NO157138B - CIS, ENDO-2-AZABISCYCLO- (3.3.0) -OCTAN-3-CARBOXYLIC ACID ESTERS WHICH ARE INTERMEDIATE PRODUCTS FOR THE PREPARATION OF PHARMACOLOGICALLY EFFECTIVE ANGIOTENSIN CONVERSION ENZYMIN INHIBITORS, AS PROMOTED. - Google Patents

Description

The invention relates to new compounds of formula Illa or Illb

where the compounds are characterized by W meaning hydrogen, alkyl with 1-6 C atoms or benzyl or nitrobenzyl, the hydrogen atoms at the bridgehead C atoms 1 and 5 are cis-configured to each other and the group at C atom 3 is oriented endo- placed to the bicyclic ring system, as well as their salts with acids and (for the case of W = hydrogen)

with bases.

The invention also relates to a process for the preparation of the above-mentioned compounds, the process being characterized in that enamines of formula VI, in which X means dialkylamino, with 2-10 C atoms, or a residue of formula VII, in which m and o mean a whole numbers from 1-3 (m + o)

and A means CH2, NH, O or S.

is reacted with N-acylated Æ -halo-*.-amino-carboxylic acid esters

2 1

with formula VIII, in which X means a nucleofuge group, Y means alkanoyl with 1-5 C atoms, aroyl with 7-9 C atoms, or other acidic, cleavable protective groups common in peptide chemistry

groups, and R 2 means alkyl with 1-5 C atoms, or aralkyl with 7-9 C atoms

1 2 or with acrylic acid esters of formula IX, in which Y and R have the above-mentioned meaning 2 1 to compounds of formula X, in which R and Y have the above-mentioned meaning, these are cyclized with the help of strong acids during acylamide and ether cleavage to the compounds of formula Xla or b these are transferred by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane-amine complexes or complex borohydrides in lower alcohols, to compounds of formula Illa or b, in which W means hydrogen and optionally esterified to compounds of formula Illa or b, in which W means alkyl with 1-6 C atoms, or aralkyl with 7-8 C atoms. The new compounds are intermediates in the production of pharmacologically active angiotensin-converting enzyme inhibitors with the formula

in which the hydrogen atoms with the bridgehead C-atoms 1 and 5 are cis-configured to each other, and the carboxyl group at C-atom 3 is oriented endo-placed to the bicyclic ring system, and in which

R" means allyl, vinyl or a side chain of an optionally protected naturally occurring α-amino acid which does not contain heterocyclic groups,

R o means hydrogen (C-C8)-alkyl, (C2-C8)-alkenyl or phenyl-(C1-C4)-alkyl,

Y means hydrogen or hydroxy,

Z means hydrogen or

Y and Z together mean oxygen,

X means (C 1 -C 8 )-alkyl, (C 2 -C 6 )-alkenyl, (C 5 -C 8 )-cycloalkyl, phenyl, which may be mono-, di- or tri-substituted by (C 1 -C 4 )-alkyl, (C-^-C^ )-Alkoxy, hydroxy or halogen,

as well as their physiologically tolerable salts.

The chirality centers on those with an asterisk (<*>) marked C-

atoms of the chain, and at C atom 3 of the bicycle can have so

well R- as well as S-configuration. However, compounds in which these centers exist in S-configuration are preferred. However, if -NH-<*>CHR''"-CO means Cys, the R configuration is the ion

of this center preferred.

The compounds of formula I can be prepared in that a compound of formula II, in which R 2 has the above meanings with the exception of hydrogen, is reacted with a compound of formula IIIa or IIIb, in which W means a carboxy-esterifying

group, such as (C^-Cg)-alkyl or (C^-Cg)-aralkyl, preferably tert.-butyl or benzyl according to known amide formation methods from peptide chemistry, and then hydrogenation or acid or/and base treatment releases compounds of type I.

Furthermore, cis, endo-2-azabicyclo-^3.3.0_7-octane-3-carboxylic acid esters of formula IIIa were found and b are available from enamines from cyclopentanone of formula VI, wherein X^" means dialkylamino with 2 to 10 C atoms or a residue of formula VII, wherein m and o are an integer from 1 to 3, (m + o) >^ 3, and A is CH 2 , NH, 0 or S, and N-acylated (3-halo-a -amino-carboxylic acid esters of formula VIII, in which X 2 means a nucleofuge group, preferably chlorine or bromine, Y<1> means alkanoyl with 1 to 5 C atoms, aroyl with 7 to 9 C atoms, or other commonly acidic in peptide chemistry , cleavable protecting groups, and R 2 means alkyl with 1 to 5 C atoms, or aralkyl with 7 to 9 C atoms, 1 2 or with acrylic acid esters of formula IX, in which Y and R have the above meaning as these are converted to compounds of formula X, in which R<2 >and Y have the above meaning, these are cyclized with the aid of strong acids during acylamide and ester cleavage to compounds of formula Xla or b

these are transferred by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane-amine complexes, or complex borohydrides to lower alcohols in compounds of formula Illa or b, in which W means hydrogen, and optionally esterifies to compounds of formula Illa or b, in which W means alkyl of 1 to 6 C atoms or aralkyl of 7 to 8 C atoms.

The bicyclic amino acids with the formulas IIIa and b have the cis,endo configuration, i.e. the -CC^W group is facing the cyclopentane ring. All further 2-azabicyclo-/3.3.o7-octane-3-carboxylic acid derivatives listed in the present invention are also present in the cis, endo configuration.

Preferred enamines are, for example, pyrrolidinocyclopentene and morpholinocyclopentene. The cyclization of the alkylation products of formula X preferably takes place with aqueous hydrochloric acid. The compounds of formula III (with W = H) can be esterified according to the methods usual with amino acids (see, for example, Houben-Weyl, Methoden der organischen Chemie, volume VIII

(1952)), e.g. with thionyl chloride/benzyl alcohol or isobutylene/sulfuric acid. After corresponding processing, they lead to a compound of formula III in the form of the free base or a salt.

The pharmacologically active end products have a long-lasting, intense blood pressure-lowering effect. They are strong inhibitors of the angiotensin-converting enzyme (ACE inhibitor) and can be used to combat high blood pressure of various origins.

Their combination with other blood pressure-lowering karut-widening or diuretic-acting compounds is also possible. Typical representatives of this active class are e.g. discussed in Erhardt-Ruschig, Arzeimittel, 2nd edition, Weinheim, 1972. The application can take place intravenously, subcutaneously or perorally.

The dosage for oral administration is 1 - 100 mg per single dose. In severe cases, it can also be increased, as no toxic properties have been observed so far. Also

a reduction in the dose is possible, and above all relevant when diuretics are administered at the same time.

The pharmacologically active end products can be administered orally or parenterally in a corresponding pharmaceutical preparation. For an oral form of application, the active compounds are mixed with the usual additives, such as carriers, stabilizers or inert diluents, and brought by means of usual methods into suitable administration forms such as tablets, dragees, suppositories, aqueous alcoholic or oil suspensions, or aqueous alcoholic or oil solutions. As an inert carrier, it can e.g. gum arabic, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, are used. Thereby, the preparation can take place as well as dry or moist granules. For example, plant or animal oil, such as sunflower oil or cod liver oil, can be considered as oily carriers or solvents.

For subcutaneous or intravenous application, the active compounds or their physiologically tolerable salts are brought into solution, suspension or emulsion, if desired with the usual substances such as solubilizers, emulsifiers or further excipients. As a solvent for the new active compounds and the corresponding physiologically tolerable salts, e.g. in question: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, furthermore also sugar solutions such as glucose or mannitol solutions or also a mixture of the various solvents mentioned.

The exceedingly strong effect of the connection with

formula I, also when administered orally, is shown by the following pharmacological data:

1. Intravenous application to anesthetized rat, 50% inhibition of the pressor reaction triggered by 310 ng of angiotensin I 30 min. after application in the dose ... ED,-q 3. When administered orally to an awake rat, it appears in a dosage of 1 mg/kg at e.g. the compound of formula I with X = 1 2

phenyl, Y and Z each = H, R = CH3, and R = ethyl one over 6

hours sustained over 90% inhibition of it by means of i.v. applied angiotensin I triggered a pressor reaction.

The invention will be explained in more detail with the help of some examples.

Example_l

N-(1-S-carboethoxy-3-phenyl-propyl)-S-alanyl-2-cis, endo-azabicyclo-/3.3.07-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 are kept in 1 liter of DMF for 24 hours at room temperature. Evaporate in a vacuum, absorb the residue in a little water, adjust with concentrated hydrochloric acid to pH 2,

and extract twice with 4 liters of vinegar each time.

When the organic phase evaporates, a pale yellow oil is left behind. Yield 290 g.

NMR: 2.02 (s,3H); 3.74 (s, 3H); 3.4-4.8 (m, 1H); (CDC13).

(2) Cis, endo-2-azabicyclo-/3.3.0/-octane-3-carboxylic acid hydrochloride

270 g of the acetylamino derivative prepared under (1) is boiled in 1 liter of 2-normal hydrochloric acid for 45 minutes under reflux. Evaporate in a vacuum, take up the residue in glacial acetic acid, mix with 5 g of Pt/C (10% Pt) and hydrogenate at 5 bar. After filtration, the mixture is evaporated and the residue crystallizes from chloroform/diisopropyl ether.

Melting point 205-209°C.

Yield 150 g.

(3) Cis, endo-2-azabicyclo-/3.3.07-octane-3-carboxylic acid benzyl ester hydrochloride 40 g of the carboxylic acid prepared under (2) is added to an ice-cold mixture of 390 g of benzyl alcohol and 65 g of thionyl chloride, and leave for 24 hours at room temperature. After evaporation in a vacuum, 47 g of the benzyl ester crystallizes from chloroform/isopropanol. Melting point 175°C (hydrochloride).

Example_el_II

(1) Cis, endo-2-azabicyclo-/3.3.07-octane-3-carboxylic acid tert-butyl ester 25 g of azabicyclo-/3.3.07-octanecarboxylic acid hydrochloride from example 1 (2) are brought into reaction in 250 ml dioxane with 250 ml of isobutylene and 25 ml of concentrated sulfuric acid. After 14 hours at room temperature, it is made alkaline with caustic soda, evaporated in vacuo, mixed with 100 ml of water, and the ester extracted. After evaporation of the ether, 15 g of colorless oil are obtained.

Claims (3)

1. Compound with formula Illa or Illb characterized in that W means hydrogen, alkyl with 1-6 C atoms or benzyl or nitrobenzyl, in that the hydrogen atoms at the bridgehead C atoms 1 and 5 to each other is cis-configured and the group at C-atom 3 is oriented endo-placed to the bicyclic ring system, as well as their salts with acids and (for that case of W = hydrogen) with bases. 2. Connection according to claim 1, characterized by the fact that in formula Illa and b means W hydrogen, tert-butyl, benzyl or nitrobenzyl. 3. Method for producing compound with the formulas Illa or Illb according to claim 1, characterized in that enamines with formula VI, in which X^ means dialkylamino, with 2-10 C atoms, or a residue of formula VII, wherein m and o represent a whole numbers from 1-3 (m + o) > 3 and A means'CH2, NH, 0 or S. is reacted with N-acylated g-halo-α-amino carboxylic acid esters of formula VIII, in which X 2 means a nucleofuge group, Y 1 means alkanoyl with 1-5 C atoms, aroyl with 7-9 C atoms, or others in peptide chemistry usual acidic, cleavable protecting groups, and R 2 means alkyl with 1-5 C atoms, or aralkyl with 7-9 C atoms or with acrylic acid esters of formula IX, in which Y 1 and R 2 have the above meaning to compound of formula X, in which R 2 and Y 1 have the above meaning these are cyclized with the aid of strong acids during acylamide and ether cleavage to the compounds of formula Xla or b. these are transferred by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane-amine complexes or complex borohydrides in lower alcohols, to compounds of formula Illa or b, in which W means hydrogen and optionally esterified to compounds of formula Illa or b, in which W means alkyl with 1-6 C atoms, or aralkyl with 7-8 C atoms.