CA1320904C - Method for the treatment of atherosclerosis, thrombosis and peripheral vessel disease - Google Patents
Method for the treatment of atherosclerosis, thrombosis and peripheral vessel diseaseInfo
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- CA1320904C CA1320904C CA000520434A CA520434A CA1320904C CA 1320904 C CA1320904 C CA 1320904C CA 000520434 A CA000520434 A CA 000520434A CA 520434 A CA520434 A CA 520434A CA 1320904 C CA1320904 C CA 1320904C
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- carboethoxy
- carboxylic acid
- alkyl
- alanyl
- phenylpropyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/14—Angiotensins: Related peptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Vascular Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Immunology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Abstract of the Disclosure:
The invention relates to a method for the treatment of atherosclerosis, thrombosis and/or of peripheral vessel disease by administration of angiotensin converting enzyme inhibitors. Administration of compounds of the formula I
The invention relates to a method for the treatment of atherosclerosis, thrombosis and/or of peripheral vessel disease by administration of angiotensin converting enzyme inhibitors. Administration of compounds of the formula I
Description
1 320qO~
A method for the treatnent of atherosclerosis, thro~-bosis and peripheral vessel disease The invention relates ~o a method for the treatment of atheroscleros;s, o~ thrombosis and/or of peripheral vessel dise~se by oral or parenteral ad~in;stration of compounds which inhibit angiotensin converting enzyme.
S Particularly suitable for th;s purpose are compounds of the formula I
~ l5 ~ o~2 in wh;ch n ;s 1 or 2, R - hydrogen, an optionally subst;tuted al;phatic radical having 1-8 carbon atoms, an opt;onally sub-stituted alicyclic radical having 3~9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted arali-phati~ radical having 7-14 carbon atoms, an aption-aLly substituted alicyclic-aliphatic radical having 7-14 rarbon atoms, or a radical ORa or SRa, in which Ra represents an opticnally subs~i~uted aliphatic radical having 1-4 c~rbon atoms, an opt-ionally substituted aromatie radical having 6-12 carbon atoms, or an optionally substituted hetero-aroma~ic radical having 5-12 ring atoms, R denotes hydrogen, an optionally substituted ali-phatic radical having 1-6 carbon atoms, an option-ally substi~uted alicyclic radical having 3-9 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 4-13 carbon ato~s, an optionally substituted aromatic radical having 6-12 carbon atoms, an option2lly ~ubstituted araliphat;c radical havin~ 7-16 carbon atoms, an option3lly substituted heteroaromatic radic~l having 5-12 r;ng atoms, or the side chain, pro~ected where necessary, of a naturally occurring ~-amino acid, R2 and R3 are identical or different and denote hydro-gen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted alicyclic radical having 3 9 carbon atoms~ an opt-ionally substituted aromatic radical having 6-12 carbon atoms, or an optionally subs~ituted aralipha-tic radical having 7-16 carbon atoms, and 1D R4 and R5 form, together ~ith the ~toms carrying them, a heterocyclic, mono-, bi- or ericyclic ring system having 4 to 15 carbon atoms.
Particularly suitable ring systems of this type are those of the following group:
Tetrahydroisoquinol;ne tA); decahydroisoquinoline (~j;
octahydroindoLe (C3; octahydrocyclopenta~b~pyrrole tD);
A method for the treatnent of atherosclerosis, thro~-bosis and peripheral vessel disease The invention relates ~o a method for the treatment of atheroscleros;s, o~ thrombosis and/or of peripheral vessel dise~se by oral or parenteral ad~in;stration of compounds which inhibit angiotensin converting enzyme.
S Particularly suitable for th;s purpose are compounds of the formula I
~ l5 ~ o~2 in wh;ch n ;s 1 or 2, R - hydrogen, an optionally subst;tuted al;phatic radical having 1-8 carbon atoms, an opt;onally sub-stituted alicyclic radical having 3~9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted arali-phati~ radical having 7-14 carbon atoms, an aption-aLly substituted alicyclic-aliphatic radical having 7-14 rarbon atoms, or a radical ORa or SRa, in which Ra represents an opticnally subs~i~uted aliphatic radical having 1-4 c~rbon atoms, an opt-ionally substituted aromatie radical having 6-12 carbon atoms, or an optionally substituted hetero-aroma~ic radical having 5-12 ring atoms, R denotes hydrogen, an optionally substituted ali-phatic radical having 1-6 carbon atoms, an option-ally substi~uted alicyclic radical having 3-9 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 4-13 carbon ato~s, an optionally substituted aromatic radical having 6-12 carbon atoms, an option2lly ~ubstituted araliphat;c radical havin~ 7-16 carbon atoms, an option3lly substituted heteroaromatic radic~l having 5-12 r;ng atoms, or the side chain, pro~ected where necessary, of a naturally occurring ~-amino acid, R2 and R3 are identical or different and denote hydro-gen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted alicyclic radical having 3 9 carbon atoms~ an opt-ionally substituted aromatic radical having 6-12 carbon atoms, or an optionally subs~ituted aralipha-tic radical having 7-16 carbon atoms, and 1D R4 and R5 form, together ~ith the ~toms carrying them, a heterocyclic, mono-, bi- or ericyclic ring system having 4 to 15 carbon atoms.
Particularly suitable ring systems of this type are those of the following group:
Tetrahydroisoquinol;ne tA); decahydroisoquinoline (~j;
octahydroindoLe (C3; octahydrocyclopenta~b~pyrrole tD);
2-azaspiro~4.53decane (E); 2-azaspiroC4.4]nonane (F);
spirot(bicyclo~2.2.1~heptane)-2,3'-pyrrolidine~(G);
spiro~(bicyclo~2.2.2~octane)-2,3'-pyrrolidine~ tH);
2-azatricyclo~4.3Ø16,9]decane (I); decahydrocyclQ-hepta~b]pyrrole (J); octahydroisoindole tK); octahydro-cyclopentaZc~pyrrole (I); 2~3,3a,4,5,7a-hexahydroindole (M); 2-azabicyclo~3.1.D~hexane (N); all of uhich can optionally be substituted. However, the unsubs~ituted Z5 systems ~re preferred.
In the case of compounds which have several chiral ato~s, all possible diastereomers are suitabLe, as racemates or enantiomers or ~ixtures of various dia-st~reomers.
~he cycli~ amino acid esters ~hich are suitable have the foLlo~ing structural formulae.
1 320qo4 COOR3 ~ COOP~3 ~ N~
A B ~N~LCOOR3 '~-C~'o~33_coo~3 3_, ' G H
~) COOR3~COOR3 ~3_ 3 J . X L
~COOR3 ~COOR3 M N
A preferred embodiment compr;ses use of compounds of the formula I in ~h;ch n is 1 or 2~
R denot~s hydrogen, alkyl having 1-8 carbon atoms, alkenyl hav;ng 2-6 carbon atoms, cycLoalkyl having 3-9 carbon atoms, aryL ~hich has 6-12 carbon at~ms and can be ~ono-, di- or trisubsti~uted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogsn, nitro9 amino, amino~ethyl, (C1-C4)-alkylamino~ di-(C1-C4)-, .
' 1 ;~20904 alkylamino, (C1-C4)-alkanoyl~mino, ~ethylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms~ aryloxy ~hich has 6-12 carbon atoms and can be subs~i~uted as described above for aryl, S mono- or bicyclic heteroaryloxy ~hich has 5-7 or 8-10 ring atoms respectively, 1 to 2 of ~hese ring atoms representing sulfur or oxygen a~oms and/or 1 to 4 of these ring atoms rPpresenting nitrogen, and which can be substituted as described above for aryl, amino-(C1-C~)-alkyl, (C1-C4)-alkanoylamino-tC1-C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C
C4)-alkoxycarbony~amino-tC1-C~)-alkyL, ~C6-S~
aryl-~C1-C4)-alkoxycarbonylamino-(C1-C4)-all(yl, (C~,-C1~)-aryL-(Cl-C4)~alkylamino-(C1-C43-3lkyl, (C1 C4)-alkyla~ino-(C1-C4)-alkyl, di-(C1-C4)-alkyl-amino-(C1-C~)-alkyl, guanidino-(C~-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C~-C12)-arylthio (C1 C4 alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C1z)-aryl-(C1-C4~-alkyLthio ~hich can be su~stituted in the aryl ~oi~ty as described ab~ve for aryl, carboxy-(C~-C~3-alkyl, carboxyl, carbamoyl, carbamoyl-~Cl-~4)-alkYl~ (c1-c4~-alkoxycarbonyl~ -c4)-alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl ~hich can be substituted in the aryl maiety as descr;bed above for aryl, or (C6-C12)-aryl-(C1-C4~-alkoxy which can be subs~ituted ir, the aryl moiety as described above for aryl, R denotes hydrogen~ alkyl having 1-6 carbon 3toms, alkenyl having 2-6 carbon atomsy alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms~
cycloalkenyl having 5-9 c~rbon atoms, (C3~Cg)-cycloalkyl-~C1-C4)-alkyl, (C~-Cg)-cyclo3lkenyl-(C1-C43-alkyl, optionally partiaLly hydrogenated aryl which has 6-12 carbon atoms and can be subst;
tuted as described above for R, Sr6-C1~)-aryl-(C1-C43-alkyl or ~C7-C13)-aroyl (C1 or C23-alkyl, both 1 32nqo4 of ~hich can be substituted as the abovementioned aryl, mono- or bicyclic, op~ionally partially hydro-genated heteroaryl which has 5-7 or 8-10 rin~ atoms respectively, 1 or 2 of these ring atoms represent-;ng sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and ~hich can be substituted as the abovementioned aryl, or the optionally protected side chain of a naturally occurring ~ am;no acid R1-CH(NH2) COOH~
R2 and R3 are identical or different and denote hydro-gen, alkyl having 1-6 carbon a~oms, alkenyl having 2-6 carbon atoms, di-(C1-C4)-aLkyLam;no-(C1-C4)-alkyL, tC1-Cs)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6)-alkoxycarbonyloxy-(C1-C4) alkyl, tC7-C13)-aroyloxy-(C1-C4)-alkyl, (C6-C1z)-aryloxycarbonyloxy-(C1-C4)-alkyl, aryl hav;ng 6-12 carbon atoms, (C6-C123-aryl-(C1-C4)-alkyl, (t3-Cg)-cycloalkyl or (C3~Cg)-cycloalkyl-(C1-C4~-alkyl, and R4 and R5 have the abovement;oned meaning.
A particularly preferred embodimEnt romprises u~e of compounds of the for~ula I in which n is 1 or 2, R denotes (C1-C6)-alkyl~ (C2-C6)-alkenyl, (C3-Cg)-cycloalkyl, amino-(C1-C4)-alkyl, (Cz-Cs3-acylamino-(C1-C4)-a~kYl~ (~7-c13)-aroylamino-tc1-c4)-alkyl~
(C1-C4)-alkoxycarbonylamino~(C1-C4)-alkyl9 (C6-tl2) aryl-(Cl-C4)-alkoxycarbonylamino-(C~-C4)-alkyl, tC6-C12)-aryl ~hich can be mono-, di- or trisub-~tituted by ~C1-C4)-alkyl~ (C1-C4)-alkoxy, hydroxyl, halogen, nitro~ am;no~ (C1-C4)-alkylamino, di-(C1-C4)-alkylamino and/or methylened;oxy, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert.-butoxycar~onyla~ino-(C1-C4~-alkyl, benzoyloxycarbon-ylamino-(C1-C4)-alkyl, or phenyl ~hich can be mono-or disubstituted, or in the case of methoxy tri-substituted, by phenyl~ (C1-C2~-alkyl, tC1 or C23-alkoxy, hydro~yl, fluorine~ chlorine, bromine, amino, (t1-C4)-alkylamino, di-(C1-Cb)-alkylamino~
) nitro and/or methylened;oxy, R1 denot~s hydrogen or (C1 C6)-alkyl which can option-ally be substituted by amino, (C1-C6)-acylamino or benzoylamino~ (C2-C6)-alkenyl, (C3-Cg)-cycloalkyl~
(Cs-Cg)-cycloalkenyl~ (C3-C7)-cycloalkyl-(~ 4)-alkyl, (C6-C121-aryl or partially hydrogenated aryl, each of which ean be substituted by (C1-Cb)-alkyl~
(C1 or C2)-alkoxy or halogen, (C6-C17~-aryl-(C1 to C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-alkyl, both of which can be substituted in ~he aryl radical as de-fined above, a mono- or b;cyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respect-ively, 1 ~o 2 of these ring atoms representing sulfur or oxygen atoms andtor 1 to 4 of these ring atoms representing nitrogen a~oms, or a side chain of a naturally occurring, optionally protected -amino acid, but in par~icular hydrogen, (C1-C3)-alkyl, (C2 or C3)-alkenyl~ the opt;on3lly protected side chain or lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyL or benzoyl-methyl, R2 and R3 denote identical or different rad;cals hydro-gen, (C~-C6)-alkyl~ ~C2-C6)-alkenyl or (C6-C12)-aryl-(C1-C~)-alkyl, but in particular hydrogen, (C1-C4)-alkyl or benzyl, and R4 and RS have the abovement;oned meaning.
It is particularly preferred to ~se compounds sf the formula I in which n is 2, R denotes phenyl, R1 denotes ~ethyl, R2 and R3 denote identical or different (C1-C6)-alkyl radicals or ~C7-C10)-araLkyL radicals such as benzyl or nitrobenzyl, and R4 and R5 together represent a radicaL of the for0ula --lCH2 in ~hich m denotes 0 or 1, p denotes 0, 1 or ?, and X denotes -CH2-, -CH2-CH2- or -CH=CH-, it also be;ng possible for a 6-ring formed with X to be a ben-zene ring.
In this context and in the following, aryL is to be understood preferably to be substituted phenyl, bi-phenylyl or naphthyl. A corresponding statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl is particularly understood to be benzoylO Aliphatic radicals can be seraight-chain or branched.
A mono- or bicyclic heterocyclic radical h3ving 5 to 7 or 2 to 10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atQms andJor 1 to 4 of these ring ato~s representing nitrogen atoms~
is~to be understood to be~ for example, thienyLO benzo-~b]thienyl, ~uryl~ pyranyl, benzofuryl, pyrroL~l, im;d-azoLyl, pyrazolyl~ pyridyl, pyrimidinyl, pyridaz;nyl~
indazolyl, isoindolyl, indolyl, purinyl9 quinolizinyl, isoquinolinyl, phthalazinyl, naph~hyridinyl, quinoxal-inyl, quinazolyl, cinnolinyl, pteridinyl, ox~zolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be part;ally or completely hydrogenated.
Naturally occurring ~-amino acids are described in~ for example~ Houben-~eyl~ Methoden der Organischen Chemie (Methods of Organic Chemistry)~ Vols. XV/1 and XVJ2.
~here R1 repr~sents a side ehain of a protected naturally occ~rring ~ 3mino acid such as, for e~ample, 1 320qO4 protected Ser, Thr, Asp, Asn, Glu, GLn, Arg, Lys, Hyl, Cys~ Orn, C;t, Tyr, Trp, H;s nr Hyp, the preferred pro-tective groups are the ~roups customary in peptide chemistry (ct. Houben-~eyl, Yols. XV/1 and XY/2)~ In the case ~here R1 denotes the protected side chain of lysine, the known a~ino protective groups, but in par-ticular Z, Boc or ~C1-C6)-alkanoyl, are preferred.
Suitable and preferred as O-protective groups for tyro~
sine are ~C1-C6)-alkyl, in particular methyl or ethyl.
AC inh;bitors o~ the formuLa I can be prepared by reacting together their fragments in a suitable sol-vent, ~here appropriate in the presence of a base and/
or of a coupling auxiliary9 ~here appropriate reduction of unsaturated compounds ~hich have resulted as inter-mediates, such as Schiff's bases, and elimination ofprotective groups which have been introduced temporar-ily to protect reactive groups and, ~here appropr;ate, conversion of the resulting compounds into their physi-ologically tolerated salts.
It is possible in the said manner to react rompounds of the forMula V ~ith compounds of the formula VI
R300C-~C -N~H ~OOC~ CH ( H2)n~R
(V) (VI) The reaction of these compounds can, ~or example, be carried out in analogy to kno~n peptide coupling pro~
cesses in the presence of coupling auxiliaries such as carbodiimides ~for examPle dicycLohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N~N-succinimidyl car-bonates in CH3CN. Amino groups in compounds of ~he formula V can be activated ~ith tetraethyl diphosphite.
The compounds of the formula VI can be converted into .
1 320qO4 _ 9 _ active esters ~for example ~ith 1-hydroxybenzotri-azole), mixed anhydr;des (for example with chloroformic esters), azides or carbodiimide derivatives, and thus be activated (cf. Schroder, LBbke, The Peptides, Vol.
1, New York, 1965, pages 76 136).
It is likewise possible to react compounds of the for-mula YII ~ith compounds of the 70rmula VIII, ~ith the formation of compounds of the formula I
R OOC-ICH-~ - C IM-~ Y~ lH t H2)n-R
O R OOR
(V~I ) ('VIII ) in ~hich either y1 represents amino and y2 represents a leaving group, or y1 represents a leaving group and y2 represents amino. Examples of suitable Leaving groups are Cl, ar, I~ alkylsulfonyloxy or arylsulfonyl-oxy .
Alkylations of this typB ~re advantageous~y carried outin water or an or~anic solvent, in the presencs of a base.
Furthermore, compounds of the for~ula IX san be con-densed ~ith co~pounds of the formula X
R300C_~H_ _ c~ l Q2~f -lC 2)~-R
0 R C~R
~IX) (X3 in ~hich either ~1 represents amino 4 hydrogen and ~2 represents oxo, or Q1 represents oxo and ~2 represents amino + hydrogen The condensation is advantageously carried out ;n ~ater 'I 320qO4 or an organic solvent such as a lo~er alcohol, and ;n the presence of a reducing agent such as Na8H3CN, whereupon compounds of the formula I are obtained dir-ec~ly. However, ;t ;s also possible to reduce the Schiff's bases or enamines ~hich result as intermedi-ates~ ~here appropriate after previous isolation, with the format;on of compounds of the formula I, for exam-ple by hydrogena~;on in the presence of a transi~ion metal catalyst.
Finally, reaction of compounds of the f~rmula IX (a1 =
H + N~2) w;th compounds of the formula XI, or their reaction with compounds of the for~ulae XII and XlII, also results in compounds of the formula I (n=2)~ !
R~OC-C~-CH-~O-R
~XI~
OCH-CO~R2 R-CO-~H3 tXII) (XIII) there being reduction of Schi~f~s bases produced as intermediates, and conversion of a carbonyl group into nethrlene by reduction.
In the above~entioned formulae V-XIIl, R-RS and n are as de~ined in formula I. Protective groups introduced temporarily to protect reactive groups not involved in the reac~;on are elim;nated a~ter reaction is complete in ~ manner known per se (cf. Schroder, Lubke~ lOca cit., pages 1~7S and 246-270)~
It is possible and part;cularly advantageou~ to use the follo~ing co~pounds in the ~ethod according to the in-vention:
N~ S-carboethoxy-3-phenylPropyl~-s-alanyl-s-1~2~3~4 tetrahydroisoquinoline-3-sarbQxylis acid N-tl-S-carboethoxy-3-cyc~ohexylpropyl)-S-alanyl-S-1~2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-Lysyl-S-1~2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-e~hyl-S-~yrosy(-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl~-S-alanyl-3S-deca-hydro-isoquinoline-3-carboxylic acid H-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-(2S~3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-(2S,3aS~7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-(2S,3aS,7aS)-octahydroindoLe-2-carboxylic acid N-(1-S-carboethoxy-3-phenylPropyL)-0-methyl-S-tyrosyl-(25,3aS,7aS)-octahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-phenylprop~l)-0-ethyl-S-tyrosyl (2S,3aS,7aS)-sctahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-~3,4-d;methylphenylpropyl)-S-al3nyl-tZS,3aS,7aS)-oetahydroindole-2-carboxylic acid N-~1-S-carboethoxy-3-(4-fluorophenyl~-propyl]-S-alanyl-~2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-~4-~ethoxyphenylj-propyl~-S-alanyl-(2S,3aSJ7aS)-octahydroindole-2-carboxylic acid N-C1-S-carboethoxy-3-(3,4-dimethoxyphenyl)-propyl]-S-alanyl-~2S,3aS~7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-~2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-~2S,3aR,7aS)-octahydroindole-Z-carbo~ylic ~cid N (1-S-carboethoxy-3-cyclohexylPropyl3-S-alanyl-(2S,3aR,7aS~-octahydro;ndole-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S lysyl-~2S,3aR~7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-5-lysyL-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-(?s~3as~7aR)-octahydro;ndole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-(2S,3aR~7aR)-oc~ahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,7aS)-octahydroindoLe-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-1D (2S,3aR~7aR)-octahydroindole-2-carboxylic acid N-(1-S-c~rboe~hoxy-3-cyclohexylpropyl)-0-ethyl-S-tyro-syl-~2S,3aR,7aR)-nctahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-(25~3aS,7aR)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl~-0-ethyl-S-tyrosyl-(ZS,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3~4-dimethylphenylpropyl3-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-E1-S-carboethuxy-3-(4-fluorophenyl)-propyl~-S-alanyl-t2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-~1-S-carboethoxy-3-(4-~ethoxyphenyl)-propyl]-S-al3nyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-C1-S-carboethoxy-3-5394-dimethoxyphenyl)-propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-~-carboxylic acid N-(1-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-: (2S,3aS~7aS)-octahydroindole-2-carboxyl;c acid N-(1-S-carboethoxy 3-phenylpropyl)-S-alanyl-cis-endo-2-azabicyclo~3~3.0]octane-3-S-carboxylic acid N-(1-S-carboeth3xy-3-phenylpropyl)-S-lysyl-cis-endo-2-azabicycloC3.3.0~octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cis-endo-2-azabicycloC3.3.0~oct~ne 3-S~carboxylic acid ~-51-S-carboxy-3-cyclohexylpropyl)-S-alanyl-cis-Lndo-2-azabicyclo~3.3.0~octane-3-S-carboxylic acid N-~1-S-carboethoxybutyL)-S-alanyl-cis-endo-2-azabicycLo-C3.3~0~oct~ne-3-S-carboxylic acid N-l1-S-carboethoxy-3-(3~4-di0ethoxyphenylpropyl)-S-aLanyl-cis-endo-2-azabicyclot3.3aO]ost3ne-3-S-carboxylic acid ~ S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-cis-endo-azabicyclo-C3.3.0]octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl) 0-methyl-S-tyrosyl-S cis-endo-2-azabicyclo~3.3.0~octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-5-tyrosyl-cis-endo-2-azabicyclot3.3.03Octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-(4-fluorophenylpropyl)-S-alanyl-cis-endo-azab;cyclo~3.3.0]octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-(4-methoxyphenylpropyl)-S-alanyl-cis-endo-2-azabicyclo~3.3.0]octane-3~5-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,6aS)-octahydrocyclopenta~b~pyrrole-2-carboxylic acid N~ S-carboethoxy-3-cyclohexylpropyl)-lysyl-(2S,3a,6aS)-octahydrocyclopentatb3pyrrole-2-tarboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-(2S,3aR,6aS)-octahydrocyclopenta~b~pyrrole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-a~anyL-2-Z0 (2S,3aR,6aS)-octahydrocyclopen~atb~pyrrole-2-carboxyl;c acid N (1-S-carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-t4~5]decane-3-S-carboxylic acid N-~1-S-carbo~thoxy-3-phenylpropyl)-0-ethyL-2-tyrosyl-azaspiro-C4~5~decane-3-S- arboxylic acid N-(1-S-carboethoxy-3~phenylpropyl)-S-lysyl-2-azaspiro-E4.53decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyL)-S-alanyl-~-aza-spiro~4.5~d2cane-3-S-carboxylic ac1d N-t1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-2-aza~
spiroC4.5~decane-3-S-carboxylic acid N-(1-S-c2rboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-C4.4~nonane-3-S-carboxylic acid N-(1-S-carbo~thoxy~3~Phenylpropyl)-o-ethyl-s~tyrosyL-2 azaspiro~4.4~nonane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl 2 azaspiro-t4.4~non3ne-3-S-carboxylic acid N-t1-S-carbo~thoxy-3-cyclohexylpropyl)-5-alanyl-2-aza-spiro[4.4~nonane-3~S-carboxylic acid N-(l-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-2 azaspirot4.4~non3ne-3-S-carboxylic acid N-t1-S-carboethoxy-3-cyclopentylpropyl)-S-lysyl-2-aza-spirol4.4]nonane-3-S-carboxylic acid N-51-S-carboethoxy-3-phenylpropyl)-S-alanyl-spiro-tbicyclo~2.2.1]heptane-2,3'-pyrrolidine~-5'-S-carboxylic acid N~ S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-spiroCbicyclol2.2.1]heptane-2,3'-pyrrolidine~-5'-S-carboxylic acidN-(1-S-carboe~hoxy-3-phenylpropyl3-S-lysyl-sp;ro-tbicyclo t2.201~heptane-2~3'-pyrrolidineJ-S'-S-carboxyiic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-spiro-Cbicyclo~2.2~1~heptane 2,3'-pyrrolidine3-5'-S-carboxy-lic acidN-t1-S-carboethoxy-3-cyclohexylpropyl)-S~lysyl-spiro~
tbicyclo~2.201~heptane-2,3'-pyrrolidine3-S'-S-carboxy-l;c ac;d N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-spiro-tbi-cyclot2.2.Z~octane-2,3'-pyrrolidine]-S'-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-tyrosyl-~piro~bicyclot2.2.2~octane-2,3'-pyrrolidine~-5'-S-carboxylic acid N-(1-S-carboethoxy-3-phenyLpropyl)-S-lysyL-spiro~bi-cycloC2.2.2]octane-2,3'-pyrrolidine~-5'~S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-spiro-CbicycLo~2.2.2]o&tane-2,3'-pyrrolidine]-S'-S-carboxylic acid N~ S-sarboethoxy-3-ph~nylpropyl)-S-alanyl-2-azatri-cyclo~4.3Ø16'9~decane-3-S-carboxyl;c acid N-(1-S-carboethoxy-3-phenylpropyl~-0-ethyl S-tyrosyL-2-azatricyclo~4.3Ø1~'9]decane-3 S-carboxylic acid N-~1-S-carboethoxy-3-PhenylPropyl)-S-lysyl-2-azatri-cycloC4.3Ø16'~idecane-3 S-carboxylic acid N-t1-S-carboethoxy~3-cyclohexylPropyl)-s-alanyl-2 azatricyclo[4.3Ø16'9~decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyL-2-aza-tricycLo~4.3Ø16'9]decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenyLpropyla-S-alanyl-decahydro-cycloheptalb]pyrrole-2-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyL)-0-ethyl-S-tyrosyl-decahydrocyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-decahydro-cyclohepta~b3pyrrole-2-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-deca-hydrocyclohepta~b]pyrrol~-2-S-carboxylic acid N-(1-S-carboethoxy-3-cyclo~exylpropyl)-S-lysyl-deca-hydrocycloheptaLb]pyrrale-2-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-trans-octa-hydroisoindole-1-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyL)-S-alanyl-cis-octa-hydroisoindole-1-S-carboxylic ac;d N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-trans-octahydro;soindole-1-S-carboxyLic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cis-octa-hydroisoindole-1-S-carboxylic acid N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis octa-hydrocyclopentaCc]pyrrole-1-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-aLanyl-cis-octahydrocyclopentatc~pyrrole-1-S-carboxylic acid benzyl ester N-(1-S-c~rboethoxy-3-cyclohexylpropyl)-S-lysyl-cis-octa-hydrocyclopenta~c~pyrrole-1-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-2,3,3a,4,5, ~a-hexahydroindole-cis-endo-2-S-carboxylic ~cid 0 N-(1-S-carboethoxy~3-phenylpropyl~-S-lysyl-2,3,3a,4,5 7a-hexahydroindol?-cis-endo-2-S-carboxylic acid N-(1 S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-2~aza-bicyclQ~3.1.D~hexane-3-S-carboxylic acid N-(1-S-c~rboxy-3-phenylpro~yl~-S-lysyL-2-azabicyclo-C3.1.0~hexane-cis-endo-3-S-carboxyLic acid N-(1-S-carboethoxy~3-cyclopentylpropyl)-S-alanyl-2--aza-bicyclot3~1.0~hex~ne-3-carboxylic acid N-(1-S-carboethoxy-3-phenrlpropyl~-S~alanyL-cis~endo-2-1 320~0~
~ 16 -a~abicycloC3.1.0]hexane-3-S-cArboxylic acid N-(1-S~carboethoxy-3-cyclohexyLpropyl)-S-alanyl-cis-endo-2-azabicycLo~3~1.o]hexane-3-s-carboxylic acid.
These compounds can be prepared by, for example, the process described in German Patent Application P
3,333,455.2, in which process the tsrt.-butyl or benzyl esters described in the application are converted into the monocarboxylic acid derivatives in known man-ner by acid or alkaLine hydrolysis or by hydrogenolysis catalyzed by noble met~ls. The N-benzyloxycarbonyl protective group of ~he lysine derivatives is removed by hydrogenolysis catalyzed by noble m~tals~ The com-pounds listed above can be readily converted ~ith physiologicaLly tolerated acids or bases (in the czse of mono- or d;carboxylic acids) into the corresponding salts (for exa~ple hydrochlorides, maleates, fumarates etc.) and be used as salts zccording to the invention~
The compounds of the formula I are inhibitors of angio-tensin converting enzyme (ACE) or intermediates in the preparation of s~ch inhib;tors, and they can also be used to control high blood pressure of various etiolo-gies. The compounds of the formula I are disclosed in, for exa~ple, US Patent 4,129,571, US Patent 4,374,829, European ~atent A-79,522, Furopean Patent A-7~,022, European Patent A-49,658, European Patent A-51,301~ US
Patent 4,454,292, US Patent 4,374,847, European Patent A-72,352, US Patent 4,35U,704, European Patent A-50,8Q0, European Patent Ao46,~53, US Patent 4~344,949, European Patent A-84~164, US Patent 4,470,972, European Patent A-65,301 and European Patent A-52,991.
Also advantageous are or~lly effective ACE inhibitors such as, for exam~le, ra~ipril, enalapril, t~ptopr;l, lisinopril, perindopril, cilazapril, RHC 3659, CGS
13945, CGS 13928C, CGS 14B24A~ CI-9D6, SCH 31846~
zofenopril~ fosenopril~ alacepril and others. Orally 1 ')2090~
- ~7 -effective ACE inhibitors are described in, for example, ~runner et al., J. Card;ovasc. Pharmacol. 7 (Suppl. I) (~985) S2-S11.
Preferred ACE inhibitors are ~hose disclosed in Europ-ean Patent d-79022, of the formula III
C~ ~S) ~S~ (III) H N~ C~2 ~ I H~
O CH3 ~00R
in ~hich R denotes hydrogen, ~ethyl, ethyl or benzyl, in particular the compound o~ the ~ormula III in which R denotes ethyl (ramipril).
Other preferred ACE inhibitors are those disclosed in European Patent A-84~164, of the formula IV
B
COOH (IV) ~ N~ ~S9 IS) ~r-~
O ~ q ~H - C~ CH2 o G~2 ~3 ~ooR4 o in ~hich R4 denotes hydrogen, (C1-C4~-alkyl or benzyl, in particular the compound of the formula IV~ in ~hich R4 denotes ethyl.
In carrying out the method according to the invention, the angiotensin conYerting enzyme inhibitors described above can be admini tered to mammals such as ~onkeys, dogs, cats, rat~, humans etc. The compounds ~hich are suitable for the use according to ~he invention are ad-vantageou~ly incorporated in pharmaceutical products incustomary manner~ They can be converted into the CU5-tomary administratiDn forms, such as capsules, tablets, coa$ed tablets~ solutioQs, oint~ents and emulsions, as weLl as into a depot form. The active compound can~
~ 320904 ~here appropriate, also be in microencapsulated fc~rm.
The products can contain additional, tolerated organic or inorgan;c substances, for example granulating auxi-liaries~ adhesives and b;nders, lubr;cants, suspend;ng agents, solvents, antibacterial agents, ~ett;ng agents and preservatives~ Forms for oral and parenteral ad-ministration are preferred. ~he compounds of the formula l can be administered in dosages of 0.1-50 mg per dose once to three times a day.
It is also poss;ble according to the invention to use the ACE inhibitors in combination wi~h substances ~hich influence prostaglandin met~bolis~. Examples of such substances are stable prostacyclin analogs, inhibi~ors of thromboxane synthetase, and thromboxane an~agonists.
Hence the invention also reiates to pharmaceuticaL com-positions containing a) an AC inhibitor or ies physio-logically tolerated salt and b) a substance ~hich influences prostaglandin metabolism or its physiologi-cally tolerated salt, and to ~he;r use for the treat-ment of atherosclerosis~ of thrombosis and/or ofperipheral vessel dis~ase.
The invent1on furthermore relates quite generally to products containing the substances mentioned above under a~ and b~, as combination products for conçur-ZS rent~ separate or sequential administration for thetreatment of atherosclerosis, of thr~mbos;s and/or of peripheral vessel disease.
An increased a~gregability of the blood platelets plays a particularly important part in the development of atherosclerosis. Examples of sequelae are thromboses and peripheral vessel d;sease; these d;seases are the main cause of the incr~ased morbidity and mortality a sociated with high blood pressure~ alood platelets cont3in an anyiotensin-I-processin~ system, and their 1 ~20904 membrane has binding sites ~ith high affinity for angiotensin II. The fact that angiotensin converting enzyme (ACE) is preponderantly located on the luminal cytoplasmic membrane of the endo~helial cells points to S platelet/endothelium interactions being associated ~ith local angiotensin II produc~ion; ACE ;nh;bitors can ;nterfere ~;th this Furthermore, inh;bit;on of ACE poten~iates the action of bradykinin by preventing ;ts breakdo~n. It is known tha~ bradykin;n is a potent stimulator of the release of prostacycl;n from endo-theliai cells; bradykinin is in turn a potent ;nhibitor of platelet aggregation.
The activ;ty of the compounds of ~he for~ula I on platelet aggregation and thus on atherosclerosis, thrombosis and peripheral vessel disea~e, as well as other disease states associated ~;th ;ncreased aggreg-ab;lity of the blood platelets, can be deduced from a variety of test model~.
In each of the examples ~hich follow use is made of the results ~ith N~ S-carboethoxy-3-Phenylpropyl)-s-alanyl-cis-endo-2-azabicyclo~3.3.û~octane-3-S-carboxylic acid (Formula II~.
.
~,COOH
g) E~H-~H - C~-CH2 - CH2~ II
I~H3 ~ 2C2H5 A In vitro results Platelet-rich rabbit pl~s~a ;s obtained as stated by ~orn tArzneimittel-Forsch~ 31, 2012 (1~81)). Platelet aggreg3tion is measured by the increase in light pass-1 320qO4 ing through a ceLl ~hich contains this plasma. The pla~elet count is adjusted to 450,000/mm3 by dilut;on ~ith autologous, platelet-poor plasma. The sompound of the formula II has, in concentrat;ons of 0.1-10 ~g/ml of plasma, no effect on the aggregation induced by 0.24 mmol/l arachidonic aciJ, 5 mmol/l ADP or 4 ~g/ml colla-gen. In contrast, the inh;bition, brought about by 4 ~g/ml PGI2, of aggregation caused by arachidonic acid is increased to 100% by the compound of the formula II
in the said dose range.
8 l~ vi~
1. Acute study .
Conscious rabb;ts received a single oraL dose of 1.0-10.0 mg/kg of the co~pound o~ the formula II.
After 1 hour, the animals are sacrificed, and platelet-rich plasma is obtainedO Platele~ aggreg-ation is determined as describ~d under A).
There is fsund to be a reduction in aggregation in response to the three stimulators described there, in particular in response to ~rachidonic acid. A
potenti3tion of the PGI2 effect is also observed.
2. Chronic study Conscious rabbits received 1 mg/kgtd of the compound of the formula IE for 14 days~ and then the proce-dure was continued as described under 1). Pro-nounted inhibition of the platelet aggregation induced by ~rachidonic acid and A~P is ~ound in all animals.
The examples ~hich follo~ indicate the forms ~or admin-istration to treat atheroscl~rosis, thrombosis and peripheral vessel d;seas4 by the method according to - 2~ -the invention. The compounds of the formula I can be converted into the corresponding forms for adminis-traeion in analogy eO the examples.
Exam Preparation of the a~ent used according ~o the inven-tion for oral adm;nistrat;on in the treatment of atheroscLerosis, of thrombosis and of peripheral vessel diseaseO
1000 table~s each containing 10 mg of 1-N-(1-S-carbo-ethoxy-3-phenylpropyl)-S-alanyl-1S,3S,5S-2-azab;cycLo-C3.3.0]octane-3-carboxylic acid are prPpared ~ith the following auxiliaries:
N-(1-S-carboethoxy-3-phenypropyl)-S-alanyl-1S~35,5S-~-azabicycloC3~3.0]octane-3-carboxyliç acid 10 9 rorn starch 140 9 6elatine 7~5 ~
Microcrystalline cellulose 2.5 9 Magnesium stearate 2~5 9 N~ S-carboethoxy-3-phenylpropyl)-S-alanyl-15,3S,5S-: 2-azabicyclot3.3.0]octane-3-carboxylic acid and corn starch are mixed ~ith an aqueous gelatine solution.
The mixture is dried and milled to granules. Micro-crystalline cellulose and magnesiu~ steara~e are mixed ~ith the granules. The resultin~ granules are cDm-pressed to form 1300 table~s, each tablet containing 10 ~g of the ACE inhibi~or.
These tablets can be us~d ~or the treatment o~ a~hero-sclerosis~ of thrombosis and/or of peripheral vessel 3D disease.
1 32090~
Example 2 ~ .
1000 tablets each conta;n;ng 10 mg of N~ S-carbo-ethoxy-3-phenylpropyl~-S-alanyl~2S,3aR,7aS)-octahydro-;ndole-2-carboxylic acid hydrochloride are prepared in analogy to Example 1.
Example 3 6elat;ne capsules each containing 10 mg of N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-1$,3S,5S-2-aza-b;cycloC3.3.5]octane-3-carboxylic acid are filled ~ith lD the foLlo~ing ~ixture:
!
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-1$,3S,SS-2-azabicyclo~3~3.0~octane-3-carboxyl;c acid 10 mg Magnesium stearate 1 mg Lactose 214 mg These capsules can be used for the treatment of athero-sclerosis, of thrombosis and/or o~ peripheral vessel diseaseO
Example 4 . .
2U The preparation of an injection solut;on for the treat-~ent of atherosclerosis, of thrombosis and/or of peri-pheral vessel disease is de-~cribed below:
N~ S-carboxy-3-phenylpropyl)-S-alanyl-15,3S95S-2-azabicycloC3.3.0~octane-3-carboxylic acid 250 mg ~ethylparaben 5 9 Propylparaben 1 9 Sodiu~ chlorîde 25 9 ~ater for injections 5 1 3'20qO4 N-(1 S-carboxy-3-phenyLpropyl)-S-alanyl-lS,3S~SS-Z-azabicyclot3.3.0~octane-3-carboxylic acid, the preser-vat;Yes and sodium chloride are dissolved in 3 l of ~ater for injections, and the solution is made up to 5 L ~ith water for injections~ The solution is filtered sterile, and d;spensed aseptically into presterilized bottles, which are closed ~ith s~erilized rubber caps.
Each bottle contains 5 ml of solution.
Example 5 Tablets which can be used for ~he treatment of athero-sclerosis, o~ thrombosis and/or of peripheral vessel disease are prepared as described in Example 1, ~ith the exception that in place of N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-15,3S,SS-Z-azabicycloC3.3.0]-uc~ane-3S-carboxylic acid N-f1-S-carboxy-3-phenylpropyl)-S-alanyl-1S~35,5S-2-azabicyclo~3.3.0]octane-3-carboxy~;c acid or H-(1AS-carboxy-3-phenylpropyl~-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid or N-(1-S-carboethoxy-3-phenylprspyl)-5-3lanyl-cis-2"3,3a,4~5f7a-hexahydro~1H~indole-~-S-endo-carboxylic acid or N (1-S-carboxy-3-phenyLpropyl)-S-alanyL-cis-2,3,3a,4, 5,7a-hexahydro~1H~indole-25-endo-carboxylic ac;d or N-(1-S-carboxy-3-phenylpropyL)-S-lysyl-1S,3S,5S-2-a~abicyclo~3.3.0~octane-3-carboxylic acid or N-~1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyL-1S,3S,5S-2-azabicyclor3.3.0]octane-3-carboxylic acid or N-~1-S-carboxy-3-cycLohexyLpropyl)-S-lysyl-1S~3S,5S-2 azabicyclo[3.3.0]octane-3-carboxylic acid are used.
Example 6 An injection solution is prepared in analogy to the procedure described in Example 4, ~ith thP excep~ion that in pLace of N-(1-s-carboeehoxy-3-phenylpropyl) alanyL-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid N-t1-S-carboxy-3-phenylpropyl)-S-alanyl-lS,35,5S-2-azabicyclor3.3.0~octane-3-carboxyl;c acid or N-(1-S-carboethoxy-3~phenylpropyl)-S-al~nyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid hydrochloride or N-~1-S-carboxy-3-phenylpropyl)-S---alanyl-25,3aR,7aS-octahydroindole-2-carboxylic acid or N-(1-S-carboethoxy-3-cyclohexylpropyl3-S-al~nyl~cis-2,3,3a~4,5,7a-hexahydroC1H]indole-2-S-endo-carboxylic acid or N-(1-S-carboxy-3-phenylpropyl)-S-alanyl-c;s-2,3,3a,4,5, 7a-hexahydroC1H]indole-2-S-endo-carboxylic acid or N-(1-carboxy-3-phenylpropyl)-S-lysyl-1S,3S,5S-2-aza-bicycloC3.3.0~octane-3-carboxylic acid or N~ S-carboethoxy-3-cyclohexyl)-S-alanyl-15,3S,5S-2-azabicyclot3.3.0]octane-3-carboxylic acid or N-~1-S-carboxy-3-cyclohexylpropyl)-S-lysyl-1S,3S,5S-2-azabicyclot3.3.D~octane-3-carboxylic acid are used.
spirot(bicyclo~2.2.1~heptane)-2,3'-pyrrolidine~(G);
spiro~(bicyclo~2.2.2~octane)-2,3'-pyrrolidine~ tH);
2-azatricyclo~4.3Ø16,9]decane (I); decahydrocyclQ-hepta~b]pyrrole (J); octahydroisoindole tK); octahydro-cyclopentaZc~pyrrole (I); 2~3,3a,4,5,7a-hexahydroindole (M); 2-azabicyclo~3.1.D~hexane (N); all of uhich can optionally be substituted. However, the unsubs~ituted Z5 systems ~re preferred.
In the case of compounds which have several chiral ato~s, all possible diastereomers are suitabLe, as racemates or enantiomers or ~ixtures of various dia-st~reomers.
~he cycli~ amino acid esters ~hich are suitable have the foLlo~ing structural formulae.
1 320qo4 COOR3 ~ COOP~3 ~ N~
A B ~N~LCOOR3 '~-C~'o~33_coo~3 3_, ' G H
~) COOR3~COOR3 ~3_ 3 J . X L
~COOR3 ~COOR3 M N
A preferred embodiment compr;ses use of compounds of the formula I in ~h;ch n is 1 or 2~
R denot~s hydrogen, alkyl having 1-8 carbon atoms, alkenyl hav;ng 2-6 carbon atoms, cycLoalkyl having 3-9 carbon atoms, aryL ~hich has 6-12 carbon at~ms and can be ~ono-, di- or trisubsti~uted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogsn, nitro9 amino, amino~ethyl, (C1-C4)-alkylamino~ di-(C1-C4)-, .
' 1 ;~20904 alkylamino, (C1-C4)-alkanoyl~mino, ~ethylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms~ aryloxy ~hich has 6-12 carbon atoms and can be subs~i~uted as described above for aryl, S mono- or bicyclic heteroaryloxy ~hich has 5-7 or 8-10 ring atoms respectively, 1 to 2 of ~hese ring atoms representing sulfur or oxygen a~oms and/or 1 to 4 of these ring atoms rPpresenting nitrogen, and which can be substituted as described above for aryl, amino-(C1-C~)-alkyl, (C1-C4)-alkanoylamino-tC1-C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C
C4)-alkoxycarbony~amino-tC1-C~)-alkyL, ~C6-S~
aryl-~C1-C4)-alkoxycarbonylamino-(C1-C4)-all(yl, (C~,-C1~)-aryL-(Cl-C4)~alkylamino-(C1-C43-3lkyl, (C1 C4)-alkyla~ino-(C1-C4)-alkyl, di-(C1-C4)-alkyl-amino-(C1-C~)-alkyl, guanidino-(C~-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C~-C12)-arylthio (C1 C4 alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C1z)-aryl-(C1-C4~-alkyLthio ~hich can be su~stituted in the aryl ~oi~ty as described ab~ve for aryl, carboxy-(C~-C~3-alkyl, carboxyl, carbamoyl, carbamoyl-~Cl-~4)-alkYl~ (c1-c4~-alkoxycarbonyl~ -c4)-alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl ~hich can be substituted in the aryl maiety as descr;bed above for aryl, or (C6-C12)-aryl-(C1-C4~-alkoxy which can be subs~ituted ir, the aryl moiety as described above for aryl, R denotes hydrogen~ alkyl having 1-6 carbon 3toms, alkenyl having 2-6 carbon atomsy alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms~
cycloalkenyl having 5-9 c~rbon atoms, (C3~Cg)-cycloalkyl-~C1-C4)-alkyl, (C~-Cg)-cyclo3lkenyl-(C1-C43-alkyl, optionally partiaLly hydrogenated aryl which has 6-12 carbon atoms and can be subst;
tuted as described above for R, Sr6-C1~)-aryl-(C1-C43-alkyl or ~C7-C13)-aroyl (C1 or C23-alkyl, both 1 32nqo4 of ~hich can be substituted as the abovementioned aryl, mono- or bicyclic, op~ionally partially hydro-genated heteroaryl which has 5-7 or 8-10 rin~ atoms respectively, 1 or 2 of these ring atoms represent-;ng sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and ~hich can be substituted as the abovementioned aryl, or the optionally protected side chain of a naturally occurring ~ am;no acid R1-CH(NH2) COOH~
R2 and R3 are identical or different and denote hydro-gen, alkyl having 1-6 carbon a~oms, alkenyl having 2-6 carbon atoms, di-(C1-C4)-aLkyLam;no-(C1-C4)-alkyL, tC1-Cs)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6)-alkoxycarbonyloxy-(C1-C4) alkyl, tC7-C13)-aroyloxy-(C1-C4)-alkyl, (C6-C1z)-aryloxycarbonyloxy-(C1-C4)-alkyl, aryl hav;ng 6-12 carbon atoms, (C6-C123-aryl-(C1-C4)-alkyl, (t3-Cg)-cycloalkyl or (C3~Cg)-cycloalkyl-(C1-C4~-alkyl, and R4 and R5 have the abovement;oned meaning.
A particularly preferred embodimEnt romprises u~e of compounds of the for~ula I in which n is 1 or 2, R denotes (C1-C6)-alkyl~ (C2-C6)-alkenyl, (C3-Cg)-cycloalkyl, amino-(C1-C4)-alkyl, (Cz-Cs3-acylamino-(C1-C4)-a~kYl~ (~7-c13)-aroylamino-tc1-c4)-alkyl~
(C1-C4)-alkoxycarbonylamino~(C1-C4)-alkyl9 (C6-tl2) aryl-(Cl-C4)-alkoxycarbonylamino-(C~-C4)-alkyl, tC6-C12)-aryl ~hich can be mono-, di- or trisub-~tituted by ~C1-C4)-alkyl~ (C1-C4)-alkoxy, hydroxyl, halogen, nitro~ am;no~ (C1-C4)-alkylamino, di-(C1-C4)-alkylamino and/or methylened;oxy, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert.-butoxycar~onyla~ino-(C1-C4~-alkyl, benzoyloxycarbon-ylamino-(C1-C4)-alkyl, or phenyl ~hich can be mono-or disubstituted, or in the case of methoxy tri-substituted, by phenyl~ (C1-C2~-alkyl, tC1 or C23-alkoxy, hydro~yl, fluorine~ chlorine, bromine, amino, (t1-C4)-alkylamino, di-(C1-Cb)-alkylamino~
) nitro and/or methylened;oxy, R1 denot~s hydrogen or (C1 C6)-alkyl which can option-ally be substituted by amino, (C1-C6)-acylamino or benzoylamino~ (C2-C6)-alkenyl, (C3-Cg)-cycloalkyl~
(Cs-Cg)-cycloalkenyl~ (C3-C7)-cycloalkyl-(~ 4)-alkyl, (C6-C121-aryl or partially hydrogenated aryl, each of which ean be substituted by (C1-Cb)-alkyl~
(C1 or C2)-alkoxy or halogen, (C6-C17~-aryl-(C1 to C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-alkyl, both of which can be substituted in ~he aryl radical as de-fined above, a mono- or b;cyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respect-ively, 1 ~o 2 of these ring atoms representing sulfur or oxygen atoms andtor 1 to 4 of these ring atoms representing nitrogen a~oms, or a side chain of a naturally occurring, optionally protected -amino acid, but in par~icular hydrogen, (C1-C3)-alkyl, (C2 or C3)-alkenyl~ the opt;on3lly protected side chain or lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyL or benzoyl-methyl, R2 and R3 denote identical or different rad;cals hydro-gen, (C~-C6)-alkyl~ ~C2-C6)-alkenyl or (C6-C12)-aryl-(C1-C~)-alkyl, but in particular hydrogen, (C1-C4)-alkyl or benzyl, and R4 and RS have the abovement;oned meaning.
It is particularly preferred to ~se compounds sf the formula I in which n is 2, R denotes phenyl, R1 denotes ~ethyl, R2 and R3 denote identical or different (C1-C6)-alkyl radicals or ~C7-C10)-araLkyL radicals such as benzyl or nitrobenzyl, and R4 and R5 together represent a radicaL of the for0ula --lCH2 in ~hich m denotes 0 or 1, p denotes 0, 1 or ?, and X denotes -CH2-, -CH2-CH2- or -CH=CH-, it also be;ng possible for a 6-ring formed with X to be a ben-zene ring.
In this context and in the following, aryL is to be understood preferably to be substituted phenyl, bi-phenylyl or naphthyl. A corresponding statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl is particularly understood to be benzoylO Aliphatic radicals can be seraight-chain or branched.
A mono- or bicyclic heterocyclic radical h3ving 5 to 7 or 2 to 10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atQms andJor 1 to 4 of these ring ato~s representing nitrogen atoms~
is~to be understood to be~ for example, thienyLO benzo-~b]thienyl, ~uryl~ pyranyl, benzofuryl, pyrroL~l, im;d-azoLyl, pyrazolyl~ pyridyl, pyrimidinyl, pyridaz;nyl~
indazolyl, isoindolyl, indolyl, purinyl9 quinolizinyl, isoquinolinyl, phthalazinyl, naph~hyridinyl, quinoxal-inyl, quinazolyl, cinnolinyl, pteridinyl, ox~zolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be part;ally or completely hydrogenated.
Naturally occurring ~-amino acids are described in~ for example~ Houben-~eyl~ Methoden der Organischen Chemie (Methods of Organic Chemistry)~ Vols. XV/1 and XVJ2.
~here R1 repr~sents a side ehain of a protected naturally occ~rring ~ 3mino acid such as, for e~ample, 1 320qO4 protected Ser, Thr, Asp, Asn, Glu, GLn, Arg, Lys, Hyl, Cys~ Orn, C;t, Tyr, Trp, H;s nr Hyp, the preferred pro-tective groups are the ~roups customary in peptide chemistry (ct. Houben-~eyl, Yols. XV/1 and XY/2)~ In the case ~here R1 denotes the protected side chain of lysine, the known a~ino protective groups, but in par-ticular Z, Boc or ~C1-C6)-alkanoyl, are preferred.
Suitable and preferred as O-protective groups for tyro~
sine are ~C1-C6)-alkyl, in particular methyl or ethyl.
AC inh;bitors o~ the formuLa I can be prepared by reacting together their fragments in a suitable sol-vent, ~here appropriate in the presence of a base and/
or of a coupling auxiliary9 ~here appropriate reduction of unsaturated compounds ~hich have resulted as inter-mediates, such as Schiff's bases, and elimination ofprotective groups which have been introduced temporar-ily to protect reactive groups and, ~here appropr;ate, conversion of the resulting compounds into their physi-ologically tolerated salts.
It is possible in the said manner to react rompounds of the forMula V ~ith compounds of the formula VI
R300C-~C -N~H ~OOC~ CH ( H2)n~R
(V) (VI) The reaction of these compounds can, ~or example, be carried out in analogy to kno~n peptide coupling pro~
cesses in the presence of coupling auxiliaries such as carbodiimides ~for examPle dicycLohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N~N-succinimidyl car-bonates in CH3CN. Amino groups in compounds of ~he formula V can be activated ~ith tetraethyl diphosphite.
The compounds of the formula VI can be converted into .
1 320qO4 _ 9 _ active esters ~for example ~ith 1-hydroxybenzotri-azole), mixed anhydr;des (for example with chloroformic esters), azides or carbodiimide derivatives, and thus be activated (cf. Schroder, LBbke, The Peptides, Vol.
1, New York, 1965, pages 76 136).
It is likewise possible to react compounds of the for-mula YII ~ith compounds of the 70rmula VIII, ~ith the formation of compounds of the formula I
R OOC-ICH-~ - C IM-~ Y~ lH t H2)n-R
O R OOR
(V~I ) ('VIII ) in ~hich either y1 represents amino and y2 represents a leaving group, or y1 represents a leaving group and y2 represents amino. Examples of suitable Leaving groups are Cl, ar, I~ alkylsulfonyloxy or arylsulfonyl-oxy .
Alkylations of this typB ~re advantageous~y carried outin water or an or~anic solvent, in the presencs of a base.
Furthermore, compounds of the for~ula IX san be con-densed ~ith co~pounds of the formula X
R300C_~H_ _ c~ l Q2~f -lC 2)~-R
0 R C~R
~IX) (X3 in ~hich either ~1 represents amino 4 hydrogen and ~2 represents oxo, or Q1 represents oxo and ~2 represents amino + hydrogen The condensation is advantageously carried out ;n ~ater 'I 320qO4 or an organic solvent such as a lo~er alcohol, and ;n the presence of a reducing agent such as Na8H3CN, whereupon compounds of the formula I are obtained dir-ec~ly. However, ;t ;s also possible to reduce the Schiff's bases or enamines ~hich result as intermedi-ates~ ~here appropriate after previous isolation, with the format;on of compounds of the formula I, for exam-ple by hydrogena~;on in the presence of a transi~ion metal catalyst.
Finally, reaction of compounds of the f~rmula IX (a1 =
H + N~2) w;th compounds of the formula XI, or their reaction with compounds of the for~ulae XII and XlII, also results in compounds of the formula I (n=2)~ !
R~OC-C~-CH-~O-R
~XI~
OCH-CO~R2 R-CO-~H3 tXII) (XIII) there being reduction of Schi~f~s bases produced as intermediates, and conversion of a carbonyl group into nethrlene by reduction.
In the above~entioned formulae V-XIIl, R-RS and n are as de~ined in formula I. Protective groups introduced temporarily to protect reactive groups not involved in the reac~;on are elim;nated a~ter reaction is complete in ~ manner known per se (cf. Schroder, Lubke~ lOca cit., pages 1~7S and 246-270)~
It is possible and part;cularly advantageou~ to use the follo~ing co~pounds in the ~ethod according to the in-vention:
N~ S-carboethoxy-3-phenylPropyl~-s-alanyl-s-1~2~3~4 tetrahydroisoquinoline-3-sarbQxylis acid N-tl-S-carboethoxy-3-cyc~ohexylpropyl)-S-alanyl-S-1~2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-Lysyl-S-1~2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-e~hyl-S-~yrosy(-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl~-S-alanyl-3S-deca-hydro-isoquinoline-3-carboxylic acid H-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-(2S~3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-(2S,3aS~7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-(2S,3aS,7aS)-octahydroindoLe-2-carboxylic acid N-(1-S-carboethoxy-3-phenylPropyL)-0-methyl-S-tyrosyl-(25,3aS,7aS)-octahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-phenylprop~l)-0-ethyl-S-tyrosyl (2S,3aS,7aS)-sctahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-~3,4-d;methylphenylpropyl)-S-al3nyl-tZS,3aS,7aS)-oetahydroindole-2-carboxylic acid N-~1-S-carboethoxy-3-(4-fluorophenyl~-propyl]-S-alanyl-~2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-~4-~ethoxyphenylj-propyl~-S-alanyl-(2S,3aSJ7aS)-octahydroindole-2-carboxylic acid N-C1-S-carboethoxy-3-(3,4-dimethoxyphenyl)-propyl]-S-alanyl-~2S,3aS~7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-~2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-~2S,3aR,7aS)-octahydroindole-Z-carbo~ylic ~cid N (1-S-carboethoxy-3-cyclohexylPropyl3-S-alanyl-(2S,3aR,7aS~-octahydro;ndole-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S lysyl-~2S,3aR~7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-5-lysyL-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-(?s~3as~7aR)-octahydro;ndole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-(2S,3aR~7aR)-oc~ahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,7aS)-octahydroindoLe-2-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-1D (2S,3aR~7aR)-octahydroindole-2-carboxylic acid N-(1-S-c~rboe~hoxy-3-cyclohexylpropyl)-0-ethyl-S-tyro-syl-~2S,3aR,7aR)-nctahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-(25~3aS,7aR)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl~-0-ethyl-S-tyrosyl-(ZS,3aS,7aS)-octahydroindole-2-carboxylic acid N-(1-S-carboethoxy-3~4-dimethylphenylpropyl3-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-E1-S-carboethuxy-3-(4-fluorophenyl)-propyl~-S-alanyl-t2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-~1-S-carboethoxy-3-(4-~ethoxyphenyl)-propyl]-S-al3nyl-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid N-C1-S-carboethoxy-3-5394-dimethoxyphenyl)-propyl]-S-alanyl-(2S,3aS,7aS)-octahydroindole-~-carboxylic acid N-(1-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-: (2S,3aS~7aS)-octahydroindole-2-carboxyl;c acid N-(1-S-carboethoxy 3-phenylpropyl)-S-alanyl-cis-endo-2-azabicyclo~3~3.0]octane-3-S-carboxylic acid N-(1-S-carboeth3xy-3-phenylpropyl)-S-lysyl-cis-endo-2-azabicycloC3.3.0~octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cis-endo-2-azabicycloC3.3.0~oct~ne 3-S~carboxylic acid ~-51-S-carboxy-3-cyclohexylpropyl)-S-alanyl-cis-Lndo-2-azabicyclo~3.3.0~octane-3-S-carboxylic acid N-~1-S-carboethoxybutyL)-S-alanyl-cis-endo-2-azabicycLo-C3.3~0~oct~ne-3-S-carboxylic acid N-l1-S-carboethoxy-3-(3~4-di0ethoxyphenylpropyl)-S-aLanyl-cis-endo-2-azabicyclot3.3aO]ost3ne-3-S-carboxylic acid ~ S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-cis-endo-azabicyclo-C3.3.0]octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl) 0-methyl-S-tyrosyl-S cis-endo-2-azabicyclo~3.3.0~octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-5-tyrosyl-cis-endo-2-azabicyclot3.3.03Octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-(4-fluorophenylpropyl)-S-alanyl-cis-endo-azab;cyclo~3.3.0]octane-3-S-carboxylic acid N-(1-S-carboethoxy-3-(4-methoxyphenylpropyl)-S-alanyl-cis-endo-2-azabicyclo~3.3.0]octane-3~5-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,6aS)-octahydrocyclopenta~b~pyrrole-2-carboxylic acid N~ S-carboethoxy-3-cyclohexylpropyl)-lysyl-(2S,3a,6aS)-octahydrocyclopentatb3pyrrole-2-tarboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-(2S,3aR,6aS)-octahydrocyclopenta~b~pyrrole-2-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-a~anyL-2-Z0 (2S,3aR,6aS)-octahydrocyclopen~atb~pyrrole-2-carboxyl;c acid N (1-S-carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-t4~5]decane-3-S-carboxylic acid N-~1-S-carbo~thoxy-3-phenylpropyl)-0-ethyL-2-tyrosyl-azaspiro-C4~5~decane-3-S- arboxylic acid N-(1-S-carboethoxy-3~phenylpropyl)-S-lysyl-2-azaspiro-E4.53decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyL)-S-alanyl-~-aza-spiro~4.5~d2cane-3-S-carboxylic ac1d N-t1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-2-aza~
spiroC4.5~decane-3-S-carboxylic acid N-(1-S-c2rboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-C4.4~nonane-3-S-carboxylic acid N-(1-S-carbo~thoxy~3~Phenylpropyl)-o-ethyl-s~tyrosyL-2 azaspiro~4.4~nonane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl 2 azaspiro-t4.4~non3ne-3-S-carboxylic acid N-t1-S-carbo~thoxy-3-cyclohexylpropyl)-5-alanyl-2-aza-spiro[4.4~nonane-3~S-carboxylic acid N-(l-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-2 azaspirot4.4~non3ne-3-S-carboxylic acid N-t1-S-carboethoxy-3-cyclopentylpropyl)-S-lysyl-2-aza-spirol4.4]nonane-3-S-carboxylic acid N-51-S-carboethoxy-3-phenylpropyl)-S-alanyl-spiro-tbicyclo~2.2.1]heptane-2,3'-pyrrolidine~-5'-S-carboxylic acid N~ S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-spiroCbicyclol2.2.1]heptane-2,3'-pyrrolidine~-5'-S-carboxylic acidN-(1-S-carboe~hoxy-3-phenylpropyl3-S-lysyl-sp;ro-tbicyclo t2.201~heptane-2~3'-pyrrolidineJ-S'-S-carboxyiic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-spiro-Cbicyclo~2.2~1~heptane 2,3'-pyrrolidine3-5'-S-carboxy-lic acidN-t1-S-carboethoxy-3-cyclohexylpropyl)-S~lysyl-spiro~
tbicyclo~2.201~heptane-2,3'-pyrrolidine3-S'-S-carboxy-l;c ac;d N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-spiro-tbi-cyclot2.2.Z~octane-2,3'-pyrrolidine]-S'-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-tyrosyl-~piro~bicyclot2.2.2~octane-2,3'-pyrrolidine~-5'-S-carboxylic acid N-(1-S-carboethoxy-3-phenyLpropyl)-S-lysyL-spiro~bi-cycloC2.2.2]octane-2,3'-pyrrolidine~-5'~S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-spiro-CbicycLo~2.2.2]o&tane-2,3'-pyrrolidine]-S'-S-carboxylic acid N~ S-sarboethoxy-3-ph~nylpropyl)-S-alanyl-2-azatri-cyclo~4.3Ø16'9~decane-3-S-carboxyl;c acid N-(1-S-carboethoxy-3-phenylpropyl~-0-ethyl S-tyrosyL-2-azatricyclo~4.3Ø1~'9]decane-3 S-carboxylic acid N-~1-S-carboethoxy-3-PhenylPropyl)-S-lysyl-2-azatri-cycloC4.3Ø16'~idecane-3 S-carboxylic acid N-t1-S-carboethoxy~3-cyclohexylPropyl)-s-alanyl-2 azatricyclo[4.3Ø16'9~decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyL-2-aza-tricycLo~4.3Ø16'9]decane-3-S-carboxylic acid N-(1-S-carboethoxy-3-phenyLpropyla-S-alanyl-decahydro-cycloheptalb]pyrrole-2-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyL)-0-ethyl-S-tyrosyl-decahydrocyclohepta[b]pyrrole-2-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-decahydro-cyclohepta~b3pyrrole-2-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-deca-hydrocyclohepta~b]pyrrol~-2-S-carboxylic acid N-(1-S-carboethoxy-3-cyclo~exylpropyl)-S-lysyl-deca-hydrocycloheptaLb]pyrrale-2-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-trans-octa-hydroisoindole-1-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyL)-S-alanyl-cis-octa-hydroisoindole-1-S-carboxylic ac;d N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-trans-octahydro;soindole-1-S-carboxyLic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cis-octa-hydroisoindole-1-S-carboxylic acid N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis octa-hydrocyclopentaCc]pyrrole-1-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-aLanyl-cis-octahydrocyclopentatc~pyrrole-1-S-carboxylic acid benzyl ester N-(1-S-c~rboethoxy-3-cyclohexylpropyl)-S-lysyl-cis-octa-hydrocyclopenta~c~pyrrole-1-S-carboxylic acid N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-2,3,3a,4,5, ~a-hexahydroindole-cis-endo-2-S-carboxylic ~cid 0 N-(1-S-carboethoxy~3-phenylpropyl~-S-lysyl-2,3,3a,4,5 7a-hexahydroindol?-cis-endo-2-S-carboxylic acid N-(1 S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-2~aza-bicyclQ~3.1.D~hexane-3-S-carboxylic acid N-(1-S-c~rboxy-3-phenylpro~yl~-S-lysyL-2-azabicyclo-C3.1.0~hexane-cis-endo-3-S-carboxyLic acid N-(1-S-carboethoxy~3-cyclopentylpropyl)-S-alanyl-2--aza-bicyclot3~1.0~hex~ne-3-carboxylic acid N-(1-S-carboethoxy-3-phenrlpropyl~-S~alanyL-cis~endo-2-1 320~0~
~ 16 -a~abicycloC3.1.0]hexane-3-S-cArboxylic acid N-(1-S~carboethoxy-3-cyclohexyLpropyl)-S-alanyl-cis-endo-2-azabicycLo~3~1.o]hexane-3-s-carboxylic acid.
These compounds can be prepared by, for example, the process described in German Patent Application P
3,333,455.2, in which process the tsrt.-butyl or benzyl esters described in the application are converted into the monocarboxylic acid derivatives in known man-ner by acid or alkaLine hydrolysis or by hydrogenolysis catalyzed by noble met~ls. The N-benzyloxycarbonyl protective group of ~he lysine derivatives is removed by hydrogenolysis catalyzed by noble m~tals~ The com-pounds listed above can be readily converted ~ith physiologicaLly tolerated acids or bases (in the czse of mono- or d;carboxylic acids) into the corresponding salts (for exa~ple hydrochlorides, maleates, fumarates etc.) and be used as salts zccording to the invention~
The compounds of the formula I are inhibitors of angio-tensin converting enzyme (ACE) or intermediates in the preparation of s~ch inhib;tors, and they can also be used to control high blood pressure of various etiolo-gies. The compounds of the formula I are disclosed in, for exa~ple, US Patent 4,129,571, US Patent 4,374,829, European ~atent A-79,522, Furopean Patent A-7~,022, European Patent A-49,658, European Patent A-51,301~ US
Patent 4,454,292, US Patent 4,374,847, European Patent A-72,352, US Patent 4,35U,704, European Patent A-50,8Q0, European Patent Ao46,~53, US Patent 4~344,949, European Patent A-84~164, US Patent 4,470,972, European Patent A-65,301 and European Patent A-52,991.
Also advantageous are or~lly effective ACE inhibitors such as, for exam~le, ra~ipril, enalapril, t~ptopr;l, lisinopril, perindopril, cilazapril, RHC 3659, CGS
13945, CGS 13928C, CGS 14B24A~ CI-9D6, SCH 31846~
zofenopril~ fosenopril~ alacepril and others. Orally 1 ')2090~
- ~7 -effective ACE inhibitors are described in, for example, ~runner et al., J. Card;ovasc. Pharmacol. 7 (Suppl. I) (~985) S2-S11.
Preferred ACE inhibitors are ~hose disclosed in Europ-ean Patent d-79022, of the formula III
C~ ~S) ~S~ (III) H N~ C~2 ~ I H~
O CH3 ~00R
in ~hich R denotes hydrogen, ~ethyl, ethyl or benzyl, in particular the compound o~ the ~ormula III in which R denotes ethyl (ramipril).
Other preferred ACE inhibitors are those disclosed in European Patent A-84~164, of the formula IV
B
COOH (IV) ~ N~ ~S9 IS) ~r-~
O ~ q ~H - C~ CH2 o G~2 ~3 ~ooR4 o in ~hich R4 denotes hydrogen, (C1-C4~-alkyl or benzyl, in particular the compound of the formula IV~ in ~hich R4 denotes ethyl.
In carrying out the method according to the invention, the angiotensin conYerting enzyme inhibitors described above can be admini tered to mammals such as ~onkeys, dogs, cats, rat~, humans etc. The compounds ~hich are suitable for the use according to ~he invention are ad-vantageou~ly incorporated in pharmaceutical products incustomary manner~ They can be converted into the CU5-tomary administratiDn forms, such as capsules, tablets, coa$ed tablets~ solutioQs, oint~ents and emulsions, as weLl as into a depot form. The active compound can~
~ 320904 ~here appropriate, also be in microencapsulated fc~rm.
The products can contain additional, tolerated organic or inorgan;c substances, for example granulating auxi-liaries~ adhesives and b;nders, lubr;cants, suspend;ng agents, solvents, antibacterial agents, ~ett;ng agents and preservatives~ Forms for oral and parenteral ad-ministration are preferred. ~he compounds of the formula l can be administered in dosages of 0.1-50 mg per dose once to three times a day.
It is also poss;ble according to the invention to use the ACE inhibitors in combination wi~h substances ~hich influence prostaglandin met~bolis~. Examples of such substances are stable prostacyclin analogs, inhibi~ors of thromboxane synthetase, and thromboxane an~agonists.
Hence the invention also reiates to pharmaceuticaL com-positions containing a) an AC inhibitor or ies physio-logically tolerated salt and b) a substance ~hich influences prostaglandin metabolism or its physiologi-cally tolerated salt, and to ~he;r use for the treat-ment of atherosclerosis~ of thrombosis and/or ofperipheral vessel dis~ase.
The invent1on furthermore relates quite generally to products containing the substances mentioned above under a~ and b~, as combination products for conçur-ZS rent~ separate or sequential administration for thetreatment of atherosclerosis, of thr~mbos;s and/or of peripheral vessel disease.
An increased a~gregability of the blood platelets plays a particularly important part in the development of atherosclerosis. Examples of sequelae are thromboses and peripheral vessel d;sease; these d;seases are the main cause of the incr~ased morbidity and mortality a sociated with high blood pressure~ alood platelets cont3in an anyiotensin-I-processin~ system, and their 1 ~20904 membrane has binding sites ~ith high affinity for angiotensin II. The fact that angiotensin converting enzyme (ACE) is preponderantly located on the luminal cytoplasmic membrane of the endo~helial cells points to S platelet/endothelium interactions being associated ~ith local angiotensin II produc~ion; ACE ;nh;bitors can ;nterfere ~;th this Furthermore, inh;bit;on of ACE poten~iates the action of bradykinin by preventing ;ts breakdo~n. It is known tha~ bradykin;n is a potent stimulator of the release of prostacycl;n from endo-theliai cells; bradykinin is in turn a potent ;nhibitor of platelet aggregation.
The activ;ty of the compounds of ~he for~ula I on platelet aggregation and thus on atherosclerosis, thrombosis and peripheral vessel disea~e, as well as other disease states associated ~;th ;ncreased aggreg-ab;lity of the blood platelets, can be deduced from a variety of test model~.
In each of the examples ~hich follow use is made of the results ~ith N~ S-carboethoxy-3-Phenylpropyl)-s-alanyl-cis-endo-2-azabicyclo~3.3.û~octane-3-S-carboxylic acid (Formula II~.
.
~,COOH
g) E~H-~H - C~-CH2 - CH2~ II
I~H3 ~ 2C2H5 A In vitro results Platelet-rich rabbit pl~s~a ;s obtained as stated by ~orn tArzneimittel-Forsch~ 31, 2012 (1~81)). Platelet aggreg3tion is measured by the increase in light pass-1 320qO4 ing through a ceLl ~hich contains this plasma. The pla~elet count is adjusted to 450,000/mm3 by dilut;on ~ith autologous, platelet-poor plasma. The sompound of the formula II has, in concentrat;ons of 0.1-10 ~g/ml of plasma, no effect on the aggregation induced by 0.24 mmol/l arachidonic aciJ, 5 mmol/l ADP or 4 ~g/ml colla-gen. In contrast, the inh;bition, brought about by 4 ~g/ml PGI2, of aggregation caused by arachidonic acid is increased to 100% by the compound of the formula II
in the said dose range.
8 l~ vi~
1. Acute study .
Conscious rabb;ts received a single oraL dose of 1.0-10.0 mg/kg of the co~pound o~ the formula II.
After 1 hour, the animals are sacrificed, and platelet-rich plasma is obtainedO Platele~ aggreg-ation is determined as describ~d under A).
There is fsund to be a reduction in aggregation in response to the three stimulators described there, in particular in response to ~rachidonic acid. A
potenti3tion of the PGI2 effect is also observed.
2. Chronic study Conscious rabbits received 1 mg/kgtd of the compound of the formula IE for 14 days~ and then the proce-dure was continued as described under 1). Pro-nounted inhibition of the platelet aggregation induced by ~rachidonic acid and A~P is ~ound in all animals.
The examples ~hich follo~ indicate the forms ~or admin-istration to treat atheroscl~rosis, thrombosis and peripheral vessel d;seas4 by the method according to - 2~ -the invention. The compounds of the formula I can be converted into the corresponding forms for adminis-traeion in analogy eO the examples.
Exam Preparation of the a~ent used according ~o the inven-tion for oral adm;nistrat;on in the treatment of atheroscLerosis, of thrombosis and of peripheral vessel diseaseO
1000 table~s each containing 10 mg of 1-N-(1-S-carbo-ethoxy-3-phenylpropyl)-S-alanyl-1S,3S,5S-2-azab;cycLo-C3.3.0]octane-3-carboxylic acid are prPpared ~ith the following auxiliaries:
N-(1-S-carboethoxy-3-phenypropyl)-S-alanyl-1S~35,5S-~-azabicycloC3~3.0]octane-3-carboxyliç acid 10 9 rorn starch 140 9 6elatine 7~5 ~
Microcrystalline cellulose 2.5 9 Magnesium stearate 2~5 9 N~ S-carboethoxy-3-phenylpropyl)-S-alanyl-15,3S,5S-: 2-azabicyclot3.3.0]octane-3-carboxylic acid and corn starch are mixed ~ith an aqueous gelatine solution.
The mixture is dried and milled to granules. Micro-crystalline cellulose and magnesiu~ steara~e are mixed ~ith the granules. The resultin~ granules are cDm-pressed to form 1300 table~s, each tablet containing 10 ~g of the ACE inhibi~or.
These tablets can be us~d ~or the treatment o~ a~hero-sclerosis~ of thrombosis and/or of peripheral vessel 3D disease.
1 32090~
Example 2 ~ .
1000 tablets each conta;n;ng 10 mg of N~ S-carbo-ethoxy-3-phenylpropyl~-S-alanyl~2S,3aR,7aS)-octahydro-;ndole-2-carboxylic acid hydrochloride are prepared in analogy to Example 1.
Example 3 6elat;ne capsules each containing 10 mg of N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-1$,3S,5S-2-aza-b;cycloC3.3.5]octane-3-carboxylic acid are filled ~ith lD the foLlo~ing ~ixture:
!
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-1$,3S,SS-2-azabicyclo~3~3.0~octane-3-carboxyl;c acid 10 mg Magnesium stearate 1 mg Lactose 214 mg These capsules can be used for the treatment of athero-sclerosis, of thrombosis and/or o~ peripheral vessel diseaseO
Example 4 . .
2U The preparation of an injection solut;on for the treat-~ent of atherosclerosis, of thrombosis and/or of peri-pheral vessel disease is de-~cribed below:
N~ S-carboxy-3-phenylpropyl)-S-alanyl-15,3S95S-2-azabicycloC3.3.0~octane-3-carboxylic acid 250 mg ~ethylparaben 5 9 Propylparaben 1 9 Sodiu~ chlorîde 25 9 ~ater for injections 5 1 3'20qO4 N-(1 S-carboxy-3-phenyLpropyl)-S-alanyl-lS,3S~SS-Z-azabicyclot3.3.0~octane-3-carboxylic acid, the preser-vat;Yes and sodium chloride are dissolved in 3 l of ~ater for injections, and the solution is made up to 5 L ~ith water for injections~ The solution is filtered sterile, and d;spensed aseptically into presterilized bottles, which are closed ~ith s~erilized rubber caps.
Each bottle contains 5 ml of solution.
Example 5 Tablets which can be used for ~he treatment of athero-sclerosis, o~ thrombosis and/or of peripheral vessel disease are prepared as described in Example 1, ~ith the exception that in place of N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-15,3S,SS-Z-azabicycloC3.3.0]-uc~ane-3S-carboxylic acid N-f1-S-carboxy-3-phenylpropyl)-S-alanyl-1S~35,5S-2-azabicyclo~3.3.0]octane-3-carboxy~;c acid or H-(1AS-carboxy-3-phenylpropyl~-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid or N-(1-S-carboethoxy-3-phenylprspyl)-5-3lanyl-cis-2"3,3a,4~5f7a-hexahydro~1H~indole-~-S-endo-carboxylic acid or N (1-S-carboxy-3-phenyLpropyl)-S-alanyL-cis-2,3,3a,4, 5,7a-hexahydro~1H~indole-25-endo-carboxylic ac;d or N-(1-S-carboxy-3-phenylpropyL)-S-lysyl-1S,3S,5S-2-a~abicyclo~3.3.0~octane-3-carboxylic acid or N-~1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyL-1S,3S,5S-2-azabicyclor3.3.0]octane-3-carboxylic acid or N-~1-S-carboxy-3-cycLohexyLpropyl)-S-lysyl-1S~3S,5S-2 azabicyclo[3.3.0]octane-3-carboxylic acid are used.
Example 6 An injection solution is prepared in analogy to the procedure described in Example 4, ~ith thP excep~ion that in pLace of N-(1-s-carboeehoxy-3-phenylpropyl) alanyL-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic acid N-t1-S-carboxy-3-phenylpropyl)-S-alanyl-lS,35,5S-2-azabicyclor3.3.0~octane-3-carboxyl;c acid or N-(1-S-carboethoxy-3~phenylpropyl)-S-al~nyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid hydrochloride or N-~1-S-carboxy-3-phenylpropyl)-S---alanyl-25,3aR,7aS-octahydroindole-2-carboxylic acid or N-(1-S-carboethoxy-3-cyclohexylpropyl3-S-al~nyl~cis-2,3,3a~4,5,7a-hexahydroC1H]indole-2-S-endo-carboxylic acid or N-(1-S-carboxy-3-phenylpropyl)-S-alanyl-c;s-2,3,3a,4,5, 7a-hexahydroC1H]indole-2-S-endo-carboxylic acid or N-(1-carboxy-3-phenylpropyl)-S-lysyl-1S,3S,5S-2-aza-bicycloC3.3.0~octane-3-carboxylic acid or N~ S-carboethoxy-3-cyclohexyl)-S-alanyl-15,3S,5S-2-azabicyclot3.3.0]octane-3-carboxylic acid or N-~1-S-carboxy-3-cyclohexylpropyl)-S-lysyl-1S,3S,5S-2-azabicyclot3.3.D~octane-3-carboxylic acid are used.
Claims (13)
1. An angiotensin converting enzyme inhibitor of the formula I
(I) in which n is 1 or 2, R = hydrogen, an aliphatic radical having 1-8 carbon atoms, an alicyclic radical having 3-9 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-14 carbon atoms, an alicyclic-aliphatic radical having 7-14 carbon atoms, or a radical ORa or SRa, in which Ra represents an aliphatic radical having 1-4 carbon atoms, an aromatic radical having 6-12 carbon atoms, or a mono- or bicyclic heteroaryl which may be partially hydrogenated and which has 5 to 7 or 8 to 10 ring atoms, respectively, 1 or 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, R1 denotes hydrogen, an aliphatic radical having 1-6 carbon atoms, an alicyclic radical having 3-9 carbon atoms, an alicyclic-aliphatic radical having 4-13 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-16 carbon atoms, mono- or bicyclic heteroaryl which may be partially hydrogenated and which has 5-7 or 8-10 ring atoms, respectively, 1 or 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms/ or the side chain, protected where necessary of a naturally occurring .alpha.-amino acid, R2 and R3 are identical or different and denote hydrogen, an aliphatic radical having 1-6 carbon atoms, an alicyclic radical having 3-9 carbon atoms, an aromatic radical having 6-12 carbon atoms, or an araliphatic radical having 7-16 carbon atoms, and R4 and R5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 4 to 15 carbon atoms, or it physiologically tolerated salt, for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
(I) in which n is 1 or 2, R = hydrogen, an aliphatic radical having 1-8 carbon atoms, an alicyclic radical having 3-9 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-14 carbon atoms, an alicyclic-aliphatic radical having 7-14 carbon atoms, or a radical ORa or SRa, in which Ra represents an aliphatic radical having 1-4 carbon atoms, an aromatic radical having 6-12 carbon atoms, or a mono- or bicyclic heteroaryl which may be partially hydrogenated and which has 5 to 7 or 8 to 10 ring atoms, respectively, 1 or 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, R1 denotes hydrogen, an aliphatic radical having 1-6 carbon atoms, an alicyclic radical having 3-9 carbon atoms, an alicyclic-aliphatic radical having 4-13 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-16 carbon atoms, mono- or bicyclic heteroaryl which may be partially hydrogenated and which has 5-7 or 8-10 ring atoms, respectively, 1 or 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms/ or the side chain, protected where necessary of a naturally occurring .alpha.-amino acid, R2 and R3 are identical or different and denote hydrogen, an aliphatic radical having 1-6 carbon atoms, an alicyclic radical having 3-9 carbon atoms, an aromatic radical having 6-12 carbon atoms, or an araliphatic radical having 7-16 carbon atoms, and R4 and R5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 4 to 15 carbon atoms, or it physiologically tolerated salt, for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
2. An angiotensin converting enzyme inhibitor of the formula I as claimed in claim 1 in which R4 and R5 together with the atom carrying them represent a system which may be substituted, from the series comprising tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, octahydrocyclopentalb]pyrrole, 2-azaspiro[4.5]decane, 2-azaspiro[4.4]nonana, sprio [(bicyclo [2.2.1] heptane )-2, 3'-pyrrolindine], spiro[bicyclo[2.2.2]octane)-2,3'-pyrrolidine], 2-azatricyclo[4.3Ø16,9]decane, decahydrocyclohepta[b] pyrrole, octahydroisoindole, octahydrocyclopenta[c]pyrrole, 2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo[3.1.0]hexane, for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
3. An angiotensin converting enzyme inhibitor of the formula I as claimed in claim 1 in which n is 1 or 2, R denotes hydrogen, alkyl having 1-8 carbon atoms, alkenyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl which has 6 - 12 carbon atoms and can be mono-, di- or trisubstituted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, one or both of cyano and sulfamoyl, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and which can be substituted as described above for aryl, amino-(C1-C4)-alkyl, (C1-C4)-alkanoylamino-(C1 C4)-alkyl, (C7-C13)-aroylamino-(C1-C4-alkyl, (C1-C4)-alkoxycarbonylamino-(C1-C4)alkyl, (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl, di-(C1-C4)-alkyl-amino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl, imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-alkylthio-(C1-C4)-alkyl, (C6,-C12)-arylthio-(C1-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-C12) aryl-(C1-C4)-alkylthio which can be substituted in the aryl moiety as described above for aryl, carboxy-(C1-C4)-alkyl, carboxyl, carbamoyl, carbamoyl-(C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl-(C1-C4)-alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl which can be substitu-ted in the aryl moiety as described above for aryl, or (C6-C12-aryl-(C1-C4)-alkoxy which can be substituted in the aryl moiety as described above for aryl, R1 denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (C3-C9)-cycloalkyl-(C1-C4)-alkyl, (C5-C9-cycloalkenyl-(C1-C4)-alkyl, aryl which may be partially hydrogenated which has 6-12 carbon atoms and can be substi-tuted as described above for R, (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-(C1 or C2)-alkyl, both of which can be substituted as the abovementioned aryl, mono- or bicyclic, heteroaryl which may be partially hydrogenated which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and which can be substituted as the abovementioned aryl, or the side chain of a naturally occurring .alpha. -amino acid R1-CH(NH2)-COOH, which may be protected R2 and R3 are identical or different and denote hydro-gen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C5)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6,)-alkoxycarbonyloxy-(C1-C4)-alkyl, (C7-C13)-aroyloxy-(C1-C4)-alkyl, (C6-C12)-aryloxycarbonyloxy-(C1-C4-alkyl, aryl having 6-12 carbon atoms, (C6-C12)-aryl-(C1-C4)-alkyl, (C3-C9)-cycloalkyl or (C3-C9)-cycloalkyl-(C1-C4)-alkyl, and R4 and R5 are defined as in claim 1, for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
4. [S,S,S,S,S]-N-carboethoxy-3-phenylpropyl)-alanyl-octahydroindole-2-carboxylic acid, N-[1-(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-octahydroindole-2-carboxylic acid, [S,S,S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-decahydroisoquinoline-3-carboxylic acid, [S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydroisoquinoline-3-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid or N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2,3,3a,4,5, 7a-hexahydroindole-2-S-carboxylic acid for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
5. (S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl)-alanyl-2-azabicyclo[3.3.0] octane-3-carboxylic acid for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
6. The dicarboxylic acid of [S,S,S,S,S]-N-(1-carboethoxy-3-phenylpropyl)-alanyl- octahydroindole-2-carboxylic acid, N-[1-(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-octahydroindole-2-carboxylic acid, [S,S,S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-decahydroisoquinoline-3-carboxylic acid, [S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydroiso-quinoline-3-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid or N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2,3,3a,4, 5,7a-hexahydroindole-2-S-carboxylic acid for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
7. The diacarboxylic acid of (S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl)-alanyl-2-azabicyclo[3.3.0]-octane-3-carboxylic acid for use in the treatment of one or more of antherosclerosis, thrombosis and peripheral vessel disease in mammals.
8. Use of a compound of the Formula I as defined in claim 2, 3 or 4 for use in the treatment of one or more of atheroselerosis, thrombosis and peripheral vessel disease in mammals.
9. Use of [S,S,S,S,S]-N-(1-carboethoxy-3-phenylpropyl)-alanyl- octahydroindole-2-carboxylic acid, N-[1-(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-octahydro-indole-2-carboxylic acid, [S,S,S,S,S] N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-decahydroisoquinoline-3-carboxylic acid, [S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydro isoquinoline-3-carboxylic acid, N-(l-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo 2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid or N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-eis-endo-2,3,3a,4,5,7a-hexahydroindole-2-S-carboxylic acid for use in the treatment of one or more of atheroselerosis, thrombosis and peripheral vessel disease in mammals.
10. Use of (S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl) -alanyl-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
11. Use of the dicarboxylic acid of [S,S,S,S,S]-N-(1-carboethoxy-3-phenylpropyl)-alanyl-octahydro indole-2-carboxylic acid, N-[1-(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-octahydroindole-2-carboxylic acid, [S,S,S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-decahydro-isoquinoline-3-carboxylic acid, [S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydroisoquinoline-3-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2-azabicyclo [3.1.0]hexane-3-S-carboxylic acid or N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2,3,3a,4,5,7a-hexahydroindole-2-S-carboxylic acid for use in the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
12. Use of the diacarboxylic acid of (S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl)-alanyl-2-azabicyclo [3.3.0] octane-3-carboxylic acid for use in the treatment of one or more of antherosclerosis, thrombosis and peripheral vessel disease in mammals.
13. A pharmaceutical agent containing a compound of the formula I as defined in any one of claims 1 to 7 or its physiologically tolerated salt and a pharmaceutically acceptable carrier, diluent or excipient, for administration for the treatment of one or more of atherosclerosis, thrombosis and peripheral vessel disease in mammals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853536687 DE3536687A1 (en) | 1985-10-15 | 1985-10-15 | METHOD FOR TREATING ATHEROSCLEROSIS, THROMBOSIS AND PERIPHERAL VESSEL DISEASE |
| DEP3536687.7 | 1985-10-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1320904C true CA1320904C (en) | 1993-08-03 |
Family
ID=6283587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000520434A Expired - Fee Related CA1320904C (en) | 1985-10-15 | 1986-10-14 | Method for the treatment of atherosclerosis, thrombosis and peripheral vessel disease |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0219782B1 (en) |
| JP (1) | JPS6287524A (en) |
| KR (1) | KR930008094B1 (en) |
| AT (1) | ATE95064T1 (en) |
| AU (1) | AU594711B2 (en) |
| CA (1) | CA1320904C (en) |
| DE (2) | DE3536687A1 (en) |
| DK (1) | DK490486A (en) |
| ES (1) | ES2059301T3 (en) |
| IE (1) | IE60767B1 (en) |
| PT (1) | PT83535B (en) |
| ZA (1) | ZA867771B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4962105A (en) * | 1987-10-19 | 1990-10-09 | Ciba-Geigy Corporation | Potentiation of antihypertensive effect of ace inhibitors |
| DE3818245A1 (en) * | 1988-05-28 | 1989-12-07 | Hoechst Ag | COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH COLD CHANNEL MODULATORS AND THEIR USE IN MEDICINAL PRODUCTS |
| US4931464A (en) * | 1989-02-15 | 1990-06-05 | E. R. Squibb & Sons, Inc. | Method of reducing pre- and post-ischemic myocardial arrhythmias and fibrillation |
| CA2016467A1 (en) | 1989-06-05 | 1990-12-05 | Martin Eisman | Method for treating peripheral atherosclerotic disease employing an hmg coa reductase inhibitor and/or a squalene synthetase inhibitor |
| DE3923402A1 (en) * | 1989-07-14 | 1991-01-17 | Thera Patent Verwaltungs Gmbh | USE OF ACE INHIBITORS FOR THE PROPHYLAXIS AND THERAPY OF THE CHRONIC-VENOESE INSUFFICIENCY |
| DE3925759A1 (en) * | 1989-08-03 | 1991-02-07 | Thera Patent Verwaltungs Gmbh | USE OF ACE INHIBITORS FOR ATHEROSKLEROSEPROPHYLAXE |
| US5061694A (en) * | 1989-10-23 | 1991-10-29 | E. R. Squibb & Sons, Inc. | Method for stabilizing or causing regression of atherosclerosis in coronary arteries employing an ace inhibitor |
| US5212165A (en) * | 1989-10-23 | 1993-05-18 | E. R. Squibb & Sons, Inc. | Method for rehabilitating the vasorelaxant action of the coronary arteries impaired through atherosclerosis or hypercholesterolemia employing an ace inhibitor |
| CA2040865C (en) * | 1990-05-15 | 2002-07-23 | James L. Bergey | Method for preventing, stabilizing or causing regression of atherosclerosis employing a combination of a cholesterol lowering drug and an ace inhibitor |
| US5298497A (en) * | 1990-05-15 | 1994-03-29 | E. R. Squibb & Sons, Inc. | Method for preventing onset of hypertension employing a cholesterol lowering drug |
| US5140012A (en) * | 1990-05-31 | 1992-08-18 | E. R. Squibb & Sons, Inc. | Method for preventing onset of restenosis after angioplasty employing pravastatin |
| US5622985A (en) * | 1990-06-11 | 1997-04-22 | Bristol-Myers Squibb Company | Method for preventing a second heart attack employing an HMG CoA reductase inhibitor |
| US5130333A (en) * | 1990-10-19 | 1992-07-14 | E. R. Squibb & Sons, Inc. | Method for treating type II diabetes employing a cholesterol lowering drug |
| US5190970A (en) * | 1990-10-19 | 1993-03-02 | E. R. Squibb & Sons, Inc. | Method for preventing onset of or treating Type II diabetes employing a cholesterol lowering drug alone or in combination with an ace inhibitor |
| US5157025A (en) * | 1991-04-01 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Method for lowering serum cholesterol employing a phosphorus containing ace inhibitor alone or in combination with a cholesterol lowering drug |
| US6369103B1 (en) * | 1994-01-18 | 2002-04-09 | Bristol-Myers Squibb Company | Method for preventing or reducing risk of onset of cardiovascular events employing an HMG CoA reductase inhibitor |
| DE69734405T2 (en) | 1996-07-15 | 2006-08-03 | Sankyo Co., Ltd. | Use of CS-866 (Olmersartan) for the manufacture of a medicament for the treatment of arteriosclerosis |
| US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4470972A (en) * | 1981-04-28 | 1984-09-11 | Schering Corporation | 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids |
| US4374847A (en) * | 1980-10-27 | 1983-02-22 | Ciba-Geigy Corporation | 1-Carboxyalkanoylindoline-2-carboxylic acids |
| SU1327787A3 (en) * | 1981-11-05 | 1987-07-30 | Хехст Аг (Фирма) | Method of producing cis,endo-2-azabicyclo-(3,3,0)-octane-3-carboxylic acids or acid-additive salts thereof |
| DE3438545A1 (en) * | 1984-10-20 | 1986-04-24 | Merck Patent Gmbh, 6100 Darmstadt | PEPTIDE |
-
1985
- 1985-10-15 DE DE19853536687 patent/DE3536687A1/en not_active Withdrawn
-
1986
- 1986-10-11 EP EP86114097A patent/EP0219782B1/en not_active Expired - Lifetime
- 1986-10-11 ES ES86114097T patent/ES2059301T3/en not_active Expired - Lifetime
- 1986-10-11 DE DE86114097T patent/DE3689099D1/en not_active Expired - Fee Related
- 1986-10-11 AT AT86114097T patent/ATE95064T1/en not_active IP Right Cessation
- 1986-10-14 AU AU63890/86A patent/AU594711B2/en not_active Ceased
- 1986-10-14 JP JP61242206A patent/JPS6287524A/en active Pending
- 1986-10-14 CA CA000520434A patent/CA1320904C/en not_active Expired - Fee Related
- 1986-10-14 DK DK490486A patent/DK490486A/en not_active Application Discontinuation
- 1986-10-14 IE IE271186A patent/IE60767B1/en not_active IP Right Cessation
- 1986-10-14 PT PT83535A patent/PT83535B/en not_active IP Right Cessation
- 1986-10-14 ZA ZA867771A patent/ZA867771B/en unknown
- 1986-10-15 KR KR1019860008638A patent/KR930008094B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IE862711L (en) | 1987-04-15 |
| AU594711B2 (en) | 1990-03-15 |
| PT83535A (en) | 1986-11-01 |
| ZA867771B (en) | 1987-05-27 |
| EP0219782A3 (en) | 1990-05-30 |
| EP0219782B1 (en) | 1993-09-29 |
| AU6389086A (en) | 1987-04-16 |
| DK490486A (en) | 1987-04-16 |
| KR930008094B1 (en) | 1993-08-25 |
| ATE95064T1 (en) | 1993-10-15 |
| EP0219782A2 (en) | 1987-04-29 |
| IE60767B1 (en) | 1994-08-10 |
| DE3689099D1 (en) | 1993-11-04 |
| KR870004054A (en) | 1987-05-07 |
| DK490486D0 (en) | 1986-10-14 |
| DE3536687A1 (en) | 1987-04-16 |
| PT83535B (en) | 1989-05-31 |
| JPS6287524A (en) | 1987-04-22 |
| ES2059301T3 (en) | 1994-11-16 |
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| MKLA | Lapsed |