Note: Descriptions are shown in the official language in which they were submitted.
~6~3i~
4~13493/CGC 949/1-1-2/-~
Benzazepin-2-ones
The present invention is based upon the discovery that certain
substituted 3-amino-[l]benzazepin-2-one-l-alkanoic acids and deri-
vatives represent a new class of potent angiotensin-converting
enzyme (ACE) inhibitors.
The foregoing attributes render the 3-amino-[l]benzazepin-2-ones
of this invention particularly use~ul when administered, alone or
in combination, ~o mammals, e.g. for the treatmen-t of prevention
of diseases responsive to inhibition of angiotensin converting enzyme
e.g., cardiovascular disorders such as hypertension and cardiac con-
ditions such as congestive heart failure.
This invention relates to novel 3-amino-[l]benzazepin-2-one-1-
aLkanoic acids, and derivatives useful as angiotensin-converting
enzyme inhibitors, processes for preparing same, pharmaceutical
compositions comprising said compounds, and me-thods of treating
diseases responsive to inhibition of angiotensin-converting enzyme
by administration of said compounds and compositions to mammals.
The compounds of the invention are characterized by -the general
formula 1 X
R 6 ll 4
7 ~ ~q/5 \ /R5 (I)
8 ~ 2
B
wherein RA and RB are radlcals of the formula
63~
2 --
-- 2
_CH/Rl and-C~ 2 , respectively9
o o
in which R is carboxy or a functionally modified carboxy;
Rl is hydrogen, lower alkyl, amino~lower) alkyl~ aryl, aryl (Iower)
alkyl, cycloalkyl or cycloalkyl (lower) alkyl; R2 is hydrogen or
lower alkyl; R3 and R4, each independently, represent hydrogen,
lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, tri-
fluoromethyl, or R3 and R4 taken together represent lower alkylene-
dioxy; R5 is hydrogen or lower alkyl~ and X represents oxo, two
hydrogens, or one hydro~y together with one hydrogen~ and wherein
~he carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro;
and salts and complexes thereof.
The functionally modified carboxyl group in the meaning of the
symbol R is e.g. an esterified carboxyl group or a carbamoyl group
optionally substituted on the nitrogen atom.
More specifically one or both of Ro represented by COR6 in radical
RA and represented by COR7 in radical RB independently represent
carboxy, esterified carboxy, carbamoyl or substitu-ted carbamoyl.
The salts and complexes of the compounds of formula I are derived
Erom those compo~mds which have salt formlng properties and are
preferably pharmaceutically acceptable salts and complexes.
A carl~oxyl gro~lp R is represented by COR6 (in radical RA) wherein
R6 is hydroxy or COR7 (in radical RB) wherein R7 is hydroxy.
An esterified carboxyl group R is especially one in which the
esterifying radical represents optionally substituted lower alkyl
or optionally substituted phthalidyl and is represented by the
partial formula -COR6 ~in radical RA) or the partial formula -COR7
(in radical RB), wherein one or both of R6 and R7 represents lower
alkoxy7 (amino, mono- or di-lower alkylamino)-substituted lower
alkoxy, carboxy-substituted lower alkoxy~ e.g. a-carboxy substituted
lower alkoxy, lower alkoxycarbonyl-substituted lower alkoxy, e.g.
~-lower alkoxycarbonyl-substituted lower alkoxy; aryl-substituted
lower alkoxy, e.g. optionally substituted benzyloxy or pyridylmethoxy;
(hydroxy~ lower alkanoyloxy or lower alkoxy) substituted lower alkoxy,
e.g. pivaloyloxymethoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-
substituted lower alkoxymethoxyj bicycloalkoxycarbonyl-substituted
lower alkoxy, e.g. bicyclo [2,2~1]heptyloxycarbonyl-substituted
lower alkoxy, especially bicyclo~2,2,1]heptyloxycarbonyl-substitllted
methoxy; 3-phthalidoxy; (lower alkyl, lower alkoxy~ halo)-substi-
tuted 3-phathalidoxy.
An optionally N-substituted carbamoyl group ~ is especially one
which is represented by the partical formula -COR6 ~in rad;cal RA)
or the partial formula -COR7 (in radical RB), wherein one or both
of R6 and R7 represent amino; lower alkylamino; di-lower alkylamino;
di-lower alkylamino in which both allcyl groups are linked by a
carbon to carbon bond and together with the amino nitrogen Eorm a 5-,
6- or 7 ~ membered heterocyclic ring, e.g. pyrrolidino, piperidino,
or perhydroazepino; (amino or acylamino)-substituted lower alkyl-
amino; ~-(carboxy or lower alkoxycarbonyl)-substituted lower alkyl-
amino~ aryl substituted lower alkylamino in which aryl is preEerably
phenyl or indolyl and which can be substituted on the ~-carbon atom
by carboxy or lower alkoxycarbonyl.
Any prodrug derivatives of compounds of this invention e.g. any
pharmaceutically acceptable esters and amides of the mono- or di-
carboxylic acids of this invention that may be convertible by sol-
volysis or under physiological conditions to the said carboxylic
acids, e.g. esters and amides cited above, represent a particular
object of the invention.
ii3~
-- 4 --
Said esters are pre~erably, e.g., tile straight chain or branched
lower al.kyl esters unsubstituted or sui~ably substituted such as the
pivaloyloxymethyl9 bornyloxycarbonylmethyl, benzyl, pyridylmethyl~
~-carboxyethyl or suitabl.y esterified ~-carboxyethyl esters, and the
like.
Said amides are preferably e.g. simple primary and secondary amides
and amides derived from the amino acids or derivati-ves thereof, such
as the amides derived from a]anine, phenylalanine and the like.
More particularly, the illvention relates to compounds of formula IA
IR5
Il ! -N-CH-Rl (IA)
R ~ \N / CO-R6
o
wherein Rl is ilydrogen~ lower alkyl, amino(lower)alkyl, aryl, aryl-
(lower)allcyl, cycloalkyl(lower)alkyl, R2 and R5 represent hydrogen
or lower alkyl, R3 and R~ represent hydrogen, lower alkylg lower
alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluormethyl, or R3
and R4 taken together represent lower alkylendioxy, X represents oxo,
two hydrogens or one hydroxy group and one hydrogen~ R6 and R7 in-
dependently represent hydroxy, amino, mono- or di-(lower)alkylam:ino,
.I.ower alkoxy, aryl(lower)alkoxy, lower alkanoyloxymethoxy, (amino,
mono- or di-lower alkylamino,carboxy, or lower alkoxycarbonyl)--lower
alkoxy; or the pharmaceutically acceptable salts or complexes there-
oE.
Preferred embodiments o~ this invention relate to compounds oE
formula IA, wherein Rl i~ hydrogen~ lower alkyl, amino(lower)-
alkyl, aryl(lower)alkyl where aryl represents phenyl unsubsti-
tuted or mono- or disubstituted by lower alkyl, hydroxy~ lower
alkoxy, lower alkylenedioxy, lower alkanoyloxyg halogen or tri-
Eluoromethyl, R2 and R5 are hydrogen or lower alkyl, R3 and R4 are
hydrogen, lower alkoxy, lower alkyl, halogen or trifluoromethyl;
3~
or R3 and R4 taken together represent alkylenedioxy, X represents
oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 in-
dependently represent hydroxy, amino, lower alkoxy, phenyl(lower)
alkoxy, lower alkoxycarbonyl(lower)alkoxy, or pharmaceutically
acceptable salts thereof.
Very useful are compounds of formula I~, wherein Rl is hydrogen,
lower alkyl, ~-amino(lower)alkyl, aryl(lower)alkyl were aryl repre-
sents phenyl unsubstituted or mono-substituted by lower alkyl,
hydroxy; lower alkoxy9 lower al.kanoyloxy, halogen or trifluoromethyl,
R2 and R5 are hydrogen or lower alkyl, R3 and R4 are hydrogen, lower
alkoxy, lower allcyl, halogen, or trifluoromethyl; or R3 and R4 taken
together represent lower alkylendioxy, X represents oxo, one hydroxy
and one hydrogen, or 2 hydrogens, R6 and R7 independently represent
hydroxy, amino, lower alkoxy, phenyl(lower)alkoxy, lower alkoxycar-
bonyl(lower)alkoxy, or pharmaceutically acceptable salts thereof.
Particularly useful are compounds oE formula IA wherein Rl is hy-
drogen, lower alkyl, ~-amino(lower)alkyl, aryl(lower) alkyl, R2
and R5 are hydrogen or lower alkyl, R3 is hydrogen, R4 is hydrogen,
lower alkoxy, lower alkyl, halogen, or trifl.uoromethyl, X repre-
~ents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7
independently represent hydroxy, amino, lower alkoxy, phenyl(lower)
alkoxy, lower alkoxycarbonyl(lower)alkoxy, or pharmaceuticall.y
acceptable salts thereof.
Especially useful are compounds of formul.a IA wherein Rl is hydrogen9
methyl, ethyl, isopropyl, ~ -aminopropyl, ~-aminobutyl, aryl-
(methyl, ethyl, propyl) where aryl represents phenyl unsubstituted
or substituted by one methyl~ hydroxy~ methoxy, methylenedioxy,
acetyloxy, chloro or trifluoromethyl group, R2 and R5 are hydrogen or
methyl, R3 and R4 represents hydrogen, methoxy, methyl~ chloro or
63~
-- 6
trifluoromethyl, X represents oxo, one hydroxy and one hydrogen
or 2 hydrogens, P~6 and R7 independently represent hydroxy, amino~
ethoxy, methoxy, benzyloxy, ethoxycarbonylmethoxy or pivaloyloxy-
methoxy; or pharmaceutically acceptable salts thereof.
~xceedingly useful are compounds of formula IB
NH-CE ~ n 2n 8 (IB)
CH2-CO-R7
wherein n represents an integer from 1 to 4, R8 is hydrogen, phenyl
unsubstituted or monosubstituted by lower alkyl, lower alkoxy, lower
alkanoyloxy, halogen, hydroxy, or trifluoromethyl, R6 and R7 inde-
pendently represent hydroxy, lower alkoxy of up to 4 carbon atoms,
benzyloxy~ or amino, or pharmaceutically acceptable salts thereof.
Especially valuable are compo~mds of formula IB, wherein C ll2 re-
presents ethylene, R8 represents phenyl or phenyl mono-substituted
by lower alkoxy with up to 4 carbon atoms, lower alkyl with up to 4
carbon atoms, halogen or trifluoromethyl, R6 and R7 independently
represent hydroxy or lower alkoxy with up to 4 carbon atoms, or
pllarmaceutically acceptable salts thcreof.
The present invention also relates to the stereoisomers of compounds
of formula I. A number of racemates are obtainable when, e.g~ in
36
7 --
formula IA at least one of Rl and R2 is not hydrogen and/or X re-
presents H(OLI).
The individual enantiomers of said racemates may in turn be obtained.
Certain specific said isomers are preferred as angiotensin-converting
enzyme inhibitors.
Outstanding are compounds of formula IC
/ ~ / \ (S)/Cn~l2n R8
il I (S) s-NH-C~l (IC)
CO-R6
l O
CH2-CO-R7
wherein S represents the chirality, n represents an integer from 1
to ~, R8 is hydrogen, phenyl unsubstituted or monosubstituted by
lower alkyi, lower alkoxy, lower alkanoyloxy, halogen, hydroxy, or
trifluoromethyl, R6 and R7 independently represent hydroxy, lower
alkoxy of up to 4 carbon atoms, benzyloxy or amino, or pharma~
ceutically acceptable salts thereof.
The general definitions used herein have the following meanings
within the scope of the present invention.
~ryl represents a carbocyclic or heterocyclic aromatic radical
preferably being phenyl, unsubstituted or mono or di-substituted by
lower alkyl9 lower alkoxy, lower alkylenedioxy, lower alkanoyloxy9
hydroxy, halogen or trifluoromethyl.
6~1~
-- 8 --
The term cycloalkyl represents a cyclic hydrocarbon radical which
preferably contains 3 to 8 carbons and is, for example, cyclopentyl
or cyclohexyl~
The term aryl(lower)alkyl represents preferably benzyl, l-or 2-
phenylethyl, 1- 9 2- or 3-phenylpropyl 1-,2-,3- or 4-phenylbutyl,
wherein the phenyl ring is unsubstituted or mono- or disubstituted
by lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower
alkanoyloxy, halogen or trifluoromethyl.
~he term cycloalkyl(lower)alkyl represents preferably l-or 2-(cyclo-
pentyl or cyclohexyl)ethyl, 1-,2- or 3-(cyclopentyl or cyclohexyl)
propyl, or 1-,2-,3- or 4~cyclopentyl or cyclohexyl)-bu-tyl.
The term "lower" referred to above and hereinafter in connection
with organic radicals or compounds respectively defines such with
up to and including 7, preferably up and including 4 and advantage-
ously one or two carbon atoms.
A lower alkyl group preferably contains 1-4 carbon atoms and re-
presents for example ethyl~ propyl, butyl or advantageously methyl.
lower alkoxy group preferably contains 1-4 carbon atoms and re-
presents for exclmple methoxy, propoxy, iSOpl-OpOXy or advantageously
ethoxy. ~ mono-~lower)alkylamino group preEerably contains 1-
~carl)on atoms in the alkyl portion and is Eor example N-methylam;no,
N propylamino or advantageously N-ethylamino. A di-(lower~alkylamino
group preierably contains 1-4 carbon atoms in each lower alkyl
portion and represents, for example, N,N-dimethylamino, N-methyl-
N-ethylamino and advantageously N,N-diethylamino.
3~
Lower alkanoyloxy represen~s preferably acetoxy, propionyloxy or
pivaloyloxy.
Alkylenedioxy represents preferably ethylenedioxy, and advan~.ageously
methylenedioxy.
Aryl lower alkoxy represents advantageously e.g. benzyloxy, benzyloxy
substituted by methyl, methoxy or chloro, and pyridylmethoxy
Carboxy ].ower alkoxy represents advantageously e.g. l-carboxy-
ethoxy.
Lower alkoxycarbonyl. lower alkoxy represents advantageously e.g.
l-(ethoxycarbonyl)ethoxy.
Amino(lower)alkoxy~ mono-(lower)alkylamino lower alkoxy, di-(lower)
alkylamino lower alkoxy advantageously represent respectively e.g.
aminoethoxy, ethylaminoethoxy, diethylaminoethoxy.
Lower alkanoyloxymethoxy represents advantageously e.g. pivaloyl-
oxymethoxy.
Bicycloalkylaxycarbonyl-(lower)alkoxy pre~erably represents bicycLo-
[2,2,1]heptyloxycarbonyl-(lower)alkoxy unsubstituted or substi
tutecl by lower alkyl advantageously bornyloxycarbonylmethoxyO
~m:ino(lowcr)alkyl and~ -amino(lower)alkyl represent preferably
amino(ethyl, propyl or butyl) and C~-amino(ethyl, propyl or butyl)
respectively.
Halogen preferably represents chlorine, but may also be bromine,
fluorine or iodine.
3~
-- 10 --
According to the present invention one or both of the carboxyl
groups oE the d;carboxylic acids, i.e. compounds of formula IA
or IB wherein R6 and R7 are hydroxy, may be functionalized as esters
or amides. These functional derivatives are preferably the mono or
bis lower alkyl esters e.g. methyl, ethyl, n- or i-propyl9 butyl or
benzyl esters; the mono- or bis-amides, the mono- or di N-alkylated
amides9 e.g. mono- or diethylamides; the mono or bis substituted
lower alkyl esters, e.g. the ~-(amino, mono- or dimethylamino9
carboxy or carbethoxy) -(ethyl9 propyl or butyl) esters. Highly
preferred functional derivatives are the mono esters of formula IA,
e.g. wherein one of R~ and R7 represents hydroxy and -the other re-
presents lower alkoxy.
Pharmaceutically acceptable salts are preferably metal or ammonium
salts of said compounds of formula I wherein R represents carboxy
or of formula IA wherein COR6 and/or COR7 represent carboxy9 more
particularly alkali or alkaline earth metal salts9 e.g., the sodium,
potassium, magnesium or calcium salt; or advantageously easily cry-
stallizing ammonium salts derived from ammonia or organic amines9
such as mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl)-
amines, lower alkylenediamines or lower hydroxyalkyl or aralkyl)-
alkylammonium bases, e.g., methylamine, diethylamine, triethylamine,
di.cyclohexylamine, triethanolamine, ethylenediamine, tris~(hydroxy-
methyl)aminomethane or benzyltrimethylammonium hydroxide. Said com-
po~mds of Fornmla ~ form acid addition salts, which are preferably
such of therapeutically acceptable inorganic or organic acids, such
as strong mineral acids, Eor example hydrohalic, e.g. hydrochloric
or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid9
aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic,
acetic, propionic, succinic, glycolic, lactic, malic, tartaric,
gluconic, citric, ascorbic, maleic9 fumaric, hydroxymaleic, pyruvic9
phenylace~ic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic9
salicylic, 4-aminosalicylic9 pamoic, nicotinic; methanesulfonic,
ethanesulfonic, hydroxyethanesulfonic, ben~enesulfonic, p-toluene-
sulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid.
The compounds of formula I exhibit valuable pharmacological
properties, e.g. cardiovascular effects, by inter alia inhibiting
the release of Angiotensin Il through selective inhibition of angio-
tensin-converting en~yme in mammals. The compounds are thus useful
for treating diseases responsive to angiotensin-converting enzyme
inhibition in mammals including man.
The compounds of this invention exhibit primari]y hypotensive/
antihypertensive and cardiac effects. These properties are demon-
strable by in vivo or in vitro tests, using advantageously mammals,
_
e.g., rats, cats, dogs or isolated organs -thereof, as test objects.
The animals may either be normotensive or hypertensive e.g., geneti-
cally spontaneous hyper-tensive rats, or renal hypertensive rats and
dogs, and sodium-depleted dogs. The compounds can be applied to the
test animals enterally or parenterally, advantageously orally or
intravenously, for examRle within gelatin capsules or in the form
of starchy suspensions or aqueous solutions. The applied dosage
may range between about 0.01 and 100 mg/kg/day, preferably between
about 0.05 and 50 mg/kg/day, advantageously between about 0.1 and
25 mg/kg/day.
The in vivo lowering effect on the blood pressure is recorded,
__
eitller directly by means oE a catheter, placed in the test animal's
Eemoral artery, or indirectly by sphygmomanometry at the rat's tail
and a transducer. The blood pressure is recorded prior to and after
dosing in mm Eg.
Thus the antihypertensive effec~s are demonstrable in spontaneously
hypertensive rats by indirect measurement of systolic pressure.
Conscious rats are placed individually in restraint cages within a
~ f ~ ~
~.~3~
- 12 -
gently warmed chamber. A pulse se~sor is placed distal to an inflat~
able occulsive cuff on each rat9s tail. The cuff is periodically in-
flated to occlude the tail artery. The pressure in the cuff is con-
tinously reduced and the systolic pressure corresponds to the pressure
in the cuff, at which the pulse waves reappear. After obtaining con-
trol values of blood pressure and heart rate, test compounds are
administered ora]ly once daily for 4 consecutive days. Additional
blood pressure measurements are usually made at 2.0, ~.0 and 23.5
hours after each daily dosing, and responses are compared to those
of rats dosed with the treatment vehicle.
As an illustration of the invention, the antihypertensive effect of
tlle ~higher melting" l-carboxymethyl-3-(l-ethoxycarbonyl-3-phenyl-
propylamino)~2,3,4,5-tetrahydro-lH~l]benzazepin-2-one of example 1
is reported: at a dose of 3 mg/kg p.o. it lowers blood pressure by
40 mm Hg as the average effect measured at 2 and 4 hours after the
last two daily dosings. The corresponding S9S enantiomer of example
12 at a dose of 1 mg/kg p.o. lowers blood pressure by 30 mm Hg.
Tlle compounds of this invention when administered intravenously or
orally also e~hibit an inhibitory effect against the Angiotensin I
induced pressor response of normotensive rats. Angiotensin I is
hydrolyzed by the reaction of said c:onverting enzyme to the potent
pressor substance Angiotensin II. The inhibition of said enzyme
prevents the generation of Angiotensin II from Angiotensin I. In
this manner the increase of blood pressure provoked by Angiotensin I
is attellucltetl.
The corresponding in vivo test for intravenously administered com-
__
pounds is performed with male9 normotensive rats, which are anesthe-
tized with sodium 5-ethyl-5-(1-methylpropyl)-2~thiobarbiturate.
A femoral artery and saphenous vein are cannulated respectively for
direct blood pressure measurement and the i.v. administration of
Angiotensin I and a compound of this invention. After the basal
blood pressure is stabilized, pressor responses to 3 challenges of
333 ng/kg ~ngiotensin I i.v., at 5 minute intervals, are obtained.
Such pressure responses are usually again obtained at 5, 10, 155 30
and 60 minutes after i.v. administration of the compound to be tested,
and compared with the initial responses. Any observed decrease of
said pressor response is an indication of Angiotensin I converting
enzyme inhibition. Illustrative of this invention, the "higher
melting" l-carboxymethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH[l]benza~epin-2-one of example 1 and the corres-
ponding S,S enantiomer of example 12 completely inhibit the pressor
response following ~ngiotensin I challenge through 30 minutes after
administration of either oE the said compounds at a dose of 1 mg/kg
i .v . .
The in vitro inhibition of the angiotensin-converting enzyme by the
compounds of this invention can be demonstrated by a method analogous
to Biochim. Biophys. ~cta 2939 451 (1973). According to this method,
said compounds are dissolved at about 1 mM concentration in phos-
phate buffer. To 100 microliters of solutions of the test compound
in phosphate buffer, d;luted -to the desired concentration, are added
100 microliters of 5 mM hippuryl-histidyl-leucine in phosphate
buffer, fo]lowed by 50 microliters of the angiotensin- converting
enzyme preparation (from lungs of adult male rabblts) in Tris bufEer,
containing potassium and magnesium chloride, as well as sucrose.
Said solutions are incubated at 37C for 30 minutes and combined with
0.75 ml oE 0.6 N aqueous sodium hydroxide to stop further reaction.
Then 100 microliters oE a 0.2% solution of o-phthalaldehyde in
meetlanol are added at room temperature, and 10 minutes later 100
microliters of 6N hydrochloric acid. These samples are read agains-
~water in a spectrophotometer set at 360 nm, and the optical densities
thereof estimated. They are corrected for the standard curve via
conversion factor expressing nanomoles of histidyl-leucine formed
during said 30 minute incubation period. The results are plotted
36
against drug concentration to determine the IC50, i.e., the drug
concentration which gives half the activity of the control sample
containing no drug. Illustrative of the invention, the "higher
melting" l-carboxymethyl-3-(l-carboxy-3-phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[l]benza~epin-2-one of example 9 and the corresponding
S,S enantiomer of example 19 show an IC50 of 5.2 x 10 9M and
1.7 x 10 9M respec-tively. The corresponding "lower melting" 1-
carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3~4,5-tetrahydro-lH-
[l]benzazepin-2-one of example 8 shows an IC50 of 5.8 x 10 M.
L~ngiotensin-converting enzyme not only participates in the
conversion of ~ngiotensin I to ~ngiotensin II, but also plays a role
in the control of bradykinin and aldos-terone levels. The effect of
the compounds of this invention on these factors may also contribute
to the antihypertensive and cardiac effects of these new compounds.
The aforementioned advantageous properties render the compounds of
this invention of great value as specific therapeutic agents
for mammals including man.
~ccordingly, the compounds of this invention are valuable antihyper-
tensive agents, especially useful for ameliorating hypertension
~regardless of etiology) and~or cardiac conditions, such as con-
gestive heart fai.l~lre, and/or other edemic or ascitic diseases.
They are also useful intermediates in the preparation of other
valuable products, especially of corresponding pharmaceutical com-
positions.
The compounds of formula I according to the invention can be pre-
pared in a manner which is known per se, in that, e.g.
a~ in a compound oE the formula
3~
- 15 `
R4~xo~ lU, "
NH-R5 (II)
~<~ u/
RB o
in which the carbocyclic ring may also be hexahydro or 6,7,8,9-
tetrahydro, and wherein X, RBg R3, R4 and R5 have the meanings given
hereinbefore, RA is introduced by alkylation with a compound of
the formula
A (IIIA)
wherein Z is a reactive es~erified hydroxyl group and RA has the
meanings given hereinbefore, or with a compound of the formula
Rl - CO - Ro (IV)
wherein Rl and Ro have ~he ~Q~n;ngs given hereinabove, in the
presence of a reducing agent9 with a temporary protection oE any
primary and secondary amino groups and/or~ op-tionally~ hydroxyl
anc~or oxo groups, which may be present in any one of the sub-
stituents X, RA, RB~ Rl, R3~ 4 5
or
~) a compound of the formula
R4~ 1 1
~ ~ N Il A (V)
3 H O
in which the carbocyclic ring may also be hexahydro or 6~7,8~9-
~3~i3~
- 16 -
tetrahydro, and wherein X, R3, R4 and R5 have the meanings given
hereinabove and ~ is hydrogen or R~ as defined hereinabove, is
alkylated with a compound of the formula
R~ - Z (IIIB~
wherein Z is a reactive esterified hydroxyl group and R~ has the
mP~nings given hereinabove, while protecting temporarily any primary
and secondary amino groups and/or, optionally, hydroxyl and/or oxo
groups which may be present in any one of the residues X, R~, RB9
R3, R4 and R5, or
c) a compound of the formula
R4 ~
i! ! ,~=Y ~VI)
J/
o
~B ,
in which the carbocyclic ring may also be hexahydro or 6,7,8,9-
tetrahydro and wherein Y is oxo or a reactive esteriEied hydroxyl
group Z together with hydrogen, and X, ~ , R3 and R4 have the
n~Q~ningg given hereinabove, is condensed with an amine of the
formula
R~ - ~H ~ R5 (VII)
wherein RA and R5 have the meanings given hereinabove, with the
proviso that in the case Y is OX09 the condensation is carried
out in the presence oE a reducing agent and with a temporary pro-
tection of the oxo group which may be present as the substituent X,
or
3~;
d) in a compound of the fo~nula
R4 ~ .~ I I ~ R5 R
~ N-C~I (VIII)
\R 7
/CH ~
in which the carbocyclic ring may also be hexahydro or 697~8,9-
tetrahydro, and wherein X and Rl to R5 have the meanings given herein-
above, one oE the symbols R? and R'l is cyano and the other one is
cyano or Ro as defined hereinabove, the cyano group(s) is (are) sub-
jected to solvolysis, or
e) a compound of the formula
o
4 ~ 0 11~ .
o ~0/ \ R5
H CO ~HRA (IX)
RB
in which the carbocyclic ring may also be he~ahydro or 6,7,8,9-
tetrahydro and wherein X, R~, RB~ R3, R~ and R5 have thc meani~gs
gi.ven hereinabove, or an ester thereoE, is cyclised, or
E) a compotmd ~hich i.s structurally identical with a con~pound of
formula I specified above9 except for having an additional double
bond located at C-3, or between the nitrogen atom a~d the adjacent
carbon atom within the group RA, is treated with a reducing agent
in order to saturate this~double bond, or
- 18 -
g) in order to produce a compound of formula I as specified herein-
above, in which ~ is oxo, condensing a compound of the formula
R4~<o~ ~
Il I ~ (X~
\N ~ /
RB o
in wh:ich the carbocyclic ring may also be hexahydro or 6,7,8~9-
tetrahydro, and wherein RB, R3 and R4 have the ~e~nings given herein-
above~ with an amine of the Eormula
RA ~ NH - R5 (VII)
wherein RA and R5 have the r-~n;ng given hereinabove, and
h) if desired, a resulting compound oE formula I as specified above
is converted into another com~o-md of formula I within. its above-
specified scope, andior
i) if desired, a resulting compound of formula I as specifiecl
above and having salt-forming properties is converted into a salt
thereo:E or a free compound is liberated from such a salt, and/or
j) if desired, a resulting compound of formula I as specified
above and having complex--forllling properties is converted into a
complex thereof~ and/or
k) if so required, an optical iso~er which has a specific configura-
tion with respect to at least one center of chirality is enriched
from a mixture of stereoisomeric forms oE a resulting compound of
formula I.
63~
- 19 -
The alkylation according to processes a) and b), which serves for
introduction of residues RA and ~ , respectively, is carried out in
a conventional manner, advantageously by treating a corresponding
starting material of ~ormulae II and V, respectively, with an
alkylating agent of the formula RA-Z (IIIA) or RB-Z (IIIB),
respectively9 wherein RA or RB have the meanings given hereinabove
and Z is a reactive esterified hydroxyl group 9 such as a hydroxyl
group esterified with a strong organic acid, e.g. an aliphatic or
aromatic sulfonic acid (such as a lower alkane sulfonic acid,
especially methane sulEonic, tri-fluoromethanesulfonic acid,
especially ben~enesulfonic, p-toluenesulfonic, p-bromobenzenesulfonic
and p~nitrobenzenesulfonic acid) or with a strong inorganic acid,
such as, especially, sulfuric acidp or a hydrohalic acid, such as
hydrochloric or, most preferably, hydriodic or hydrobromic acid.
The alkylation is carried out under conventional general conditions
at tempera-tures ranging between about 0C up to the boiling tempera-
ture of the reaction mixture, preferably at temperatures between
room temperature to about lOO~C. The reaction takes place advantage-
ously in the presence of a solvent which is inert with respect to
the reactants, such as chlorinated lower alkane (e.g. chloroform or
methylene chloride), an acyclic or cyclic ether (e.g. diethyl ether,
~ dimethoxyethane, dioxane or tetrahydrofuran) and, in particular,
a low-molecular weight tertiary amide (e.g. N,N-dimethylformamide,
N,N-dimetllylacetamide, N-methylpyrrolidone, N-ethylpiperidone and
he~ametllylphosp~oric acid triamide). Advantageously, the strong acid
~IZ liberated during the reaction is bouLId by the addition oE an acid-
binding agent, such as, preferablyp an inorganic acid-scavenger
such as an alkali metal bicarbonate, carbonate or hydroxide, an
organic quaternary ammonium salt ~e.g. a tetrabutylammonium salt)
or an organic tertiary base, such as triethylamine, N-ethylpiperi-
dine, pyridine or quinoline.
i3~i
- 20 -
In process a) 9 the alkylation can also be carried out under the
conditions of reductive alkylation in ~he manner generally kno~l and
used in the art. In carrying out the alkylation, a compound of the
general formula
Rl - C0 - R (IV)
in which Rl and R have the ~ningS given hereinabove~ is reacted
with the starting bicyclic compound II and, simultaneously or in a
subsequent step, with a reducing agent. Among reducing agents which
are used simultaneously with the alkylating agent, mention should be
made of formic acid and complex metal hydrides such as sodium cyano-
borohydride, among reducing agents used predominantly in a separate
subsequent operation9 i.e. reduction of a preformed imine (Schiff's
base~, mention should be made of diborane and complex metal hydrides,
such as, sodium borohydride, sodium cyanoborohydride which are added
advantageously to the primary reaction mixture wi~hout isolating
an intermediate, e.g. the imine. In this case~ the alkylation is
carried out advantageously in an organic solvent inert to the re-
ducing agent9 such as in an aliphatic or cyclic e-ther (such as di-
ethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or
tetrahydrofuran) or an aliphatic alcohol (such as methanol, ethanol,
isopropyl alcohol, glycol, glycol monomethyl ether or diethylenegly-
col~, preferably at about 0-80C. A principal reducing agent, how~
ever~ which can be used both simu]taneously and subsequentlyg is
hydrogen, especia]ly catalytically activated hydrogen. The catalysts
are those conventionally used as hydrogenation catalys~s9 i.e. pre-
~erably those of the class o precious metals (such as palladium,
platinum and rhodium) on a carrier (such as calcium carbonate9
aluminium oxide or barium sulfate)9 in a finely dispersed suspension
without carrier or, in form of complexes9 in a homogeneous phase.
Also, finely dispersed transition metals, such as Raney metals,
especially Raney nickel9 are very suitable catalysts for the re-
ductive alkylation. The specific reaction conditions depend9 to a
3~;
- 2l -
large extent, on the particular hydrogenation catalyst and its pre-
cise activity, and do not differ from those generally k~own for
hydrogenation. Temperatures ranging from room temperature to about
150C, and pressures of hydrogen ranging from atmospheric pressure
to about 300 atmospheres are applicable according to the standard
procedures of the art. In addition to the inert solvents which were
mentioned above in connection with the hydride reduction, also low-
molecular weight amides, especially tertiary amides (such as N9N-
dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-
ethylpiperidone, hexamethylphosphoric acid triamide) 'but also form-
amide and acetamide can be used as suitable solvents. Specia'l
measures have to be taken with starting materials of formula II which
have an easily reducible functional group, such as the 5-oxo group;
in order to preserve these groups, selective reduction conditions,
as known in the prior art, have to be applied, or, if a simultaneous
reduction of these groups is desired or required, vigorous reagents
and/or conditions are employed accorclingly.
The preformed imines referred to above are preferably prepared by
condensing an amine of formula II with a compound of formula IV
in an inert solvent, e.g. toluene or methylene chloride, advantage-
ously in the presence of' a dehydrating catalyst, e.g. boron tri-
fluoride etherate, p-toluenesulfonic acid or molecular sieves.
Process b) is preferably carried out in the presence of very strong
bas~s, such as alka'li metal hydrides (e.g. sodium or potassium
hydride), alkoxides (e.g. sodium methoxide or ethoxide, potassium
tert-butoxide) or amides (e.g. lithium diisopropylamide)9 whereby
ethers and amides mentioned above are preferred as solvents. In a
special modification of process b), starting materials are used in
which RA is hydrogen, and at least two equivalents of the reactant
IIIB is employed. In the resulting product, both RA and RB are identi
cal and within the scope of the meanings of RB.
36
- 22 -
In any of the alkylation proesses, primary and secondary amino
groups in starting materials, except for the secondary amino group
to be alkylated, must be in a temporarily protected form during the
alkylation. Suitable protecting groups, as well as procedures for
their introduction and removal are well known in the art being
elaborated in great detail in particular as general methods for the
synthesis of peptides, cf. Houben-Wey'l: Methoden der organischen
Chemie; ~th edition, ~ol. 15/I and II, E.Wiinsch (editor): Synthese
von Peptiden (Georg Thieme Verlag, Stuttgart; 1974~. The narrower
selection of the protecting groups depends on the specific purpose,
it being necessary to take into account in particular the speciEic
properties oE the particular starting materials and the reaction
conditions of the speciEic process. In the case of several functional
groups to be protected, advantageous combinations can be selected.
PreEerably, for example~ similar or, even better9 identical amino
protecting groups, are used both in the radicals R and in the
radical Rl and are simultaneously removed following alkylation.
Suitable as amino-protecting groups are especially amino-protecting
groups that can be removed by reduction, for example especially
tllose of the benzyloxycarbonyl type in which the 'benzyloxycar'bonyl
group may be substituted in the aromatic moiety by halogen atoms,
lower alkoxy groups and/or lower alkyl raclicals ancl, especiaLly,
hy Llitro groups, such as the p-chloro- and p-'bromobenzyloxycarbonyl,
~methoxybenzyloxycarbonyl, p-methylbenzyloxycarbonyl and, especial]y,
p=nitrobenzyloxycarbonyl group, or alternatively the isonicotinyloxy-
carbonyl group. An advantageous amino-protecting group is an ethoxy-
carbonyl group which carries in the ~-position a silyl group substi-
tuted by three hydrocarbon radicals, such as triphenylsilyl, dimethyl-
tert.butylsilyl or, especially, trimethylsilyl. A ~-(trihydrocarbonyl-
silyl)-ethoxycarbonyl group of this type, such as a ~-(tri-lower
alkylsily])-ethoxycarbonyl group, for example, especially ~-(tri-
methylsilyl~-ethoxycarbonyl, forms with the amino group to be pro-
tected a corresponding ~-trihydrocarbylsilylethoxycarbonylamino group
~ 2
- 23
(for example the ~-trimethylsi]ylethoxycarbonylamino group)g which
may be removed under very specific 9 very mild conditions by the action
of fluoride ions.
It is also possible to use groups that can be removed by acidolysis,
such as the tert~butoxycarbonyl groups and analogous groups, as well
as those of the aralkyl type, such as benzhydryl, di-(4-methoxy)-benæ-
hydryl and triphenylmethyl (trityl), or certain aralkoxycarbonyl
groups of the 2-(p-biphenylyl)-2-propoxycarbonyl -type, which are
described in Swiss Patent Specification No. 509 266. It should be
noted that protecting groups derived Erom esters o carbonic acids
are in most cases also removable by basic hydrolysis.
For the optional temporary protection of hydroxy groups, protecting
groups may be used advantageously that can be removed by reduction,
c the above-cited text (Houben-Weyl), and also groups that can be
removed by acidolysis 9 such as 2~tetrahydropyranyl 9 tert-butoxy-
carbonyl and tert-butyl. Preferred hydroxy-protecting groups that
c~m be removed by reduction are, for example, benæyl groups that may
be substituted in the aromatic moiety by halogen, lower al.kyl~ lower
alkoxy and/or, especially7 nitro, especially the ~-nitrobenæyl group.
It is also possible to use acyl groups that can be removed under
weakly basic conditions7 such as formyl or trifluoroacetyl.
For tlle optional protecti.on of oxo groups, these are preferably
protected as ketals, especia].ly as ketals derived from lower
alkal~ols~ such as methanol or ethanol, or advantageously of ethylene
glycol, or as corresponding thioketals preferably those o 172-
ethanedithi.ol. All these groups can liberate oxo groups under the
conditions indicated further below.
The subsequent removal of protecting groups in accordance with the
invention depends on their nature and is carried out in each case in
a conventional manner known per se taking into consideration the
` f ` ~
- 24 -
general properties of the derived product. If the protecting groups
for amino, hydroxy and oxo have been so selected tha~ they can be
removed under similar conditions (especia].ly preferred here are the
groups removable by acidolysis or, for amino and hydroxy7 by reduction,
that have already been given special mention)7 then all of ~hese
protecting groups are advantageously removed in a single operation;
in special cases7 however7 it is possible to use different types of
groups and remove each of them individually.
The groups that can be removed by reduction7 especially those that
contain halogenated lower alkyl radicals (for example 2~2,2-trichlor-
ethyl radicals), isonicotinyl radicals (for example isonicotinyloxy-
carbonyl) and, especially, substituted benzyl radicals, especially
4-nitroben~yl radicals of any kind7 are preferably removed by zinc
reduction, usually in the presence of an acid7 preferably acetic acid7
and with or without the addition of an inert organic solvent, usually
at room temperature. The removal of a protecting group by acid hy
drolysis (acidolysis) is carried out in the case of groups of the
tert-butyl type by means of hydrogen chloride, hydrogen fluoride or
trifluoroacetic acid,and in the case of acid-sensitive protecting
groups chiefly by means of a lower aliphatic carboxylic acid, such
as formic acid and/or acetic aci.d, in the presence of water and,
optionally, a polyhalogenated lower alkanol or lcwer alkanone, such
as l,l,:L,3,373-hexaluoropropan-2-ol or hexafluoroacetone. In this
manner it is possible, for example, for an N-trityl group to be re-
moved by an organic acid, such as formic acid, acetic aci.~, chloro-
acetic acid or trifluoroacetic acid, in aqueous or absolute triEluoro-
etllanol as solvent (cf. German ~ffen.legungsschrift DT 2 346 147) or by
aqueous acetic acid; for the tert-butoxyca-rbonyl group to be removed
by trifluoroacetic acid or hydrochloric acid; and for the 2-(p-bi-
phenylyl)-isopropoxycarbonyl group to be removed by aqueous acetic
acid or, for example, by a mixture of glacial acetic acid, formic
acid (82.8% strength) and water (7:1:2) or in accordance with the
process in DT 2 346 147. The ~-silylethyl ester groups are pre-
3~
ferably removed by ~luoride ion-yielding reagents, ~or example
fluorides of quaternary organic bases, such as tetraethylammonium
fluoride.
Ketalized and thioketali~ed oxo groups are converted into free oxo
groups by acidolysis with usual strong inorganic acids, or with oxalic
acid, in the presence of water, the latter ones advantageously by
treatment with a sul~ur-binding agent, e.g. a mercury II - sal-t and/
or cadmium carbonate. Protecting groups that are unstable to basic
conditions, for example Eormyl, trifluoroacetyl and carbonic acid
ester groups7 can be carefully removed by the action of an aqueous
sodium or potassium bicarbonate or carbonate solution or, also,
aqueous ammonia, in an organic solvent, usually at room temperature.
The protecting groups are preferably removed under the reaction con-
ditions of the examples, or under analogous conditions.
Those of the end products according to -the invention that contain
bas;c groups are obtained, depending on the manner of isolation, in
the form of bases or acid addition salts; analogously, end products
having acidic groups may also be obtained in the form of sal-ts. Each
form can be converted into the other in known manner. The bases can
be obtained rom the acid addition salts in a manner known per se.
From the bases it is in turn possible to obtain acid addition salts,
especially thera~eutica:Lly useful acid addition salts, by reaction
with acids, for example with acids of the type that form the above
-mentioned salts. ~cids and their salts also stand in a similar re-
lationship to one another. Compounds that have both a free carboxy
group and a basic group may be in the form of inner salts and these
are obtained, for example, by establishing the isoelectric point.
The starting materials of formula IIIA7 IIIB and IV, that is to say
the alkylating agents, are known or, if they are unknown~ can be
simply obtained by conventional synthetic processes.
636
- 26 -
The starting materials o~ formula II and V can be obtained by con-
ventional synthetic processes, and advantageously in the manner which
is described in more detail and exemplified for specific inter-
media-tes hereinafter.
Process c), also being an alkylation reaction is performed according
to the same general considerations and under the same experimental
conditions as the above processes a) and b) as described in detail
above for the treatment with an alkylating agent of formula IIIA,
LII~ or IV (i.e. substitutive alkylation or reductive alky]ation).
Starting materials of formula VI can be obtained by conventional
processes known per se, e.g. in the manner described more specifi-
cally hereinafter. The amines of formula VII are known, or if unknown,
they are easily accessible by conventional synthetic methods.
Process d), is also carried out in a conventional manner under the
general conditions of solvolysis, which are known to convert cyanides
(nitriles) into free carboxylic acids or their sa]ts, esters or
imides. - For the conversion into a free acid, hydrolysis with water
is carried out advantageously in ~n inert organic solvent ~hich is
at least partially miscible with water, such as ethers ~e.g. diethyl
and diisopropyl ether, 19~-dimethoxyethane or, especia]ly dioxane or
tetrahydrofurane) or lower alkanols (e.g. methanol, ethanol, iso-
propyl alcohol, butyl alcohols, especially tert-butyl alcohol),
a larger amount of water being required in the latter cases in order
to prevent alcoholysis. The hydrolysis can be catalysed both by
strong acids, especially inorganic acids such as sulfuric acicl or,
preferably hydrohalic acids (e.g. hydrobromic or, as a first choice,
hydrochloric acid), or by bases, especially inorganic bases such as
hydroxides and carbonates of alkali metals, e.g. sodium and potassium
hydroxide. The bases are usually employed in at least stoichiometric
quantities giving rise to carboxylic acid salts as primary products.
- 27 -
The acidic catalysts are advantageously applied as dilute aqueous
solution for the best result. Final products oE formula I, in which
R represents an esterified carboxyl group, can be obtained by carry-
ing out the solvolysis of the nitrile with the corresponding alcohol
(alcoholysis) in the presence of a catalytic amount of ~n anhydrous
strong acid, advantageously gaseous hydrogen chloride. Usually7
excess alcohol is used as solvent; however, inert organic solvents
can be added, such as acyclic and cyclic ethers (especially these
mentioned above), and/or halogenated lower alkanes (especially chloro-
form an dichloromethane). If the alcoholysis is carried out under
strictly anhydrous conditions, the primary product (imino ester) is
to be hydrolyzed, advantageously by adding water to the reaction
mixture, otherwise, by carrying out the alcoholysis in the presence
of an approximately stoichiometric equivalent of water, the desired
ester is obtained directly. In order to obtain a corresponding amide
ti.e. a compound of formula I, wherein R is carbamoyl), a corres-
ponding nitrile of formula VIII can preferably be subjected to
alkaline hydrolysis in the presence of hydrogen peroxide.
The starting materials of formula VIII can be obtained by conventional
methods known per se, e.g. by a condensation analogous to that of
process c), in which a starting material oE the above-defined
formula VI is treated with an amine of the fonnula
R5-N~I-CH\ (VII')
wherein Rl and R5 have the r^~n;ngs given hereinabove, and which
corresponds to the above-defined amine of formula VII. Also,
processes a) and b) can analogously be used for the preparation of
the nitriles of formula VIII.
36
- 28 -
The cyclization according to process variant e) can also be carried
OIIt in the manner known per se, e.g. by dehydration. Especially use-
ful general methods for this purpose are those developed in connection
with the formation of the amide bond in peptides9 as reviewed in com-
pilative works, e.g~ Houben-Weyl, Volumes 15/1 and 15/2 as cited
hereinabove. According to one preferred modification, the amino group
to be cyclized is rendered inactive by protonation (i.e. in the form
of an acid addition salt), and the carboxyl group is converted into
an activated ester, such as that with 2,4,5-trichlorophenol, penta-
chlorophenol, pentafluorophenol, 2-nitrophenol or, especially,
4--nitrophenol, or with an N-hydroxy compound, such as N-hydroxysuc-
cinimide, l-hydroxybenztriazole or N~hydroxypiperidine, or alter-
na~ively with an N,N'-di-substituted isourea, such as, especially,
N,N'-dicyclohexylisourea, or a similar generally Icnown activating
agent. The cyclization is effected by basification preferably by
the addition of an organic base, for example a quaternary a~onium
salt, or especially a tertiary amine, such as triethylamine, N-
ethylmorpholine or N-methylpiperidinea in order to re-activate the
amino group to be cyclized by converting it into thè unprotonated
Eorm. The reaction temperature is usually from -20 to ~50C, pre-
ferably approximately at room temperature~ and customary solvents
are used9 Eor example, dîoxan, tetrahydrofuran, acetonitrlle, pyri-
dine, dimethylEormamide, dimethylacetamide, dimethyl sulEoxide,
N-metIIyl.pyrrolidone, hexamethylphosphoric acid triamide, a~ weLl as
chloroorm and methylene chloride, and expedient mixture thereof.
In a special variant oE the process9 the carboxy group can be
directly activated in situ by the action oE the free acid with a
carbodiimide,such as N,N'-dicyclohexylcarbodiimide (optionally with
the addition of N-hydroxysuccinimide, an unsubstituted or, for
example, halogen , methyl- or methoxy-subs~ituted l-hydroxy-
benztriazole or 4-hydroxybenzo-1,2,3~triazine-3 oxide or N-hydroxy-
5-norbornene-2,3-dicarboximide), or with N,N~-carbonyldiimidazoleO
- 2~ -
Starting materials of formula IX can be obtained according to general
methods known per se, e.g. as discussed in more specific examples
hereinafter.
Also, reduction according to process f) can be carried out in a
manner generally known per se for saturation of such double bonds.
More specifically, ~he double bond in the unsaturated starting
materials corresponding to formula I can be located between C-3 and
C-4 or between C-3 and the adjacent nitrogen atom, or between the
nitrogen atom and the adjacent carbon atom within a group R~. The
saturation of the double bond is advantageously carried out by cata-
lytic hydrogenation, e.g. under the preferred conditions discussed
in detail hereinbefore9 and also be metal reduction, such as zinc
reduction in neutral or acidic mediumg or, especially in the case
of the C-N double bond, by diborane or complex hydrides such as
sodium borohydride, as mentioned hereinbefore. The unsaturated
starting materials for this process variant are obtained according
to known general methods, e.g. those discussed in processes a) and
c) and/or, in a more specific form hereinaEter.
The condensation according to process g) is carried out under con-
ventional general conditions at ~emperatures ranging between about
0C and 100C in a solvent which is inert to the reactants~ e.g.
n~ethylene chloride, 1,2-dimethoxyethane, N,N-dimethylformamicle
optionally in the presence of a base, e.g. a tertiary amine such
as triethylamine or an alkali metal hydride such as sodium hydride.
In performing the optional in-terconversions of a resulting final
product of formula I, into another compound within the above-
speciEied scope of formula I~transformations such as the following
are carried out: an amino group is alkylated, and/or an oxo group,
especially that of the symbol X~ is converted into hydroxyl (plus
hydrogen) or into two hydrogens by reduction and/or hydroxyl is
converted into oxo by oxidation or into hydrogen by reduction,
3~i
- 30 -
and/or a free hydroxyl or carboxyl group is liberated from its esteri-
Eied form by hydrolysis or hydrogenolysis and/or a hydroxyl or amino
group is acylated and/or a free carboxyl is esterified, and/or the
aromatic carbocyclic ring in formula I is hydrogenated to hexahydro or
6,7,~99-tetrahydro, and/or the hexahydro carbocyclic ring is
dehydrogenated to the 6,7,8,9-tetrahydro or aromatic carbocyclic ring.
All these optional interconversions are carried out by well-known
conventional methods. By the alkylation reaction, e.g. the lower
alkyl as represented by R5 can be introduced into the Einal product
oE formula I, wherein R5 is hydrogen, using any of the modifications
discussed in detail in connection with process variant a)~ Both
substitutive and reductive alkylation can be employed~ the former
with alkyl halides, the latter with lower aliphatic aldehydes and
ketones and catalytically activated hydrogen or, in the case of
formaldehyde, advantageously with formic acid as the reducing agent.
By the substitutive alkylation, lower alkyls can also be intro-
duced into an amino group which is a component of the carbamoyl
group represented by symbol R . Also the reduction of the 5-oxo
group to hydroxy is carried ou-t in the usual manner, e.g. using a
complex metal hydride, especially a mild one, such as an alkali
metal borohydride (e.g. sodium borohydride), or according to
the method of Meerwein-Ponndorf, or a modification thereof using
nn alkanol, especially isopropyl alcohol, as both solven~ and re-
ducing ngent ~md a metal alkoxide~ preferably one corresponding
to t~e reducing alcohol, such as aluminium isopropoxide, as a
catalyst. The reduction of the oxo group to two hydrogens can
advantageously be accomp]ished e.g. by treatment with amalgamated
inc and hydrochloric acid, or by Raney-nickel desulfurization of
a corresponding dithioketal. The oxidation of hydro~yl to form oxo
can be preferabLy carried out with a derivative of hexavalent
chromium such as chromic acid and its salts, with a per~ng~n~te
salt ~especially potassium permanganate) or under the conditions of
i3~
- 31 -
the Oppenauer oxidation, with acetone or cyclohexanone as oxidant
and aluminium isopropoxide as catalyst. Esterified hydroxyl groups
are liberated in particular by methods discussed in detail herein-
above in connection with removing hydroxyl-protecting groups9 the
acylation of both hydroxyl and amino groups is carried out in the
usual way, preferably using a corresponding acid anhydride or halide.
For esterification, a carboxyl group can be reacted directly with a
diazoalkane, especially diazomethane, or with a corresponding alcohol
in the presence of a strong acid catalyst (e.g. sulfuric acid or an
organic sulfonic acid) and/or a dehydrating agent ~e.g. dicyclohexyl-
carbodiimide). Alternatively, the carbo~yl group can be converted
into a reactive derivative thereof, such as an active ester
mentioned in connection with process e), or into a mixed anhydrideg
e.g. with an acid halide (i.e., especially acid chloride) or with
trifluoroacetic acid, and this activated intermediate reacted with
the desired alcohol.
The free carboxyl group can be liberated from an esterified carboxyl
in a manner generally known, especially by base~catalyzed hydrolysis.
Of special interest, however, are methods capable of selectively
liberating one particular carboxy group represented by the symbols
-COR6 and -COR7. :[n such a case, use can be made of a proper
combination of ester groups known in the art especially as carboxyl-
protectin~ groups and developed in a grea~ variety in particular
for the synthesis of peptides, cf. Houben-Weyl, Volumes 15/1 and
15/2 as cited hereinabove. Radicals suitable for selective removal
with liberation of the carboxyl are esters derived, for example,
from alcohols that yield radicals that can be removed by acidolysis,
such as cyanomethyl alcohol, ben~oylmethyl alcohol or tert-butyl
alcohol) but especially alcohols tha-t yield radicals w~ich can be
removed by reduction, such as 2 7 2,2-trichloroethanol a benzyl
alcohol, and especially 4-ni-troben~yl alcohol, or al-ternatively iso-
nicotinyl alcohol. An especially advantageous class o substituted
32 -
alkanols are ethyl alcohols which carry in the ~-position a tri-
substituted silyl group, such as triphenylsilyl, dimethylbutylsilyl
or, especially, trimethylsilyl. As is described, Eor e~ample, in
Belgian Patent No. 851.576, these alcohols are particularly sui.table
for selective removal because the corresponding ~-silylethyl esters,
for example ~(trimethylsilyl)-ethyl ester9 have the stability of
customary alkyl esters but can sel.ectively be removed under mild
conditions by the action of fluoride ions to retain other esterified
carboxyl groups, for example alkoxycarbonyl groups.
The removal of esterifying groups depends on their nature and
is carried out in each case in a conventional manner known per se
taking into consideration the properties of the other radicals in-
volved. The groups that can be removed by reduction9 especially
those that contain halogenated lower alkyl radicals (for example
2,2,~-trichloroethyl radicals),isonicotinyl radicals (for example
isonicotinyloxycarbonyl) and, optionally substituted benzyl radicals,
especially 4-nitrobenzyl radicals of any kind, are pre~erably removed
by zinc reduction, usually in the presence oE an acid, preEerably
acetic acid, and with or without the addition of an inert organic
solvent, usually at room temperature, those of the benzyl type,
especially unsubstituted benzyl esters9 also by hydrogenolysis
techniques conventionally used for benæyl groups.
The removal of an ester group by acid hydrolysis (acidolysis) can
be carried out especially in the case of groups of the tert butyl
type, by means of hydrogen chlori.de, hydrogen fluoride or tri-
fluoroacetic acid. The ~-silylethyl ester groups are preferably re-
moved by fluoride-ion-yielding reagentsS for example fluorides of
quaternary organic bases9 such as tetraethylammonium fluoride. Ester
groups that are base-lmstable can be carefully removed by the
rapid action of an aqueous sodium or potassium bicarbonate solut;on
or9 preferably, aqueous ammonia in an organic solvent9 usually at
room temperature. The ester groups are preferably removed under the
,27
- 33 -
reaction conditions of the examples? or under analogous conditions.
proper combina~ion of the ester groups can be chosen in the earlier
stages of the synthesis, or by a proper choice of starting materials
and reactants, e.g. in process a), a selectively removable ester
group being introduced with a carboxyl which is to be libera~ed in
the last sLage.
The compounds of formula I in general, and IA in particular, are
prepared advantageously according to reaction sequence 1, which
involves an advantageous selection of starting materials and inter-
mediates, and comprises the followlng steps: a) condensing under
conditions of basic catalysis, a compound of the formula
X'
3 ~ o
R9 (XI )
~><~ ~--o/
O
wherein R3 and R~ represent hydrogen, lower alkyl, lower alkoxy,
lower alkanoyloxy, halogen, triEluoromethyl or R3 and R~ taken to-
gether represent lower alkylendioxy, X' presents 2 hydrogens ? one
hydrogen and one etherified or esterified hydroxy, oxo or oxo pro-
tected in ~orm of a ketal or thioketal and Rg is amino, lower alkyl-
amino, azido or acylamino, e.g. lower allcanoylamino or alkyloxy-
carbonylamino,with a compo~nd of the formula
R2 - CH - COR7 (III'B)
wherein R2 represents hydrogen or lower alkyl, Z represents
3~
- 34 -
reactively esterified hydroxy, and R7 rep~esents hydroxy9 di(lower)
alkylamino, lower alkoxy, aryl(lower)alkoxy, lower alkanoyloxymethoxy
or lower alkoxycarbonyl(lower)alkoxy, b) optionally reducing,
hydrogenolyzing, hydrolyzing or alkylating the resulting intermediate
to obtain a compound of the formula Il'
~'
R' 11R'
4 ~~ \ 15
il I / -NH (II')
R~ N~
~CH~
R2 CO-R7
wherein R3, R4, X' are as defined for formula XI; R2 and R5 repre-
sent hydrogen or lower alkyl, R7 represents hydroxy, amino, mono-
or di(lower)alkylamino, lower alkoxy, aryl(lower)alkoxy, lower
alkanoy].oxymethoxy, di(lower alkylamino)lower alkoxy or lower
alkoxycarbonyl(lower)alkoxy, c) conden.sing a compound of formula II'
above under conditions of reductive alkyl.ation with a compound of
the formula IV' O
Rl - C - COR6 (IV')
wlle~ein Rl is hyclrogen, lower alkyl, acylated amino (lower)
alkyl, aryl, aryl(lower)alkyl, cycloalkyl(lower)alkyl and R6 re-
presents hydroxy, di(lower)alkylamino, lower alkoxy, aryl(lower)
alkoxy, lower alkanoyloxymethoxy or lower allcoxycarbonyl(lower)
alkoxy, or condensing under alkylation conditions a compound of
formula II' above with a compound of the formula III'A
Rl - CH - COR6 (III'A)
i;3~
~ 35 -
wherein Rl and R6 have meanings given above in formula IV7 and Z
represents reactively esterified hydroxy, d) op~ionally hydrolyzing
or derivatizing the resulting productg e) converting any resulting
compound of formula IA into another compound of the inven-tion.
Compounds of formula Xl are obtained from the corresponding optionally
substituted and/or derivatized 2,3,4,5-tetrahydro-lH[l]benzazepin-
2-ones (J. Chem. Soc. 19373 456; British patent 1,3599285; Liebigs's
Annalen Chemie 574, 171 (1951)o Novel appropriately derivatized
starting [l]benzazepin-2-ones are advantageously prepared by ~eclcmann
rearrangement of the correspondingly derivatized naphthalen-l-ones
using procedures known to the art and exemplified herein.
Said tetrahydro-~l]benzazepin-2-ones are converted to the 3-halo-,
e.g. 3-chloro-2,3,4,5-tetrahydro-lH[l~benzazepin-2-one under con-
ditions exemplified herein, e.g. by treatment with phosphorus penta-
chloride followed by hydrogenation. Substitution of said halo
derivative with a metal azide, e.g. sodium azide and optional re-
duction, or substitution with ammonia or a lower alkylamine and
optional acy'lation, yields compounds of formula XI.
Alternatively, compounds of formula XI wherein ~9 represents amino,
aIkylamino or acylamino are obtained by reduction and cyclization
oL t~e appropriate'Ly substituted and/or derivatized 4-(o-nitro-
phcnyl)-2-aminobuty~ric acid and optional subsequent N-alkylation
or N-acylation.
~n alternate syllthesis for the optically active compounds of this
invention starts with the natural amino acid tryp~ophane. Specifi-
cally L-4-(o-aminophenyl)-4-oxo-2-amino-butyric acid (L-kynurenine,
J.A~.Chem. Soc. 76, 1708 (1954), derived from L-tryptophane) is
converted to an optically active starting material of formula XI
wherein Rg is acylamino, e.g. 3-(S)-t-butyloxycarbonylamino-2,3,4,5-
3~;
- 3~ -
tetrahydro-lH[l]benza~epin-2,5-dione as described in the Australian
Journal of Chemistry 33 9 633 ~0 (1980). The lactam alkylation of a
compound of formula XI with a reactant of Eormula III'P" well known
in the art, is preferably carried out in the presence of bases such
as alkali metal hydrides, e.g. sodium or potassium hydricle, alkali
metal alkoxides, e.g. potassium t-butoxide or sodium methoxide9
organometallic reagents, e.g. lithium diisopropylamide or under con-
ditions of phase transEer catalysis e.g. in the presence of a tetra-
butylammonium salt9 preferably in a solvent e.g. tetrahydrofuran,
dimethylEormamide, at a temperature pre~erably between about 0
and 75.
Condensa-tion of intermediates of formula IIl with the known cl-keto-
acid derivatives of formula IV~ (e.g. Chem. ~er. 31, 551, 3133)
by reductive N-alkylation is carried out under conditions known to
the art, e.g. by catalytic hydrogenation with hydrogen in the
presence of platinum, palladium or nickel catalysts or with chemical
reducing agents such as simple or complex light metal hydrides,
advantageously an alkali metal cyanoborohydride such as sodium cyano-
borohydride. The reductive amination with an alkali metal cyano-
borohydride is pre~erably carried out in an inert solvent, e.g.
methanol or acetonitrile7 advantageously in the presence of an acid,
e.g. hydrochloric acicl or acetic acid at a temperature between about
0 and 50, pre~erably room -temperature.
Alkylation of intermediate amines oE formula II' with a reactant
o~ Eormula III'~, well known to the art, is carried out with or
without basic catalysts such as triethylamine or potassium carbonate
in an inert solvent.
~he compounds o~ ~ormula I in general, and IA in particular ? can
also be prepared by sequences 2 and 3.
- 37 -
Sequence 2 comprises the following steps: a) condensing ~mder
conditions of reductive alkylation a compound of the formula
X'
R l
NH (XII)
o
wherein R3, R4 and X~ have m~n;ngs as defined for formula XI~
and R'. is hydrogen or lower alkyl, with a compound of the Eormula lV'
Rl - C - CO - R6 (IV')
wherein Rl and R6 have m~n;ngs as previously defined, or under
alkylation conditions with a compound of formula IIIIA
Rl OEl - COR6 (III~A)
wherein Rl, R6 and Z have m~n;ngs as previously defined,to obtain
a compound oE the formula V'
X'
il ~T \~ N C ~ (V~)
R3 N iI CO-R6
wherein Rl , R39 R4, R' , R~ and X' have meanings as previously
defined, b~ condensing under conditions of basic catalysis a re-
sulting compound of the formula V' with a compound of the formula
III'B
~6~i3~
- 38 -
R2 ~ CH - COR7 (III'B)
wherein R2 and R7 and Z have meanings as previously defined,
c) optionally hydrolyzing or derivatizing the resul~ing product,
d) optionally converting any resulting compound of formula I into
another compound of the invention.
Sequence 3 comprises the following steps: a) condensing a compound
of the formul~ VII'
R5 Rl
HN - CEI - COR6 (VII')
wherein Rl is hydrogen? lower alkyl, acylated amino(lower)alkyl,
aryl, aryl(lower)alkyl, cycloalkyl(lower)alkyl; R5' represents
hydrogen or lower alkyl; an.d R6 represents hydroxy, di(lower)alkyl-
amlno, lower alkoxy, aryl(lower)alkoxy9 lower alkanoyl.oxymethoxy
or lower alkoxycarbonyl(lower)alkoxy~ with a compound of the
form~lla VI'
X"
R4 ~ , (VI')
~ '' /
/c~
R2 CO-R'7
wherein R2 represents hydrogen or lower alkyl, R3 and R4 represent
hyd~ogen~ lower alkyl, lower alkoxy, lower alkanoyloxy, halogen,
trifluoromethyl or R3 and R4 taken together represent lower
3~
- 39 ~
alkylenedioxy; X" represents 2 hydrogens, one hydrogen and one etheri-
fied or esterified hydroxy, oxo or oxo protected in the form of a
ketal or thioketal; R7 represents hydroxy, di(lower)alkylamino, ]ower
alkoxy7 aryl~lower)alkoxy, lower alkanoyloxymethoxy or lower alkoxy-
carbonyl(lower)alkoxy; and Y represents oxo or dichloro- under con-
ditions of reductive N-alkylation, or condensing a compound of
formula VII' with a compound of the above formula VI' wherein X"
represents oxo, Y represents hydrogen and one reactively esterified
or etherified hydroxy, or with a 3,4-dehydro elimination product of
said compound or with a 3,4-dehydro derivative of said compound;
b) op~ionally reducingS hydrolyzing or derivatizing the result;ng
product; c) optionally converting any resulting compound into another
compound of the invention.
In the preceding sequences 2 and 3 the steps of lactam alkylation~
reductive N-alkylation and al~ylation of amines are advantageously
carried ou~ under the condltions described for process 1.
In sequences 1, 2 and 3 described herein, reactants of e.g. formulae
III'A, III'B and VII' may be replaced with the corresponding
nitriles, e.g. R2'CH(Z)CN~ Rl'CII(~)CN and R5NHCH(Rl)CN respec~ively.
The nitriles thus obtained may be converted to the carboxylic acids,
esters and amides of formula I using methods well ~no~n to the art.
Tile starting materials of formula VII' represent amino acids and
derivatives well known to the art. It is noteworthy that the
optica]ly active compounds of this invention may be synthesized
starting ~ith an optically active compound oE formula VII', e.g.
L-~-aminophenylbutyric acid, L-phenylalanine and derivatives thereof.
In the case of reactants of formula III'A, III'B, IV' and VII'
wherein R7~ R6 or R~ represents hydroxy, an appropriate carboxylate
salt is prepared, preferably in situ9 be~ore condensation with the
described intermediates cited above.
3Ç~
~ 40 -
Certain terms used in the foregoing processes have the meanings
as defined below.
A reactively esterified hydroxy represents such esterified by
a strong inorganic or organic acid~ above all a hydrohalic acid,
e.g. hydrochloric, hydrobromîc or hydriodic acid, an aliphatic or
aromatic sulfonic acida e.g. methanesulfonic acid or p-toluenesulfonic
acid~
Etherified hydroxy represents preferably lower alkoxy, e.g. methoxy,
ethoxy or t-butoxy.
The optional steps of reducing, hydrogenolyzing hydrolyzing or
derivatizing the initial products of the aforesaid processes and
the conversion of a resulting product into another compound of this
invention are performed by chemical methodology known to the art
and exemplified herein.
Compo~mds of formula I or IA wherein R6 and/or R7 is lower alkoxy
may be amidized with ammonia, mono- or di-(lower)alkylamines to yield
compounds of formula I or IA wherein R6 and/or R7 represents unsub-
stituted, mono- or di-tlower)alkylamino.
Conversion of compounds of formula I or IA wherein R6 and/or R7 is
lower alkoxy, aryl(lower)alkoxy~ amino, mono- or di-(lower)amino
to comyounds of formula I or IA wherein R6 and/or R7 represents
hydroxy is advantageously carried out by hydrolysis with inorganic
acids such as hydrohalic or sulfuric acid or with aqueous alkalies
preferably alkali metal hydroxides such as lithium or sodium
hydroxide.
The selective conversion of compounds of Eormula I or IA wherein
R6 and/or R7 represents ~-aryl(lower)alkoxy, e.g. benzyloxy to
compounds of formula I or IA wherein R6 and/or R7 represents hydroxy
3 Ei
~ 41 -
is advantagcously carried out by hydrogenolysis using hydrogen in
the presence of ~ catalyst, e.g. palladium.
Compounds of formula I or IA wherein neither R6 nor R7 represents
hyd-roxy may be converted to monocarboxylic acids of formula I or
I~ wherein one of R6 ancl R7 is hydroxy. Such conversion is carried
out by selective hydrolytic or hydrogenolytic procedures well kno~n
to the art and based on the chemical character of the R6 and R7
subs~;ituents.
Free carboxylic acids of formula I or IA wherein R6 and/or R7 re-
present hydroxy or salts thereof may be esterified with the
appropriate alcohols or reactive derivatives thereof well known to
the art to give the corresponding mono- or bis-ester, namely compounds
of formula I or IA wherein R6 and/or R7 is lower alkoxy, aryl(lower)
alkoxy, lower alkanoyloxymethoxy, or lower alkoxycarbonyl(lower)
alkoxy. Furthermore the free carboxylic acids may be converted via
reactive intermediates to mono- or bis-amides of formula I wherein
R6 and/or R7 represents amino9 mono~ or di-(lower)alkylamino.
Compcunds of formula I or I~, and intermediates therefor, e.g. of
formulae X and V', wherein X or X' represents oxo may be converted
to the corresponding compounds wherein X or X' represents one
hyclrogen and one hydroxy by reduction, e.g. by catalytic
hydrogenation, e.g. with hydrogen in the presence of a platinum
catalyst, or with a metal hydride reducing agent such as sodium
borohydride. ~esulting compounds wherein X or X' represents one
hydrogen and one hydroxy may be converted to compounds wherein X or
X' represents two hydrogensS e.g. by catalytic hydrogenation of
the adduct of a carbodiimide, e.g. the adduct formed by condensation
of a compound wherein X or X' represents one hydrogen and one hydroxy
with dicyclohexylcarbodiimide in the presence of cuprous chloride
according to the general method described in Chem. ~er.~ 107, 1353
(1974).
- 42 -
Alternately the compounds wherein X or X' represents one hydrogen and
one hydroxy may be first converted to the corresponding compounds
wherein X or X' represents one hydrogen and one acyloxy (e.g. acetoxy)
and subsequently reduced, e.g. by catalytic hydrogenation in the
presence of a palladium catalyst, to compounds wherein X or X' re-
presents two hydrogens.
The above~mentioned reactions are carried out according to standarcl
metllods, in the presence or absence of diluents, preferably such
as are inert to the reagents and are solvents thereof, of catalysts3
condensing or said other agents respectively and/or inert atmospheres,
at low temperatures~ room temperature or elevated temperatures,
preferably at the boiling point of the solvents used, at a-tmospheric
or superatmospheric pressure.
The invention further includes any variant of the present processes,
in which an intermediate product obtainable at any stage thereof is
used as starting material and the remaining steps are carried out,
or the process is discontinued at any stage thereof, or in which the
starting materials are formed under the reaction conditions, or in
which the reaction components are used in the form of their salts
or optically pure antipodes. Mainly those starting mater;aLs should
be used in said reactions, that lead to ~he formation of those com-
poun~ls indicated above as being especially useful.
The invention also relates to novel starting materials ancl
processes for their manufacture.
Depending on the choice oE starting materials and methods, the new
compounds may be in the form of one of the possible isomers or
mixtures thereof, for example, depending on the number of asymmetric
carbon atoms, as pure optical isomers, such as antipodes~ or as
36
- 43
mixtures of optical isomers such as racemates or mix~ures o~
diastereoisomers.
Resul-ting mixtures of diastereoisomers and mixtures of racemates
can be separated on the basis of the physicochemical differences oE
the constituents, in known manner, into the pure isomers, dia-
stereoisomers or racemates, for example by chromatography and/or
fractional crystallisation.
Resulting racemates can furthermore be resolved into the optical
antipodes by known methods, for example by recrystallisation from
an optically active solvent, by means of microorganisms or by
reacting an acidic end product with an optically active base that
Eorms salts with -the racemic acid, and separating the salts obtainèd
in this manner9 for examp]e on the basis of their different solu-
bilities, into the diastereoisomers~ from which the antipodes can
be liberated by the action of suitable agents. ~asic racemic products
can likewise be resolved into the antipodes, for example, by separa-
tion of diastereomeric salts thereof, e.g. by the fractional cry-
stallization of d- or l-tartrates. Any racemic intermediates or
starting materials can li.cewise be resolved.
~dv~ntageously, the more active of the two antipodes is isolated.
Finally~ the compounds of the invention are either obtained in the
Erce form, or as a salt thereof. Any resulting base can be converted
into a corresponding acid addition salt, preferably with the use
of a pllarmaceutically acceptable acid or anion exchange preparation,
or resulting salts can be converted into the corresponding free
bases3 for example, with the use oE a stronger base, such as a metal
or ammonium hydroxide or a basic salt, e.g. an alkali metal
hydroxide or carbonate, or a cation exchange preparationO A compound
of formula I wherein R represents carboxy or of formula IA wherein
~ 96 3
- 44 -
COR6 and/or COR~ represent carboxy can thus also be converted into
the corresponding metal or ammonium salts. These or other salts,
for example, the picrates, can also be used for purification of the
bases obtained, the bases are converted into salts9 the salts are
separated and the bases are liberated ~rom the salts. In view of
the close relationship between the free compounds and the compounds
in the form of their salts, whenever a compound is referred to in
this eontextl a corresponding salt is also intended, provided such
is possible or appropriate under the cirumstances.
The compounds, inc]uding their salts, can also be obtained in the
~orm of their hydrates, or include other solvents used for the
crystallization~
The pharmaceutical compositions according to the invention are those
suitable for enteral, such as oral or rectal, and parenteral admini-
stration to mammals, including man, for the treatment or prevention
o~ diseases responsive to inhibition of angiotensin-converting
en~yme, e.g. cardiovascular diseases such as hypertension and con-
gestive heart failure comprising an effective amount of a pharma-
cologically active compound of formula 1, or pharmaceutically
acceptable salts thereo~, alone or in combination wlth one or more
pharltlaceutically acceptable carriers.
The pharmacologically active compounds of the inventlon are useful
in the manuacture oE pharmaeeutical compositions comprisi~g an
effective amount thereof in conjunction or admixture with e~cipients
or carriers suitable for either enteral or parenteral application~
Preferred are tablets and gelatin capsules comprising the active
ingredient together with a) diluents, e.g. lactose, dextrose~
sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants~
e.g. silica, talcum, stearic acid9 its magnesium or calcium salt
and/or polyethyleneglycol, Eor tablets also c) binders, e.g.
6~3~
- 45 -
magnesium aluminium silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or polyvinyl-
pyrrolidone, if desired, d) disintegrants, e.g. starches, agar3
alginic acid or its sodium salt, or effervescent mixtures and/or
e) absorbents, colorants, flavors and sweeteners. Injectable com-
positions are preferably aqueous isotonic solutions or suspensions,
and suppositories are advantageously prepared from fatty emulsions
or suspensions. Said compositions may be steriliæed and/or contain
adjuvants, such as preserving, stabilizing, wetting or emulsifying
agents, solution promoters, salts for regulating the osmotic
pressure and/or buffers. In addition, they may also contain other
therapeutically valuable substances. Said compositions are prepared
according to conventional mixing, granulating or coating methods,
respectively, and contain about 0.1 to 75%, preferably about 1 to
50%, of the active ingredient. A unit dosage for a mammal of about
50 to 70 kg may contain between about 10 to 200 mg of the active
ingre~ient.
The following examples are intended to illustrate the invention
and are not to be construed as being limitations thereon.
Temperatures are given in degrees Centigrade, and all parts
wherever given are parts by weight. If not mentioned otherwise,
aLl evaporations are performed under reduced pressure, preferably
between about 15 and 100 mmHg.
In the case of compounds of formula I or IA wherein more than one
asymmetric center exists the resulting diastereoisomeric compounds
are denoted as A, B, etc., in the said examples. The respective
diastereoisomeric compounds are characterized by physical properties,
e.g. melting point, relative migration on chromatography, infra-
red, or nuclear magnetic resonance spectral properties.
~f~ 636
In the case of compounds o~ formula I or IA wherein X is H2 and an
asymmetric center exists in the side chain at the carbon atom bearing
the nitrogen atom, the symbols A and B have been assigned as follows
to the respective isomers on the basis of their relative migration
on chromatography. On the basis of migration on thin-layer chromato-
graphy and normal phase high pressure liquid chromatography employing
silica gel as the stationary phase, the fast moving isomer is
called isomer A and the slow moving isomer is called isomer e. On
the basis of mi.gration on reverse phase high pressure liquid chromato~
graphy the slow moving isomer is called isomer A and the fast moving
isomer is called isomer B.
- 47 -
Example l:
l-Carboxymethyl-3~ ethoxycarbonyl-3-phenylpropylam;no)-2,3 94 ,5-
tetrahydro-lH-[l]benæazepin-2-one (Higher melting isomer)
A solution of 3-amino-l-carboxymethyl-2,3,4,5-tetrahydro-lH-[l]benz-
azepin-2-one (10.0 g) and ethyl benzylpyruvate ~26.4 g) in acetic
acid (75 ml3 and methanol (75 ml) is stirred at room temperature under
nitrogen for 1 hour. Sodium cyanoborohydride (3.4 g) in methanol
(25 ml) is added dropwise over 4 hours. The reaction mixture is
stirred at room temperature for 24 hours. ~oncentrated hydrochloric
acid (4 ml~ is added dropwise, and the mixture stirred at room tem-
perature for 1 hour. The reaction mixture is evaporated to dryness.
The residue is partitioned between 150 ml of water and 50 ml of ether
and adjusted to pH 9 with 40 ~0 aqueous sodium hydroxide solution. The
layers are separated and the ether layer is discarded. The aqueous
layer is adjusted to pH 4.3 with concentrated hydrochloric acid and
extracted with 3 x 75 ml of ethyl acetate. The organic portions are
dried (magnesium sulfate) and concentrated to dryness. Hydrogen
chloride gas is bubbled into a solution of the crude product in 310 ml
of methylene chloride for 5 minutes. The solution is evaporated and
the residue is stirred in 225 ml of ether. The product is collected
by filtration to give a 70:30 diastereomeric mixture as determined
by high pressure liquid chromatography. The product is recrystallized
from ethanol/ethyl acetate (1:3) to give 1-carboxymethyl-3-(1-etho~y-
carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-
one hydrochloride melting at 246-248 (decomposition) and corresponding
to the racemic isomer B.
A solution of the above hydrochloride salt (0.9 g) and propylene oxide
(10 ml) in ethanol (150 ml) is stirred under nitrogen for 18 hours.
The solution is evaporated to dryness, and the residue is dissolved
in 3 ml of ethanol. Ether (75 ml~ is added, precipitating a small
3~i
- 48 -
quantity of the starting hydrochloride. The filtrate is evaporated to
dryness and stirred with ether/petroleum ether (1:9). The solid is
filtered off to give l-carboxymethyl-3-(1-ethoxycarbonyl-3-phenyl-
propylamino)-2~3,4,5-tetrahydro-lH-[llbenzazepin-2-one melting at
139-1419 and being the higher melting racemic isomer B of th~ com-
pound of formula IB wherein C ~i2 is ethylene, R6 is ethoxy, R7 is
hydroxy and ~8 is phenyl.
Resolution under standard conditions with an optically active amine andseparation of the diastereoisomeric salts yields pure enantiomer, e.g.
l-carboxymethyl~3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2-one of example 12.
Using high pressure liquid chromatography on a reverse phase column
(solvent system: methanol, water (3:1) containing 0.025 % acetic acid)
isomer B is faster moving than lower melting racemic isomer A of
example 5.
The starting material, 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-lH-
[l]benzazepin-2-one is prepared as follows:
mixture of 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (48.3 g, see
~riggs et al., J. Chem. Soc. 1937, ~56), phosphorus pentachloride
(188 g), and xylene (1300 ml) is heated with stirring under an
atmosphere of nitrogen to 90 (oil bath temperature) during 30 min
with pauses at 30 (to allow the phosphorus pentachloride to dissolve)
and at 50. There is a copious evolution of hydrogen chloride~ The
temperature is maintained at 90 for 30 minutes. The reaction mixture
is filtered while hot to remove a small amount of suspended solid,
and the filtrate is evaporated under reduced pressure until all the
solvent is removed. The residue is added with stirring to saturated
aqueous sodium carbonate (100 ml). The product is filtered after the
- 49 -
solidification process is complete, then slurried in ethanol (150 ml) 3
filtered, washed with ethanol (50 ml) and ether ~50 ml) and dried to
give 3,3-dichloro-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one, m.p.
185-187.
A solution of 3,3-dichloro-2,3,4,5~tetrahydro-lH-[l]benzazepin-2-one
(20 g, 0.174 mol) and anhydrous sodium acetate (15.4 g, 0.188 mol) in
glacial acetic acid (920 ml) is hydrogenated at atmospheric pressure
using 5 % Pd-C (1.72 g) as catalyst until the uptake of hydrogen
ceases. ~he catalyst is filtered off and the acetic acid evapora~ed
under reduced pressure. The residue is equilibrated between 10 %
NaHC03 (900 ml) and dichloromethane (300 ml). The aqueous layer (pH 8)
is further extracted wi~h dichloromethane (3 x 300 ml) and the
combined organic solutions are dried over anhydrous sodium sulfate
and evaporated to give 3-chloro-2,3,4,5-tetrahydro-lH-[l]benzazepin-
2-one, m.p. 163-167.
A solution of 3-chloro-2,3,4,5-tetrahydro-1~-[l]benzazepin-2-one
(15. 9 g, 0.08 mol) and sodium azide (6.36 g, 0.10 mol) in dimethyl-
sulEoxide (320 ml) is maintained at 80 under an atmosphere of nitro-
gen for 3 hours. At this time, the IR spectrum of an aliquot shows a
strong peak at 2150 cm characteristic of the azide group. rhe reac-
tion mix~ure is poured into 1000 ml of ice/water and the suspension
is stirred for 30 min. The solid is filtered off, washed with water
(250 ml) and dried to give 3-azido-2,3,4,5-tetrahydro~lH-[l]benzazepin-
2~one, m.p. 1~2-145o
A solution of 3-azido-2,3,495-tetrahydro-lH-[l]benzazepin-2-one
(8.7 g, 0.043 mol), in dry dimethylformamide (75 ml) is added during
30 min to a stirred suspension of sodium hydride [from ~0 % mineral
oil dispersion (1.9 g) washed with petroleum ether (3 x 150 ml)] in
dry dimethylformamide (250 ml) maintained at 0 under a nitrogen at-
- 50 -
mosphere. Stirring is continued for an additional 1.5 hours, then
benzyl bromoacetate (10.8 g; 0.047 mol) in dry dimethylformamide
(75 ml) is added during 45 minutes, the temperature being maintained
at 0. The reaction mixture is then al'lowed to warrn to room tempera-
ture while stirring for an additional 18 hours. The dimethylformamide
is removed under reduced pressure and the residue partitioned between
water (500 ml) and dichloromethane (500 ml). The aqueous phase is
extracted with additional dichloromethane (3 x 500 ml). The combined
extracts are dried over sodium sulfate and the solvent is removed
under reduced pressure to give the crude ester-azide as an oil. This
material is dissolved in toluene (500 ml) and silica gel (48 g) is
added. Filtration and removal of the solvent under reduced pressure
gives 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l~-
benzazepin~2-one, as an oil, used without further purification in the
next synthetic step.
~ suspension of Raney nickel active catalyst in water (15 ml) is
washed with ethanol (5 x 100 ml) and added to a mechanically stirred
solution of 3-azido-1-'ben~yloxycarbonylmethyl-2~3,4,5-tetrahydro lH-
[l]benzazepin-2-one (5.0 g) in ethanol (300 ml), and the suspension
is stirred for 18 hours at room temperature under nitrogen. The
catalyst is filtered off and the solvent removed under reduced
pressure. Ille residue is dissolved in 2H hydrochloric acid (200 ml)
and the solution extracted with ether (2 x 250 ml). The aqueous solu-
tion is made basic (pH 9) with concentrated aqueous ammonia, and the
sol-ltion ext~acted with ether (3 x 200 ml). The combined ether solu-
tions are dried over sodium sulfate and evaporated under reduced
pressure to give 3 amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-
lH-[l]ben2a2epin-2-one as an oil, used without further purification
for the next synthetic step.
3-~mino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benz~
3~
- 51 -
azepin-2-one is also prepared as follows: A solution of 3-amino-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (5.0 g9 0.028 mol), in di-
methylformamide (100 ml) is added under a nitrogen atmosphere to a
stirred suspension of sodium hydride ~prepared from the 60 ~ mineral
oil dispersion (1.2 g) by washing with petroleum ether (3 x 150 ml)]
in dimethylformamide (400 ml) to which tetrabutylammonium bromide
(10.0 g, 0.031 mol) has been added. The reaction mixture is maintained
at 50 for 15 minutes, then a solution of benzyl bromoacetate (7.2 g,
0.031 mol) in dimethylformamide (25 ml) is added. The reaction mix-
ture is stirred for an additional 18 hours at 50, then cooled to
room temperature, and the dimethylformamide removed under high vacuum.
The residue is stirred with toluen~/dichloromethane (1:1, S00 ml) to
precipitate inorganic salts. After filtration~ the solution is evapor-
ated under reduced pressure, and the residue chromatographed on silica
gel (200 g). Elution with 0-15 % ethyl ace-tate in toluene gives
3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-
2-one as a major product.
solution of 3-amino-1 benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-
lH-[l]-benzazepin-2-one (1.3 g) in ethanol (250 ml) is hydrogenated at
room temperature and atmospheric pressure, using 10 % Pd-C (0.20 g)
as catalyst~ until upta~e of hydrogen ceases. The catalyst is Eiltered
off and the solvent removed under reduced pressure to give a white
Eoam (0.90 g). This material is triturated with ether to give 3-amino-
l-carboxymethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one, m.p.
147-150.
solution of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-
lH-[l]benzazepin-2-one (14.0 g, 0.04 mol) in ethanol (300 ~1) is
hydrogenated for 25 hours at 3.1 at at room temperature using 5 % Pd-C
(2.0 g) as catalyst. The catalyst is filtered off and the solvent
removed under reduced pressure. The residue is dissoLved in water
3~
(500 ml) and the solution extracted with dichloromethane (2 x 400 ml).
The aqueous solution is filtered, and evaporated under reduced
pressure. Ethanol (50 ml) is added and the solution evaporated under
reduced pressure. More ethanol (50 ml) is added, and the evaporation
repeated. The res;due is recrystallized from ethanol/ethyl acetate to
give 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-lH-[l]benza~epin-2-one,
rl~.p. 147-150.
Example 2:
l-Benzyloxycarbonylmethyl-3 (1-carboxy-3-phenylpropylamino)-2,3,4,5-
tetrahyclro-lH-[l]benzazepin-2-one
Sodium cyanoborohydride (0.152 g, 0.0014 mol) is added to a solution
of l-benzyloxycarbonylmethyl~3-amino-2,3,4,5-tetrahydro-lH-[l~benz-
azepin-2-one (0.45 g, 0.0014 mol~ and benzylpyruvic acid (0.48 g,
0.0028 mol) in methanol (35 ml). The reaction mixture is stirred at
room temperature under nitrogen for 2 hours. ~dditional benzylpyruvic
acid (0.48 g, 0.0028 mol) is added, and the reaction mixture stirred
for an additional 18 hours. Concentrated hydrochloric acid (0.5 ml)
is added and the resulting solution stirred for 1 hour. The solvents
are removed under reduced pressure and the residue is treated with di-
chloromethane (lO0 ml~ to precipitate sodium chloride. ~fter filtra-
tion, the solvent is removed under reduced pressure ancl the residue
chromatographed on silica gel (30 g). Elution with ethyl ace~ate/
methanol/acetic acid (90:10:0.2) gives 1 benzyloxycarbonylmethyl-3-
(l-cai-~oxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-lH-[l]benzazepin-
2-one as an oil; NMR(CDCl3) ~ ~.35(m,14H), 5.10(s,2H), 4.60(m,2H),
3.00(m,12H).
- 53 -
Example 3:
],-Benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH [l]benzazepin-2-one
A solution of l~benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropyl-
amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (0.364 g, 0.00075 mol),
sodium bicarbona~e (O.l90 g, 0.0022 mol), and ethyl iodide (0.315 g,
0.002 mol) in dimethylacetamide (15 ml) is stirred at room temperature
under nitrogen for 72 hours. The reaction mixture is filtered and
evaporated under reducecl pressure. Water (100 ml) is added, and the
resulting solution extracted with dichloromethane (4 x 50 ml). The
combined extracts are dried over sodium sulfate and the solvent
removed under reduced pressure to give the diester as an oil. This
material is separated by high pressure liquid chromatography into
three fractions, using ethyl acetate/toluene (30:70) as solvent.
The first fraction yields isomer A of the title compound as an oil;
the second fraction contains a mixture or isomers A and B and the
third fraction yields isomer B of the title compound. Using high
pressure li~uid chromatograp~y on a reverse phase column (solvent
system: methanol, water (3:1) cont;aining 0.0~5 % acetic acid) isomer A
moves more slowly than isomer B.
Example 4:
l-Carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,S-
tetrahydro-lH-[l]benzazepin-2-one (lligher melting isomer)
solution of l-benzyloxycarbonylmethyl-3-(l-ethoxycarbonyl-3-
phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (isomer B
of example 3, 0.9 g) in ethanol (150 ml) is hydrogenated at room tem-
perature and atmospheric pressure~ using 10 % palladium on charcoal
(0.5 g) as catalyst. After uptake of hydrogen has ceased, the
catalyst is filtered off, and the solvent removed under reduced
pressure to give a solid. This material is triturated with ether
(8 ml) to give the title compound melting at 133-140 and identical
- 54 -
to the compound obtained in Example 1.
Example 5:
l-Carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetra-
hydro-lH-[l]benzazepin-2-one (Lower melting isomer)
A solution of l-benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenyl-
propylamino)-2,3,4,5-tetrahydro-1~1-[llbenzazepin-2-one (isomer A of
example 3; 1.2 g) in ethanol (125 ml) is hydrogenated at room tem-
perature and atmospheric pressure, using 10 % palladium on charcoal
(0.5 g) as catalyst, After uptake of hydrogen ceases, the catalyst
is filtered off, and the solvent removed under reduced pressure to
give a solid. This material is triturated with ether (8 ml) to give
l-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2-one melting at 126-129, and being the
lower melting racemic isomer ~.
Using high pressure liquid chromatography on a reverse phase column
[solvent system: methanol, water (3:1) containing 0.025 ~ acetic
acid] isomer A moves more slowly than higher melting racemic isomer
B of oxample 1.
Example 6:
l-Benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropy:Lamino)-
2,3,4,5-tetrahydro--1ll-[l~benzazepin-2-one
~ solution of 3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetra-
hydro-lll-[l]benzazepin-2-olle (5.0 g), in dry dimethylformamide
(20 ml) is added under a nitrogen atmosphere to a stirred suspension
of sodium hydride [prepared from the 60 % mineral oil dispersion
(0.6 g) by washing with petroleum ether (3 x 75 ml)] in dry dimethyl-
formamide (85 ml) to which tetrabutylammonium bromide (4.4 g) has
been added. The reaction mixture is stirred at room temperature for
- 55 -
30 minutes, then a solution of benzyl bromoacetate (3.2 g) in dry
dimethylformamide (lO ml) is added. The reaction mixture is stirred
for an additional 30 minutes at room temperature, heated to 60~ and
maintained at that temperature for 18 hours. The reaction mixture
is cooled to room temperature, and the solvent removed under high
vacuum. Water (]50 ml) is added, and the resulting solution extracted
with ethyl acetate (2 x 250 m]). The combined ethyl acetate extracts
are washed with water (lO0 ml)~ dried over magnesium sulEate, and
the solvent removed under reduced pressure to give a brown oil. This
material is chromatographed on silica gel (150 g). Rlution with
toluene/ethyl acetate (3:1) first gives isomer A of l-benzyloxy
carbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2~3,4,5-
tetrahyclro-lH-[l]benzazepin-2-one followed by isomer B. Isomer ~ and
~ are identical to compounds of example 3 as determined by high
pressure liquid chromatography on a reverse phase column (solvent
system: methanol, water (3:1) containing 0.025 % acetic acid).
The starting material is prepared as follows:
A solution of diethyl acetamidomalonate (33.2 g) in ethanol (150 ml)
is added to a solution of sodium ethoxide in ethanol [prepared from
sodium (3.8 g) and ethanol (200 ml)]. The reaction mixture is stirred
~t room temperature Eor 30 minutes and a solution of 2-nitrophenethyl
bromide (J. Med. Chem. 20, 1020 (1977), ~iO.0 g) in ethanol (lO0 ml)
is added dropwise during 20 minutes. After addition is complete, the
rcaction mi~ture is refluxed for 18 hours, then cooled to room tem-
perature and evaporated under reduced pressure. The residue is dis-
solved in water ~350 ml) and the solution extracted with ethyl
acetate (2 x 350 ml). The combined ethyl acetate extracts are washed
with water (200 ml) and dried over magnesium sulfate. Removal of
the solvent under reduced pressure gives diethyl 2-acetamido-2-(o-
nitrophenethyl)-malonate as a low melting solid, used without further
3~
- 56 -
purification for the next synthetic step.
A solution of diethyl 2-acetamido-2-(o-nitrophene-thyl)-malonate (80 g)in 3N hydrochloric acid (900 ml) is refluxed for 12 hours. The solu-
tion is cooled and extracted with ethyl acetate (200 ml). The aqueous
solution is Eiltered, and evaporated to dryness under reduced
pressure. The residue is recrystallized from ethanol/ether to give
2-amino-4-(2-nitrophenyl)butyric acid hydrochloride, m.p 219-221
(decomposition).
solution oE 2-amino-4-(2-nitrophenyl)buryric acid hydrochloride
(38.0 g) in 10 % ethanolic hydrogen chloride (1200 ml) is refluxed
with stirring for 18 hours. The reaction mixture is evaporated to
dryness under reduced pressure, water (250 ml) is added, and the
a~ueous solution made basic by the addition of 2N sodium hydroxide.
The solution is extracted with dichloromethane (2 x 500 ml), and the
combined dichloromethane solutions washed with water (2 x 150 ml),
and dried over anhydrous magnesium sulfate. Evaporation gives e~hyl
2-amino-4-(2-~TIitrophenyl)butyrate~ used without further purification
Eor the next synthetic step.
solution of ethyl 2-amino-4-(2-nitrophenyl)butyrate (27 ~) in ethanol
(600 ml) is hydrogenated at room temperature and atmospheric pressure,
sin~ lO % palladinm on charcoal (2.5 g) as catalyst, until hydrogen
nptake ceases. The cata]yst is filterefl off and evaporation to dryness
gives ethyl 2-amino-4-(2-aminophenyl)butyrate used without purification
or the next synthetic step.
~ solution of ethyl 2-amino-4-(2-aminophenyl)butyrate (35.0 g) in
methanol (100 ml) is added to a solu-tion of sodium methoxide in
methanol [prepared from sodium (l.0 g) and methanol (400 ml)] with
stirring, under a nitrogen atmosphere. The reaction mixture is
3~
~ 57 -
refluxed for 65 hours and evaporated under reduced pressure. The
residue is distributed between water (100 ml) and dichloromethane
(400 ml). The aqueous solution is extracted with dichloromethane
(400 ml), and the combined organic solutions washed with water (100 ml)
and dried over magnesium sulfate. Evaporation to dryness and tri-
turation with ether (250 ml) gives 3-amino-2,3,4,5-tetrahydro-lH-~l]-
benzazepin-2~0ne7 m.p. 161-162.
Alternatively, a solution of 2-amino-4-(2-nitrophenyl)-butyric acid
hydrochloride (2.5 g) in water (200 ml) is hydrogenated at room tem-
perature and atmospheric pressure, using 10 % Pd-C (0.5 g) as catalyst.
After uptake oE hydrogen ceases, the catalyst is filtered off, and
the filtrate evaporated to dryness. The residue is dissolved in water
(50 ml) and the pH adjusted to 7 by the add~tion of 10 % sodium
hydroxide. The solid is filtered oEf, washed with water, and dried to
give 2-amino-4~(2-aminophenyl)butyric acid. A solution of the 2-amino-
4-(2-aminophenyl)butyric acid (1.0 g), hexamethyldisilazane (5.4 g),
and chlorotrimethylsilane (0.1 g) in xylene (125 ml) is refluxed for
65 hours. The reaction mixture is cooled, poured into ethanol (200 ml)
and evaporated under reduced pressure. Water (100 ml) is added, and
the solution extracted with dichloromethane (2 x 125 ml). The combined
dichloromethane solutions are washed with water (50 ml), dried over
mfl~nesium sulfate, and evaporated under reduced pressure to give
3-al~ o~2,3,4,5-tetrahydro--lH-[l]benzazepin-2-one as above.
3-~mino-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one is aLso prepared
as follows:
To a solution of 3-azido-2,3,4,5-tetrahydro-1~-[l]benzazepin-2-one
(see Example 1) (27 g) in ethanol (3500 ml) while stirring at room
temperature under an atmosphere of nitrogen, a suspension of Raney
nickel in water (50 ml, washed with 10 volumes of ethanol) is added.
3~
- 58 -
The mixture is stirred at room temperature for 2 hours when an addi-
tional 30 ml of Raney nickel suspension is adcded. After stirring for
an additional 30 minutes, the catalyst is filtered off and the solvent
removed under reduced pressure to give an oil which solidifies on
addition of ether to give 3-amino-2,3,4,5-tetrahydro-lH-[l]benz-
azepin-2-one, melting at 161-162.
A solution of 3-amino-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (8.0 g)and benzylpyruvic acid (18.0 g) in methanol (450 ml) is stirred at
room temperature under nitrogen for 3~ minutes. Sodium cyanoborohydride
(4.5 g) is added, and the resulting solution stirred at room tempera-
ture for 48 hours. Concentrated hydrochloric acid (7 ml) was added
dropwise during 10 minutes and stirring is maintained for an additional
1 hour. The reaction mixture is evaporated to dryness, dichloromethane
(150 ml) is added9 and the mixture stirred for 30 minutes. The solid
is filtered off, stirred with water (100 ml) for 15 minutes, then
filtered, washed with water (50 ml), and dried to give 3-(1-carboxy-
3-phellylpropylamino)-2,3,4~5-tetrahydro-lH-[l~benzazepin-2-one, m.p.
L73-175 as a mixture of isomers.
A solution of 3-(1-carboxy-3-phenylpropylamino)-2,3,~,5-tetrallydro-
Ill-[l~benzazepin-2-one (6.0 g), sodium bicarbonate (~.0 g), and ethyl
ioclide (11.6 g) ln dimethylacetamide (200 ml) is stirred at room
temperature under nitrogen for 72 hours. The reaction mixture is
filtered and evaporated under high vacuum. Water (250 ml) is added,
ancl the rcsulting solutioll ex~racted with dichloromethane (2 x 400 ml).
The combined extracts are dried over magnesium sulfate and the solvent
removed under reduced pressure to give 3-(1-ethoxycarbonyl-3-phenyl-
propylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one as a mixture
of isomers. NMR(CDC13) ~ 9.22(s, lH), 4.10(2 superimposed q-lartets,
2H), 1.13(2 superimposed trip]ets, 3H).
6~
- 59 -
Example 7:
l-Benzyloxycarbonylmethyl-3-(]-benzyloxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one
A solution of 3-(1-benzyloxycarbonyl-3--phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[l]-benzazepin-2-one (4.0 g) in dry dimethylformamide
is added under a nitrogen atmosphere to a stirred suspension of sodium
hydride [from the 60 % mineral oil dispersion (0.42 g) washed with
petroleum ether (3 x 80 ml)] in dry dimethylformamide (100 ml) at room
temperature to which tetrabutylammonium bromide (3.1 g) has been
added. Stirring is continued for an additional 30 minutes at room tem-
perature, when a solution of benzyl bromoacetate (2.2 g) in dry di-
methylformamide (10 ml) is added. After an additional 30 minutes at
room temperature, the reaction mixture is heated to 50~ and main-
tained at that temperature for 18 hours. The reaction mixture is
cooled to room temperature, and the solvent removed under high vacuum.
Water (150 ml) is added and the solution extracted with ethyl acetate
(2 x 300 ml). The combined ethyl acetate solutions are washed with
water (100 ml), dried over magnesium sulfate, and the solvent removed
under reduced pressure to give a brown oil which is chromatographed
on silica gel (250 g). Elution with toluene/ethyl acetate (1:1, 600ml)
gives an oil9 characterized as isomer A of the title compound; N~IR
(CDC13) ~ 5.12(s, 4H), 4.50(q, 2H). Elution with an additionaL 2000 ml
of the solvent mixture gives an oil characterized as isomer ~ of
the title compound; NMR(CDC13) ~ 5.17(s, 2~1), 5.03~d, 2H), 4.60(q, 2H).
The starting material is prepared as follows:
A solution of 3-(l-carboxy-3-phenylpropylamino)-2,3,495-tetrahydro-
lH-~l]benzazepin-2-one (as described in example 6, 13.0 g), sodium
bicarbonate (10.0 g), and benzyl bromide (19.0 g) in dimethylacet-
amide (750 ml) is stirred at room temperature under a nitrogen
~6~3~
- 60 -
atmosphere for 72 hours. The reaction mixture is filtered an~
evaporated under high vacuum. Water (150 ml) is added, and the
resulting solution extracted with dichloromethane (2 x 400 ml)~ The
combined extracts are washed with water (100 ml), dried over magnesium
sulfate and evaporated under reduced pressure to give the crude benzyl
ester. ~ecrystallization Erom ethyl acetate gives 3-(1-benzyloxy-
carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-
oLIe, m.p. 139-141.
Example 8:
l-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-
lH-[l]benzazepin-2-one (Lower melting isomer)
A solution of l-benzyloxycarbonylmethyl-3~ benzyloxycarbonyl-3-
phenylpropylamino)-2~3,4,5-tetrahydro-lH-~l~benzazepin-2-one (isomer A
of example 7, 2.7 g) in ethanol (800 ml) is hydrogenated at room tem-
perature and atmospheric pressure, using 10 % palladium on charcoal
(0.5 g) as catalyst. After uptake of hydrogen has terminated, the
catalyst is filtered off, and the solvent removed under reduced
pressure to give the title diacid, ~haracterized as isomer A, m.p.
256-259.
The identical compound is obtained on hydrolysis of the compound of
example 5.
~xample 9:
l-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-
lH-(l)benzazepin-2-one (~Iigher melting isomer)
solution of l-benzyloxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-
phenylpropylamino)~2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (isomer
of example 7, 5.0 g) in ethanol ~950 ml) is hydrogenated at room
temperature and atmospheric pressure, using palladium on charcoal
- 61 ~
(0.5 g) as catalyst. After uptake of hydrogen has terminated, the
catalyst is filtered off, and the solvent removed under reduced
press~]re to give the title diacid, characterized as isomer B, m.p.
280-282.
The identical compound is obtained on hydrolysis of the compound of
example 1 (isomer B) or compound of example 10 (isomer B).
Example 10:
l-Ethoxycarbonylmethyl-3-(1-e~hoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]ben~azepin-2-one
A solution of 3~ ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5--tetra-
hydro-lH-Ll]benzazepin-2-one (see example 6, 3.0 g) in dry dimethyl-
formamide (10 ml) is added dropwise during 10 minutes to a stirred
suspension of sodium hydride ~from -the 60 % mineral oil dispersion
(0.36 g) washed with petroleum ether (3 x 75 ml)] in dry dimethyl-
formamide (100 ml) at room temperature under nitrogen. Stirring is
maintained for an additional 30 minutes, a solution of ethyl bromo-
acetate (1.4 g) in dimethylformamide (IS ml) is added and the reaction
mixture is maintained at 60 for ~8 hours. After the reaction mixture
is cooled to room temperature, the solvent is removed under high
vacuum. Water (100 ml) is added, and the solution extracted with ethyl
acetate (2 x 200 ml). The combined ethyl acetate solutions are
washed wi.th water (50 ml), dried over magnesium sulfate, and the sol-
vent removed under reduced pressure to give a yellow oil (3.8 g).
This material is chromatographed on silica gel (120 g). Elution with
toluene/ethyl acetate (1:1; 250 ml) gives isomer A of the desired
product. Elutiorl with an additionaL 250 ml of solvent mixture gives
an oil which contains mostl~ isomer B and some isomer A o the
desired product as determined by analytical high pressure liquid
chromatography (see Example 6). Elution with a further 250 ml of
solvent mixture gives an oil which is essentially pure isomer B
i3~
- 62 -
(slower moving). This material is dissolved in methanol (25 ml~ and
converted to the maleate salt by addition of an equimolar quantity of
maleic acid in methanol. Evapo~ation of the solvent and recrystalliza~
tion of the residue from methanol/ether yields pure isomer B of
l~ethoxycarbonylmethyl 3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one as the maleate salt melting
at 114-116.
Example 11:
]-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-lH-[l]benz-
azepin-2 one
solution oE l-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one ~4.8 g; 0.01 mol) in ethanol
(550 ml) is hydrogenated at room temperature and atmospheric pressure
using 5 % Pd-C (0.85 g) as catalyst until uptake of hydrogen ceases.
Water (300 ml) is added, the catalyst filtered off, and the solvent
removed under reduced pressure. The residue is triturated with ether
to give the title diacid, m.p. 232-236.
The starting material is prepared as follows:
~ solution of 3~amino-2,3,~,5-tetrahydro-lH-[l]benzazep;n-2-one (S.0 g,
0.028 mol) in dimethylformamide (100 ml) is added under a nitrogen
atmosphere to a stirred suspension of sodium hydride [prepared from
the 60 7~ mineral oil dispersion (1~2 g) by washing with petroleum
e.ther (3 x 150 ml)] in dimethylformamide (400 ml) to which tetrab~ltyl-
amlllonium bromide (10.9 g, 0.031 mol) has been added. The reaction
mixture is maintained at 50 for 15 minutes, then a solution oE benzyl
bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) is added.
The reaction mixture is stirred for an additional 18 hours at 50,
then cooled to room temperature, and the dimethylformamide removed
under high vacuum. The residue is stirred with toluene/dichloro-
- ~3 -
methane (1:1~ 500 ml) to precipitate inorganic salts. After filtration,
the solution is evaporated under reduced pressure, and the residue
chro~latographed on silica gel (200 g). Elution with 0-15 % ethyl
acetate in toluene gives l-benzyloxycarbonylmethyl-3-benzyloxycarbonyl-
methylamino-2,3,4,5-tetrahydro~ [l]benzazepin-2-one as the first
fraction. Further elution gives 3-benzyloxycarbonylamino-2,3,4,5-
tetrahydro-lH-[l]benzazepin~2-one, m.p. 124-127 and 3-amino-1-benzyl-
oxycarbonylmethyl-2~3~ 5-tetrahydro-lH-[l]benzazepin-2-one (see
example l).
Example 12:
l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3~4,5-
tetrahydro-lH-[l]benzazepin-2-one
3(S~-Antino-l-carboxymethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one
when treated with ethyl benzylpyruvate in the presence of sodium
cyanoborohydride by the procedure described in example 1 for the
racemic compound gives after purification l-carboxymethyl-3S-(lS-
ethoxycarbonyl-3-phenylpropylamino)-2,3,4,S-tetrahydro-lH-[l]benz-
azepin-2-one, as descrihed below.
A solution of sodium hydroxide (2.1 g) in water (5 ml) is addecl to a
solution of 3(S)-amino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-
[l]benzctzepin-2-one (14.0 g) in methanol (150 ml) at room temperature,
and the solution is stirred for two hours. The solvents are evaporated
and the residue is thoroughly dried, then slurried with ether, to
give 3(S)-amino-l-carboxymethyl~2,3,4,5-tetrahydro-lH-[l~benzazepin-
2-olle sodium salt. This i9 used without further purification.
A solution of the above sodium salt (12.9 g~ and ethyl ~enzylpyruvate
(31 g) in acetic acid (100 ml) and methanol (75 ml) is stirred at room
temperature under a dry nitrogen atmosphere ~or one hour. A solution
6~ -
of sodium cyanoborohydride (3.8 g) in methanol (30 ml) is then added
dropwise over a 4 hour period. The combined solutions are stirred
overnight at room temperature. Concentrated hydrochloric acid (10 ml)
is added dropwise and the mixture stirred at room temperature for 1
hour followed by the evaporation of solvents. The residue is parti-
tioned between water (400 ml) and ether (100 ml) and the pH adjusted
to 9'3 with 40 ~ sodium hydroxide. The layers are separated and the
ether layer is discarded. The aqueous layer is adjusted to pH 4.3
with concentrated hydrochloric acid and extraxted with ethyl acetate
(3 x 100 ml). The organic phases are combined9 dried (magnesium
sulfate), and evaporated. Hydrogen chloride gas is bubbled through
a solution of the crude product in methylene chloride (150 ~1) for
5 minutes. The solvent is evaporated and the res~llting foam is dis-
solved in hot methyl ethyl ketone (100 ml). The solid which precipi-
tated is collected by filtration to give a 95:5 diastereomeric mixture
as determined by high pressure liquid chromatography. The product is
recrystallized from 3-pentanone/methanol (10:1~ to give l-carboxy-
methyl-3(S)-(l(S)-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetra-
hydro-lH-[l]benzazepin-2-one hydrochloride, m.p. 188-190, [a]D =
~141.0 (c=0.9 in ethanol), of formula IIa wherein C H2 is ethylene,
R6 is ethoxy, R7 is hydroxy and R8 is phenyl.
A solution of the above hydrochloride salt (0.035 g) and propylene
o~ide (O.S ml) in ethanol (4 ml) is stirred under nitrogen overnight
at room temperature. The solution is evaporated to dryness. Ether
(2 ml) is adcled, and the solid is filtered off to give l-carboxy-
methyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,394,5-teirahydro-
lH-[l]ben~azepin-2-one, m.p. 148-149, [a]D = -159 (c = 1.2 in
ethanol).
The optically active starting material is prepared as indicated below~
36
- 65 -
a) A solution of 0.4 g of 3(S)-t-butyloxycarbonylamino-2,3,4,5-tetra-
hydro-lll-[l]benzazepin-2,5-dione [prepared from L-kynurenine as
described in Australian J. Chemistry ~ol. 33, 633-40 (1980)], and
ethyl bromoacetate (0.23 g) in dry tetrahydrofuran (30 ml) is stirred
at 0 under a dry nitrogen atmosphere. Potassium t-butoxide (0.254 g)
is added in one portion. After 1 hour at 0, an additional quantity
of ethyl bromoacetate (0.23 g) is added and the reaction mixture is
stirred at 0 for a further 1 hour. Water (100 ml~ is added and the
mixture is extracted with ethyl acetate (2 x 50 m'L). The combined
ethyl acetate solutions are washed with water (100 ml) and dried over
magnesium sulfate. Removal of the solvent under reduced pressure gives
a yellow gum which on trituration with ether/petroleum ether (bp
30-60) gives 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2,5-dione, m.p. 86-88, [~]D =
-203 (c = 1 in dimethylformamide).
A solution of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-
2,3,4,5-tetrahydro-lEI-[l]benzazepin-2,5--dione (0.14 g) and sodium
borohydride (7 mg) in ethanol (10 ml) is stirred at room temperature
for 18 hours. The ethanol is removed under reduced pressure~ and the
residue dissolved in dichloromethane (25 ml). The solution is
extracted with 2N hydrochloric acid (2 x 20 ml) and saturated aq-leous
sodium chloride soLution (20 ml), and dried over sodium sulfate.
'I'he solvent is removed uncler reduced pressure, and the residue
triturated with ether to give 3tS)-t-butYloxycarbonylamino-l-ethoxY-
carbonylmethyl-S-hydroxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one,
Dl.p. 167-169.5, [~]D = -193 (c = 0.52 in dimethylformamide). The
substance is also obtained by hydrogenation of the benzazepin-2,5-
dione derivative with E12/Pt in ethanol.
A mixture of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-5-
hydroxy-2,3,4,5-tetrahYdro-lH-[l]benzazepin-2-one (0.076 g), dicyclo-
3~
- 66 -
hexylcarbodiimide (0.064 g) and cuprous chloride (7 mg) is heated
at 60 under nitrogen for 32 hours. The reaction mixture is allowed to
cool to room temperature. The residue is dissolved in methylene
chloride (50 ml) and washed with dilute ammonium hydroxide (2 x 15 ml)
followed by water (20 ml). The organic phase is dried over sodium
sulfate and evaporated to give a mixture of the desired adduct and
excess dicyclohexylcarbodiimide.
This mixture (0.100 g) is dissolved in ethyl acetate (L~O ml) ancl placed
in a pressure bottle. 10 % Pd/C (0.010 g) is added and the mixture is
hydrogenated at 3 atmospheres pressure and at 40 for 16 hours. The
catalyst is filtered off and the filtrate evaporated. The residue
is triturated with e-ther, and the ether solution evaporated to give
3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-
lH-[l]benzazepin-2-one, m.p. 115-116.5, [~]D = -182 (c = 2.6 in di-
methylformamide).
b) Tartaric acid (12.6 g) and racemic 3-amino-1-ethoxycarbonylmethyl-
2,3,4,5-tetrahydro-lH~[l]benzazep;n-2-one (22 g) are dissolved in hot
ethanol (200 ml). This solution is cooled and allowed to stand over-
night at room temperature. The solid which precepitates is collected
b~t filtration and recrystallized twice from ethanol (200 ml) to give
3(S)-amino~l-ethoxycarbonylmethyl-2~3,~i,5-tetrahydro-lH-~l~benzazepin-
2-one tartrate salt. This is dissolved in water (100 ml) and the pH
ad~justed to 9 with dilute ammonium hvdroxide and extracted with
methyler~e chloride (2 x 50 ml). The combined extracts are washed
with water (75 ml)~ dried (magnesium sulfate) and evaporatecl to give
3(S)-amino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[I]benzazepin-
2-one, r,l.p. 104-106, [~]D = -285.5 (c = 0.99 in ethanol).
c) Hydrogen chloride gas is bubbled through a solution oE 3(S)-t-butyl-
oxycarbonylamino-l-ethoxycarbonylmethyl-2,3,~,5-tetrahydro-lH-[ll-
benzazepin-2-one (under a) above, 0.225 g) in ethyl acetate (25 ml)
3~
- 67 -
for 45 minutes. Nitrogen is then bubbled through this solution for
30 minutes. The ethyl acetate is washed with water (30 ml) and lN
hydrochloric acid (30 ml). The ethyl acetate layer is discarded and
the aqueous phases are combined. The aqueous solution is adjusted to
pH 9 with dilute ammonium hydroxide, extracted with ethyl acetate
(3 x 50 ml); the organic phases are combined, dried (sodium sulfate)
and evaporated to give 3(S)~amino-l-ethoxycarbonylmethyl-2,3,4,5-tetra-
hydro-lH-[llbenzazepin-2-one, m.p. 101-102, [~3D = -298 (c = 0.46 in
ethanol).
Treatment with ethanedithiol/boron trifluoride etherate or trifluoro-
acetic acid/anisole to remove the protecting group yields 3(S)-amino-
l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one.
Alternately 3(S)-amino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-
[l]benzazepin-2-one is also prepared as follows:
d) A solution of 3(S)-t~butyloxycarbonylamino-l-ethoxycarbonylmethyl-
5-hydroxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (previously
described, l.0 g) in acetic anhydride (20 ml) is maintained at 80
for 3 hours. The reaction mixture is cooled to room temperature and
the solvents are removed under reduced pressure. Ether (100 ml) is
added, and the resulting solution washed with water (50 ml) and dried
over ma~nes;um su].fate. The solvent is removed under recluced pressure
to give 5-acetoxy-3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-
2,3,4,5-tetrahydro-lH-[I]benzazepin-2-one as a pale yellow oil which
is used without further purification.
A solution of 5-acetoxy-3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyl-
methyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (0.7 g) in ethanol
(50 ml) is hydrogenated at 2.9 atmospheres for 24 hours at 70 using
- 68 -
10 % palladium on charcoal (0.5 g) as catalyst. The catalyst is
filtered off and the solvent removed under reduced pressure to give
3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-2,3,4,5-tetra-
hydro-lH-[l]benzazepin-2-one whicll, without further purification is
converted to 3(S)-amino-l-ethoxycarbonylmethyl-2~3,~,5-tetrahydro-lH-
~l]benzazepin-2-one by the procedure described above; m.p. 99-lOl,
[a]D = -297 (c = 1 in ethanol).
e) A solution of 3(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-lH-
[~]benzazepin-2,5-dione (12.5 g) prepa~ed from L-kynurenine as
described in Australian J. Chemistry Vol. 33, 633-40 (1980), and
t-butyl bromoacetate (10.1 g) in acetone (700 ml) is stirred at room
temperature under a dry nitrogen atmosphere. Potassium carbonate
(12.5 g) is added in one portion and the resulting suspension is
stirred at room temperature for 16 hours. The potassium salts are
filtered off and the filtrate evaporated to dryness. The residue is
partitioned between ethyl acetate (250 ml) and ~ater (250 ml). The
layers are separated and the organic phase is dried (sodium sulfate).
The residue is triturated with petroleum ether (350 ml; bp 30-60) to
give 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2,5-dione, m.p. 75-77, [alD = 172
(c = 0.96 in dimethylformamide).
solution of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-
2,3,~i,5-tetrahydro-1~1-[l]`benzazepin-2,5-dione (8.0 g) in ethanol
(500 ml) containing platinum oxide (300 mg) is hydrogenated at atmos-
pheric pressure and at room temperature for two hours. The catalyst
is filtered off and the filtrate evaporated to give 3(S)-t-butyloxy-
carbonylamino-l-t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-
lH-[l]benzazepin-2-one9 [a]D = -173 (c = 1.8 in dimethylformamide).
- 69 -
A suspension of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyl-
methyl-5-hydroxy-2,3,4~5-tetrahydro-lH-[l]benzazepin-2~one (3.0 g),
dicyclohexylcarbodiimide (5.0 g), and cuprous chloride (500 mg) is
mechanically stirred and heated at 80 for 16 hours under a dry nitro-
gen atmosphere. The mixture is cooled, diluted with methylene chloride
(100 ml), and filtered. The solids are discarded. The filtrate is
washed with 7 % ammonium hydroxide (4 x 75 ml), followed by 1 x 100 ml
wi-th water and saturated aqueous sodium chloride solution (100 ml).
The organic phase is dried (sodium sulfate) and evaporated to give a
mixture of the desired adduct and excess dicyclohexylcarbodiimide.
This mixture (5.5 g~ is dissolved in ethyl acetate (200 ml and placed
in a pressure bottle. 10 % Pd/C (3.0 g) is added and the mixture is
hydrogenated at 3 atmospheres pressure and at 40 for 16 hours. The
catalyst is filtered off and the filtrate evaporated. The residue is
triturated with ether (75 ml) to give a white solid, 3(S)-t-butyloxy~
carbonylamino-l-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]-
benzazepin-2-one, m.p. 145-147, [a]D = ~ 194 (c = 0.46 in dimethyl-
Eormamide).
solution of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-
5-hydroxy-2,3,4,5-tetrahydro-lH~[l]benzazepin-2-one ~described above,
3.0 g) in tcetic anhydride (50 ml) is heated at 80 under a dry
nitrogen atmosphere for 2 hours. The acetic anhydride i9 evaporated.
'rhe residue is dissolved in ethyl acetate (75 ml) and washed with
saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml)~
and saturated aqueous sodium chloride solution (50 ml). The organic
phase is dried (sodium sulfate), evaporated, and the residuetriturated
with ether (50 ml) to give 3(S)-t-butyloxycarbonylamino-l-t-butyloxy-
carbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one,
m.p. 164-166.5, [a]D = -169 (c = 0.36 in dimethyl~ormamide).
36
- 70 -
A solution of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-
5-acetoxy-2,3,4,5-tetrahydro-l~-[l]benæazepin-~-one (2.2 g) in ethanol
(3Q0 ml) containing 10 % Pd/C (2.0 g) is placed in a pressure bot~le
and hydrogenated at 3 atmospheres pressure and 70 for 3 days. The
catalyst is filtered off and the filtrate evaporated to give 3(S)-t-
butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-
lH-[l]benzazepin-2-one, m.p. 16~-165, [~]D = -200.6 (c = 0.64 in
dimethylformamide).
~Iydrogen chloride gas i9 bubbled through a solution of 3(S)-~-butyloxy-
carbonylamino-l-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]-
benzazepin-2-one (0.85 g) in ethyl acetate (40 ml) for 2 hours. Nitro-
gen is then bubbled through the solution for 0.5 hour. The ethyl
acetate is evaporated and the white solid residue immediately dis~
solved in ethanol (40 ml). Propylene oxide (5 ml) is adcled and the
mixture is stirred at room temperature for 16 hours. The white solid
which precipitates is collected by filtration to give 3(S)-amino-l-
carboxy~nethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one, m.p. 275-276,
[a]D = -287 (c = 0.71, in lN hydrochloric acid) which is condensed
with ethyl benzylpyruvate in the presence of sodium cyanoborohydride
as described above.
Example 13:
l-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-5-hydroxy-2,3,~,5-
tetrahydro-lH-[l]benzazepin-2-one
To a solution of l-benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropyl-amino)-2,5-dihydro-lH-[l]benzazepin-2,5-dione (1.00 g) in glacial
acetic acid (50 ml) is added platinum oxide (0.10 g). The resulting
mixture contained in a pressure bottle is hydrogenated at 2.9 atmos-
pheres for 5 hours. The catalyst is removed by filtration, the
filtrate concentrated, and the resulting oil triturated with anhydrous
ethanol. The resulting solid is collected, dried, and suspended in
~6~
water (lO ml). The suspension is stirred for 1.5 hours. ~he solid is
collectecl and dried to give impure l-carboxymethyl-3-(1-carboxy-3-
phenylpropylamino)-5-hydroxy-2,3,4,5-tetrahydro-lH-~l]benzazep;n-2-
one melting with decomposition at 179.
The starting material is prepared as follows:
Benzyl bromoacetate (9.16 g, 0.0~ mole) is added dropwise to a mixture
of 3-methoxy-2,5-dihydro-lH-[l]benzazepine-2,5~-dione [8.13 g, 0.04 mol,
prepared as described in the Canadian J. Chem., 52, 610 ~1974)]
powdered potassium hydroxide (2.24 g, 0.04 mole) and tetrabutyl-
ammonium bromide (1.29 g, 0.004 mol) in 1000 ml of acetonitrile with
stirring at room temperature. Upon complete addition, the suspension
is stirred at room temperature for 64 hours, filtered, and the fil-
trate concentrated under reduced pressure to give a partially crystal-
line oil. This oil is triturated with ether to give a solid which is
suspended and stirred in ethyl acetate (100 ml) for 1.5 hours. The
insoluble material is filtered off and the filtrate concentrated to
give the crude l-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro-lH-[l]-
benzazepin-2,5-dione which is used direc-tly in the next step.
To a l.OM solution of potassium t-butoxide (0.64 g, 0.0057 mol) in
t-butanol ~5.7 ml) 9 while stirring under nitrogen at room temperature
is aclded (-~)-homophenylaLanine (1.02 g; 0.0057 mol) in one portion.
The resulting suspension and t-butanol (4.3 ml) is heated until most
of the suspended solid is dissolved. Upon cooling, a suspension is
obtailled. This suspension is added, in portions, via pipette to a
refluxing solution of l-benzyloxycarbonylmethyl-3-methoxy-2,5-dihydro-
lH-[l]benzazepin-2,5-dione (2.00 g) in t-butanol (~0 ml) stirring
under nitrogen over a period of 10 minutes. During the addition, a
yellow precipitate forms. Upon complete addition, the resulting sus-
pension is refluxed for 3 hours. The suspension is ~iltered, the
3~
- 72 -
resulting gummy solid is washed with petroleum ether and dissolved in
water (20 ml). The solution is filtered, acidified to pH 5 with 3N
hydrochlorid acid, the resulting crude l-benzyloxycarbonylmethyl-3-
(l-carboxy-3~phenylpropylamino)-295-dihydro-lH-[l]benzazepin-2,5-
dione is collected and used directly for the preparation of the title
compound.
Example 14.
Analogous to the methods disclosed herein, the following compounds
o~ formulaIA wherein X = H2, R2 and R5 H, ~6 2 5 7
are prepared
No. Rl R3 R4
1 C6H5CH2 H H
2 C6H5CH2CH2 7-OCH3 8-OCH3
3 C6H5CH2CH2 7-Cl H
4 C6H5CH2CH2 8-CH3 H
S C6H5CH2CH2 8-OCH3 H
6 p-ClC6H4CH2CH2 H H
7 CH3 H H
The starting substituted 2,394,5-tetrahydro-lH-[l]benzazepin-2-ones
~or compounds 2~5 are prepared as follows:
The 7-chloro-2,3,4,5-tetrahydro-lH-ll]benzazepin-2-one, m.p. L64-165,
is prepared as described in British Patent 1,359,285.
The 8-methyl-2,3,4,5-tetrahydro-lH-~l]benzazepin-2-one is prepared by
the method of Huisgen, Liebigs Ann. Chem. 574, 171 (1951), m.p.
153-154.
The 7,8 dimethoxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2~one is preparedas ~ollows:
~ ~36~3~
- 73 ~
solution of 24 g of 6,7-dimethoxy-~-tetralone [Snider, T. et al,
Org. Prep. Proced. Int., 5, 291 (1973)] in ethanol (300 ml) and water
(60 ml) is treated at reElux for two hours wi~h hydroxylamine hydro~
chloride (16 g) and sodium hydroxide (25 g) to form the oxime. The
reaction mixture is poured into 500 ml of an ice/water mixture and
extracted with 3 x 300 ml portions of dichloromethane. The combined
extracts are washed with 200 ml water, dried over anhydrous magnesium
sulfate and evaporated to yield 25 g of the oxime, m.p. 154-156.
The oxime is redissolved in 170 ml of dichloromethane and 170 ml oE
polyphosphate ester (Fieser and Fieser: Reagents for Organic Sy~
thesis, Wiley N.Y. 1967, P. 892) was added. The reaction mixture is
refluxed for 18 hours. The dichloromethane layer is separated, treated
with charcoal and dried over magnesium sulfate to yield the 798-di-
methoxy-2,374,5-tetrahydro-[lH]-[l]benzaæepin-2-one, m.p. 153-156.
The 8-methoxy-2,3,4,5-tetrahydro-lH-[l]'benzazepin-2-one, m.p. 132-134is similarly prepared from 7 methoxy-~-tetralone.
3-~mino-7-chloro-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one is syn-
thesized as follows:
solution of 3-amino-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one
(4,0 ~), 2-t-butyloxycarbonyloxyimino-2-phenylacetonitrile (6.1 g)
and triethylamine (5 ml) in water (20 ml) and dioxane (25 m'L) is
stirred at room temperature for 18 hours. The resulting soLid is
filtered off cmd washed Witil water. Recrystallization from ethyl
acetate gives 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-lH-[l]-
benzazepin-2-one, m.p. lg9-201.
Chlorine gas is bubbled through a solution of 3-t-butyloxycarbonyl-
amino-2,3,4,5-tetrahydro-lH-[l~benzazepin-2-one (1.5 g) in acetic acid
- 74 ~
(20 ml3 for 10 minutes. The reaction mixture is stirred for an
additional 10 minutes. The solid which precipitates is collected,
suspended in water (30 ml) and aqueous ammonia is added until basic.
Filtration gives 3-amino-7-chloro-2~3,~75-tetrahydro-lH-[l]benza~epin-
2-one, m.p. 170-171.
Example 15: Preparation of 109000 tablets each containing 10 mg of
the active ingredient of ~xample 1:
Formula:
l-Carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropyl
amino)-2,3,4,5-tetrahydro-lH-[l~ben~a~epin-2-one100 g
Lactose 1,157 g
Corn starch 75 g
Polyethylene glycol 6,000 75 g
Talcum powder 75 g
Magnesium stearate 18 g
PuriEied water q.s.
Procedure:
All the powders are passed through a screen with openings of 0.6 mm.
Then the drug substance, Iactose, talcum, magnesium stearate and hal~
o~ the starch are mixed in a suitable mixer. The other half of the
starch is suspended in 40 ml of water and the suspension added to
the boiling solution of the polyethylene glycol in lS0 ml of water.
The paste formed is added to the powders which are granulated~ if
necessary, wîth an additional amount oE water. The granulate is dried
overnight at 35, broken on a screen with 1.2 mm openings and
compressed into tablets using concave punches with 6.4 mm diameter,
uppers bisected.
~6~
Example 16: Preparation of an in;ectable formulation containg 25 mg
of the active ingredîent of Example 1 per 5 ml of solution:
Formula:
l-CarbGxymethyl-3-(1-ethoxycarbonyl-3-phenylpropyl-
amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one
hydrochloride 25.0 g
Propylparaben 1.0 g
Water for injection q.s. 5000.0 ml
Procedure:
The active ingredient and preservative are dissolved in 3500 ml of
water for injection and the solution is dilnted to 5000 ml. The solu-
tion is filtered through a sterile filter and illed into injection
vials under sterile conditions each vial containing 5 ml of the solu-
tion.
Example 17: Preparation of 109 000 capsules each containing 20 mg of
the active ingredient of Example 9.
Formula:
l-Carboxymethyl-3~ carboxy-3-phenylpropyl-
a~ o)-2,3,~,5-tetrahydro-lH-Ll]benzazepin-2 one200 g
Lactose 1,700 g
Talcum powder 100 g
Procedure: ~11 the powders are passed througll a screen with openings
oE 0.6 mm. Then the drug substance is placed in a suitable mixer and
mixed first with the talcum, then with the lactose until homogenous.
No. 3 capsules are filled with 200 mg; using a capsule filling machine.
36
- 76 -
Analogously, tablets, injectable formulations or capsules areprepared
Erom the remaining compounds of the invention, e.g., those illustrated
by the examples hereiri.
Example 18:
l-Carboxymethyl-3S-(lR-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2-one
The methyl ethyl ketone filtrate from the crystallization of l-carboxy-methyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
lH-[l]benæazepin-2-one hydrochloride in Example 12 is evaporated, and
the residue triturated with ethyl acetate (50 ml). The resulting
solid is distributed;between ethyl acetate (100 ml) and water
(100 ml), and adjusted to pH 4.3 with concentrated hydrochloric acid.
The layers are separated and the aqueous phase is extracted with ethyl
acetate (2 x 100 ml) The combined ethyl acetate solutions are dried
over sodium sulfate and the solvent removed under reduced pressure~
The residue is separated into its components by high pressure liquid
chromatography with a C18 reverse phase preparative column and using
water/methanol (3:7) containing 0.05 % acetic acid as the solvent. ~n
additional quantity of the S,S isomer of example 12 is thus obtained,
as well as the S,R isomer. The material corresponding to the S,R
isomer is dissolved in dichloromethane (75 ml), and hydrogen chlo-ride
gas bubbled in for five minutes. The solvent is evaporated lmder
reduced pressure and the residue recrystallized from methyl ethyl
ke~.ol~e to give l-carboxymethyl-3S-(lR-ethoxycarbonyl-3-phenylpropyl-
amino)-2,3,~,5-tetrahydro-lH-[l]benzaæepin-2-one hydrochloride, m.p.
181-183, [~Y]D = -188 (c - 0.8 in ethanol).
~xample ]9:
l-Carboxymethyl-3S-(lS-carboxy-3-phenylpropylamino)-2,3,~1,5-tetra-
hydro-lH-[l]benzazepin-2-one
A solution of sodium hydroxide (0.27 g) in water (2 ml) is added to
a solution of l-carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropyl-
3~
amino)-2,3,~,5-tetrahydro-lH-[l]benzazepin-2-one hydrochloride (1 g)
in methanol (10 ml). The reaction mixture is stirred for 18 hours at
room temperature and the solvents removed under reduced pressure. The
residue is dissolved in water (25 ml), and tiie p~l adjusted to 3 by
the addition of 4N hydrochloric acid. The resulting solid is filtered
off, washed with water, and dried to give l-carboxymethyl-3S-(lS-
carboxy-3-phenylpropylamino)-2,3,4,5~tetrahydro-lH-[l]benza~epin-2-one,
m.p. 270-272, [~]D = -200.5 (c = 1, in 3 % aqueous ammonia).
Example 20:
l-Ethoxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one
A solution of 3-(l~benzyloxycarbonyi-3-phenylpropylamino)-2,3,~,5-
tetrahydro-lH-[l]benzazepin-2-one (5.0 g) in dry dimethylformamide
is added under a nitrogen atmosphere to a stirred suspension of
sodium hydride [from the 60 % mineral oil dispersion (0.5 g) washed
with petroleum ether (3 x 80 ml)] in dry dimethylformamide (100 ml)
at room temperature. Stirring is continued for an additional 30 minu-
tes at room temperature, when a solution of ethyl bromoacetate (2.0 g)
in dry dimethylformamide (10 ml) is added. After an additional 30
minutes at room temperature the reaction mixture is heated to 50, and
maintained at that temperature for 18 hours. The reaction mixture is
cooled to room temperature and the solvent removed under high vacuum.
Water (150 ml) is added and the solution extracted with ethyl acetate
(2 x 300 ml). The combined ethyl acetate solutions are washed with
water (lO0 ml), dried over magnesium sulfate, and the solvent removed
utlder reduced pressure to give a brown oil which is chromatographed
on silica gel (250 g). Elution with toluene/ethyl acetate (9:1;
600 ml) gives an oil, characterized as isomer A of the title compound.
Elution with an additional 1000 ml of the solvent mixture gives an
oil characterized as isomer B of the title compound.
3Ç~
- 78 -
Example 21:
l-Ethoxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4~5-
tetrahydro-l~-~l]ben~azepin-2-one
l-Ethoxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-phenylpropylamino-
2,3,4,5-tetrahydro-lH~[l]benzazepin-2-one (isomer B of Example 20,
1.1 g) in ethanol (150 ml) is hydrogenated at room temperature and
atmospheric pressure using palladium on charcoal (0.5 g) as catalyst.
After uptake o hydrogen tenninates, the catalyst is filtered off,
and the solvent removed under reduced pressure to give a semi-solid.
Trituration with ether (30 ml) yielded isomer B of the title com-
po-md, m.p. 175-177.
Example 220
l-Carboxymethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-8-methoxy-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one(isomer B)
A solution of 3-amino-1-carboxymethyl-8-methoxy-2,3,4,5-te-trahydro-lH-
[l]ben7azepin-2-one (4.0 g) and ethyl benzylpyruvate (9.4 g) in a
mix~ure of acetic acid (35 ml) and methanol (35 ml) is stirred for
1 hour. ~ solution of sodium cyanoborohydride (1.1 g) in methanol
(50 ml) is then added 510wly over the course of 5 hours. ~fter
stirring an additional I6 hours, concentrated hydrochloric acid (4 ml)
is added and stirring is continued for 1 hour. The solvents are
removed at reduced pressure and the residue is partitioned between
water (75 ml) and ether (35 ml). The pU is adjusted to 9.4 and the
ether layer is separated and discarded. The aqueous layer is
acidL~ied to p~l 4.3 and extracted with ethyl acetate (3 x 50 ml~. The
combined ethyl acetate solutions are dried over magnesium sulEate and
the solvent is removed at reduced pressure. Hydrogen chloride gas
is bubbled into a solution of the crude product in methylene chloride
(100 ml) for 5 minutes. The solution is evaporated and the residue is
stirred in ether (75 ml). The product is collected by filtration to
6~36
- 79 -
give an approximately 70:30 diastereomeric mixture as determined by
high pressure liquid chromatography.
The product is recrystalliæed from 3--pentanone to give l-carboxymethyl-
8-methoxy-3~ ethoxycar~onyl-3-phenylpropyl-amino)-2~3~4~5-tetra
hydro-lll-[l]benzazepin-2-one hydrochloride (isomer ~) melting at
240-245 (decomposition).
The starting material is prepared as follows: A solution of 8-methoxy-
2,3,~,5-tetrahydro-l~-[l]benzazepin-2-one (7.0 g, described in
E~ample 14) and phosphoru6 pentachloride (30.0 g) in xylene (200 ml~
is heated with stirring under an atmosphere of nitrogen to 90 ~oil
bath temperature) during 30 minutes with pauses at 30 and at 50.
There is a copious evolution of hydrogen chloride gas. The
temperature is maintained at 90 Eor 30 minutes. The reaction mixture
is filtered while hot to remove a small amount of suspended solid3
and the filtrate is evaporated under reduced pressure until all the
solvent is removed. The residue is added with stirring to saturated
aqueous sodium carbonate (20 ml). The product is filtered after the
solidification process is complete, slurried in ethanol (30 ml),
washed with ethanol (10 ml) and ether (10 ml~ and dried to give
3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-lFI-[l]benzazepin-2-one,
m.p. 148-lS0.
~ solu~ion of 3,3-dichloro-8-me-~ho~y-2,3,4,5-tetrahydro-lH-[l]-
benzazepin-~.-one (20g) and anhydrous sodi~lm acetate tl3.2 g) in glacial
acctic acid (250 ml) is hydrogenated at atmospheric press~ire using
10 % Pd/C (lg) as catalyst, until the uptake of hydrogen ceases.
The catalyst is filtered off and the acetic acid is evaporated under
reduced pressure. Water (100 ml) is added to the residue and the
suspension stirred for 1 hour. The solid is filtered, washed with
3~
- 80 -
water (50 ml~, and dried to give 3-chloro-8-methoxy-2,3,4,5-tetra-
hydro-lH-[l]benzazepin-2-onet m.p. 162-163.
A solution o~ 3~chloro-8-methoxy-2,3,4,5-tetrahydro-lH-[L]benZazepin
2-one (12.5 g) and sodium azide (4.3 g) in dimethylsulfoxide (150 ml)
is maintained at 80 under an atmosphere of nitrogen for 3 hours. The
reaction mixture is poured into ice/water (300 ml) and the
suspension is stirred for 30 minutes. The solid is filtered off,
washed with water (50 ml) and dried to give 3-azido-8-methoxy-2,39~l,5-
tetrahydro-lH-[l]benzazepin-2-one~ m.p. 136-138.
3-Azido-8-methoxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (5g) is
added in one portion to a stirred suspension of potassium hydroxide
(1.3 g) and tetrabutylammonium bromide (0.7 g) in tetrahydrofuran
(50 ml) maintained at 0 under a nitrogen atmosphere. Stirring is
continued for 5 minutes, then a solution of ethyl bromoacetate
(3.6 g) in tetrahydrofuran (15 ml) is added during 5 minutes. The
reaction mixture is allowed to warm to room temperature while stirring
for an additional 2 hours. The reaction mixture is filtered and the
tetrahydrofuran is removed at red~tced pressure. The residue is
partitioned between water (50 ml~ and ether (100 ml). The organic
phase is washed with 2N hydrochloric acid (10 ml), dried over
mngnesium sulfate and the solvent removed under reduced press~lre to
give 3-azido-1-ethoxycarbonylmethyl-8-methoxy 2,3,~,5-tetrahydro-lH-
[l~benzazepin-2-one~ m.p. 90-91.
suspension of 3-azido~l-ethoxycarbonylmethyl-8-methoxy-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2-one (13.8 g) in methanol (75 ml) is
treated with a solution of sodium hydroxide (1.9 g) in water (75 ml).
The reaction mixture is stirred at 40-45 for 2 hours. Water (100 ml)
is added and the mixture is acidified with concentrated hydrochloric
acid (10 ml) and extracted with methylene chloride (3 x 75 ml). The
3~
- 81 -
combined methylene chloride solutions are dried over magnesium
sulfate and evaporated at reduced pressure to give 3-azido-l~carboxy-
methyl-8-methoxy-2~3~4~5-tetrahydro-lH-[l~benzazepill-2-one~ m.p.
145-147.
A solution of 3-azido-1-carboxymethyl-8-methoxy-2,3,4,5-tetrahydro-lH-
[l]benzazepin-2-one (llg) in a mixture of ethanol (250 ml) and
water (50 ml) is hydrogenated for 3 hours at 3 atmospheres pressure
and room temperature using 10 % Pd-C (0.5 g) as catalyst. 2N
Hydrochloric acid (50 ml) is added, and the catalyst is filtered off.
The solvent is removed at reduced pressure, and the residue dissolved
in a mixture of water (50 ml) and ethanol ~50 m:L). Propylene oxide
(25 ml) is added and the mixture is stirred for 1 hour. The solvents
are removed under reduced pressure to give 3-amino-1-carboxymethyl-8-
methoxy-2,3,4,5-tetrahydro-1~-[l]benzazepin-2-one, m.p. >300.
Example 23:
l-(l-Carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[l]benzaæ.epin-2-one hydrochloride
A solution of 3-amino-1-(1-carboxyethyl)~2,3,4,5-tetrahydro-lH-[13-
benzazepin-2-one hydrochloride (3 g) and ethyl benzylpyruvate ~6.5 g)
in acetic acid (30 ml) and methanol (30 ml) is stirred at room
temperature Eor 1 hour. Sodium cyanoborohydride (0.3 g) in methanol
(10 ml) is added over 4 hours. The reaction mixture is stirred at
room temperature for 24 hours. Concentrated hydrochloric acid ~2 ml)
is added and the mixture is stirred for 1 hour. The solvents are
removed at reduced pressure and the residue is partitioned between
water (50 ml) and e~her (30 ml~. The pH is adjusted to 9.4, the ether
layer i5 separated and discarded. The aqueous solution is adjusted
to pH 4.3 and extracted with ethyl acetate (3 x 50 ml). The combined
ethyl acetate solutions are dried over magnesium sulfate and the
solvent removed under reduced pressure. Hydrogen chloride is bubbled
3~
- 82 -
into a solution of the crude product in methylene chloride ~10 ml)
for 2 minutes. The solution is evaporated to give l-(l-carboxyethyl)-3-
(l-ethoxycarbonyl-3-phenylpropylamino)-293,~,5-tetrahydro-lH-[l]-
benzazepin-2-one hydrochloride, as a mixture of diastereomers,
m.p. 87-94.
The starting material is prepared as follows: 3-Azido-2,3,4,5-tetra-
hydro-lH-[l]benzazepin-2-one (as prepared in example 1, 5 g) is
added in one portion to a stirred suspension of potassium hydroxide
(l.8 g) and tetrabutylammonium bromide (0.8 g) in tetrahydrofuran
(50 ml) maintained at 0 under a nitrogen atmosphere. Stirring is
continued for 5 minutes, then (R)-t-butyl 2-bromopropionate
~J.P. Greenstein et al., J. Am. Chem. ~oc. 76, 6054 (1954),
~1. Niedrich and G. Koller, J. Prakt. Chem. 316, 729 (1974)] (5.2 g)
in tetrahydrofuran (15 ml) is added during 5 minutes. The reaction
mixture is allowed to war~ to room temperature while stirring for an
additional 2 hours. The reaction mixture is filtered and the tetra-
hydrofuran removed at reduced pressure. The residue is parti~ioned
between water (50 ml) and ether (100 ml). I'he organic phase is washed
with 2N hydrochloric acid (10 ml), dried over magenesium sulfate, and
the solvent evaporated under reduced pressure to give 3-azido-1~
(I.-t-butyloxycarbonylethyl)-2,3,ll,5--tetrahydro-lH~[l]benzazepin-2-one
as an oil that is used without further purification.
A solution of 3-azido-1-(1-t-butyloxycarbonylethyl)-2,3,4,5-tetra-
hydro-lH-[l]benzazepin-2-one (7g) in ethanol (70 ml) is hydrogenated
at 3 atmospheres pressure for 3 hours using 10 % Pcl C (0.5 g) as
catalyst. The catalyst is removed by filtration and the ethanol
removed under reduced pressure to give 3-amino-1~ t-butyloxy-
carbonylethyl)-2,3,~,5-tetrahydro-lH-[l]benæazepin-2-one as an oil.
High pressure liquid chromatography (HPL~) indicates that the product
is an approximately 1:1 mixture of diastereomers. Thi;, material is
3~
- 83 -
used without fur~her purifica~ion.
A solution of the above 3-amino-1-(1-t-butyloxycarbonylethyl)-2,3,4,5
tetrahydro-lH-[l]benzazepin-2-one (4.7 g) in trifluoroacetic acid
(25 ml) is stirred at room temperature for 1 hour. The trilfuoroacetic
acid is removed under reduced pressure and the residue dissolved in
ether (100 ml). Hydrogen chloride gas is bubbled into the solution
until precipitation ceases. The solid is collected by filtration to
give 3-amino-l-(l-carboxyethyl)-2,394,5~tetrahydro-lH-[l]benzazepin-
2-one hydrochloride, m.p. 165-176. HPLC indicated that the product
is an approximately 1:1 mixture of diastereomers.
Example 24:
l-Ethoxycarbonylmethyl-3S-(lS-ethoxycarbonyl-3~phenylpropylamino)-
2,3,4,5-tetrahydro lH-[l]benzazepin-2-one
A solution of 3S-amino l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-
[l]benzazepin-2-one (1.5 g), ethyl 2-bromo-4-phenylbutyrate (1.6 g),
and triethylamine (0.3 ml) in dimethylformamide (37 ml) is stirred
under nitrogen for 18 hours at 70. The dimethylformamide is then
removed under reduced pressure. The residue is taken up in ethyl
acetate (70 ml), washed with water (5 x 25 ml), dried over
magnesium sulfate, and evaoprated. The product mixture is then
separated on a silica gel chromatography system with ethyl acetate/
hexane (40:6a) as solvent to yield about eqwal quantities of l-ethoxy-
c~rbonylmetllyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-
tetrahydro-lH-[13benzazepin-2-one ~NMR (CDC13) ~4.52 (q,2H)] the S,S
enantiomer of the compo~lnd of example 10, and its diastereomer,
l-ethoxycarbonylmethyl-3S-(lR-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin~2-one; NMR (CDC13): ~4.50 (q, 2H).
TLC: (silica gel, ethyl acetate/hexane 40:60): the (S,S) isomer has
Rf=0.24 and the (S,R) isomer Rf=0.33.
- 8~ -
Example 25
l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylproyylamino)-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2-one
2N Potassium hydroxide (0.26 ml) is added dropwise to a solution of
l-ethoxycarbonylmethyl-3S-~lS-ethoxycarbonyl-3-phenylpropylamino)-
2,3,495-tetrahydro-lH-[l]benzazepin-2-one (0.25 g) in ethanol (5 ml),
while stirring at room temperature under a nitrogen atmosphere. After
stirring for one hour the ethanol is evaporated and the residue is
dissolved in water (5 ml), acidified with 2N hydrochloric acid to pH2
and extracted with ethyl acetate (2 x 30 ml). The combined ethyl
acetate solutions are washed with saturated sodium chloride solution
(5 ml), dried over magnesium sulfate and evapora-ted to dryness to
yield l-carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one, the compound o~ example 12.
Example 26:
l-Carboxymethyl-7-chloro-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3j4,5-tetrahydro-lH-~l]benzazepin-2-one, isomer B
Chlorine is bubbled through a solution of l-carboxymethyl-3-(1-ethoxy-
carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepine-2-
one(isomer B, 1.5 g) in acetic acid ~25 ml), with stirring at room
temperature. A white solid precipitates out; chlorine is bubbled
through the reaction mixture until the reaction is complete. The solid
is filtered off and separatecl b~ reverse phase HPLC using a C18
column and methanol/0.1 % aqueous ammonium carbonate (1:1) as solvent.
The appropriate Eraction is dissolved in methanol/ethyl acetate
(1:1, 50 ml) and hydrogen chloride bubbled through the solution.
The solution is evaporated, the residue is suspended in ether (100 ml)
and the suspension is filtered to give l-carboxymethyl-~-chloro-3-
(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro~lH-[l]-
benzazepin-2-one hydrochloride, m.p. 149-151 (isomer B).
3~
- ~5 -
Example 27:
l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,~,5-
tetrahydro-lH-[l]benzazepin-2-one hydrochloride
3(S)-Amino-l~carboxymethyl-2,3~4,5-tetrahydro-lH-[l]ben~azepin-2-one
sodium salt (619 g) having [a]D 5= -304.4 (c=1.08 in water) 7 ethyl
benzylpyruvate (1960 g), anhydrous ethyl alcohol (5880 ml) and
glacial acetic acid (5880 ml) are combined and stirred at 20-25 for
1.5 hours. A s~lution of sodium cyanobrohydride (179 g) in anhydrous
ethyl alcohol (2200 ml) is added at a constant slow rate over 24 hours.
After addition is complete, the reaction mixture is stirred for
24 hours. 12N Hydrochloric acid (500 ml) is added to the reaction
mixture and the solvent is evaporated at 35-~0/3 mm Hg. The oil which
remaines is combined with ice (3000 g) water (3000 ml) and diethyl
ether (3000 ml), and the pH of the mixture is adjusted to 9-9.5 with
lON sodium hydroxide solution (1735 ml). The aqueous portion is
removed and an additional 8000 ml oE diethyl ether is added to the
ether portion to oil out additional product. The ether immiscible
yortion is removed and combined with the aqueous portion. m e ether
extract is then washed with water (2 x 1000 ml), the washes are
incorporated with the aqueous/oil portions from above and the mixture
is adjusted to pH 4.25-4.35 with 12N hydrochloric acid (550-650 ml)A
Tlle mixture is extracted with ethyl acetate (3x2000 ml), the combined
ethyl acetate portions are washed with water (2000 ml) and dried with
anhydrous magnesium sulfate (500 g). The drying agent i9 removed by
Eiltration and the solvent is thoroughly removed by evaporation at
40/3 mlll Hg. The resulting oil is dissolved in ethyl acetate (4500 ml)
and 28 % ethereal hydrogen chloride (309 g) was added with vigorous
stirring. Diethyl ether (1500 ml) is added and the mixture is stirred
for 1 hour. The solid is collected and is washed with ethyl acetate
(2x500 ml) and diethyl ether (3xlO00 ml)O Drying at 50/3 mm Hg
affords crude product consisting of approximately 65 % of the desired
l-carboxymethyl 3S (lS-ethoxycarbonyl-3-phenylpropylamino~-2,3, 4, 5-
63~
- 86 -
tetrahydro-lH-~l]benzazepin-2-one, identical to the material of
example 12, as determined by reverse phase HPLC on a Cl8 column with
a mixture of methanol, water, and acetic acid (75:25:0.02) as eluent.
Hydrogen chloride gas is ad~led in a steady stream to a suspension of
the above crude product in dichloromethane (26900 ml). A solution is
obtained after 40 minutes when the addition o~ the gas is stopped.
The solution is filtered to remove trace insolubles and diethyl ether
(10750 ml) was added.
The suspension is stirred overnight at ambient temperature and the
solid is collected by filtration and washed with dichloromethane
(4 x 500 ml) and diethyl ether (3 x 1000 ml). Drying affords purer
product as the hydrochloride salt, m.p. 175-178.
1880 g of above hydrochloride salt is combined with dichloromethane
(18000 ml). The suspension is again trea-ted with hydrogen chloride gas
to complete solution. Diethyl ether (7200 ml) is added. The suspension
is stirred for 3 hours and filtered. The collected solid is washed
with dichlorometIIane (2 x 1000 ml) and diethyl ether ~2 x 1000 ml) and
is dried to give product m.p. 183-185 (~IPLC indicated that the
product was approximately 96 % pure).
1280 ~ of the above salt is combined with chloro~orm (4000 ml) and
the mixture is heated at reflux temperature for 10 minutes. Heating
is di.scontinued and the mixture is stirred for 4 hours and filtered.
TIIe solid is washed with chloroform (2 x 200 ml) and diethyl ether
(3 x 500 ml), dried and sieved to give 1-carboxymethyl-3S-(LS-ethoxy-
carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-l~i-[l]benzazepin-2-
one hydrochloride, m.p. 184-186, [~]D5 ~ -139.26 (c = 0.92,
absolute ethanol), and identical to the hydrochloride salt of
example 12.
- 87
Example 28:
3 (1-benzyloxycarbonyl-3-phenylpropylamino)-l-carboxymethyl-2,3,4,5-
tetrahydro-lH-[l]benzazepin-2-one hydrochloride (Isomer B)
Dry hydrogen chloride gas is bubbled through a solution of
3-(1-benzyloxycarbonyl-3-phenylpropylamino)-1-t-butyloxycarbonyl-
methyl-2,3,~,5-tetrahydro-lH-Ll]benzazepin-2-one (4.0 g, see
Example 7) in ethyl acetate (100 ml) for 20 minutes while stirring at
0~. The reaction mixture is evaporated under reduced pressure and the
resulting solid triturated with ether (50 ml). The solid is filtered
oEf, washed wit'h ether (15 ml) and ethyl acetate (15 ml), and then
boilded with ethyl acetate (50 ml). The product is recrystallized from
methanol/ethyl acetate to give the title compound. m.p. 197-19~
(isomer B)o
The starting material is prepared as followsD Potassium t-butoxlde
(1.2 g) is added to a solution of 3-(1-benzyloxycarbonyl-3-phenyl-
propylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (3.0 g) and
t-butyl bromoacetate (2.2 g) in tetrahydrofuran (100 ml) stirring at
room temperature under an atmosphere of dry nitrogen. The reaction
mixture is stirred for 20 hours at room temperature, then po~lred into
water (250 ml) and extracted with dichloromethane (2 x 150 ml). The
combined dichloromethane solutions are washed with water (lO0 m'L) and
dried over magnesium sulfate. Evaporation of the solvent gives
3-(l-benzyloxycar'bonyl-3-phenylpropylamino)-1 t-butyloxycarbonyl-
metllyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one.
Example 29:
l-Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one
A solution of ethyl 2-(1-ethoxycarbonyl-3-phenylpropylamino)-~i-
[o-(ethoxycarbonylmethylamino)~phenyl]-butyrate (5.6 g) in methanol
(100 ml) is added to a solution of sodium methoxide in methanol
6~3~
~ 88
~prepared from sodium (0.25 g) and methanol ~50 ml)3 with stirring
under a nitrogen atmosphere. The reaction mixture is refluxed for
65 hours, then evaporated under reduced pressure. The residue is
distributed between water (50 ml) and dichloromethane (20Q ml). The
aqueous solution is extracted with dichloromethane (200 ml) and the
combined organic solutions washed with water (50 ml) and dried over
potassium carbonate. Evaporation of the solvent gives as a mixture
of isomers A and B of l-ethoxycarbonylmethyl-3-(1-ethoxycarbony~-3-
yhenylpropylamino)-2,3,~,5-tetrahydro-lH-[l]benzazepin~2~one~ which is
seyarated by chromatography on silica gel and converted to the
individual maleate salts as described in example 10.
e starting material is obtained as follows- To a solution of ethyl
2-amino-4-(o-nitrophenyl)-butyrate (17~4 g) in 50 % aqueous dioxane
(130 ml) is added triethylamine (10.5 g) and 2-(tert-butyloxycarbonyl-
oxyimino)-2-phenylacetonitrile (18.~ g). The reaction mixture is
stirred at room temperature for 4 hours and then diluted with water
(300 ml). The mixture is extracted with ether (2 x 150 ml), the
aqueous phase acidified with ice-cold 2N hydrochloric acid and
extracted with ethyl acetate (2 x 250 ml). The ethyl acetate layers
are combined, washed with water (150 ml) and dried over sodlum
sulfate. The solvent is removed under reduced pressure to give ethyl
2-tt)utyloxycarbonylamino-~-(o nitrophenyl)-butyrate, used wit'hout
further purification.
solution of ethyl 2-t-butyloxycarbonylamino-~-(o-nitrophenyl)-
b~ltyrate (13.0 g) in ethanol (300 ml) is hydrogenated at room
temperature and atmospheric pressure, using lQ ~ palladium on charcoal
(1 g) as catalyst, untll uptake ceases. The catalyst is filtered off.
Evaporation of the solvent gives ethyl 2~t-butyloxycarbonylamino~
(o-aminophenyl)-butyrate which is used without further purification
for the next step.
3~
- 89 -
A solution of ethyl 2-t-butyloxycarbonylamino-~-(o-aminophenyl)-
butyrate (10.0 g) and ethyl glyoxylate (4.2 g) in ethanol ~120 ml) is
hydrogenated at 80 and 3 atmospheres pressure for 72 hours using
10 % palladium on charcoal (3 g) as catalyst. The reaction mixture is
cooled to room temperature and the catalyst filtered off. The solvent
is removed under reduced pressure and the residue distributed between
ethyl acetate (150 ml) and water (75 ml). The organic phase is dried
over sodium sulfate and the solvent removed under reduced pressure to
give ethyl 2-t--butyloxycarbonylamino 4-[o-(ethoxycarbonylmethylamino)-
phenyl]-butyrate which is used without further puri~ication for the
next s-tep.
Hydrogen chloride gas is bubbled through a solution of ethyl
2-t-butyloxycarbonylamino-4-[o~(ethoxycarbonylmethylamino)-phenyl]-
butyrate (8.5 g) in ethyl acetate (150 ml) for 3~ minutes at room
temperature. The solu~ion is evaporated under reduced pressure and the
residue dissolved in ethyl acetate (100 ml. The solution is washed
with water (3 x 100 ml) and dried over sodium sulfa-te. The solvent is
removed under reduced pressure to give ethyl 2-amino-4-[o-(ethoxy-
carbonylmethylamino)-phenyl]~bu~yrate used without further
purification for the ne~t step.
solution o~ ethyl 2-amino-4-[o-(ethoxycarbonylmethylamino)-phenyl~-
butyrate (4.7 g) and ethyl benzylpyruvate (12.4 g) in acetic acid
(35 ml) and methanol (35 ml) is stirred at room temperature under
ni~rogen ~or 1 hour. Sodium cyanoborohydride (1.6 g) in methanol (15 ml)
is a(l(led dropwise over 4 llours. The reaction mixture is stirred at
room temperature for 24 hours. Concentrated hydrochloric acld (2 ml)
is added dropwise, and the mixture stirred at room temperature for
1 hour. ~he reaction mixture is evaporated ~o dryness, and the
residue partitioned between water (75 ml) and ether (75 ml) and
adjusted to pH 2 with 6N hydrochloric acid. The layers are separated,
3~
-- 90 --
and the aqueous phase extracted with ether (2 x 75 ml). The ether
extracts are discarded and the aqueous layer adjusted to pH 9 with
40 % sodium hydroxide, and extracted with ethyl acetate (3 x 50 ml).
The ethyl acetate ex-~racts are dried over sodium sul~ate and the
solvent removed under reduced pressure to give ethyl 2~(1-ethoxy-
carbonyl-3-phenylpropylamino)-4-(o-ethoxycarbonylmethylamino)-
phenyl]butyrate which is used directly ~or preparing the final
procluct above.
~xample 30:
Ethyl 2-amino-4 phenylbutyrate is treated under conditions of
reductive alkylation as described in the previous examples with
l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2,3-dione
to give l-ethoxycarbonylmethyl-3-(l~ethoxycarbonyl-3-phenylpropyl-
amino)-2,3~4,5-tetrahydro-lH-[l]benza~epin-2-one o~ example 10.
The starting material is prepared as ~ollows: A solution of 3,3-di-
chloro-2,3,4,5-tetrahydro-lH-[l]ben~azepin-2-one (1.0 g, 4.32 mmol)
and ethyl bromoacetate (0.51 ml) in tetrahydroEuran (30 ml) is added
dropwise with stirring during 15 minutes to a SO].UtiOIl O~ sodium
hydride (4.76 mmol) in tetrahydrofuran (20 ml) at room temperature
under a nitrogen atmosphere. Stirring is continued Eor an additional 2
hours. ~he solution :is quenched by addition of saturated aqueous
ammonium chloride and the soLvents are removed under reduced pressure.
The residue is extracted with ether (3 x 20 ml),the combined ether
solutions washed with saturated aqueous sodium chloride solution
(20 ml) and dried over magnesium sul~ate. Removal o~ the solvent
under reduced pressure gives 3,3-dichloro-1-ethoxycarbonylmethyl
2,3,4,5-tetrahydro-lH-[l]benza~epin-2-one. NMR(CDC13): ~1.27 (t,3H);
3.22 (m, 4H); 4.25 (q, 2H); 4.65 (s, 2H~ and 7.3 (m, 4H)~
3~
~ 91 -
A mixture of morpholine (0.315 ml, 3.6 mmol) and 333-dichloro-l-
ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (0.5 g)
is stirred under nitrogen at 110 for 18 hours. The solution is diluted
to 10 ml with chloroform and cooled to 0. 20 % sulfuric acid (1 ml)
is added and the solution stirred for 2 hours at 0. The solution is
e~xtracted with chloroEorm (2 x 20 ml) and the extracts are washed
with 2 N hydrochloric acid (2 x 10 ml) and saturated aqueous
sodium chloride solution (5 ml). The solution is dried over magnesium
sulfate and evaporated under reduced pressure to yield l-ethoxy- o
carbonylmethyl-2,3,4,5-tetrahydro-1~1-[llbenæazepin-2,3-dione. NMR
(CDC13): ~1.25 (t,3H); 2.6 (m,2H); 3.6 (m~2H); ~.2 (q, 2H) and 7.3
(m, 4H).
Example 31:
Ethyl 2-amino-4-phenylbutyrate is treated in the presence of
potassium carbonate in methylene chloride with 3-bromo-1-ethoxycarbonyl-
methyl-2,3,4,5-tetrahydro-lH~[l]benzazepin-2-one to give l-ethoxy-
carbonylmethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetra-
hydro-lH~l]benzazepin-2-one of example 10.
The starting material is prepared as follows To a solution of
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (2.5 g) in chloroform (30 ml),
phosphorous pentachloride (3.2 g) is added in portions, while
maitltalning the temperature at 0-5. ~len the addition is complete,
iodine (30 mg~ is added followed by bromine (2.5 g), which is added
dropwise over 5 minutes. The mixture is then refluxed Eor 4 hours. The
chloroEorm solution is evaporated and the residue is partitioned
between ice-water (30 ml) and dichloromethane (75 ml). The organic
phase is dried over magnesium sulfa-te and evaporated under reduced
pressure. The cr~lde residue is purified by chromatography over silica
gel, eluting with ether and hexane (7:3). Concentration of the
appropriate fractions yields 3-bromo 2~3,~,5-tetrahydro-lH-[l]-
benzazepin-2 one, m.p. 146-148~.
3~
- 92 ~
3-Bromo-2,394,5-tetrahydro-lH-[l]benzazepin-2-one (300 mg) is added
in one portion to a stirred suspension of potassium hydroxide (90 mg)
and tetrabutylammonium bromide ~40 mg) in tetrahydrofuran (10 ml~
maintained at 0 under a nitrogen atmosphere. Stirring is continued for
5 minutes, then ethyl bromoacetate (200 mg) is added in one portion.
The reaction mixture is allowed to warm to room temperature while
stirring for an additional 3 hours. The tetrahydrofuran is removed
under reduced pressure and the residue partitioned between water (S ml)
and ether (25 ml). The organic phase is washed with 2N hydrochloric
acid (S ml), dried over magnesium sul~ate, and the solvent removed
under reduced pressure to give 3-bromo-1-ethoxycarbonylmethyl-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one, m.p. 114-116.
3-Chloro-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l~benzazepin-2-
one is similarly prepared.
A solution of 3-chloro-2,3,4,5-tetrahydro-lH-~l]benzazepine-2-one
(1.95 g) in dimethylformamide (10 ml) is added dropwise with stirring
to a solution of potassium t-butoxide (1.12 g) in dimethylformamide
(10 ml) at 5. The solution is stirred for an additional 15 minutes
at 5, then ethyl bromoacetate (1.78 g) in dimethylformamide (5 ml) is
added dropwise. ~tirring is continued for an adclitional 30 minutes at
5 and then for 3 hours at room temperature. The reaction mixture is
cooled to 10 and water (100 ml) is added. The solution is extracted
with chloroform (100 ml) and the chloroform solution washed with
water (2 x 10 ml) and dried over sodium sulfate. The solvent is
removed under reduced pressure to yield 3-chloro-1-ethoxycarbonyl-
methyl-2,3,4~5-tetrahydro-lH-[1]benzazepin-2-one; NMR (DMS0-d6):
~1.2 (t,3H); 2.65 (m, 4H); 4.15 (q, 2H); 2.6 (d,2H) and 7.3 (m).
3~
- 93 -
Example 32:
l-carboxymethyl-3S-(lS-pivaloyloxymethoxycarbonyl-3-phenylpropylamino)
2,3,4,5-tetrahydro-l~-[l]ben~a~epin-2-one
l-Benzyloxycarbonylmethyl-3S-(lS-pivaloyloxymethoxycarbonyl-3-phenyl-
propylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one (3 g) is
dissolved in ethanol (50 ml) and 10 % Pd-C (0.3 g) is added and the
solution hydrogenated at 1 atmosphere pressure and room temperature
for 2 hours. The reaction mixture is filtered and evaporated to yield
l-carboxymethyl-3S-(lS-pivaloyloxymethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin~2-one.
The starting material is prepared as follows: l-benzyloxycarbonyl-
methyl-3S-(lS-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-
Cl]benzazepin-2-one (5 g, Example 2) is dissolved in 2N potassium
hydroxide solution (5~15 ml) and the solution evaporated to dryness.
Iodomethyl pivalate (2.3 g) and dimethylformamide (50 ml) are added,
and the reaction mixture is stirred at room ~emperature for 18 hours
under a nitrogen atmosphere. The dimethylformamidè is evaporated,
the residue is taken up in ethyl acetate (lOO ml) and washed with
saturated sodium bicarbonate (3 x 25 ml), water (3 x 25 ml), and
saturated sodium chloride (25 ml),l and dried over magnesium sulfQ~e.
~vaporation gives l-benzyloxycarbonylmethyl-3S-(lS-pivaloyloxy-
methoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l~-
benzaæepin-2-one.
S~milarly prepared are:
a) l-carboxymethyl-3S-(lS-~-bornyloxycarbonylmethoxycarbonyl-3-phenyl-
propylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one using e-bornyl
iodoacetate as starting material.
~6~
- 94 -
b) l-carboxymethyl-~S-(lS-~-methoxyethoxymethoxycarbonyl-3-phenyl-
propylamino~-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-one using
~-methoxyethoxymethyl chloride as starting material.
c) l-carboxymethyl-3-S-~lS-(3-phthalidoxycarbonyl)-3-phenylpropyl-
amino]-2~3~4~5-tetrahydro-lH-[l]benzazepin-2-one using 3-bromophthalide
as starting material.
d) l-carbox~methyl-3S-[lS-(3-pyridylmethoxycarbonyl)~3-phenylpropyl-
amino]-2,3,4,5-tetrahydro-lH-[l]benzazepin 2-one using 3-pyridylmethyl
chloride as starting material.
~xample 33:
l-CarboxymethyL-3S-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5,5a9-
697,8,9,9a-decahydro-lH-[13benzazepin-2-one
solution of 3(S)-amino-l-carboxymethyl-2,3,4,5,5a,6,7,8,9,9a-
decahydro-lH-[l]benzazepin-2-one sodium salt (0.6 g) and ethyl benzyl-
pyruvate (1.5 g) in acetic acid (5 ml) and methanol (3 ml) is stirred
at room temperatur`e under an atmosphere of dry nitrogen for l hour.
A so]ution of sodi~ml cyanoborohydride (0.2 g) in methanol (2 ml) is
then added over a 4 hour period. The reaction mixture is skirred at
room temperature for 1~ hours. Concentrated hydrochloric acid (0.5 mL)
:i8 added and the mixture stirred at room temperature for 1 hour. The
solvents are removed under reduced pressure and the residue
partitioned between water (20 ml) and ether (20 ml). The p~l is adjusted
to ~.3 with 40 % sodium hydroxide. The ]ayers are separated and the
ether layer discarded. The aqueous phase is adjusted to pH 4.3 with
concentrated hydrochloric acid and extracted with ethyl acetate
~3 x 25 ml). The extracts are dried over magnesium sulfate and the
solvent removed under reduced pressure. Hydrogen chloride is bubbled
into a solution of the residue in dichloromethane (70 ml) for
;3~;
- 95 -
5 minutes. The solution is evaporated and the residue recrystallized
from ethanol/ether to give l-carboxymethyl-3S-(1 ethoxycarbonyl-3-
phenylpropylamino)-2,3,4,5,5a,6,7,8,9,9a-decahydro-lH-[l]benzazepin-
2-one-hydrochloride as a mixture o~ isomers.
The starting material is prepared as follows: A solution of 3(S)-t-
butyloxycarbonylamino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro- 1~l-
[l]benzazepine-2,5-dione (3.6 g) in acetic acid (50 ml) is hydrogenated
for 120 hours at 3 atmospheres pressure using platinunl oxide (1.2 g)
as catalyst. The catalyst is filtered off and the filtrate evaporated
under reduced pressure. The residue is distributed between dichloro-
methane (200 ml) and saturated aqueous sodium bicarbonate (lO0 ml).
The dichloromethane solution is washed with water (50 ml~, dried over
sodium sulEate and the solvent removed under reduced pressure. The
residue is chromatographed on silica gel eluting with 0-50 % ethyl
acetate in toluene. The fraction eluting with 50 % ethyl acetate in
toluene is collected to give 3(S~-t-butyloxycarbonylamino~l-ethoxy-
carbonylmethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-lH-[l]benzazepin-2,5-
dione used without further purification for the next synthetic step.
A solution of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-
2,3~4,5,5a,6,7,8,9,9a-decahydro-lH-[l]benzazepin-2,5-dione (2.7 g)
and sodium borohydride (0.2 g) in ethanol (lO0 ml) is stirred at room
temperature for 18 hours. The solvent is removed under reduced
pressure, and the residue dissolved indichloromethane (100 ml). The
solution is extracted with ice-cold 2N hydrocllloric acid (2 x 50 ml)
and saturated aqueous sodium chloride solution (50 ml) and dried over
sodium sulfate. The solvent is removed under reduced pressure and the
residue triturated with ether to give 3(S)~t-butyloxycarbonylamino-l
ethoxycarbonylmethyl-5-hydroxy-2,3,~,5,5a,6;7,8,9,9a-decahydro-lH-
[l]ben7azepin-2-one.
3~
- 96 -
A mixture of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-5-
hydroxy-2,3,4,5,5a~6,7,8,9,9a-decahydro~ [l]benzazepin-2-one (2.1 g),
dicyclohexylcarbodiimide (1.8 g) and cuprous chloride (0.2 g ) is
heated at 80 under nitrogen for 32 hours. The reaction mixture is
cooled to room temperature, the residue is dissolved in methylene
chloride (200 ml), washed with dilute ammonium hydroxide (2 x 50 ml)
and water (50 ml). The organic phase is dried over sodium su]~ate and
evaporated to give a mixture of the desired adduct and excess dicyclo-
hexylcarbodiimide. This mixture is clissolved in ethyl acetate (100 ml)
and placed in a pressure bottle. 10 ~ Pd/C (0.~ g) is added and the
mixture hydrogenated at 3 atmospheres pressure and 40 for 16 hours.
The catalyst is filtered oEf and the filtrate is evaporated to give
3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-2,3,4,5,5a,6,7,8,9,
9a-decahydro-lH-[l]benzazepin-2-one, used without further purification
for the next synthetic step.
Hydrogen chloride gas is bubbled through a solution of the above
compound (1.1 g) in ethy] acetate (50 ml) for 45 minutes. The
reaction mixture is evaporated under reduced pressure, the residue
dissolved in ethyl acetate (50 ml) and washed with water (3 x 30 ml~.
The ethyl acetate solution is dried over sodium sulfate and the
solvent removed under reduced pressure to give 3(S)-amino-l-ethoxy~
carbollyllllethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-lH [llhenzazepin-2-one~
which is used without further purification ~or the next step.
solution oE sodium hydroxide (O.lg) in water (0.25 ml) is added to
a solu~.ion of the above amine (o.6 g) in methanol (7.5 ml) at room
temperature, and the solution is stirred ~or 2 hours. The solvents
are evaporated and the residue thoroughly dried, then slurried with
ether, to give the sodium salt of 3(S)-amino-l-carboxymethyl-
2,3,4,5,5a,6,7,8,9,9a-decahydro-lH-[l]benzazepin-2-one.
63~
- 97 -
Example 34:
N-[l-(l-carboxymethyl)-2,3,4,5-tetrahydro-2-oxo-lH-[l]benzazepin-3S-
ylamino)-3-phenylpropyl-1-carbonyl]-L-phenylalanine.
L-Phenylalanine methyl ester hydrochloride is condensed with l-benzyl-
oxycarbonylmethyl-3S-(lS-carboxy-3-phenylpropylamino)-2,3,4,5-tetra-
hydro-lEI-[l]benzazepin-2-one in methylene chloride in the presence o~
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room
temperature to yield after workup the N-[l-(l-benzyloxycarbonyl-
methyl-2,3,4,5-tetrahydro-2-oxo-lH-[l]benzazepin-3S-ylamino)-3-phenyl-
propyl-l-carbony]]-L-phenylalanine methyl ester.
Hydrogena~ionllusing 10 % Pd/C catalyst in ethanol gives N-[l-(l-
carboxymethyl-2,3,4~5-tetrahydro-2-oxo-lH-[l]benzazepin-3S-ylamino~-
3-phenylpropyl-1-carbonyl]-L-phenylalanine methyl ester.
Elydrolysis with dilute aqueous sodium hydroxide at room temperature
for 18 hours yields the ~-[1-(1-carboxymethyl-2,3,4,5-tetrahydro-2-
oxo-lH-[l]benzazepin-3S-ylamino)-3-phenylpropyl-1-carbonyl]-L-
phenylalanine.
~xalllple 35:
l-~thoxycarbonyl~ethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-
2,3,4,5-tetrahydro-lH-[l]benzazepin-2-olle
Treatment of 3-(l~carboxy-3-phenylpropylamino)-1-cyanomethyl-
2,3,~,5-tetrahydro~lH-[l]benzazepin-2-one wîth ethanol-ether (1:1)
saturated with hydrogen chloride at room tempera~ure for 48 hours
gives a~ter workup l-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-
phenylpropylamino)-2,3,4,5-tetrahydro-lH-~l]benzazepin-2-one identical
to the compound o~ example 10.
- 98 -
The starting ma-terial is prepared as follows: 3-(1-carboxy-3-phenyl-
propylamino)-2~3~4~5~tetrahydro-lH~El]-benzazepin-2-one is alkylated
with bromoacetonitrile in dimethylformamide solution in the
presence of sodium hydride to yield after work-up~ 3-(1-carboxy-3-
phenylpropylamino)-l-cyanomethyl-2,3,4,5-tetrahydro-].H-[l]benzazepin-
2-one, used directly in the next step.
Example 36:
Preparation of 10,000 tablets each containing 10 mg of the active
ingredient of ~xample 12:
Formula:
l-CarboXymethyl-3s-(ls-ethoxycarbonyl-3-phenylpropylamino)-2~3 ,~!, 5-
tetrahydro-lH-[l]benzaæepin-2-one100 g
Lactose 1,157 g
Corn starch 75 g
Polyethylene glycol 6,000 75 g
Talcum powder 75 g
Magnesium stearate 18 g
Purified water q.s
Procedure: As described in Example 150
~xample 37:
Preparation of 10,000 capsules each containing 20 mg of the hydro-
chloride sa]t of the active ingredient of Example 12.
Formula:
l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,~,5-
tetrahydro-lH-[l]benzazepin-2-one hydrochloride 200 g
Lactose 19700 g
Talcum powder 100 g
Procedure: As described in Example 17.
i3~
Cardiovascular pharmacology of compounds of the invention
Testing of compounds is carried out by methods for evaluation of the
inhibition of the angiotensin converting enzyme (~CE). Biochemical
assessment of in vitro ACE inhibi~ion (ACEI) gauges the inhibition
of peptidolytic activity of a compound in rabbit lung tissue. In in
vivo studies angiotensin I (AI) pressor response inhibition of the
compounds are conducted in rats.
In the in vivo test method an increase in the blood pressure is first
caused by administration of angiotensin I (AI) to the test animal.
The inhibitory action of the individual compounds on this increase
in blood pressure is then determined.
Biochemical Testing Methodology
A rabbit lung tissue preparation [Das and Saffer3 J. Biol. Chem.
250: 6762, (1975)] was used for assessment of ACE by the method of
Cheung and Cushman [Cheung and Cushman, Biochim. Biophys. Acta 293:
451, (1973)]. This test system incorporates spectrophotometric
evaluation of the amount o histidyl-leucine liberated from a syn-
thetic substrate after 30 min. of 37C incubation. IG50 values for
ACE inhibition were determined graphically as the concentration of
test drug required to reduce the amount of histidyl-leucine formed
to 50% of that generated in the absence of the test compound.
Methodology o angiotensin [ (~I) pressor response inhibition
ollowing intravenous administration of test compounds (~ AI)
In these studies catheters were placed in a femoral artery and a
saphenous vein oE anesthetized rats as described above. Arterial
pressure was continously recorded rom the arterial catheter, while
AI and the test compounds were injected through the venous catheter.
~I pressor response inhibition was expressed as percent decrease of
the response from pretreatment control values and tabulated as the
average inhibition recorded within 30 minutes after test drug ad-
ministration.
636
-- 100 --
Results:
Angiotensin I pressor response inhi-
bition in rats
Compound of in vitro i.v. Dose (mg/kg) % AI inhibition
Example ACEI
50 ( )
1 6 x lO 7 10 1~0
l.O 100
0.1 50
2 x 10 7 0.1 37
9 5 x 10 9 0.3 g3
0.1 80
0.03 ~0
1 x 10 5 1.0 80
Maleate
Salt
12 4 x 10 7 1.0 100
HCl Salt 0.3 95
0.1 82
0.06 74
0.03 29
19 2 x 10 9 0.1 93
0.06 84
0.03 70
0.02 69
0~01 28
0.007 14
28 1 x lO 7 0.1 92
Isomer B,
HCl Sal~
