JPH0559105B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula cis, endoazabicyclo [3.3.
0] Concerning derivatives of octanecarboxylic acid and physiologically acceptable salts thereof. In the above formula, the hydrogen atoms at bridgehead carbon atoms 1 and 5 are mutually in cis configuration and the carboxy group at carbon atom 3 is oriented inward to the bicyclic system (i.e. -CO _2H group faces the cyclopentane ring), chain star (*)
Carbon atoms labeled with and carbon atoms of bicyclic systems 3
The chirality centers in each are in the S configuration,
And in the above formula, R ¹ means a side chain of methyl, lysine or O-lower alkylated side chain of tyrosine,
R ² is hydrogen, lower alkyl or phenyl lower alkyl, X is phenyl, Y is hydrogen or hydroxy and Z is hydrogen or Y and Z taken together mean oxygen. however,
R ¹ is methyl, R ² is hydrogen or lower alkyl,
Except when X means phenyl and Y and Z each mean hydrogen. In particular, salts include hydrochloride, maleate,
Tartrate or alkali salts, Ca salts, Mg salts and
Zn salt can be mentioned. The present invention further provides the formula (wherein R ² has the above-mentioned meaning other than hydrogen) is a compound of formula b or a compound of formula b
A mixture of a compound of formula b and a compound of formula a containing 50% or more of a compound of

【formula】

[wherein the hydrogen atoms at bridgehead carbon atoms 1 and 5 are mutually in the cis configuration, and the -CO ₂ W group at carbon atom 3 is oriented inward to the bicyclic system (i.e. -CO ₂ W group faces the cyclopentane ring), W is a carboxy-esterifying group]

by the known amide-forming methods of peptide chemistry, the product is hydrogenated and/or treated with an acid or base, the diastereomeric mixture is resolved at appropriate steps if necessary, and the resulting The present invention also relates to a process for the preparation of a compound having the above formula or a physiologically acceptable salt thereof, which comprises converting the compound having the above formula into a physiologically acceptable salt thereof. Compounds of the formula in which X is phenyl, Y is hydrogen, Z is hydrogen and R ² is methyl or ethyl are known (e.g. European Patent No. 0037231) and are available through various routes. I can do it. Benzyl ester (R ² = benzyl)
can be prepared in a similar manner. Furthermore, the Mannitz reaction of an acetophenone of formula a (wherein X represents an aryl optionally substituted as described above) with a glyoxylic acid ester and an α-amino acid ester yields a compound of the formula (wherein Y and Z taken together It is also known to yield compounds of the formula (meaning oxygen). When W' in the formula denotes a group decomposable by hydrogenolysis, base decomposition or acid decomposition, it is preferably benzyl or tert-butyl, and X is optionally as defined above. Substituted aryl, R ¹ and R ² are as defined above. However, if it is a benzyl ester (W'=benzyl) then R ² cannot be benzyl. Hydrogenolysis of this compound using Pd yields a compound of formula where Y and Z are hydrogen. Compounds of the formula (where Y and Z taken together mean oxygen) can also be obtained in high yields by Michael addition of the corresponding keto-acrylic esters with α-amino acid esters. Esterlysis produces the same products as in the Mannitz reaction. Diastereomers with the preferred S,S-configuration occur in predominant amounts when using L-alanine esters and can be obtained by crystallizing the esters of the formula or by chromatographic separation on silica gel. Furthermore, cis, endo-2-azabicyclo[3.3.0]octane- with formulas a and b
3-carboxylic acid ester has the formula [wherein X ¹ is dialkylamino having 2 to 10 carbon atoms, or (Here, m and o represent integers from 1 to 3,
(m+o)3 and A is CH ₂ , NH, O
cyclopentanone enamine having the formula (wherein X ² is a nucleophilic group, preferably chlorine or bromine, and Y ¹ is an alkanoyl having 1 to 5 carbon atoms, an aroyl having 7 to 9 carbon atoms or other conventional peptide chemistry). N-acylated β-halogen-α which represents an acid-cleavable protecting group and R ² represents alkyl having 1 to 5 carbon atoms or aralkyl having 7 to 9 carbon atoms -amino-carboxylic acid ester or formula (In the formula, Y ¹ and R ² have the above-mentioned meanings) by reacting with an acrylic ester having the formula (wherein R ² and Y ¹ have the above-mentioned meanings), which is cyclized by decomposing the acylamide and ester using a strong acid to form a compound of formula XIa or XIb. A compound having the formula a or b (wherein W is (representing hydrogen) and optionally esterified to give a compound of formula a or b
It has also been found that it can be obtained by forming a compound having the formula: alkyl having 1 to 6 carbon atoms or aralkyl having 7 to 8 carbon atoms. Bicyclic amino acids of formulas a and b have a cis, endo configuration, ie the _-CO2W group points towards the cyclopentane ring. All other 2-azabicyclo[3.3.0]octane-3-carboxylic acid derivatives presented in the present invention also exist in the cis, endo configuration. Preferred enamines are, for example, pyrrolidinocyclopentene and morpholinocyclopentene.
Cyclization of the alkylated product of formula is preferably carried out using aqueous hydrochloric acid. Compounds of formula (W=H) can be prepared using conventional methods for amino acids [e.g. Houben-
"Methoden der organischen" edited by Mr. Weyl
Chemie, Volume 1 (1952)] using, for example, thionyl chloride/benzyl alcohol or isobutylene/sulfuric acid. This gives rise to the compounds of the formula in free base or salt form by corresponding work-up. The new compound of formula has a strong, long-lasting hypotensive effect. They are potent inhibitors of angiotensin-converting enzyme (ACE inhibitors) and can be used to treat hypertension of various origins. It is also possible to combine them with other hypotensive, vasodilating or diuretic compounds.
Representatives of these types of action are, for example, Erhardt-
It is described in "Arzneimittel" 2nd edition (1972) by Messrs. Ruschig and Messrs. Use can be accomplished intravenously, subcutaneously or orally. The dosage for oral administration is 1 to 100 mg at a time. No toxic properties have been observed so far, so the dose may be increased in severe cases. It is also possible to reduce this amount, which is especially appropriate if diuretics are administered simultaneously. The compounds according to the invention can be administered orally or parenterally in the form of corresponding pharmaceutical preparations. For oral use forms, the active compound is mixed with customary excipients, such as carriers, stabilizers or inert diluents, and prepared in the usual manner into suitable dosage forms, such as tablets, dragees, capsule rods, aqueous, alcoholic or oily. Solution or aqueous, alcoholic or oily suspension. As inert carriers, for example gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch, can be used. The preparation can then be carried out as dry or wet granulation. Oily carrier materials or solvents include, for example, vegetable and animal oils, such as sunflower oil or cod liver oil. For subcutaneous or intravenous administration, the active compound or its physiologically acceptable salts may be dissolved, suspended or emulsified, if desired, using the substances customary therefor, such as solubilizers, emulsifiers or other auxiliaries. Liquid and eggplant. As solvents for the novel active compounds and the corresponding physiologically acceptable salts, mention may be made, for example, of water, saline solutions or alcohols (for example ethanol, propanediol or glycerin), other sugar solutions of these, for example glucose or mannite solutions. Alternatively, it is a mixture of the various solvents mentioned above. The following pharmacological data demonstrate the very strong efficacy of the compound of formula even when administered orally.

【table】

[Table] 3 In oral administration to awake rats, for example, if the formula (where X is phenyl and Y and Z
are each hydrogen, R ¹ is methyl, and R ² is ethyl) which persists for 6 hours at a dose of 1 mg/Kg against the hypertensive response elicited by intravenous administration of angiotensin. Showing more than 90% inhibition. The method of the present invention will be explained in more detail with reference to the following examples, but the present invention is not limited thereto. Example 1 N-(1-S-carboethoxy-3-phenyl-propyl)-S-alanyl-2-cis, endo-azabicyclo[3.3.0]octane-3
-S-carboxylic acid (1) 2-acetylamino-3-(2-oxo-cyclopentyl)-propionic acid methyl ester 269 g of 3-chloro-2-acetyl-amino-propionic acid methyl ester and 257 g of cyclopentenopyrrolidine were dissolved in DMF1 Keep at room temperature for 24 hours in .5. Concentrate in vacuo, take up the residue in a little water, adjust the pH to 2 with concentrated hydrochloric acid and extract twice with 4 portions of acetic acid ester. Concentration of the organic phase leaves a pale yellow oil. Yield 290g. NMR (CDCl ₃ ): 2.02 (s, 3H), 3.74 (s, 3H),
4.4-4.8 (m, 1H) Elemental analysis value C% H% N% Calculated value: 58.1 7.54 6.16 Actual value: 58.5 7.2 6.5 (2) Cis, endo-2-azabicyclo [3.3.
0] Octane-3-carboxylic hydrochloride Acetylamino derivative prepared in (1) above
Boil 270 g in 2N hydrochloric acid 1.5 at reflux for 45 minutes. Concentrate in vacuo, take up the residue in glacial acetic acid and dissolve Pt/
Add 5 g of C (10% Pt) and hydrogenate at 5 bar. After filtration, it is concentrated and the residue is crystallized from chloroform/diisopropyl ether.
Melting point 205-209℃, yield 150g. (3) cis, endo-2-azabicyclo [3.3.
0] Octane-3-carboxylic acid benzyl ester hydrochloride 40 g of the carboxylic acid prepared in (2) above is added to an ice-cooled mixture consisting of 390 g of benzyl alcohol and 65 g of thionyl chloride and left at room temperature for 24 hours. This benzyl ester after concentration under vacuum
47 g crystallize from chloroform/isopropanol. Melting point 175℃ (hydrochloride). (4) N-(2-S-carboethoxy-3-phenyl-propyl)-S-alanyl-cis, endo-2-azabicyclo[3.3.0]octane-
3-S-carboxylic acid benzyl ester 14 g of the benzyl ester prepared in (3) above
HOBt6.7g, N-(1-S-carboethoxy-3
13.8 g of -phenylpropyl)-S-alanine and 10.2 g of dicyclohexylcarbodiimide are reacted in 200 ml of dimethylformamide. 3 at room temperature
After stirring for an hour, the precipitated dicyclohexylurea is filtered off with suction, concentrated, taken up in 1 part of acetic acid ester and extracted by shaking three times with 500 ml portions of 5% NaHCO ₃ solution. The organic phase is concentrated and the acetate ester/
Chromatograph on a 1 kg column of silica gel using petroleum ether (2:1). The isomer eluted first is the S,S,S-compound, and when the subsequent eluate is concentrated, the S,S,R-compound is obtained. 8.0 g of product are obtained in each case as an oil. NMR ( _CDCl3 ): S, S, S-compound, characteristic signals: 1.20 (d, 3H), 1.27 (t, 2H), 4.17
(q, 3H), 5.13 (s, 2H), 7.18 (s, 5H),
7.32 (s, 5H). Elemental analysis value (as _C30H38N2O5 ) C% _H % N% calculated value: 71.1 7.56 _5.53 Actual value: 70.8 7.8 5.7 (5) N-(1-S-carboethoxy-3 _- phenyl-propyl )-S-alanyl-cis, endo-2-azabicyclo[3.3.0]octane-
3-S-carboxylic acid 8.0 g of L,L,L-benzyl ester obtained in (4) above was dissolved in 100 ml of ethanol, and 10
%Pd/C0.5g is added and debenzylated by hydrogenolysis under normal pressure. This reaction can also be carried out under pressure and with a shortened reaction time. After the calculated amount of hydrogen has been absorbed, the catalyst is removed and concentrated under vacuum. The zwitterion crystallizes from the ether in almost quantitative yield. Melting point 110-112℃ (decomposition). hydrochloride (120
By adding an aqueous zinc salt to a concentrated methanolic solution of the title compound, a particularly thermally stable Zn complex salt (decomposing above 160°C) can be obtained. Elemental analysis values (as C ₂₃ H ₃₂ N ₂ O ₅ ) C% H% N% Calculated value: 66.3 7.7 6.73 Actual value: 66.1 7.8 6.6 The obtained NMR and mass spectrum are consistent with the predetermined structure. [α] _D = +15.6° (c = 1, methanol). Example 2 (1) cis, endo-2-azabicyclo [3.3.
0] Octane-3-carboxylic acid tert-butyl ester Azabicyclo[3.3.0] obtained in Example 1 (2)
Octane carboxylic acid hydrochloride 25g to dioxane 250
ml of isobutylene and 25 ml of concentrated sulfuric acid. After 14 hours at room temperature, make alkaline with caustic soda, concentrate under vacuum, and add 100 ml of water.
is added and the ester is extracted with ether. Evaporation of the ether gives 15 g of a colorless oil. Elemental analysis value (as C ₁₂ H ₂₁ NO ₂ ) C% H% N% Calculated value: 68.2 10.2 6.63 Actual value: 67.9 10.1 6.3 (2) N-(1-S-carbobenzyloxy-3-
Oxo-3-phenyl-propyl)-S-alanine tert-butyl ester 12.0 g of acetophenone, 17 g of glyoxylic acid benzyl ester and 31.7 g of alanine tert-butyl ester toluenesulfonate in 200 ml of glacial acetic acid
Heat to ~50 °C for 24-48 hours. The reaction is followed by thin layer chromatography and stopped at the optimal reaction time. Concentrate under vacuum, make basic with aqueous bicarbonate solution and extract with acetate. The organic phase is concentrated as fully as possible and the S,S-isomer is crystallized from cyclohexane/petroleum ether. The R,S-compound remains substantially in solution. Triethylamine to obtain seed crystals
Preferably, the crude mixture is chromatographed on silica gel in a cyclohexane/acetate (2:1) solvent system with addition of 0.1%. S, S-
The compound elutes as the second of the two diastereomers and precipitates in the greater amount. yield
9g. Elemental analysis value (as C ₂₄ H ₂₉ NO ₅ ) C% H% N% Calculated value: 70.1 7.1 3.4 Actual value: 70.0 6.9 3.5 (3) N-(1-S-carbobenzyloxy-3-
Oxo-3-phenyl-propyl)-S-alanine trifluoroacetate 8 g of the Mannitz condensation product obtained in (2) above are dissolved in 25 ml of trifluoroacetic anhydride and left at room temperature for 1 hour. Concentrate under vacuum, add diisopropyl ether and precipitate with petroleum ether. 7.2 g of amorphous material are obtained. Elemental analysis value (as C ₂₂ H ₂₂ NO ₇ F ₃ ) C% H% N% Calculated value: 56.3 4.7 3.0 Actual value: 56.0 4.8 3.1 Molecular weight 469. (4) N-(1-S-carbobenzyloxy-3-
oxo-3-phenyl-propyl)-S-alanyl-2-cis, endo-azabicyclo[3.
3.0] Octane-3-carboxylic acid tert-butyl ester 35.5 g of N-substituted alanine obtained in (3) above was mixed with 21.1 g of azabicyclooctanecarboxylic acid tert-butyl ester obtained in Example 2 (1). The reaction is carried out in the same manner as in Example 1 (4). After chromatography on silica gel, 20.3 g of the title compound are obtained. Elemental analysis value (as C ₃₂ H ₄₀ N ₂ O ₆ ) C% H% N% calculated value: 70.04 7.35 5.10 Actual value: 69.6 7.4 5.3 (5) N-(1-S-carbobenzyloxy-3-
oxo-3-phenyl-propyl)-S-alanyl-2-cis, endo-azabicyclo[3.
3.0] Octane-3-carboxylic acid 20g of tertiary butyl ester obtained in (4) above
Dissolve in 100 ml of TFA and leave for 1 hour at room temperature. Concentrate under vacuum, take up the remaining resin in acetic acid ester and neutralize with aqueous bicarbonate solution. 14 g of the title compound are obtained from the acetate ester phase. Elemental analysis value (as _C28H32N2O6 ) C% _H % N% calculated value: 68.27 6.55 _5.69 Actual value: 68.1 6.4 5.7 (6) N-(1-S _- carboxy-3-R,S- Hydroxy-3-phenyl-propyl)-S-alanyl-cis, endo-2-azabicyclo[3.3.0]octane-3--carboxylic acid N-(1-S-carbobenzyloxy-3-oxo-3 -phenyl-propyl)-S-alanyl-cis, endo-2-azabicyclo[3.3.
0] 1 g of octane-3-carboxylic acid in ethanol
50 ml, add 150 mg of Pd/BaSO ₄ and hydrogenate under normal pressure. After the calculated amount of hydrogen has been absorbed, filter, concentrate and transfer the solvent system onto silica gel.
Chromatograph using CHCl ₃ /CH ₃ OH/CH ₃ COOH (50:20:5). Yield 0.6g. (7) N-(1-S-carbobenzyloxy-3-
R,S-hydroxy-3-phenyl-propyl)-S-alanyl-cis, endo-2-azabicyclo[3.3.0]octane-3-carboxylic acid N-(1-S-carbobenzyloxy-3- oxo-3-phenyl-propyl)-S-alanyl-2-cis, endo-azabicyclo[3.3.
0] 1 g of octane-3-carboxylic acid is dissolved in 50 ml of a mixture of acetonitrile and water and reduced with 150 mg of NaBH ₄ . After 12 hours, the mixture is concentrated to dryness, neutralized using dilute hydrochloric acid, and the title compound is extracted using acetic acid ester.
Solvent system _CHCl3 / _CH3OH / _CH3COOH (50:10:5) to remove boric acid and other impurities
Chromatograph on medium silica gel. Elemental analysis value (as C ₂₈ H ₃₄ N ₂ O ₆ ) C% H% N% Calculated value: 67.99 6.93 5.66 Actual value: 67.7 6.6 5.3 Example 3 Preparation of esters for the preparation of compounds with formula (R ² =H) Saponification (general method) Ethyl or benzyl ester of the corresponding formula
Dissolve 10 g in 200 ml of dimethoxyethane.
To this is added a drop of a dilute indicator solution, for example bromothymol blue, and to this is added an equivalent of 4nKOH (aqueous) in 5 minutes with vigorous stirring, the indicator shows a pH of 9-10 at the end of the reaction. The pH is then adjusted to 4 using hydrochloric acid, concentrated to dryness under vacuum, taken up in 250 ml of acetic acid ester and filtered. Concentrating the acetate ester precipitates the dicarboxylic acid as solid crystals or an amorphous compound. Yield is 80-95%
It is. Example 3a N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis, endo-2-
Azabicyclo[3.3.0]Octane-3-S
-carboxylic acid N-(1-S-carboethoxy-3-phenyl-propyl)-S-alanyl- obtained in Example 1(5)
2-Azabicyclo[3.3...]octane-3-
1 g of S-carboxylic acid is saponified (1 hour) and worked up as described in Example 3. yield
0.85g. m/e:388. Example 4 N-(1-S-carboethoxy-3-oxo-
3-Phenyl-propyl)-S-alanine benzyl ester 65.7 g of 4-phenyl-4-oxo-butene-2-carboxylic acid ethyl ester (benzoyl acrylic acid ethyl ester) was dissolved in 225 ml of ethanol, and 1 ml of triethylamine was dissolved therein. Add. A solution of 70 g of S-alanine benzyl ester in 90 ml of ethanol is rapidly added dropwise into this solution at room temperature. This is stirred for 2 hours at room temperature and then the solution is cooled. The S,S-isomer crystallizes out.
Yield 94.3g, melting point 83-74℃. [α] ²⁰ _D = +17.8゜ [c=
1, _CH3OH ). Example 5 N-(1-S-carboethoxy-3-oxo-
3-Phenyl-propyl)-S-alanine 0.5 g of the compound obtained in Example 4 is dissolved in 40 ml of ethanol, 0.1 g of 10% Pd/C is added and hydrogenated at room temperature and under normal pressure. Yield 300mg, melting point
210-220℃. ^1H -NMR (DMSO- _d6 ): 1.0-1.4 (t, 6H),
3.2-5.0 (m, 8H), 7.2-8.2 (m, 5H). Example 6 N-(1-S-carboethoxy-3-oxo-
3-phenyl-propyl)-S-alanyl-cis, endo-2-azabicyclo[3.3.0]
Octane-3-S-carboxylic acid benzyl ester cis, endo-2-azabicyclo[3.3.
0] Octane-3-S-carboxylic acid benzyl ester hydrochloride and N-(1-S-
Prepared from carboethoxy-3-oxo-3-phenyl-propyl)-S-alanine analogously to the method described in Example 1(4). Example 7 N-(1-S-carboethoxy-3-oxo-
3-phenyl-propyl)-S-alanyl-cis, endo-2-azabicyclo[3.3.0]
Octane-3-S-carboxylic acid 1 g of the benzyl ester obtained in Example 6 is dissolved in 30 ml of ethanol and hydrogenated using 100 mg of 10% Pd/C at room temperature under normal pressure. Hydrogenation is stopped after 1 molar equivalent of hydrogen has been absorbed. The catalyst is filtered off and the solution is concentrated. Oil yield
600mg. ^1H -NHR (DMSO- _d6 ): 1.0-3.0 (m, 15H),
3.3-5.0 (m, 10H), 7.2-8.1 (m, 5H). Example 8 N〓-(1-S-carboethoxy-3-phenyl-propyl)-S-lysyl-cis, endo-2
-Azabicyclo[3.3.0]octane-3-
S-carboxylic acid dihydrochloride (1) N〓-(1-S-carboethoxy-3-oxo-3-phenyl-propyl)-N〓-benzyloxycarbonyl-S-lysine benzyl ester 4-phenyl-4- 10 g of oxo-butene-2-carboxylic acid ethyl ester are dissolved in 100 ml of ethanol. To this are added 19.1 g of N-benzyloxycarbonyl-S-lysine benzyl ester and 0.2 g of triethylamine. The solution is stirred at room temperature for 3 hours, then concentrated under vacuum. The oily residue (31 g) is dissolved in isopropanol/diisopropyl ether and cooled.
N〓-(1-S-carboethoxy-3-oxo-3
13 g of -phenyl-propyl)-N-benzyloxycarbonyl-S-lysine benzyl ester crystallize. [α] ²⁰ _D = 3.5° (c = 1, CH ₃ OH). ^1H -NMR ( _CDCl3 ): 1.0~1.4 (t, 3H), 1.0~
2.0 (m, 9H), 2.0~2.6 (bs, 1H), 2.9~3.9
(m, 6H), 3.9-4.4 (q, 2H), 4.6-4.9 (bs,
1H), 5.0-5.2 (double s, 4H), 7.1-8.1 (m,
15H). (2) N〓-(1-S-carboethoxy-3-phenyl-propyl)-N〓-benzyloxycarbonyl-S-lysine 4.0 g of the lysine benzyl ester derivative prepared in Example 8 (1) was added to 50 ml of glacial acetic acid. Dissolve in this 10%
Add 0.6 g of Pd/C and 0.6 g of concentrated sulfuric acid. Hydrogenate for 6 hours at room temperature and normal pressure. The catalyst is then filtered off with suction and the ethanolic solution is stirred with 1.4 g of solid sodium bicarbonate. The solution is evaporated using a rotary evaporator and the residue is dissolved in water.
The aqueous phase is extracted with acetic ester and methylene chloride. The organic phase is discarded and the aqueous phase is evaporated to dryness under vacuum. The residue is stirred and extracted with methanol. After evaporating off the methanol an oily residue remains which becomes solid upon treatment with diisopropyl ether. N〓-(1-S-carboethoxy-
Yield of 3-phenyl-propyl)-S-lysine
2.0g. ^1H -NMR ( _D2O ): 1.0-1.4 (t, 3H), 1.0-2.5
(m, 9H), 2.5-4.4 (m, 9H), 3.9-4.4 (q,
2H), 4.5-5.0 (m, 1H), 7.1-7.6 (m, 5H) m/e: 336. 3.4 g of N-(1-S-carboethoxy-3-phenyl-propyl)-S-lysine are dissolved in 30 ml of methylene chloride and cooled to 0°C. To this was added 2.1 g of triethylamine under ice cooling, and then 1.9 g of benzyl chloroformate was added dropwise.
Stir at 0° C. for 1 hour and come to room temperature. The methylene chloride solution is sequentially shaken with water, sodium carbonate solution and water. After drying, it is concentrated and the oily residue is chromatographed on silica gel using methylene chloride/methanol. N〓-(1-S
-carboethoxy-3-phenyl-propyl)-
N-benzyloxycarbonyl-S-lysine
2.0g is obtained. ^1H -NMR ( _D2O ): 1.0-1.4 (t, 3H), 1.0-2.5
(m, 9H), 2.5-4.4 (m, 9H), 3.9-4.4 (q,
2H), 4.5~5.0 (m, 1H), 5.1 (s, 2H), 7.1~
7.5 (m, 10H). (3) N〓-(1-S-carboethoxy-3-phenyl-propyl)-N〓-benzyloxycarbonyl-S-lysyl-cis, endo-2-azabicyclo[3.3.0]octane-3- S-Carboxylic acid benzyl ester a) 560 mg of 2-azabicyclo[3.3.0]octane-3-carboxylic acid benzyl ester hydrochloride prepared by the method described in Example 1(3) in Example 8(2)
N〓-(1-S-
Carboethoxy-3-phenyl-propyl)-
N-benzyloxycarbonyl-S-lysine
940 mg and reacted in the same manner as described in Example 1 (4). Work-up gives 1.5 g of an oil, which is a mixture of two diastereomeric compounds. This diastereomeric mixture is separated into its individual components by column chromatography using silica gel and a cyclohexane/acetic acid ester (2:1) mixture as eluent. The first eluting isomer is the above compound. 0.6 g of oil is obtained. ^1H -NMR ( _CDCl3 ) (after H/D conversion using _D2O ): 1.0-2.6 (m, 20H), 2.6-4.5 (m,
8H), 4.6-5.0 (m, 2H), 5.1-5.3 (double s,
4H), 7.1-7.6 (m, 15H). b) N〓-(1-S-carboethoxy-3-phenyl-propyl)-N〓-benzyloxycarbonyl-S-lysyl-cis,
Endo-2-azabicyclo[3.3.0]octane-3-R-carboxylic acid benzyl ester
0.4g is obtained. ¹ H-NMR (CDCl ₃ ) (after H/D conversion using D ₂ O): 1.0 to 2.6 (m, 20H), 2.6 to 4.4 (m,
8H), 4.5-5.0 (m, 2H), 5.1-5.3 (double s,
4H), 7.1-7.5 (m, 15H). (4) N〓-(1-S-carboethoxy-3-phenyl-propyl)S-lysyl-cis, endo-2
-Azabicyclo[3.3.0]octane-3-
S-carboxylic acid dihydrochloride N〓-(1-S-carboethoxy-3-phenyl-propyl)-N〓ε-benzyloxycarbonyl-S-lysyl-cis, endo- 2-Azabicyclo[3.3.0]octane-
500 mg of 3-S-carboxylic acid benzyl ester was dissolved in 20 ml of ethanol and 0.1 g of 10% Pd/C.
is added and debenzylated by hydrogenolysis under normal pressure. After hydrogen absorption is completed, the catalyst is removed,
Ethanolic hydrogen chloride solution is added to the ethanolic solution to bring the pH to 1, and the ethanol is evaporated off under vacuum. Addition of diisopropyl ether to the residue results in a solid product. You get 200mg. ^1H -NMR of betaine (after H/D conversion using _CDCl3 , _D2O ): 1.0-2.5 (m, 20H), 2.6-4.4
(m, 8H), 4.4-5.1 (m, 2H), 7.2 (s, 5H). Example 9 N〓-(1-S-carboxy-3-phenyl-propyl)-S-lysyl-cis, endo-2-azabicyclo[3.3.0]octane-3-S-
Carboxylic hydrochloride salt N〓-(1-S-carboethoxy-3-phenyl-propyl)-S-lysyl-cis, endo-2-azabicyclo[3.3.0]octane obtained in Example 8(4) 0.5 g of -3-S-carboxylic acid dihydrochloride is suspended in 20 ml of dimethoxyethane. to this
Add 4nKOH aqueous solution until pH becomes 9-10. 30
Stir for a minute. Next, adjust the pH to 4 using hydrochloric acid,
Concentrate to dryness under vacuum, take up the residue in acetic acid ester and filter. Concentrate the acetate solution and triturate the residue with diisopropyl ether to a solid. Yield 0.35g. ^1H -NMR ( _D2O ): 1.2-2.5 (m, 17H), 2.5-4.5
(m, 6H), 4.5-5.0 (m, 2H), 7.2 (s, 5H). Example 10 N-(1-S-carboethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-cis, endo-2-azabicyclo[3.3.0]
-Octane-3-S-carboxylic acid (1) N-(1-R,S-carboethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosine benzyl ester As in Example 4, 100 ml of ethanol 24 g of ethylbenzoyl-acrylate dissolved in
Reacted with 30 g of O-ethyl-S-tyrosine benzyl ester in the presence of 0.5 ml of triethylamine. The solution was concentrated, the residue was aged with diethyl ether/petroleum ether (1:1) and dried in vacuo. 42 g of RS,S-compound was obtained. (2) N-(1-R,S-carboethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosine 40 g of the product from (1) above was dissolved in 800 ml of glacial acetic acid and the solution was hydrogenated in the presence of 4 g PD/C (10%) at 100 bar and room temperature. After chromatographing the crude product on silica gel in a solvent of ethyl acetate/cyclohexane 1:3 and concentrating the solution to dryness, 25 g of the title compound were obtained. It was found to be almost single by thin layer chromatography. Melting point 205-213
℃. Elemental analysis value (as C ₂₃ H ₃₉ NO ₅ (399.5)) C% H% N% Calculated value: 69.15 7.31 3.50 Actual value: 69.5 7.4 3.3 (3) N-(1-S-carboethoxy-3-phenyl- propyl)-O-ethyl-S-tyrosyl-
cis, endo-2-azabicyclo [3.3.
0]-Octane-3-S-carboxylic acid obtained from Example 1(3) by treatment with alkali and extraction with diethyl ether analogously to Example 1(4).
5 g of free benzyl ester to 8 g from Example 12(2) in the presence of 2.7 g 1-hydroxybenzotriazole
and 4.4 g of dicyclohexylcarbodiimide. After subsequent chromatography as described in Example 1(4), 2.9 g of oil, the intermediate benzyl ester, were obtained. ¹ H-NMR and mass spectra were consistent with the given structure. The benzyl ester was dissolved in 50 ml of ethanol, PD(C) was added and hydrogenation was carried out at normal pressure. The mixture was filtered, the liquid was concentrated, the residue was aged and dried in vacuo. yield
2.2g. ^1H -NMR ( _CDC3 ): 1.2-3.0 (m, 15H), 1.27
(t, 3H), 1.4 (t, 3H), 3.0~4.3 (m, 4H),
3.8~4.2 (m, 4H), 6.5~7.1 (2d, 4H), 7.3
(s, 5H). Example 11 N-(1-S-carboethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-cis, endo-2-azabicyclo[3.3.0]
Octane-3-S-carboxylic acid O-methyl-
The title compound was prepared from S-tyrosine benzyl ester. The ¹ H-NMR spectrum was consistent with the given structure.

Claims (1)

[Claims] 1 formula or a physiologically acceptable salt thereof [wherein the hydrogen atoms at bridgehead carbon atoms 1 and 5 in the above formula are mutually in the cis configuration and the carboxy group at carbon atom 3 is in a bicyclic system. (i.e. the −CO ₂ H group faces the cyclopentane ring), and the asterisk (*) on the chain
Carbon atoms labeled with and carbon atoms of bicyclic systems 3
The chirality centers in each are in the S configuration,
And in the above formula, R ¹ means a side chain of methyl, lysine or O-lower alkylated side chain of tyrosine,
R ² is hydrogen, lower alkyl or phenyl lower alkyl, X is phenyl, Y is hydrogen or hydroxy and Z is hydrogen or Y and Z taken together mean oxygen. however,
R ¹ is methyl, R ² is hydrogen or lower alkyl,
except when X means phenyl and Y and Z each mean hydrogen]. 2 2-[N-α-(1-S-carboethoxy-3
-phenyl-propyl)-S-lysyl]-cis, endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid or a physiologically acceptable salt thereof. Compound according to item 1. 3 2-[N-α-(1-S-carboxy-3-phenyl-propyl)-S-lysyl]-cis, endo-2-azabicyclo[3.3.0]octane-3
-S-carboxylic acid or a physiologically acceptable salt thereof. 4 2-[N-(1-S-carboethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl]
-cis, endo-2-azabicyclo [3.3.
0] The compound according to claim 1, which is octane-3-S-carboxylic acid or a physiologically acceptable salt thereof. 5 2-[N-(1-S-carboethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl]
-cis, endo-2-azabicyclo [3.3.
0] The compound according to claim 1, which is octane-3-S-carboxylic acid or a physiologically acceptable salt thereof. 6 formula [wherein the hydrogen atoms at bridgehead carbon atoms 1 and 5 in the above formula are mutually in the cis configuration and the carboxy group at carbon atom 3 is oriented inward to the bicyclic system (i.e. -CO _2H group faces the cyclopentane ring), chain star (*)
Carbon atoms labeled with and carbon atoms of bicyclic systems 3
The chirality centers in each are in the S configuration,
And in the above formula, R ¹ means a side chain of methyl, lysine or O-lower alkylated side chain of tyrosine,
R ² is hydrogen, lower alkyl or phenyl lower alkyl, X is phenyl, Y is hydrogen or hydroxy and Z is hydrogen or Y and Z taken together mean oxygen. however,
R ¹ is methyl, R ² is hydrogen or lower alkyl,
except when X means phenyl and Y and Z each represent hydrogen] or a physiologically acceptable salt thereof, the formula (wherein X, Y, Z and R ¹ have the same meanings as defined above, and R ² ' means lower alkyl or phenyl lower alkyl) as a compound of formula b or a compound of formula b
A mixture of a compound of formula b and a compound of formula a containing 50% or more of the compound [Formula] [Formula] [In the formula, the hydrogen atoms at the bridgehead carbon atoms 1 and 5 are mutually in the cis configuration, and The _-CO2W group at carbon atom 3 is oriented inward to the bicyclic system (i.e. the _-CO2W group faces the cyclopentane ring), and W is a carboxy-esterifying group. ], the product is hydrogenated and/or treated with an acid or base, the diastereomeric mixture optionally separated at appropriate stages, and optionally the resulting compound having the formula A method for producing a compound having the above formula or a physiologically acceptable salt thereof, which comprises converting the compound into a physiologically acceptable salt thereof.