Benzofused lactams useful as cholecystokinin antagonists

Benzofused lactams and pharmaceutically-acceptable salts thereof which are useful as cholecystokinin antagonists.

Cholecystokinins (CCK) are neuropeptides which include CCK-33, a 
neuropeptide of thirty-three amino acids in its originally-isolated form 
(see, Mutt and Jorpes, Biochem. J. 125 678 (1971)), its carboxyl terminal 
octapeptide, CCK-8 (a naturally-occurring neuropeptide also, and the 
minimum fully-active sequence), and 39- and 12-amino acid forms. CCK's are 
believed to be physiological satiety hormones and, therefore, may play an 
important role in appetite regulation (G. P. Smith, Eating and Its 
Disorders, A. J. Stunkard and E. Stellar, Eds., Raven Press, New York, 
1984, p. 67). They exist in both gastrointestinal tissue and in the 
central nervous system (V. Mutt, Gastrointestinal Hormones, G. B. J. 
Glass, Ed., Raven Press, N.Y., (1980) p. 169). 
Among additional effects, CCK's stimulate colonic motility, gall bladder 
contraction and pancreatic enzyme secretion, and they inhibit gastric 
emptying. CCK's reportedly co-exist with dopamine in certain mid-brain 
neurons and thus may also play a role in the functioning of dopaminergic 
systems in the brain, as well as serving as neurotransmitters in their own 
right. See: A. J. Prange et al., "Peptides in the Central Nervous System", 
Ann. Repts. Med. Chem. 17 31, 33 (1982) and references cited therein; J. 
A. Williams, Biomed. Res. 3, 479 107 (1982); and J. E. Morley, Life Sci. 
30 (1982). 
Antagonists of CCK's have been useful for preventing and treating 
CCK-related disorders of the gastrointestinal, central nervous and 
appetite regulatory systems of animals, especially of humans. CCK 
antagonists are also useful in potentiating and prolonging opiate-mediated 
analgesia, and thus have utility in the treatment of pain [see, P. L. 
Faris et al., Science 226, 1215 (1984)]. 
Three distinct chemical classes of CCK-receptor antagonists have been 
reported. The first class comprises derivatives of cyclic nucleotide, of 
which dibutyryl cyclic GMP has been shown to be the most potent be 
detailed structure-function studies (see: N. Barlos et al., Am. J. 
Physiol., 242, G161 (1982) and P. Robberecht et al., Mol., Pharmacol., 
17, 268 (1980)). The second class comprises peptide antagonists which are 
C-terminal fragments and analogs of CCK, of which both shorter 
(Boc-Met-Asp-Phe-NH.sub.2, Met-Asp-Phe-NH.sub.2) and longer 
(Cbz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2) C-terminal fragments of 
CCK's can function as CCK antagonists, according to recent 
structure-function studies [see: R. T. Jensen et al., Biochim. Boiphys. 
Acta., 757, 250 (1983) and M. Spanarkel et al., J. Biol. Chem., 258, 6746 
(1983)]. The latter compound was recently reported to be a partial agonist 
[see, J. M. Howard et al., Gastroenterology 86 (5) Part 2, 1118 (1984)]. 
Then, the third class of CCK receptor antagonists comprises the amino acid 
derivatives, proglumide, a derivative of glutaramic acid, and the N-acyl 
tryptophans, including para-chlorobenzoyl-L-tryptophan (benzotript) [see, 
W.F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) and R. 
T. Jensen et al., Biochem. Biophys. Acta., 761, 269 (1983)]. All of these 
compounds, however, are relatively weak antagonists of CCK (IC.sub.50 
:generally 10.sup.4 M, but down to 10.sup.-6 M in the case of peptides), 
and the peptide CCK-antagonists have substantial stability and absorption 
problems. 
It was, therefore, an object of this invention to identify substances which 
more effectively antagonize the function of cholecystokinins in disease 
states in mammals, especially in humans. It was another object of this 
invention to develop a method of antagonizing the functions of 
cholecystokinins in disease states in mammals. It was still another object 
of this invention to develop a method of preventing or treating disorders 
of the gastrointestinal, central nervous and appetite regulatory systems 
of mammals, especially of humans. 
SUMMARY OF THE INVENTION 
It has now been found that the benzofused lactams of this invention are 
antagonists of cholecystokinins (CCK), which are useful in the treatment 
and prevention of CCK-related disorders of the gastrointestinal, central 
nervous and appetite regulatory systems of mammals, especially of humans. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of this invention are benzofused lactams of the formula: 
##STR1## 
wherein: X is absent or carbonyl; 
R is 
unsubstituted or mono-, di-, or trisubstituted C.sub.1 -C.sub.8 -straight- 
or branched-alkyl, where the substituent(s) is/are selected from the group 
consisting of C.sub.1 -C.sub.4 -alkylthio, C.sub.1 -C.sub.4 -alkyloxy, 
C.sub.1 -C.sub.4 -alkylamino, unsubstituted or mono-, di-, or 
trisubstituted C.sub.6 - or C.sub.10 -aryloxy, unsubstituted or mono-, 
di-, or trisubstituted C.sub.6 - or C.sub.10 -arylthio, unsubstituted or 
mono-, di-, or trisubstituted C.sub.6 - or C.sub.10 -aryl, and 
unsubstituted or mono-, di-, or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl, the one-to-three heteroatoms in the hetero-C.sub.3 -C.sub.9 -aryl 
being selected from O, S and N atoms, and the substituent(s) on the 
C.sub.6 - or C.sub.10 -aryloxy, the C.sub.6 - or C.sub.10 -arylthio, the 
C.sub.6 - or C.sub.10 -aryl and the hetero-C.sub.3 -C.sub.9 -aryl being 
selected from C.sub.1 -C.sub.8 -straight- or branched-alkyl, hydroxy, 
C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio 
or mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
substituted carbonyl-C.sub.1 -C.sub.4 -alkyl, which carbonyl group is 
substituted with hydroxy, C.sub.1 -C.sub.8 -straight- or branched-alkoxy, 
C.sub.1 -C.sub.8 -straight- or branched-alkyl, unsubstituted or mono-, 
di-, or trisubstituted C.sub.6 - or C.sub.10 -aryl, unsubstituted or 
mono-, di- or trisubstituted C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.8 
-alkyl, and unsubstituted or mono-, di-, or trisubstituted C.sub.6 - or 
C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkoxy, where the substistuent(s) on the 
C.sub.6 - or C.sub.10 -aryl, the C.sub.6 - or C.sub.10 -aryl-C.sub.1 
-C.sub.8 -alkyl or the C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.4 
-alkoxy is/are selected from the groups consisting of hydroxy, C.sub.1 
-C.sub.8 -straight- or branched-alkyl, C.sub.1 -C.sub.4 -alkoxy, halo, 
nitro, amino, C.sub.1 -C.sub.4 -alkylthio, and mono- or di-C.sub.1 
-C.sub.4 -alkylamino, or NR.sup.4 R.sup.5, where R.sup.4 and R.sup.5 are 
independently selected from hydrogen, C.sub.1 -C.sub.6 -straight- or 
branched-alkyl, unsubstituted or mono-, di-, or 
trisubstituted-carboxy-C.sub.1 -C.sub.8 -straight- or branched-alkyl, or 
unsubstituted or mono-, di-, or trisubstituted-carboxamido-C.sub.1 
-C.sub.8 -straight- or branched-alkyl, wherein the substituent(s) on the 
carboxy-C.sub.1 -C.sub.8 -straight- or branched-alkyl or on the 
carboxamido-C.sub.1 -C.sub.8 -straight- or branched-alkyl is/are selected 
from the group consisting of C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 
-alkoxy, amino-C.sub.1 -C.sub.4 -alkyl, unsubstituted or mono-, di-, or 
trisubstituted C.sub.6 - or C.sub.10 -aryl, unsubstituted or mono-, di- or 
trisubstituted C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.8 -alkyl, and 
unsubstituted or mono-, di-, or trisubstituted C.sub.6 - or C.sub.10 
-aryl-1C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkoxy, where the substituent(s) 
on the C.sub.6 - or C.sub.10 -aryl, the C.sub.6 - or C.sub.10 
-aryl-C.sub.1 -C.sub.8 -alkyl or the C.sub.6 - or C.sub.10 -aryl-C.sub. 1 
-C.sub.4 -alkoxy is/are selected from the group consisting of hydroxy, 
C.sub.1 -C.sub.8 -straight- or branched-alkyl, C.sub.1 -C.sub.4 -alkoxy, 
halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio, and mono- or di-C.sub.1 
-C.sub.4 -alkylamino; 
R.sup.1 is R.sup.a or R.sup.b ; 
R.sup.a is 
unsubstituted or mono-, di- or trisubstituted aryl, where the 
substituent(s) is/are selected from the group consisting of C.sub.1 
-C.sub.8 -straight- or branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, 
halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio and mono- or di-C.sub.1 
-C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl, the one-to-three heteroatoms of which are selected from O, N and S 
atoms and the substitutent(s) is/are selected from the group consisting of 
C.sub.1 -C.sub.8 -straight- or branched-alkyl, hydroxy, C.sub.1 -C.sub.4 
-alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio and mono- or 
di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted C.sub.6 - or C.sub.10 
-aryl-C.sub.1 -C.sub.8 -straight- or branched-alkyl, where the 
substituent(s) is/are selected from the group consisting of C.sub.1 
-C.sub.8 -straight- or branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, 
halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio and mono- or di-C.sub.1 
-C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl-C.sub.1 -C.sub.8 -straight- or branched-alkyl, the one-to-three 
heteroatoms of which are selected from O, N and S atoms, and the 
substituent(s) is/are selected from the group consisting of C.sub.1 
-C.sub.8 -straight- or branched alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, 
halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio and mono- or di-C.sub.1 
-C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted C.sub.6 - or C.sub.10 
-aryl-C.sub.2 -C.sub.4 -alkenyl, where the substituent(s) is/are selected 
from the group consisting of C.sub.1 -C.sub.8 -straight- or branched- 
alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, C.sub.1 
-C.sub.4 -alkylthio and mono- or di- C.sub.1 -C.sub.4 alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl-C.sub.2 -C.sub.4 -alkenyl, the one-to-three heteroatoms of which are 
selected from O, N and S atoms, and the substituent(s) is/are selected 
from the group consisting of C.sub.1 -C.sub.8 -straight- or 
branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, 
C.sub.1 -C.sub.4 -alkylthio and mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted C.sub.6 - or C.sub.10 
-aryloxy, where the substituent(s) is/are selected from the group 
consisting of C.sub.1 -C.sub.8 -straight- or branched-alkyl, hydroxy, 
C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkyl-thio 
and mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryloxy, the one-to-three hetero-atoms of which are selected from O, N 
and S atoms, and the substituent(s) is/are selected from the group 
consisting of C.sub.1 -C.sub.8 -straight- or branched-alkyl, hydroxy, 
C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio 
and mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted C.sub.6 - or C.sub.10 
-arylthio, where the substituent(s) is/are selected from the group 
consisting of C.sub.1 -C.sub.8 -straight- or branched-alkyl, hydroxy, 
C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio 
or mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-arylthio, the one-to-three hetero-atoms of which are selected from O, N 
and S atoms, and the substituent(s) is/are selected from the group 
consisting of C.sub.1 -C.sub.8 -straight- or branched alkyl, hydroxy, 
C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkylthio 
or mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted C.sub.6 - or C.sub.10 
-aryl-C.sub.1 -C.sub.4 -alkyloxy, where the substituent(s) is/are selected 
from the group consisting of C.sub.1 -C.sub.8 -straight- or 
branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, 
C.sub.1 -C.sub.4 -alkylthio or mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl-C.sub.1 -C.sub.4 -alkyloxy, the one-to-three heteroatoms of which 
are selected from O, N and S atoms, and the substituent(s) is/are selected 
from the group consisting of C.sub.1 -C.sub.8 -straight- or 
branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, 
C.sub.1 -C.sub.4 -alkylthio or mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
unsubstituted or mono-, di- or trisubstituted C.sub.6 - or C.sub.10 
-aryl-C.sub.1 -C.sub.4 -alkylthio, where the substituent(s) is/are 
selected from the group consisting of C.sub.1 -C.sub.8 -straight- or 
branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, 
C.sub.1 -C.sub.4 -alkylthio and mono- or di-C.sub.1 -di-C.sub.1 -C.sub.4 
-alkylamino; 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl-C.sub.1 -C.sub.4 -alkylthio, the one-to-three heteroatoms of which 
are selected from O, N and S atoms, and the substituent(s) is/are selected 
from the group consisting of C.sub.1 -C.sub.8 -straight- or 
branched-alkyl, hydroxy, C.sub.1 -C.sub.4 -alkoxy, halo, nitro, amino, 
C.sub.1 -C.sub.4 -alkylthio and mono- or di-C.sub.1 -C.sub.4 -alkylamino; 
C.sub.1 -C.sub.8 -straight- or branched-alkyls; 
C.sub.3 -C.sub.10 -cycloalkyl; 
C.sub.3 -C.sub.10 -cycloalkyl-C.sub.1 -C.sub.4 -alkyl; 
C.sub.1 -C.sub.6 -straight- or branched-alkyl-Q-(CH.sub.2).sub.m, where m 
is 1-to-3, and Q is O, S, SO, SO.sub.2, --HC.dbd.CH--, or 
substituted-amino, wherein the substituent is hydrogen, C.sub.1 -C.sub.8 
-straight- or branched-alkyl, unsubstituted or mono-, di- or 
trisubstituted C.sub.6 - or C.sub.10 -aryl, unsubstituted or mono-, di- or 
trisubstituted hetero-C.sub.3 -C.sub.9 -aryl, the one-to-three heteroatoms 
of which are selected from O, N and S atoms, unsubstituted or mono-, di- 
or trisubstituted C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkyl, or 
unsubstituted or mono-, di- or trisubstituted hetero-C.sub.3 -C.sub.9 
-aryl-C.sub.1 -C.sub.4 -alkyl, the one-to-three heteroatoms of which are 
selected from O, N and S, where the substituent(s) on the C.sub.6 - or 
C.sub.10 -aryl, the hetero-C.sub.3 -C.sub.9 -aryl, the C.sub.6 - or 
C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkyl, or the hetero-C.sub.3 -C.sub.9 
-aryl-C.sub.1 -C.sub.4 -alkyl is/are selected from the group consisting of 
C.sub.1 -C.sub.8 -straight- or branched-alkyl, hydroxy, C.sub.1 -C.sub.4 
-alkoxy, halo, nitro, amino, C.sub.1 -C.sub.4 -alkyl-thio and mono- or 
di-C.sub.1 -C.sub.4 -alkylamino; 
C.sub.9 -C.sub.12 -benzofused cycloalkyls; or 
C.sub.8 -C.sub.10 -benzofused heterocycloalkyls, the one heteroatom of 
which is selected from O, N and S; and 
R.sup.b is --CHR.sup.2 R.sup.3, where R.sup.2 is R.sup.a, as defined above, 
and 
R.sup.3 is 
substituted carbonyl, wherein the substituent is hydroxy, C.sub.1 -C.sub.4 
-alkoxy, C.sub.1 -C.sub.4 -alkyl, hydroxy-C.sub.1 -C.sub.4 -alkyl, amino, 
C.sub.1 -C.sub.8 -straight- or branched-alkylamino, C.sub.6 - or C.sub.10 
-aryloxy, C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.6 -alkylamino, 
C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkyloxy, carboxy-C.sub.1 
-C.sub.8 -straight- or branched-alkylamino, or carboxamido-C.sub.1 
-C.sub.8 -straight- or branched-alkylamino; 
NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected 
from hydrogen, substituted carbonyl, unsubstituted or mono-, di- or 
trisubstituted-carboxy-C.sub.1 -C.sub.8 -straight- or branched-alkyl, and 
unsubstituted- or mono-, di- or trisubstituted-carboxamido-C.sub.1 
-C.sub.8 -straight- or branched-alkyl, where the substituents on the 
carbonyl, the carboxy-C.sub.1 -C.sub.8 -alkyl or the carboxamido-C.sub.1 
-C.sub.8 -alkyl is/are selected from C.sub.1 -C.sub.4 -alkyl, C.sub.1 
-C.sub.4 -alkyloxy, amino- C.sub.1 -C.sub.4 -alkyl, unsubstituted or 
mono-, di- or trisubstituted C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.8 
-alkyl, unsubstituted- or mono-, di- or trisubstituted C.sub.6 - or 
C.sub.10 -aryl, unsubstituted- or mono-, di- or trisubstituted C.sub.6 - 
or C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkoxy, and mono-, di- or 
trisubstituted-C.sub.1 -C.sub.8 -alkyl, wherein the substituents(s) on the 
C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.8 -alkyl, the C.sub.6 - or 
C.sub.10 -aryl, the C.sub.6 - or C.sub.10 -aryl-C.sub.1 -C.sub.4 -alkoxy 
or the C.sub.1 -C.sub.8 -alkyl is/are selected from hydroxy, C.sub.1 
-C.sub.8 -straight- or branched-alkyl, C.sub.1 -C.sub.4 -alkoxy, halo, 
nitro, amino, C.sub.1 -C.sub.4 -alkylthio, or mono- or di-C.sub.1 -C.sub.4 
-alkylamino; 
R.sup.6 is 
hydrogen; 
halo; 
hydroxy; 
nitro; 
amino; 
C.sub.1 -C.sub.4 -alkylamino; 
C.sub.1 -C.sub.8 -alkyl; or 
C.sub.1 -C.sub.8 -alkoxy; 
y is 1 to 3; 
p is 0 to 2, with the proviso that when p is O, X is carbonyl; 
and the pharmaceutically-acceptable salts thereof. 
The compounds according to the present invention may be racemic mixtures or 
R or S enantiomer forms of these compounds. 
The straight-chain, brached saturated and unsaturated hydrocarbons (alkyl 
and alkenyl) recited above are represented by such compounds as methyl, 
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, 
n-hexyl; and vinyl, allyl, butenyl, and the like. The cycloalkyl and 
cyclo-C.sub.1 -C.sub.4 -alkyl substituents are represented, respectively, 
by groups such as cyclopropyl, cyclobutyl and cyclohexyl through 
cyclodecyl and by groups such as cyclopentylethyl, cyclohexylpropyl and 
cycloheptylmethyl. 
The alkoxy substituent represents an alkyl group attached through an oxygen 
bridge. 
The arylalkyl and heteroarylalkyl groups recited above represent aryl or 
heteroaryl groups as herein defined attached through a straight- or 
branched-chain alkyl group of from one to eight carbon atoms, such as, for 
example, benzyl, phenethyl, 3,3-diphenylpropyl, 3-indolylmethyl, and the 
like. 
Halo means chloro, bromo, iodo, or fluoro. 
The aryl substituent is illustrated by phenyl, naphthyl, or biphenyl. 
The heteroaryl substituent recited above represents any 5- or 6-membered 
aromatic ring containing from one-to-three O, N or S heteroatoms such as, 
for example, pyridyl, thienyl, furyl, imidazolyl, and thiazolyl, as well 
as any bicyclic group in which any of the above heterocyclic rings is 
fused to a benzene ring such as, for example, indolyl, quinolinyl, 
isoquinolinyl, benzimidazolyl, benzothiazolyl, and benzthienyl. 
The Formula I compounds which bear acidic or basic groups may be used in 
the form of salts derived from inorganic or organic acids and bases, 
whereby water- or oil-soluble or dispersible products are obtained. 
Included among such acid addition salts are acetate, adipate, alginate, 
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, 
camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, 
dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, 
glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, 
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, 
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, 
pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, 
succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts 
include ammonium salts, alkali metal salts, such as sodium and potassium 
salts, alkaline earth metal salts, such as calcium and magnesium salts, 
salts with organic bases such as dicyclohexylamine and 
N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, 
and so forth. 
In the compounds of Formula I, the preferred stereochemistry at the 
3-position is R, the preferred ring size is realized when y is 2 or 3, and 
the preferred side chain off the the lactam is one wherein X is carbonyl, 
most preferably when p is 0. 
Preferred compounds according to the present invention include: 
1-carbomethoxymethyl-3-(3-indolemethyl)aminohomodihydrocarbostyril; 
1-carboxymethyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(2-naphthylacetyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(D-N-acetyltryptophanyl)aminohomodihydrocarbosty 
ril; 
1-t-butoxycarbonylmethyl-3-(L-N-acetyltryptophanyl)aminohomodihydrocarbosty 
ril; 
1-t-butoxycarbonylmethyl-3-(L-N-carbobenzyloxytryptophanyl)aminohomodihydro 
carbostyril; 
1-t-butoxycarbonylmethyl-3-(D-N-carbobenzyloxytryptophanyl)aminohomodihydro 
carbostyril; 
1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminohexahydrobenzoazocine-2 
-one; 
1-t-butoxycarbonylmethyl-3-(2-naphthoyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(2-naphthylmethyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(2-naphthylmethyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(3,4-dichlorobenzoyl)aminohomodihydrocarbostyril 
; 
1-t-butoxycarbonylmethyl-3-(2-indolemethyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(3,4-dichlorobenzyl)aminohomodihydrocarbostyril; 
1-benzyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril; 
1-ethoxycarbonylmethyl-3-(2-naphthoyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3(R)-(2-indolemethyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3(R)-(3,4-dichlorobenzyl)aminohomodihydrocarbostyr 
il; 
1-t-butoxycarbonylmethyl-3(R)-(2-naphthylmethyl)-aminohomodihydrocarbostyri 
l; 
1-t-butoxycarbonylmethyl-3(R)-(2-naphthoyl)aminohomodihydrocarbostyril; and 
1-t-butoxycarbonylmethyl-3(R)-(carbonyl-2-indolyl)aminohomodihydrocarbostyr 
il. 
More preferred compounds according to this invention include: 
1-carboxymethyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril; 
1-benzyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(2-indolemethyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3-(3,4-dichlorobenzyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3(R)-(2-indolemethyl)aminohomodihydrocarbostyril; 
1-t-butoxycarbonylmethyl-3(R)-(3,4-dichlorobenzyl)aminohomodihydrocarbostyr 
il; 
1-t-butoxycarbonylmethyl-3(R)-(2-naphthylmethyl)aminohomodihydrocarbostyril 
; 
1-t-butoxycarbonylmethyl-3(R)-(2-naphthoyl)aminohomodihydrocarbostyril; and 
1-t-butoxycarbonylmethyl-3(R)-(carbonyl-2-indolyl)aminohomodihydrocarbostyr 
il. 
The ability of the compounds of Formula I to antagonize CCK makes these 
compounds especially useful in the treatment and prevention of disease 
states in mammals, especially in humans, wherein CCK may be involved. 
These disease states include, for example, gastrointestinal disorders, 
such as irritable bowel syndrome, ulcers, excess pancreatic or gastric 
secretion, acute pancreatis, motility disorders, central nervious system 
disorders caused by CCK's interaction with dopamine, such as neuroleptic 
disorders, tardive, dyskinesia, Parkinson's disease, psychosis or Gilles 
de la Tourette Syndrome, and disorders of appetite regulatory systems or 
pain. 
Screening of the novel benzofused lactams according to the present 
invention to determine biological activity and obtain an IC.sub.50 value 
for them, in order to identify significant CCK-antagonism, has been 
accomplished using an .sup.125 I-CCK-receptor binding assay and in vitro 
isolated tissue preparations. 
CCK receptor binding (pancreas) method 
CCK-33 was radiolabeled with .sup.125 I-Bolton Hunter reagent (2000 
Ci/mmole) as described by Sankara et al. [J. Biol. Chem. 254: 9349-9351, 
(1979)]. Receptor binding was performed according to Innis and Snyder 
[Pro. Natl. Acad. Sci. 77: 6917-6921, (1980)], with the minor modification 
of adding the additional protease inhibitors, phenylmethane sulfonyl 
fluoride and o-phenanthroline, which have no effect on the .sup.125 I-CCK 
receptor binding assay. 
The whole pancreas of a male Sprague-Dawley rat (200-350 g), which had been 
sacrificed by decapitation, was dissected free of fat tissue and 
homogenized in 20 volumes of ice-cold 50 mM, Tris HCl (pH 7.7 at 
25.degree. C.) with a Brinkman Polytron PT 10. The homogenates were 
centrifuged at 48,000 g for 10 minutes, then the resulting pellets were 
resuspended in Tris Buffer, centrifuged as above, and resuspended in 200 
volumes of binding assay buffer (50 mM Tris HCl, pH 7.7 at 25.degree. C., 
5 mM dithiothriethel, 0.1 mM bacitracin, 1.2 mM phenylmethane sulfonyl 
fluoride and 0.5 mM o-phenanthroline). 
For the binding assay, 25 .mu.l of buffer (for total binding), or unlabeled 
CCK-8 sulfate sufficient to give a final concentration of 1 .mu.M (for 
nonspecific binding) or the compounds of Formula I according to the 
instant invention (for determination of inhibition of antagonism to 
.sup.125 I-CCK-binding) and 25 .mu.l of .sup.125 I-CCK-33 (30,000-40,000 
cpm) were added to 450 .mu.l of the membrane suspensions in microfuge 
tubes. All assays were run in duplicate or triplicate, and the reaction 
mixtures were incubated at 37.degree. C. for 30 minutes and centrifuged in 
a Beckman Microfuge (4 minutes) immediately after adding 1 ml of ice-cold 
incubation buffer. The supernatant was aspirated and discarded, and the 
pellets were counted with a Beckman Gamma 5000. For Scatchard analysis to 
determine the mechanism of inhibition of .sup.125 I-CCK-33 binding by the 
most potent compounds (Ann. N.Y. Acad. Sci., 51, 660, 1949), .sup.125 
I-CCK-33 was progressively diluted with increasing concentrations of 
CCK-33. 
CCK receptor binding (Brain) method 
CCK-33 was radiolabeled and the binding was performed according to the 
description for the pancreas method with modifications according to Saito, 
et al. (J. Neurochem, 37, 483-490 (1981)). 
Male Hartley guinea pigs (300-500 g) were sacrificed by decapitation, and 
the brains were removed and placed in ice-cold 50 mM, Tris HCl plus 7.58 
g/l Trizma-7.4 (pH 7.4 at 25.degree. C.). The cerebral cortex was 
dissected and used as a receptor source, and each gram of fresh guinea pig 
brain tissue was homogenized in 10 ml of Tris/Trizma buffer with a 
Brinkman Polytron PT-10. The homogenates were centrifuged at 42,000 g for 
15 minutes, then the resulting pellets were resuspended in Tris Buffer, 
centrifuged as above and resuspended in 200 volumes of binding assay 
buffer (10 mM of N-2-hydroxy-ethylpiperazine-N'-2-ethane-sulfonic acid 
(HEPES), pH 7.7 at 25.degree. C., 5 mM MgCl.sub.2, 1 mM ethylene 
glycol-bis-.beta.-amino-ethyl-ether-N,N'-tetraacetic acid (EGTA), 0.4% BSA 
(bovine serum albumin) and 0.25 mg/ml bacitracin, pH 6.5). 
The remainder of the binding assay was as described for the pancreas 
method, except that the reaction mixtures were incubated at 25.degree. C. 
for 2 hours before centrifugation. 
In Vitro Effect of Representative Compounds of Formula I on .sup.125 
I-CCK-33 Receptor Binding 
Compounds of Formula I competitively inhibited specific .sup.125 I-CCK-33 
binding in a concentration-dependent manner with an IC.sub.50 (pancreas) 
of less than or equal to 100 .mu.M, such as, for example: 
1-t-butoxycarbonylmethyl-3-(D-N-acetyltryptophanyl)aminohomodihydrocarbosty 
ril, IC.sub.50 =1.6 .mu.M; 
1-t-butoxycarbonylmethyl-3-(L-N-acetyltryptophanyl)aminohomodihydrocarbosty 
ril, IC.sub.50 =2.8 .mu.M; 
1-t-butoxycarbonylmethyl-3-(L-N-carbobenzyloxytryptophanyl)aminohomodihydro 
carbostyril, IC.sub.50 =1.2 .mu.M; 
1-methyl-3-(1-carboethoxy-3-phenyl-1-propyl)aminohomodihydrocarbostyril, 
IC.sub.50 =60 .mu.M; 
1-carbomethoxymethyl-3-(3-indolemethyl)aminohomodihydrocarbostyril, 
IC.sub.50 =15 .mu.M; 
1-benzyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril, IC.sub.50 =65 
nM; 
1-ethoxycarbonylmethyl-3-(2-naphthoyl)aminohomodihydrocarbostyril, 
IC.sub.50 =110 nM; 
1-methyl-3-(2-naphthoyl)aminohomodihydrocarbostyril, IC.sub.50 =8700 nM; 
1-t-butoxycarbonylmethyl-3-(2-naphthylacetyl)aminohomodihydrocarbostyril, 
IC.sub.50 =3000 nM; 
1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminohomodihydrocarbostyril, 
IC.sub.50 =20 nM; 
1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminohexahydrobenzoazocine-2 
-one, IC.sub.50 =80 nM; 
1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminodihydrocarbostyril, 
IC.sub.50 =130 nM; 
1-t-butoxycarbonylmethyl-3(S)-(carbonyl-2-indolyl)aminohomodihydrocarbostyr 
il, IC.sub.50 =640 nM; 
1-t-butoxycarbonylmethyl-3(R)-(carbonyl-2-indolyl)aminohomodihydrocarbostyr 
il, IC.sub.50 =8.7 nM; 
1-t-butoxycarbonylmethyl-3-(2-naphthoyl)aminohomodihydrocarbostyril, 
IC.sub.50 =9.4 nM; 
1-t-butoxycarbonylmethyl-3(R)-(2-naphthoyl)aminohomodihydrocarbostyril, 
IC.sub.50 =4.7 nM; 
1-t-butoxycarbonylmethyl-3(R)-(2-naphthylmethyl)aminohomodihydrocarbostyril 
, IC.sub.50 =4 nM; 
1-t-butoxycarbonylmethyl-3-(2-naphthylmethyl)aminohomodihydrocarbostyril, 
IC.sub.50 =8.7 nM; 
1-t-butoxycarbonylmethyl-3-(benzoyl)aminohomodihydrocarbostyril, IC.sub.50 
=4600 nM; 
1-t-butoxycarbonylmethyl-3-(4-chlorobenzoyl)aminohomodihydrocarbostyril, 
IC.sub.50 =500 nM; and 
1-t-butoxycarbonylmethyl-3-(3,4-dichlorobenzoyl)aminohomodihydrocarbostyril 
, IC.sub.50 =100 nM. 
Thus, in accordance with the present invention, there is provided a 
pharmaceutical composition for and a method of treating gastrointestinal 
disorders, central nervous system disorders, or regulating appetite, which 
comprises administering to a patient in need of such treatment a 
pharmaceutically-effective amount of a compound of Formula I. 
For administration, the compositions of the invention may also contain 
other conventional pharmaceutically-acceptable compounding ingredients, as 
necessary or desired, such as carriers or diluents. Conventional 
procedures for preparing such compositions in appropriate dosage forms may 
be utilized, in order to assure that in whatever dosage form, the 
composition will contain a pharmaceutically-effective amount of the 
compounds of the invention. 
The present compositions may be administered orally or other-than-orally 
(e.g., parenterally, by insufflation, topically, rectally, etc.), using 
appropriate dosage forms (e.g., tablets, capsules, suspensions, solutions, 
and the like, for oral administration; suspension emulsions, and the like, 
for parenteral administration; solutions for intravenous administration; 
and ointments, transdermal patches, and the like, for topical 
administration). 
Compositions intended for oral use may be prepared according to any method 
known to the art for the manufacture of pharmaceutical compositions, and 
such tablets or other compositions may contain one or more agents selected 
from the group consisting of sweetening agents, flavoring agents, coloring 
agents, preserving agents, and non-toxic excipients in order to provide 
pharmaceutically-elegant and palatable preparations. The excipients used 
may be, for example (1) inert diluents, such as calcium carbonate, sodium 
carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating 
and disintegrating agents, such as corn starch, or alginic acid; (3) 
binding agents, such as starch, gelatin or acacia, and (4) lubricating 
agents, such as magnesium stearate, stearic acid or talc. The tablets may 
be uncoated or they may be coated by known techniques with, for example, 
glyceryl monostearate or glyceryl distearate as a time delay material, to 
delay disintegration and absorption in the gastrointestinal tract and 
thereby provide a sustained action over a longer period. They may also be 
coated by the techtechniques described in U.S. Pat. Nos. 4,256,108; 
4,160,452; and 4,265,874 to form osmotic therapeutic tablets for 
controlled release. In some cases, these formulations for oral use may be 
in the form of hard gelatin capsules, wherein the active ingredient is 
mixed with an inert solid diluent, such as calcium carbonate, calcium 
phosphate or kaolin, or in the form of soft gelatin capsules wherein the 
active ingredient is mixed with water or an oil medium, such as peanut 
oil, liquid paraffin, or olive oil. 
Aqueous suspensions normally contain the active materials in admixture with 
excipients suitable for the manufacture of aqueous suspensions. Such 
excipients include: (1) suspending agents, such as sodium 
carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, 
sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) 
dispersing or wetting agents which may be (a) a naturally-occurring 
phosphatide, such as lecithin; (b) a condensation product of an alkylene 
oxide with a fatty acid, for example, polyoxyethyolene stearate; (c) a 
condensation product of ethylene oxide with a long chain aliphatic 
alcohol, for example, heptadecaethyleneoxycetanol; (d) a condensation 
product of ethylene oxide with a partial ester derived from a fatty acid 
and a hexitol, such as polyoxyethylene sorbitol monooleate; or (e) a 
condensation product of ethylene oxide with a partial ester derived from a 
fatty acid and a hexitol anhydride, for example, polyoxyethylene sorbitan 
monooleate. 
The aqueous suspensions may also contain one or more preservatives, such as 
ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or 
more flavoring agents; and one or more sweetening agents, such as sucrose 
or saccharin. Oily suspensions may be formulated by suspending the active 
ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil 
or coconut oil, or in a mineral oil such as liquid paraffin, and may 
contain a thickening agent, such as beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents and flavoring agents may be added to provide a 
palatable oral preparation, and these compositions may be preserved by the 
addition of an antioxidant, such as ascorbic acid. 
Dispersible powders and granules, which provide the active ingredient in 
admixture with a dispersing or wetting agent, a suspending agent and one 
or more preservatives, are suitable for the preparation of an aqueous 
suspension. Suitable dispersing or wetting agents, suspending agents, and 
sweetening, flavoring and coloring agents described above may also be 
present. 
The pharmaceutical compositions of the invention may be in the form of 
oil-in-water emulsions. The oily phase may be a vegetable oil, such as 
olive oil or arachis oils, or a mineral oil, such as liquid paraffin or a 
mixture thereof. Suitable emulsifying agents include (1) 
naturally-occurring gums, such as gum acacia and gum tragacanth, (2) 
naturally-occurring phosphatides, such as soy bean and lecithin, (3) 
esters or partial esters derived from fatty acids and hexitol anhydrides, 
such as sorbitan monooleate, and (4) condensation products of said partial 
esters with ethylene oxide, for example, polyoxyethylene sorbitan 
monooleate. These emulsions may also contain sweetening and flavoring 
agents. 
Syrups and elixirs may be formulated with sweetening agents, for example, 
glycerol, propylene glycol, sorbitol or sucrose, and may also contain a 
demulcent, a preservative and flavoring and coloring agents. 
These compositions may be in the form of a sterile injectable aqueous or 
oleagenous suspension, formulated according to known methods using those 
suitable dispersing or wetting agents and suspending agents mentioned 
above. The injectable preparation may also be a sterile injectable 
solution or suspension in a non-toxic parenterally-acceptable diluent or 
solvent, for example, as a solution in 1,3-butane diol, Among the 
acceptable vehicles, suspending medium and solvents that may be employed 
are water, Ringer's solution, isotonic sodium chloride solution, and 
sterile, fixed oils. For this purpose, any bland fixed oil may be 
employed, including synthetic mono- or diglycerides, and fatty acids, such 
as oleic acid. 
A composition of the invention may also be administered in the form of 
suppositories for rectal administration of the drug. These compositions 
may be prepared by mixing the drug with a suitable non-irritating 
excipient, such as cocoa butter or polyethylene glycols, which is solid at 
ordinary temperatures, but liquid at the rectal temperature and will 
therefore melt in the rectum to release the drug. 
For topical use, creams, ointments, jellies, solutions or suspensions, and 
other forms, containing the compositions of the invention, are employed. 
Treatment dosage for human beings may be varied, as determined by the 
administering professional, but daily dosages of the compounds of the 
invention generally range from about 0.5 mg to about 1,000 mg, and 
preferably, from about 5 mg to about 500 mg. The amount of active 
ingredient that may be combined with the carrier materials to produce a 
single dosage form will vary depending upon the host treated and the 
particular mode of administration. For example, a formulation intended for 
oral administration may contain, for example, from 5 mg to 500 mg of 
active agent compounded with an appropriate and convenient amount of 
carrier material which may vary from about 5 to about 95 percent of the 
total composition. 
It will be understood, however, that the specific dose level for any 
particular patient will depend upon a variety of factors including the 
activity of the specific compound employed, the age, body weight, general 
health, sex, diet, time of administration, route of administration, rate 
of excretion, drug combination and the severity of the particular disease 
undergoing therapy. 
The compounds of Formula I may be prepared by the methods shown in the 
following Reaction Scheme, wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, 
R.sup.5 and R.sup.6, y and p are as defined above, unless otherwise 
indicated. Also, as will be evident to those skilled in the art and as 
demonstrated in the Examples hereinafter, reactive groups not involved in 
the reactions, such as amino, carboxy, mercapto, etc., may be protected by 
methods standard in peptide chemistry prior to the coupling reactions and 
subsequently deprotected to obtain the desired products. 
##STR2## 
Process A 
Benzofused lactam 2 ring size ranging from 6 to 8, prepared from a 
precursor ketone by a procedure of Blicke et al., J. Am. Chem. Soc., 76, 
2317 (1954), is converted to (3), with PX.sub.5 where X=Br or Cl [Nagasawa 
et al., J. Med. Chem., 14, 501 (1971)]. Reaction of (3) with sodium or 
lithium azide in a suitable solvent such as DMF or ethanol [see, for 
example, Brenner et al., Helv. Chem. Acta, 41, 181 (1958)] affords (4) 
which can be alkylated with an alkylhalide or iodoalkylester in the 
presence of a strong base, like sodium hydride, in a solvent such as DMF 
or THF to produce (5). Reduction of (5) with hydrogen and a suitable 
catalyst, such as palladium on carbon, affords (6). 
Alternatively, (3) may be alkylated in the presence of a strong base, like 
sodium hydride, and the intermediate (6) converted to (7) by reaction with 
an azide salt as described above. 
Intermediate 7 may be reductively coupled with an aldehyde, ketone, keto 
acid or ketoester in a solvent such as ethanol using a catalyst such as 
palladium on carbon to afford 1a (X=absent). 1a may also be prepared using 
sodium cyanoborohydride to effect reduction. 
Alternatively, intermediate 7 may be coupled with a carboxylic acid using a 
coupling agent such as dicyclohexylcarbodiimide (DCC) and an activator 
such as 1-hydroxybenzotriazole (HOBt) in an aprotic solvent such as 
chloroform or THF to afford 
##STR3## 
Compound 1b can also be prepared by reacting 7 with an acid chloride and a 
tertiary amine such as triethylamine in an aprotic solvent such as 
chloroform or THF. The acid chloride is prepared from a carboxylic acid 
and thionyl chloride or PCl.sub.3 in an aprotic solvent such as 
chloroform. 
The compounds claimed may also be prepared as their R- or S-enantiomers, 
chiral at the C-3 amino group by resolution of compounds of structure 7 
with resolving agents, such as D- or L-tartaric acid, in a solvent, such 
as acetone. After recrystalization of the resulting salt in solvents, such 
as ethanol, the free amine is isolated by dissolving the salt in water and 
adjusting the pH to 9 with ammonium hydroxide. The free amine is extracted 
from water with a solvent, such as methylene chloride. Claimed compounds 
may then be prepared via procedures outlined above. 
Process B 
Compound 1a (R.sup.3 =CO.sub.2 H) may be further elaborated as follows. The 
acid 1a can be reacted with an alkoxychloroformate (such as 
ethylchloroformate), a tertiary amine (such as triethylamine) in an 
aprotic solvent such as tetrahydrofuran (THF) to give, upon filtration, a 
mixed anhydride intermediate which is then reacted with an excess of 
diazomethane in ether to give diazomethylketone (8). Reaction of (8) with 
trifluoroacetic acid (TFA). Followed by stirring in methanol or ethanol 
gives hydroxymethyl ketone 
##STR4## 
In the above preparations, the keto acid or ester can be represented by the 
formula 
##STR5## 
and may be, for example, 2-oxo-4-phenyl-butyric acid. Other .alpha.-keto 
acids or esters may be utilized to prepare other compounds of the present 
invention for various definitions of R.sup.a and Y. Such .alpha.-keto 
acids are readily available or may be prepared by well-known techniques. 
For example, synthons such as 
##STR6## 
can be converted to .alpha.-keto acids or esters using methods involving 
alkylation followed by hydrolysis as described in the literature. An 
excellent method involves the reaction of Grignard reagents R.sup.a MgX 
with ClCOCO.sub.2 Y or YO.sub.2 CCO.sub.2 Y. Another method involves 
condensing substituted acetic acid esters with diethyl oxalate followed by 
hydrolytic decarboxylation under acidic conditions to obtain .alpha.-keto 
acids. Carefully controlled acid hydrolysis in alcohol of acyl cyanides, 
which are prepared from acid chlorides and cuprous cyanide, also proves to 
be a viable synthetic route to .alpha.-keto esters. Nucleophilic 
displacement reactions on chloro or bromo pyruvic acid (ester) can also be 
used to produce a variety of interesting .alpha.-keto acids (esters). In 
these formulae, Y is a group such as loweralkyl or benzyl. 
Additional compounds of Formula I can be prepared by employing the keto 
acids and esters listed in Table I below. 
TABLE I 
______________________________________ 
##STR7## 
______________________________________ 
(a) 
##STR8## 
(b) 
##STR9## 
(c) 
##STR10## 
(d) 
##STR11## 
(e) 
##STR12## 
(f) 
##STR13## 
(g) 
##STR14## 
(h) 
##STR15## 
(i) 
##STR16## 
(j) 
##STR17## 
(k) 
##STR18## 
(l) 
##STR19## 
(precursor for the corresponding amino compound) 
(m) 
##STR20## 
(precursor for the corresponding amino compound) 
(n) 
##STR21## 
(o) 
##STR22## 
(p) CH.sub.3 SCH.sub.2 CH.sub.2 COCOOH 
(q) (CH.sub.3).sub.2CH.sub.2 CH.sub.2 COCOOH 
(r) CBZHN(CH.sub.2).sub.4COCOOH 
(precursor for the corresponding amino compound) 
(s) 
##STR23## 
(t) 
##STR24## 
(u) 
##STR25## 
______________________________________ 
The following examples set forth the best mode currently known for 
preparing the compounds of the invention and are not intended to be 
construed as limitative, but rather illustrative, thereof. Unless 
otherwise indicated, all temperatures are in degrees Celcius.