Note: Descriptions are shown in the official language in which they were submitted.
~2~;:t72~
-- 2
- This Application is a Divisional of Canadian Pa-tent
Application Serial Number 443,407, Filed December 15, 1983.
The invention relates to derivatives of seasoned-
Z--azabicyclo~5.3.0]decane-3-carboxylic acid of the formula
I
C / ON
C0
I x I
Cockney cll~c~l2-c~x (I)
R CO n z
in which the hydrogen atoms on the bridgehead carbon atoms 1
and 5 have the c;s-conf;gura~;on relative to one another
and the carboxyl group on C atom 3 is oriented end to
the bicycle ring system and in which
R denotes hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl or
(C6~C12)~arY~-tc1-c4)-alkyl~
R1 denotes hydrogen, ally, vinyl or a side chain of an
optionally protected naturally occurring amino acid
RICH tNH2)-CooH,
R2 denotes hydrogen (C1 Colloquial tC2 C6)-alkenyl
or tC6 C12)-a~`yl-tc1-c4)-alkyl~
Y denotes hydrogen or hydroxyl,
Z denotes hydrogen or
Y and Z together denote oxygen
Y denotes tC1 Colloquial, tC2 C6~ Allen ,
~227~
cycloalkyl, tC6-C12)-aryl, preferably phenol, Lucia can
be substituted once, twice or three times by ~C1-C~
alkyd, (C1-C4)-alkoxy, hydroxyl, halogen, vitro, amino,
(C1-C4)-alkyiam;no, di-(C1-C4) alkylamino actor ethylene-
Dixie or denotes indol-3-yl,
and their physiologically acceptable salts.
Those compounds of the formula I in which
R denotes hydrogen,
R denotes methyl, the optionally assaulted side chain
of Lawson or the 0-alkylated side chain of Tarzan,
R denotes hydrogen, methyl, ethyl, bouncily or left.-
bottle,
X denotes phenol or phenol substituted once or twice with
flowerier and/or chlorine,
Y denotes hydrogen or hydroxyl and
Z denotes hydrogen or
Y and Z togetl1er denote oxygen
are preferred. In this context and in the following text,
aureole is understood to be preferably phenol.
Particularly preferred compounds which may be Men-
toned are:
N(1-S-carboethoxy-3-phenylpropyl)~S-alanyl-cis,endoo-2-
azabic~cloC5.3.0~decane-3-S-carboxylic acid,
N-!1-S~carboxy-3-phenylpropyl) S-alanyl-cis,endo assay
bicycloC5.3.0]decane-3-S-carboxylic acid,
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-cis,enddyes-
bicycloC5.3.0~decane-3-S-carboxyl;c acid,
N-(1-S-carboxy-3-phenylpropyl)-S lysyl-cis,endo-2-azabi
cycloC5~3.0~decane-3-s-carboxylic acid,
-- 4 --
N (1-Scarboethoxy-3-phenylpropyl)-0-ethyl-S-~yrosyl-c;s,,
end azabicyclo[5.3.0~decane-3-S-carboxylic acid and
N-t1-S-carboethoxy-3-phenylpropyl)-0-methyl~S-tyroosyl-cis,
endo-2-azabicyclo~5.3.0~decane-3-S-carboxylic acid.
S In the case where R1 represents a side chain of
a protected naturally occurringi~-aminoacid, such as, for
example, protected Son, Thy, Asp, Awn, Glut Gin, Argo Lye,
Hal, Cyst Own, Ott, Try, rip, His or loupe, tl1en the pro-
furred protective groups are the groups customary in pep-
tide chemistry (cf. Hobnail, Vol. XV/1 and XV (2)).
In the case where R1 denotes the protected Lawson side
chain, the known amino protective groups, but in pyrrhic-
far (C1-CO)-alkanoyl, are preferred. In the case where
R1 denotes the protected tersely side chain, the pro-
tect;ve group on oxygen Sian ether protective group, in particular (C1 G6)-alk~rl; methyl and ethyl are particularly
preferred protective groups,
Particularly suitable salts are the hydrochlor;des,
Maltese, tart rates and the alkali metal, Cay My and Zen
ZOO salts.
The centers of cruelty at the carbon atoms on the
chain and at C atom 3 of the b;cycl;c System weakly are
labeled with an asterism (*), can have either the R or the
S conf;gurat;on. However, those compounds on winch these
Z5 centers have the S configuration are preferrer with the
exception that when I~H-CHR1-CO) = Cyst the R configure-
ton of thus center is preferred.
The invention also relaxes to a process for the
preparation of the compounds ox the formula I, which come
Lo
-- uprises reacting a compound of the formula II in Welch I
has the meanings mentioned above h the exception of
hydrogen with a compound of the formulae IIIa or IIIb or
the race mate on which W denotes a group esterifying car-
biaxial such as (C1-C6)-al~yl or (C7 C8) anal y
preferably ter~.-butyl or Bunnell, by methods of amid for-
motion known in peptize chemistry optionally converting
the compounds of the formula I thus obtained by hydrogen-
atom, treatment with acid and/or base into compounds of
10 the formula I (R and/or R2= H), optionally esterifying
the compounds thus obtained in a manner known per so and/
or optionally converting them into their physiologically
acceptable salts.
D;astereomers of true formula I can be separated
from one another, for example, by crystallization or
chromatography.
OR
X-c-cH2-c~ H~cH-co2~l (II)
CRY
. H
HO (IIIa)
I J
~102C I ,
INN \
~IIIb )
J
~02C H
I
---6
Compounds of the formula II have already been proposed.
Those having X = phenol, Y Z H, R1 - SHEA and R2 _
SHEA or C2H5 are known (for example from European
Patent 0,037,231) and are accessible by various routes.
The bouncily esters (R2 = bouncily) can be prepared analog-
out my .
The auntie reaction of acetophenones of the for-
mule Ivan in which X represents aureole optionally subset
tuned as above, with glyoxylic esters and ammonias
esters leads to compounds of the formula II in which Y and
Z together denote oxygen (formula It n the formula lo,
1J denotes a radical which can be split off by hydrogen-
louses, base or acid, preferably bouncily or tert.-butyl and
X represents optional meanings as defined above. Ivory
in the case of the ber,zyl ester ~rJI bouncily), DO Lucite no
be Bunnell. On hydrogenolysis of these compounds with Pod
compounds of the formula II in which Y and Z are hydrogen
are produced.
., F.~1
2QX-CO-CH3 I- ECHO H2~-CH-C02~1 C02X2 X'
2 X-CO-C~2-CH~ SCHICK
viva) (I")
Compounds of the formula Inn which Y and Z to-
getter denote oxygen can likewise be obtained in high
yields by Michael add ton of appropriate ketoacrylic
esters with amino acid esters. Ester cleavage leads to
25 the same products as the Mannish reaction.
- 7 _ I 2
O . R1
X-C-CH~C~-C02R2 -I NH2-CH-C02W' , {IV)
The diastereomers Thea the preferred S,S-configurâtion are
produced by employing L-alanine esters in excess and can
be obtained by crystallization or chromatographic swooper-
lion of the esters on silica gel.
Cis,endo-2-azab;cyclo~5.3.0~decane-3-carboxylic
esters of the formula III a and b are accessible frown en-
ammonias of cycloheptanone having the formula VI in which
x1 represents dialkylamino having 2 to 10 carbon atoms or
represents a radical of the formula VII on witch m and o
denote a whole number from 1 to 3, (m o) -, 3 and A den
owes Chihuahuas, NH, 0 or S,
X1 (VI)
.
Jo C1~2 em\
N A (VII)
Jo I
and N-acylated ~-halogeno-~-am;nocarboxylic esters of the
formula VIII in which yo-yo represents a nucleoFugic group,
preferably chlorine or brom;ne, ye represents alkanoyl
having 1 to 5 carbon atoms, aureole having 7 to carbon atoms
or other protective groups which can be split off Whitehall acid
and are customary in popped chemistry, and R2 represents
alkyd leaving 1 to 5 carbon atoms or aralkyl having 7 to 9
carbon atoms
\C1~2
t V I l I )
Y 1 H,! COORS
or with acrylic esters of the formula IX in which ye and
R2 have the above meaning,
/ kiwi
OH - C (IX)
NH-Y
5 by reacting these compounds to give compounds of the for-
mute X in which R2 and ye have the above meaning,
I COREY (X)
SHEA - OH
cyclizing the latter using strong assiduous with cleavage o-f
the acylarn;de and ester, to give compounds ox the formula
10XI a or b,
I\
... I
Jo .
COO
/~\ . (XI)
COO
I b
converting the latter by catalytic hydrogenation in the
presence of transition metal catalysts or by reduction
with borane-am;ne complexes or complex borohydrides in
lower alcohols into compounds of the formulae Iliac and/or
b in which W represents hydrogen, and optionally esterify-
no to give compounds of the formula III a and/or b in
which Jo represents alkyd having 1 to 6 C atoms or aralkyl
having 7 to 8 C atoms.
Rhizomic mixtures comprising compounds of the For-
mule IIIa and IIlb can, when desired, be separated freemen another by the Nolan methods of racer Nate resolution
(cf. for example Quart. Rev. 25 (1971) 323 et seq.).
The bicyclic amino acids of the formulae IIIa and
b have the seasoned configuration, i.e. the -KIWI group
faces towards the cycloheptarte ring All the other assay-
bicycloC5.3~0~decane-3-carboxylic acid derivatives detailed
on the present invention are also in the seasoned confi-
urchin
Examples of preferred examines are pyrrolidino-
cycloheptene and morphol;nocycloheptene. The alkyla~;onproducts of the formula X are preferably cyclized using
aqueous hydrochloric acid. The compounds OKAY the formula
III a and b (having lo H) or the rhizomic mixture thereof
can be esterified using the methods customary for amino-
acids (see, for example, Houben Lyle ~lethoden don organic
skin Chemise (Methods in Organic Chemistry Volt VIII
~1952)), for example using thinly chloridetbenzyl alcohol
or isobu~ylene/sulfuric acid. After appropriate working
up, compounds of the formula IT a and/or b are obtained
3 in the form of tile free base or of a salt
- 10
I
The new compounds of the formula I have a long-
lasting and intense hypotensive effect. They are strong
inhibitors of angiotensin converting enzyme (ACE inhibit
ions) and can be employed to control high blood pressure
5 of various etiologies. It is also possible to combine
them with other compounds having hypotens;ve, vasodilator
or diuretic activity. Typical representatives of these
classes of active compounds are described, for example,
in Erhardt-Ruschig, Arzneimi~tel Drugs end edition,
10 Weinheim, FRY, 1972. They can be used intravenously, sub-
cutaneously or orally.
On oral administration, the dose is 1 - 100 my,
preferably 1- 5Q, in particular 1- 30 my, per single dose
for an adult of normal weight which corresponds to 0.013
15 to 1.3 mg~g/d2y9 preferably 0.013 Jo 0.7 mg/k~/daJ~ on
particular 0.013 to 0.4 mg/kg/~ay. It can also be raised in
severe cases, since toxic properties have not hitherto
been observed. It is also possible to decrease the dose
and this is particularly appropriate when diuretics are
administered at the same tome.
The compounds according to the invention can be
administered orally or parenterally in an appropriate
pharmaceutical formulation. For a form for oral use, the
active compounds are mixed with the additives customary
I for this purpose, such as vehicles, stabilizers or inert
delineates and converted by customary methods unto suitable
pharisee for administra~;on, such as tablets, coated tablets,
hard capsules, aqueous alcoholic or oily suspensions or
aqueous alcoholic or oily solutions. Examples of inert
vehicles which can be used are gum Arabic, ma~rles;uln car-
I
Bennett, potassium phosphate, lactose, glucose or starch,
especially corn starch. In this context,. the formulation
can be either as dry or moist granules. Examples of suit
able only vehicles or solvents are vegetable and animal
oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration,
the active compounds or their physiologically tolerated
salts are converted into a solution, suspension or Emil-
soon, if desired loath the substances customary for thus
purpose, such as solubilizers, emulsifiers or other Audi-
lyres. Examples of suitable solvents for the new active
compounds and the corresponding physiologically tolerated
salts are: water, physiological saline solutions or Alcoa
hots, such as ethanol, propanediol or glycerol, on add;-
lion sugar solutions, such as solutions of glucose or,mannitolr or a mixture of the various solvents rnent;oneo'.
The examples below are intended to explain the
procedures according to the invention hut restricting
the invention to the substances mentioned here as repress
entatives.
Unless otherwise indicated, the 1H-11M~ data
relate to CDCl3 solutions and are S values.
Example I:
N~(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis,~nndo-Z~
Z5 azabicycloC5~3.~]dccane-3-S-carboxylic acid
(1) methyl 2-acetylamino 3-(2-oxocy~oheDtyl)p~ ovate
25.7 g of methyl 3-chloro-2--accA~ylaminopropionate
and 30 g of cycloheptenopyrrolidine in 170 ml of DMF are
-- maintained at room temporary f-or 36 flours. The mixture
I
- 12 -
is evaporated on vacua, the residue is taken up 1rl a
little water, the pi is adjusted to 2 with concentrated
hydrochloric acid and the mixture us extracted twice with
200 ml of ethyl acetate each crime. h pale yellow oil
S remans after evaporation of the organic phase
Yield: 44 g
H NOR: 2.1 (s, OH); 3.7 (s, 31~); 4.4-'.8 to, OH)
(2) c;s~endo-2-AzabicycloC5.3.n~decane-3 carboxy~;c acid
hydrochloride
44 g of the acetylamino derivative prepared under
(1) in 250 ml of 2 N hydrochloric acid are boiled under
reflex for 90 minutes. The mixture is evaporated OF)
vacua, the residue us taken up in glacial acetic acid, 2
of I ~10~ Put are added and the mixture us hydrogenated.
After filtration, the filtrate us evaporated and the ryes;-
due us crystallized from ethyl acetate/d;;sopropyl ether.
Melting point: 252-256C (still contains acetic acid
from the IMMURE)
Yield: 20 g
(3) Bouncily c;s,endo-2~azab;cycloC5.3.0]decane-3-carboxyl-
ye horde
7~7 g of the carboxyl;c acid prepared under (2)
are added to an ice-cold mixture of 70 ml of bouncily Alcoa
hot and 7.1 ml of thinly chloride and the mixture is left
at 5C for hours. After evaporation in vacua, 7.3 9
of the bouncily ester crystallizes from isopropyl ether.
Al NAMER (of tile base in CDCl3, 400 MY 1.1-2.~ (m,
11H); 2.1 (s, OH); 2~2-2.4 my OH); 3.3 (mar OH); 3.3 (m,
-- OH); 3.7 (m, OH); 5~2 (dud, OH); 7~3 (s OH
7~2~ Z
(~) sinuously l~-t1-5-carboethoxy-3-phenylpropyl)-S-alanyl
cisrendo-2-azabicycloC5.3~0~decane-3-S-carboxylatee
3.5 g of the bouncily ester prepared according to
(3) are brought to reaction with 1.7 g of Hot, 3.6 g of
~-(1-S-carboethoxy-3-phenylpropyl)~S-alanine, 2.7 g of dip
cyclohexylcarbodiim;de and 1.6 ml of N-ethylmorphol;ne in
15 ml of d;methylformam;de. Aster stirring at room them-
portray for 10 hours, the precipitated dicyclohexylurea
us filtered off, the filtrate is evaporated, the residue
is taken up in ethylene chloride and the solution is
extracted 2 x loath saturated Nikko solution. After drying
the organic phase, it us evaporated and the crude product
obtained (6.3 9) is chromatographed over a column of
silica gel using cyclohexane/ethyl acetate in the ratio
2 : 8. The isomer eluded first is the S,S,S-compound,
and a later equate provides the S,S,R-compound after
evaporation.
Of of the S,S,S-compound: 0.46 (Sue; cyclohexane/
ethyl acetate 1 : 4)
I of the S,S,R-compound: 0.38
I No S-Carboe~hoxy-3-phenylpropyl)-S-alanyl-^cis~endo-
2-azabicycloC5.3~0~decane-3-S--carboxylic acid hydra
chloride
Out g of tile S~S,S-benzyl ester from (4) us disk
solved in 15 ml of ethanol and the bouncily group is removed
by hydrogenolysis under atmospheric pressure loath the
addition of 0.1 g Or 10~ Pd/C. After the calculated
amount of hydrogen has beer taken up the catalyst is isle
toned off and the filtrate is evaporated in vacua
- 14 ~27~
Yield: 0.45 g ox oil. This is dissolved in ethanol
and the pi is adjusted to So with ethanolic Hal. The
solution is evaporated and the residue is tritura~ed with
diisopropyl ether. Melting point: decomposition above
124C. A zinc complex salt which is particularly stable
to heat can be obtained by adding aqueous zinc salts to a
concentrated methanolic solution of the title compound
(zwitter;on~.
OH Nor 0~-3.1 em, 24H); 3.2-4~9 em OH); 7.2 (s, Sly)
(6)1~-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis,eendow
2-azabicyclo[5.3.0~decane-3-R-carboxylic acid hydra-
chloride
The compound is prepared in analogy to the process
on Example I I prom tile S,S,R-benzyl ester prom Example
I I
OH MY 1.0-3~1 my 24H); 3.3-4.~ em, OH); 7.2 us, OH).
Example II
I tert.-Butyl c;s,endo-2-azab;cyc Lowe .3 deacon-
carbon late
Y
2.5 g of 2-azabicyclo~5.3.0~decane-3-carboxyl;c
.,
acid hydrochloride prom Example I I on 25 ml ox Dixon
are brought to reaction with 25 ml of ;sobutylene and
2.5 ml ox concentrated sulfuric acid. Aster 10 hours at
room temperature the mixture us made alkaline ~J;th sodium
25 hydroxide solution, evaporated in vacua, 100 ml ox plater
is added and the ester is extracted with ether. hater
evaporating -the ether, 2 g ox- colorless oil are obtained.
OH r~lR~ 2.0 em, 11H); 1.2 us, OH), 2~1 us,. Nil);
--- 2.2-2.5 (m, 211); 3.2--3.4 (m, OH); 3.6-3.S (m, OH
- 15 - ~.æ~ I
(2) tert~-Butyl ester of No S-carboberlzyloxy-3-oxo-3-
phenylpropyl) S-alanine
1Z.0 9 of acetophenone, 17 9 of bouncily glyo~ylate
and 31.7 g of the toluenesulfonate of tert.-butyl ester
of S-alanine in 200 ml of glacial acetic acid are heated
at 45~50C for 24 to I hours The reaction is follolled
by thin-layer chromatography and discontinued at the point
of optimal conversion. The mixture is thoroughly evapora-
ted in vacua, gasified with aqueous bicarbonate solution
and extracted tlith ethyl acetate. The organic phase is
evaporated to as small a volume as possible and the SO
isomer is crystallized from cyclohexane/petroleum ether.
The Recompound mostly remains in solution. In order to
obtain seeding crystals, it is advisable to chromatography
the crude mixture on silica gel in the system cyclohexare/
ethyl acetate 2 : 1 to which 0~1% of triethylamine is
added. The S~S-compound us eluded as the second of the
two diastereomers.
9 g are obtained.
20 Analysis: C H N
Clue calculated 70.1 7.1 3.4
found 70.0 6~9 3.5
(3)N-(1~S--Carbobenzyloxy-3-oxo-3-phenylpropyl)-S-alaanise
trifluoroacetate
8 9 of the Mannish condensation product from to)
are dissolved in 25 ml of an hydrous trifluoroacetic acid
and left arc room temperature ,-or one hour. The solution
is evaporated in vacua diisopropyl ether is added and the
product is precipitated loath petroleum other. 7~2 of
- 16 I
- amorpi1ous substance are obtained
Analysts: C H N
Cliff calculated 56~3 4.73.0
found 56.04.~ 3.1
S Molecular weight: 469
(4) tert~-~utyl No S-carbobenzyloxy-3-oxo-3-phenylpro-
pyl~-S-alanyl-c;s,endo-2-azabicycloC5.3~0~decane-33-
carboxylate
3.5 g of the N-substituted ala nine from I reacts
with 2~1 g of tert.-butyl c;s,endo-2-azab;cycloC5.3~0]-
decane-3-carboxylate from Example I (1) on analogy to
Example I I After chromatography over slick Mel, 2 y
of the title compound are obtained.
(5)~-(1-S-Carbobenzyloxy-3-oxo~3-phenylpropyl)-S-alannil-
cis,endo-2-a,zabicycloC5.3.0~decane-3-carboxylic acid
2 9 OX the tert~-butyl ester from I are disk
solved on 50 ml of tr;fluoroacetic acid and left at room
temperature for one hour.
the solution is evaporated in vacua, the remaining
resin us taken up on ethyl acetate and neutralized With
aqueous bicarbonate. 1.4 g of the title compound are
obtained from the ethyl acetate phase.
hnalys;s: C H N
Cowan calculated 69.2 7.0 I
found 6~.9 7r1 5.Z
I S-Carboxy-3~,S-hydroxy~3-phenylpropyl)-S-alanyl
c;s,endo~2-azab;cyclo[5.3.0~decane-3-carboxylic acid
1 9 of I S-carbobenzyloxy-3-oxo-3-phenylpropyl)-
S-alanyl~cis"endo-2-azabicyclo~5~3~0~decane-3--carrboxylic
~11 rub Jo
_ I _
acid are dissolved in 50 ml of ethanol, 150 my of Pd/BaS04
are added and the mixture is hydrogenated under atmospheric
pressure. After the calculated amount of hydrogen has
been taken up, the mixture is filtered, the it ltrate is
evaporated and the residue is chromatographed over silica
gel using the solvent CHCl3/Ci~30H/CH3C02l~ 50 : ,0 : 5.
Yield: 0.6 g
t-') No S~Carbobenzyloxy~3-R,S-hydroxy-3-phenylpropyl)-
S-alanyl-cis,endo-2-azal)icycloC5.3;0~decane-3-carboxy-
fig acid
1 g of N-t1-S-carbobenzyloxy~3-oxo 3-phenylpropyl)-
S-~alanyl-cis,endo-2-azabicycloi5.3.0~decane-3-carrboxylic
acid are dissolved in 50 ml of a mixture of ace.onitrile
and water and reduced with 150 my of Nub. After 12
hours the mixture is evaporated to dryness, neutralized
with dilute hydrochloric acid and the title compound is
extracted with ethyl acetate. In order to remove boric
acid and other impurities, the product is chromatographed
over silica gel using the solvent CHCl3/CH30H/C~l3COOH
50 : 10 : 5.
Example III
General method: Ester hydrolysis to prepare compounds of
the formula I with R = H. _ _
1 g of the appropriate ethyl or bouncily ester of-
the formula I (R-H) is dissolved in 200 ml of dimetlloxy~
ethanes One drop of a dilute indicator solution, for
example bromo~l1ymol blue, is added and an equivalent
amount of 4 N icon (aqueous) is added h Vows Syria
ring, over the course of 5 minutes so aye the indicator
awry Jo I
shoals a pi of 9 - 10 at the end of the reaction the
pi us mediately adjusted to 4 with hydrocilloric acid
the mixture is evaporated to drools in vacua and tile
residue is~~aken up in 25 ml of ethyl acetate and filtered.
On evaporating the ethyl acetate, the dicarboxylic acids
are produced as solid, crystalline or amorpl1ous~ colnpounds.
The yields are between I and 55%.
Example III a
N-(l-S-Carboxy-3-phenylpropyl)-S-alanyl-cisrendo---assay-
bicycloC5.3~0]decane-3-S-carboxylic acid
1 g of N~(1-S-carboethoxy-3-phenylpropyl)-S~
alanyl-cis,endo-2-azabicyclo~5.3.0]decane-3-s-carbboxlike
acid prom Example I (5) is hydrolyzed as described under
Example III o'er 1 flour) and worked up.
Yield: 0.~5 g
m/e: 416
Bouncily ester of N-~1-S--carboethoxy-3-oxo-3-phenylpropyl)-
S-alanine _ _ _ _
ZOO 65.7 g of ethyl 4-phenyl-4-oxobutene-2-carboxylate
(ethyl benzoylacrylate) are dissolved in 225 ml of ethanol
and 1 ml of triethylamine is added. A solution of 70 g
of bouncily ester of Solon on 90 ml of ethanol is
rapidly added drops to this solution at room tempera-
lure. The solution us stirred at room temperature for 2
hours and they'll cooled Dylan.
The Seymour crystallizes out.
- Yield: 9403 9 Melting point: 73 - 74C
_ I _ ~27~
Example V
~l-(1-S Carboe~hoxy-3-oxo 3-phenylpropyl)-S-alan;ne
0.5 g of the compound from Example Ill is dissolved
in 40 ml of ethanol, 0.1 g of 10~ Pd/C is added and the
mixture is hydrogenated under atmospheric pressure at room
temperature
Yield: 3Q0 my Melting pun: 21û - 220C
H Nor (DMS0-d6~: 1.0-1.4 (t, 61-l~; 3.2-5~0 (m, OH);
7.2-8.2 (m, OH)
10 Example_VI
ensoulN-(1-S-carboethoxy-3-oxo-3-phenylpropyl)-s-alanyl--
cisrendo-2-azabicycloC5.3.0]decane-3-s~carboxyla~ee
The compound is prepared from bouncily seasoned-
azabicycloC5.3.0]decane-3-S-carboxylate hydrochloride and
15 N-(1~S-carboethoxy-3-oxo-3-phel1ylpropyl)-S-alaninno from
Exarr,ple V in analogy to the process described in Example I
I
Example VII
N-(1-S-Carboethoxy-3-oxo-3-phenylpropyl)-S alany~-cis,endo-
Z0 2--azab;cycloC5.3.0]decane-3-S-carboxylic acid
-
1 g of the bouncily ester from Example VI us disk--
solved in 30 ml of ethanol and hydrogenated loath 100 my of
Pd/C (10%) under atmospheric pressure at room temperature.
The hydrogenation is discontil1ued after one mole-equ;va-
I lent of hydrogen has been taken up. The catalyst us filtered off tooth suction and the solution is evaporated.
Yield: 600 my of o; in
MIX tDMso-d6): 1.0--3~0 (my 19H); 3.2 4~9 (m, 10H);
- 7.2~.1 (m, OH)
- 20 _ ~227~
Example
-(1-S-Carboethoxy-3-phenylpropyl)-S~lysyl-cis,endoowe
aza_;cyclo~5.3.0]decane-3-S-carboxylic acid dihydrochloride
(1) Bouncily ester of N~-(1-S-Carboethoxy-3-phenylpropyl)-
of benzyloxycarbonyl-S-lys;ne
10 9 of ethyl 4-phenyl-4-oxobutene-2-carboxylate
are dissolved in 100 ml of ethanol. 19.1 9 of the bouncily
ester of N -benzyloxycarbonyl-S-lysine and 0.2 9 of in-
ethylalnine are added to this solution. The solution is
stirred at room temperature for 3 hours and then evapora-
ted in vacua. The oily residue (31 9) is dissolved in
isopropanol/d;;sopropyl ether and cooled down. 13 g of
the bouncily ester of N~-(1-S-carboethoxy-3-oxo-3-phenyl-
propyl)-N&-benzyloxycarbonyl-S-lysine crystallize.
15 ~2D0 = 3 5 (c 1, SHEA)
OH Nil (CDCl3): 1.0-1.4 (if, OH); 1.0-2.0 (m, OH
2.0-Z.6 (broad s, isle); 2.9~3.9 (m,
OH); 3.9-4.4 (q, 211); 4.6-~.9 (broad
s, 11l); 5.0-5.2 (doubled s, 4H0 7.1-
8.1 (m, 15l~)
I N -(1-S-Carboethoxy-3-phenylpropyl)~iY -Benelux-
carbonyl-S-lysine
4.0 9 of the Lawson bouncily ester derivative pro-
pared in Example ~/III (1) are dissolved in 50 ml of glacial
acetic acid, and 0~6 9 of PdlC (10%) and 0.6 g of concern-
treated sulfuric acid are added to this solution The mix-
lure us hydrogenated under atmospheric pressure at room
temperature for 6 howls. The catalyst is then filtered
off with sicken and the ethanolic solution is stirred
::~L.,rC~272~3L2
- 21 -
with 1.4 g of solid sodium bicarbonate. The solution is
evaporated in a rotary evaporator and the residue is do
solved in water. the aqueous phase is extracted with
ethyl acetate and ethylene chloride. The organic phases
are discarded and the assay phase is evaporated to dry-
news in vacua. The residue is extracted by stirring with
methanol. After evaporating the methanol, where remains
an oily residue which solidifies on treatment with dyes-
propel ether. Yield o-F S-carboethoxy-3 phenylpro-
pyl)-S~lysine: 2.0 9
OH NOR (D20): 1.0-1.4 (if, OH); 1.0~2.5 (m, 9H0~
2.5-4~4 (my OH); 3.9-4.4 (q, OH
4.5-5.0 (m, OH); 7.1-7.6 (m, OH)
mule: 336
3.4 g of No S-Carboethoxy-3-phenyLpropyl)-S-
Lawson are dissolved in 30 ml of ethylene chloride and
cooled down to 0C. 2.1 g of triethylamine are added
Jo this solution Chile cooling in ice and then 1.9 9 of
bouncily chloroform ate are added drops. The mixture us
stirred at 0C for 1 hour and then warmed Jo room rem-
portray. The ethylene chloride solution us then extract
ted by shaking with water sodium carbonate solution and
waxer. After drying, the solution is evaporated and the
oily residue is chromatograplled over silica gel using
ethylene chloride/rnethanol.
2.C g of No (1-S-carboethoxy-3-phenylpropyl)-N~-
benzyloxycarbonyl-S-lysine are obtained.
OH Nor (CDCl3/D20~: 7.0-1.4 (if, OH); 1.0-2~5 (m,
I 2~5~ .4 run OH); 3 9-4.4
22 -
(q, OH); 6,.4-5.0 em, OH); 5.1
(s, OH); 7~1-7~5 (m, 10H).
(3) Bouncily No S-Carboethoxy-3-phenylpropyl)-N~benzyl-
oxycarbonyl-S-lysyl-cis,endo-Z azabicycloC5~3.0~decane-
3 S-carboxylate
a) 560 my of bouncily 2-azabicycloC5~3.0]decane-3-
carboxylate hydrochlor;der prepared in accordance with
Example I (3), are reacted on analogy to Example I (4)
with 940 my of ~x-(1-S-Carboethoxy-3-phenylpropyl)-N~-
benzyloxycarbonyl-S-lysine, prepared in accordance with
example VIII (2). After working up, 1.5 9 of oil which
us a mixture of two diastereomeric compounds are obtained
The mixture of diastereomers is separated into the
in visual co~poncr~s by column chromatography with silica
gel and cyclohexane/e~hyl acetate 2 : 1 as the eluding
agent. foe isomer which is eluded first is the above coy
pound. 0.6 9 of oil is obtained.
OH NOR (CDCl3): 1.0-2.6 (m, 24H); 2.6-4.5 em, OH);
after H/D exchange 4.6-5~0 (m, OH); 5.1-5.3 (doubled s,
with D20) OH), 7.1-7.6 (m, 15H)
b) The later equate provides 0.4 9 of bouncily N~-(1-C-
carboethoxy-3-phenylpropyl)-N~-benzyloxycarbonyl-SSleazily-
cis,endo-2-azab;cycloCS.3.0Jdecane-3-R-carboxylatee.
OH NOR (CDCl~): 1.0-2.6 (m, 24H); 2.6-4.4 (m, OH);
(after H/D exchancJe 4.5-5.0 (m, OH); 5.1-5.3 (doubled s,
with D20) OH); 7.1-7~5 (m, 15H)
I (1-S-Carboethoxy-3-phenylpropyl.)-S~lysyl-cis,encllo-
2-azabicycloC5~3.0~decane-3-S-carboxylic acid dowdily-
chloride
- 23 2
500 my of Bunnell N~-(1-S-carboethoxy-3-phenyl-
propyl)-N~-benzyloxycarbonyl-S-lysyl-cis,endo-Z-azzebu
cycloC5.3.0~decane-3-S-carboxylate from Example VIII (pa)
are dissolved in 20 ml of ethanol and the bouncily group us
removed by hydrogenolysis under atmospheric pressure loath
the addition of 0.1 g of 10 Pd/C. After completion of
hydrogen uptake, the catalyst is filtered off, ethanolic
hydrogen chloride solution is added to the ethanolic soul-
ton to pi 1 and the ethanol is evaporated in vacua.
on Diisopropyl eclair is added to the residue whereupon the
product solidifies. 200 my are obtained.
OH NOR of the retain 1~0~2n5 (m, 24H), 2.6-4.4 (M, OH);
(CDCl3, after H/D 4.4-4.9 (m, OH); 7.2 (s, OH)
exchange with D20):
Example IX
-t1-S-Carboethoxy-3-phenylpropyl)-S-lysyl-cjs,endoo-2-
azabicycloCS.3~0]decane~3-R-carboxylic acid dihydrochloride
0.3 my of the appropriate Bunnell ester from
Example VIII (3 b) are reacted in analogy to Example VII l
(4) and worked up. 130 my of the carboxyl;c acid are
obtained as the dihydrochloride.
OH NOR of the button 1~0-2~6 on, 24H)r 2~6-4~4 rum OH);
(CDCl~r after H/D 4~4-4.8 (m, 211); 7.2 (s, OH
exchange with D20):
No S~Carboxy-3-pl1enylpropyl)-S lysyl-c1s,endo-2-aza-
b;cycloC5.3.0~decane-3-S-carboxyl;c acid ho' chloride
- 0.5 of ~-(1-S-Carboethoxy-3-phel1ylpropyl)-S~
lysyl-cisrendo~2-azablcycloCS.3~0~decane-3--S--carrboxylic
- 2 it - ~.~2'7;~ Z
acid dihydrocl1loride from Example VIII (4) are suspended
on 20 ml of dimethoxye~hane. The suspension us stirred
for half an hour. The pi us then adjusted to 4 with
hydrochloric acid, the mixture us evaporated to dryness
in vacua and the residue is taken up on ethyl acetate and
the mixture us filtered. rho ethyl acetate sultan us
evaporated and the residue us triturated with isopropyl
ether whereupon it solidifies.
Yield: 0.30 g
OH NOR (D20) 1.2-2.5 (m, 21H); 2.5--4.5 (m, I
4.5-'~.9 (my OH); 7.2 (s, OH)
Example XI
N~-(1-S-Carboxy-3-phenylpropyl)-s-lysyl-cis,endo-2assay-
bicyclo~5.3.0~decane 3-R-carboxylic acid hydrochloride
500 my of N~-(1-S-Carboethoxy-3-phenylpropyl)-S-
lysyl-cis,endo-2-azabicyclo[5.3.0]decane-3-R-carbooxyl;c
acid d;hydrochlor;de from Example IX are hydrolyzed and
worked up in analogy to Example X.
Yield: 0.30 g
OH Nor (D20): 1.2-2.5 (m, 21H); 2 5~4n5 (m, OH);
4.5-4.9 (m, OH); 7.2 (s, OH)
Exan1ple XII
N-(1-S-Carboethoxy-3-phenylpropyl)-0-ethyl-S~tyrossulkies,
endo-2-azabicyclo~5.3.n]decane~3~S-sarboxylic acid
-
(1) Bouncily ester of N-(1-R~S-carboe~hoxy-3 phenylpropyl)-
0-ethyl-S-tyrosine
In analogy to Example IVY 24 g of ethyl bouncily-
acryla~e on 100 ml of ethanol are reacted Whitehall 30 g of the
bouncily ester of 0-e~hyl~S-tyrosine in the presence of
2~L2
- 25 -
OHS ml of triethylamine and after evaporation of the
solution and digestion of the residue with Doyle ether/
petroleum ether (1:1~ and drying in vacua, 42 g of the
RS~S-compound are obtained.
5 (2)N~(1-R~S-Carboethoxy~3-phenylpropyl)-0-ethyl-S~tYrrosin
40 g of the compound obtained in accordance loath
XII (1) are hydrogenated in ~00 nil of acetic acid Wylie 4 g
of Pd/C (10%) under 100 bar pressure and at room tempera
lure. The yield after chromatography on silica gel using
the elating agent ethyl ace~ate/cyclohexane (1:3) and dry-
no the residue on evaporation is 25 g of title compound
which is almost homogeneous by thin layer chromatography.
Melting point SKYE
Clue (39~ I) calculated C 69~15 H 7.31 3.50
found C 6~.5 H 7.4 N 3.3
(3)N~(1-S-Carboethoxy-3~phenylpropyl)-O~ethyl-S-tyrossol-
cis,endo-2-azabicyclo~5.300~decane-3-S-carboxylic acid
_ . _ _ _ . _ _ _ . _ . _ _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _
1 g of the free bouncily ester obtained in accord-
ante with Example I (3) followed by extraction from alga
line solution with deathly ether is reacted in analogy to
Example I (4) with 1.6 g of the compound obtained on
accordance with XII (2) using 0.9 of dicyclohexylcarbo-
doomed in the presence of 0.55 9 of 1-hydroxybenzotri-
azalea. After the chromatography described under Example I
(4), 0.7 g of oily bouncily ester is obtained as an inter-
mediate product
he Al MY and mass spectra are consistent with
the structure indicated.
The bouncily ester is catalytically hydrogenated on
26
Pod if 15 ml of ethanol under atmospheric pressure.
Aster filtering of, the catalyst and d;st;ll;ng out the
solvent there remains a solid residue tush is digested
with deathly ether/petroleum ether and dried
Yield: 0.4 g
OH NOR (C~Cl3j: 1.2-3.0 (m, OH 1.27 (t, OH 1.4
(t, OH 3.0-4.3 (m, OH 3.~-4.2 (m,
OH 6~5-7.1 (Ed, Al 7 n 3 (s, OH).
Example XIII
10 N-(1-S-Carboetloxy-3-phenylpropyl)-C-me~hyl~S-tyroosyl-cis,
end-_ azabicyclo~5.3.0~decane-3-S-carboxylic acid
The procedure is as described in Example XII but,
in the step analogous to XII (1), the Bunnell ester of 0-
methyl-S-~yrosine is employed, and lie title compound is
obtained, the H NllR spectrum o, Lucia is consistent
with the structure indicated.
