Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- ~3~'1f~8
THIS APPLICATION IS A DIVISIONAL OX CANADIAN PATENT
APPLICATION SERIAL NUMBER 444,858, FILED JANUARY 6, 1984.
The invention relates to compounds of the formula I
R2
(I)
I ON
CUR
on which
R1 and R2 are identical or different and represent
straight-chain or branched alkyd having 1 to 6 carbon
atoms or represent (C6 to Charlie, preferably phenol,
or together represent one of the chains -Sheehan- or
~~CH2)p~CH~C~I~(CH2)q, n, p and q each being an
integer, n being 3-6 and pi being 1-4, and
R3 denotes straight-chain or branched alkyd having 1 to
5 carbon atoms or (C6 to Charlie, preferably phenol.
It is known that substituted praline derivatives
can be prepared by various classical methods of amino acid
synthesis. A review of the known work on this topic has
been published by AHAB. Mauler and B. Witkop (Chum. Rev.
66, I (1966)). In the processes described on this
reference, the compounds usually result as complex mix-
lures of isomers. Since certain 4,5-disubstituted is-
mews which were required as starting compounds for
Z0 further syntheses could only be obtained in poor yield
or not at all by known processes with subsequent swooper-
lion of isomers, the object was to search for new sync
theta routes leading to isomers of this type.
'
sluice
-- 3 --
The praline derivatives of the formula I accord-
no to the invention are valuable intermediate products
on a synthetic route of thus type. Preferred compounds
of the formula I are those in which R1 and R2 together
form one of the above mentioned chains and have the trays
configuration with respect to one another. If R1 and R2
are not linked together by a chain, these radicals can
have the us or trays configuration with respect to one
another and to the ON group.
10 The compounds of the formula I can occur in the
diastereomeric forms Idea, it being possible to represent
the relative configurations of these by the following
formulae:
H
I "" 2
R ` Jo ON R Pi ON
CUR CUR
(It) jib)
aye form 2.~,4~,5~ form
H H
15R2 , 2
R1 ", ON
CUR CUR
tic) (Id)
I forum 2~,4~,5~ form
The specification "I" means that the substituent
on the relevant position is beneath the plane of the
f;ve-membered ring and the specification "I" means that
~35128
-- 4 --
it us above this plane. If R1 and R2 are connected
together, the numbering is modified to accord with the
conventions for bicyclic ring systems.
The invention also relates to a process for the
preparation of compounds of the formula I in which R1,
I and R3 have the abovement;oned meanings, which
comprises reacting an organomercury compound of the
formula II
R2 Hex
(II)
R CRY
on which R1, R2 and I have the above mentioned meaning
and X denotes halogen, preferably chlorine or bromide,
pseudo halogen or acetate, with 2-chloroacrylon;trile and
sodium bordered or potassium bordered to give a
compound of the formula III
Of
R2 C~2~CH \
y (III)
R1 NH-CO-R3
on which R1, R2 and R3 have the abovement;oned meaning.
The reaction is carried out on an alcoholic sol-
vent, preferably ethanol, with a one to f;fteen-fold,
preferably a three to eightfold excess of sheller-
20 acrylon;tr;le, at -20C to 60C, preferably at 0C to
I, 30C.
1'\
1235~28
-- 5 --
The compound of the formula III us then cyclized
to give the compound of the formula I by reaction with a
suitable base, preferably sodium hydrides in an aprotic
bipolar solvent, such as dim ethyl sulfoxide or dim ethyl-
formamide, or with potassium carbonate or potassium hydroxide in an aprotic solvent, such as, preferably,
acetonitriLe, with the addition of a phase-transfer gala-
lust, preferably triethylbenzylammonium chloride, at
-20C to 80C, preferably at 0C to 40C.
The invention also relates to compounds of the
formula III in which R1, R2 and R3 have the above-
mentioned meaning.
Moreover, the invention relates to the use of
compounds of the formula I, in which R1, R2 and R3 have
the above mentioned meaning, in a process for the prepare-
lion of compounds of the formula IV
I (IV)
I / COG
'I .
in which R1 and R2 have the above mentioned meanings and
R represents hydrogen, alkyd having 1 to 10 carbon atoms,
aralkyl having 7 to 9 carbon atoms cycloalkyl having 5
to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon
atoms or cycloalkylalkyl having 6 to 12 carbon atoms,
which comprises subjecting the compounds of the formula I
to solvolysis with compounds of the fornlula ROW in which
R has the above meaning.
Hydrolysis is preferred. For this, the compounds
.
. . .
:
,
35~28
-- 6
of the formula I are converted in the presence of a
strong acid, preferably a mineral acid such as hydra-
caloric acid or hydrobromic acid, in aqueous solution at
20C to 160C, preferably at 70C to 120C, into the
amino acids of the formula IV in which R denotes hydrogen.
The resulting mixtures of isomers can be swooper-
ted into the isomers at the various stages in the process
(compounds of the formulae III, I and IV) by methods of
separation known per so, such as, for example, fractional
crystallization or column chromatography.
The starting materials for the preparation of
compounds of the formula I are known from J. Pratt. Chum.
311, 737 (1969) and from J. Org. Chum. 41, 192 (1976):
they are produce by addition of a mercury salt and a
nitrite to the double bond of an olefin of the formula V
in which R1 and R2 have the above mentioned meaning.
R1-CH-CH-R2 (Y)
The addition of the two components to the double
bond takes place from opposite sides. The result of this
is that, starting from cis-disubstituted olefins of the
formula Via
H H (Via)
R1 R
the trans-disubstituted compounds of the formula Ivy are
obtained
- 7 _ 123 5~2
I
R1 I' COO (Ivy)
since the Stacy in the process according to the invention
take place with retention of the configuration at each
carbon atom. In analogy, starting from trans-disub-
stituted olefins of the formula Vb
R1 H
(Vb)
H , R
the cis-disubstituted compounds of the formula Ivy are
obtained R2
R COG
. Jo (Ivy)
and starting from cycloolefins of the formulae Via and Vim
respectively
CHIC
CRY: ) (OH Schick (Vim)
in which m denotes a number from 1 to 4, bicyctic come
pounds of the formulae Viva and VIIb respectively are
obtained
, .. . ..
- 8- ~35128
COO / (Shop
H (Vouch CooR(vIIb)
Schick H
the two rungs on these being linked together trans.
The compounds of the formulae I and IVY are value
able intermediate products on the preparation of forum-
S ceuticals, especially of inhibitors of the ang;otens;nconverting enzyme (ACE). Compounds of thus type are
known, for example, from Canadian Patent Application
3~8,336, and Canadian Patent Application 418,453 also
relates to them.
Examples of ACE inhibitors of this type are sub-
statewide azalea derivatives of the formula VIII
CCH I
COO
Azalea
on which m us defined as above and azalea represents, for
example, a radical of the formula IX
Y'
* `*
-CO-CH-NH-CH-CH2-C-X' (IX)
R Corey Z'
in which
R4 denotes hydrogen, (C1-C6)-alkyl which can optionally
be substituted by amino, (C1-C4)-acylamino or benzoy;amino,
(C2-C6)-alkenyl, (C5-C9)-cycloalkyl, (C5-C9)-cyclo-
5 C7) cycloalkyl-tC1-C4)-alkyl a
..~
. _ 9 _ ~235~28
partially hydrogenated aureole, each of which can be sub-
u Ed by ~C1 Cz)-alkyl, (C1-C2~-alkoxy or halogen,
aryl-(C,I-C4)-alkyl, the aureole radical of which can be
substituted as defined above, a monocyclic or bicycle
heterocyclic radical having 5 to 7 or 8 to 10 ring atoms,
1 to 2 of these ring atoms being sulfur or oxygen atoms
and/or 1 to 4 of these ring atoms being nitrogen atoms,
or a side chain of a naturally occurring am;noac;d,
R5 denotes hydrogen (C1-C6)-alkyl, (C2 C6) alkeny
or aryl-(C1-C4~-alkyl,
Y' denotes hydrogen or hydroxyl,
Z' denotes hydrogen or
Y' and Z' together denote oxygen,
X' denotes (C1 Colloquial (C2-C6)-alkenyl~ (C5 C9
cycloalkyl, aureole which can be moncsubst;tuted, disubst;-
tuned or trisubstituted by (C1-C4)-alkyl, (C1-C4) alkoxy,
hydroxyl, halogen, Nero amino, (C1-C4)-alkyl3mino, d;-
(C1-C4)-alkylamino or methylenedioxy, or 3-;ndolyl,
and their physiologically acceptable salts.
Compounds of the formula VIII can be prepared by
N-acylation of compounds of the formula IV, on which R1
and R2 have the abovement;oned meaning and R has the
above meaning with the exception of that of hydrogen,
with compounds of the formula azalea, on which azalea us
defined as above, and subsequent hydrogenolyt;c, acid or
base el;m;nat;on of the radicals R and, of appropriate,
R5
.
~:~ The condensation of the compounds of the formula
azalea with the esters of the formula IV preferably
:;
: I, . . , - - -
- 1235~2~3
- 10 -
takes place by processes known from peptize chemistry.
Those processes which provide adequate protection from
racemization, such as, for example, the DCC/HOst method
or the alkanephosphonic android method described in
German Offenlegungsschrift 2,901,843, are particularly
preferred.
The compounds of the general formula VIII have a
long-lasting and potent hypotensive effect. They are
well absorbed after oral administration and can be
employed to control hypertension of various etiologies
and can be used alone or combined with other compounds
having hypotens;ve, vasodilator or diuretic activity.
Adm;n;strat;on can be intravenous, subcutaneous or oral,
oral administration being preferred. The dosage on oral
administration is 0.01-10 mg/kg per day, preferably
0.05-1.5 mg/kg per day, especially 0.05-0.5 mg/kg per day.
The dose can also be raised in severe cases,
since no toxic properties have hitherto been observed.
It us also possible to decrease the dose and this is
particularly appropriate when diuretics are administered
concurrently. For intravenous or subcutaneous adrninis-
trat;on, the single dose should be between 0.1 and 250
gig per day.
The following examples are untended to Lucy-
irate the ;nvent;on.Example 1
2~,3a~,7a~-Octahydro;ndole-2-carboxylic acid
a) trans-1-Acetam;do-2-chloromercur;ocyclohexane
20 ml (0.2 mole) of cyclohexene on 50 ml of
.
I'
~L235;~ 28
- 11
acetonitrile are added drops over the course of pa
minutes to a suspension of 65 9 (0.2 mole) of mercurial)
nitrate in 150 ml of acetonitrile at 0C. kiter 1 hour
at room temperature, the yellow solution is poured into
a mixture of 100 ml of saturated sodium chloride solution
and S00 ml of water; the precipitated product is filtered
off with suction, washed with water and dried in vacua
75 g of colorless crystals of melting point 200-201C are
obtained.
b) trueness Acetamido-2-(2-chloro-2-cyanoethyl)cyclohexane
31 9 of trans-1-acetam;do-2-chloromercur;ocyclo-
hexane are suspended in 250 ml of 95% strength ethanol:
187 In (4 equivalents) of 2-chloroacrylon;trile are added.
While cooling in ice, a solution of 3 9 of sodium boron
hydrides in 50 ml of ethanol us added as rapidly as posy
Sibley After warming up to room temperature, the prows-
pitted elemental mercury is filtered off with suction
over kieselguhr, thoroughly washed with ethanol and the
filtrate is evaporated. The residue is taken up in
ethylene chloride, washed three times with 1 N sodium
hydroxide solution to destroy the boric esters, dried
over sodium sulfate and evaporated. 13 9 of the title
compound are obtained as a yellow oil.
c) 1-Acetyl-2-cyano-trans-octahydroindole
3.2 9 of trans-1-acetamido-2-~2-chloro-2-cyano-
ethyl)cyclohexane are dissolved in 25 ml of dimethylform-
aside and added drops, at 0C, to a suspension of
0~7 9 of sodium hydrides (50% in oil, washed three times
with hexane) in 10 ml of dimethylformamide. After 1 hour
.
- - 12 - ~23S12~
at room temperature, the mixture is poured into water,
acidified with 5 N hydrochloric acid and extracted with
ethylene chloride. The extract is washed four times
with water, dried over sodium sulfate and evaporated.
The crude product contains a mixture of 18.5 parts of the
aye isomer and 1 part of the aye isomer.
On trituration with diisopropyl ether; 0.7 g of the I
aye isomer crystallizes out. Chromatography of the
mother liquor on silica gel using acetic acid/cyclohexane
(2:1) as the mobile phase provides a further 0.2 g of the
aye isomer and 45 my of the aye isomer.
Physical data:
awry isomer:
Melting point 110 113C
OH NOR data (270 MHz, DMSO-d6, 100C): = 4.90
do = 5Hz, OH); 3.05 (do, Jo = 5 I Jo = 1.5 It, OH ;
2.60 (d, OH); 2.17 (d, OH); 2.03 (s, OH); 1.95 (broad,
d, OH); 1.85-1.6 to, OH); 1.4-1.0 (m, OH) ppm. MS tome
192 (M+, 32%); 150 (M-CH2=C=0, 59%); 149 (18%); 139
ZOO (14%) 107 (100%); 95 (15~); 43 (39%).
aye isomer:
of l
OH NOR data (270 MHz, DMSO-d6, 10ûC): = 4.66
(t, J = Shy, OH); 3.10-3~0 (m, OH); 2.75-2.6 (m, OH); 2.08
(s, OH); 2.0-1.4 (m, OH); 1.4-1~2 (m, OH) ppm.
d) 2~,3a~,7a~-octahydroindole-2-carboxylic acid
2.8 9 of aye acetyl-2-cyanooctahydro-
dole are bowled under rollicks with 30 ml of 5 N hydra-
choleric acid for 4 hours, evaporated to dryness, the
- 13 - ~235~28
residue is taken up with water, the pi is adjusted to 4.7
with a weakly basic ion exchanger (Amberlite~ IRA 93,
OH form), this is filtered off, the filtrate is evapora-
ted, the residue is taken up with ethanol, and acetone is
added to precipitate. Filtration with suction and drying
provides 1.9 g of the title compound of melting point 2~6-
Z88C (decomposition).
OH NOR data (D20, 270 MHz): = 4.15 (d, J = 5Hz,
OH); 2~88 (dud, Jo = 12 HO Jo = 3.8 Ho, OH); 2.55 (ma, OH);
Z.3-1.1 (no, 10H) ppm.
Example 2
2l~r3a~,7a~-OrtahydrocyclopentaCb~pyrrole-2-carboxxxylic acid
a) trans-1-Acetamido-2-chloromercuriocyclopentane
10 ml of cyclopentene in 3C ml of acetonitrile
are added drops to a suspension of 38.3 g of rnercury(II)
nitrate in 80 ml of acetonitriLe at 0~. After 1
hour at room temperature, the mixture is poured unto a
mixture of 60 ml of saturated sodium chloride solution
and 250 ml of water, and the solid is filtered off Thea
suction, washed with water and dried. 26 9 of the title
compound are obtained as an amorphous powder.
b)trans-1-Acetamido-2-(Z-chloro-2-cyanoethyl)cycloopeentwine
16.1 g of trans-1-acetam;do-2-chloromercurio-
cyclopentane are suspended on 200 ml of ethanol. 10.7 ml
of 2-chloroacrylon;tr;le are added, followed by 1.7 of
sodium bordered on 40 ml of ethanol as rapidly as posy
sable whole cooling in ice. After 1 hour at room tempera-
lure, the mixture us filtered with suction through cozily-
Gore the filtrate is evaporated, the residue is taken up
1235~L2~
- 14 -
with ethylene chloride, this solution is washed twice
with 1 N sodium hydroxide solution, and the organic. phase
is dried over sodium sulfate and evaporated. Cremate-
graph on silica gel (mobile phase ethyl acetate) pro-
dupes 2.2 g of crystalline product, melting point 114-
117C.
OH NOR data (CDCl3~: = 5.4 (broad s, OH); 4.67 (t,
J = 7Hz, OH 3.95 (ma, OH); 2.6-1.0 (m, OH 1.97 (s,
OH) ppm
MS (Moe: 214 (My, ~%~; 179 (10~; 140 (20,~); 137 (35%);
98 (48%); 6û (78%); 56 (100%); 43 I
c)1-Acetyl-2-cyano-trans-octahydrocyclopenta[b]pyrRoy
0.75 9 of trans-1-acetamido-2-(2-chloro-2-cyano-
ethyl)cyclopentane is dissolved in 20 ml of DMF and added
to 200 my of sodium hydrides (50% in oil, washed twice
with hexane~ and the mixture is stirred a room tempera-
lure for 1 hour. It is then poured into 1 N hydrochloric
acid, extracted with ethylene chloride, and the organic
phase is washed four times with water, dried and evapora-
ted. Chromatography on silica gel with ethyl acetate/cyclohexane (2:1~ as the mobile phase provides 0.12 g of
the aye isomer as an oil and 0.45 g of the aye
aye isomer as colorless crystals of melting point 115-
117C
OH NOR data (CDCl3): S = 5.02 (d, J = 7.5 Ho, OH
3.33 (do, Jo = 11Hz, Jo = 6 Ho, OH 2.9~1.0 (m, OH
2.07 (s, OH ppm.
d)2~,3a~,6a~-Octahydrocyclopenta[b~pyrrole-2~carbooxyyolk
acid
28
- 15 -
0.45 9 OX 2~,3ac~6af~-1 acetyl-Z-cyanooctahydro-
cyclopenta~b]pyrrole are heated to reflex for 3 hours
with 5 ml of S N hydrochloric acid, then evaporated to
dryness, the residue is taken up with water, the pi is
adjusted to 6 with a weakly basic ion exchanger (Amber-
liter IRA 93, OH form), this is filtered off, the lit-
irate is evaporated and crystallized with ethanol/ether.
Yield: 0.26 g
Melting point: > 250C (decomposition)
OH NOR data (D20): = 4.5 (t, OH); 3.6-3.0 (m, OH
2.6-1.0 (m, OH) ppm. MS (m/e): 155 (M+, 1%); 154 (M+7H,
3%); 110 (MCKEE, 100%); 67 (24%).
Example 3
1-Acetyl-2-cyano-4 5-cis-diethylpyrrolidine
a) erythro-3-Acetamido-4-chloromercuriohexane
39 9 of murkier) nitrate are suspended in 50 ml
of acetonitrile, and 10 9 of transection in 20 ml of
acetonitrile are added drops at 0C. After 45
minutes at room temperature, the mixture is poured into
500 ml of saturated sodium chloride solution. The title
compound initially separates out as an oil, but crystal-
lives completely after a short time. Melting point
Yield 41.5 9.
b) 2~Chloro-threo-5-acetam;do-4-ethylheptanonitrile
15 9 of erythro-3-acetamido-4-chloromercur;o-
hexane and 9.6 ml of-2-chloroacrylonitrile are dissolved
on 250 ml of ethanol. 1.52 9 of sodium bordered is
added rapidly while cooling in ice. After 45 minutes,
the elemental mercury formed is filtered off with suction
~23~2~3
- 16 -
through kieselguhr, the filtrate is evaporated, the nest-
due is waken up with ethylene chloride, and the solution
is washed three times with 1 N sodium hydroxide solution,
dried over magnesium sulfate and evaporated 6.6 g of a
1:1 mixture of the isomers at the 2 position are obtained.
c) 1-Acetyl-Z-cyano-4,5-cis-diethylpyrrolidine
6.6 9 of 2-chloro-threo-5-acetamido-4-ethylhep-
tanonitrile are dissolved in 10û ml of dimethylformamide
and added drophise at 0C to 1.7 9 of sodium hydrides
(50'~ in oil, washed 2 x with hexane). After 2 hours at
room temperature, the mixture is poured into 1 N hydra-
caloric acid and this is extracted twice with ethylene
chloride. The organic phase is washed four times with
water, dried and evaporated. 4.6 9 of a brown oil are
obtained, from which the two isomers of the title come
pound are isolated by column chromatography on silica
gel using ethyl acetate/cyclohexane (2:1) as the mobile
phase.
Isomer 1 (1.63 y)
2~,4~,5~ form: Of value (ethyl acetate/cyclohexane 4:1)
0 5 oil; OH NOR data: 5.0-4.4 (m, OH); 4.0-3.3 (m,
OH); 2.6-0.7 (m, 13 H); 2.15 + 2.12 (us, OH) ppm.
MS (m/e): 194 (M+, 8%), 165 (MCKEE, 4%); 123
(M -CH3C0-C2H5, 1û0%); 43 (17%).
25 Isomer 2 (1~63 9)
2~,4~,5~ form: Of value (ethyl acetate/cyclohexane 4:1)
-0.43, melting point 144-1~t9C: OH NOR data: 5.8-5.4
(m, OH); 4.3-3.9 (m, OH); 3.0-2.5 (m, OH); 2.03 (s, 3!1);
2.2-1.1 (m, OH); 1.08~0.97 (it, 61i) ppm: MS (m/e): YO-YO
~LZ~Z8
- 17 -
(M , I 165 (M -C2H5, 4%), 123 (M -CH3CO-C2H5,
100%); 43 (14%).
Example 4
2~,4~,5~-Diethylproline
1.63 g of 2~,4~,5~-1-acetyl-2-cyano-4,5-diethyl-
pyrrolidine (Example 3c, isomer 1) are heated to reflex
for 2.5 hours with 20 rnl of 5 N hydrochloric acid. Aster
evaporation to dryness, the pi is adjusted to 6 using
Amberlite~ IRA 93 (OH form), and the mixture is lit-
toned, evaporated, the residue is taken up with ethanol
acetone and filtered with suction. Purification is by
chromatography on silica gel using ethylene chloride/
methanol/glacial acetic acid/water t10:3:1:1) as the
mobile phase. 1.05 9 of the title compound ox melting
point 230-235 (decomposition is obtained.
OH NOR data (D20): = 4.1 (t, J = 9 Ho, OH); 3.25 (do,
Jo = 7Hz, Jo = 6 Ho, OH); 2~9-1.0 (m, OH); 1.0 (t,
J = 7Hz, OH) ppm.
MS (m/e): 171 (M+, I 142 (MCKEE, 100%); 126
2û (MCKEE, 74~); 115 (12%); 96 (30%); 83 (10%); 69 (33%);
55 (19%).
Example 5
2~,4~,5~-Diethylproline
1.63 9 of 2~,4~,5~ acetyl-2-cyano-4,5-diethyl-
pyrrolidine (Example 3c, isomer 2) are reacted with 20 ml
of 5 N hydrochloric acid in accordance with the process
described in Example 4. 0.72 9 of the title compound of
melting point 158-162C is obtained.
OH NOR data (D20): I= 4.15 (to J = 8 Ho, OH); 3.68
51~3
18 -
to, J = 6Hz, OH); 2.5~ m, OH); 1.0 (t, J = 7Hz~ OH)
ppm.
MS (m/e): 171 (My, 1%); 142 (M+-CzH5) 100%);
126 (MCKEE, 96%); 115 (19%); 96 (33%); 83 (11%);
69 t36%); 55 ~22%).
Example 6
1-Acetyl-2-cyano-4,5-cis-dimethylpyrrol;dine
Prepared from trans-2-butene in analogy to the
procedures described in Example 3 a to c.
Example 7
4,5-cis-Dimethylproline
Prepared from 1-acetyl-2-cyano-4,5-cis-dimethyl-
pyrrolidine in analogy to the procedure described in
Example 4.
Example 8
1-Acetyl-2-cyano-4 5-trans-dimethylpyrrolidine
Prepared from cis-2-butene in analogy to the pro-
seeders described in Example pa to c.
Example 9
2û 4 5-trans-Dimethylprol;ne
Prepared from 1-acetyl-2-cyano-4,5-trans-dimethyl-
pyrrol;d;ne on analogy to the procedures described in
Example 4.
Example 10
2~,3a~,8a~-DecahydrocycloheptaCb]pyrrole 2-carboxyl;c acid
Prepared from cycloheptene on analogy to the pro-
seeders described on Example pa to d.
~2~51X8
- 19 -
Example 11
2G,3a~,9ag-Decahydrocycloocta[b]pyrrole-2-carboxylfig acid
Prepared from cyclooctene in analogy to the pro-
seeders described in Example pa to d.
