JPS61293967A - Cis,endo-2-azabicyclo(3,3,0)octane-3-carboxylic acid derivative and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of the formula fla or mb [wherein W is hydrogen, (01-C6) alkyl or (07
The present invention relates to a compound or a salt thereof having ~Ca) aralkyl, and a method for producing the same.

The above compounds having the formula Iota or l1llb are novel compounds and are useful as intermediates in the synthesis of the derivatives of cis, endoazabicyclo[3,3,03 octane carboxylic acid having the formula I and their physiologically acceptable salts. be. Here, in the above formula,
bridge-head The hydrogen atoms at C atoms 1 and 5 are mutually in cis configuration and the C
The carboxy group at atom 3 is oriented on the Fl'3 side with respect to the bicyclic system, and in the above formula R1 is hydrogen, allyl,
Vinyl or optionally protected naturally occurring α-
Amino acid R1-C) ((NH2)-Coo) (0) side chain, R2 is hydrogen, (01-C6)-alkyl, (C
2-06) -7kkenyl or aryl-(C1-C
4) -alkyl, Y is hydrogen or hydroxy and Z is hydrogen or Y and 2 together are oxygen and -CX is (cl-C6)-alkyl, (C2
-C6)-alkenyl, (C5-C9)-cycloalkyl, (C6-C12) -71J-ruColeIt'd
(01-04) -7/I/ * Le, (C1~Ca)
-Alkoxy, hydroxy, halogen, nitro, amino, (C1-c4)-alkylamino, di(C1-c4
)-may be mono-, di- or tri-substituted by alkylamino or methylenedioxy] preferably phenyl or indol-3-yl.

R1 is an optionally acylated methyl or lysine or O-alkylated side chain of tyrosine;
2 is hydrogen, methyl, ethyl or benzyl, X is phenyl or phenyl mono- or di-substituted with fluorine and/or chlorine, Y is hydrogen or hydroxy and Z is hydrogen Preference is also given to compounds of formula I in which Y and 2 taken together mean oxygen.

R1 is e.g. protected Ser, ThrSAsp,
Asn.

Gtu, GtnSArg, Lys, Hyt, C
ysSOrn, Clt.

When representing the side chain of a protected naturally occurring α-amino acid, such as Tyr % Tr 9% ) il 8 or HYp, the groups customary in peptide chemistry are preferred as anchoring groups (rHouben-Weyl J Part XV). /Volume 1 and Volume XV/2). When R1 means a protected lysine side chain, known amino protecting groups, especially (C1-C
6)-Alkanoyl is preferred. The preferred 0-protecting group for tyrosine is methyl or ethyl.

Salts include, in particular, the hydrochlorides, maleates, tartrates or alkali salts, Ca salts, mafic salts and Zn salts.

The carbon atom labeled with an asterisk (umbrella) in the chain and the center of polarization at carbon atom 3 of the bicyclic system can have the R and S configurations. However, compounds in which these centers are present in the S configuration are preferred, however -NH-C! (R'-Co
When - represents Cys, it is preferred that this center is in the R configuration.

The final target compound, the compound of formula I, has the formula ■ (wherein R2
has the above-mentioned meaning other than hydrogen) of the present invention, a compound of the formula nla or tab [wherein W is a group that esterifies carboxy, for example (C1<,5)-alkyl or (
C7-C3)-araral Φl, preferably tert-butyl, meaning benzyl] by the known amide-forming methods of peptide chemistry and then by hydrogenation or by acid and/or base treatment. It is produced by eliminating W and converting it into hydrogen.

Compounds of the formula 2 in which X is phenyl, Y is hydrogen, 2 is hydrogen and R2 is methyl or ethyl are known (eg European Patent No. 00372!1).
No. 1) and available through various routes. Benzyl esters (R2=benzyl) can be prepared in a similar manner.

The cis, endo-2-azabicyclo[3,3,0]octane-3-carboxylic acid ester and its salt having formulas 1na and mb according to the present invention are synthesized as follows.

First, formula ■ [wherein x1 is dialkylamino having 2 to 1011I carbon atoms, or formula ■ (where m and 0 represent integers of 1 to 3, and (m+o
)≦6 and A stands for CH2, NH, O or S) cyclo represents a group having the enamine of ntanone with the formula , Yl represents alkanoyl having 1 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or other acid-cleavable protecting groups customary in peptide chemistry, and R2 represents 1 to 5 carbon atoms. alkyl having carbon atoms or aralkyl having 7 to 9 carbon atoms)
α-Amino-carboxylic acid ester or an acrylic ester having the formula Guided by compounds. The compound of formula It is converted by reduction with a borane-amine complex or a complex borohydride into a compound of formula 11a or mb (wherein W represents hydrogen) and optionally esterified to a compound of formula 111a or mb (wherein W represents hydrogen). represents alkyl with 1 to 6 carbon atoms or aralkyl with 7 to 8 carbon atoms).

The binomial amino acids of formulas 1na and mb have a cis, endo configuration, ie, the -co2w group points towards the cyclopentane destruction.

Preferred enamines are, for example, pyrrolidinocyclopentene and morpholinocyclopentene. Cyclization of the alkylated product of formula X is preferably accomplished using aqueous hydrochloric acid. Compounds of formula 1 [[(W=H) can be prepared using conventional methods for amino acids [e.g., Mr. Houben-Wey1@rMeth
Oden der Organischen Chem
For example, thionyl chloride/benzyl alcohol'! Can be esterified using 7'jU inftylene/sulfuric acid. This gives rise to the compound in free base or salt form by corresponding work-up.

The novel compound of formula I synthesized using the compound according to the present invention as a raw material has a strong, long-lasting hypotensive effect. These are potent inhibitors of angiotensin-converting enzyme (AC
E inhibitor) and can be used in the treatment of hypertension of various origins. It is also possible to combine them with other hypotensive, vasodilatory or diuretic compounds.

Representatives of these types of action include, for example, Shhardt-Rus.
It is described by Messrs. Chig and Arzneimitte, 2nd edition (1972). Use can be accomplished intravenously, subcutaneously or orally.

The dosage for oral administration is 1 to 100 ml per dose. Toxic properties have not been observed so far and may be exacerbated 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 such as glucose or mannitol. solutions or also mixtures of the various solvents mentioned above.

A very strong formula even when administered orally! The efficacy of the compound is demonstrated by the following pharmacological data.

1. Intravenous administration to anesthetized rats (50% inhibition of blood pressure normalization response induced by 310 ng of angiotensin IK 30 minutes after administration...ED5o) X Y Z R' R2ED5o (μg
/Kf) C6H5HHCH3C2H58,3 C6H5HHCH3H2,7 2 Intraduodenal administration to nine anesthetized rats
King ``2'' ni ni plate night helmet C6H5HHCH3C2H
550 C,sHs HHCH3H600C6H5-OC
H3CH3350 C6H5-OOH5C2H5280 C6Hs -OCH3H720C6H5-
OCH3CyHy 250C6H5HOHCH3C
2H5380 p-CL-C6H4HHOH5C2H555p-Ct-
C6H4-OCH3H7806, for example, for oral administration to awake rats, a compound of the formula ■ (wherein X is phenyl, Y and 2 are each hydrogen, R1 is methyl and R2 is ethyl) 9, which persisted for 6 hours at a dose of 111 g/Kf in response to the hypertensive response elicited by intravenous administration of angiotensin I.
Shows inhibition of 0% or more.

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 Threat of cis,endo-2-azabicyclo[3,3,0]octane-3-carboxylic hydrochloride (1) 2-acetylamino-ro-(2-oxo-cyclopentyl)-propionic acid methyl ester 6- Chloro-2-acetyl-amino-propionic acid methyl ester 269t and cyclopentenopyrrolidine 2
57t is kept at room temperature for 24 hours in DMF 1.5. Concentrate in vacuo, take up the residue in a little water, adjust to I) H2 with concentrated hydrochloric acid and extract twice with 4t each of acetic ester. Concentration of the organic phase leaves a pale yellow oil. Accommodation t290? .

NMR (CDCAg): 2f)2(s, 3Hχ3.74
(S,! With IH 4.4-4.8 (m, IH) Elemental analysis value Calculated value: 58.1 7.54 6.16 Actual value:
58.5 7.2 6.5(2) Cis, endo-2-azabicyclo[3-5,0]octane-6-carboxylic hydrochloride Acetylamino derivative prepared in (1) above 270t
Boil at reflux in 2N salt e1.5 for 45 minutes. Concentrate in vacuo, take up the residue in glacial acetic acid and dissolve Pt/C (Pt
10%) and hydrogenate at 5 bar. After filtration, it is concentrated and the residue is crystallized from chloroform/diisopropyl ether. Melting point 205-209
C, collection 11f5cl? 6 Example 2 Cis, endo-2-azabicyclo I: 3. lO]Octane-3-carboxylic acid benzyl ester hydrochloride (2)
The carboxylic acid AQf prepared in benzyl alcohol 6
901 and thionyl chloride 65? and left at room temperature for 24 hours. After concentration under vacuum, the benzyl ester 47f crystallizes from chloroform/improper tool. Melting point 175C (hydrochloride).

Example 6 cis, endo-2-azabicyclo Ij, 3.0) octane-6-carvone & tert-butyl ester Azabicyclo[3,3,O)octanecarboxylic hydrochloride 25F obtained in Example 1 (2) was converted to diochitin. Isobutylene 2 in 2511d
50d and sulfurized e25d. After 14 hours at room temperature, the mixture is made alkaline using caustic soda, concentrated under vacuum, 100 g of water is added and the ester is extracted with ether. Remove ether by evaporation to obtain colorless oil 1
Get st.

Elemental analysis value (as C12H21NO2) Calculated value:
6B, 2 fO, 26, 63 Actual position: 6″7.9
10.1 6.3 The production of the final target product will be explained below using reference examples.

Reference Example 1 2-[N-(1-8-carboethoxy-3-7enyluprovir)-8-alanyl)-2-cis.

Endo-azabicyclo[6゜6.0]octane-6-8
-Carboxylic acid sweet acid (1) 2-(N-(1-8-carboethoxy-6-
phenyl-propyl)-8-7? Nyl]-cis, endo-2-azabicyclo[3,3,0]octane-3-8-
Benzyl carboxylic acid ester Example 2r The benzyl ester 141F prepared in HO
Bt 6.7? , N-(1-8-carboethoxy-3
-phenylpropyl)-3-7 uran 15°8rb and dicyclohexylcarbodiimide 10.21°C are reacted in dimethylformamide 20°. After stirring for 6 hours at room temperature, the precipitated dicyclohexylurea was filtered off with suction, concentrated, the acetic acid ester 1 was taken up and 5 To NaH
Extract by shaking three times using 500ml of CO3 solution. The organic phase was concentrated and diluted with acetate/petroleum ether (2:
1) on a silica gel 1Kf column. The isomer eluted first is the S, S, S-compound, and when the subsequent eluate is concentrated, the S, S, R-compound is obtained. 8.02 of the product is obtained in each case as an oil.

NMR (cvcts) 2S,S,S-compounds, characteristic signals: i, 20(d, 3H, 1°27(t,
2H), 4.17 (q, 5.13 (s, 2H) with 3H),
Z18 (s, 5H), 7.32 (s, 5H).

Elemental analysis value (as C30H4BN205) Calculated value:
71.1 7.56 5.53 Actual value: 70.8
7.8 5.7(2) 2-CN-1-3-carboethoxy-6-phenyl-propyl)-8-alanyl]-cis, endo-2-azabicyclo[3,3,0]
Octane-6-8-carboxylic acid obtained in (1) above, L, L-benzyl ester 8, Of is dissolved in 100 d of ethanol and 1
Add 0% Pd/C0.5f and remove benzylation 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°C (decomposition).

By adding an equivalent amount of hydrochloric acid, the hydrochloride salt (decomposes above 120°C) is obtained, or by adding an aqueous zinc salt to a concentrated methanolic solution of the title compound, a particularly thermally stable Zn-complex salt (decomposed above 160°C) is obtained. (decomposed above) can be obtained.

Elemental analysis value (as C23H52N205) 0% N
% N% Calculated value: 66.3 7.7 6.73 Actual value:
66.1 7.8 6.6 The obtained power and mass spectra are consistent with the given structure. [α]D=+15. <S
° (C=1, methanol).

Reference example 2 2-CN-(1-8-carboxy-6-phenyl-propyl)-8-7ranyl]-cis, endo-2-azabicyclo(3,3,0)octane-6-8-carboxylic acid fc2-[N-(1-8-carboethoxy-5-phenyl)-furobirnosy-ranyl]- obtained in Synthesis Reference Example 1
cis, endo-2-azabicyclo[3,3,01octane-3-8-carboy[1t'jt, commonly understood as dimethoxyethane. To this is added a drop of a dilute indicator bath solution, for example bromothymol blue, and to this is added an equivalent of 4 n KOH (aqueous) fzc over a period of 5 minutes with vigorous stirring, and the indicator exhibits 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 acetic acid ester and treated with P. When the acetate ester is concentrated, the dicarboxylic acid is solid crystallized or 7'c is precipitated as an amorphous compound. Yield α85f0m/e: 388° Patent Applicant Hoechst Akchengesellschaft and 2 others Continuing from page 1 Priority claim 019 July 17, 2019 [phase] West Germany (
DE) [Stock] P3226768゜;・Inventor Rolf Geiger Federal Republic of Germany Tim Finn
50 Heistrasse 33 ;・Inventor Hansjörg Urba Federal Republic of Germany Tetsuha Taunus, Relavan D Inventor Reinhard Becker Federal Republic of Germany
Federal Republic of Germany Cirkens Taunus, Amkenfri'--6000 Frankfurt-Anrich-Bleicher-'--6242 Kronberg/Daustrasse 41'--6200 Wiesba'-den.

Larse 101 --6233 Kelkheim / -Dergarten 1

Claims (1)

[Claims] 1) Formula IIIa or IIIb ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIIa) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIIb) [In the formula, W is hydrogen, (C_1 to C_6) Alkyl or (
C_7-C_8) meaning aralkyl] and its salts with acids or bases (when W is hydrogen). 2) The compound according to claim 1, wherein W is hydrogen, tert-butyl or benzyl. 6) Formula IIIa or IIIb ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIIa) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IIIb) [In the formula, W is hydrogen, (C_1 to C_6) alkyl or (
C_7-C_8) meaning aralkyl] and its salt with an acid or (when W is hydrogen) a base, the formula X I a or X I b ▲ Numerical formula, chemical formula, table, etc. There are ▼ (X I a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X I b) Catalytic hydrogenation of a compound having Reduction with a borohydride compound converts it into a compound of formula IIIa or IIIb, where W is hydrogen, and optionally esterifies the product so that W is (C_1~
C_6) alkyl or (C_7-C_8) aralkyl, and optionally converting said product into a salt; (When W is hydrogen) Preparation of its salts with bases.