CA1227802A - Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use as intermediates and processes for their preparation - Google Patents
Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use as intermediates and processes for their preparationInfo
- Publication number
- CA1227802A CA1227802A CA000516572A CA516572A CA1227802A CA 1227802 A CA1227802 A CA 1227802A CA 000516572 A CA000516572 A CA 000516572A CA 516572 A CA516572 A CA 516572A CA 1227802 A CA1227802 A CA 1227802A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- atoms
- acid
- cis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to compounds of the formula
The invention relates to compounds of the formula
Description
This Application its a Divisional of Canadian Patent 12~7802 Application Serial Number 424,127, Filed March 23, 1983.
The invention relates to new derivatives of the bicyclic amino acids of the Norma I, .
O R
' H j 2 I/ \* * Y
o oh - NH - IT (Clown in wish COG R2 Z
! n denotes 0 or l, - lo R denotes hydrogen, (Of to Colloquial or aralkyl having 7 to 9 C atoms, Al denotes hydrogen or (Of to C6 alkali, which can optionally be substituted by amino, (Of to Cozily-Juno, preferably (C1-C4)-alkanoylamino, or bouncily no, (C2 to C5)~
alkenyl, (C5 to Cg)-cycloalky1., (C5 to Cg)-cycIoaLkenyl, (C5 to C7)-key ( 1 C4) alkyd, (C6-C10)-aryl or isle hydrogenated (C6-C10)-aryl, which each can be substituted by (C1 to Colloquial, (C1 or C2)-alkoxy or halogen, (C6-C10)-aryl-(C1 to Coequal or (C7-C11)-aroyl-C1-alkyl, both of which can be substituted in the aureole radical as defined in the foregoing, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to lo ring atoms respectively, of which l to 2 ring atoms represent sulfur or oxygen atoms and/or of which l to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring amino acid, R2 denotes hydrogen, (Of to Colloquial, (C2 to C6)-alkenyl or aryl-(Cl to Colloquial, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or . - -- y 7~31[12 Y and Z together denote oxygen and X denotes (Of to Colloquial, (C2 to Colonial, ..... _ . _ _ Jo .. . .. . _ .. . ., ., .. . _ . . .
(C5 to Cg)-cycloaIkyl, (C6-C10)-aryl, ah can be monosubstituted, . _ _ .. _ _ __ _,, _ _ __ __.. . _ . . _ __ _ .,. _ _ _ .
disubstituted or trisubsti~tuted by (Of to Colloquial, (C
to C4)-alkoxy, hydroxyl, halogen, vitro, amino, (Of to C4)-alkylamino, decal to C4)-alkylamino or ethylene-_ _ _ _ _ _ _ . _ _ . _ . _ _ _ . . . .. _ _ _ . _ _ _, _ _ . _ . ... _ . _ Dixie or 3-i.ndolyl, and their physiologically acceptable salts. ....................... .... . .
Particularly suitable salts are alkali metal and - 10 alkaline earth metal salts,.... salts with physiologically - . . tolerated amine and salts with inorganic or organic acids, such as, for example, Hal, Her, H2S04, malefic acid or fumaric acid.
In this context and the fulling text, aureole is ..
- 15 by be understood preferably as optionally substituted phenol or _ _ _ _ _ _ _ _ _ _ , _ _ . _ _ _ _ _ naphthyl. Alkyd can be straight-chain or branched.
Two possible configurations of the carboxyl - -group are suitable in the preferred configuration of the H atoms on Kiwi and Kiwi of the bicycle, namely those in the ego position (part formula Ian and the end post-Zion (part formula IBM of the carboxyl group.
: The end position ox the corbel group on C-2 is defined such that the oarboxyl group is turned to-wards the direction of the 6-membered ring of the bit cycle, i e the concave side of the bicycle (part forum-lo IBM
Accordingly, the ego position of the carboxyl group on C-2 is defined such that the carboxyl group is ,, -.: ' - ' 2Z:78~Z
oriented in the direction of the relevant bridgehead H atoms part formula Ian C02~ (I b) Compounds of the formula I have choral C atoms in positions C-2, Kiwi, Kiwi and in the C atoms in the side chain marked with an asterisk. The invention lo relates to both the R and S configurations at all centers. The compounds ox the formula I can thus be present as optical isomers, as diastereomers as race mates or as mixtures of these. However, the compounds of the formula I are preferred in which the C atom 2 in - 15 tune bicyclic ring system and the C atoms in the side chain marked with an asterisk (~) have the S configu-ration.
Those compounds ox the formula I are portico-laxly preferred in which n denotes l, R devotes hydrogen or alkyd having l to 4 C atoms, Al denotes hydrogen, (Of to Keelhaul, (C2 or C3)-alkenyl, bouncily, phenethyl, 4-aminobutyl or bouncily-methyl, R denotes hydrogen, (Of to Colloquial or bouncily and, X denotes phenol, which can be monosubstituted or disubstituted, or in the case ox methoxy, trisubsti-tuned, by (Of or Colloquial, (Of or C2)-alkoxy, hydroxyl, .
x780z fluorine, chlorine, bromide, amino, (Of to Colloquial-amino, decal to CL~)-al~:ylamino, vitro or ethylene Dow, in particular those compounds of the formula I
in which n denotes 1, R denotes hydrogen, R1 denotes methyl, X denotes phenol, R2 denotes hydrogen or ethyl, the bicycle has the is configuration, the corbel group is oriented ego or end and the choral C atoms, which are identified with an asterisk I and C atom 2 have the S configuration.
, The invention further relates to processes for the preparation of the compounds of the formula I.
One process variant comprises reacting, by the know methods of aside formation in peptize chemistry, a come I pound of the I formula II, ,' ' 1 -
The invention relates to new derivatives of the bicyclic amino acids of the Norma I, .
O R
' H j 2 I/ \* * Y
o oh - NH - IT (Clown in wish COG R2 Z
! n denotes 0 or l, - lo R denotes hydrogen, (Of to Colloquial or aralkyl having 7 to 9 C atoms, Al denotes hydrogen or (Of to C6 alkali, which can optionally be substituted by amino, (Of to Cozily-Juno, preferably (C1-C4)-alkanoylamino, or bouncily no, (C2 to C5)~
alkenyl, (C5 to Cg)-cycloalky1., (C5 to Cg)-cycIoaLkenyl, (C5 to C7)-key ( 1 C4) alkyd, (C6-C10)-aryl or isle hydrogenated (C6-C10)-aryl, which each can be substituted by (C1 to Colloquial, (C1 or C2)-alkoxy or halogen, (C6-C10)-aryl-(C1 to Coequal or (C7-C11)-aroyl-C1-alkyl, both of which can be substituted in the aureole radical as defined in the foregoing, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to lo ring atoms respectively, of which l to 2 ring atoms represent sulfur or oxygen atoms and/or of which l to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring amino acid, R2 denotes hydrogen, (Of to Colloquial, (C2 to C6)-alkenyl or aryl-(Cl to Colloquial, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or . - -- y 7~31[12 Y and Z together denote oxygen and X denotes (Of to Colloquial, (C2 to Colonial, ..... _ . _ _ Jo .. . .. . _ .. . ., ., .. . _ . . .
(C5 to Cg)-cycloaIkyl, (C6-C10)-aryl, ah can be monosubstituted, . _ _ .. _ _ __ _,, _ _ __ __.. . _ . . _ __ _ .,. _ _ _ .
disubstituted or trisubsti~tuted by (Of to Colloquial, (C
to C4)-alkoxy, hydroxyl, halogen, vitro, amino, (Of to C4)-alkylamino, decal to C4)-alkylamino or ethylene-_ _ _ _ _ _ _ . _ _ . _ . _ _ _ . . . .. _ _ _ . _ _ _, _ _ . _ . ... _ . _ Dixie or 3-i.ndolyl, and their physiologically acceptable salts. ....................... .... . .
Particularly suitable salts are alkali metal and - 10 alkaline earth metal salts,.... salts with physiologically - . . tolerated amine and salts with inorganic or organic acids, such as, for example, Hal, Her, H2S04, malefic acid or fumaric acid.
In this context and the fulling text, aureole is ..
- 15 by be understood preferably as optionally substituted phenol or _ _ _ _ _ _ _ _ _ _ , _ _ . _ _ _ _ _ naphthyl. Alkyd can be straight-chain or branched.
Two possible configurations of the carboxyl - -group are suitable in the preferred configuration of the H atoms on Kiwi and Kiwi of the bicycle, namely those in the ego position (part formula Ian and the end post-Zion (part formula IBM of the carboxyl group.
: The end position ox the corbel group on C-2 is defined such that the oarboxyl group is turned to-wards the direction of the 6-membered ring of the bit cycle, i e the concave side of the bicycle (part forum-lo IBM
Accordingly, the ego position of the carboxyl group on C-2 is defined such that the carboxyl group is ,, -.: ' - ' 2Z:78~Z
oriented in the direction of the relevant bridgehead H atoms part formula Ian C02~ (I b) Compounds of the formula I have choral C atoms in positions C-2, Kiwi, Kiwi and in the C atoms in the side chain marked with an asterisk. The invention lo relates to both the R and S configurations at all centers. The compounds ox the formula I can thus be present as optical isomers, as diastereomers as race mates or as mixtures of these. However, the compounds of the formula I are preferred in which the C atom 2 in - 15 tune bicyclic ring system and the C atoms in the side chain marked with an asterisk (~) have the S configu-ration.
Those compounds ox the formula I are portico-laxly preferred in which n denotes l, R devotes hydrogen or alkyd having l to 4 C atoms, Al denotes hydrogen, (Of to Keelhaul, (C2 or C3)-alkenyl, bouncily, phenethyl, 4-aminobutyl or bouncily-methyl, R denotes hydrogen, (Of to Colloquial or bouncily and, X denotes phenol, which can be monosubstituted or disubstituted, or in the case ox methoxy, trisubsti-tuned, by (Of or Colloquial, (Of or C2)-alkoxy, hydroxyl, .
x780z fluorine, chlorine, bromide, amino, (Of to Colloquial-amino, decal to CL~)-al~:ylamino, vitro or ethylene Dow, in particular those compounds of the formula I
in which n denotes 1, R denotes hydrogen, R1 denotes methyl, X denotes phenol, R2 denotes hydrogen or ethyl, the bicycle has the is configuration, the corbel group is oriented ego or end and the choral C atoms, which are identified with an asterisk I and C atom 2 have the S configuration.
, The invention further relates to processes for the preparation of the compounds of the formula I.
One process variant comprises reacting, by the know methods of aside formation in peptize chemistry, a come I pound of the I formula II, ,' ' 1 -
2 oh NH oh- (C~12)n_c_x IT
Pi CRY Z ' wherein n, Al, R2, X, Y and Z have the meanings as in formula I, with a compound of the formula III, H . . . .
in which 1 2 W denotes hydrogen or a radical which can be spilt off by acid, in particular a left -bottle radical, and then optionally splitting off the radical W by acid treatment and optionally also splitting off the radical ::.. , - . ... . .
" .. ~1.~2780;2 -- 6 _ R2 by additional acid or base treatment, the free car-bullock acidsbeingob-tained in each case Further synthetic processes for the preparation ox the compounds of the forum I, in which Y and Z to-- 5 getter denote oxygen, comprise reacting, in a Nemo manner in a Michael reaction (Organikum, Thea edition, page 492, 1967), a compound of the formula IV, I .
IVY :
0 ' I j cow . COHESION
in which lo Al has the meaning as in formula I and W has the meaning as in formula III, with a compound of the formula V
R202C-CH=CH-C0-X TV) wherein R and X have the meanings as in formula I, and optionally splitting off the radical W and/or the radical . R , as described above, or reacting, in a known manner in a Mannish reaction (Bull.Soc.Chim.France 1973, page 6253, a compound of the above mentioned formula IV with a compound of the general formula Al, rerun R2 has the meaning as in formula I, and with a compound of the gene-fat formula VII;
(VI) (VII) wherein ; ;
X has the meaning as in formula I, and then optionally splitting off the radical W and/or the .,. , . . I .
12Z~ B02 radical R2 as described above with formation of the free carboxyl groups.
Furthermore, compounds of the formula I, with - Y and Z each being hydrogen, can also be prepared in a manner such that a compound of the above mentioned forum-lo IV is reacted, in accordance with the procedure desk cried in J. Amen Chem.Soc 93,2897 (Wyeth a come pound of the formula VIII, CRY
0 = C (VIII) .
wherein - R2 and X have the meanings as in formula I, the Schiff'sbases obtained are reduced and then the radical W and/or Ike radical R2 are optionally split off as desk cried above, with formation of the free carboxyl groups The reduction of the Schiff'sbases can be carried out electrolytically or with reducing agents, such as, for example, sodium bordered or sodium cyanoborohydride.
Compounds of the formula I, with Y being hydroxyl and Z being hydrogen, can also be obtained, for example, by reduction of a compound I, with Y and Z together being oxygen, obtained according to the above procedures This reduction can be carried out with a reducing agent, such as sodium bordered and other complex burnouts or, for example, borane-amine complexes.
Compounds of the formula If in which R represents hydrogen, can optionally be converted by methods known per so into their esters of -the formula I, wherein R
.. . .
~2Z7~0Z
denotes (Of to Colloquial or (C7-C9)-aralXyl The invention also relates to compounds ox the ` formula III, 2 . IIXI~ . .
YO-YO
H ¦
in which H
the H atoms on the C atoms pa and pa have the is configuration relative to one another and. the group -C02~ on C atom 2 is oriented ego or end to the bicyclic ring system and wherein . ..
W denotes hydrogen or a radical which can be split off by acid These compounds serve according to the invention as starling materials for t~lè swoons of compo~îds of the formula I and can according to the invention, be prepared by the following procedure:
Compounds of the formula IX, IT
Pi CRY Z ' wherein n, Al, R2, X, Y and Z have the meanings as in formula I, with a compound of the formula III, H . . . .
in which 1 2 W denotes hydrogen or a radical which can be spilt off by acid, in particular a left -bottle radical, and then optionally splitting off the radical W by acid treatment and optionally also splitting off the radical ::.. , - . ... . .
" .. ~1.~2780;2 -- 6 _ R2 by additional acid or base treatment, the free car-bullock acidsbeingob-tained in each case Further synthetic processes for the preparation ox the compounds of the forum I, in which Y and Z to-- 5 getter denote oxygen, comprise reacting, in a Nemo manner in a Michael reaction (Organikum, Thea edition, page 492, 1967), a compound of the formula IV, I .
IVY :
0 ' I j cow . COHESION
in which lo Al has the meaning as in formula I and W has the meaning as in formula III, with a compound of the formula V
R202C-CH=CH-C0-X TV) wherein R and X have the meanings as in formula I, and optionally splitting off the radical W and/or the radical . R , as described above, or reacting, in a known manner in a Mannish reaction (Bull.Soc.Chim.France 1973, page 6253, a compound of the above mentioned formula IV with a compound of the general formula Al, rerun R2 has the meaning as in formula I, and with a compound of the gene-fat formula VII;
(VI) (VII) wherein ; ;
X has the meaning as in formula I, and then optionally splitting off the radical W and/or the .,. , . . I .
12Z~ B02 radical R2 as described above with formation of the free carboxyl groups.
Furthermore, compounds of the formula I, with - Y and Z each being hydrogen, can also be prepared in a manner such that a compound of the above mentioned forum-lo IV is reacted, in accordance with the procedure desk cried in J. Amen Chem.Soc 93,2897 (Wyeth a come pound of the formula VIII, CRY
0 = C (VIII) .
wherein - R2 and X have the meanings as in formula I, the Schiff'sbases obtained are reduced and then the radical W and/or Ike radical R2 are optionally split off as desk cried above, with formation of the free carboxyl groups The reduction of the Schiff'sbases can be carried out electrolytically or with reducing agents, such as, for example, sodium bordered or sodium cyanoborohydride.
Compounds of the formula I, with Y being hydroxyl and Z being hydrogen, can also be obtained, for example, by reduction of a compound I, with Y and Z together being oxygen, obtained according to the above procedures This reduction can be carried out with a reducing agent, such as sodium bordered and other complex burnouts or, for example, borane-amine complexes.
Compounds of the formula If in which R represents hydrogen, can optionally be converted by methods known per so into their esters of -the formula I, wherein R
.. . .
~2Z7~0Z
denotes (Of to Colloquial or (C7-C9)-aralXyl The invention also relates to compounds ox the ` formula III, 2 . IIXI~ . .
YO-YO
H ¦
in which H
the H atoms on the C atoms pa and pa have the is configuration relative to one another and. the group -C02~ on C atom 2 is oriented ego or end to the bicyclic ring system and wherein . ..
W denotes hydrogen or a radical which can be split off by acid These compounds serve according to the invention as starling materials for t~lè swoons of compo~îds of the formula I and can according to the invention, be prepared by the following procedure:
Compounds of the formula IX, IT
3 N SHEA
2' in which R2 denotes (Of to Colloquial or (C7 to C8)-~ralkyl, are reacted with assaulting agents, which trays-per the group -Corey, wherein the radical R3 represents (Of to Colloquial, (C5 to Cg)-cycloalkyl, (C2 to C6)-alkenyl, (Of to C6)-alkoxy, aureole, airlocks, aryl-(Cl to Colloquial or aryl-(Cl to C4)-alkoxy, to give compounds ox the formula X, .:
~2Z7~ Z
. . 9 I .
" '.
I 3 C~2 I
CUR
in which R2 and I have the foregoing meaning, the latter are cyclized to give a mixture of stereoisomeric compounds of the formula XI, - R
., , ', . 02R2 (XI) 1 [ ICKY " ' "
in which R2 and R3 have the foregoing meaning and the hydrogen atoms on the bridgehead C atoms haze the is Jo configuration this mixture of stereo isomers, in which pairs of dias~ereomer3 are present, depending on whetiler the starting compounds of the formula IX . had the R or S
- configuration or were rhizomic, of the formulae Jib and d or Via and, or mixtures of the formulae XIa-d, no-speotively, H
CRY "CRY
CUR CUR
(XI a YO-YO b) Lowe R2 0 Corn . ¦ 3 2 I I CUR
- , - lo _ l~Z780Z
in which R2 and I each have the foregoing meaning, is hydrolyzed, optionally after previous separation into enantiomers, pairs of diastereomers or race mates, to give compounds of the formula III, in which W repro-sets hydrogen, and the latter are optionally esterified to give compounds of the formula III, in which W represents a radical which can be split off by acid.
The synthesis of compounds of the formula IX starts prom an al~ylglycine ester of the formula XII, Ho * CO R2' (XII) SHEA ,,.
earn pi is (Of to Colloquial or (C7 or By alkyd, preferably (Of to Colloquial or bouncily. The allylgly-cone ester can be employed in the synthesis as the ray comic compound or as optically pure R or S form The synthesis of the rhizomic allylglycine is described in Monatshefte don Chemise 85, 1071 (1954); that ox the R
and the S compound-s in J.biol.Chem.223, page 40 (1955).
` The esterification is carried out by know methods of - organic chemistry. The preparation of the ethyl ester is described in the article in Monatshefte don Chemise.
The compound of the formula XII is reacted with crotonaldehyde in an organic solvent, with separation out ox water, to give the Schiff'sbase of the formula IX.
The reaction is carried out at temperatures in the range from -40 to ~80C, preferably at ~20C. Aprotic -OX
solvents, such as, for example, Bunsen, Tulane, carbon tetrachloride or chloroform are used. The water of reaction is removed from the reaction equilibrium with a water-binding agent, such as, for example, McCoy, Nazi, molecular sieves or an organic auxiliary, such as, for example, orthoformates or by means of azeotropic separation out of water The Showoffs base is preferably assaulted in an aprotic solvent, such as, for example, mel;hylene Shelley-- 10 ride, chloroform, Tulane or dimethylformamide, in the presence of a base, such as, for example, triethylamine, colliding J pardon or other amine, with an assaulting - agent, such as, for example, an acid chloride to give the dienamide of the formula X. The reaction is tarried out at temperatures in the range from -80 to +40C. Preferably, the reaction is started at -80C
and completed at 20C.
In the assaulting agent which transfers the group -Corey, R3 preferably denotes phenol, tert.-butoxy, methyl, methoxy or ethics The compound of the forum lo X is preferably heated in a high boiling organic solvent and cyclized, in an intramolecular D~els-~lder reaction, to give the bicyclic amino acid dirts XIa-d, which are produced as a mixture of stereo isomers.
Those solvents can be used which boil in a -them-portray range between 80 and 250C, such as, for exam-pie, Tulane, zillion or dichlorobenzene. The then-molasses is also possible with a lower boiling solvent in a pressure apparatus. Preferably, the thermolysis ---Z~7~)2 is carried out in a temperature range between 100 and 180C under normal pressure. In order to deactivate the glass surface of the reaction vessel, if appropriate, bistrimethylsilylacetamide or customary deactivating compounds or acid traps and a radical trap such as, for example, tert.-butylcatechol to suppress radical side reactions are added.
The endo-cis compounds Via and Jib and the ego--- is compounds Tic and Rid are each present as race mates when the rhizomic allylglycine ester XII is used. On using the allylglycine ester with the S configuration as the starting compound, the amino acid derivatives - Via having the cis-endo-S configuration and Tic having the Sussex configuration are obtained, the S confi~u-; 15 ration relating to the C atom 2. Correspondingly, on using the allylglycine ester with the R configuration, -the amino acid derivatives Jib and Rid having the R con-figuration at carbon 2 are obtained. The race mates XIa/XIb and XIc/XId or the diastereomers Via andXIc or Jib and Rid can be separated, for example, by fractional crystallization or by column chromatography on silica gel by customary methods. The race mates or the opt tidally pure diastereomers can be employed in the fur-then reactions.
The amino acids of the formula III, wherein W
denotes hydrogen, are obtained by acid or alkaline ho-drolysis. The amino acids can optionally be esterified.
The preferred ter-t.-butyl esters of the amino acids of the formula III (W _ tert.-butyl) are obtained by the .
.' . ' ' ' .
methods customary in pep-tide chemistry, such as, for example, by reaction of the acids with isobutyl~ne in an inert organic solvent (for example Dixon) in the presence of acids (such as, for example, sulfuric acid).
5 The following process has been found to be particularly advantageous: the appropriate amino acid is assaulted on the nitrogen with a group which can be split off by base, such as, or example, the methylsulfonyIethoxycar-bony group (= MSC), Tosser, Balvert-Geers, Int.J.Pept.
Protein Rest 7,295 (1975~. The carboxylic acid is reacted, in the neutral to weakly basic pi range, with tert.-butanol in an organic solvent, such as, for example, pardon, in the presence of propylphosphonic android to give -the corresponding tert.-butyl ester.
The tert.-butyl ester of the formula III (W = left.-bottle) is obtained by splitting off the I protective group in the strongly alkaline pi range with alkali in an aqueous solvent.
- The compounds of the formula II, with n being 1, ; 20 Y and being hydrogen, Al being methyl and R2 being methyl or ethyl and X being phenol, used as starting materials for the preparation of the compounds of the - formula I, are known ( ETA
37,231). The compounds of the formula II can be pro-pared by various procedures. One synthetic variant starts from a kitten of the above mentioned formula VII, which is reacted, by known procedures in a Mannish no-action, with a compound of the above mentioned formula VI, together with amino acid esters of the formula XIII, 4_ ~L;Z27~30z I cozy w 02C-CH-N~E-C~-~}1 2-CO-X
.
(XIII) TV
- wherein R has the above mentioned meaning and W' denotes a radical which can be split off by hydrogenolysis or by acid, in particular a bouncily or a left -bottle radical, to give a compound of the formula XIV, wherein Al, R2, X and We have the above mentioned meanings, with the restriction that when W' denotes a radical which can be - split off by hydrogenolysis, in particular benzylj R2 may not have the meaning of I'. If the radical I is split off by hydrogenolysis using, for example, palled-; I'm, compounds of the formula II~with Y and Z being ho drogen are obtained on uptake of 3 mole-equivalents of hydrogen. If the uptake of hydrogen is stopped at 1 mole-equivalent, compounds of the formula II with n being 1 and Y and Z together being oxygen are obtained and these Ayers obtained when the radical Woof the formula 2G XIV is split off with acids, such as, for example, trip - fluoroacetic acid or hydrochloric acid, in an inert organic solvent, such as, for example, Dixon Compounds of the formula XIV can also be ox-twined by Michael additions of a compound of the above mentioned formula V with a compound of the above mentioned formula XIII by known procedures. This process is particularly suitable for the preparation of those come pounds of the formula XIV in which R denotes methyl, R denotes ethyl and X denotes aureole.
, ; . , .
Z' The compounds of the formula XIV are produced as mixtures of diastereomers. Preferred duster-mews of the forum XIV are those in which the choral C atoms marked with an asterisk each have the S configu ration. These can be separated out, for example, by crystallization or by chromatography 9 for example, on silica gel. On subsequently splitting off the radical W', the configurations of the choral C atoms are no-tanned.
The compounds of the above mentioned formula IV
used as starting materials for the preparation of the compounds of the formula I are obtained by known pro-seeders from the compounds of the above mentioned forum-lo III by reaction with a N-protected 2-aminocarboxylic acid of the formula XV, :R1 wherein V is a protective group and Al has the above-mentioned meaning. An example of a suitable pro-tective group V, which is split off again after there-action is complete, is tert.-butoxycarbonyl.
The reaction of a compound of toe formula II
with a compound of the formula III to prepare a camped of the formula I is carried out in accordance with a condensation reaction known in peptize chemistry, dyes clohexylcarbodiimide and l-hydroxybenzotriazole,for example being added as the-condensing agent. On subsequently splitting off the radical W with acid trifluoroacetic acid or hydrogen chloride are preferably - 16 _ ~L2Z~80z employed as the acids In the reactions for the preparation of the compounds of the formulae III, IV end I, described above, the configurations of the intermediate products a-t the bridgehead C atoms pa and pa are retained in each case.
The compounds of the formula III obtained according to the procedure described above are produced as a mixture and can be separated from one another, for example, by recrystallization or by chromatography.
The compounds of the formula III are produced as rhizomic mixtures and can be employed as such in the further syntheses described above. However, they can also be employed as the pure enantiomers after sepal ration of the race mates into the optical antipodes using customary methods, for example via salt formation with optically active bases or acids The pure en-antiomers can also be obtained.
If the compounds of the formula I are produced as race mates, these can also be resolved into their enantiomers by the customary methods, such as, for example, via salt formation with optically active bases or acids, or can be separated by chromatography.
The compounds of the formula I according to the invention aye, if R is hydrogen, in the form of internal salts.
Since they are amphoteric compounds thy can form salts with acids or bases. These salts are prepared in a cuss tumor manner by reaction with one equivalent of acid or base.
The compounds of the formula I and their salts Jo . ., - 17 _ I ~80~
have long-lasting and powerful h~potensive activities.
They are strong inhibitors ox the angiotensin converting enzyme (ACE ir~ibitors). They can be employed to control high blood pressure of various etiologies.
It is also possible to combine them with other compounds having hypotensive, vasodilator or diuretic activity.
Typical representatives of these classes of active come pounds are described, for example, in Erhardt-Ruschig, ~rzneimittel (Drugs), end edition, Weinheim, 1972 lo They can be used intravenously, subcutaneously or per-orally.
The dosage on oral administration is 1-100 my, preferably 1-40 my, for a single dose for an adult patient of normal eta, which corresponds to a dose of 0.013-1.3 mg/kg/day, p~efexably 0,013-0,53 mg/kg/day. This can also be increased in severe cases, since no toxic properties have been observed hitherto. A decrease in the dose is also possible and is particularly appxopxiate when diuretics are administered concurrently.
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 loath the additives cuss Tory or this purpose, such as vehicles, stabilizers or inert delineates and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily soul-lions. Inert vehicles which can be used are, for example, gum Arabic magnesium carbonate, potassium - 18~ 27~ 2 phosphate, lactose, glucose or starch, particularly corn starch In this context, the formulation con either be as dry or as moist groins. Examples ox suitable oily vehicles or solvents are plant and animal oils, such as sunflower oil or cod-liver oil.
or subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or Emil-sons, if desired together with the substances gusto-many for this purpose such as solubilizers,emulsifiersor other auxiliaries. Examples of suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are- water, physiolcgi-eel saline or alcohols, for example ethanol, preparedly or glycerol, additionally also sugar solutions, such as glucose or minutely solutions, or also a mixture of the various solvents mentioned.
The extremely high activity of the compounds according to formula I is demonstrated by the forum-ecological data in the following tables:
intra-duodenal administration to the anaesthe-tired rat, 50~0 inhibition of the presser reaction in-duped by 310 no of angiotensin I 30 min. after ad-ministration in the dose ......... = EDDY:
Table 1 (H atoms on Kiwi and Kiwi in formula I have the is configuration, the carboxyl group on C-2 has the end configuration and the C atoms identified with and C-2 have the S configuration, unless otherwise , , ~22~30Z
specified in the -table) X , Z R2 R EDDY Irk 1 . 2 s SHEA 40 .
1 H C H I 80(R,S-. 2 5, 3 H . configuration on C-2 in . . . formula I) I) O - C285 'I
_ _ . . . .. _ . . . _ . . . . . _ The symbols n, X, Y, Z, R, Al and R2 relate to the : compounds of the formula I.
Table II
(H atoms on Kiwi and Kiwi in formula I have the is configuration, the carboxyl group has the ego con-figuration and the C atoms identified with and C-2 haze the S configuration) n X Y Z R R ~D50 (~gJkg3 - :
. H H C~3 H 700 C2~5 SHEA H 500 - 20 _ ~LZ2~8~
The snowballs n, X, Y, 27 R, Al and R2 relate to the come pounds of the formula I.
The hollowing examples serve to illustrate the invention, but without restricting it to the compounds mentioned as being representatives.
The lo NO data reported in the following examples were found by measurement in CDC13 and are no-ported in (Pam).
sample 1 N-~lS-carboethoxy-3-phenylpro~ Alan cis-2.3,~a,4,5L7a-hexahydro~ indole-2R?S-endo-carbo~y~-fig acid .
a) Ethyl ester of N-benzoyl-N-(1,3-butadienyl)~R
S-allyl-glycine 28.6 g of R,S-allylgiycine ~hylesterYiere dissolved in 140 ml of Tulane, and 14.0 g of crotonaldehyde were added. After adding 30 g of an hydrous magnesium sulfate, the mixture was stirred at room temperature for 3 hours.
The magnesium sulfate was then filterer off with sue- 0 lion and the Tulane was removed in vacua.
Residue: 44.4 g of oil.
750 ml of ethylene chloride were cooled down to -70C and 44.4 g of triethylamine and 2~.1 g ox bouncily chloride were added. To this were added the 44.4 g of Showoffs base obtained above. The mixture was stirred at -75C for 2 hours. It was then allowed to warm to 0C. The solvent was removed in a rotary evaporator at room temperature. The nest-due was -then taken up in Tulane, washed with water, .
_ 21 --dried and the Tulane was remove din artery evaporator.
the residue was filtered through a short column of silica gel (500 ml). Ethylene chloride was used to elude. After evaporating off the ethylene chloride, 49 g of ethyl ester of N-benzoyl-N-(1,3-butadienyl?-R,S-allylglycine were obtained.
lo NOR data:
1.1 - 1.4 (t, OH), 2.7 - 3.1 (m, OH), lo 4.0 4. 5 (m, OH),
2' in which R2 denotes (Of to Colloquial or (C7 to C8)-~ralkyl, are reacted with assaulting agents, which trays-per the group -Corey, wherein the radical R3 represents (Of to Colloquial, (C5 to Cg)-cycloalkyl, (C2 to C6)-alkenyl, (Of to C6)-alkoxy, aureole, airlocks, aryl-(Cl to Colloquial or aryl-(Cl to C4)-alkoxy, to give compounds ox the formula X, .:
~2Z7~ Z
. . 9 I .
" '.
I 3 C~2 I
CUR
in which R2 and I have the foregoing meaning, the latter are cyclized to give a mixture of stereoisomeric compounds of the formula XI, - R
., , ', . 02R2 (XI) 1 [ ICKY " ' "
in which R2 and R3 have the foregoing meaning and the hydrogen atoms on the bridgehead C atoms haze the is Jo configuration this mixture of stereo isomers, in which pairs of dias~ereomer3 are present, depending on whetiler the starting compounds of the formula IX . had the R or S
- configuration or were rhizomic, of the formulae Jib and d or Via and, or mixtures of the formulae XIa-d, no-speotively, H
CRY "CRY
CUR CUR
(XI a YO-YO b) Lowe R2 0 Corn . ¦ 3 2 I I CUR
- , - lo _ l~Z780Z
in which R2 and I each have the foregoing meaning, is hydrolyzed, optionally after previous separation into enantiomers, pairs of diastereomers or race mates, to give compounds of the formula III, in which W repro-sets hydrogen, and the latter are optionally esterified to give compounds of the formula III, in which W represents a radical which can be split off by acid.
The synthesis of compounds of the formula IX starts prom an al~ylglycine ester of the formula XII, Ho * CO R2' (XII) SHEA ,,.
earn pi is (Of to Colloquial or (C7 or By alkyd, preferably (Of to Colloquial or bouncily. The allylgly-cone ester can be employed in the synthesis as the ray comic compound or as optically pure R or S form The synthesis of the rhizomic allylglycine is described in Monatshefte don Chemise 85, 1071 (1954); that ox the R
and the S compound-s in J.biol.Chem.223, page 40 (1955).
` The esterification is carried out by know methods of - organic chemistry. The preparation of the ethyl ester is described in the article in Monatshefte don Chemise.
The compound of the formula XII is reacted with crotonaldehyde in an organic solvent, with separation out ox water, to give the Schiff'sbase of the formula IX.
The reaction is carried out at temperatures in the range from -40 to ~80C, preferably at ~20C. Aprotic -OX
solvents, such as, for example, Bunsen, Tulane, carbon tetrachloride or chloroform are used. The water of reaction is removed from the reaction equilibrium with a water-binding agent, such as, for example, McCoy, Nazi, molecular sieves or an organic auxiliary, such as, for example, orthoformates or by means of azeotropic separation out of water The Showoffs base is preferably assaulted in an aprotic solvent, such as, for example, mel;hylene Shelley-- 10 ride, chloroform, Tulane or dimethylformamide, in the presence of a base, such as, for example, triethylamine, colliding J pardon or other amine, with an assaulting - agent, such as, for example, an acid chloride to give the dienamide of the formula X. The reaction is tarried out at temperatures in the range from -80 to +40C. Preferably, the reaction is started at -80C
and completed at 20C.
In the assaulting agent which transfers the group -Corey, R3 preferably denotes phenol, tert.-butoxy, methyl, methoxy or ethics The compound of the forum lo X is preferably heated in a high boiling organic solvent and cyclized, in an intramolecular D~els-~lder reaction, to give the bicyclic amino acid dirts XIa-d, which are produced as a mixture of stereo isomers.
Those solvents can be used which boil in a -them-portray range between 80 and 250C, such as, for exam-pie, Tulane, zillion or dichlorobenzene. The then-molasses is also possible with a lower boiling solvent in a pressure apparatus. Preferably, the thermolysis ---Z~7~)2 is carried out in a temperature range between 100 and 180C under normal pressure. In order to deactivate the glass surface of the reaction vessel, if appropriate, bistrimethylsilylacetamide or customary deactivating compounds or acid traps and a radical trap such as, for example, tert.-butylcatechol to suppress radical side reactions are added.
The endo-cis compounds Via and Jib and the ego--- is compounds Tic and Rid are each present as race mates when the rhizomic allylglycine ester XII is used. On using the allylglycine ester with the S configuration as the starting compound, the amino acid derivatives - Via having the cis-endo-S configuration and Tic having the Sussex configuration are obtained, the S confi~u-; 15 ration relating to the C atom 2. Correspondingly, on using the allylglycine ester with the R configuration, -the amino acid derivatives Jib and Rid having the R con-figuration at carbon 2 are obtained. The race mates XIa/XIb and XIc/XId or the diastereomers Via andXIc or Jib and Rid can be separated, for example, by fractional crystallization or by column chromatography on silica gel by customary methods. The race mates or the opt tidally pure diastereomers can be employed in the fur-then reactions.
The amino acids of the formula III, wherein W
denotes hydrogen, are obtained by acid or alkaline ho-drolysis. The amino acids can optionally be esterified.
The preferred ter-t.-butyl esters of the amino acids of the formula III (W _ tert.-butyl) are obtained by the .
.' . ' ' ' .
methods customary in pep-tide chemistry, such as, for example, by reaction of the acids with isobutyl~ne in an inert organic solvent (for example Dixon) in the presence of acids (such as, for example, sulfuric acid).
5 The following process has been found to be particularly advantageous: the appropriate amino acid is assaulted on the nitrogen with a group which can be split off by base, such as, or example, the methylsulfonyIethoxycar-bony group (= MSC), Tosser, Balvert-Geers, Int.J.Pept.
Protein Rest 7,295 (1975~. The carboxylic acid is reacted, in the neutral to weakly basic pi range, with tert.-butanol in an organic solvent, such as, for example, pardon, in the presence of propylphosphonic android to give -the corresponding tert.-butyl ester.
The tert.-butyl ester of the formula III (W = left.-bottle) is obtained by splitting off the I protective group in the strongly alkaline pi range with alkali in an aqueous solvent.
- The compounds of the formula II, with n being 1, ; 20 Y and being hydrogen, Al being methyl and R2 being methyl or ethyl and X being phenol, used as starting materials for the preparation of the compounds of the - formula I, are known ( ETA
37,231). The compounds of the formula II can be pro-pared by various procedures. One synthetic variant starts from a kitten of the above mentioned formula VII, which is reacted, by known procedures in a Mannish no-action, with a compound of the above mentioned formula VI, together with amino acid esters of the formula XIII, 4_ ~L;Z27~30z I cozy w 02C-CH-N~E-C~-~}1 2-CO-X
.
(XIII) TV
- wherein R has the above mentioned meaning and W' denotes a radical which can be split off by hydrogenolysis or by acid, in particular a bouncily or a left -bottle radical, to give a compound of the formula XIV, wherein Al, R2, X and We have the above mentioned meanings, with the restriction that when W' denotes a radical which can be - split off by hydrogenolysis, in particular benzylj R2 may not have the meaning of I'. If the radical I is split off by hydrogenolysis using, for example, palled-; I'm, compounds of the formula II~with Y and Z being ho drogen are obtained on uptake of 3 mole-equivalents of hydrogen. If the uptake of hydrogen is stopped at 1 mole-equivalent, compounds of the formula II with n being 1 and Y and Z together being oxygen are obtained and these Ayers obtained when the radical Woof the formula 2G XIV is split off with acids, such as, for example, trip - fluoroacetic acid or hydrochloric acid, in an inert organic solvent, such as, for example, Dixon Compounds of the formula XIV can also be ox-twined by Michael additions of a compound of the above mentioned formula V with a compound of the above mentioned formula XIII by known procedures. This process is particularly suitable for the preparation of those come pounds of the formula XIV in which R denotes methyl, R denotes ethyl and X denotes aureole.
, ; . , .
Z' The compounds of the formula XIV are produced as mixtures of diastereomers. Preferred duster-mews of the forum XIV are those in which the choral C atoms marked with an asterisk each have the S configu ration. These can be separated out, for example, by crystallization or by chromatography 9 for example, on silica gel. On subsequently splitting off the radical W', the configurations of the choral C atoms are no-tanned.
The compounds of the above mentioned formula IV
used as starting materials for the preparation of the compounds of the formula I are obtained by known pro-seeders from the compounds of the above mentioned forum-lo III by reaction with a N-protected 2-aminocarboxylic acid of the formula XV, :R1 wherein V is a protective group and Al has the above-mentioned meaning. An example of a suitable pro-tective group V, which is split off again after there-action is complete, is tert.-butoxycarbonyl.
The reaction of a compound of toe formula II
with a compound of the formula III to prepare a camped of the formula I is carried out in accordance with a condensation reaction known in peptize chemistry, dyes clohexylcarbodiimide and l-hydroxybenzotriazole,for example being added as the-condensing agent. On subsequently splitting off the radical W with acid trifluoroacetic acid or hydrogen chloride are preferably - 16 _ ~L2Z~80z employed as the acids In the reactions for the preparation of the compounds of the formulae III, IV end I, described above, the configurations of the intermediate products a-t the bridgehead C atoms pa and pa are retained in each case.
The compounds of the formula III obtained according to the procedure described above are produced as a mixture and can be separated from one another, for example, by recrystallization or by chromatography.
The compounds of the formula III are produced as rhizomic mixtures and can be employed as such in the further syntheses described above. However, they can also be employed as the pure enantiomers after sepal ration of the race mates into the optical antipodes using customary methods, for example via salt formation with optically active bases or acids The pure en-antiomers can also be obtained.
If the compounds of the formula I are produced as race mates, these can also be resolved into their enantiomers by the customary methods, such as, for example, via salt formation with optically active bases or acids, or can be separated by chromatography.
The compounds of the formula I according to the invention aye, if R is hydrogen, in the form of internal salts.
Since they are amphoteric compounds thy can form salts with acids or bases. These salts are prepared in a cuss tumor manner by reaction with one equivalent of acid or base.
The compounds of the formula I and their salts Jo . ., - 17 _ I ~80~
have long-lasting and powerful h~potensive activities.
They are strong inhibitors ox the angiotensin converting enzyme (ACE ir~ibitors). They can be employed to control high blood pressure of various etiologies.
It is also possible to combine them with other compounds having hypotensive, vasodilator or diuretic activity.
Typical representatives of these classes of active come pounds are described, for example, in Erhardt-Ruschig, ~rzneimittel (Drugs), end edition, Weinheim, 1972 lo They can be used intravenously, subcutaneously or per-orally.
The dosage on oral administration is 1-100 my, preferably 1-40 my, for a single dose for an adult patient of normal eta, which corresponds to a dose of 0.013-1.3 mg/kg/day, p~efexably 0,013-0,53 mg/kg/day. This can also be increased in severe cases, since no toxic properties have been observed hitherto. A decrease in the dose is also possible and is particularly appxopxiate when diuretics are administered concurrently.
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 loath the additives cuss Tory or this purpose, such as vehicles, stabilizers or inert delineates and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily soul-lions. Inert vehicles which can be used are, for example, gum Arabic magnesium carbonate, potassium - 18~ 27~ 2 phosphate, lactose, glucose or starch, particularly corn starch In this context, the formulation con either be as dry or as moist groins. Examples ox suitable oily vehicles or solvents are plant and animal oils, such as sunflower oil or cod-liver oil.
or subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or Emil-sons, if desired together with the substances gusto-many for this purpose such as solubilizers,emulsifiersor other auxiliaries. Examples of suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are- water, physiolcgi-eel saline or alcohols, for example ethanol, preparedly or glycerol, additionally also sugar solutions, such as glucose or minutely solutions, or also a mixture of the various solvents mentioned.
The extremely high activity of the compounds according to formula I is demonstrated by the forum-ecological data in the following tables:
intra-duodenal administration to the anaesthe-tired rat, 50~0 inhibition of the presser reaction in-duped by 310 no of angiotensin I 30 min. after ad-ministration in the dose ......... = EDDY:
Table 1 (H atoms on Kiwi and Kiwi in formula I have the is configuration, the carboxyl group on C-2 has the end configuration and the C atoms identified with and C-2 have the S configuration, unless otherwise , , ~22~30Z
specified in the -table) X , Z R2 R EDDY Irk 1 . 2 s SHEA 40 .
1 H C H I 80(R,S-. 2 5, 3 H . configuration on C-2 in . . . formula I) I) O - C285 'I
_ _ . . . .. _ . . . _ . . . . . _ The symbols n, X, Y, Z, R, Al and R2 relate to the : compounds of the formula I.
Table II
(H atoms on Kiwi and Kiwi in formula I have the is configuration, the carboxyl group has the ego con-figuration and the C atoms identified with and C-2 haze the S configuration) n X Y Z R R ~D50 (~gJkg3 - :
. H H C~3 H 700 C2~5 SHEA H 500 - 20 _ ~LZ2~8~
The snowballs n, X, Y, 27 R, Al and R2 relate to the come pounds of the formula I.
The hollowing examples serve to illustrate the invention, but without restricting it to the compounds mentioned as being representatives.
The lo NO data reported in the following examples were found by measurement in CDC13 and are no-ported in (Pam).
sample 1 N-~lS-carboethoxy-3-phenylpro~ Alan cis-2.3,~a,4,5L7a-hexahydro~ indole-2R?S-endo-carbo~y~-fig acid .
a) Ethyl ester of N-benzoyl-N-(1,3-butadienyl)~R
S-allyl-glycine 28.6 g of R,S-allylgiycine ~hylesterYiere dissolved in 140 ml of Tulane, and 14.0 g of crotonaldehyde were added. After adding 30 g of an hydrous magnesium sulfate, the mixture was stirred at room temperature for 3 hours.
The magnesium sulfate was then filterer off with sue- 0 lion and the Tulane was removed in vacua.
Residue: 44.4 g of oil.
750 ml of ethylene chloride were cooled down to -70C and 44.4 g of triethylamine and 2~.1 g ox bouncily chloride were added. To this were added the 44.4 g of Showoffs base obtained above. The mixture was stirred at -75C for 2 hours. It was then allowed to warm to 0C. The solvent was removed in a rotary evaporator at room temperature. The nest-due was -then taken up in Tulane, washed with water, .
_ 21 --dried and the Tulane was remove din artery evaporator.
the residue was filtered through a short column of silica gel (500 ml). Ethylene chloride was used to elude. After evaporating off the ethylene chloride, 49 g of ethyl ester of N-benzoyl-N-(1,3-butadienyl?-R,S-allylglycine were obtained.
lo NOR data:
1.1 - 1.4 (t, OH), 2.7 - 3.1 (m, OH), lo 4.0 4. 5 (m, OH),
4.8 - 6.8 (m, OH), 7.3 - 7.6 (s, OH).
b) Ethyl N=benzoyl-cis-2,3,3a,4,5l7a-hexahydro ClH~indole-2P~,S-endo-carboxylate 49 g of N-benzoyi-N-(1,3-butadienyl)-R,S-allyl-_ __ ..... ___ _ _ _ __ _ _ __ _ Gleason ethyl ester were dissolved in 1,000 rnl OX Lyon, and 0.1 g of tert.-butylcatechol and 5 drops of bistrimethyl-silylacetamide Lowry added. The mixture was heated to rollicks under nitrogen for 6 hours, a further 0.1 g ox tert.-butylcatechol and 5 drops of bistrimethylsilyl-acetamide being added after 3 hours. The x~lene was removed in a rotary evaporator and 43 g of an oily nest-due remained.
70 g of oil were chromatographed on silica gel with toluene/ethyl acetate 4:1. 53 g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydroLlH~indole-2R,SSunday-cal~boxylate (Of: 0.18) were obtained as an oil and 7.5 g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH~in-d~-2R,S-exo-carboxylate (Of: 0.26, melting point: 96-- 22- ~227~302 98C) were obtained.
Both compounds are in the form of rhizomes.
c) Swiss axe.:: Lowe endo-carbox~lic acid , 1.5 g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexa-hydro[lH]indol~2-endo-R,S-carboxylate were dissolved in 10 ml of ethanol. 0.35 g of potassium hydroxide disk solved in 5 ml of water was added to this. The mix-lure was stirred at room temperature for I hours, dip lute with water and extracted with ethyl acetate.
The aqueous solution was acidified with ON hydrochloric acid and again extracted with ethyl acetate. After drying and evaporation on a rotary evaporator, 0.9 g of N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole-~eend-I carbolic acid of melting point 153-15~C was obtained.
13.4 g of the N-benzoyl carboxylic acid were dissolved in a mixture of 200 ml of ON hydrochloric acid and 67 ml of ethanol and heated under nitrogen at a bath temperature of 110C for 22 hours. The alcohol was removed in vacua and the aqueous phase was extracted wit h ethylene chloride. The pi was then adjusted to 7.0 with concentrated sodium hydroxide solution and the solution was evaporated to dryness in vacua. The residue was taken up in ethylene chloride/methanol, salt was removed by filtration, the filtrate was evapo-rated and recrystallized fromethanol/ether. Yield 7.0 g, melting point: 220C (decomposition).
d) N~(lS-carboethoxy-3-~henyl~ro~l)-S-alanyl- I`
cis-2,3,3a~4,5~7a-hexahydro~lH~indole OR Sunday- -- I ~LZ278[)~
carboxylic acid .
0 84 g of N-(lS-carboethox~y-3-phenylpropyl)-S--alanine,0.69 g ox N-hydroxysuccinimide and 0.66 g ox dicyclohexylcarbodiimide were dissolved in 8 ml of dry dimethylformamide at 0C. The solution was then stirred at room temperature for 3 hours. A solution of 0 5 g of cis-2,3,3a,4,5,7a-hexahydro[lH]indole-2R,S-endo-carbox~lLc acid in 10 ml of dimethyl~ormamide end 10 ml ox water, in the presence of 0.27 g of concentrated sodium hydroxide solution, was then added. The mix-lure was stirred at room temperature for 12 hours, the dicyclohexylurea formed was filtered off with suction and the filtrate was neutralized with ON hydrochloric acid. It was then evaporated to dryness in vacua, I taken up in ethyla~etate, insoluble were filtered off : and the ethyl acetate solution was evaporated in vacua.
The residue was purified over silica gel 7 eluding with ethylene chloride/methanol 9:1. Yield: 0 13 g (Of:
.74).
I Example 2 - Jo - N-(lS-~arboetho.~y-3-~henYl~ro~yl~-S-alanyl-cis-acceder r indo~~~S-endo-carbox~lic acid - The compound was obtained by separating the mixture of diastereomers Roy Example id on a sufficient amount of silica get, eluding with ethylene chloride/
methanol 9:1 Of: 0.65.
Example 3 N-(lS-carboethoxy-3-phenylpropyll-S-alanyl-cis-2 3 7 3a,l~577a-he~ahydrorlHlindo~aR-endo-carbo~ylic acid . ' .
- Al ~L22~7802 The compound was obtained by separating the mixture of dias-tereomers from Example id on a sufficient mount of silica gel, eluding with ethylene chloride/
methanol 9:1. Of: 0.8.
Example 4 s-2 3,~a,4.5~7a-hexahydro~lH no 2R~S-endo-carbo~late - 3.35 g of cis-2,3,3a,4,5,7a-hexahydro~lH~indole-2R,S-endo-carboxylic acid were dissolved in 50 ml of dimethylformamide, and 5.3 g of methylsulfonylethyl succinimidocarbonate and 2.3 g of ethylmorpholine were added. The mixture was allowed to stand at room temperature for 12 hours, the solvent was evaporated off in vacua and the residue was dissolved in ethyl ace-late. The ethyl acetate solution was extracted bushwhacking with saturated sodium bicarbonate solution this was adjusted to pi 3.5 with ON hydrochloric acid, and extracted several times with ethyl acetate. after drying, the combined ethyl acetate solutions were evapo-rated.- The residue obtained was 8 5 g of N-methyl-sullonylethyloxycarbonyl-cis-2,3,3a,4,557a-hexahyddrywall]
indole-~R~-endo carboxylic acid, which was dissolved in 10 ml of pardon. To this were added, at 0C, 10 ml of tert.-butanol and 12 ml of a 50% strength solution of propylphosphonic android in ethylene chloride.
The mixture was stirred at 40C for 6 hours, 200 ml of ethyl acetate were added and potassium bisulfate solution was added until a pi of 3.5 was reached. The mixture was extracted with ethyl acetate, the ethyl acetate 1'22~ z solution was washed with water, dried and evaporated in vacua. The oil remaining was purified on silica gel eluding with ethyl acetate. The left -bottle ester was obtained as an oil.
lo NOR data:
- 1.4 (s, OH), 1.0 - 2.8 (m, lo), 2.9 (s, OH), 3 .1 - 3 . 5 (my I
3.7 - 4.8 (m, OH),
b) Ethyl N=benzoyl-cis-2,3,3a,4,5l7a-hexahydro ClH~indole-2P~,S-endo-carboxylate 49 g of N-benzoyi-N-(1,3-butadienyl)-R,S-allyl-_ __ ..... ___ _ _ _ __ _ _ __ _ Gleason ethyl ester were dissolved in 1,000 rnl OX Lyon, and 0.1 g of tert.-butylcatechol and 5 drops of bistrimethyl-silylacetamide Lowry added. The mixture was heated to rollicks under nitrogen for 6 hours, a further 0.1 g ox tert.-butylcatechol and 5 drops of bistrimethylsilyl-acetamide being added after 3 hours. The x~lene was removed in a rotary evaporator and 43 g of an oily nest-due remained.
70 g of oil were chromatographed on silica gel with toluene/ethyl acetate 4:1. 53 g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydroLlH~indole-2R,SSunday-cal~boxylate (Of: 0.18) were obtained as an oil and 7.5 g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH~in-d~-2R,S-exo-carboxylate (Of: 0.26, melting point: 96-- 22- ~227~302 98C) were obtained.
Both compounds are in the form of rhizomes.
c) Swiss axe.:: Lowe endo-carbox~lic acid , 1.5 g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexa-hydro[lH]indol~2-endo-R,S-carboxylate were dissolved in 10 ml of ethanol. 0.35 g of potassium hydroxide disk solved in 5 ml of water was added to this. The mix-lure was stirred at room temperature for I hours, dip lute with water and extracted with ethyl acetate.
The aqueous solution was acidified with ON hydrochloric acid and again extracted with ethyl acetate. After drying and evaporation on a rotary evaporator, 0.9 g of N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole-~eend-I carbolic acid of melting point 153-15~C was obtained.
13.4 g of the N-benzoyl carboxylic acid were dissolved in a mixture of 200 ml of ON hydrochloric acid and 67 ml of ethanol and heated under nitrogen at a bath temperature of 110C for 22 hours. The alcohol was removed in vacua and the aqueous phase was extracted wit h ethylene chloride. The pi was then adjusted to 7.0 with concentrated sodium hydroxide solution and the solution was evaporated to dryness in vacua. The residue was taken up in ethylene chloride/methanol, salt was removed by filtration, the filtrate was evapo-rated and recrystallized fromethanol/ether. Yield 7.0 g, melting point: 220C (decomposition).
d) N~(lS-carboethoxy-3-~henyl~ro~l)-S-alanyl- I`
cis-2,3,3a~4,5~7a-hexahydro~lH~indole OR Sunday- -- I ~LZ278[)~
carboxylic acid .
0 84 g of N-(lS-carboethox~y-3-phenylpropyl)-S--alanine,0.69 g ox N-hydroxysuccinimide and 0.66 g ox dicyclohexylcarbodiimide were dissolved in 8 ml of dry dimethylformamide at 0C. The solution was then stirred at room temperature for 3 hours. A solution of 0 5 g of cis-2,3,3a,4,5,7a-hexahydro[lH]indole-2R,S-endo-carbox~lLc acid in 10 ml of dimethyl~ormamide end 10 ml ox water, in the presence of 0.27 g of concentrated sodium hydroxide solution, was then added. The mix-lure was stirred at room temperature for 12 hours, the dicyclohexylurea formed was filtered off with suction and the filtrate was neutralized with ON hydrochloric acid. It was then evaporated to dryness in vacua, I taken up in ethyla~etate, insoluble were filtered off : and the ethyl acetate solution was evaporated in vacua.
The residue was purified over silica gel 7 eluding with ethylene chloride/methanol 9:1. Yield: 0 13 g (Of:
.74).
I Example 2 - Jo - N-(lS-~arboetho.~y-3-~henYl~ro~yl~-S-alanyl-cis-acceder r indo~~~S-endo-carbox~lic acid - The compound was obtained by separating the mixture of diastereomers Roy Example id on a sufficient amount of silica get, eluding with ethylene chloride/
methanol 9:1 Of: 0.65.
Example 3 N-(lS-carboethoxy-3-phenylpropyll-S-alanyl-cis-2 3 7 3a,l~577a-he~ahydrorlHlindo~aR-endo-carbo~ylic acid . ' .
- Al ~L22~7802 The compound was obtained by separating the mixture of dias-tereomers from Example id on a sufficient mount of silica gel, eluding with ethylene chloride/
methanol 9:1. Of: 0.8.
Example 4 s-2 3,~a,4.5~7a-hexahydro~lH no 2R~S-endo-carbo~late - 3.35 g of cis-2,3,3a,4,5,7a-hexahydro~lH~indole-2R,S-endo-carboxylic acid were dissolved in 50 ml of dimethylformamide, and 5.3 g of methylsulfonylethyl succinimidocarbonate and 2.3 g of ethylmorpholine were added. The mixture was allowed to stand at room temperature for 12 hours, the solvent was evaporated off in vacua and the residue was dissolved in ethyl ace-late. The ethyl acetate solution was extracted bushwhacking with saturated sodium bicarbonate solution this was adjusted to pi 3.5 with ON hydrochloric acid, and extracted several times with ethyl acetate. after drying, the combined ethyl acetate solutions were evapo-rated.- The residue obtained was 8 5 g of N-methyl-sullonylethyloxycarbonyl-cis-2,3,3a,4,557a-hexahyddrywall]
indole-~R~-endo carboxylic acid, which was dissolved in 10 ml of pardon. To this were added, at 0C, 10 ml of tert.-butanol and 12 ml of a 50% strength solution of propylphosphonic android in ethylene chloride.
The mixture was stirred at 40C for 6 hours, 200 ml of ethyl acetate were added and potassium bisulfate solution was added until a pi of 3.5 was reached. The mixture was extracted with ethyl acetate, the ethyl acetate 1'22~ z solution was washed with water, dried and evaporated in vacua. The oil remaining was purified on silica gel eluding with ethyl acetate. The left -bottle ester was obtained as an oil.
lo NOR data:
- 1.4 (s, OH), 1.0 - 2.8 (m, lo), 2.9 (s, OH), 3 .1 - 3 . 5 (my I
3.7 - 4.8 (m, OH),
5.6 - 5.9 (m, OH), 1.35 g of tert.-butyl ester was dissolved in 15 ml of methanol and 1.5 ml of water. The pi was Audis-ted to 13 with ON sodium hydroxide solution and the mixture was stirred at room temperature for 2 hours.
- It was then neutralized with ON hydrochloric acid, the I- methanol was evaporated in vacua, the aqueous phase was extracted with ethyl acetate, and the ethyl acetate soul-. lion was washed with water, dried and evaporated, The oily residue was purified on silica gel;eluting with ethyl acetate.
0 3 g of tert.-butyl cis-2,3,3a,4,5,7a-hexahydro [lH~indole~2R~S-end~o-carboxylate was thus obtained as an oil.
H NOR data:
1.4 (s, OH), 1.0 - 2.7 (m, OH), 3.2 - 4.9 (m, OH), 5.8 (d, OH).
. . : , .
1227~30 Example 5 Te,rtA.-b~t~l N-~lS-,carboethoxv-~=phe Ylorooyl~-S-alan~_ri-_Z, .5,7a-hexahYdro~lH~lndole-2~s-end ____. . . ... ... .
carboxylate -0.28 g of N-(lS-carboethoxy-3-phenylpropyl)-S-ala nine was dissolved in 4 ml of dimethylformamide.
Then 0.15 g of hydroxybenzotriazole and 0.22 g of dice-clohexylcarbodiimide were added at room -temperature.
The mixture was stirred a-t room temperature for 4 hours.
- 10 Then 0.~4 g of tert.-butyl ester from Example 4 was added and the mixture was stirred at room temperature for 20 hours. It was diluted with ethyl acetate, the' urea eras filtered off with suction and the filtrate was evaporated in vacua. The residue was taken up in 15 ethyl acetate and the ethyl acetate solution was tasted with bicarbonate solution, dried and evaporated.
The oily residue (owe g) was separated into the die-strollers on silica gel, eluding with ethyl acetates-; . clohexane 2:1.
0.24 g of the tert.-butyl ester having the US-end configuration was obtained. I 0,45, Moe).
H No data:
' ' ' 1.4 (s, I
0.8 - 3,8 (m, 20H), I 4.6 (m, OH), 5.4 - owe (m, OH), 7.2 (s, OH).
Example 6 Ter,t,,-,butyl N-(lS-carboethoxy-3 phenylpro `` ~Z~7~
S-alanyl~cis-2,3,3a,4,5,7a-hexahydro~lHlindole-_P~eye-choirboy This ester was obtained on chromatography on silica gel as described in Example 5, of the mixture of diastereomers from Example 5. Ethyl acetate/cyclo-hexane was used to elude. Yield: 0.16 g (Of: 0.3;
m/e = 484).
Example 7 ! N-(lS-carboethox~-3-~henylpropyl~-S-alanyl-cis-- 10 acceder r lHlindole-2.~-endo-carbo,Yylic acid trifluoroacetate 0.16 g of the tert.-butyl ester obtained in Example 6 was dissolved in 1 ml of trifluoroacetic acid at 0C and the mixture was stirred at this temperature for 3 hours. The trifluoroacetic acid was evaporated ; off in vacua and the residue was crystallized from dip isopropyl ether. Yield of trifluoroacetate: 0.08 g of melting point: 120-121C. The trifluoroacetate can be converted into the amino acid using basic ion exchangers (OH form) in methanol/water 60:~0.
Example 8 N=~lS-carboethox~-3-phenylpro~yl~-S-aldnyl-cis-acceder r lH~indole-2S-endo-carboxylic awl_ trifluoroacetate 0.24 g of the tert.~butyl ester described in Example 5 was dissolved in 1.5 ml of trifluoroacetic acid at 0C and the mixture was stirred at this temperature for 5 Halsey. The trifluoroacetic acid was then no-moved in vacua and the residue was crystallized from - 28 ZZ~8~2 diisopropyl ether/petroleum ether Yield: 0.1 g;
m/e (after silylation) 500 sample 9 N-(lS-carboethoxy-3-~henvl~rc~ -S-alanyl-cis-4~5 7a-hexahYdro~lHlindole-~endo-carboxylic acid hydrochloride .
A solution of 0.6 g of tert.-butyl ester from Example 5 in 5 ml of ethylene chloride was saturated with dry hydrogen chloride gas and allowed to stand at - 10 20-25C for 16 hours. The solution was evaporated in Vacua. The residue was saturated with diisopropyl ether and filtered of with suction.
Yield 0.4 g H NOR data:
0.9 - 3.0 (m, 17H) 3.4 - 4.9 em, OH
5.2 - owe (m, OH) 7 2 (s, OH).
The hydrochloride can also be obtained by con-venting thetrifluoroace-tate from Example 8 with weakly basic ion exchangers (acetate form) to pi 4.0 and then t-eating with ethanolic hydrochloric acid and evapo-rating and triturating with diisopropyl ether.
Example 10 I N-(lS-carboxy-3-phenylpropyl)-S-alanyl-cis-2,3 3a,4,5,7a-hexahydro~lHlindole-2R,S-endo-carboxylicc act_ One equivalent of potassium hydroxide and a 10% excess of ON potassium hydroxide solution were added to a solution of 1 g of N-(lS-carboethoxy-3- -I
.
.-phenylpropyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydrooily]
~ndole-2R,S-endo-carboxylic acid in 10 ml ox water After Sterno at 20 to 25C or 8 hours, the reaction solution was adjusted to a pi of 4 with ON hydrochloric acid and evaporated in vacua. The residual was taken up in ethyl acetate and the precipitated salt was lit-toned off. The ethyl acetate solution was evaporated and the residue wastriturated~rith diisopropyl ether and filtered off with suction.
Yield: 0.5 g H NOR data-(after H/D exchange) - 1.5 (d, OH) 1.0 - 3.2 (my llH) 3 9 - 4.7 ~m,4H) 5.4 - owe (my OH) 7.2 (so OH) Example 11 N-(lS-carbox~-3-ph nylpropyl~-s-àlanyl-cis-2 acceder r lH1indole-~endo-carboxylic acid - this compound was prepared from the compound prom Example 8 in analogy to the process described in example 10.
lo NOR data:
1.5 (d, OH) 1.0 - 3.2 (m, OH) 3 9 - 4.7 (m, OH) 5.4 - 6.0 (m, OH) 7.2 (s, OH) -_ 30 ~22780Z
Example 12 N-(lS-carboetho~-3-~hen~rl~ro~ Sue anuses-2 aye 4,5 7a-hexahydro~lHlindole-2RIS=exo-carbox~l~c acid a) exo-carbox lakeside This compound was prepared prom ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole-2R,S-exo-ca~boxy late which is described in example lb, in analogy to the pro-cuss described in Example lo H NOR data: . .
- (aster Hold exchange) 1.6 - 2.5 (m, OH) 4.4 (s, lo) 4.8 (m, lo) 5.4 (m, lo) 5.8 (m, I
b) N-(lS-carboethoxy-3-phenylPropYl)-S-alanyl-Swiss 3 pa axe dro~ H¦indole-2R,S-exo-carboxylic acid This compound was prepared from the compound of Example aye and N-(lS-carboethoxy-3-phenylpropyl)-S-ala nine in analogy to the process described in Example id.
lo OR data:
(after H/D exchange) 1.0 - 1.5 (m, OH) -1.6 - 3.4 (m, 13H) 3.5 - I (m, OH) " `
\
5 2 6.0 (m, OH) 7.2 (s, OH).
zoom 13 N-(lS-carboethoxY-~-phenYlpropyl~-S-alan~ is-2 Lowe acceder r lHlindole-2S-e~o-carbox~lic acid This compound is obtained from the mixture ox diastereomers from Example 12b by column chromatography on silica gel, eluding with ethylene chloride/methanol I I 0 6).
- 10 lo NOR data:
(after H/D exchange) I.
1.0 - 1.5 (dot OH) 106 - 3.5 (m, 13H) ~~~
3.5 - 4.8 (m, OH) 5.3 - 6.0 (my OH) 7.2 (so OH).
Example 14 ~l~rt~-butyl Swiss aye 5 7a-hexahydroilHlindole-Jo : OR S-exo-carboxvlate This compound was prepared from the compound from Example aye in analogy to the process described in Example 4.
lo NOR data:
1~1 - 2.8 (m, OH) .
25 1.4 (So OH) I - 4.9 (m, OH) 5.8 (my 2X).
Example 15 '~er~.-but~l N-(lS-carboethoxy-3-phen~lpropyl?-, - 32 ~L.;2~78~2 S-alanyl-c's-2,3,3a,4,5,7a--hexah~o~lHlindole-2.S=eye carbonate This compolmd was prepared from the compound from Example 14 and M-(lS-carboethoxy-3-phenylpropyl)-S-alanine in analogy to the process described in Example I The mixture of diastereomers was separated on silica gel with ethyl acetate/cyclohexane 2:1.
~~S-exo-ter-t.-bu-tyl ester (Of: 0,5) ! 2-R-exo-ter-t.-butyl ester (Of: 0.4) Example 16 N-(lS-carboethoxy-~-phenyl~ro~vl~-S-alanyl-cis~
I I 5 . 7 acceder t lHlindole-2S_exo-carboxylic acid hydrochloride A solution of 0.8 g of tert.-butyl ester from lo Example 15 in 5 ml OX ethylene chloride was saturated with dry hydrogen chloride gas and allowed to stand at 20-25C for 16 hours. The solution was evaporated in vacua; the residue was triturated with diisopropyl ether and filtered off with suction.
Yield: 600 my H NOR data:
0.8 - 3.1 (m, 17H) 3.5 - 4.8 (m, OH) 5.3 6.0 (m, OH) 7.2 (s, OH).
- Example 17 -(lS-carboxy-3-Phenyl~ropyl~-S-alanv~
,~al4,5,7a-hexahydro~lHlindol~2S exo-carboxylic acid This compound was prepared prom the compound .
33~ ~2;:7~302 from Example 16 in analogy -to the process described in - Example 10.
H NOR data: .
1.5 (d, OH) 0.9 - I (m, llH) 3.9 - 4.8 (m, LO
5.2 - 5.9 (m, OH) - 7.2 (s, OH).
Example 18 N-~lS-carboxy-3-phenylpropyl)-S-alanyl-cis-2 3.
3a,4,5t7a-hexahydrorlHIindole-2R,S-exo-carboxylic acid .
This compound was prepared from the compound prom Example 12 in analogy to the process described in : Example 10.
î5 if IVY data:
1 5 (d! OH) 0.9 - 3.4 (m, llH) 3.8 - 4.8 (m, OH) 5.2 - owe (m, OH) 7.2 (s, I
: Example 19 . N-(lS-carboethox~-3-~henylpro~vl~ -S-alanyl-cis-aye 4,5 Za-hexahydro~lH~indole-~ndo-carboxYlic acid . This compound is identical with the compound described in Example 2.
a) Ethyl ester of S-allyl~lycine The preparation was carried out in the manner ..
as described in Monatshefte don Chemise 85, 1071 (1954) G
b) Ethyl ester ox N-benzoyl-N-(1,3-butadienyl)-, ' ' , , ` . .
Solely Gleason This compound was prepared in analogy to the process described in Example lay . H NOR data: .
1.1 - 1.4 (if, OH) 217 - 3.1 (m, OH) owe - 4.5 (m, OH) 4.8 - 6.8 (m, OH) ! 7.3 7.6 us, OH) c) Ethyl N-benzoYl~cis-2L3,3a 4 5 acceder ~lHlindole-~endo-carbo~late and ethyl N-benzo~l-cis-2,3 2 3a,4,5,7a-hexah~dro[lHlinfio~-~exo carboxylate This mixture of diastereomers was prepared from the compound from Example lob in analogy to the process described in example IBM The mixture was separated on silica gel using toluene/ethyi acetate 4:1. Of value of the end compound: 0.18; Of value of the ego compound- 0.26.
. H NOR data:
. 0.8 - 2 8 (m, lo) 3.8 - 4.8 (m, OH) 5.5 - 5.9 (broad s, OH) 7.4 us, OH) d) Swiss 3 3a,4,5,7a-hexah~drorlHlindo~ endow carbolic acid - This compound was prepared from the compo-md from Example l9c in analogy to the process described in Example to.
lo NOR data:
,. . :
.
~2;~:7 (D20 ) 1.1 - 2,9 (m, OH) 3.9 - 4.4 (m, I
5.5 - 6,4 (my OH) e) N-(lS-carboe-thoxY-~-~henylpro~y1)-S-al&ny Swiss acid This compo~md was prepared from the compound from Example lid and N-(lS-carboethoxy-3-phenylpropyl)-S-alanine in analogy to the process described in Example id.
lo NOR data (after H/D exchange) 1.0 - 2.9 (m, 17H) 3.0 - 4.6 (m, OH) 5.2 - 6.0 (m, OH) 7.2 (s, OH) sample 20 Tert,-butyl cis-213,3a,4L~,7a-hexahydrorlHiindole~
2S-endo-carbo~Ylate This compound was prepared from the compound from Example lid in analogy to the process described in Example 4.
H NOR data: .
1.4 (s, OH) 1.0 - 2.7 (m, OH) 3.2 - 4.9 (m, OH) ..
. 5.8 (d, OH).
Example 21 - I I I
Tert.-butyl N-(lS-carboethox~t-3-F)heny1pro~y S-a]anvl=cis-2,3,3a,4,5,7a-hexahydrorl~lindole~ endow ~carboxylate .
This compound was prepared prom the compound from Example 20 and N-(lS-carboethox~y-3-phenylpropyl)-S-alanine in analogy to -the process described in Example 5. .
H NOR data: . , .
, 1.4 (so I ' ' 10 ' 0.8 - 3.8 (m, 20H) Jo - 3.9 - 4.6 (m, OH) 5.4 - 6.0 (m, OH) 7.2 (s, OH) Example 22 -(iS-carboet}loxy-3-Phenylpropyl)-S-alanyl-cis-acceder r lHlindo~2~ exo-carbox~lic acid -- a) succeeder r Al indole-2S-exo-carboxylic acid This compound eras prepared from the ego compound from Example l9c in analogy to the process described in Example to.
(D20 ) - 1,0 - 2.8 (m, lo) 3.6 - 4.4 (m, OH) 5.5 - 6.4 (m, OH) b) N=(lS-carboethox~-3-phenYlpropYl)-s-alan cis~213,3a,4,5,7a-hexahydro[lHlindole-~exo-carboxyyolk .......
acid 37- ~2~80;~
. This compound was prepared from the compound from Example aye and N-(lS-carboethoxy-3-phenylproplJl)-S-alanine in analogy -to the process described in Example id.
lo OR data:
(after H/D exchange) 1.0 - 2.9 (m, 17H) 3.0 - 4.6 (m, OH) 5.2 - 6.0 (m, OH) !, .
7.2 (s, OH) '"
Example 23 . Tert.-butyl cis-2,3,3a~4,5t7a-hexahydro r lHlindole-2S-exo-carboxylate This compound was prepared from the compound fry Example aye in analogy 'owe eye process described in Example 4.
lo NOR data:
1.4 (s, OH) - Ox - 2.8 (m, OH) -3.3 - 4.9 (m, OH) 5.4 - 5.8 em, OH) Example 24 . .
Tert.-butyl N-(lS-carboethox~-3-phen~lpropyl)-S-alanyl-cis-2,3,3a,4L5,7a_hexah-~Jdro~lHlindole-_Sioux_ t, 25 carboxylate This camped was prepared from the compound from Example 23 and.. N-(lS-carboethoxy-3-phenylpropyl)-S-ala nine in analogy to -the process described on Example H NOR data:
1.3 (s, OH
0.9 - I (m, ZOO) 3.8 - 4.7 (m, OH) 5.4 - owe (m, OH) 702 (s, OH) Tert.-butyl N-(lS-carboetho~y~3-phenyl-3-oxopro-pyl)-S-alanyl-cis-213,3a,~_5,7a-hexahydro~lHlindolLucy-endo-car~ox~late 2.5 g of N-(lS-carboethoxy-3-phenyl-3-oxopropyl)-S-alanine, together with 1.2 g of l-hydroxybenzotria-Zulu g of tert.-butyl cis-2,3,3a,4,5,7a-hexahydro[lH]-indole-2S-~o-carboxylate and 2 g of dicyclohexylcarbo-doomed in 20 ml ox dimethylformamidc were stirred at0C`for 1 hour and then at 20-25C for 12 hours. The reaction solution was diluted with 25 ml of ethyl ace-late. The precipitated urea was filtered off with suction, After evaporation in vacua, the residue obtained was taken up in ether, the ethereal solution was washed with saturated aqueous sodium bicarbonate and with water, dried and evaporated.
Yield: 2.5 g lo NOR data:
1.2 (s, OH) 0.9 - 2.9 (m, 15H) 3.4 - 5,0 (m, OH) 5.2 - owe (m, OH) 7.2 - 8.2 (m, OH) .
_ 39 _ lo 2'7 Example 26 Tert.-butyl M-(lS-carbo.e-thoxy-3-~hen~l ~-ox~ro--S-alanvl-cis-2,3 pa 4,5 acceder Dallas-exo-carbocvlate -This compound was prepared from the compound from Example 23 and N-(lS-carboethoxy-3-phenyl-3-oxopro-pyl)-S-alanine in analogy to the process described in Example 25.
lo NOR data: .
- 1.3 (sty OH) 1.0 - 2.8 (my 15H) 3.3 - 4.9 (m, OH) 5.3 6.0 em, OH) - 7.2 - 8~2 (m, OH) Example 27 ' , `
N-(lS-carboethoxy-3-phenyl-3-oxo~roPyl~-S-alanyl Swiss, 7 aye 5 acceder r lHlindole ~-endo-carboxylic , acid trifluoroacetate 1~3 g off compound from Example 25 were stirred in 5 ml of trifluoroacetic acid at 20-25C for 2 hours. The solution was evaporated in awoke., and the residue was triturated with diisopropyl ether and filtered off with suction. - -Yield: 0.4 g lo NOR data: .
(after H/D exchange) 1.0 - 3.6 em, 15H) 3.9 - 4.6 (m, OH) 5.2 - 5.9 (m, OH) ' ;`~ - ' . - , 122~8C~
7.3 - 8.1 (m, I
Example 2 N-(lS-carboethox~ henyl-3-o,copro~l?-s-alan~
Swiss Jo 3a~4,_,7a-he~ahYdro~lHlindole_2S-exo-carboxylic acid hydrochloride 0.5 g of the compound from Example 26 was disk solved in 5 ml of ethylene chloride, the solution was saturated with hydrogen chloride gas and allowed to stand at 20-25C for 16 hours. It was evaporated in vacua and the residue triturated with diisopropyl ether and filtered off with suction.
Yield: 0.3 g lo NOR data:
- (after H/D exchange) 0.9 - 3.5 (m, 15H) 3.9 - 4.8 (m, OH) 5.3 - 6.0 (m, OH) 7.1 - I (m, OH
Example 29 -N-(lS-carboxy~-3-phenyl-3-oxopro~yl~-S-alanyl-cis-2,.3,3a,4,5,7a-hexahydro~lHli.ndolf~ endo-carboxylic acid Owe g of the compound from Example 27 were no-- acted with 2 equivalents of potassium hydroxide in I analogy to the procedure described in Example 10.
Yield: 0.25 g lo No data:
- (after H/D exchange) 1.1 - 3.6 (m, 12H) - -~2~7~80 _ 41 --3,7 - 4.6 (m, I
5.2 - 5.9 (I, OH) 7.1 - 8.0 (m, I
Example 30 N-~lS-carbo~_3-Phenyl-3-oxoProPyl~-S-alan~l-cis-2,3,3a,~5,7a-hexa~ydro Hlindol~exo-carboxylic __ acid 0.5 g of the compound from Example 28 were no-acted with 2 equivalents of potassium hydroxide in analogy to the procedure described in Example 10.
Yield: 0.3 g H NOR data (after H/D exchange) 1.0 - I (m, 12H) 3.6 - 4.8 (m, OH
5.2 - 5.9 (m, OH) - 7.2 - 8.0 (m, OH) Example 31 Tert.-butyl S-alanyl-cis-2 t acceder L1H~ndO1e~e~do-carboxylate a Tert.-butyl N-methylsulfonylet~y~oxycarbonyl (MSC)-S-alanvl-cis-2,~,3a,4~5,7a-hexahYdro~ indwells endo-carboxYlate .
- It was then neutralized with ON hydrochloric acid, the I- methanol was evaporated in vacua, the aqueous phase was extracted with ethyl acetate, and the ethyl acetate soul-. lion was washed with water, dried and evaporated, The oily residue was purified on silica gel;eluting with ethyl acetate.
0 3 g of tert.-butyl cis-2,3,3a,4,5,7a-hexahydro [lH~indole~2R~S-end~o-carboxylate was thus obtained as an oil.
H NOR data:
1.4 (s, OH), 1.0 - 2.7 (m, OH), 3.2 - 4.9 (m, OH), 5.8 (d, OH).
. . : , .
1227~30 Example 5 Te,rtA.-b~t~l N-~lS-,carboethoxv-~=phe Ylorooyl~-S-alan~_ri-_Z, .5,7a-hexahYdro~lH~lndole-2~s-end ____. . . ... ... .
carboxylate -0.28 g of N-(lS-carboethoxy-3-phenylpropyl)-S-ala nine was dissolved in 4 ml of dimethylformamide.
Then 0.15 g of hydroxybenzotriazole and 0.22 g of dice-clohexylcarbodiimide were added at room -temperature.
The mixture was stirred a-t room temperature for 4 hours.
- 10 Then 0.~4 g of tert.-butyl ester from Example 4 was added and the mixture was stirred at room temperature for 20 hours. It was diluted with ethyl acetate, the' urea eras filtered off with suction and the filtrate was evaporated in vacua. The residue was taken up in 15 ethyl acetate and the ethyl acetate solution was tasted with bicarbonate solution, dried and evaporated.
The oily residue (owe g) was separated into the die-strollers on silica gel, eluding with ethyl acetates-; . clohexane 2:1.
0.24 g of the tert.-butyl ester having the US-end configuration was obtained. I 0,45, Moe).
H No data:
' ' ' 1.4 (s, I
0.8 - 3,8 (m, 20H), I 4.6 (m, OH), 5.4 - owe (m, OH), 7.2 (s, OH).
Example 6 Ter,t,,-,butyl N-(lS-carboethoxy-3 phenylpro `` ~Z~7~
S-alanyl~cis-2,3,3a,4,5,7a-hexahydro~lHlindole-_P~eye-choirboy This ester was obtained on chromatography on silica gel as described in Example 5, of the mixture of diastereomers from Example 5. Ethyl acetate/cyclo-hexane was used to elude. Yield: 0.16 g (Of: 0.3;
m/e = 484).
Example 7 ! N-(lS-carboethox~-3-~henylpropyl~-S-alanyl-cis-- 10 acceder r lHlindole-2.~-endo-carbo,Yylic acid trifluoroacetate 0.16 g of the tert.-butyl ester obtained in Example 6 was dissolved in 1 ml of trifluoroacetic acid at 0C and the mixture was stirred at this temperature for 3 hours. The trifluoroacetic acid was evaporated ; off in vacua and the residue was crystallized from dip isopropyl ether. Yield of trifluoroacetate: 0.08 g of melting point: 120-121C. The trifluoroacetate can be converted into the amino acid using basic ion exchangers (OH form) in methanol/water 60:~0.
Example 8 N=~lS-carboethox~-3-phenylpro~yl~-S-aldnyl-cis-acceder r lH~indole-2S-endo-carboxylic awl_ trifluoroacetate 0.24 g of the tert.~butyl ester described in Example 5 was dissolved in 1.5 ml of trifluoroacetic acid at 0C and the mixture was stirred at this temperature for 5 Halsey. The trifluoroacetic acid was then no-moved in vacua and the residue was crystallized from - 28 ZZ~8~2 diisopropyl ether/petroleum ether Yield: 0.1 g;
m/e (after silylation) 500 sample 9 N-(lS-carboethoxy-3-~henvl~rc~ -S-alanyl-cis-4~5 7a-hexahYdro~lHlindole-~endo-carboxylic acid hydrochloride .
A solution of 0.6 g of tert.-butyl ester from Example 5 in 5 ml of ethylene chloride was saturated with dry hydrogen chloride gas and allowed to stand at - 10 20-25C for 16 hours. The solution was evaporated in Vacua. The residue was saturated with diisopropyl ether and filtered of with suction.
Yield 0.4 g H NOR data:
0.9 - 3.0 (m, 17H) 3.4 - 4.9 em, OH
5.2 - owe (m, OH) 7 2 (s, OH).
The hydrochloride can also be obtained by con-venting thetrifluoroace-tate from Example 8 with weakly basic ion exchangers (acetate form) to pi 4.0 and then t-eating with ethanolic hydrochloric acid and evapo-rating and triturating with diisopropyl ether.
Example 10 I N-(lS-carboxy-3-phenylpropyl)-S-alanyl-cis-2,3 3a,4,5,7a-hexahydro~lHlindole-2R,S-endo-carboxylicc act_ One equivalent of potassium hydroxide and a 10% excess of ON potassium hydroxide solution were added to a solution of 1 g of N-(lS-carboethoxy-3- -I
.
.-phenylpropyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydrooily]
~ndole-2R,S-endo-carboxylic acid in 10 ml ox water After Sterno at 20 to 25C or 8 hours, the reaction solution was adjusted to a pi of 4 with ON hydrochloric acid and evaporated in vacua. The residual was taken up in ethyl acetate and the precipitated salt was lit-toned off. The ethyl acetate solution was evaporated and the residue wastriturated~rith diisopropyl ether and filtered off with suction.
Yield: 0.5 g H NOR data-(after H/D exchange) - 1.5 (d, OH) 1.0 - 3.2 (my llH) 3 9 - 4.7 ~m,4H) 5.4 - owe (my OH) 7.2 (so OH) Example 11 N-(lS-carbox~-3-ph nylpropyl~-s-àlanyl-cis-2 acceder r lH1indole-~endo-carboxylic acid - this compound was prepared from the compound prom Example 8 in analogy to the process described in example 10.
lo NOR data:
1.5 (d, OH) 1.0 - 3.2 (m, OH) 3 9 - 4.7 (m, OH) 5.4 - 6.0 (m, OH) 7.2 (s, OH) -_ 30 ~22780Z
Example 12 N-(lS-carboetho~-3-~hen~rl~ro~ Sue anuses-2 aye 4,5 7a-hexahydro~lHlindole-2RIS=exo-carbox~l~c acid a) exo-carbox lakeside This compound was prepared prom ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole-2R,S-exo-ca~boxy late which is described in example lb, in analogy to the pro-cuss described in Example lo H NOR data: . .
- (aster Hold exchange) 1.6 - 2.5 (m, OH) 4.4 (s, lo) 4.8 (m, lo) 5.4 (m, lo) 5.8 (m, I
b) N-(lS-carboethoxy-3-phenylPropYl)-S-alanyl-Swiss 3 pa axe dro~ H¦indole-2R,S-exo-carboxylic acid This compound was prepared from the compound of Example aye and N-(lS-carboethoxy-3-phenylpropyl)-S-ala nine in analogy to the process described in Example id.
lo OR data:
(after H/D exchange) 1.0 - 1.5 (m, OH) -1.6 - 3.4 (m, 13H) 3.5 - I (m, OH) " `
\
5 2 6.0 (m, OH) 7.2 (s, OH).
zoom 13 N-(lS-carboethoxY-~-phenYlpropyl~-S-alan~ is-2 Lowe acceder r lHlindole-2S-e~o-carbox~lic acid This compound is obtained from the mixture ox diastereomers from Example 12b by column chromatography on silica gel, eluding with ethylene chloride/methanol I I 0 6).
- 10 lo NOR data:
(after H/D exchange) I.
1.0 - 1.5 (dot OH) 106 - 3.5 (m, 13H) ~~~
3.5 - 4.8 (m, OH) 5.3 - 6.0 (my OH) 7.2 (so OH).
Example 14 ~l~rt~-butyl Swiss aye 5 7a-hexahydroilHlindole-Jo : OR S-exo-carboxvlate This compound was prepared from the compound from Example aye in analogy to the process described in Example 4.
lo NOR data:
1~1 - 2.8 (m, OH) .
25 1.4 (So OH) I - 4.9 (m, OH) 5.8 (my 2X).
Example 15 '~er~.-but~l N-(lS-carboethoxy-3-phen~lpropyl?-, - 32 ~L.;2~78~2 S-alanyl-c's-2,3,3a,4,5,7a--hexah~o~lHlindole-2.S=eye carbonate This compolmd was prepared from the compound from Example 14 and M-(lS-carboethoxy-3-phenylpropyl)-S-alanine in analogy to the process described in Example I The mixture of diastereomers was separated on silica gel with ethyl acetate/cyclohexane 2:1.
~~S-exo-ter-t.-bu-tyl ester (Of: 0,5) ! 2-R-exo-ter-t.-butyl ester (Of: 0.4) Example 16 N-(lS-carboethoxy-~-phenyl~ro~vl~-S-alanyl-cis~
I I 5 . 7 acceder t lHlindole-2S_exo-carboxylic acid hydrochloride A solution of 0.8 g of tert.-butyl ester from lo Example 15 in 5 ml OX ethylene chloride was saturated with dry hydrogen chloride gas and allowed to stand at 20-25C for 16 hours. The solution was evaporated in vacua; the residue was triturated with diisopropyl ether and filtered off with suction.
Yield: 600 my H NOR data:
0.8 - 3.1 (m, 17H) 3.5 - 4.8 (m, OH) 5.3 6.0 (m, OH) 7.2 (s, OH).
- Example 17 -(lS-carboxy-3-Phenyl~ropyl~-S-alanv~
,~al4,5,7a-hexahydro~lHlindol~2S exo-carboxylic acid This compound was prepared prom the compound .
33~ ~2;:7~302 from Example 16 in analogy -to the process described in - Example 10.
H NOR data: .
1.5 (d, OH) 0.9 - I (m, llH) 3.9 - 4.8 (m, LO
5.2 - 5.9 (m, OH) - 7.2 (s, OH).
Example 18 N-~lS-carboxy-3-phenylpropyl)-S-alanyl-cis-2 3.
3a,4,5t7a-hexahydrorlHIindole-2R,S-exo-carboxylic acid .
This compound was prepared from the compound prom Example 12 in analogy to the process described in : Example 10.
î5 if IVY data:
1 5 (d! OH) 0.9 - 3.4 (m, llH) 3.8 - 4.8 (m, OH) 5.2 - owe (m, OH) 7.2 (s, I
: Example 19 . N-(lS-carboethox~-3-~henylpro~vl~ -S-alanyl-cis-aye 4,5 Za-hexahydro~lH~indole-~ndo-carboxYlic acid . This compound is identical with the compound described in Example 2.
a) Ethyl ester of S-allyl~lycine The preparation was carried out in the manner ..
as described in Monatshefte don Chemise 85, 1071 (1954) G
b) Ethyl ester ox N-benzoyl-N-(1,3-butadienyl)-, ' ' , , ` . .
Solely Gleason This compound was prepared in analogy to the process described in Example lay . H NOR data: .
1.1 - 1.4 (if, OH) 217 - 3.1 (m, OH) owe - 4.5 (m, OH) 4.8 - 6.8 (m, OH) ! 7.3 7.6 us, OH) c) Ethyl N-benzoYl~cis-2L3,3a 4 5 acceder ~lHlindole-~endo-carbo~late and ethyl N-benzo~l-cis-2,3 2 3a,4,5,7a-hexah~dro[lHlinfio~-~exo carboxylate This mixture of diastereomers was prepared from the compound from Example lob in analogy to the process described in example IBM The mixture was separated on silica gel using toluene/ethyi acetate 4:1. Of value of the end compound: 0.18; Of value of the ego compound- 0.26.
. H NOR data:
. 0.8 - 2 8 (m, lo) 3.8 - 4.8 (m, OH) 5.5 - 5.9 (broad s, OH) 7.4 us, OH) d) Swiss 3 3a,4,5,7a-hexah~drorlHlindo~ endow carbolic acid - This compound was prepared from the compo-md from Example l9c in analogy to the process described in Example to.
lo NOR data:
,. . :
.
~2;~:7 (D20 ) 1.1 - 2,9 (m, OH) 3.9 - 4.4 (m, I
5.5 - 6,4 (my OH) e) N-(lS-carboe-thoxY-~-~henylpro~y1)-S-al&ny Swiss acid This compo~md was prepared from the compound from Example lid and N-(lS-carboethoxy-3-phenylpropyl)-S-alanine in analogy to the process described in Example id.
lo NOR data (after H/D exchange) 1.0 - 2.9 (m, 17H) 3.0 - 4.6 (m, OH) 5.2 - 6.0 (m, OH) 7.2 (s, OH) sample 20 Tert,-butyl cis-213,3a,4L~,7a-hexahydrorlHiindole~
2S-endo-carbo~Ylate This compound was prepared from the compound from Example lid in analogy to the process described in Example 4.
H NOR data: .
1.4 (s, OH) 1.0 - 2.7 (m, OH) 3.2 - 4.9 (m, OH) ..
. 5.8 (d, OH).
Example 21 - I I I
Tert.-butyl N-(lS-carboethox~t-3-F)heny1pro~y S-a]anvl=cis-2,3,3a,4,5,7a-hexahydrorl~lindole~ endow ~carboxylate .
This compound was prepared prom the compound from Example 20 and N-(lS-carboethox~y-3-phenylpropyl)-S-alanine in analogy to -the process described in Example 5. .
H NOR data: . , .
, 1.4 (so I ' ' 10 ' 0.8 - 3.8 (m, 20H) Jo - 3.9 - 4.6 (m, OH) 5.4 - 6.0 (m, OH) 7.2 (s, OH) Example 22 -(iS-carboet}loxy-3-Phenylpropyl)-S-alanyl-cis-acceder r lHlindo~2~ exo-carbox~lic acid -- a) succeeder r Al indole-2S-exo-carboxylic acid This compound eras prepared from the ego compound from Example l9c in analogy to the process described in Example to.
(D20 ) - 1,0 - 2.8 (m, lo) 3.6 - 4.4 (m, OH) 5.5 - 6.4 (m, OH) b) N=(lS-carboethox~-3-phenYlpropYl)-s-alan cis~213,3a,4,5,7a-hexahydro[lHlindole-~exo-carboxyyolk .......
acid 37- ~2~80;~
. This compound was prepared from the compound from Example aye and N-(lS-carboethoxy-3-phenylproplJl)-S-alanine in analogy -to the process described in Example id.
lo OR data:
(after H/D exchange) 1.0 - 2.9 (m, 17H) 3.0 - 4.6 (m, OH) 5.2 - 6.0 (m, OH) !, .
7.2 (s, OH) '"
Example 23 . Tert.-butyl cis-2,3,3a~4,5t7a-hexahydro r lHlindole-2S-exo-carboxylate This compound was prepared from the compound fry Example aye in analogy 'owe eye process described in Example 4.
lo NOR data:
1.4 (s, OH) - Ox - 2.8 (m, OH) -3.3 - 4.9 (m, OH) 5.4 - 5.8 em, OH) Example 24 . .
Tert.-butyl N-(lS-carboethox~-3-phen~lpropyl)-S-alanyl-cis-2,3,3a,4L5,7a_hexah-~Jdro~lHlindole-_Sioux_ t, 25 carboxylate This camped was prepared from the compound from Example 23 and.. N-(lS-carboethoxy-3-phenylpropyl)-S-ala nine in analogy to -the process described on Example H NOR data:
1.3 (s, OH
0.9 - I (m, ZOO) 3.8 - 4.7 (m, OH) 5.4 - owe (m, OH) 702 (s, OH) Tert.-butyl N-(lS-carboetho~y~3-phenyl-3-oxopro-pyl)-S-alanyl-cis-213,3a,~_5,7a-hexahydro~lHlindolLucy-endo-car~ox~late 2.5 g of N-(lS-carboethoxy-3-phenyl-3-oxopropyl)-S-alanine, together with 1.2 g of l-hydroxybenzotria-Zulu g of tert.-butyl cis-2,3,3a,4,5,7a-hexahydro[lH]-indole-2S-~o-carboxylate and 2 g of dicyclohexylcarbo-doomed in 20 ml ox dimethylformamidc were stirred at0C`for 1 hour and then at 20-25C for 12 hours. The reaction solution was diluted with 25 ml of ethyl ace-late. The precipitated urea was filtered off with suction, After evaporation in vacua, the residue obtained was taken up in ether, the ethereal solution was washed with saturated aqueous sodium bicarbonate and with water, dried and evaporated.
Yield: 2.5 g lo NOR data:
1.2 (s, OH) 0.9 - 2.9 (m, 15H) 3.4 - 5,0 (m, OH) 5.2 - owe (m, OH) 7.2 - 8.2 (m, OH) .
_ 39 _ lo 2'7 Example 26 Tert.-butyl M-(lS-carbo.e-thoxy-3-~hen~l ~-ox~ro--S-alanvl-cis-2,3 pa 4,5 acceder Dallas-exo-carbocvlate -This compound was prepared from the compound from Example 23 and N-(lS-carboethoxy-3-phenyl-3-oxopro-pyl)-S-alanine in analogy to the process described in Example 25.
lo NOR data: .
- 1.3 (sty OH) 1.0 - 2.8 (my 15H) 3.3 - 4.9 (m, OH) 5.3 6.0 em, OH) - 7.2 - 8~2 (m, OH) Example 27 ' , `
N-(lS-carboethoxy-3-phenyl-3-oxo~roPyl~-S-alanyl Swiss, 7 aye 5 acceder r lHlindole ~-endo-carboxylic , acid trifluoroacetate 1~3 g off compound from Example 25 were stirred in 5 ml of trifluoroacetic acid at 20-25C for 2 hours. The solution was evaporated in awoke., and the residue was triturated with diisopropyl ether and filtered off with suction. - -Yield: 0.4 g lo NOR data: .
(after H/D exchange) 1.0 - 3.6 em, 15H) 3.9 - 4.6 (m, OH) 5.2 - 5.9 (m, OH) ' ;`~ - ' . - , 122~8C~
7.3 - 8.1 (m, I
Example 2 N-(lS-carboethox~ henyl-3-o,copro~l?-s-alan~
Swiss Jo 3a~4,_,7a-he~ahYdro~lHlindole_2S-exo-carboxylic acid hydrochloride 0.5 g of the compound from Example 26 was disk solved in 5 ml of ethylene chloride, the solution was saturated with hydrogen chloride gas and allowed to stand at 20-25C for 16 hours. It was evaporated in vacua and the residue triturated with diisopropyl ether and filtered off with suction.
Yield: 0.3 g lo NOR data:
- (after H/D exchange) 0.9 - 3.5 (m, 15H) 3.9 - 4.8 (m, OH) 5.3 - 6.0 (m, OH) 7.1 - I (m, OH
Example 29 -N-(lS-carboxy~-3-phenyl-3-oxopro~yl~-S-alanyl-cis-2,.3,3a,4,5,7a-hexahydro~lHli.ndolf~ endo-carboxylic acid Owe g of the compound from Example 27 were no-- acted with 2 equivalents of potassium hydroxide in I analogy to the procedure described in Example 10.
Yield: 0.25 g lo No data:
- (after H/D exchange) 1.1 - 3.6 (m, 12H) - -~2~7~80 _ 41 --3,7 - 4.6 (m, I
5.2 - 5.9 (I, OH) 7.1 - 8.0 (m, I
Example 30 N-~lS-carbo~_3-Phenyl-3-oxoProPyl~-S-alan~l-cis-2,3,3a,~5,7a-hexa~ydro Hlindol~exo-carboxylic __ acid 0.5 g of the compound from Example 28 were no-acted with 2 equivalents of potassium hydroxide in analogy to the procedure described in Example 10.
Yield: 0.3 g H NOR data (after H/D exchange) 1.0 - I (m, 12H) 3.6 - 4.8 (m, OH
5.2 - 5.9 (m, OH) - 7.2 - 8.0 (m, OH) Example 31 Tert.-butyl S-alanyl-cis-2 t acceder L1H~ndO1e~e~do-carboxylate a Tert.-butyl N-methylsulfonylet~y~oxycarbonyl (MSC)-S-alanvl-cis-2,~,3a,4~5,7a-hexahYdro~ indwells endo-carboxYlate .
6.7 g of l-hydroxybenzotriazole Andy g of tert.-butyl cis-2,3,3a,4,5,7a-hexahydro[lH]indole-ZS-endo-carboxylate were added to a solution of 10 g of MSC-ala-OH in 50 ml of dimethylformamide. The pi was adjusted to 8.0 with N-ethylmorpholine. The mixture was cooled in an ice bath and 10~5 g of , - ' :,~
.
12~780 -- I --dicyclohexylcarbodiimide were added. The mixture was stirred at 20-25C for 15 hours. The precipitated urea was filtered off with suction, two filtrate was evaporated in vacua and taken up in ethyl acetate.
The organic phase was washed consecutively loath poles-slum bisulfate, potassium bicarbonate and sodium Shelley-ride solution dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate/
cyclohexane 1:1.
yield: 10 g H NOR data:
I (s, OH) 1 3 (d, OH) 1 1 - 2.6 (m, OH) 3.0 (s, OH) 3.2 - 3.5 (m, OH) - 3.5 - 4.9 (m, OH) 5.6 - 5.9 (m, OH) b) Turtle S-alanyl-cis-2,3,3a,4~5~7a-hexa-hydra r lHlindole-2~ondo-carboxylate 2.0 g of the compound from Example aye were dissolved in 15 ml of methanol and 1.5 ml of water The pi was adjusted to 13 with ON sodium hydroxide soul--lion and the mixture was stirred at room temperature or 2 hours. It was then neutralized with ON hydra-caloric acid, the methanol was evaporated off in vacua and the aqueous phase was extracted with ethyl acetate, the ethyl acetate solution was washed with water, dried and evaporated. The residue was filtered through .
~ZZ780;~:
. . . . .
silica gel, elu-tiIlg with ethyl acetate.
yield: 0,8 g lo NOR data: ' 1,4 (s, OH) 1.3 (d, OH) 1.0 - 2,4 (m, OH) 3.5 - 4,8 (I, OH) 5,5 5,9 (m, OH) Example 32 Tert.-butyl S-alanvl-cis-223,3a,4,5,7a-hexahydro rlHlindo~-~exo-car-~boxylate This compound was prepared from the compound from Example 23 in analogy to the process described in Example 31, H NOR data:
- 1~2 (d, OH) - 1.4 (s, OH) 0.9 - 2,3 (my OH) 3.4 - 4,7 (m, OH) I - 5.9 (m, I
Example 33 Tert,-butyl N-(lS-carboethoxy-3-oxo-3-phenyl~ro~yl~-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro ~Hlindole-2S-endo-carboxylate 5 moles of the compound from Example 31b, to-getter with 5 moles of ethyl 3-ben70ylacrylate and 5 drops ox triethylamine, were dissolved in 50 ml of - anhydrousethanol andthemixture was stirred at 20-25C
for 24 hours. It was evaporated to dryness and the 27~3C3%
residue was taken up in ethyl acetate. It was then wished with water, dried and evaporated.
The mixture of diastereomers was chromatographed on silica gel, eluding with ethyl acetate/cyclohexane.
The lo NOR data agree with the data of the compound from Example 25.
-. xampl e Lo Tert.-butyl N-(lS-carboethoxy-~-oxo-~-Phenylpro=
pyl)=S-al~nyl-cis-2~3~at4~5~7a=hexa~dro[lHlindole~US
exo-carboxylate This compo~md alas prepared from the compound from Example I with ethyl benzoylacrylate in analogy to - -the process described in Example 33.
Example 35 Tort -bottle N-(lS-carboethoxy-3-phenylprop-yl)-S-alanYl=cis~ 3a,4,5,7a-hexahYdro~lHlindole-2S-endo-carbonate 5 moles ox tert.-butyl S-alanyl-cis-2,3,3a,4,5, 7a-hexahydro[lH]indole-~endo-carboxylate were disk solved in 15 ml of an hydrous ethanol The pi of the solution was adjusted to 7 0 with ethanolic potassium hydroxide, and 0.7 g of powdered molecular sieves I
and then 5 moles of ethyl 2-keto-4-phenylbutyra-te were added. A solution of 0.6 g of sodium cinnabar-drive in 6 ml of an hydrous ethanol was slowly addeddropwise. After a reaction time of 20 hours at 20 to 25C, the solution was filtered and the solvent was distilled off. The residue was taken up in ethyl ; acetate/water. After evaporation of the ethyl sty -- 1~5 --: acetate phases, the residue was chromatographed on silica gel with ethyl acetate/cyclohexane 1:4.
The lo NOR data agree with the data ox the come pound from Example 21.
5 . Example 36 ~rt,-butYl N-(lS-carboetho.Yy-~-~hen~ ripples-alanyl=cis-2,3,3a,4,517a-hexahydrorlHlindole-2S-e,okra-boxy late This compound was prepared from the compound from Example 32 and ethyl 2-keto-4-phenylbutyrate in analogy to the process described in Example 35.
The H NOR data agree with the data of the come pound from Example 24.
Example 37 Tert.-but~ -(lS-carboethoxy-~-oxo-3=ph~ o-pyl)-S-alanyl-cis-2,3,3a,4t5,7a-hexahYdro~lHlindolLucy-endo-carboxylate 10 moles of acetophenone, 10 moles ofethyl.~ly-oxylate and 10 moles oftert.-butyl S-alanyl-cis-2,3,3a, 4,5,7a-hexahydro[lH~indole- endo-carboxyiate in 30 ml of glacial acetic acid were heated at 45C for 36 hours.
After evaporation in vacua, the residue was neutralized with sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate phase wisp-rated and chromatographed on silica gel, eluding with - ethyl acetate/cyclohexane 1:1.
The H NOR data agree with the data of the come .. pound from Example 25.
. . .
-` Z27 Example 38 Tert.-butvl N-(lS-carboetho~y--3-o~o yo-yo=
alanvl~cis-2 3 pa AL 5 acceder indwells--? . 1 . . 1__. _ _ exo-carboxylate This compound was prepared from the compound from example 32 and ethyl glyoxylate and acetophenone in analogy to the process described in Example 37 The lo NOR data agree with the data owe the come pound from Example 24. .
Example 39 N-(lS-carboethoxy-~R,S-hvdroxy__~-phen~lprop~l)-S-alanyl-cis~ Lyle 7a-hexahydrorlHJindole-2S-endo-carbox~lic_acid -- 0.5 g of N-(lS-carboethoxy-3-oxo-3-phenylpropyl)-15 S-alanyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole-2S--end-.carboxylic acid were dissolved in 5 ml ox aqueous ethanol, and 0.1 g of sodium bordered was added.
The mixture was stirred at room temperature for 14 hours.
Then ethyl acetate was added, and the ethyl acetate 20 solution was washed with water, dried and evaporated.
The crude product was filterer through silica jollily-tying with ethyl acetatelmethanol 9:1.
Yield: 0.3 g - lo IMMURE data:
(after H/D exchange) 1.0 - 3 5 (m, 15H) 3.8 - 4.8 (m, OH) 5.3 - 5.8 (m, OH)
.
12~780 -- I --dicyclohexylcarbodiimide were added. The mixture was stirred at 20-25C for 15 hours. The precipitated urea was filtered off with suction, two filtrate was evaporated in vacua and taken up in ethyl acetate.
The organic phase was washed consecutively loath poles-slum bisulfate, potassium bicarbonate and sodium Shelley-ride solution dried and evaporated. The residue was chromatographed on silica gel with ethyl acetate/
cyclohexane 1:1.
yield: 10 g H NOR data:
I (s, OH) 1 3 (d, OH) 1 1 - 2.6 (m, OH) 3.0 (s, OH) 3.2 - 3.5 (m, OH) - 3.5 - 4.9 (m, OH) 5.6 - 5.9 (m, OH) b) Turtle S-alanyl-cis-2,3,3a,4~5~7a-hexa-hydra r lHlindole-2~ondo-carboxylate 2.0 g of the compound from Example aye were dissolved in 15 ml of methanol and 1.5 ml of water The pi was adjusted to 13 with ON sodium hydroxide soul--lion and the mixture was stirred at room temperature or 2 hours. It was then neutralized with ON hydra-caloric acid, the methanol was evaporated off in vacua and the aqueous phase was extracted with ethyl acetate, the ethyl acetate solution was washed with water, dried and evaporated. The residue was filtered through .
~ZZ780;~:
. . . . .
silica gel, elu-tiIlg with ethyl acetate.
yield: 0,8 g lo NOR data: ' 1,4 (s, OH) 1.3 (d, OH) 1.0 - 2,4 (m, OH) 3.5 - 4,8 (I, OH) 5,5 5,9 (m, OH) Example 32 Tert.-butyl S-alanvl-cis-223,3a,4,5,7a-hexahydro rlHlindo~-~exo-car-~boxylate This compound was prepared from the compound from Example 23 in analogy to the process described in Example 31, H NOR data:
- 1~2 (d, OH) - 1.4 (s, OH) 0.9 - 2,3 (my OH) 3.4 - 4,7 (m, OH) I - 5.9 (m, I
Example 33 Tert,-butyl N-(lS-carboethoxy-3-oxo-3-phenyl~ro~yl~-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro ~Hlindole-2S-endo-carboxylate 5 moles of the compound from Example 31b, to-getter with 5 moles of ethyl 3-ben70ylacrylate and 5 drops ox triethylamine, were dissolved in 50 ml of - anhydrousethanol andthemixture was stirred at 20-25C
for 24 hours. It was evaporated to dryness and the 27~3C3%
residue was taken up in ethyl acetate. It was then wished with water, dried and evaporated.
The mixture of diastereomers was chromatographed on silica gel, eluding with ethyl acetate/cyclohexane.
The lo NOR data agree with the data of the compound from Example 25.
-. xampl e Lo Tert.-butyl N-(lS-carboethoxy-~-oxo-~-Phenylpro=
pyl)=S-al~nyl-cis-2~3~at4~5~7a=hexa~dro[lHlindole~US
exo-carboxylate This compo~md alas prepared from the compound from Example I with ethyl benzoylacrylate in analogy to - -the process described in Example 33.
Example 35 Tort -bottle N-(lS-carboethoxy-3-phenylprop-yl)-S-alanYl=cis~ 3a,4,5,7a-hexahYdro~lHlindole-2S-endo-carbonate 5 moles ox tert.-butyl S-alanyl-cis-2,3,3a,4,5, 7a-hexahydro[lH]indole-~endo-carboxylate were disk solved in 15 ml of an hydrous ethanol The pi of the solution was adjusted to 7 0 with ethanolic potassium hydroxide, and 0.7 g of powdered molecular sieves I
and then 5 moles of ethyl 2-keto-4-phenylbutyra-te were added. A solution of 0.6 g of sodium cinnabar-drive in 6 ml of an hydrous ethanol was slowly addeddropwise. After a reaction time of 20 hours at 20 to 25C, the solution was filtered and the solvent was distilled off. The residue was taken up in ethyl ; acetate/water. After evaporation of the ethyl sty -- 1~5 --: acetate phases, the residue was chromatographed on silica gel with ethyl acetate/cyclohexane 1:4.
The lo NOR data agree with the data ox the come pound from Example 21.
5 . Example 36 ~rt,-butYl N-(lS-carboetho.Yy-~-~hen~ ripples-alanyl=cis-2,3,3a,4,517a-hexahydrorlHlindole-2S-e,okra-boxy late This compound was prepared from the compound from Example 32 and ethyl 2-keto-4-phenylbutyrate in analogy to the process described in Example 35.
The H NOR data agree with the data of the come pound from Example 24.
Example 37 Tert.-but~ -(lS-carboethoxy-~-oxo-3=ph~ o-pyl)-S-alanyl-cis-2,3,3a,4t5,7a-hexahYdro~lHlindolLucy-endo-carboxylate 10 moles of acetophenone, 10 moles ofethyl.~ly-oxylate and 10 moles oftert.-butyl S-alanyl-cis-2,3,3a, 4,5,7a-hexahydro[lH~indole- endo-carboxyiate in 30 ml of glacial acetic acid were heated at 45C for 36 hours.
After evaporation in vacua, the residue was neutralized with sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate phase wisp-rated and chromatographed on silica gel, eluding with - ethyl acetate/cyclohexane 1:1.
The H NOR data agree with the data of the come .. pound from Example 25.
. . .
-` Z27 Example 38 Tert.-butvl N-(lS-carboetho~y--3-o~o yo-yo=
alanvl~cis-2 3 pa AL 5 acceder indwells--? . 1 . . 1__. _ _ exo-carboxylate This compound was prepared from the compound from example 32 and ethyl glyoxylate and acetophenone in analogy to the process described in Example 37 The lo NOR data agree with the data owe the come pound from Example 24. .
Example 39 N-(lS-carboethoxy-~R,S-hvdroxy__~-phen~lprop~l)-S-alanyl-cis~ Lyle 7a-hexahydrorlHJindole-2S-endo-carbox~lic_acid -- 0.5 g of N-(lS-carboethoxy-3-oxo-3-phenylpropyl)-15 S-alanyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole-2S--end-.carboxylic acid were dissolved in 5 ml ox aqueous ethanol, and 0.1 g of sodium bordered was added.
The mixture was stirred at room temperature for 14 hours.
Then ethyl acetate was added, and the ethyl acetate 20 solution was washed with water, dried and evaporated.
The crude product was filterer through silica jollily-tying with ethyl acetatelmethanol 9:1.
Yield: 0.3 g - lo IMMURE data:
(after H/D exchange) 1.0 - 3 5 (m, 15H) 3.8 - 4.8 (m, OH) 5.3 - 5.8 (m, OH)
7 2 (s, OH) - ' . '' .
~L22~80'~
Example 40 .
N-(lS=carboetho,cv-,~R,S-hvdrox,,v-3-~hen~
S-alanyl-cis-2,3,3a,4,5,7a-hexah~d-ro ndole-2$-exo-. __ v .
carboxylic acid 0.5 g of ~-(lS-carboethoxy-3-oxophenylpropyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole~2S--ego-carboxylic acid were reacted with 0.1 g of sodium boron hydrides in analogy to the process described in Example 39. , ;"
Yield: 0,2 g H NOR data Atari H/D exchange) 0.9 - 3.4 (m, 15H) 3.7 - 4.9 (m, OH) 5.2'- 5.9 (m, OH) 7.2 (s, OH) ' ' ' .
~L22~80'~
Example 40 .
N-(lS=carboetho,cv-,~R,S-hvdrox,,v-3-~hen~
S-alanyl-cis-2,3,3a,4,5,7a-hexah~d-ro ndole-2$-exo-. __ v .
carboxylic acid 0.5 g of ~-(lS-carboethoxy-3-oxophenylpropyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro[lH]indole~2S--ego-carboxylic acid were reacted with 0.1 g of sodium boron hydrides in analogy to the process described in Example 39. , ;"
Yield: 0,2 g H NOR data Atari H/D exchange) 0.9 - 3.4 (m, 15H) 3.7 - 4.9 (m, OH) 5.2'- 5.9 (m, OH) 7.2 (s, OH) ' ' ' .
Claims (2)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula III
III
in which the H atoms on the C atoms 3a and 7a have the cis configuration relative to one another and the group -CO2W on the C atom 2 is oriented exo or endo to the bicyclic ring system and wherein W denotes hydrogen or a radical which can be split off by acid, which comprises a cyclizing compound of the formula X, X
in which R2' denotes (C1 to C6)-alkyl or (C7 to C8)-aralkyl and R3 represents (C1 to C6)-alkyl, (C5 to C9)-cycloalkyl, (C2 to C6)-alkenyl, (C1 to C6)-alkoxy, aryl, aryloxy, aryl-(C1 to C4)-alkyl or aryl-(C1 to C4)-alkoxy.
to give a mixture of stereoisomeric compounds of the formula XI
XI
in which R2' and R3 have the foregoing meanings and the hydrogen atoms on the bridgehead C atoms have the cis configuration, hydrolizing this mixture of stereoisomers, in which pairs of diastereomers are present, of the formulae XIb and d or XIa and c, or mixtures of the formulae XIa-d, respectively XIa XIb XIc XId in which R2' and R3 each have the foregoing meaning, hydrolizing, if appropriate, after previous separation into enantiomers, pairs of diastereomers or racemates, to give a compound of the formula III in which W represents hydrogen and if appropriate, esterifying the latter to give a compound of the formula III in which W represents a radical which can be split off by acid.
III
in which the H atoms on the C atoms 3a and 7a have the cis configuration relative to one another and the group -CO2W on the C atom 2 is oriented exo or endo to the bicyclic ring system and wherein W denotes hydrogen or a radical which can be split off by acid, which comprises a cyclizing compound of the formula X, X
in which R2' denotes (C1 to C6)-alkyl or (C7 to C8)-aralkyl and R3 represents (C1 to C6)-alkyl, (C5 to C9)-cycloalkyl, (C2 to C6)-alkenyl, (C1 to C6)-alkoxy, aryl, aryloxy, aryl-(C1 to C4)-alkyl or aryl-(C1 to C4)-alkoxy.
to give a mixture of stereoisomeric compounds of the formula XI
XI
in which R2' and R3 have the foregoing meanings and the hydrogen atoms on the bridgehead C atoms have the cis configuration, hydrolizing this mixture of stereoisomers, in which pairs of diastereomers are present, of the formulae XIb and d or XIa and c, or mixtures of the formulae XIa-d, respectively XIa XIb XIc XId in which R2' and R3 each have the foregoing meaning, hydrolizing, if appropriate, after previous separation into enantiomers, pairs of diastereomers or racemates, to give a compound of the formula III in which W represents hydrogen and if appropriate, esterifying the latter to give a compound of the formula III in which W represents a radical which can be split off by acid.
2. A compound of the formula III
III
in which the H atoms on the C atoms 3a and 7a have the cis configuration relative to one another and the group -CO2W on the C atom 2 is oriented exo or endo to the bicyclic ring system and wherein W denotes hydrogen or a radical which can be split off by acid, whenever prepared according to the process as claimed in claim 1, or by an obvious chemical equivalent thereof.
III
in which the H atoms on the C atoms 3a and 7a have the cis configuration relative to one another and the group -CO2W on the C atom 2 is oriented exo or endo to the bicyclic ring system and wherein W denotes hydrogen or a radical which can be split off by acid, whenever prepared according to the process as claimed in claim 1, or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000516572A CA1227802A (en) | 1982-03-23 | 1986-08-21 | Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use as intermediates and processes for their preparation |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3210496.0 | 1982-03-23 | ||
| DE19823210496 DE3210496A1 (en) | 1982-03-23 | 1982-03-23 | NEW DERIVATIVES OF BICYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF, AND NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND METHOD FOR THE PRODUCTION THEREOF |
| CA000424127A CA1223868A (en) | 1982-03-23 | 1983-03-22 | Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use and new bicyclic aminoacids as intermediates and processesfor their preparation |
| CA000516572A CA1227802A (en) | 1982-03-23 | 1986-08-21 | Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use as intermediates and processes for their preparation |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000424127A Division CA1223868A (en) | 1982-03-23 | 1983-03-22 | Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use and new bicyclic aminoacids as intermediates and processesfor their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1227802A true CA1227802A (en) | 1987-10-06 |
Family
ID=25669976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000516572A Expired CA1227802A (en) | 1982-03-23 | 1986-08-21 | Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use as intermediates and processes for their preparation |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1227802A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117643897A (en) * | 2024-01-29 | 2024-03-05 | 成都岷山绿氢能源有限公司 | Selective semi-hydrogenation catalyst for N-heterocycle and preparation method thereof |
| CN117643897B (en) * | 2024-01-29 | 2024-05-03 | 成都岷山绿氢能源有限公司 | Selective semi-hydrogenation catalyst for N-heterocycle and preparation method thereof |
-
1986
- 1986-08-21 CA CA000516572A patent/CA1227802A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117643897A (en) * | 2024-01-29 | 2024-03-05 | 成都岷山绿氢能源有限公司 | Selective semi-hydrogenation catalyst for N-heterocycle and preparation method thereof |
| CN117643897B (en) * | 2024-01-29 | 2024-05-03 | 成都岷山绿氢能源有限公司 | Selective semi-hydrogenation catalyst for N-heterocycle and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4668797A (en) | Bicyclic aminoacids as intermediates and processes for their preparation | |
| EP0354583B1 (en) | DC-88A derivatives | |
| CA1281330C (en) | Intermediates for the preparation of n-alkylated dipeptides and their esters | |
| AU2016217496B2 (en) | Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide | |
| CZ576590A3 (en) | Derivatives of amino acids, process of their preparation, their use and medicaments based thereon | |
| HU201329B (en) | Process for production of substituated on nitrogen atom of methil-amin group of staurosporen derivatives and medical compositions containing them | |
| JPH01301659A (en) | Novel bicyclic compound | |
| NZ206574A (en) | 1-(n-(1-carboxyalkyl)-alpha-aminoalkanoyl)-octahydro2s,3as,8as-cyclohepta(b)pyrrol-2-ylcarboxylic acid derivatives | |
| CA2121391A1 (en) | Indoloylguanidine derivatives | |
| CZ471190A3 (en) | Inhibitors of retroviral proteases | |
| NZ236550A (en) | Indole-substituted polyamines and pharmaceutical compositions | |
| EP0480061B1 (en) | Hepatic disorder inhibitor | |
| NZ206733A (en) | Disubstituted proline derivatives, their preparation and intermediates | |
| HU203891B (en) | Process for producing pyrrolidino-piperazine-dion derivatives and pharmaceutical compositions contianing them as active components | |
| US5635511A (en) | Treatment of heart rhythm disorders by administration of 3-phenylsulfonyl-3,7-diazabicyclo[3.3.1]nonane compounds. | |
| CA1227802A (en) | Derivatives of bicyclic aminoacids, processes for their preparation, agents containing these derivatives and their use as intermediates and processes for their preparation | |
| US4143134A (en) | Halo-phosphonopeptides | |
| HU198052B (en) | Process for producing purine derivatives substituted by side chain containing piperazinyl ring and pharmaceutical compositions comprising such compounds | |
| US4250180A (en) | Method of treating arrhythmia | |
| JPH08259532A (en) | Peptide-like compound or its pharmacologically acceptable salt | |
| JPS6045577A (en) | 2-azabicylo(2,2,2)octane derivative | |
| IE66009B1 (en) | New substituted amino acid derivatives process for preparing these and pharmaceutical compositions containing them | |
| WO2005068450A1 (en) | 4-thio coumarins | |
| US20040067959A1 (en) | Morphinoid derivatives as delta-opioid agonists and antagonists | |
| CA1227212A (en) | Derivatives of cis, endo-2-azabicyclo[5.3.0] decane-3-carboxylic acid, a process for their preparation, agents containing these derivatives and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |