CS207580B2 - Process for preparing porous derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of proline derivatives of the general formula I Rif. Rj H- S~(CH fcCH-CO-k—CH-COR (I) where R represents a hydroxyl group, an amino group NH2 or an alkoxy group with 1 to 7 carbon atoms, Ri and Ri each represent a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a phenyl group or a phenylalkyl group with 1 to 7 carbon atoms in the alkyl moiety, R3 represents a hydrogen atom, a hydroxyl group or an alkyl group with 1 to 7 carbon atoms, m represents 1, 2 or 3, n represents 1 or 2 and their basic salts. Each carbon atom having a substituent Ri, R3 and R4 is asymmetric if said substituent is a group other than a guide atom.

Description

The invention relates to a process for the preparation of prodrug derivatives of the general formula I

Rif. Rj

H-S- (CH 2 CH-CO-k-CH-COR (I) wherein is

R is a hydroxyl group, an amine group NH2 or an alkoxy group having 1 to 7 carbon atoms,

R 1 and R 1 are each a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a phenyl group or a phenylalkyl group having 1 to 7 carbon atoms in the alkyl moiety,

R3 is a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 7 carbon atoms, m number 1, 2 or 1, n number 1 or 2 and their basic salts.

Each carbon atom having R 1, R 3 and R 4 is asymmetric when said isubstituent is other than a hydrogen atom.

Of the compounds of formula I, the preferred compounds are those in which they are

R is a hydroxyl group or a (C 1 -C 7) alkoxy group,

R1 is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

R3 and R4 are each hydrogen, m is 2 and n is 1 or 2.

Particularly preferred compounds of formula I are compounds of formula II

where it means

R is hydroxyloy or C1-C7alkoxy,

R 1 is hydrogen or C 1 -C 7 alkyl and η 1 or 2.

Of the compounds of formula (II), compounds of the subgroups are of particular interest.

a) R is a hydroxyl group, b] u is 1, cj R1 is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

d] R 1 represents a hydrogen atom or a methyl group, R 1 being a hydroxyloive group, R 1 atom, a guide or a methyl group,

f) R is a hydroxyl group, R 1 is hydrogen or methyl, n is 1 or 1;

g) R is a hydroxyl group, R 1. a hydrogen atom and n zero, hj R is a hydroxyl group, R 1 is a hydrogen atom and n is 1,

i) R is a hydroxyl group, R 1 is a methyl group, and n is 1, j is R is a hydroxyl group, R 1 is a hydrogen atom, and n is a number 1, k] R is a hydroxyl group, R 1 is a methyl group and n is 1;

l) R represents a hydroxyl group, R 1 is a hydrogen atom and n is 1,

m] R represents a hydroxyl group, an Rj atom, a hydrogen or an alkyl group having 1 to 7 carbon atoms, in particular a hydrogen atom or a methyl group, n zero, the number 1 or 2, in particular the number 1.

It is recalled that preferred groups of the compounds also include compounds with optional combinations of said groups.

Particularly preferred are stereoisomers in which proline is in the gray L-fortma.

C 1 -C 7 alkyl groups are straight or branched chain hydrocarbyl groups, from methyl to heptyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopeptyl and similar groups. C 1 -C 7 alkoxy groups are of the same type of bonded atom, oxygen, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like. Among the alkyl groups and alkoxy groups having 1 to 7 carbon atoms, groups having 1 to 4 carbon atoms, and especially groups having 1 to 2 carbon atoms, are preferred. A preferred phenylalkyl group is phenylmethyl.

The compounds of formula (I) are added by the process of the invention by acylating a compound of formula (II) with a compound of formula (II).

s-c = o (III) wherein R, R 1, R 3, Rd, to and n are as defined above.

According to the process of the present invention, salts of the compounds of formula I are also prepared.

The thiolactone of the formula III used is, for example, [beta] -propio-biolactone, [alpha] -methyl- [beta] -propio-thiolactone or the like.

In the acylation of an ester of a compound of formula (II), for example when R is C 1 -C 7 alkoxy, in particular tert -butoxy, thiolactone, for example β-propyl-thialo-ketone, α-methyl-β-propiothioalikitoin or the like, For example, the reaction may be carried out in a dry solvent such as tetrahydrofuran, dioxane, methylene chloride or the like at a temperature of from 0 ° C to room temperature. The ester group can then be cleaved by treating the ester with trifluoroacetic acid and anilsol to give the corresponding free acid.

The products of formula I have one or more asymmetric carbon atoms. When R 1, R 3 or -R 4 has a meaning other than atoim of hydrogen, the carbon atom, n, and which are bound, is asymmetric. The compounds thus prepared are in stereoisomeric form or in the form of racemic mixtures. All of these isomers fall under the general formula I. In the process of the invention, rlacetoate or one of the enantiomers may be used as starting material. When a racemic starting material is used in the process of the invention, the stereoisomers obtained can be separated by conventional chromatography or fractional crystallization. In general, the L-isomer with respect to the carbon atom of the amino group is the preferred isomeric form. Also, the D-isomeir with respect to the α-carbon atom in the acyl side chain (e.g., the carbon atom bearing the R 1 group) is preferred.

The compounds prepared by the process of the invention form basic salts with various inorganic and organic bases; salts are also included in the invention. Such salts include ammonium salts, alkali metal salts such as isodium and potassium, which are preferred, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamino salt, behizathine, N-methyl-D-glucamine, hydrabaminol salt, salts with amino acids such as arginine, lysine and the like. Non-toxic, physiologically acceptable salts are preferred, any other salts are also useful, for example, in isolating the melbo purification product.

The salts are prepared in a conventional manner by reacting the free acid product with one or more equivalents of a suitable base to provide the desired cation in a solvent or salt-insoluble environment, or in water by removing the water by freeze-drying. Treatment of the salt with an insoluble acid with a cation exchange resin in a hydrogen form (for example, a polystyrene sulfonic acid resin such as Dowex 50} or a water acid and extraction with an organic solvent such as ethyl acetate, dichloromethane or the like ¹ can be obtained from the salt in free form. prepare another salt.

In the attached example, a case and a preferred embodiment of the method according to the invention is described.

The compounds of formula (I) prepared by the process of the invention inhibit the conversion of decapeptidangiotensin I to amgiotensin II and are therefore useful for reducing or eliminating angioteinsin-mediated hypertension. The action of the enzyme remin on angiotensinogem, piseudoglobulin in the blood plasma, produces angiotenisin I. Angibtemshim I is converted by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II is an active, pressure-lowering agent, known to be the cause of various torque hypertension in various mammalian species, such as rats and dogs. The compounds prepared by the process of the invention are involved in the sequence.

angiotensin (remin) -> angiotensin I - »-> angiotensin II by inhibiting the angiotensin converting enzyme and reducing or eliminating the formation of pressure-acting angiotensin II substances.

Thus, administration of a composition comprising a single compound of Formula I or a combination of compounds of Formula I, or a physiologically acceptable salt thereof, removes angiotensin-induced hypertension in a mammal suffering therefrom. A single dose or preferably wild to four divided daily doses of 0.1 to 100 .mu.g / kg, preferably 1 to 50 .mu.g / kg / day, as shown in the polluisis of animals described by SL Engl, is suitable for lowering blood pressure. TR Schiaeffer, Μ, H. Waugh. and B. Rubineni in Proc. Soc. Exp. Biol. Copper. 143, 483 (1973). The agent is preferably administered iperoirally, but a parenteral route such as suibcutaneous, intramufecular, imtinalvenous or introperitoneal may also be used.

The compounds prepared by the method of the invention may be used to lower blood pressure in the processing of rta tablets, capsules or elixirs for oral administration or into sterile solutions or suspensions for parenteral administration. About 10 to 50 mg of a compound of formula I or a mixture of compounds of formula I or their physiologically acceptable salts are treated with physiologically acceptable binders, carriers, excipients, preseiratives, stabilizers, fragrances, etc., and unit doses, which are acceptable for pharmaceutical practice. The amount of active ingredient in such formulations and formulations is such that a suitable dosage for the indicated use is obtained.

Auxiliaries which can be used for tablets, capsules, and the like include: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as cereal starch, potato starch, aiginic acid and the like; lubricants such as magnesium stearate; sweetening agents such as sucrose, lactoisia or saccharin; fragrances such as peppermint, libayl oil or cherry concentrate. If the dosage form is a capsule, it may contain, in addition to the aforementioned substances, liquid carriers such as fatty oils. Various other substances may also be used, such as coatings or other physical dosage unit modifying agents. For example, the tablets may be coated with a shake, layman, sugar or, as shellac, talk sugar. A syrup or elixir may contain the active compound, sachairose as a sweetener, methyl and propylparaben as a preservative, a colorant and a flavoring such as a cherry or orange essence.

Sterile injectable preparations may be formulated by known methods of pharmaceutical practice by dissolving or suspending the active ingredient in a binder such as water for injection, natural vegetable oils such as soybean oil, coconut oil, ground oil, cottonseed oil etc., or synthetic fatty ointments. binders such as ethyl oleate or the like. If desired, buffers, preservatives, antioxidants and the like can be added.

The method according to the invention is illustrated by the appended example, which describes a particularly preferred embodiment of the invention.

He did

1- (S-mercapitopropanoyl J-L-prolime tert-butyl ester)

To a solution of t-butyleste.ru L-proline (3.42 g) in dry tetrahydrofuran (10 ml) cooled in an ice bath was added propiothioactone (1.76 g), after a 5 minute dwell in the ice bath and after three hours. at room temperature, the reaction mixture was diluted with ethyl acetate (20 * 0 mL) and washed with 5% potassium sulphate solution and water. The organic layer was dried over magnesium sulphate and evaporated to dryness in hydrogen chloride to give 1- (3-mercaptopropapoyl) tert-butyl ester. 1-L-proline is recrystallized from ether-hex * a * n, yield 3.7 g, mp 57-58 ° C.

Claims (1)

SUBJECT Process for the preparation of proline derivatives of the formula I obeoného f ³ Kf H ₂ C - (CHlnt H - S - (CH 2 CH - CO - k - CH - COR (U where R is a hydroxyl group, an amino-osjucipine N 1 H 2 or an alkoxy group having 1 to 7 carbon atoms, R 1 and R 1 are each a hydrogen atom, a C 1 -C 7 alkyl group, a phenyl group or a C 1 -C 7 phenylalkyl group in an alkyl group, R3 is hydrogen, hydroxyl or C1-C7alkyl, to 1, 2 or 3, n to 1 or 2 Of the invention and their basic salts, characterized in that the compound of formula (II) is acylated HH-CH-COR III with a compound of formula (III) R 1 -c = o (III wherein R, R 1, R 3, R 4, m and n are as defined above). severografia, n. p., xivod 7, Most