CA1283249C - Process for the resolution of racemates of optically active bicyclic imino- -carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptides - Google Patents
Process for the resolution of racemates of optically active bicyclic imino- -carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptidesInfo
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- CA1283249C CA1283249C CA000446349A CA446349A CA1283249C CA 1283249 C CA1283249 C CA 1283249C CA 000446349 A CA000446349 A CA 000446349A CA 446349 A CA446349 A CA 446349A CA 1283249 C CA1283249 C CA 1283249C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
Abstract
Abstract of the disclosure:
The invention relates to a process for resolving racemic mixtures of bicyclic imino-.alpha.-carboxylic esters into the components by crystallization of diastereomeric salts, which comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-amino-carboxylic acids which contain a phenyl nucleus, recrystal-lizing then from an organic solvent, decomposing the precipitated, optically homogeneous diastereomeric salts in a manner known per se, and isolating the enantiomers and, where appropriate, converting the latter into the free acids by hydrolysis in a manner known per se. The inven tion also relates to compounds of the formulae Ia and Ib indicated in the description, to diastereomeric salts of these compounds,and to a process for the preparation of optically pure compounds of the formula in which two of the radicals A, B1, B2 and C form a carbon chain and the others denote hydrogen, and r, R1, R2, X, Y
and Z have the indicated meanings, which comprises reacting, in the presence of a condensing agent or, where appropriate, as the active esters, optically pure compounds of the indicated formulae Ia or Ib with optically pure compounds of the indicated formula III, eliminating the radical R by hydrogenolysis or hydrolysis and, where appropriate, con-verting the resulting optically pure compounds into physio-logically tolerated salts.
The invention relates to a process for resolving racemic mixtures of bicyclic imino-.alpha.-carboxylic esters into the components by crystallization of diastereomeric salts, which comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-amino-carboxylic acids which contain a phenyl nucleus, recrystal-lizing then from an organic solvent, decomposing the precipitated, optically homogeneous diastereomeric salts in a manner known per se, and isolating the enantiomers and, where appropriate, converting the latter into the free acids by hydrolysis in a manner known per se. The inven tion also relates to compounds of the formulae Ia and Ib indicated in the description, to diastereomeric salts of these compounds,and to a process for the preparation of optically pure compounds of the formula in which two of the radicals A, B1, B2 and C form a carbon chain and the others denote hydrogen, and r, R1, R2, X, Y
and Z have the indicated meanings, which comprises reacting, in the presence of a condensing agent or, where appropriate, as the active esters, optically pure compounds of the indicated formulae Ia or Ib with optically pure compounds of the indicated formula III, eliminating the radical R by hydrogenolysis or hydrolysis and, where appropriate, con-verting the resulting optically pure compounds into physio-logically tolerated salts.
Description
~;~83X~9 HOE 83iF 016 K
- The resolution of racemates of aminoacids via crystallization of diastereomeric salts is a widely used process (~euiew: Boyle, Quart. Rev. 25 (1971) 323)~
Usually, N-acylated aminoacids are employed, the salts with alkaloid bases are crystallized, and the homogeneous diastereomeric salts are decomposed by, for example, extraction of the N-acyl--aminoacids from the acidified solution (J. Amer. Chem. Soc. 71 (1949) 2541, 3251). It is also possible to carry out the converse process and to crystallize aminoac;d es.ers or amides w;th optically active acids (Chem. Ber. 8~ 53) 1524).
Opt;cally active compounds, such as 10-camphor-sulfonic acid, abietic acid or tartaric ac;d or their 0 der;vat;ves, for example, are used for this purpose. This procedure is particularly appropriate when the intention is to employ optically active aminoacid esters as starting compounds for further syntheses. In this case, it is not advantageous init;ally to prepare a N-acyl compound and then undertake resolution of the racemate via salt forma-tion with op~ically active bases, split off tne acyl radi-cal and then ester;fy the free am;noac;d.
A process suitable for bicyclic imino-~-carboxylic esters has not hitherto been described. It emerged from experim~ntal tests that all customary acids are unsuitable .
1~83Z49 for resolution o~ the racemates~ A process is kno~ln, from European Patent A 37,231~ for octahydroindole-2-carboxylic acid, using which the N-benzoyl compound of the racemate can be resolved v;a the salt w;th opt;calLy act;ve -phenylethylam;ne. However, for the reasons mentioned,this process is uneconomic when the esters are requ;red as ;ntermediates for further syntheses.
It has now been found, surpr;s;ngly, that N-acyl der;vat;ves of opt;cally active R- or S-aminoaci~c; which contaîn a phenyl nucleus, such as, for example, S-phenyl-alan;ne, tyros;ne or .yros;ne 0-der;vat;ves are suitable as cl1;ral partners for bicyclic imino-~-carboxyl;~ esters.
Th;s ;s because the (S,S) or (R,R)-salts usually precipi-tate spontaneously from su;table solvents, wh;le (S,R)-and (R,S)-salts remain in solut;on. It ;s poss;bler ;n just a single step, to achieve a greater than 95 per cent enrichment, and a single recrystallizat;on Leads ~o the opt;caLly homogeneous salts ;n h;gh y;eld, and these are - decomposed in a known rnanner.
Thus the inven~ion relates to a process for resolv-ing racemic m;xtures of bicyclic ;mino a-carhoxyl;c esters ;nto the components of the formulae Ia and Ib .
COOR H
t . .
~L~8;32~
in which R represen~s an aliphatic radical having 1 to 6 carborl atoms, an alic~clic rad;cal having ~ to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or arl araliphatic radical having 7 to 15 carbon atoms, a~ A and B1 denote hydrogen, and ~2 and C together form a chain of the formula -CCH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula ~CCll2~p~CH=CH~CCH2~q-, with ~p+q) being 1, 2, 3 or 4, b) C and B2 denote hydrogen, and A and B1 together form a chain of the formula -~CH2~n-, with n being 3, 4, 5 or 6, or a chain of the formula ~[CHz~p-CH=CH~[CH2]q-, with (p-~q) bein~ 1, 2, 3 or 4, or c) A and C denote hydrogen, and B1 ?nd B2 toyether form a chain of the formula -[CH2]m-, ~ith rn being 4, 5, 6 or 7, by crystallizat;on of diastereomeric salts, which process compr;ses preparing the salts of the racem;c esters with opt;cally active N-acylated R or S-aminocarb~xylic acids which contain a phenyl nucleus, recrystallizing them froM
an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decompos;ng the precipitated, optically homogeneous diastereomer;c salts in a manner known per se, and isolatil1g the enantiomers of the formulae Ia and Ib and, where appropriate, converting the latter into the free acids by hydrolysis or hydrogenolysis in a manner known per se.
Resolution of racemates of compounds of the for-mula Ia and Ib ;n which a) A and B1 denote hydrogen, and B2 and C together forrn a cha;n of the formula -~CH~]n-, with n being 3, 4, 5 or 6, or a chain of the - formula ~CH2]p~CH=CH~[CH2]q~ with (p~) being 1, 2. 3 or 4, or b) C and B2 denote hydrogen, and A and B1 together form one of the chains defined above under a) ; s pref erred.
A particularly preferred variant of the process comprises precip;tating, preferably as crystals, the salts of racemic bicyclic esters of the formulae Ia and Ib ;n wh;cil the two br,dgehead hydro~en etoms have the cis con figuration and the COOR-group is oriented endo with respect to the bicyclic ring system.
Particularly suitable imino-~-carboxylic esters are este s with aliphatic, alicyclic or araliphat;c alco-holsr which can be cleaved by hydrogenolysis or hydrolysis,as are described in, for example, Houben-Weyl, Methoden der organischer) Chemie (Methods of Organic Chcmistry), Yolume XV/1, Stuttgart 1974, on pages 314 427, or "Peptide Synthesis", by Bodanszky et al.~ 2nd edition (1976), John l~iLey & Sons. Esters of the formula Ia + Ib in which R
represents alkyl having 1 to 6 carbon atoms, cycloalkyl having Jt to 8 carbon atoms or aralkyl having 7 to 13 car-bon atoms, which can optionall~ be substituted by N02~ are preferred, ;li particular alkyl esters having up to 4 alkyl ~'~8~9 carbon atoms alld aralkyl esters, such as benzyl, nitrobenzyl or benzhydryl esters.
Examples of suitable N-acylated aminocarboxylic acids containing a phenyl nucleus are derivatives of R- or S-phenylalanine, -C-phenylglycine, -~-phenyl-a-aminobutyric acid, -3,4-dihydroxyphenylalanine, -~-phenylserine and -tyrosine. N-Acyl derivatives of R- or S-phenylalanine, -C-phenylglycine and -tyrosine are preferred.
The N-acyl protective groups which can be used are the customary NH2 protective groups described in, for example, Houben-Weyl, Volume XV/l, pages 46-305 or Bodanszky et al., "Peptide Synthesis", 2nd edition (1976), John Niley & Sons.
Alkanoyl having 1 to 6 carbon atoms, in particular formyl, tert.-butoxycarbonyl, and benzyloxycarbonyl are preferred.
Any free OH groups present can, where appropriate, be O-alkylated by alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl or tert.-butyl, by benzyl or by other OH
protective groups customary in peptide chemistry (cf. for example Houben-Weyl, Volume XV/1 or Bodanszky et al., "Peptide Synthesis", 2nd edition (1976), John Wiley & Sons).
Suitable and preferred solvents are aprotic organic solvents, such as, for example, esters, ethyl acetate, cyclohexane and tetrahydrofuran, but it is also possible to use alcohols having up to 6 carbon atoms.
Octahydroindole-2-carboxylic acid is known from U.S.
Patent 4,350,704. Canadian Patents 1,187,087, 1,193,607 and 1,197,252 relate to 2-azabicyclo[3.3.0]octane-3-carboxylic acid, and Canadian Patents 1,223,868 and 1,227,802 relate to 33~g 2,3,3a,4,5,7a-h~xahydro[lH]indole-2-carboxylic acid. Canadian Patent 1,198~ relates to octahydroisoindole-l-carboxylic acid and 3-azabicyclo[3.3.0]octane-4-carboxylic acid.
Racemic bicyclic cis, endo-imino-a-carboxylic acids of the formulae Ia + Ib, in which C and B2 denote hydrogen, and A and Bl toge~her denote the abovemen~ioned chain, can be prepared fxom, for example, enamines of a cycloalkanone and N-acylated ~-halogeno-a-aminocarboxylic esters of the formula IV, in which X' represents a nucleofugic group, preferably chlorine or bromine, Y' represents alkanoyl having 1 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or other protective groups which are customary in peptide chemistry and which can be split off with acid, and R4 represents alkyl having 1 to 5 carbon atoms or aralkyl having 7 to 9 carbon atoms, X' \CH2 ( IV ) CH
Y ' -HN COOR
or with acrylic esters of the formula Y, in which Y' and R4 have the abovementioned meaning, ~ CoOR4 2 \~ ( V ) NH-Y' by reacting the latter to give compounds of the formula V
in which A, B1, R4 and Y' have the abovementioned meaning, B / COOR
C~3~ = C \
~ ~H-~' (VI) A O
cycl;zing the latter using strong ac;ds, with cleavage of the acrylamide and ester, to give compounds of the formula VIIa or b, A ~ COO~I (VII~) ~31 ~ ~ ~ Coo,~ ~VI~) corlvert;ng the latter, by catalytic hydrogenat;on ;n the presence of transit;on metal catalysts or by reduction w;th borane-am;ne complexes or complex borohydrides in lower alcohols, into compounds of the formulae Ta and Ib in which R represents hydrogen, and esterify;ng the latter to ~ive compounds of the forMulae Ia and Ib ;n which R has the mean;ng def;ned ahove.
~ acemic bicyclic imino~a-carboxylic acids of the formuLae Ia and Ib~ in which A and B1 denote hydrogen and 8~
9 _ B2 and C together denote the chain mentioned, can be pre-pared from, ~or example, compounds of the formula VIII
~32 C
~ ( H
- ~ ~ (VIII) in which the br;dgehead hydrogen atoms are oriented cis or trans with respect to one another, and B2 and C have the abovementioned mean;ng.
Compounds of the formula VIII with n ~ 1 are known from R. Griot, Helv. Chim. Acta 42, 67 (1959), and those ~ith n = 2 are known from C.M. Rice et al., J. Org. Chem.
Z1, 1687 (195a).
These compounds-of the formula VIII are acylated in a known mannerr an aliphatic or aromatic acyl radical, preferably an acetyl or benzoyl radical, being bonded to the nitrogen atom, and the resulting N-acylated compounds 1S are subjected to anodic oxidation (in analogy to Liebigs Ann. Chem. 1 _ , page 1719) in an aliphatic alcohol, pre-ferabLy an aLcohol having 1 to 4 carbon ato~,s, in particular methanol, in the presence of a conducting salt, pre-ferably at temperatures in the range from 0 to +40C, ~lith the formation of a compound of the formula IX in which ~2 and C have the abovementioned meaning and R5 = C1-C4-alkyl.
83~9 B G
13 7 ~1 (IX) yl Thc result;ng compound of the general formula IX
is reacted w;th trimethyls;lyl cyanide by the method of Tetrahedron Le~ters 1981, page 141, in a hydrocarbon or halogenated hydrocarbon, in ether or in THF, at tempera-tures in the range from -60C to +20C~ preferably -40C
to +0C, ;n the presence oF a Lewis acid, such as, for exaMple, ZnCl2, SnCl2, SnCl4, TiCl4 or BF3-etherate, preferably BF3-etherate, and the resulting compound of the formula X
E C
< ~ CN ~X) Acyl in which the bridgehead hydrogen atoms are cis or trans with respect to one another, the Cl~ group being located cis with respect to the bridgehead hydrogen atom on carbon atom (4~n~, and in which n, B2 and C have the aLovelnentioned meanings, ;s, after pur;f;cation and resolution of the mixture of diastereomers by recrystallization or colurnn chromatography, hydrolyzed in a known ~anner by the action of acids or bases to sive a compound of the formulae Ia and Ib, with R = hydro~ien, and the latter is esterified.
83~3 HCl or ~IBr, in par~icular, is used as the acid for the acid hydrolysis of the ni~rile group. In this instance and in those ~hich follow~ the es~erification is carried out by ~he procedures cus~omary in aminoacid chemistry.
The invention also relates to optically hoMogeneous compounds of the forrnula Ia or Ib`in which the two bridge-head hydrogen atoms have the cis configuration, the COOR
group is oriented endo w;th respect to the bicycl;c r;ng system, the carbon atom a to the COOR group has the R or S configuration~
P. represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms, which can optionally be substituted by N02, and A, B1, B2 and C are defined as above, and to those compounds of the formulae Ia or Ib in which R denotes hydrogen a~d a) A and B1 denote hydrogen, and B2 and C together form a chain of the forMula -CCH2~n-, with n being 3, 4, 5 or 6, or a cha;n of the formula ~~CH2]p~CH=CH~CH2]q~~ ~ith (p+q) bring 1, 2, 3 or 4, or b) C and B2 denote hydrogen, and A and B1 together form one of the chains defined abovc a), with n being 3, 5 or ~ and (p~q) being 1, 2~ 3 or 4, and their salts.
The invention also relates to diastereomeric salts of a bicyclic cis, endo imino~a~carboxylic ester of the form(lla Ia or Ib, ;n which A, B1, B2, C and ~ have the meanings def;ned above as bein~r~ preferred, anrJ an optically ~332~9 active N-acylated R- or S-aminocarbox~lic ac;d which con-tains a phenyl nucleus and which is protected as defirl~d above~
The invention aiso relates to.the use of the opti~
S cally pure compounds of the formula Ia or Ib ;n a process for the preparation of optically pure compounds of the general formulae IIa or IIb ~1 ~;2 C
COOII
A \ ~
I * # Y
O = C - Cl-l -- N13 ~ C~H -- ~C~2~r ~1 co B1 ~32 C
A ~ C i ! O ' i o = c - c.~ - c;~ c.~ c - :~ (rr R Co2r~ ~, in which it ;s possible for the carbon atoms !abeled with an asterisk (*) each, ;nciependently of one ano~her, to have the R- or the S-configuration, a~ A and B1 denote hydrogen, and B2 and ~ together forr,~ a chain of the formula [CH2~n-, n being 3, 4, 5 or 6, or a chain of the formula -LCH2ip-Ch=CI~-[CH23~- , l'Z8~9 tp+q) being 1, 2, 3 or 4, b) C and B2 denote hydrogen, and A anG s1 together form a chain of the formula -C~H2]n-, w;th n being 3, 4, 5 or 6, or a chain of the formula ~CCH2]p~CH-CH~~CHz~q~, with (p+q3 being 1~ 2, 3 or 4~ or c) A and C denote hydrogen, and B1 and B2 together form a cl,ain of the formula -tCHz~n-, with m being 4, S, 6 or 7, r denotes 0 or 1, R1 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 $o ~ carbon atoms, an optionally substituted aLicyclic-aliphatic radical hav;ng 4 to 11 carbon atoms, an optionally subst;tuted aromatic radical hav;ng 6 to 12 carbon atoms, ~hich can also be partially hydrogena~ed, an optionally subst;tuted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroyl-aliphatic radical having 8 to 13 carbon atoms, an optionally substituted monocyclic or bicyclic hetero-cycl;c radical having S to 7 or 8 to 10 ring atoms respectively, 1 or Z of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these rin~ ato,ns being n;trogen atoms, or a side chain of a naturally occurring aminoac;d ~Jhich is optionally protected, R2 denotes hydrogen, an optionally substituted aliphatic radical havillg 1 to 6 carbon atoms, or an optionally substituted aralipha~ic radical having 7 to 1S carhor 24~3 atomS r Y denotes hydrogen or hydro~yl, Z denotes hydrogen, or Y and Z together denote oxygen, and X d~notes an aLiphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 5 to 9 carbon atoms, an optionalLy subst;tuted aromatic radical having 6 to 12 carbon atorns, or indolyl~
which process comprises reacting, in the presence of a condensing agent or, where appropriate, as an active ester, optically pure compounds of the formulae Ia or Ib, in which A, 81, B2 and C llave the abovementioned meanings, and R represents an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 4 to 10 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms or an optionally substituted araliphatic radical having 7 to 15 carbon atoMs, with optically pure compouncds of the formula III
~ (I I I) HOOC - J~ N}l - Cll - [ CH~ ] C~ X
C2F~ Z
in which the two carbon atoms labeled with an asterisk (*) have the (S,R~, ~R,S), (R,R) or~ preferably, (S,S) configuration, and R, ~1, R2, X, Y and Z have the abovement;oned meanings, splitting off the radical R by hyclrogenolysis or hydroly-s;s~ and, where appropr;ate, converting the optically ~83249 pure compounds of the forrnulae IIa or IIb ;nto physio-logically tolerated salts~
A preferred embodiment of the process according to the invent;on compr;ses preparing compounds of the for-mulae IIa or IIb, in which r denotes 0 or 1, R denotes hydrogen, (C1 to C6)-alkyl or araLkyl having 7 to 9 carbon atoms, R1 denotes hydrogen or (C1 to C6)-a(kyl, which can opt;onally be substituted by amino, (C1 to C6)~acYl-amino or benzoylamino, (C2 to C6)-alkenyl, (C5 to C9)-cycloalkyl, ~C5 to C9)-cycloalkenyl, 5C5 to C7)-cyclo-alkyl-(C1 to C4)-alkyl, aryl or partially hydrogenated aryl hav;ng 6 to 12 carbon atoms, each of which can be substitut~d by (C~l to C4)~alkyl, (C1 or C2)-alkoxy or halogen, (C6 to C12) aryl-(C1-C4) alkyl or ~c7-c13)-aroyl-(c1~c2)-alkyl~ bo~h of which can be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocycl;c radical having 5 to 7 or 8 to 10 r;ng atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms be;ng n;trogen atoms, or an optionally protected side chain of a naturally occurring aminoacid, `
R2 denotes hydroyen, (C1 to C6)-alkyl, (C2 to C6)-a~kenyl or (C6 to C12)-ary~(C1 to C4)-al~yl~
Y denotes hydrogen or hydroxyl, Z denotes hydroger1~ or Y and Z together denote oxygen~ and lX~33Z49 X denotcs tC1 to C6)~al~yl, (C2 to C6~-alkenyl~
tC5 to C~-cycloalkyl~ (C6 to C12)-aryl, which can be monosubstituted, disubstituted or trisubstituted by (C1 to C4)-alkyl, (C1 to C4)-alkoxy, hydroxyl, halogen, nitro, amino, ~C1 to C4)~alkylamino, di-(C1 to C~
alkylamino and/or methylenedioxyt or 3 indolyl.
The preparation of the S,S,S-compounds of the formula Ila is preferred.
In this context as in the following, aryl is to be understood preferably to include optionally suhstituted phenyl or naphthyl. Alkyl can be straight-chain or branched.
Examples of a monocyclic or bicyclic heterocycliç
radical having 5 to 7 or 8 to 10 ring atoms respectively, ;n which the ring atoms have the abovementioned meanings, inclucle thienyl, benzoCb3thienyl, furyl, pyranyl, benzo-furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi-dinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, ~uinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxa-zolyl, isoxazolyl, thiazolyl or isothiazolyl. It is also possible for these rad;cals to be partially or completely hydrogenated.
Where R1 represents a side chain of a protected naturally occurring a arninoacid, such as, for example, protected or optio1lally substituted Ser, Thr, Asp, Asn, Sluf Gln, Arg, Lys~ Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the pre~erred protective groups are those groups customary in peptide chemistry (cf. Houben~1eyl, Vol.XVi1 ' ~;~8~249 and XV~2). In the c~se where R1 denot~s a protected side chain of a lysine, the known am;no protective groups, but in particular (C1-C6)-alkanoyl, are preferred. Preferred 0-protective groups for tyrosine are methyl or ethyl.
In the procedures hither~o known for preparing mixtures of stereo;somers of compounds of the formulae IIa or IIb, which s~arted from mixtures o, stereoisorners, ;t was necessary to use elaborate separating procedures to separate the reaction mixture in order to obtain the desired op~ically pure stereoisor,lers of the formula IIa or IIb. By reacting the optically homogeneous imino-a-car-boxyl;c esters of the formulae Ia or Ib according to the invent;on with optically homogeneous compounds of the for-mula III, specific synthesis of opt;cally homGgeneous com pounds of the formula IIa or IIb has become possible.
The desired compounds of the formulae IIa or IIb are obtained ;n high yields without using elaborate separating techniques.
Compounds of the formu~a III are described ;n the abovement;oned documents or are known from European Patent A 46,953. The reaction of a compound of the formula III
w;th tert. butyl 1-~2~,3~,7~ octahydro-C1H~-indole-2-carboxylate followed by el;minat;on of a t&rt.-butylester, wh~reupon a corresponding octahydro;ndole derivative of the formula IIb results, is known from Europear, Patent A 37,231.
llowever, it has been necessary to restrict this reaction to react;on of a compound of the formula Ia or Ib with C and e2 each bein3 H and A ~ B1 being (CH2)4, and ~ 2 it has hitherto only been possible to prepare this in a complicated manner via the N-benzoyl compound, crystallization of the diastereomeric salts with S-~-phenylethylamine, liberation of the N-benzoyl compound, elimination of the benzoyl group and esterification.
It has not hitherto been possible to transfer this reaction sequence to the intermediates of the formula Ia and Ib according to the invention. Nor has it been possible to resolve racemic mixtures of compounds of the formula IIa and IIb by separating conventional diastereomeric salts with optically active carboxylic or sulfonic acids. The compounds of the formula Ia and Ib have been made accessible for subsequent reactions or the first time by the procedure described above.
The process according to the invention is particularly cost-effective, since compounds of the formula III can be prepared directly in an optically pure form by straightforward routes from Canadian Patents 1,187,087, 1,193,607 and 1,197,252. However, in this reference, it was still necessary for these intermediates to be reacted with a racemic aminoacid and to be converted into an optically pure compound of the general formulae IIa and IIb by an additional purification step.
The process ~ccording to the invention, which is preferably carried out with S,S compounds of the formula III, thus represents by far the most cost-effective process for the preparation of the compounds covered since, in all the other known procedures, great losses have to be accepted due to the f1 chromatography or crystallization of mixtures . ~
~832~9 of stereo;somers, some of ~hich are complex.
The condel1sation step is carried out by one of the conventional processes of peptide syntllesis which involve little race~mization, such as are described in, for example, Houben-Weyl, Volume XV, or in "The Pept;des - Analysis, Synthesis, Biology, Vol.1 Major Methods of Peptide 80nd Eorlnat;orl, Part A", Gross, Meierhofer, Academic Press N.Y.
~1979). The DCC/HOBt method of Chem. Ber. 103 (1979), pages 788-798, is particularly advantageous. In this context, it should be taken into account that reactive functional groups in the radical R1 must be temporarily pro-tected by the known methods of peptide chem;stry tfor exarnple Houben-Weyl, Volume XV, or Bodanszky et al. in "Peptide Synthesis", 2nd edition (1976), John ~liley & Sons).
The optically homogeneous compounds of the forMula IIa or IIb are obtained, after eliminat;ng R and, where appropriate, R2, in high yield in a manner known per se w;thout using elaborate separating techn;ques.
The compounds of the formula IIa and IIb and their salts have long-lasting and powerful hypotensive activity.
They are potent inh;b;tors of angiotensin convert;ng enzyme (ACE) and can be employed to control high bLood pressure of a variety of etiologies. ACE inhi~itors of this type are known from, for ex~ampler U.S~ Patent 4,344,949, European Patent A 49,658, European Patent A
46,953, European Patcnt A 50,~00 and European Patent A
79~022.
It is also possible to combine them with other compounds having hypotensive, vasodilator or diuret;c . - :
.
.
- ' .
~Z~33~49 ~, act;vity. Typ;cal representat;ves of these classes of ~ctive co~pounds are descrihed in, for example, Erhardt-Rusch;g~ Arzneir,littel (Drugs), 2nd edit;on, ~e;nhein, 1972.
They can be administered intrave~ously, subcutaneously or oraLly.
The dosage on oral adm;nistration is generally 1-S00 n~g, preferably 1-100 mg, per single dose for an adult patient of normal weight. It is also possible to increase this ;n severe cases, s;nce no tox;c propert;es have h;therto been observed. It is also poss;ble to reduce - the dose and this is part;cularly appropr;ate when diure-tics are adm;nistered concurrently.
The compounds according to the invention can be administered orally or parenterally in appropr;ate pharma-~5 ceut;cal formulations. For a form for oral use~ the activecompounds are mixed with ~he add;t;ves customary for this purpose, such as vehicles, stab;l;zers or inert diluentsr and converted by customary methods ;nto su;table forms for adm;n;strat;on, such as tablets, coated tablets, hard gelat;n capsules, aqueous, alcohol or o;ly suspens;ons or aqueousr alcollol or oily s~lutions. Examples o-f su;table inert vehicles which can be used are ~um arabic, ma~nesium carbonatet potassium phosphate, lactose, glucose or starch, ;n particular corn starch. Th;s can entail formulation e;ther as dry or as rnoist granules. Examples oF su;table o;ly vehicles or solvents are vegetable or an;mal oils, such as sunFlower o;l or fish liver o;l.
For subcutaneous or intravenous administration~
the act;ve compounds or their phys-,ologically tolerated , ~
lf2~1133~49 salts are converted into a solution, suspension or emulsion, where appropriate with the substances customary for this purpose, such as solubilizers, emulsif;ers or other aux;liaries. Examples of suitable solvents for the new ac~ive compo~lnds and the corresponding physiologic3lly tolerated salts are: water, phys;ological saline or alco-hols, for example ethanol, propanediol or glycerol, but also sugar solutions, such as glucose or mannitol solutions, or even a mixture of the various solvents or solutions mentioned~
The Examples which follow illustrate the process, but there is no intention to restrict the invention to these specific ~xamples.
Example 1:
Benzyl (1Sr 3S, 5S)-2-azabicyclo~3.3~0~octane-3-carboxylate hydrochloride _abbreviated to (S _ Aoc-OBzl-HCl) _ _ _ (A) Mettlyl 2-acetylamino-3-(2-oxocyclopentyl)propionate:
269 g of methyl 3-chloro-2-acetylaminopropionate and 257 g of cyclopentenopyrrolidine in 1.5 liters of DMF
are kept at room te~perature for 24 hours~ The mixture is evaporated in vacuo, and the residue is taken up in a little water~ the pH is adjusted to 2 with concentrated hydrochloric acid and the solution is extracted twice with 4 liters of ethyl acetate each time. A pale yellow oil remains on evaporating the organic phase.
Yield: 2~0 9.
1H-NMR:2.02 (s,3H); 3.74 (s,3H~; 4.4-4.8 (m,1H), (CDCl3) 3 ;~ Z4g - 2~ -Analysis: C H N
calculated 58.1 7~S4 6.16 found 5~.5 7.2 6.5 (~) c ~endc-2-Azabicyclo[3.3.n]octane-3-carboxylic acid S hydrochlor_de 270 g of the acetylaminG der;vative prepared under (~) ;n 1.5 liters of 2 N hydrochloric acid are boiled under reflux for 45 minutes~ The mixture is evaporated in vacuo, and the res;due is taken up in glacial acetic acid, 5 y oF Pt/C (10% Pt) are added and hydrogenation is carried under S bar. After filtration, the filtrate is evaporated and the residue is crystall;zed from chloroforrn/diisopropyl ether.
Melt;ng point: 205-209C, Yield: 150 g (C~ Racemic Aoc-OBzl.~lCl .. . . .
1.2 liters (11.5 mol) of benzyl alcohol are cooled to -10C. 126 ml (1.73 mol) of thionyl chloride are added dropw;se, with cooling and stirring, and then 126.5 g ~D.66 mole) of crude Aoc.HCl are added at -10C, with stirring, and the mixture is then stirred at this tenpera-ture for 30 minutes. The temperature is then allowed to r-ise slowly to 20-25C with stirring, the product dissol-ving within 5 hours. After standing overnight, the brown solution is run into 4uO liters of diisopropyl ether uith stirriny. After 1 hour, the precipitated crystals are filtered off, washed with diisopropyl ether and dried in - 23 ~ 24'~
vacuo. A further precipitate separates out of the com bined diisopropyl ether solutions overni~ht~
Yield: 168.5 9 ~O.~X~
~D) (S~-Aoc-ORzl.~-Phc~OH
166.0 9 (0.589 mol) of racemic Aoc-OBzl.HCl are suspended in 500 ml of methylene chloride and thorouqhly sha~en with 25 9 (O.ti25 mol) of NaOH in 250 rnl of ~ater.
A solution is proc'uced. After a short time the initially formed emuls;on has separated. The methylene chloride phase ;s separated off, washed ~lith 100 mL of 0.1 N NaOI!
and twice with 50 rnl of water each time and the combined aqueous phases are extracted twice ~lith 100 ml of methylene chloride each time. The combinetd methylent? chloride phases are dried over sodium sulfate and evaporated ur~der m;ld cond;tions w;th waterpump vacuum. The remainins oil is imrnediately taken up in 100 ml of ethyl acetate, and a solution of 117.6 9 (0~39 mol) of N-benzyloxycarbonyl-S
phenylalanine (7~Phe~O~J) in 200 ml of ethyL acetate is added. The flask ;s rinsed with 100 ml of ethyl acetate.
2C 1,600 ml of cyclohexane (- 4 times the amount by volume) are added, w;th stirring, to the clear solution at rcorn ternperature. After scratching, crystallization starts, and th;s is completed by standing overn;gh~ in a cold room.
The crystalline precipitate is filtered off, washed ~ith 250 ml of ethyl acetate/cyclohexane (1+4) and dried.
Yield: 133.6 g of (S) Aoc-OBzl.Z-Phe-OH (50.9%~ corres-ponding to 102% of theory), melt-ing point 101-103C; ta~D7: ~5 3 (c = 1, rnethanol).
After recrystallization from ethyl acetate/cyclo-- 24 ~ 3~49 hexane ~1:1), the follouing data are found for the Z-Phe-OI-I
salt:
melting point: 103-10'~C, Ca]D7: -6.1 (c = 1, in methanol).
(E) ~S)-Aoc-OBzl.HCl 63.0 g (0.142 mole) of the Z-Phe-OH salt obta,ned according ~o (D) are dissolved in 300 rnl of methylene chloride and the Solutiol1 is thoroughly shaken with $
(0.15 mole~ of NaOH in about 150 ml of water. Phase separation takes some time because of a small amount of 1Q insolubles. The methylene chloride phase is separated off, washed with 50 ml of D.1 ~ NaOH and twice with 50 rill of water each tirne and dried. The solution is evaporated to about 100 ~l, diluted with 100 ml of diisopropyl ether and, ~;th stirring, 25 ml of 6 N HCl in ether are added. After 1 hour, the mixture is filtered, and the precipitate is washed with diisopropyl ether and dried.
Yield: 3Z.5 9 (~1.3%) Melting point: 185-186C
~a]D -42.5 (c = 1, water) Methylene chloride is removed from the basic aqueous phase in vacuo, and it is acidified with toncen trated HCl. The prec;pitated Z-Phe-OH ;s washed with water and dried.
The R compound and further Z-Phe-OH are obtained from the methylene c`hloride mother liquor from Example I(D~
in the manner describecl~
- 2 5 - ~.Z~3324~9 r-- G O
O ~~t '1 f~~f\l ,_ ~ ~~ =r o.~3 f~ `
rl ~;oL) O~ O~') ~_ f~l c~ ~D
O t~
C~ CO
Cl E~
f`) ~f~ O O O O O O O O O
CJ~~f~ C~ O C~ - CV f~ :r ^ f~l r-- O~ C'~ .-- C~ CJ~ O~ ~D CO
S tf~ :r s s ` rfl f,~l f~ .. 0 ~) I I I I 1 1' ~ I I '~' ~0 o~ a ~" r~
0~C~ V OU 0~ OC~ 0;~ OC~
<~ n u~ f~ f 0~ CO C.~ C~ COCOCO Lf~
C~ ,fl I=l I CO r.
E C~ C~ ~ C C Cl~
~ ~ ~_ _ _ _ ,_ ~
.~
- T~ :C o ~ ~ C~ C
C~ O O O
O O O O t-- O O O O ~ ~--~J ~ CO~J ~ ~ r,~ f? ,f~ r_ O ~O=J' ~'~ O f'~
,~ + ~ I +
a .~
V V V ;) V V ~ ~J V ~ c C~ o o o o o o o o o o o tu ~u~ _r=r o ~ n c~_. ~ co ~ ' tf~ C~C~ t~ t,~ ~C,._ ,_ ,_ ~n. I I I I \ I I I I I I
f~ n30 ~c~ t~J n :. -- f ~ _~-- ~-. , _ ,_ ~ _, _,_ ,. ~_ ,_ , ._ s . ~O à) ~ ~ à~ ~d ~ ~ ~
fa a, s^ ~ a) ~ o a~ ~ aJ c: a~ to a~
a, s- a~ aJ f`' 'ILJ~ ~Xa ~J' ~ C ( ) tll N
,c~t S,tl~ CJ n~ CJ ~(D ~,a~ aJ S. fV tO CJ 11~ C) -~ ~) J O~' -~ O J J OJ OC~ --J -- O --' O
o f-~ S ~-- L ~ r_1 L
aJj~ L~111i~ L~i~ L~ V LLI L~ i~; i ~) C t iL ~~C ~ 5~
C~C~ IS I I ~ rl f~. C) J, t!?
c~ P.r~_ P~ E-~ ~-- '~i S. S-~. P. t ~3 1 i II I I I rt~ O
~ tii t~ C`l ~ LL, C~ ti t~l , 1 ,"~ , .~ O ~t '~
tL~ S_ c~ ~ s^S` c c~ ~ S~ t' ;~
L ~? ~ ~li)C; C; CvC?, C~ ;) (li C) tl_ t~ t~t~ ~tl~ t' . P~ r~ ~ t G)I X H i H
Jo S_ ~3 -D H H t- I H H H H H H 1-1 t- I
t E ,;~, X ~ X: C X :~ ~C X X
L f~ t~ n ~D t-- co C~ C~
o sv ~ ~ ~
IIJ Q
- ~6 - ~ 9 The Ccis,endo~-imino-~ carboxylic esters in Tablt-~ 1 are prepared and subjected to racemate resoLution in an analogGus manner. This Table details their optically acti~e crystallization par~ners, and the solvents, yields and properties of the salts and the final products in the form of the ester hydrochlorides or ester ~osylates.
Explanations of Table 1 .
(XI) - ~ ~
~ N~COOR and mirror image (XII) H
and mirror image ~ H
10 (XIII) ~\
~ /~ COO~ and mirror image The free iminocarboxylic acids can be prepared from the esters by hydrolysis or hyrlro~enolysis.
Exa_ple 13 N-t1S- _rboethoxy 3~phenylpropyl)-S-alanyl-2-cis~endo-1S azabicycloL3.3.0]octane-7S-carboxyl,c acid - 27 - ~8~249 (A) Benzyl N-(2S-ca_boethox_-3-phenylpropy()-S-alanyl-c;s,endo-2-azab;cycloC3.3.0]octane-3S-carboxylate 11~ 9 of the benzyl ester hydrochloride prepared according to Example 1 E are converted into the free ester S by extracting by shak;ng the alkal;ne aqueous solution w;th d;ethyl ether, and~ after dist;ll;ng out the e.her, are reacted w;th 6.7 9 of Hos~ 13.8 g of N-(1S-carbo-ethoxy~3-phenylpropyl)-S-alan;ne and 10~Z g of d;cyclo-hexylcarbod;;mide ;n 200 ml of dimethylformam;de. After st;rr;ng at room temperature for 3 hours, the precip;tated d;cyclohexylurea is filtered off, and the filtrate is evaporated, and the residue is taken up in 1 liter of ethyl acetate and th;s solut;on is extracted by shaking with 3 x 500 ml of 5 per cent NaHC03 solution. The organic phase ;s evaporated.
22.4 9 (90X) of product are obtained as an oil.
SHNMR of the S,S,S-compound, characteristic signals:
1.20 td,3H~, 1.27 ~t,2H~, 4.17 (q,3H), 5.13 (s,2H~
7.18 (s,5H~, 7~32 (s,5H) (CDCl3) Analysis: C H N
C30H3~N20s calculated 71.1 7.56 5.53 found 70.8 7.8 5.7 (B) N-(1S-Carboethoxy-3-pher)ylpropyl)-S-alanyl-c;s,endo-2-azabicycLoC3.3.0]octane-3S-carboxylic ac;d 8.0 g of the S,S,S-benzyl ester from Example 1 E
are d;ssolved in 100 ml of ethanol, and the benzyl group is removed by hydrogenolysis under atmospheric pressure with the addit;on of 0.5 g of 10% PdtC. This reactiol can also be carried out urder elevated pressure which ;nvolves 2~ 33249 shortenin~ of the reaction time. After the caLculated amount of hy(lrogen has been taken up, the catalyst is fil-tered off and the fil~rate is evaporated in vacuo. The ~itterion crystallizes from ether in a virtually quanti-tative yield:melting point: 110-112C (decomp,osition) A hydrochloride ~decomposition above 120C) can be obtained by addit;on of an equ;valent amount of hydrochloric ac;d.
Analysis: C H N
C23H32Nz05 c~lcu~a~ed 66.3 7.7 6.73 found 66.1 7.8 6.6 The 1H NMR and mass spectra which are obtained are consistent with the structure indicatedO
~]D = ~-15~6 (c = 1, rnethanol).
Example 1~
N-(1S-Carboethoxy-2-benzoylethyl)-0 ethyl-S-tyrosyl-c7s,endo-2- zabicyclo~3.3.030ctane-3S-carboxyl;c acid (A) N-(1S~Carboethoxy-3~ y~e~pyl)-o-ethyl tyrosine benzyl ester 24 ~ of ethyl benzoylacrylate in 100 ml of ethanol are reacted w;th 30 g'of 0-ethyl-S-tyros;ne benzyl ester in the presence of 0.5 ml of triethylamine and~ after evaporating the solution and diDesting the resitdue with diethyl ether/petroleum ether (1:1) and drying in vacuo, 42 g of RS,S compound are obtained. Resolut;on of the diastereomers by chromatography on silica gel using the system ethyl acetate/cyclohexane (1:3).
Y;eld: 17 9 of the S,S conipour,d.
- 2~ .Z~33~4~
(B) N~ Carboe_hoxy-3-phel1ylpropyl_-0-ethyl-S-tyrosine 17 g of tl1e compound obta;ned accord,ng to (A) in 800 ml of acetic acid are hydrogenated with 4 9 of Pd/C
(10%) under 1Q0 bar and at roorn temperature. Yield after chromatography on silica gel using the solvent ethyl ace-tate/cyclohexane (1:3) and drying the res;due from evapora-tion: 12 g of title compound wh;ch is virtually homo-geneous by thin-layer chromatography.
Melt;ng po;nt 205-213C
10 Analys;s: C23H2gNOs (399.5~
calcula ed C 69.15 H 7.31 N 3.50 found C 69.5 H 7.4 N 3.3 (C) N-(1S-Carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-.
c;s,endo-2-azab;cycLoC3.3.0]octane 3S-carboxyl;c acid ___ In analogy to Exarnple 13 A, ~ g of the free benzyl ester obta;ned in accordance w;th Example 1 E and extracted from alkal;ne solut;on by shak;ng with d;ethyl ether are reacted w;th 8 9 of the cornpound obtained in accordance w;th Example 14 B us;ng 4.4 g of d;cyclohexylcarbod;;m;de in the presence of 2.7 g of 1-hydroxybenzotriazole, and 14.3 9 of oily benzyl ester are obta;ned as an ;nterrnediate.
The 1H NMR and mass spectra are cons;stent w;th the structure ;ndicated.
The benzyl ester in 50 ml of ethanol ;s cataly-t;cally hydrogenated on Pd/C under atmospheric pressure.
After filtering off the c-atalyst and distill;ng off the solvent~ there remains a sol;d res;due whicl1 ;s d;gested with diethyl ether/petroleurn ~ther and ;s dr;ed.
Y;eld: 11.2 g ~ 30 ~ 1Z 8 32 Exarnple 15 N-~15-Carboethoxy 3-phenylpropyl)-0-methyl-S-tyrosyl-.. . . .
cis,endo-~-azabicyclo~3~3.0~octane-3S-carboxylic acid _ _ _ , _ _ The procedure is carried out as described in Example 14~ but in the stage analogous to (A) 0-methyl-S-tyrosine benzyl ester is used and the title compound is obtained, the 1H NMR spectrum of which is consistent with the structure ;ndicated.
1H NMR (CDCl3): 1.2-3.0 (m,15H); 1.27 (t,3~l); 1.4 (t,3H);
3.0-4.3 tm,4H), 3.8-4.2 (rn,4H)~
6~5-7.1 (2d,4H); 7.3 (s,SH) Example 16 N-(1S-Carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-. . .
C4.5]decane-3S-carboxylic ac;d (A~ 1-(D;ethoxyethyl)cycloh =
51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protectivc gas at -10C, to 312.5 ml ~0.5 rnol) of a 15X strength solution of n-butyllithium ;n hexane. The mixture is st;rred for 20 rninutes and then cooled to -70C. 54.6 g of cyclohexanecarbonitrile are added dropwise over the course of 30 rninutes and, after a further 30 minutes, 98.5 g of brorooacetaldehyde diethyl acetal are added with;n 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 rml of ethyl acetate, and the organic phase is dried over sodiurn sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation.
Yield: 90 g (about 80% of theory), boiling point 7X-7~C at -~ ~ :
~ 31 - ~83Z49 S torr t10.7 mbar).
(B) 1~A_inomethyl-1-t_ ethyloxyethyl)cyclGheYane 90 g of d1e~hyloxycyclohexanecarbon;trile are dissolved in 1 ~iter of ethanol, and 60 g of sodium are added~ After the metal has d;ssolved, 100 ml of ~later are added and the solvent is largely removed in vacuo. 300 ml of ~Jater are added to the residue and the mixture is extracted 3 x with 200 ml of ether. The ethereal phase is dr;ed over sod;um sulfate, evaporated and distilled in vacuo.
Yield: 83 g (about 90% of theory), boiling point 69-72 at 8 torr (10.7 mbar) (C~ 2 AzaspiroC4.5]decane-3-carbonitrile 80.2 g of aminomethyldiethyloxycyclohexane are stirred in a mixture of 300 ml of ethanol and 300 ml of 1 N hydrochlor;c acid under a protective gas (N2 or Ar) for about 1 hour.
After the starting product has been comple~eLy cleaved, the mixture is cooled to 0C and the solution is rapidly adjusted to pll 5 by adding 2 N sodium hydroxide solution. 300 ml of glacial acetic acid are immediately added (pH about 3), and the mixture is cooled to -10C
and 17.5 9 of sodium cyanide are added. The reaction vessel is closed and left at room temperature for about 5 hours.
Completion of reaction is checked using tllin-layer chroma-to~raphy (system ethyl acetate/petroleum ether 2:1) ~Schiff's base Rr = 0.6-0.7; aminoacid nitrile Rf ~ 0~28~ and the react;on solution ;s evapora.ed to dryness. The crude aminoacid nitrile is immediately processed further in accor-- 32 ~ ~X83~9 dance ~ Example 16 D or E.
(D) 2-A_aspiroC$.5~decane-3-carbox ~
25n ml of 4 N hydrochloric acid are added to one half of- the aminoacid nitrile obtained in Example 16 C, and the mixture i~ heated under reflux for 4 hours. Traces of escaping hydrocyan;c acid are made harmless in a suitable manner (freezing out, absorption in basic iron(II) salt solution). The solut;on is neutralized, evaporated to dryness and extracted several times with n-butanol. The residue from evaporation of the organic phase is - a) crystallized from chloroform/diisopropyl ether to obtain the hydrochlor;de and, if necessary, again pre-cipitated from a mixture w;th ethanol or b) purif;ed ;n aqueous solut;on by stirring with an ion exchanger, for example IR 45 (OH form) (Amberlite(R)) and, after remov;ng the water, the zw;tter;on ;s crystal-l;zed from ethanol/ether.
Yield from a~: 31-32 g ~82%) Melt;ng po;nt 205C (decompos;tion), hydrochlor;de (E~ Benzyl 2-azaspiroC4.5~decane-3-carboxylate hydro-chloride _ _ Half of the aminoacid nitrile obtained ;n accordance w;th Example 16 C is taken up ;n 7C ml of benzyl alcohol.
A slow stream o-f HCl gas is passed through the solut;on at room temperature for 5 minutes, then it is maintained at room temperature for 2-3 hours~ evaporated to a small volume ;n vacuo, and aqueous sodium b;carbonate solution is added until the pH is 8~5 and the benzyl ester is extracted into ethyl acetate. The organic phase is dried~
_ 33 _ ~28~
an equivalent amount of ethereal hydrochloric acid is added and the mixture is evaporated. The res;due crystal lizes ~rom diisopropyl ether aod can be recrystallized from methy~ene chloride/diisopropyl ether.
Yicld: 43 9 (abou~ 80%) Melt;ng point 145C (deccmposit;o~
(F~ senzyl 2-azaspiroC4 S~decane-3S-carboxylate hydro chloride The racemic hydrochloride obtained in accordance with Example 16 E is subjected to racemate resolution in analogy to Examples 1 D and E~
(G) Benzyl N-(1S-carboethoxy-3-phenylpropyL)-S-alanyl-2-azaspiro~4.5]nonane-3S-carboxylate __ _ _ 15.6 g of benzyl 2 azaspirol4.5~nonane-3S-carboxy-late hydrochLoride, 6.7 g of 1-hydroxybenzotriazole and 13.8 g of (S,S)-N-(1-carboethoxy-3-phenylpropyl)alanine are dissolved in 200 ml of DMF and reacted overn;ght with 10.2 9 of dicyclohexylcarbodiimide. Addit;on of tertiary bases, for example 6.4 ml of N-ethylmorpholine, increases the yield only inconsiderably. The precipitated DC-urea is filtered off, the filtrate is evaporated in vacuo, the residue ;s taken up in ethyl acetate, and the solution is extracted by sllaking with aqueous sodium bicarbonate solution~ and the organic phase is dried over solid sodium sulfate and again evaporated. The 1H NMR spectra tin CDCl3) confirro the structure.
(H) N-(1S-~Carboethoxy-3-phenylpropyl)-S--alanyl-Z-aza-spiror4.5]nonane 3S~carboxylic ac;d The benzyl ester obtained in Example 16 G -i, . , taken up ;n 200 ml of methanol and the benzyl group is removed by hydrogenolysis with 1 g of Pd/C (10% Pd3~ ~fcer uptake of hydrogen ;s cornplete, the m;xture is filtered and the filtrate is evaporated in vacuo. A solid, hygroscopic foarn of the zwit~erion,c dipep~ide derivative can be obtained in ~acuo with the addition of pen~cane.
Ca]~1 - 3~.3 (c ~ 1, methanol) Example 17 N-(1S-CarLoethoxy-3-pheny propyl)-S-alanyl-cis,endo-2,3,3 _ 4~5,7a-hexahydroC1HJ;ndole-2S-carboxylic acid (a) Methyl cis-2,3,3a,4,5,7a hexahydroC1H3indole-2S-carboxylate hydrochloride Racemic methyl cis-Z,3,3a,4,5~7a~hexahydroC1H~-;ndole-2-carboxylate hydrochlor;de (obta;nable ;n analogy to ~he procedure described in German Patent Appl;cation P 32 10 496~0) ;s subjected to racemate resolution ;n analogy to Exarnples 1 D and E.
Ca] ~ = +6~ .4 (c = 1, H20) (B) N-(1S-Carboe.hoxy-3-phenylpropyl)-S-alanyl-c;s,endo-__ __ _ __ _ 2,3,~4,5,7a hexahydro~1_]indole-2S-c _boxylic acid hydrochlor;de ___ rhe title compound is obtained by a procedure analogous to that described ;n Exatnples 13 A and B.
1H N~R data 0O9-3~0 (m, 17 H);
.
3.4-4.9 (m, 6 H);
5.2-6.0 (m, 2 H);
7.2 (s, 5 H) ' .
- The resolution of racemates of aminoacids via crystallization of diastereomeric salts is a widely used process (~euiew: Boyle, Quart. Rev. 25 (1971) 323)~
Usually, N-acylated aminoacids are employed, the salts with alkaloid bases are crystallized, and the homogeneous diastereomeric salts are decomposed by, for example, extraction of the N-acyl--aminoacids from the acidified solution (J. Amer. Chem. Soc. 71 (1949) 2541, 3251). It is also possible to carry out the converse process and to crystallize aminoac;d es.ers or amides w;th optically active acids (Chem. Ber. 8~ 53) 1524).
Opt;cally active compounds, such as 10-camphor-sulfonic acid, abietic acid or tartaric ac;d or their 0 der;vat;ves, for example, are used for this purpose. This procedure is particularly appropriate when the intention is to employ optically active aminoacid esters as starting compounds for further syntheses. In this case, it is not advantageous init;ally to prepare a N-acyl compound and then undertake resolution of the racemate via salt forma-tion with op~ically active bases, split off tne acyl radi-cal and then ester;fy the free am;noac;d.
A process suitable for bicyclic imino-~-carboxylic esters has not hitherto been described. It emerged from experim~ntal tests that all customary acids are unsuitable .
1~83Z49 for resolution o~ the racemates~ A process is kno~ln, from European Patent A 37,231~ for octahydroindole-2-carboxylic acid, using which the N-benzoyl compound of the racemate can be resolved v;a the salt w;th opt;calLy act;ve -phenylethylam;ne. However, for the reasons mentioned,this process is uneconomic when the esters are requ;red as ;ntermediates for further syntheses.
It has now been found, surpr;s;ngly, that N-acyl der;vat;ves of opt;cally active R- or S-aminoaci~c; which contaîn a phenyl nucleus, such as, for example, S-phenyl-alan;ne, tyros;ne or .yros;ne 0-der;vat;ves are suitable as cl1;ral partners for bicyclic imino-~-carboxyl;~ esters.
Th;s ;s because the (S,S) or (R,R)-salts usually precipi-tate spontaneously from su;table solvents, wh;le (S,R)-and (R,S)-salts remain in solut;on. It ;s poss;bler ;n just a single step, to achieve a greater than 95 per cent enrichment, and a single recrystallizat;on Leads ~o the opt;caLly homogeneous salts ;n h;gh y;eld, and these are - decomposed in a known rnanner.
Thus the inven~ion relates to a process for resolv-ing racemic m;xtures of bicyclic ;mino a-carhoxyl;c esters ;nto the components of the formulae Ia and Ib .
COOR H
t . .
~L~8;32~
in which R represen~s an aliphatic radical having 1 to 6 carborl atoms, an alic~clic rad;cal having ~ to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or arl araliphatic radical having 7 to 15 carbon atoms, a~ A and B1 denote hydrogen, and ~2 and C together form a chain of the formula -CCH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula ~CCll2~p~CH=CH~CCH2~q-, with ~p+q) being 1, 2, 3 or 4, b) C and B2 denote hydrogen, and A and B1 together form a chain of the formula -~CH2~n-, with n being 3, 4, 5 or 6, or a chain of the formula ~[CHz~p-CH=CH~[CH2]q-, with (p-~q) bein~ 1, 2, 3 or 4, or c) A and C denote hydrogen, and B1 ?nd B2 toyether form a chain of the formula -[CH2]m-, ~ith rn being 4, 5, 6 or 7, by crystallizat;on of diastereomeric salts, which process compr;ses preparing the salts of the racem;c esters with opt;cally active N-acylated R or S-aminocarb~xylic acids which contain a phenyl nucleus, recrystallizing them froM
an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decompos;ng the precipitated, optically homogeneous diastereomer;c salts in a manner known per se, and isolatil1g the enantiomers of the formulae Ia and Ib and, where appropriate, converting the latter into the free acids by hydrolysis or hydrogenolysis in a manner known per se.
Resolution of racemates of compounds of the for-mula Ia and Ib ;n which a) A and B1 denote hydrogen, and B2 and C together forrn a cha;n of the formula -~CH~]n-, with n being 3, 4, 5 or 6, or a chain of the - formula ~CH2]p~CH=CH~[CH2]q~ with (p~) being 1, 2. 3 or 4, or b) C and B2 denote hydrogen, and A and B1 together form one of the chains defined above under a) ; s pref erred.
A particularly preferred variant of the process comprises precip;tating, preferably as crystals, the salts of racemic bicyclic esters of the formulae Ia and Ib ;n wh;cil the two br,dgehead hydro~en etoms have the cis con figuration and the COOR-group is oriented endo with respect to the bicyclic ring system.
Particularly suitable imino-~-carboxylic esters are este s with aliphatic, alicyclic or araliphat;c alco-holsr which can be cleaved by hydrogenolysis or hydrolysis,as are described in, for example, Houben-Weyl, Methoden der organischer) Chemie (Methods of Organic Chcmistry), Yolume XV/1, Stuttgart 1974, on pages 314 427, or "Peptide Synthesis", by Bodanszky et al.~ 2nd edition (1976), John l~iLey & Sons. Esters of the formula Ia + Ib in which R
represents alkyl having 1 to 6 carbon atoms, cycloalkyl having Jt to 8 carbon atoms or aralkyl having 7 to 13 car-bon atoms, which can optionall~ be substituted by N02~ are preferred, ;li particular alkyl esters having up to 4 alkyl ~'~8~9 carbon atoms alld aralkyl esters, such as benzyl, nitrobenzyl or benzhydryl esters.
Examples of suitable N-acylated aminocarboxylic acids containing a phenyl nucleus are derivatives of R- or S-phenylalanine, -C-phenylglycine, -~-phenyl-a-aminobutyric acid, -3,4-dihydroxyphenylalanine, -~-phenylserine and -tyrosine. N-Acyl derivatives of R- or S-phenylalanine, -C-phenylglycine and -tyrosine are preferred.
The N-acyl protective groups which can be used are the customary NH2 protective groups described in, for example, Houben-Weyl, Volume XV/l, pages 46-305 or Bodanszky et al., "Peptide Synthesis", 2nd edition (1976), John Niley & Sons.
Alkanoyl having 1 to 6 carbon atoms, in particular formyl, tert.-butoxycarbonyl, and benzyloxycarbonyl are preferred.
Any free OH groups present can, where appropriate, be O-alkylated by alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl or tert.-butyl, by benzyl or by other OH
protective groups customary in peptide chemistry (cf. for example Houben-Weyl, Volume XV/1 or Bodanszky et al., "Peptide Synthesis", 2nd edition (1976), John Wiley & Sons).
Suitable and preferred solvents are aprotic organic solvents, such as, for example, esters, ethyl acetate, cyclohexane and tetrahydrofuran, but it is also possible to use alcohols having up to 6 carbon atoms.
Octahydroindole-2-carboxylic acid is known from U.S.
Patent 4,350,704. Canadian Patents 1,187,087, 1,193,607 and 1,197,252 relate to 2-azabicyclo[3.3.0]octane-3-carboxylic acid, and Canadian Patents 1,223,868 and 1,227,802 relate to 33~g 2,3,3a,4,5,7a-h~xahydro[lH]indole-2-carboxylic acid. Canadian Patent 1,198~ relates to octahydroisoindole-l-carboxylic acid and 3-azabicyclo[3.3.0]octane-4-carboxylic acid.
Racemic bicyclic cis, endo-imino-a-carboxylic acids of the formulae Ia + Ib, in which C and B2 denote hydrogen, and A and Bl toge~her denote the abovemen~ioned chain, can be prepared fxom, for example, enamines of a cycloalkanone and N-acylated ~-halogeno-a-aminocarboxylic esters of the formula IV, in which X' represents a nucleofugic group, preferably chlorine or bromine, Y' represents alkanoyl having 1 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or other protective groups which are customary in peptide chemistry and which can be split off with acid, and R4 represents alkyl having 1 to 5 carbon atoms or aralkyl having 7 to 9 carbon atoms, X' \CH2 ( IV ) CH
Y ' -HN COOR
or with acrylic esters of the formula Y, in which Y' and R4 have the abovementioned meaning, ~ CoOR4 2 \~ ( V ) NH-Y' by reacting the latter to give compounds of the formula V
in which A, B1, R4 and Y' have the abovementioned meaning, B / COOR
C~3~ = C \
~ ~H-~' (VI) A O
cycl;zing the latter using strong ac;ds, with cleavage of the acrylamide and ester, to give compounds of the formula VIIa or b, A ~ COO~I (VII~) ~31 ~ ~ ~ Coo,~ ~VI~) corlvert;ng the latter, by catalytic hydrogenat;on ;n the presence of transit;on metal catalysts or by reduction w;th borane-am;ne complexes or complex borohydrides in lower alcohols, into compounds of the formulae Ta and Ib in which R represents hydrogen, and esterify;ng the latter to ~ive compounds of the forMulae Ia and Ib ;n which R has the mean;ng def;ned ahove.
~ acemic bicyclic imino~a-carboxylic acids of the formuLae Ia and Ib~ in which A and B1 denote hydrogen and 8~
9 _ B2 and C together denote the chain mentioned, can be pre-pared from, ~or example, compounds of the formula VIII
~32 C
~ ( H
- ~ ~ (VIII) in which the br;dgehead hydrogen atoms are oriented cis or trans with respect to one another, and B2 and C have the abovementioned mean;ng.
Compounds of the formula VIII with n ~ 1 are known from R. Griot, Helv. Chim. Acta 42, 67 (1959), and those ~ith n = 2 are known from C.M. Rice et al., J. Org. Chem.
Z1, 1687 (195a).
These compounds-of the formula VIII are acylated in a known mannerr an aliphatic or aromatic acyl radical, preferably an acetyl or benzoyl radical, being bonded to the nitrogen atom, and the resulting N-acylated compounds 1S are subjected to anodic oxidation (in analogy to Liebigs Ann. Chem. 1 _ , page 1719) in an aliphatic alcohol, pre-ferabLy an aLcohol having 1 to 4 carbon ato~,s, in particular methanol, in the presence of a conducting salt, pre-ferably at temperatures in the range from 0 to +40C, ~lith the formation of a compound of the formula IX in which ~2 and C have the abovementioned meaning and R5 = C1-C4-alkyl.
83~9 B G
13 7 ~1 (IX) yl Thc result;ng compound of the general formula IX
is reacted w;th trimethyls;lyl cyanide by the method of Tetrahedron Le~ters 1981, page 141, in a hydrocarbon or halogenated hydrocarbon, in ether or in THF, at tempera-tures in the range from -60C to +20C~ preferably -40C
to +0C, ;n the presence oF a Lewis acid, such as, for exaMple, ZnCl2, SnCl2, SnCl4, TiCl4 or BF3-etherate, preferably BF3-etherate, and the resulting compound of the formula X
E C
< ~ CN ~X) Acyl in which the bridgehead hydrogen atoms are cis or trans with respect to one another, the Cl~ group being located cis with respect to the bridgehead hydrogen atom on carbon atom (4~n~, and in which n, B2 and C have the aLovelnentioned meanings, ;s, after pur;f;cation and resolution of the mixture of diastereomers by recrystallization or colurnn chromatography, hydrolyzed in a known ~anner by the action of acids or bases to sive a compound of the formulae Ia and Ib, with R = hydro~ien, and the latter is esterified.
83~3 HCl or ~IBr, in par~icular, is used as the acid for the acid hydrolysis of the ni~rile group. In this instance and in those ~hich follow~ the es~erification is carried out by ~he procedures cus~omary in aminoacid chemistry.
The invention also relates to optically hoMogeneous compounds of the forrnula Ia or Ib`in which the two bridge-head hydrogen atoms have the cis configuration, the COOR
group is oriented endo w;th respect to the bicycl;c r;ng system, the carbon atom a to the COOR group has the R or S configuration~
P. represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms, which can optionally be substituted by N02, and A, B1, B2 and C are defined as above, and to those compounds of the formulae Ia or Ib in which R denotes hydrogen a~d a) A and B1 denote hydrogen, and B2 and C together form a chain of the forMula -CCH2~n-, with n being 3, 4, 5 or 6, or a cha;n of the formula ~~CH2]p~CH=CH~CH2]q~~ ~ith (p+q) bring 1, 2, 3 or 4, or b) C and B2 denote hydrogen, and A and B1 together form one of the chains defined abovc a), with n being 3, 5 or ~ and (p~q) being 1, 2~ 3 or 4, and their salts.
The invention also relates to diastereomeric salts of a bicyclic cis, endo imino~a~carboxylic ester of the form(lla Ia or Ib, ;n which A, B1, B2, C and ~ have the meanings def;ned above as bein~r~ preferred, anrJ an optically ~332~9 active N-acylated R- or S-aminocarbox~lic ac;d which con-tains a phenyl nucleus and which is protected as defirl~d above~
The invention aiso relates to.the use of the opti~
S cally pure compounds of the formula Ia or Ib ;n a process for the preparation of optically pure compounds of the general formulae IIa or IIb ~1 ~;2 C
COOII
A \ ~
I * # Y
O = C - Cl-l -- N13 ~ C~H -- ~C~2~r ~1 co B1 ~32 C
A ~ C i ! O ' i o = c - c.~ - c;~ c.~ c - :~ (rr R Co2r~ ~, in which it ;s possible for the carbon atoms !abeled with an asterisk (*) each, ;nciependently of one ano~her, to have the R- or the S-configuration, a~ A and B1 denote hydrogen, and B2 and ~ together forr,~ a chain of the formula [CH2~n-, n being 3, 4, 5 or 6, or a chain of the formula -LCH2ip-Ch=CI~-[CH23~- , l'Z8~9 tp+q) being 1, 2, 3 or 4, b) C and B2 denote hydrogen, and A anG s1 together form a chain of the formula -C~H2]n-, w;th n being 3, 4, 5 or 6, or a chain of the formula ~CCH2]p~CH-CH~~CHz~q~, with (p+q3 being 1~ 2, 3 or 4~ or c) A and C denote hydrogen, and B1 and B2 together form a cl,ain of the formula -tCHz~n-, with m being 4, S, 6 or 7, r denotes 0 or 1, R1 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 $o ~ carbon atoms, an optionally substituted aLicyclic-aliphatic radical hav;ng 4 to 11 carbon atoms, an optionally subst;tuted aromatic radical hav;ng 6 to 12 carbon atoms, ~hich can also be partially hydrogena~ed, an optionally subst;tuted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroyl-aliphatic radical having 8 to 13 carbon atoms, an optionally substituted monocyclic or bicyclic hetero-cycl;c radical having S to 7 or 8 to 10 ring atoms respectively, 1 or Z of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these rin~ ato,ns being n;trogen atoms, or a side chain of a naturally occurring aminoac;d ~Jhich is optionally protected, R2 denotes hydrogen, an optionally substituted aliphatic radical havillg 1 to 6 carbon atoms, or an optionally substituted aralipha~ic radical having 7 to 1S carhor 24~3 atomS r Y denotes hydrogen or hydro~yl, Z denotes hydrogen, or Y and Z together denote oxygen, and X d~notes an aLiphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 5 to 9 carbon atoms, an optionalLy subst;tuted aromatic radical having 6 to 12 carbon atorns, or indolyl~
which process comprises reacting, in the presence of a condensing agent or, where appropriate, as an active ester, optically pure compounds of the formulae Ia or Ib, in which A, 81, B2 and C llave the abovementioned meanings, and R represents an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 4 to 10 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms or an optionally substituted araliphatic radical having 7 to 15 carbon atoMs, with optically pure compouncds of the formula III
~ (I I I) HOOC - J~ N}l - Cll - [ CH~ ] C~ X
C2F~ Z
in which the two carbon atoms labeled with an asterisk (*) have the (S,R~, ~R,S), (R,R) or~ preferably, (S,S) configuration, and R, ~1, R2, X, Y and Z have the abovement;oned meanings, splitting off the radical R by hyclrogenolysis or hydroly-s;s~ and, where appropr;ate, converting the optically ~83249 pure compounds of the forrnulae IIa or IIb ;nto physio-logically tolerated salts~
A preferred embodiment of the process according to the invent;on compr;ses preparing compounds of the for-mulae IIa or IIb, in which r denotes 0 or 1, R denotes hydrogen, (C1 to C6)-alkyl or araLkyl having 7 to 9 carbon atoms, R1 denotes hydrogen or (C1 to C6)-a(kyl, which can opt;onally be substituted by amino, (C1 to C6)~acYl-amino or benzoylamino, (C2 to C6)-alkenyl, (C5 to C9)-cycloalkyl, ~C5 to C9)-cycloalkenyl, 5C5 to C7)-cyclo-alkyl-(C1 to C4)-alkyl, aryl or partially hydrogenated aryl hav;ng 6 to 12 carbon atoms, each of which can be substitut~d by (C~l to C4)~alkyl, (C1 or C2)-alkoxy or halogen, (C6 to C12) aryl-(C1-C4) alkyl or ~c7-c13)-aroyl-(c1~c2)-alkyl~ bo~h of which can be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocycl;c radical having 5 to 7 or 8 to 10 r;ng atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms be;ng n;trogen atoms, or an optionally protected side chain of a naturally occurring aminoacid, `
R2 denotes hydroyen, (C1 to C6)-alkyl, (C2 to C6)-a~kenyl or (C6 to C12)-ary~(C1 to C4)-al~yl~
Y denotes hydrogen or hydroxyl, Z denotes hydroger1~ or Y and Z together denote oxygen~ and lX~33Z49 X denotcs tC1 to C6)~al~yl, (C2 to C6~-alkenyl~
tC5 to C~-cycloalkyl~ (C6 to C12)-aryl, which can be monosubstituted, disubstituted or trisubstituted by (C1 to C4)-alkyl, (C1 to C4)-alkoxy, hydroxyl, halogen, nitro, amino, ~C1 to C4)~alkylamino, di-(C1 to C~
alkylamino and/or methylenedioxyt or 3 indolyl.
The preparation of the S,S,S-compounds of the formula Ila is preferred.
In this context as in the following, aryl is to be understood preferably to include optionally suhstituted phenyl or naphthyl. Alkyl can be straight-chain or branched.
Examples of a monocyclic or bicyclic heterocycliç
radical having 5 to 7 or 8 to 10 ring atoms respectively, ;n which the ring atoms have the abovementioned meanings, inclucle thienyl, benzoCb3thienyl, furyl, pyranyl, benzo-furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi-dinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, ~uinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxa-zolyl, isoxazolyl, thiazolyl or isothiazolyl. It is also possible for these rad;cals to be partially or completely hydrogenated.
Where R1 represents a side chain of a protected naturally occurring a arninoacid, such as, for example, protected or optio1lally substituted Ser, Thr, Asp, Asn, Sluf Gln, Arg, Lys~ Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the pre~erred protective groups are those groups customary in peptide chemistry (cf. Houben~1eyl, Vol.XVi1 ' ~;~8~249 and XV~2). In the c~se where R1 denot~s a protected side chain of a lysine, the known am;no protective groups, but in particular (C1-C6)-alkanoyl, are preferred. Preferred 0-protective groups for tyrosine are methyl or ethyl.
In the procedures hither~o known for preparing mixtures of stereo;somers of compounds of the formulae IIa or IIb, which s~arted from mixtures o, stereoisorners, ;t was necessary to use elaborate separating procedures to separate the reaction mixture in order to obtain the desired op~ically pure stereoisor,lers of the formula IIa or IIb. By reacting the optically homogeneous imino-a-car-boxyl;c esters of the formulae Ia or Ib according to the invent;on with optically homogeneous compounds of the for-mula III, specific synthesis of opt;cally homGgeneous com pounds of the formula IIa or IIb has become possible.
The desired compounds of the formulae IIa or IIb are obtained ;n high yields without using elaborate separating techniques.
Compounds of the formu~a III are described ;n the abovement;oned documents or are known from European Patent A 46,953. The reaction of a compound of the formula III
w;th tert. butyl 1-~2~,3~,7~ octahydro-C1H~-indole-2-carboxylate followed by el;minat;on of a t&rt.-butylester, wh~reupon a corresponding octahydro;ndole derivative of the formula IIb results, is known from Europear, Patent A 37,231.
llowever, it has been necessary to restrict this reaction to react;on of a compound of the formula Ia or Ib with C and e2 each bein3 H and A ~ B1 being (CH2)4, and ~ 2 it has hitherto only been possible to prepare this in a complicated manner via the N-benzoyl compound, crystallization of the diastereomeric salts with S-~-phenylethylamine, liberation of the N-benzoyl compound, elimination of the benzoyl group and esterification.
It has not hitherto been possible to transfer this reaction sequence to the intermediates of the formula Ia and Ib according to the invention. Nor has it been possible to resolve racemic mixtures of compounds of the formula IIa and IIb by separating conventional diastereomeric salts with optically active carboxylic or sulfonic acids. The compounds of the formula Ia and Ib have been made accessible for subsequent reactions or the first time by the procedure described above.
The process according to the invention is particularly cost-effective, since compounds of the formula III can be prepared directly in an optically pure form by straightforward routes from Canadian Patents 1,187,087, 1,193,607 and 1,197,252. However, in this reference, it was still necessary for these intermediates to be reacted with a racemic aminoacid and to be converted into an optically pure compound of the general formulae IIa and IIb by an additional purification step.
The process ~ccording to the invention, which is preferably carried out with S,S compounds of the formula III, thus represents by far the most cost-effective process for the preparation of the compounds covered since, in all the other known procedures, great losses have to be accepted due to the f1 chromatography or crystallization of mixtures . ~
~832~9 of stereo;somers, some of ~hich are complex.
The condel1sation step is carried out by one of the conventional processes of peptide syntllesis which involve little race~mization, such as are described in, for example, Houben-Weyl, Volume XV, or in "The Pept;des - Analysis, Synthesis, Biology, Vol.1 Major Methods of Peptide 80nd Eorlnat;orl, Part A", Gross, Meierhofer, Academic Press N.Y.
~1979). The DCC/HOBt method of Chem. Ber. 103 (1979), pages 788-798, is particularly advantageous. In this context, it should be taken into account that reactive functional groups in the radical R1 must be temporarily pro-tected by the known methods of peptide chem;stry tfor exarnple Houben-Weyl, Volume XV, or Bodanszky et al. in "Peptide Synthesis", 2nd edition (1976), John ~liley & Sons).
The optically homogeneous compounds of the forMula IIa or IIb are obtained, after eliminat;ng R and, where appropriate, R2, in high yield in a manner known per se w;thout using elaborate separating techn;ques.
The compounds of the formula IIa and IIb and their salts have long-lasting and powerful hypotensive activity.
They are potent inh;b;tors of angiotensin convert;ng enzyme (ACE) and can be employed to control high bLood pressure of a variety of etiologies. ACE inhi~itors of this type are known from, for ex~ampler U.S~ Patent 4,344,949, European Patent A 49,658, European Patent A
46,953, European Patcnt A 50,~00 and European Patent A
79~022.
It is also possible to combine them with other compounds having hypotensive, vasodilator or diuret;c . - :
.
.
- ' .
~Z~33~49 ~, act;vity. Typ;cal representat;ves of these classes of ~ctive co~pounds are descrihed in, for example, Erhardt-Rusch;g~ Arzneir,littel (Drugs), 2nd edit;on, ~e;nhein, 1972.
They can be administered intrave~ously, subcutaneously or oraLly.
The dosage on oral adm;nistration is generally 1-S00 n~g, preferably 1-100 mg, per single dose for an adult patient of normal weight. It is also possible to increase this ;n severe cases, s;nce no tox;c propert;es have h;therto been observed. It is also poss;ble to reduce - the dose and this is part;cularly appropr;ate when diure-tics are adm;nistered concurrently.
The compounds according to the invention can be administered orally or parenterally in appropr;ate pharma-~5 ceut;cal formulations. For a form for oral use~ the activecompounds are mixed with ~he add;t;ves customary for this purpose, such as vehicles, stab;l;zers or inert diluentsr and converted by customary methods ;nto su;table forms for adm;n;strat;on, such as tablets, coated tablets, hard gelat;n capsules, aqueous, alcohol or o;ly suspens;ons or aqueousr alcollol or oily s~lutions. Examples o-f su;table inert vehicles which can be used are ~um arabic, ma~nesium carbonatet potassium phosphate, lactose, glucose or starch, ;n particular corn starch. Th;s can entail formulation e;ther as dry or as rnoist granules. Examples oF su;table o;ly vehicles or solvents are vegetable or an;mal oils, such as sunFlower o;l or fish liver o;l.
For subcutaneous or intravenous administration~
the act;ve compounds or their phys-,ologically tolerated , ~
lf2~1133~49 salts are converted into a solution, suspension or emulsion, where appropriate with the substances customary for this purpose, such as solubilizers, emulsif;ers or other aux;liaries. Examples of suitable solvents for the new ac~ive compo~lnds and the corresponding physiologic3lly tolerated salts are: water, phys;ological saline or alco-hols, for example ethanol, propanediol or glycerol, but also sugar solutions, such as glucose or mannitol solutions, or even a mixture of the various solvents or solutions mentioned~
The Examples which follow illustrate the process, but there is no intention to restrict the invention to these specific ~xamples.
Example 1:
Benzyl (1Sr 3S, 5S)-2-azabicyclo~3.3~0~octane-3-carboxylate hydrochloride _abbreviated to (S _ Aoc-OBzl-HCl) _ _ _ (A) Mettlyl 2-acetylamino-3-(2-oxocyclopentyl)propionate:
269 g of methyl 3-chloro-2-acetylaminopropionate and 257 g of cyclopentenopyrrolidine in 1.5 liters of DMF
are kept at room te~perature for 24 hours~ The mixture is evaporated in vacuo, and the residue is taken up in a little water~ the pH is adjusted to 2 with concentrated hydrochloric acid and the solution is extracted twice with 4 liters of ethyl acetate each time. A pale yellow oil remains on evaporating the organic phase.
Yield: 2~0 9.
1H-NMR:2.02 (s,3H); 3.74 (s,3H~; 4.4-4.8 (m,1H), (CDCl3) 3 ;~ Z4g - 2~ -Analysis: C H N
calculated 58.1 7~S4 6.16 found 5~.5 7.2 6.5 (~) c ~endc-2-Azabicyclo[3.3.n]octane-3-carboxylic acid S hydrochlor_de 270 g of the acetylaminG der;vative prepared under (~) ;n 1.5 liters of 2 N hydrochloric acid are boiled under reflux for 45 minutes~ The mixture is evaporated in vacuo, and the res;due is taken up in glacial acetic acid, 5 y oF Pt/C (10% Pt) are added and hydrogenation is carried under S bar. After filtration, the filtrate is evaporated and the residue is crystall;zed from chloroforrn/diisopropyl ether.
Melt;ng point: 205-209C, Yield: 150 g (C~ Racemic Aoc-OBzl.~lCl .. . . .
1.2 liters (11.5 mol) of benzyl alcohol are cooled to -10C. 126 ml (1.73 mol) of thionyl chloride are added dropw;se, with cooling and stirring, and then 126.5 g ~D.66 mole) of crude Aoc.HCl are added at -10C, with stirring, and the mixture is then stirred at this tenpera-ture for 30 minutes. The temperature is then allowed to r-ise slowly to 20-25C with stirring, the product dissol-ving within 5 hours. After standing overnight, the brown solution is run into 4uO liters of diisopropyl ether uith stirriny. After 1 hour, the precipitated crystals are filtered off, washed with diisopropyl ether and dried in - 23 ~ 24'~
vacuo. A further precipitate separates out of the com bined diisopropyl ether solutions overni~ht~
Yield: 168.5 9 ~O.~X~
~D) (S~-Aoc-ORzl.~-Phc~OH
166.0 9 (0.589 mol) of racemic Aoc-OBzl.HCl are suspended in 500 ml of methylene chloride and thorouqhly sha~en with 25 9 (O.ti25 mol) of NaOH in 250 rnl of ~ater.
A solution is proc'uced. After a short time the initially formed emuls;on has separated. The methylene chloride phase ;s separated off, washed ~lith 100 mL of 0.1 N NaOI!
and twice with 50 rnl of water each time and the combined aqueous phases are extracted twice ~lith 100 ml of methylene chloride each time. The combinetd methylent? chloride phases are dried over sodium sulfate and evaporated ur~der m;ld cond;tions w;th waterpump vacuum. The remainins oil is imrnediately taken up in 100 ml of ethyl acetate, and a solution of 117.6 9 (0~39 mol) of N-benzyloxycarbonyl-S
phenylalanine (7~Phe~O~J) in 200 ml of ethyL acetate is added. The flask ;s rinsed with 100 ml of ethyl acetate.
2C 1,600 ml of cyclohexane (- 4 times the amount by volume) are added, w;th stirring, to the clear solution at rcorn ternperature. After scratching, crystallization starts, and th;s is completed by standing overn;gh~ in a cold room.
The crystalline precipitate is filtered off, washed ~ith 250 ml of ethyl acetate/cyclohexane (1+4) and dried.
Yield: 133.6 g of (S) Aoc-OBzl.Z-Phe-OH (50.9%~ corres-ponding to 102% of theory), melt-ing point 101-103C; ta~D7: ~5 3 (c = 1, rnethanol).
After recrystallization from ethyl acetate/cyclo-- 24 ~ 3~49 hexane ~1:1), the follouing data are found for the Z-Phe-OI-I
salt:
melting point: 103-10'~C, Ca]D7: -6.1 (c = 1, in methanol).
(E) ~S)-Aoc-OBzl.HCl 63.0 g (0.142 mole) of the Z-Phe-OH salt obta,ned according ~o (D) are dissolved in 300 rnl of methylene chloride and the Solutiol1 is thoroughly shaken with $
(0.15 mole~ of NaOH in about 150 ml of water. Phase separation takes some time because of a small amount of 1Q insolubles. The methylene chloride phase is separated off, washed with 50 ml of D.1 ~ NaOH and twice with 50 rill of water each tirne and dried. The solution is evaporated to about 100 ~l, diluted with 100 ml of diisopropyl ether and, ~;th stirring, 25 ml of 6 N HCl in ether are added. After 1 hour, the mixture is filtered, and the precipitate is washed with diisopropyl ether and dried.
Yield: 3Z.5 9 (~1.3%) Melting point: 185-186C
~a]D -42.5 (c = 1, water) Methylene chloride is removed from the basic aqueous phase in vacuo, and it is acidified with toncen trated HCl. The prec;pitated Z-Phe-OH ;s washed with water and dried.
The R compound and further Z-Phe-OH are obtained from the methylene c`hloride mother liquor from Example I(D~
in the manner describecl~
- 2 5 - ~.Z~3324~9 r-- G O
O ~~t '1 f~~f\l ,_ ~ ~~ =r o.~3 f~ `
rl ~;oL) O~ O~') ~_ f~l c~ ~D
O t~
C~ CO
Cl E~
f`) ~f~ O O O O O O O O O
CJ~~f~ C~ O C~ - CV f~ :r ^ f~l r-- O~ C'~ .-- C~ CJ~ O~ ~D CO
S tf~ :r s s ` rfl f,~l f~ .. 0 ~) I I I I 1 1' ~ I I '~' ~0 o~ a ~" r~
0~C~ V OU 0~ OC~ 0;~ OC~
<~ n u~ f~ f 0~ CO C.~ C~ COCOCO Lf~
C~ ,fl I=l I CO r.
E C~ C~ ~ C C Cl~
~ ~ ~_ _ _ _ ,_ ~
.~
- T~ :C o ~ ~ C~ C
C~ O O O
O O O O t-- O O O O ~ ~--~J ~ CO~J ~ ~ r,~ f? ,f~ r_ O ~O=J' ~'~ O f'~
,~ + ~ I +
a .~
V V V ;) V V ~ ~J V ~ c C~ o o o o o o o o o o o tu ~u~ _r=r o ~ n c~_. ~ co ~ ' tf~ C~C~ t~ t,~ ~C,._ ,_ ,_ ~n. I I I I \ I I I I I I
f~ n30 ~c~ t~J n :. -- f ~ _~-- ~-. , _ ,_ ~ _, _,_ ,. ~_ ,_ , ._ s . ~O à) ~ ~ à~ ~d ~ ~ ~
fa a, s^ ~ a) ~ o a~ ~ aJ c: a~ to a~
a, s- a~ aJ f`' 'ILJ~ ~Xa ~J' ~ C ( ) tll N
,c~t S,tl~ CJ n~ CJ ~(D ~,a~ aJ S. fV tO CJ 11~ C) -~ ~) J O~' -~ O J J OJ OC~ --J -- O --' O
o f-~ S ~-- L ~ r_1 L
aJj~ L~111i~ L~i~ L~ V LLI L~ i~; i ~) C t iL ~~C ~ 5~
C~C~ IS I I ~ rl f~. C) J, t!?
c~ P.r~_ P~ E-~ ~-- '~i S. S-~. P. t ~3 1 i II I I I rt~ O
~ tii t~ C`l ~ LL, C~ ti t~l , 1 ,"~ , .~ O ~t '~
tL~ S_ c~ ~ s^S` c c~ ~ S~ t' ;~
L ~? ~ ~li)C; C; CvC?, C~ ;) (li C) tl_ t~ t~t~ ~tl~ t' . P~ r~ ~ t G)I X H i H
Jo S_ ~3 -D H H t- I H H H H H H 1-1 t- I
t E ,;~, X ~ X: C X :~ ~C X X
L f~ t~ n ~D t-- co C~ C~
o sv ~ ~ ~
IIJ Q
- ~6 - ~ 9 The Ccis,endo~-imino-~ carboxylic esters in Tablt-~ 1 are prepared and subjected to racemate resoLution in an analogGus manner. This Table details their optically acti~e crystallization par~ners, and the solvents, yields and properties of the salts and the final products in the form of the ester hydrochlorides or ester ~osylates.
Explanations of Table 1 .
(XI) - ~ ~
~ N~COOR and mirror image (XII) H
and mirror image ~ H
10 (XIII) ~\
~ /~ COO~ and mirror image The free iminocarboxylic acids can be prepared from the esters by hydrolysis or hyrlro~enolysis.
Exa_ple 13 N-t1S- _rboethoxy 3~phenylpropyl)-S-alanyl-2-cis~endo-1S azabicycloL3.3.0]octane-7S-carboxyl,c acid - 27 - ~8~249 (A) Benzyl N-(2S-ca_boethox_-3-phenylpropy()-S-alanyl-c;s,endo-2-azab;cycloC3.3.0]octane-3S-carboxylate 11~ 9 of the benzyl ester hydrochloride prepared according to Example 1 E are converted into the free ester S by extracting by shak;ng the alkal;ne aqueous solution w;th d;ethyl ether, and~ after dist;ll;ng out the e.her, are reacted w;th 6.7 9 of Hos~ 13.8 g of N-(1S-carbo-ethoxy~3-phenylpropyl)-S-alan;ne and 10~Z g of d;cyclo-hexylcarbod;;mide ;n 200 ml of dimethylformam;de. After st;rr;ng at room temperature for 3 hours, the precip;tated d;cyclohexylurea is filtered off, and the filtrate is evaporated, and the residue is taken up in 1 liter of ethyl acetate and th;s solut;on is extracted by shaking with 3 x 500 ml of 5 per cent NaHC03 solution. The organic phase ;s evaporated.
22.4 9 (90X) of product are obtained as an oil.
SHNMR of the S,S,S-compound, characteristic signals:
1.20 td,3H~, 1.27 ~t,2H~, 4.17 (q,3H), 5.13 (s,2H~
7.18 (s,5H~, 7~32 (s,5H) (CDCl3) Analysis: C H N
C30H3~N20s calculated 71.1 7.56 5.53 found 70.8 7.8 5.7 (B) N-(1S-Carboethoxy-3-pher)ylpropyl)-S-alanyl-c;s,endo-2-azabicycLoC3.3.0]octane-3S-carboxylic ac;d 8.0 g of the S,S,S-benzyl ester from Example 1 E
are d;ssolved in 100 ml of ethanol, and the benzyl group is removed by hydrogenolysis under atmospheric pressure with the addit;on of 0.5 g of 10% PdtC. This reactiol can also be carried out urder elevated pressure which ;nvolves 2~ 33249 shortenin~ of the reaction time. After the caLculated amount of hy(lrogen has been taken up, the catalyst is fil-tered off and the fil~rate is evaporated in vacuo. The ~itterion crystallizes from ether in a virtually quanti-tative yield:melting point: 110-112C (decomp,osition) A hydrochloride ~decomposition above 120C) can be obtained by addit;on of an equ;valent amount of hydrochloric ac;d.
Analysis: C H N
C23H32Nz05 c~lcu~a~ed 66.3 7.7 6.73 found 66.1 7.8 6.6 The 1H NMR and mass spectra which are obtained are consistent with the structure indicatedO
~]D = ~-15~6 (c = 1, rnethanol).
Example 1~
N-(1S-Carboethoxy-2-benzoylethyl)-0 ethyl-S-tyrosyl-c7s,endo-2- zabicyclo~3.3.030ctane-3S-carboxyl;c acid (A) N-(1S~Carboethoxy-3~ y~e~pyl)-o-ethyl tyrosine benzyl ester 24 ~ of ethyl benzoylacrylate in 100 ml of ethanol are reacted w;th 30 g'of 0-ethyl-S-tyros;ne benzyl ester in the presence of 0.5 ml of triethylamine and~ after evaporating the solution and diDesting the resitdue with diethyl ether/petroleum ether (1:1) and drying in vacuo, 42 g of RS,S compound are obtained. Resolut;on of the diastereomers by chromatography on silica gel using the system ethyl acetate/cyclohexane (1:3).
Y;eld: 17 9 of the S,S conipour,d.
- 2~ .Z~33~4~
(B) N~ Carboe_hoxy-3-phel1ylpropyl_-0-ethyl-S-tyrosine 17 g of tl1e compound obta;ned accord,ng to (A) in 800 ml of acetic acid are hydrogenated with 4 9 of Pd/C
(10%) under 1Q0 bar and at roorn temperature. Yield after chromatography on silica gel using the solvent ethyl ace-tate/cyclohexane (1:3) and drying the res;due from evapora-tion: 12 g of title compound wh;ch is virtually homo-geneous by thin-layer chromatography.
Melt;ng po;nt 205-213C
10 Analys;s: C23H2gNOs (399.5~
calcula ed C 69.15 H 7.31 N 3.50 found C 69.5 H 7.4 N 3.3 (C) N-(1S-Carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-.
c;s,endo-2-azab;cycLoC3.3.0]octane 3S-carboxyl;c acid ___ In analogy to Exarnple 13 A, ~ g of the free benzyl ester obta;ned in accordance w;th Example 1 E and extracted from alkal;ne solut;on by shak;ng with d;ethyl ether are reacted w;th 8 9 of the cornpound obtained in accordance w;th Example 14 B us;ng 4.4 g of d;cyclohexylcarbod;;m;de in the presence of 2.7 g of 1-hydroxybenzotriazole, and 14.3 9 of oily benzyl ester are obta;ned as an ;nterrnediate.
The 1H NMR and mass spectra are cons;stent w;th the structure ;ndicated.
The benzyl ester in 50 ml of ethanol ;s cataly-t;cally hydrogenated on Pd/C under atmospheric pressure.
After filtering off the c-atalyst and distill;ng off the solvent~ there remains a sol;d res;due whicl1 ;s d;gested with diethyl ether/petroleurn ~ther and ;s dr;ed.
Y;eld: 11.2 g ~ 30 ~ 1Z 8 32 Exarnple 15 N-~15-Carboethoxy 3-phenylpropyl)-0-methyl-S-tyrosyl-.. . . .
cis,endo-~-azabicyclo~3~3.0~octane-3S-carboxylic acid _ _ _ , _ _ The procedure is carried out as described in Example 14~ but in the stage analogous to (A) 0-methyl-S-tyrosine benzyl ester is used and the title compound is obtained, the 1H NMR spectrum of which is consistent with the structure ;ndicated.
1H NMR (CDCl3): 1.2-3.0 (m,15H); 1.27 (t,3~l); 1.4 (t,3H);
3.0-4.3 tm,4H), 3.8-4.2 (rn,4H)~
6~5-7.1 (2d,4H); 7.3 (s,SH) Example 16 N-(1S-Carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-. . .
C4.5]decane-3S-carboxylic ac;d (A~ 1-(D;ethoxyethyl)cycloh =
51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protectivc gas at -10C, to 312.5 ml ~0.5 rnol) of a 15X strength solution of n-butyllithium ;n hexane. The mixture is st;rred for 20 rninutes and then cooled to -70C. 54.6 g of cyclohexanecarbonitrile are added dropwise over the course of 30 rninutes and, after a further 30 minutes, 98.5 g of brorooacetaldehyde diethyl acetal are added with;n 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 rml of ethyl acetate, and the organic phase is dried over sodiurn sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation.
Yield: 90 g (about 80% of theory), boiling point 7X-7~C at -~ ~ :
~ 31 - ~83Z49 S torr t10.7 mbar).
(B) 1~A_inomethyl-1-t_ ethyloxyethyl)cyclGheYane 90 g of d1e~hyloxycyclohexanecarbon;trile are dissolved in 1 ~iter of ethanol, and 60 g of sodium are added~ After the metal has d;ssolved, 100 ml of ~later are added and the solvent is largely removed in vacuo. 300 ml of ~Jater are added to the residue and the mixture is extracted 3 x with 200 ml of ether. The ethereal phase is dr;ed over sod;um sulfate, evaporated and distilled in vacuo.
Yield: 83 g (about 90% of theory), boiling point 69-72 at 8 torr (10.7 mbar) (C~ 2 AzaspiroC4.5]decane-3-carbonitrile 80.2 g of aminomethyldiethyloxycyclohexane are stirred in a mixture of 300 ml of ethanol and 300 ml of 1 N hydrochlor;c acid under a protective gas (N2 or Ar) for about 1 hour.
After the starting product has been comple~eLy cleaved, the mixture is cooled to 0C and the solution is rapidly adjusted to pll 5 by adding 2 N sodium hydroxide solution. 300 ml of glacial acetic acid are immediately added (pH about 3), and the mixture is cooled to -10C
and 17.5 9 of sodium cyanide are added. The reaction vessel is closed and left at room temperature for about 5 hours.
Completion of reaction is checked using tllin-layer chroma-to~raphy (system ethyl acetate/petroleum ether 2:1) ~Schiff's base Rr = 0.6-0.7; aminoacid nitrile Rf ~ 0~28~ and the react;on solution ;s evapora.ed to dryness. The crude aminoacid nitrile is immediately processed further in accor-- 32 ~ ~X83~9 dance ~ Example 16 D or E.
(D) 2-A_aspiroC$.5~decane-3-carbox ~
25n ml of 4 N hydrochloric acid are added to one half of- the aminoacid nitrile obtained in Example 16 C, and the mixture i~ heated under reflux for 4 hours. Traces of escaping hydrocyan;c acid are made harmless in a suitable manner (freezing out, absorption in basic iron(II) salt solution). The solut;on is neutralized, evaporated to dryness and extracted several times with n-butanol. The residue from evaporation of the organic phase is - a) crystallized from chloroform/diisopropyl ether to obtain the hydrochlor;de and, if necessary, again pre-cipitated from a mixture w;th ethanol or b) purif;ed ;n aqueous solut;on by stirring with an ion exchanger, for example IR 45 (OH form) (Amberlite(R)) and, after remov;ng the water, the zw;tter;on ;s crystal-l;zed from ethanol/ether.
Yield from a~: 31-32 g ~82%) Melt;ng po;nt 205C (decompos;tion), hydrochlor;de (E~ Benzyl 2-azaspiroC4.5~decane-3-carboxylate hydro-chloride _ _ Half of the aminoacid nitrile obtained ;n accordance w;th Example 16 C is taken up ;n 7C ml of benzyl alcohol.
A slow stream o-f HCl gas is passed through the solut;on at room temperature for 5 minutes, then it is maintained at room temperature for 2-3 hours~ evaporated to a small volume ;n vacuo, and aqueous sodium b;carbonate solution is added until the pH is 8~5 and the benzyl ester is extracted into ethyl acetate. The organic phase is dried~
_ 33 _ ~28~
an equivalent amount of ethereal hydrochloric acid is added and the mixture is evaporated. The res;due crystal lizes ~rom diisopropyl ether aod can be recrystallized from methy~ene chloride/diisopropyl ether.
Yicld: 43 9 (abou~ 80%) Melt;ng point 145C (deccmposit;o~
(F~ senzyl 2-azaspiroC4 S~decane-3S-carboxylate hydro chloride The racemic hydrochloride obtained in accordance with Example 16 E is subjected to racemate resolution in analogy to Examples 1 D and E~
(G) Benzyl N-(1S-carboethoxy-3-phenylpropyL)-S-alanyl-2-azaspiro~4.5]nonane-3S-carboxylate __ _ _ 15.6 g of benzyl 2 azaspirol4.5~nonane-3S-carboxy-late hydrochLoride, 6.7 g of 1-hydroxybenzotriazole and 13.8 g of (S,S)-N-(1-carboethoxy-3-phenylpropyl)alanine are dissolved in 200 ml of DMF and reacted overn;ght with 10.2 9 of dicyclohexylcarbodiimide. Addit;on of tertiary bases, for example 6.4 ml of N-ethylmorpholine, increases the yield only inconsiderably. The precipitated DC-urea is filtered off, the filtrate is evaporated in vacuo, the residue ;s taken up in ethyl acetate, and the solution is extracted by sllaking with aqueous sodium bicarbonate solution~ and the organic phase is dried over solid sodium sulfate and again evaporated. The 1H NMR spectra tin CDCl3) confirro the structure.
(H) N-(1S-~Carboethoxy-3-phenylpropyl)-S--alanyl-Z-aza-spiror4.5]nonane 3S~carboxylic ac;d The benzyl ester obtained in Example 16 G -i, . , taken up ;n 200 ml of methanol and the benzyl group is removed by hydrogenolysis with 1 g of Pd/C (10% Pd3~ ~fcer uptake of hydrogen ;s cornplete, the m;xture is filtered and the filtrate is evaporated in vacuo. A solid, hygroscopic foarn of the zwit~erion,c dipep~ide derivative can be obtained in ~acuo with the addition of pen~cane.
Ca]~1 - 3~.3 (c ~ 1, methanol) Example 17 N-(1S-CarLoethoxy-3-pheny propyl)-S-alanyl-cis,endo-2,3,3 _ 4~5,7a-hexahydroC1HJ;ndole-2S-carboxylic acid (a) Methyl cis-2,3,3a,4,5,7a hexahydroC1H3indole-2S-carboxylate hydrochloride Racemic methyl cis-Z,3,3a,4,5~7a~hexahydroC1H~-;ndole-2-carboxylate hydrochlor;de (obta;nable ;n analogy to ~he procedure described in German Patent Appl;cation P 32 10 496~0) ;s subjected to racemate resolution ;n analogy to Exarnples 1 D and E.
Ca] ~ = +6~ .4 (c = 1, H20) (B) N-(1S-Carboe.hoxy-3-phenylpropyl)-S-alanyl-c;s,endo-__ __ _ __ _ 2,3,~4,5,7a hexahydro~1_]indole-2S-c _boxylic acid hydrochlor;de ___ rhe title compound is obtained by a procedure analogous to that described ;n Exatnples 13 A and B.
1H N~R data 0O9-3~0 (m, 17 H);
.
3.4-4.9 (m, 6 H);
5.2-6.0 (m, 2 H);
7.2 (s, 5 H) ' .
Claims (25)
1. A process for resolving racemic mixtures of bicyclic imino-.alpha.-carboxylic esters into the components of the formula Ia and Ib (Ia) (Ib) wherein R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms which may be substituted by NO2, a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1,
2, 3 or 4, b) C and B2 represents hydrogen, and A and B1 together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1, 2, 3 or 4, or c) A and C represent hydrogen, and B1 and B2 together form a chain of the formula -[CH2]m-, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts which process comprises preparing the salts of the racemic esters with optically active N-acylated R-or S-aminocarboxylic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts and isolating the enantiomers of the formulae Ia and Ib and, where appropriate, converting the latter into the free acids by hydrolysis.
2. The process as claimed in claim 1, wherein a) A and B1 represent hydrogen, and B2 and C
together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q- with (p+q) being 1, 2, 3 or 4, or b) C and B2 represent hydrogen, and A and B1 together form one of the chains defined above under a).
2. The process as claimed in claim 1, wherein a) A and B1 represent hydrogen, and B2 and C
together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q- with (p+q) being 1, 2, 3 or 4, or b) C and B2 represent hydrogen, and A and B1 together form one of the chains defined above under a).
3. The process as claimed in claim 2, wherein the salts of racemic esters of the formulae Ia and Ib in which the two bridgehead hydrogen atoms have the cis configuration and the COOR group is oriented endo with respect to the bicyclic ring system are precipitated.
4. The process as claimed in claim 1, wherein R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms which may be substituted by NO2.
5. The process as claimed in claim 1, wherein the amino group of the N-acylated R- or S-aminocarboxylic acids which are used for salt formation is protected by alkanoyl having 1 to 6 carbon atoms, tert.-butoxycarbonyl, benzyloxy carbonyl or another NH2 protective group customary in peptide chemistry, and any free OH groups present in the N-acylated aminoacids may be protected by alkyl having 1 to 6 carbon atoms, benzyl or other OH protective groups customary in peptide chemistry.
6. The process as claimed in claim 1, wherein the salts of racemic esters of the formula Ia and Ib in which the two bridgehead hydrogen atoms have the cis configuration the COOR group is oriented endo with respect to the bicyclic ring system and the carbon atom ? to the COOR
group has the R or S configuration, wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q- with (p+q) being 1, 2, 3 or 4, or b) C and B2 represent hydrogen, and A and B1 together form one of the chains defined above under a), and wherein R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having
group has the R or S configuration, wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q- with (p+q) being 1, 2, 3 or 4, or b) C and B2 represent hydrogen, and A and B1 together form one of the chains defined above under a), and wherein R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having
7 to 13 carbon atoms which may be substituted by NO2 , are precipitated.
7. A compound of the formulae Ia or Ib as defined in claim 1 in which the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom .alpha. to the CooR group has the R or S configuration and wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1, 2, 3 or 4, or b) C and B2 represent hydrogen, and A and B1 together form one of the chains defined above under a), and wherein R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms which may be substituted by NO2.
7. A compound of the formulae Ia or Ib as defined in claim 1 in which the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom .alpha. to the CooR group has the R or S configuration and wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1, 2, 3 or 4, or b) C and B2 represent hydrogen, and A and B1 together form one of the chains defined above under a), and wherein R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms which may be substituted by NO2.
8. The process as claimed in claim 1, wherein the salts of racemic esters of the formula Ia and Ib in which the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system and the carbon atom a to the COOR group has the R or S configuration, wherein R represents an alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms which may be substituted by NO2, and wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1, 2, 3 or 4, or b) C and B2 represents hydrogen, and A and B1 together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q) being 1, 2, 3, or 4, are precipitated.
9. A compound of the formulae Ia or Ib as defined in claim 1, in which the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or S configuration and wherein R represents an alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms which may be substituted by NO2, and wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1, 2, 3 or 4, or b) C and B2 represents hydrogen, and A and B1 together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q) being 1, 2, 3, or 4.
10. The process as claimed in claim 6, wherein the carbon atom a to the COOR group has the S configuration.
11. The process as claimed in claim 8, wherein the carbon atom a to the COOR group has the S configuration.
12. A compound of the formula Ia or Ib (Ia) (Ib) wherein two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or S configuration and wherein R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 6 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms which may be substituted by NO2, wherein a) A and B1 represent hydrogen, and B2 and C together form a chain of the formula -[CH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2]p-CH=CH-[CH2]q-, with (p+q) being 1, 2, 3 or 4, or b) C and B2 represents hydrogen, and A and B1 together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q) being 1, 2, 3, or 4.
13. A compound of the formula Ia or Ib, as defined in claim 9, wherein the carbon atom .alpha. to the COOR group has the S
configuration.
configuration.
14. A diastereomeric salt of a bicyclic imino-.alpha.-carboxylic ester of the formulae Ia or Ib as defined in claim 7 and an N acylated, optically active R- or S-aminocarboxylic acid which contains a phenyl nucleus and is protected by alkanoyl having 1 to 6 carbon atoms, tert.-butoxycarbonyl, benzyloxycarbonyl or another NH2 protective group customary in peptide chemistry.
15. A diastereomeric salt of a bicyclic imino-.alpha.-carboxylic ester of the formulae Ia or Ib as defined in claim 12 and an N-acylated, optically active R- or S-aminocarboxylic acid which contains a phenyl nucleus and is protected as defined in claim 5.
16. A process for resolving racemic mixtures of esters of cis,endo-2-azabicyclo[3.3.0]octane-3-carboxylic acid by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-amino-carboxylic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts, and isolating the enantiomers converting the latter into the free acids by hydrolysis.
17. Cis,endo-2-azabicyclo[3.3.0]octane-3S-carboxylic acid.
18. A process for resolving racemic mixtures of esters of cis,endo-2-azabicyclo[3.3.01octane-3-carboxylic acid by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts, and isolating the enantiomers.
19. A cis,endo-2-azabicyclo[3.3.0]octane-3S-carboxylic ester in which R has the meaning defined in claim 4.
20. A process for resolving racemic mixtures of benzyl cis,endo-2-azabicyclo[3.3.0]octane-3-carboxylate by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts, and isolating the enantiomers.
21. Benzyl cis, endo-2-azabicyclo[3.3.0]octane-3S-carboxy-late.
22. A process for resolving racemic mixtures of esters of cis, endo-octahydro[1H]indole-2-carboxylic acid by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts, and isolating the enantiomers.
23. A cis,endo-octahydro[1H]indole-2S-carboxylic ester in which R has the meaning defined in claim 4.
24. A process for resolving racemic mixtures of benzyl cis,endo-octahydro[1H]indole-2-carboxylate by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-amino-carboxylic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts, and isolating the enantiomers.
25. Benzyl cis,endo-octahydro[1H]indole-2S-carboxylate.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3303112.6 | 1983-01-31 | ||
| DEP3303139.8 | 1983-01-31 | ||
| DE19833303112 DE3303112A1 (en) | 1983-01-31 | 1983-01-31 | METHOD FOR RACEMATE SEPARATION OF OPTICALLY ACTIVE BICYCLIC IMINO (ALPHA) CARBONIC ACIDS |
| DE19833303139 DE3303139A1 (en) | 1983-01-31 | 1983-01-31 | Process for the preparation of carboxyalkyldipeptides |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576609A Division CA1317067C (en) | 1983-01-31 | 1988-09-06 | Process for their resolution of racemates of optically active bicyclic imino-o-carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyl-dipeptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1283249C true CA1283249C (en) | 1991-04-16 |
Family
ID=25807929
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000446349A Expired - Lifetime CA1283249C (en) | 1983-01-31 | 1984-01-30 | Process for the resolution of racemates of optically active bicyclic imino- -carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptides |
| CA000576609A Expired - Lifetime CA1317067C (en) | 1983-01-31 | 1988-09-06 | Process for their resolution of racemates of optically active bicyclic imino-o-carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyl-dipeptides |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576609A Expired - Lifetime CA1317067C (en) | 1983-01-31 | 1988-09-06 | Process for their resolution of racemates of optically active bicyclic imino-o-carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyl-dipeptides |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0115345B1 (en) |
| JP (1) | JPH0788358B2 (en) |
| KR (1) | KR910001438B1 (en) |
| AU (1) | AU566589B2 (en) |
| CA (2) | CA1283249C (en) |
| DE (1) | DE3468415D1 (en) |
| DK (1) | DK174386B1 (en) |
| ES (2) | ES529272A0 (en) |
| FI (1) | FI88153C (en) |
| GR (1) | GR82650B (en) |
| HU (1) | HU191120B (en) |
| IE (1) | IE56654B1 (en) |
| IL (1) | IL70830A (en) |
| MA (1) | MA20020A1 (en) |
| NO (1) | NO166641C (en) |
| NZ (1) | NZ206980A (en) |
| PT (1) | PT78036B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4500713A (en) * | 1982-09-23 | 1985-02-19 | Usv Pharmaceutical Corporation | Therapeutic dipeptides |
| DE3345355A1 (en) * | 1983-12-15 | 1985-06-27 | Hoechst Ag, 6230 Frankfurt | METHOD FOR RACEMATE CLEAVING BICYCLIC IMINO (ALPHA) CARBONIC ACID ESTERS |
| CA1244041A (en) * | 1984-07-30 | 1988-11-01 | Elijah H. Gold | Process for the preparation of cis, endo- octahydrocyclopenta¬b|pyrrole-2-carboxylate |
| HU192914B (en) * | 1985-02-11 | 1987-07-28 | Richter Gedeon Vegyeszet | Process for producing new 3-/substituted amino/-5-phenyl-2/3h/-furanone derivatives and pharmaceutically acceptable salts |
| FR2620703B1 (en) * | 1987-09-17 | 1991-10-04 | Adir | PROCESS FOR THE INDUSTRIAL SYNTHESIS OF PERHYDROINDOLE CARBOXYLIC ACID - 2 (2S, 3AS, 7AS). APPLICATION TO THE SYNTHESIS OF CARBOXYALKYL DIPEPTIDES |
| HU904967D0 (en) * | 1988-04-22 | 1991-01-28 | Hoechst Ag | Process for producing new azabicyclo(3.3.o)octane-3-carboxylic acid-octylesther derivatives |
| US6407262B1 (en) | 2001-11-21 | 2002-06-18 | Brantford Chemicals Inc. | Process for the preparation of Ramipril |
| WO2006059347A2 (en) * | 2004-12-01 | 2006-06-08 | Morepen Laboratories Limited | Improved process for preparation of ramipril |
| ES2686298T3 (en) | 2010-04-20 | 2018-10-17 | Chiral Quest, Inc. | Enantioselective procedure for cycloalkenyl substituted beta alanines |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2503155A2 (en) * | 1980-10-02 | 1982-10-08 | Science Union & Cie | NOVEL SUBSTITUTED IMINO DIACIDES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR |
| IE52663B1 (en) * | 1980-04-02 | 1988-01-20 | Warner Lambert Co | Substituted acyl derivatives of octahydro-1h-indole-2-carboxylic acids |
| US4374847A (en) * | 1980-10-27 | 1983-02-22 | Ciba-Geigy Corporation | 1-Carboxyalkanoylindoline-2-carboxylic acids |
-
1984
- 1984-01-25 HU HU84312A patent/HU191120B/en unknown
- 1984-01-27 EP EP84100858A patent/EP0115345B1/en not_active Expired
- 1984-01-27 DE DE8484100858T patent/DE3468415D1/en not_active Expired
- 1984-01-27 FI FI840350A patent/FI88153C/en not_active IP Right Cessation
- 1984-01-28 KR KR1019840000396A patent/KR910001438B1/en not_active IP Right Cessation
- 1984-01-30 IE IE210/84A patent/IE56654B1/en not_active IP Right Cessation
- 1984-01-30 NO NO840350A patent/NO166641C/en not_active IP Right Cessation
- 1984-01-30 ES ES529272A patent/ES529272A0/en active Granted
- 1984-01-30 NZ NZ206980A patent/NZ206980A/en unknown
- 1984-01-30 GR GR73651A patent/GR82650B/el unknown
- 1984-01-30 DK DK198400415A patent/DK174386B1/en not_active IP Right Cessation
- 1984-01-30 PT PT78036A patent/PT78036B/en unknown
- 1984-01-30 MA MA20241A patent/MA20020A1/en unknown
- 1984-01-30 CA CA000446349A patent/CA1283249C/en not_active Expired - Lifetime
- 1984-01-30 IL IL70830A patent/IL70830A/en not_active IP Right Cessation
- 1984-01-31 AU AU23933/84A patent/AU566589B2/en not_active Expired
- 1984-04-04 ES ES531284A patent/ES8501759A1/en not_active Expired
-
1988
- 1988-09-06 CA CA000576609A patent/CA1317067C/en not_active Expired - Lifetime
-
1991
- 1991-01-30 JP JP3027801A patent/JPH0788358B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| KR910001438B1 (en) | 1991-03-07 |
| FI88153C (en) | 1993-04-13 |
| FI88153B (en) | 1992-12-31 |
| FI840350A0 (en) | 1984-01-27 |
| IL70830A (en) | 1988-02-29 |
| MA20020A1 (en) | 1984-10-01 |
| NZ206980A (en) | 1988-05-30 |
| HUT34159A (en) | 1985-02-28 |
| CA1317067C (en) | 1993-04-27 |
| PT78036A (en) | 1984-02-01 |
| HU191120B (en) | 1987-01-28 |
| ES8500228A1 (en) | 1984-10-01 |
| EP0115345A1 (en) | 1984-08-08 |
| DK41584D0 (en) | 1984-01-30 |
| FI840350A (en) | 1984-08-01 |
| NO166641C (en) | 1991-08-21 |
| DK174386B1 (en) | 2003-01-27 |
| IL70830A0 (en) | 1984-04-30 |
| AU2393384A (en) | 1984-08-02 |
| NO166641B (en) | 1991-05-13 |
| PT78036B (en) | 1986-05-30 |
| DK41584A (en) | 1984-08-01 |
| IE840210L (en) | 1984-07-31 |
| ES531284A0 (en) | 1984-12-01 |
| DE3468415D1 (en) | 1988-02-11 |
| ES8501759A1 (en) | 1984-12-01 |
| AU566589B2 (en) | 1987-10-22 |
| JPH0788358B2 (en) | 1995-09-27 |
| EP0115345B1 (en) | 1988-01-07 |
| NO840350L (en) | 1984-08-01 |
| IE56654B1 (en) | 1991-10-23 |
| ES529272A0 (en) | 1984-10-01 |
| GR82650B (en) | 1985-02-07 |
| JPH0517439A (en) | 1993-01-26 |
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