-yl)-

phenyl)-butylamine, 62%, oil was synthesized from 2-(1-

cyclohexen-1-yl)-benzonitrile⁵⁴according to route A. (b) Ethyl

4-[2-[[1-[2-(1-Cyclohexen-1-yl)phenyl]butyl]amino]-2-oxoethyl]-

benzoate, 71%, mp 125-128 °C, was synthesized from the

above amine with 13b according to procedure A4. (c) Hydroly-

sis of the above ester according to procedure B4 gave 54, 94%;

mp 206-210 °C.

4-[2-[[1-[2-(P h en yl)-p h en yl]bu tyl]a m in o]-2-oxoeth yl]-

ben zoic a cid (55), 95%, mp 217-220 °C, was synthesized,

analogously to 54, from 2-cyano-biphenyl⁵⁵via 1-[biphenyl-2-

yl)butyl-amine, 70%; oil, and ethyl 4-[2-[[1-[2-(phenyl)-phenyl]-

butyl]amino]-2-oxoethyl]-benzoate, 77%; mp 137-139 °C.

4-[2-[[1-[2-Meth oxy-p h en yl]bu tyl]a m in o]-2-oxoeth yl]-

ben zoic Acid (56). (a) To AlCl₃(112 g, 0.84 mol) in CH₂Cl₂

(112 mL) was added dropwise at -10 °C a solution of 4-chloro-

anisol (110 g, 0.70 mol) and butanoylchloride (72.7 mL, 0.70

mol). The reaction was stirred for 0.5 h at -10 °C, 2 h at 0

°C, and 2 h at room temperature. The reaction was poured

into ice-water (1.5 L). Extraction was performed with Et₂O.

The organic layer was washed with aqueous Na₂CO₃to give,

after workup and distillation, 1-(5-chloro-2-methoxy-phenyl)-

1-oxo-butane, 43%; bp_0.198-105 °C. (b) The preceding ketone

(10 g, 47 mM) in EtOH (50 mL) was reacted with H₂NOH‚

HCl (9.8 g, 141 mM) in H₂O (25 mL) and NaOH (16.9 g, 423

mM) in H₂O for 1 h at 60 °C. The reaction was poured into

ice-water and was extracted with Et₂O. Workup of the

organic phase gave 1-(5-chloro-2-methoxy-phenyl)-1-oximino-

butane, 9.6 g, 90%; mp 136-138 °C. (c) The preceding oxime

(9.5 g, 41.7 mM) in EtOH (150 mL) and NEt₃(12 mL, 86 mM)

was hydrogenated over Pd/C (10%) (1.5 g) for 12 h at 50 °C

and 3.5 bar to give, after workup and purification by column

chromatography with CHCl₃/MeOH/concentrated ammonia

(20:1:0.01), 1-(2-methoxy-phenyl)-1-butylamine, 3.1 g, 41%; oil.

(d) The preceding amine was reacted with 13b according to

procedure A4 to give ethyl 4-[2-[[1-[2-methoxy-phenyl]butyl]-

amino]-2-oxoethyl]-benzoate, 79%; mp 111-113 °C. (e) Hy-

drolysis of the above ester according to procedure B4 gave 56,

87%; mp 201-203 °C.

4-{[[[1-[2-(1-P ip er id in yl)p h en yl]eth yl]a m in o]su lfon yl]-

m eth yl}-ben zoic Acid (52). (a) A hot solution of Na₂S‚5H₂O

(26 g, 110 mM) and sulfur (3.4 g, 110 mM) in H₂O (40 mL)

was added to a solution of crude (85%) ethyl 4-bromomethyl-

benzoate (50 g, 175 mM) in EtOH (250 mL). The reaction was

refluxed for 1 h, then evaporated in vacuo. H₂O was added to

the residue, and extraction was performed with Et₂O. Workup

of the organic layer gave crude bis(4-ethoxycarbonyl-benzyl)-

disulfide (26 g, 76%; oil). (b) Cl₂was introduced at 0-10 °C

into a mixture of the above crude disulfide (12 g, 30.8 mM) in

glacial acetic acid (150 mL) and H₂O (40 mL). After a solid

began to precipitate, introduction was continued for 15 min.

The reaction was added to ice-water (500 mL) while excessive

Cl₂escaped. The resulted precipitate of (4-ethoxycarbonyl-

phenyl)methane-sulfonylchloride was filtered, washed with

H₂O, and dissolved in CH₂Cl₂. The organic solution was dried,

filtered, and adjusted to a volume of 70 mL (containing 61.5

mM of the crude sulfochloride). (c) The preceding solution of

the crude sulfochloride (29 mL, 24.8 mM) was dropped to a

solution of 12d (4.5 g, 22 mM) and NEt₃(10 mL, 71.7 mM) in

CH₂Cl₂(100 mL). After stirring for 2 h at room temperature,

the reaction was evaporated in vacuo. Hydrochloric acid was

added (ad pH 3-4), and extraction was performed with Et₂O.

Workup of the organic extract, purification by column chro-

matography with toluene/EtOAc (10:1), and crystallization

from cyclohexane gave ethyl 4-{[[[1-[2-(1-piperidinyl)phenyl]-

ethyl]amino]sulfonyl]methyl}-benzoate (3.5 g, 37%; mp 119-

120 °C). (d) The preceding ester (3 g, 7 mM) was hydrolyzed

in EtOH with 1 N NaOH at 60 °C to give 52 (2.8, 100%; mp

222-225 °C).

4-[2-[[1-[2-(1-P iper idin yl)ph en yl]bu tyl]-N-m eth ylam in o]-

2-oxoeth yl]-ben zoic Acid (57). (a) A mixture of 12o (55 g,

237 mM) and ethyl formiate (190 mL, 2370 mM) was refluxed

for 24 h. The reaction was evaporated in vacuo. The residue

was crystallized from petrolether to give N-formyl-1-(2-pip-

eridino-phenyl)-butylamine, 50 g, 81%; mp 71-73 °C. (b) To

LiAlH₄(1.44 g, 38.4 mM) in dry THF (40 mL) was added at

room temperature under N₂a solution of the above amide (5

g, 19.2 mM) in THF (80 mL). The reaction was stirred for 2

h at 100 °C. The reaction was completed after further addition

of LiAlH₄(0.72 g, and 0.36 g) and heating at 100 °C for further

3 and 2 h, respectively. After standing overnight at room

temperature, the reaction was stirred vigorously and, cau-

tiously, H₂O (2.5 mL), 15% aqueous NaOH (2.5 mL), and H₂O

(4.8 mL) were added. After stirring for 1 h at room temper-

ature, the mixture was filtered through a layer of kieselguhr

which was washed with THF. The filtrate was evaporated in

vacuo to give, after purification by column chromatography

with toluene/EtOAc/concentrated ammonia (4:2:0.01) N-meth-

yl-1-(2-piperidino-phenyl)-butylamine, 4 g, 85%; oil. (c) The

preceding amine was acylated with 13b according to procedure

A4 to give ethyl 4-[2-[[1-[2-(1-piperidinyl) phenyl]butyl]-N-

methylamino]-2-oxoethyl]-benzoate, 79%; oil; ‚HCl: mp 172-

182 °C. (d) Hydrolysis of the above ester according to

procedure B4 gave 57, 88%; mp 157-160 °C.

4-[2-[[1-[2-(1-P ip er id in yl)p h en yl]bu tyl]a m in o]-2-th io-

n oeth yl]-ben zoic Acid (58). (a) A mixture of 14a l (7 g, 16.5

mM) and Lawesson’s reagent (2,4-bis-(4-methoxyphenyl)-1,3-

dithia-2,4-diphosphetan-2,4-disulfide) (4 g, 9.9 mM) in dry

toluene (42 mL) was refluxed for 4 h at 120 °C to give, after

workup and purification by column chromatography (CHCl₃),

ethyl 4-[2-[[1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-thiono-

4-[2-[[1-[2-(Cycloh exyl)-p h en yl]b u t yl]a m in o]-2-oxo-

eth yl]-ben zoic a cid (53), 75%, mp 208-211 °C was synthe-

sized from 54 by hydrogenation in EtOH over Pd/C (10%) at

50 °C and 1 bar.

5244 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Grell et al.

ethyl]-benzoate, 3.2 g, 44%; mp 75-77 °C. (b) Hydrolysis of

the above ester according to procedure B4 gave 58, 76%; mp

80-87 °C.

4-[4-[2-(1-piperidinyl)phenyl]-2,2-ethylenedioy-heptyl]-benzo-

ic acid, 2.9 g, 33%; viscous oil. (g) To a solution of the above

ketal (2.3 g, 5.2 mM) in dioxane (12 mL) was added 2 N HClO₄

(12 mL, 240 mM). The reaction was stirred for 40 min at 80

°C; thereafter, the dioxane was evaporated in vacuo. H₂O (50

mL) was added, and the resultant viscous precipitate was

extracted with CHCl₃. The organic phase was washed with

H₂O, dried, and evaporated in vacuo to give 60‚HClO₄(mp

50-60 °C, dec 70-80 °C; from cyclohexane). Intensive shaking

of this salt with Et₂O/saturated aqueous NaHCO₃/saturated

aqueous NaCl, workup of the organic phase, and crystallization

from acetone/petrolether (1:30) gave the betaine 60, 0.9 g, 44%;

mp 88-92 °C.

4-[2-[[1-[2-(1-P ip er id in yl)p h en yl]bu tyl]a m in o]-eth yl]-

ben zoic Acid (59). (a) The above ethyl 4-[2-[[1-[2-(1-piperidi-

nyl)phenyl]butyl]amino]-2-thionoethyl]-benzoate (0.8 g, 1.82

mM) in dry dioxane (30 mL) was treated with Raney-Ni (4 g)

for 0.5 h at room temperature to give, after workup and

purification by column chromatography (CHCl₃/MeOH/con-

centrated ammonia (20:1:0.1) ethyl 4-[2-[[1-[2-(1-piperidinyl)-

phenyl]butyl]amino]-ethyl]-benzoate, 0.7 g, 94%; oil. (b) Hy-

drolysis of the above ester according to procedure B4 gave 59,

72%; mp 236-242 °C.

4-[4-[2-(1-P iper idin yl)ph en yl]-h eptyl]-ben zoic Acid (61).

(a) To a solution of 60 (0.23 g, 0.58 mM) in ethane-1,2-dithiol

(0.26 mL, 3.1 mM) was added BF₃‚Et₂O (0.5 mL). After

stirring for 3 days at room temperature, MeOH (1 mL) was

added, and the reaction was heated in an open flask for 0.75

h at 70 °C to evaporate the solvent. Further MeOH (1 mL)

was added, and the procedure of heating and evaporating (at

last in vacuo) was repeated. H₂O and CHCl₃were added to

the residue. The organic phase was washed with H₂O, dried,

and evaporated in vacuo. The residue was purified by column

chromatography (toluene/CHCl₃(1:1)) to give methyl 4-[4-[2-

(1-piperidinyl)phenyl]-2,2-ethylenedithio-heptyl]-benzoate, 0.18

g, 64%; oil. (b) The above dithioketal (0.15 g, 0.31 mM) in dry

dioxane (5 mL) was stirred under reflux at 110 °C while Raney-

Ni (∼1 g; washed previously with dioxane) was added in small

portions during 2 h. The reaction was diluted with dioxane,

filtered, and evaporated in vacuo to give, after purification

by column chromatography with toluene/CHCl₃(2:1), methyl

4-[4-[2-(1-piperidinyl)phenyl]-heptyl]-benzoate, 0.092 g, 60%;

oil. (c) Hydrolysis of the above ester according to procedure

B3 gave 61, 71%; oil which crystallized on standing (mp 60-

70 °C).

4-[4-[2-(1-P ip er id in yl)p h en yl]-2-oxo-h ep t yl]-b en zoic

Acid (60). (a) A solution of 1-(2-piperidino-phenyl)-1-oxo-

butane (30o) (20 g, 86 mM) in dry Et₂O (50 mL) was added to

a solution of the sodium salt of triethylphosphonoacetate (172

mM) in dry Et₂O (200 mL). The reaction was heated for 5 h

at 40 °C and stood for 5 days at room temperature. After

addition of Et₂O (250 mL), the reaction was poured into iced

water. The organic phase was washed with 2 N NaOH and

with H₂O, dried, filtered, and evaporated in vacuo. The

residue was purified by column chromatography with toluene/

cyclohexane (4:1) to give ethyl 3-[2-(1-piperidinyl)phenyl]-2-

1

(E)-hexenoate (6 g, 23%; oil; R_f0.42; H NMR: 5.82 ppm (s,

1H, olef. H)) and ethyl 3-[2-(1-piperidinyl)phenyl]-2-(Z)-hex-

enoate (2.7 g, 10%; oil; R_f0.24; ¹H NMR: 5.86 ppm (s, 1H,

olef. H)). (b) The preceding (E) ester (4 g, 13 mM) in EtOH

(40 mL) was hydrogenated over Pd/C (10%) (0.4 g) overnight

at room temperature and 1 bar to give ethyl 3-[2-(1-piperidi-

nyl)phenyl]-hexanoate (3.8 g, 96%; oil). (c) To a stirred solution

of EtONa in EtOH [freshly prepared from Na (1.13 g, 49.1 mM)

in EtOH (14 mL)] was added quickly at 50 °C 4-bromo-

benzylcyanide (7.4 g, 37.7 mM) and thereafter the above ethyl

ester (18 g, 59.3 mM). The reaction was immediately heated

for 2 h in a preheated bath of 90 °C. The heating was removed,

and the reaction was allowed to stand overnight at room

temperature. 1 N HCl (49.1 mL) was added, and extraction

was performed with Et₂O. Workup of the organic phase and

purification by column chromatography (toluene) gave 1-(4-

bromo-phenyl)-1-cyano-4-[4-[2-(1-piperidinyl)phenyl]-2-oxo-

heptane, 6.7 g, 39%; viscous oil. (d) The preceding cyano

compound (19.5 g, 43 mM) in concentrated H₂SO₄(12.5 mL)

was heated in a preheated bath of 110 °C. When T_i) 80-90

°C was reached, a vigorous gas evolution occurred, and T_irose

quickly up to 140 °C. By cooling, T_iwas lowered within 2 min

to 80 °C. (Total time above 80 °C was ∼5 min.) The solution

containing the intermediary amide was cooled to room tem-

perature. H₂O (62.4 mL) was added, and the mixture was

heated for 1 h in a bath of 110 °C. The reaction was cooled to

room temperature; CHCl₃and 2 N NaOH (ad alkaline pH)

were added. Workup of the organic phase and purification by

column chromatography (toluene) gave 1-(4-bromo-phenyl)-4-

[4-[2-(1-piperidinyl)phenyl]-2-oxo-heptane, 11.6 g, 63%; viscous

oil. (e) A solution of the above ketone (11.6 g, 27 mM), p-TsOH‚

H₂O (5.6 g, 29.4 mM), and ethane-1,2-diol (5 g, 80.6 mM) in

dry benzene (12 mL) was refluxed in a Dean-Stark apparatus

for 72 h. After cooling to room temperature, the reaction was

poured into stirred semiconcentrated ammonia (100 mL).

Extraction was performed with Et₂O. The organic extract was

washed with 2 N NaOH and with water (ad pH 7). Workup

of the organic phase and purification by column chromatog-

raphy with toluene/cyclohexane (2:1) gave 1-(4-bromo-phenyl)-

4-[4-[2-(1-piperidinyl)phenyl]-2,2-ethylenedioxy-heptane, 11.3

g, 88%; viscous oil. (f) To a solution of the above ketal (9.4 g,

19.9 mM) in dry Et₂O (12 mL) was added at room temperature

under N₂a solution of n-BuLi (25 mL, 1.6 M in hexane, 39.8

mM) in dry Et₂O (50 mL) while T_irose to 30 °C and declined

after 30 min to 25 °C. After stirring for 1 h, the reaction was

poured into freshly mortared solid CO₂and stood at room

temperature overnight. Aqueous NH₄Cl was added, and

extraction was performed with Et₂O. Workup of the organic

phase, purification by column chromatography with CHCl₃/

MeOH (10:0.3), and treatment with charcoal in CHCl₃gave

Sin gle-Cr ysta l X-r a y An a lysis. The crystal data for 1

(GLIB) were taken from the literature.⁴¹

Colorless prismatic crystals of 2 (GLIM; mp 200.4-201.3

°C) and of (S)-6a l (REP; mp 134.8-135.0 °C) were grown from

ethanol/water, those of (S,S′)-28 (mp 173.2 °C) from water. A

crystal of 2 (0.30 × 0.30 × 0.05 mm³), (S)-6a l (0.50 × 0.10 ×

0.10 mm³), and (S,S′)-28 (0.50 × 0.30 × 0.30 mm³), respec-

tively, was measured on a Rigaku AFC7R diffractometer with

graphite monochromated Cu KR radiation (λ ) 1.5418 Å) and

a

12 kW rotating anode generator at 20 ( 1 °C. For

calculations, the teXsan crystallographic software package⁵⁶

was used. The structures were solved by direct methods⁵⁷and

expanded using Fourier techniques. The non-hydrogen atoms

were refined anisotropically. Hydrogen atoms were included

as riding atoms.

Cr ysta l Da ta . 2 (GLIM):

C₂₄H₃₄N₄O₅S, M_r) 490.62,

monoclinic, space group P2₁/n, a ) 15.283(2) Å, b ) 9.804(3)

Å, c ) 18.149(2) Å, â ) 111.916(7)°, V ) 2523.0(10) Å³, Z ) 4,

D_c) 1.29 g/cm³, µ ) 14.42 cm^-1. 3562 reflections (Θ e 55°)

were observed; 3411 were unique (R_int) 0.026). Refinement:

2490 reflections (I > 3.00σ(I)), 307 variable parameters, R )

0.039, and R_w) 0.054.

(S)-6a l (REP):

C₂₇H₃₆N₂O₄, M_r) 452.59, orthorhombic,

space group P2₁2₁2₁, a ) 13.325(4) Å, b ) 23.087(3) Å, c )

8.383(4) Å, V ) 2579.0(15) Å³, Z ) 4, D_c) 1.17 g/cm³, µ )

6.24 cm^-1. 1909 reflections (Θ e 55°) were unique. Refine-

ment: 1657 reflections (I > 3.00σ(I)), 298 variable parameters,

R ) 0.043, and R_w) 0.055.

(S,S′)-28: C₂₃H₃₇N₃O₅(C₁₆H₂₆N₂‚C₇H₁₁NO₅), M_r) 435.6,

orthorhombic, space group P2₁2₁2₁(#19), a ) 10.996(4) Å, b )

24.155(5) Å, c ) 9.210(6) Å, V ) 2422(1) Å³, Z ) 4, D_c) 1.194

g/cm³, µ ) 6.8 cm^-1. 1481 reflections (Θ e 50°) were unique.

Refinement: 1365 reflections (I > 3.00σ(I)), 289 variable

parameters, R ) 0.037, and R_w) 0.045.

The X-ray crystallographic data of the three compounds are

deposited at the Cambridge Structural Data (CSD) Bank.

Molecu la r Mod elin g. The conformational analysis pro-

cedure was carried out using the systematic and grid search

modules of the SYBYL⁵⁸(Tripos Inc., St. Louis, MO) program

Hypoglycemic Benzoic Acid Derivatives

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5245

(3) Eliasson, L.; Renstro¨m, E.; A¨ mma¨la¨, C.; Berggren, P.-O.; Ber-

torello, A. M.; Bokvist, K.; Chibalin, A.; Deeney, J . T.; Flatt, P.

R.; Ga¨bel, J .; Gromada, J .; Larsson, O.; Lindstro¨m, P.; Rhodes,

C. J .; Rorsman, P. PKC-Dependent Stimulation of Exocytosis

by Sulfonylureas in Pancreatic â Cells. Science 1996, 271, 813-

815.

(4) Geisen, K.; Hu¨bner, M.; Hitzel, V.; Hrstka, V. E.; Pfaff, W.;

Bosies, E.; Regitz, G.; Ku¨hnle, H. F.; Schmidt, F. H.; Weyer, R.

Acylaminoalkyl-substituierte Benzoe- und Phenylalkan-sa¨uren

mit blutglukose-senkender Wirkung. Arzneim.-Forsch./ Drug

Res. 1978, 28, 1081-1083.

(5) Rufer, C.; Losert, W. Blood Glucose Lowering Sulfonamides with

Asymmetric Carbon Atoms. 3. Related N-Substituted Carbam-

oyl-benzoic Acids. J . Med. Chem. 1979, 22, 750-752.

(6) Brown, G. R.; Foubister, A. J . Receptor Binding Sites of Hy-

poglycemic Sulfonylureas and Related [(Acylamino)alkyl]benzoic

Acids. J . Med. Chem. 1984, 27, 79-81.

(7) Fussga¨nger, R. D.; Wojcikowski, C. Stimulation of Insulin

Secretion of the Isolated Perfused Rat Pancreas by a new

Hypoglycemic Agent, an Acyl-amino-alkyl Benzoic Acid Deriva-

tive. Diabetologia 1977, 13, 394-395 (Abstr. 98).

(8) Blayac, J .-P.; Loubatie`res-Mariani, M.-M.; Ribes, G. Effets in

vitro d’un de´rive´ acyl-amino-alkyl de l’acide benzoique: Le HB

699, sur la se´cre´tion d’insuline et de glucagon. J . Pharmacol.

(Paris) 1979, 10, 229-238.

(9) Henquin, J . C.; Garrino, M. G.; Nenquin, M. Stimulation of

insulin release by benzoic acid derivatives related to the non-

sulfonylurea moiety of glibenclamide: structural requirements

and cellular mechanisms. Eur. J . Pharmacol. 1987, 141, 243-

251.

(10) Ribes, G.; Trimble, E. R.; Blayac, J . P.; Wollheim, C. B.;

Loubatie`res-Mariani, M. M. Diabetologia 1981, 20, 501-505.

(11) Zu¨nkler, B. J .; Lenzen, S.; Ma¨nner, K.; Panten, U.; Trube, G.

Concentration-dependent effects of tolbutamide, meglitinide,

glipizide, glibenclamide and diazoxide on ATP-regulated K⁺

currents in pancreatic B-cells. Naunyn Schmiedebergs Arch.

Pharmacol. 1988, 337, 225-230.

(12) Panten, U.; Burgfeld, J .; Goerke, F.; Rennicke, M.; Schwan-

stecher, M.; Wallasch, A.; Zu¨nkler, B. J .; Lenzen, S. Control of

insulin secretion by sulfonylureas, meglitinide and diazoxide in

relation to their binding to the sulfonylurea receptor in pancre-

atic islets. Biochem. Pharmacol. 1989, 38, 1217-1229.

(13) Weyer, R.; Hitzel, V.; Geisen, K.; Pfaff, W. Benzoic Acids and

Their Derivatives. German Pat. Appl. 2500157, 1975.

(14) Staab, A. Neuere Methoden der pra¨parativen organischen

Chemie. IV. Synthesen mit heterocyclischen Amiden (Azoliden).

Angew. Chem. 1962, 74, 407-423.

package on Silicon Graphics Indigo2 workstations. The Tripos

force field was used for all calculations without atomic charges.

The superpositions were performed by using the rigid fit

procedure of SYBYL in order to optimally fit the central

phenylene ring and the acidic pharmacophoric group of each

molecule. The identified LECs were further optimized with

the ab initio program Gaussian 94⁵⁹using Hartree-Fock

calculation with the 6-31G* basis set.

For the hydrophobic potentials, the program Hint^60,61was

applied which is integrated by MSI Open Interface into

InsightII.⁶²For the electrostatic potentials, the point charge

model implemented in SYBYL was applied. Atomic charges

were determined by semiempirical quantum mechanics using

the AM1 method implemented in MOPAC93.⁶³

P h a r m a cology. Adult fasted female Wistar rats, strain

Chbb THOM (SPF), with a body weight of 200-220 g were

used. Animals were fed ad libitum with standard pelleted

diets and were housed under a 12/12 h light/dark cycle with 7

h 00 min to 19 h 00 min being the light phase. Food was

withdrawn 24 h before the start of the studies between 8 h 00

min and 10 h 00 min. The compounds were suspended in 1.5%

Tylose KN 2000 (methylcellulose). The suspension containing

the appropriate amount of substance was given orally via

gavage. Administration volume was 10 mL/kg.

Blood was collected from the retrobulbar venous plexus

under light halothane anaesthesia. Blood glucose was mea-

sured in whole blood by the hexokinase/glucose-6-phosphate

dehydrogenase method (Glucoquant, Boehringer Mannheim)

after the protein had been precipitated by addition of 0.5 mL

of 0.33 M HClO₄to 50 µL of blood; measurements were carried

out with an Eppendorf 5032 automatic substrate analyzer.

Blood glucose was monitored hourly up to 4 h after adminis-

tration in comparison with a control group (N ) 7). Statistical

significance was checked with Student’s t-test (P e 0.05). The

maximum percentage decrease of blood sugar (∆BG) observed

within 4 h was taken as the measure for a compound’s blood

sugar lowering activity. Calculation of ED₅₀values was

performed by fitting the function y ) b + [a × k/(k + x^nH)] to

the data by the program Sigma Plot (J andel Scientific) where

y is the measured glucose value, x is the dose of the substance

used, nH is the Hill coefficient, a is the difference between

the upper and the lower asymptotes of the dose response curve,

and b is the baseline level. ED₅₀values were defined as half-

maximal effect doses.

(15) (a) Gall, R.; Bosies, E. German Pat. Appl. 3540150, 1985,

Example 14. (b) Blicke, F. F.; Lilienfeld, W. M. Basic-alkyl Esters

of p-(Aminoalkyl)-benzoic Acids. I. J . Am. Chem. Soc. 1943, 65,

2281-2284.

(16) Hitzel, V.; Weyer, R.; Geisen, K.; Ritzel, H. Salicylsa¨urederivate,

Verfahren zu ihrer Herstellung, pharmazeutische Pra¨parate auf

Basis dieser Verbindungen und ihre Verwendung. European Pat.

Appl. 0090369, 1983, Examples 1 and 2.

(17) (a) Appel, R.; Ba¨umer, G.; Stru¨ver, W. U¨ ber die Peptidsynthese

mit Triphenylphosphin/Tetrachlorkohlenstoff als Kondensation-

sreagenz. 27. Chem. Ber. 1975, 108, 2680-2692. (b) Appel, R.;

Ba¨umer, G.; Stru¨ver, W. Notiz u¨ber die Peptidsynthese mit Tri-

phenylphosphin/Tetrachlorkohlenstoff als Kondensationsreagenz.

30. Chem. Ber. 1976, 109, 801-804.

(18) Wendlberger, G. Aktivierung mit Carbodiimiden. In Synthese

von Peptiden; Wu¨nsch, E., Ed.; Georg Thieme Verlag: Stuttgart,

1974; pp 103-117.

(19) Maillard, J .; Langlois, M.; Delaunay, P.; Van Tri, V.; Morin, R.;

Lefebvre, M.-J .; Manuel, C.; Verro, A.-M. Anti-inflammatoires

de´rive´s de l′acide phe´nylace´tique; de´rive´s substitue´s par un

he´te´rocycle sur le noyau phe´nyle. Chim. The´rap. 1973, 4, 487-

494.

Ack n ow led gm en t. We thank Wolfgang Bader, Re-

inhold Birk, Leonhard Brandt, Michael Epple, Werner

Eyrainer, Rudolf Gruber, Peter Hertwig, Hansjo¨rg

Knorr, Marlene Kuppinger, Heinrich La¨ngst, Domin-

ique Lefevre, Werner Rall, Ernst-Hugo Schmid, Kurt

Staudenrauss, Martin Steiner, Hildegard Steinhauser,

J osef Zeiler, and Gerhard Ziehe for their skillful techni-

cal assistance, and we are grateful to Dr. Ferdinand

Fraunberger for supplying us with (R)-29, to Prof. Dr.

Axel Prox, Dr. Albert Reuter, Dr. Klaus Wagner, Dr.

Klaus Daneck, and their co-workers from the Analytical

Department for managing the analytical, spectral, mass

spectrum and HPLC data, to Dr. Armin Heckel for

stimulating discussions, and to Manuela Hildbrand for

helpful assistance at preparing the manuscript.

(20) Analogously to: Dodsworth, D. J .; Pia-Calcagno, M.; Ehrmann,

E. U.; Quesada, A. M.; Nunez S. O.; Sammes, P. G. A New Route

to Dihydroisoquinolones. J . Chem. Soc., Perkin Trans I 1983,

1453-1458.

Su p p or tin g In for m a tion Ava ila ble: Spectral data for 5c,

11c, 5d , 11d , 5l, 11l, 11j, 11k , 11o, 11p , 13d -eth ylester , 13d ,

29, 12q, 14y, 6a l, (S,S′)-28, (S)-12q, (S)-14y, (S)-6a l (25

pages). Ordering information is given on any current mast-

head page.

(21) Analogously to Rufer, C.; Biere, H.; Ahrens, H.; Loge, O.;

Schro¨der, E. Blood Glucose Lowering Sulfonamides with Asym-

metric Carbon Atoms. 1. J . Med. Chem. 1974, 17, 708-715.

(22) Analogous to (a) Demailly, G.; Solladie´, G. Asymmetric Induction

in the Reduction of Chiral Imines. A Stereospecific Synthesis of

20R-Amino-5R-pregnan-3â-ol (Funtuphyllamine A) Tetrahrahe-

dron Lett. 1975, 2471-2472. (b) Frahm, A. W.; Knupp, G.

Asymmetric Synthesis of cis-2-Substituted Cyclohexaneamines

with High Optical Purity. Tetrahedron Lett. 1981, 2633-2336.

(23) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya,

H. Asymmetric Synthesis of Isoquinoline Alkaloids by Homo-

geneous Catalysis. J . Am. Chem. Soc. 1986, 108, 7117-7119.

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(35) Presented in part at the IXth International Symposium on

Medicinal Chemistry, Sept 14-18, 1986, Berlin, West-Germany.

Short Communication (Abstract SC 74). Grell, W.; Griss, G.

(deceased); Hurnaus, R.; Sauter, R.; Rupprecht, E. Structure-

Activity Relationships of Novel Hypoglycemic Benzoic Acids.

(36) Presented in part at the 16th International Diabetes Federation

Congress, Helsinki, Finland, J uly 20-25, 1997. Grell, W.;

Hurnaus, R.; Griss, G. (deceased); Rupprecht, E.; Mark, M.;

Luger, P. Repaglinide, a Potent and Orally Active Hypoglycaemic

Benzoic Acid Derivative. Diabetologia 1997, 40 (Suppl. 1), A325

(No. 1278).

(37) Presented in part at the XVIth Congress and General Assembly

of the International Union of Crystallography, August 21-29,

1993, Beijing, China. Grell, W.; Mark, M.; Luger, P. X-ray

Analysis of the New Hypoglycemic Drug Repaglinide: Common

Structural Features with Glibenclamide. Acta Crystallogr. 1993,

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J M9810349

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Repaglinide and related hypoglycemic benzoic acid derivatives

DOI: 10.1021/jm9810349

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Full text of DOI:10.1021/jm9810349

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