Method of preparation of carboxylic acids aza-bicyclo-octane.

This invention relates to a method for preparing substituted aza bicyclo alkane carboxylic acids.■

More particularly, it relates to compounds of the general formula

wherein a represents a vinylene or dimethylene

q is 0 or 1,

R represents a lower alkyl radical which may have an amino group

X represents - o - - or THE NH -

P

1 represents a hydrogen atom or a radical of formula

- CH2 - THE R,

1³

co R.₂

R₂ represented a hydroxyl group or a lower AI coxy

Rj represents a hydrogen atom, a linear or branched alkyl radical, cycloalkylalkyl or phenylalkyl, having at most and in total 8 carbon atoms, or a radical of formula:

- (CH2₂ )_{the P} - O - HM - RJ45

* 4

wherein:

The R ^ is HR, a lower alkyl radical or cycloalkyl (C.₃ C_grams ), R5 is HR, a cycloalkyl (C.₃ - C._grams ) or alkoxy carbonyl (drops), and

p is 1 or 2.

The term alkyl or alkoxy groups containing from 1 lower confectioneries 4 carbon atoms.

The L * present invention also relates to salts of compounds of general formula (I-) obtained: with a mineral or organic base thérapeutiquement is compatible. '

The invention also relates. addition salts of the compounds of formula (I in) in which X is NH with a mineral or organic acid therapeutically is compatible.

The compounds of formula. (I-) comprise at least 2 asymmetric carbon atoms. According to the position of the substituents and the degree of hydrogenation, there are 2 8 centers of asymmetry confectioneries.

Racemates can be split on the EH mixtures thereof of diastirêoisomères or spinal, or split into their enantiomers in a known manner. These various isomers are part of 1' invention as well as the racemates.

The invention comprises more particularly the compounds of general formula (I-) wherein X represents NH and R ^ phênylalkyle or represents an alkyl group having at most 8 carbon atoms;

Furthermore, the compounds of formula (I-) wherein a represents a dimethylene group are preferred and R is preferably a methyl group.

The compounds of the invention as well as their salts are endowed with interesting pharmacological properties. In particular they inhibit the conversion of the decapeptide angiotensin I into angiotensin II by inhibiting Voctapeptide ace.

The compounds of 1' invention have inhibitory action on the enzyme as the carboxypolypeptidases or enképhalinases.

Their use in therapy in thus minimizes or even eliminating the action of these enzymes, by acting on a mechanisms directly responsible for hypertension or heart failure.

Thus the invention relates to the use in therapy the compounds of general formula (I-) and salts thereof, particularly for the treatment of arterial hypertension of heart failure.

The invention also extends to pharmaceutical compositions containing as active ingredient at least one compound of general formula I or one of its addition salts, with an inert carrier, non-toxic, pharmaceutically acceptable carrier.

For use in therapy, the compounds of general formula hr

(The I) or their salts are presented in dosage forms

suitable for intravenous administration or oral administration.

The pharmaceutical compositions of the invention comprise, in addition to the active ingredient, one or more inert excipients, nontoxic suitable for pharmaceutical use and/or a binding agent, a flavoring agent, a disintegrant, a sweetening agent, a lubricating agent or even a suitable liquid vehicle

to intravenous administration.

The pharmaceutical compositions of the invention may further contain another active principle having a complementary or synergistic action. Among the latter active ingredients, cite a diuretic and, especially, a saliuretic, conrne e.g. a thiazide, a dihydrothiazide, chloro sulfonamide, dihydrobenzofuran 2-carboxylic acid or a derivative of the phenoxy acetic acid.

Examples of such compounds are N (3 '- chlorophenyl 4' sulfamyl - benzamido) indolin - 2 mêthyl, ethacrynic acid, furosemide.

It will also add a substance --adrënolytique, a β blocker, calcium unantagoniste a dopamine receptor agonist or a VAS dead end areas.

The useful dosage can vary broadly depending on the age, the weight of the patient, the severity of the therapeutic indication

as well as the route of administration. The route of administration

(■

preferred is the oral route but the intravenous route is also perfectly suitable for the treatment of hypertension.

In general, the unit dosage will take between 10 and 200 RNGs.

The invention also includes a method of obtaining compounds of general formula (I-), whereby an azabicyclooctan carboxylic acid or 1' ester thereof, of general formula (III)

wherein the definition of the substituent a is the same as in the formula (I-), and R ' represents hydroxy or lower alkoxy,

to the action of a substituted carboxylic acid of general formula (II):

the R - (CH2₂ )_Q. - CH2 - C00H (LLL)

THE R "

wherein Q has the meaning mentioned for the formula

(I in), and is a lower alkyl or aminoalkyl protected

The X ' represents an NH or shush ^ protected by the acyl groups such as usual acëtyle, a benzyloxy carbonyl or terbutoxyçarbonyle,

or a functional derivative thereof

To obtain ' acid derivative of general formula (VI):

in which the substituents have the meanings mentioned above;

which is subjected to the usual dêprotection methods such as saponification and/or hydrogenolysis and thus provides a compound of formula (I-) wherein an RJ ' is H, then if necessary, subjecting the cornposé of formula (1) wherein is H, X is NH and a reductive alkylation reaction with a compound of general formula (V-)

R₂ - OC - OC - (V.)

wherein R_? - and R have the meanings given in the fornu -51. (U.

to obtain a compound of formula (I in) in which X is NH and Rj is

- CH2 - THE R, .

" 3

oRC₂

The intermediate compounds of^- general formula (III) are novel and are included in the present invention. They have been prepared by a pro-10cédé subjecting an imidazo-pyridine of general formula

wherein a has the meaning mentioned above and R_grams is a radical as substituted or unsubstituted phênyle

15a a hydrolysis reaction by one of the common methods such as boiling with an aqueous sodium hydroxide solution. The compounds of formula VI are described by relief pattern ISHA1 and Goldstein (27 Têtrahedron, PPs. 3119 - 3127 (1971).

The following examples illustrate the invention.

20 Example 1

N is 3 (R)- Jjnercapto methyl - 2 - aza-propionylj 2 (R)- 3 carboxyl substituted bicyclo [2.2 " ^ 2|octane number

An aza - 2 (R)- 3 - carboxy-cycloaliphatic di [2, 2, 2, j-octane rating.

3 * 8 g (0.0148 mole -) dihydro - 8.8 - 1.3 - ethano-dioxo-phenyl 2 - 5.8 (2 hr, 5 hr) imidazolo [I, 5 - has] pyridine derivatives (prepared in d.

Relief pattern ISHAI and e. Goldstein's, Tétrahédron, v. 27, 3119 - 3127 P) are suspended in a solution of 30 ml of soda 4 n and of 10 ml of methanol. The mixture is refluxed for 24 hours, cooled, filtered and the filtrate acidified by hydrochloric acid 30 ml 4 n-then passed over 200 ml of ion exchange resin Dowex 50 hr⁺ .

After washing the resin die with distilled water until it is free of chloride ion in Véluat, the compound-sought is eluted by 500 ml of ammonia n/l. Eluates ammoniacal evaporated to leave a dry ' residue which is the product sought.

Weight: 1.8 grams (78 %)

Melting point (block Kofier): 253 - 255®

The n [acetylthio - 3 (R)- methyl 2 propionylj] - 2 (R) aza-carboxy 3 the bicyclo [2, 2, 2] octane number

0,850 grams (0.0055 mole) D.¹ An aza - 2 (R)- 3 carboxyl substituted bicyclo [2, 2, 2j octane number obtained from the preceding step are suspended in a solution of 1.33 grams (0,011 mole) of n substituted dimethyl aniline in 40 ml of methylene chloride.

1 grams (0.0055 mole) of acid chloride acét - ylthio. 3.^I (Rs) methyl-2 propionic acid are added dropwise in 5 minutes to the previous solution stirred at room temperature. The stirring is continued for 15 hours. The solution obtained is poured onto a mixture comprising 150 g of crushed ice and 30 ml of normal aqueous solution

hydrochloric acid. The organic phase is drawn off, washed with n-HCI

filtered and then distilled water until neutrality, dried on so4 AC, concentrêe/dry and evaporation residue chromatographed on silica by eluting the Merck F. 254 chloride by-one mixture (95/5) methylene-mêthanol.

0,550 grams (34 %) product sought is obtained as an oil which has a IR and NMR spectra conform to the structure caused by loving.

Step c

The n [(R) 3 - mercapto-mëthyl, 2 - 2 - aza-propionylj (R)- carboxy-substituted bicyclo [2, 2, 2] octane number 3

Under nitrogen, the g (0.0017 mole) 0,500 n [acêtylthio - 3 (R)- 2 mêthyl or propionyl] - 2 (R) aza-carboxyl substituted bicyclo [2, 2, 2] - 3 octane derivatives prepared in the previous step are dissolved in a mixture of 1.7 ml aqueous sodium hydroxide and 25 ml normal ethanol. After 15 hours contact ethanol is evaporated under vacuum and the aqueous solution extracted with ether, neutralized exactemeniP ^.^{the R} , 7 ml of aqueous hydrochloric acid is evaporated confectioneries normal dry. The residue is the product sought (0.3 grams, in admixture with 0.0995 g of sodium chloride. The product is controlled by NMR in solution in BMD:

1

integration is coherent.

Example 2

N - [the n - (R) êthoxycarbonyl - 1 pentyl ether (3) AI anyl] - 2 (R) aza-carboxyl substituted bicyclo (2, 2, 2) 3 - 4 (R), (R)- octene 7 5.

An aza - 2 (R)- carboxy-3 bicycloj2, 2.2) 4 (R), (R-O) 7 - octene 5.

34.5 grams (0,119 mol) 1.3 - dioxo - ethano 5.8 (chloro 4 a-phënyl)

-2 (Η 2, 5 Η) iroidazo [L-, 5a] pyridine derivatives prepared according to relief pattern ISHAI et al.

(see e.g. 1,a) are carried under reflux under nitrogen for 5 hours. with 355 ml (1.42 mol) of 4n aqueous sodium hydroxide solution.

After cooling to 5 degrees, 14 g of aniline-platinic 4 are dewatered and the filtrate is acidified to pH 1 by concentrated HCl. The filtered solution is passed over 800 ml resin (Dowex (hr⁺ ) 50 TSB AND 8). After washing with distilled water until it is free of chloride ion, the product sought is éluë by 2,250 ml ammonia in vivo. Ammoniacal eluates are concentrated dry vacuum of the trumpet watercooled 40°. 17.5 Grams (rt=96.2 %).

Analysis C._grams N0₂

N-HR

7.24 9.14 6.87 9.10

V.^WITH by Za-a 2 (R) mêthoxycarbonyl and 3 the bicyclo (2, 2, 2) 4 (R), (R) 7 octene and 5, hydrochloride.

1 gm (0.00655 mol) amino acid prepared in the previous step are dissolved dansJ. 5 ml of anhydrous methanol and added, dropwise and without exceeding 5 degrees *, of 1.5 moles) thiônyle chloride. The mixture is.

refluxed for 2 hr then concentrated to dry vacuum of the masking calculated %

Found %

An IR: 0:00 and NH

C00

2

C

62.72

62.30

3600 - 3200 cm.

1630 cm "¹

lAN

pE through water to 40°. Obtained 1.2 gm (90% RTs.) of product sought.

F=207 (dec.) An IR: coextruded .1740 (esters) cms "¹

' THE NH₂⁺ 2800 - 2200 cm."¹

The crude product is used in the subsequent step ' without further purification.

Step c < ■

N - [the n (T-butoxycarbonyl} alanyi] aza 2 (SRV) methoxycarbonyl-3 the bicyclo (2, 2, 2) 4 (R), (R) 7 octene and 5.

8.9 grams (0,044 moles) ester prepared according to the process at the former dissolved in 70 ml of fail are dimëthylformamide (from DMF) in the presence de.6, 15 ml of triethylamine (0,044 moles). To the resulting solution, maintained at room temperature I-, added sequentially:

- 8.3 g of (e) tert. through Boc, dissolved in 45 ml of DMF-alanine

- 6.45 (0,044. moles) of hydroxy-to-benztriazole (h0bt) dissolved in 55 ml of DMF, and

- 9.05 (0,044 moles) of dicyclohexylcarbodiimide (DCCI was) dissolved in 80 ml of chloroform.

After 24 hr. agitation, the dicyclohexylurée (DCU) formed is filtered and the filtrate concentrated to dry vacuum of the horn to water§50 °c. The residue is taken up by 250 ml of ethyl acetate, and the solution is filtered and washed successively with:

2 x 50 ml of saturated aqueous solution, NaCl

3 x 50 ml of aqueous solution of citric acid to 10%

2 x 50 ml of saturated aqueous solution of NaCl

the X 50 ml of saturated aqueous solution of NaHCO ^

2 x 50 ml of saturated aqueous solution of NaCl,

and then dried on AC OS ^, filtered and concentrated to dry.

Obtained 12.8 grams (86.5 %) product sought form " of: a high viscosity oil.

Analysis: ^ - ^ 05 toxogonin C.

The g '■fl.. NR

Calculated % 60.34 7.74 8.28

Found % 60.10 7.79 8.21

5 IR-: 3400 - 3300 cm from the NH "¹

Coextruded amid 1700 cm "¹ and 1510 cm '

Coextruded ester of 1750 cm "^{1 -}

NMR 2:00 (6, 1 - 6, 8 ppm)

1:00 (5, 2 - 5, 8 Ppm) exchangeable

10 3:00•|(4, 2 - 4, 9 ppm)

3:00 (3.73 Ppm)

1:00 (3.2 Ppm)

98 (1.5 ppm)

(1, 2 - 2, 2 Ppm) 9.ï 7:00

15 Stage, D.

The n<- [the n - (T-butoxycarbonyl) alanyl amino acids (O)] aza 2 (SRV) bicyclo-carboxylmethyl

. (2, 2, 2) 4 (R), (R) 7 octèrie and 5.

12.8 grams (0,038 mol) of compound obtained in the previous step are dissolved in 140 ml of methanol in the presence of 40 ml of soda in vivo. After 8 b..

20d^{the L} §stirring at room temperature, the solution is concentrated to dry vacuum of the horn e 30° to water and residue, in 150 ml water jçedissous, is extracted by a little ethyl acetate to separate the unsaponifiable fractions, then acidified by 40 ml of HCl in vivo. The precipitate is removed by acid 2 x 100 ml sulfuric ether, the ethereal solution is 25séchée on CASO line ^, filtered and concentrated dry confectioneries. Obtained 11.1 grams (90 RTs %) product sought.

An IR: NH and 0:00 3420 cm "¹ and 3300 - 2300 cm in "¹

Coextruded (acid and amide) 1700 cm "¹

Coextruded (tertiary amide) 1635 cm "¹ and 1500 cm "¹

30 NMR: 1:00 (8.4 ppm) exchangeable

- 2:00 (6, 3 - 6, 6 Ppm)

1 Η (5.5 ppm) exchangeable

3:00 (3.9 And 4 ,B ppm.)

1:00 (2, 9 - 3, 5 Ppm)

(1 - 2 Ppm based) 16:00

Stade_E

The n [(e)-alanyl] aza 2 (the R %) carboxy 3 the bicyclo (2, 2, 2) 4 (R), (R) 7 of OC tene-a 5 -; (compound no. 2 of the following table):

11.1 grams (0,034 mol) of compound obtained in the previous step are dissolved in 95 ml of methylene chloride and confectioneries this solution, cooled confectioneries 0, + 5 degrees, under stirring, are added dropwise th drop 75 ml fluoroacetic acid in solution in 80 ml sorting of methylene chloride. After stirring 1 hr contact confectioneries 0, + 5 degrees, then 1 hr + 25 additional to the solution is concentrated under vacuum dry confectioneries fallopian tube to water and then of the vane pump (0.1 mm Hg).

The crude residue (13.6 grams) obtained, is passed in aqueous solution on resin (W-d0wex 50.⁺ ), the resin is washed with distilled calf and then the product is eluted by inventing 11. both in ammonia. The evaporation dry eluates ammoniacal provides the desired product.

6.3 Grams (RTs " 83 9.ï)*

^0 Nanograms analysis

N-H

Calculated % 58, 91 7.19 12.50

Found % 57.80 7.09 12.83

IR and NMR: see table.

Stade_F

The n [the n - (R) ethoxycarbonyl-1 (e) pentyl ether-alanyl] aza 2 (SRV) carboxy 3 the bicyclo (2, 2, 2) 4 (R), (R) 7 octene and 5; (compound N^than1 8 of the following table).

1 gm (0,045 mol) of compound obtained in the previous step is dissolved under stirring in 55 ml of anhydrous ethanol in the presence of 13 grams of Ta -O

4 molecular carried a and 2.85 grams (0,018 moles) of oxo-to-2 hexanoate (89 and 91°=Ejg, prepared by A.R. MAN1S and M.W. RATHKE, J..

92. Mal. 45 4952 - 54 (1980). After 1 hr. stirring at room temperature, a solution of 0.28 grams (0.0045 moles) of sodium cyano borohydride in 2.25 ml of anhydrous ethanol is added in 6 hr. Stirring is continued for 15 H, then the solution was filtered and concentrated to dry is resumed by 50 ml of aqueous NaCl solution. After extraction with ether for separating excess keto ester, the aqueous phase is brought to pH 3 by a little HCl in-and then extracted with ethyl acetate. The organic phase is dried on AC s0 ^ filtered and then concentrated to dry. The evaporation residue is the product sought in sodium salt form.

In the following table are assembled compounds examples above as well as other compounds of formula (I-) prepared in the same manner.

" r.

i

4,

the m

the n

"

** - CDS

V

Pharmacological study of the compounds of the invention.

The compounds of the invention were tested by i.v administration. on the hammer PO or awake.

Blood pressure dogs was measured by a pressure sensor ("P-next several dB of 23") after catheterization of the aorta by the intermédia ire of femoral artery. The recording is carried out by a recorder ("chiefly 400").

Angiotensin I and angiotensin II are injected animals intravenously at the dose of 0.3 γ / kg body weight. Onêtablit dosage/activity curve for each of these hormones. Then administered compounds of the invention orally or intravenously at the dose of 1 to 10 mg/kg body weight. Setting a second curve dosage/activity for angiotensin let builder for 1' angiotensin II following administration of the product tested.

Inhibited activity to hypertensive ranging from 50 to 100 % after 30 to 90 minutes and maintaining of 40 to 80 % to more than 6 hours. after administration. Certain compounds remain active after 24 H, unlike the case of any compound of this type known to date. Furthermore, the compounds of the invention are devoid of toxicity aiglie (DLq>500 meters/kg of mouse orally).

The n [mercapto 3 (SRV) mêthyl-a 2 or propionyl] aza 2 (SRV) carboxy 3 the bicyclo [2, 2, 2j octane number 20 grams wheat starch 105 grams corn starch 90 grams casein formalin-containing 20 grams magnesium stearate 15 g to 20 g for 1000 tablets of talc.