CS207579B2 - Method of preparation of the proline derivatives - Google Patents

Description

(54) Process for preparing proline derivatives

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

R, ^R 1 R II

R ' _R S-CHCH-CO' N-CHCOR

2 (I) where is

R is hydroxy, NH2 or C1-C7alkoxy,

R 1 and R 4 are each hydrogen, alkyl of 1 to 7 carbon atoms, phenyl or phenylalkyl of 1 to 7 carbon atoms in the alkyl moiety,

R @ 2 is hydrogen, C1 -C7 alkyl, phenyl optionally substituted by halogen, C1 -C7 alkyl, C1 -C7 alkoxy, phenyl, diphenylalkyl or triphenylalkyl having 1 to 7 atoms in each case C1 -C7 alkylthiomeithyl, C1 -C7 phenylalkylmethyl, C1 -C7 alkanoyl, alkanoyl, C1 -C7 alkylthiomeithyl;

O

Rs — C—,

M

Rs — M — C—,

M

R 5 —NH — C—, or

Re — S—, where is

R 8 is C 1 -C 7 alkyl, phenyl or C 1 -C 7 phenylalkyl in the alkyl moiety,

C 1 -C 7 -alkyl, phenyl optionally substituted by halogen, C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy, hydroxyalkyl207579, C 1 -C 7 -alkoxycarbonyl; share

M oxygen or sulfur atom,

R3 is a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 7 carbon atoms, m is 1, 2 or 3, and their basic salts.

Each carbon atom having R 1, R 3 and R 4 is asymmetric, if said, the substituent is other than a hydrogen atom.

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

R is hydroxyl or alkoxy of 1 to 7 carbon atoms,

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

R @ 2 is hydrogen, R @ 5 --CO is R @ 6 --S--,

R 3 and R d are each hydrogen,

R 5 is C 1 -C 7 alkyl, in particular (methyl or phenyl,

Is C1-C7alkyl, in particular methyl or ethyl, and is 2.

Particularly preferred compounds of formula I are those of formula II of formula Π

COR (II1)

R is hydroxyl or alkoxy of 1 to 7 carbon atoms,

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

R @ 2 is hydrogen, a group of formula

R 5 —CO—, R 6 —S—,

R 8 is C 1 -C 7 alkyl or phenyl, in particular C 1 -C 7 alkyl, and

C 1 -C 7 alkyl.

Among the compounds of formula (II), particular preference is given to subgroups whose preference rises from subgroup a) to subgroup q), which subgroups are particularly preferred compounds prepared by the process of the invention.

a) R represents a hydroxyl group,

b) R 6 represents hydrogen atoms or an alkanoyl group having 1 to 7 carbon atoms,

(c) Rž destroyed by a hydrogen atom,

d) R 2 represents an acetyl group,

e) R 1 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms,

f) R 1 represents a hydrogen atom or a methyl group,

g) R is a hydroxyl group, R1 is a hydrogen atom or a methyl group,

h) R represents a hydroxyl group, R 1 is a hydrogen atom or a methyl group, R 2 is a hydrogen atom or an acetyl group,

i) R is a hydroxyl group, R 1 and R 2 are each a hydrogen atom,

J) R is a hydroxyl group, R 1 is a hydrogen atom, R 2 is an acetyl group,

k) R represents a hydroxyl group, Rr a methyl group, R a = acetyl group,

R 1 represents a hydroxyl group, R 1 and R 2 each represent a hydrogen atom,

m) R is hydroxyl, R 1 is methyl, R 2 is hydrogen, nj R is hydroxyl, R 1 is hydrogen, R 1 is C 1 -C 7 alkylthio,

o) R represents a hydroxyl group, R 1 is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, in particular a hydrogen atom or a methyl group,

p) R 2 represents a group of the general formula

M

II

R5 — M— € -, where M is an oxygen or sulfur atom,

q) R 6 represents a group of the general formula

M

II

R 5 —NH — C—, wherein M represents an oxygen or sulfur atom, preferably a sulfur atom.

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

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

C1-C7alkyl groups are straight-chain or branched alkyl groups from the methyl-heptyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and the like groups. Alkoxy groups having 1 to 7 carbon atoms are groups of the same type but having an atom; oxygen, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isotouloxy, t, t-butoxy, and the like. Of alkyl and alkoxy groups, groups are preferred; C 1 -C 4 and especially C 1 -C 2. A preferred phenylalkyl group is phenynylmethyl. Possibly eagle207579

The term 'lower' is always understood to mean a group having 1 to 7 carbon atoms.

Alfcanoyl groups are those having an acyl radical of an aliphatic acid of 2 to 7 carbon atoms, such as, for example, acetyl, piropionyl, butyryl, isobutyryloy and the like. Preferred are alkanoyl groups having up to 4 carbon atoms, and in particular acetyl groups.

By halogen is meant chlorine, bromine, fluorine or iodine, but chlorine and bromine are preferred. The substituted femyl group preferably has a substituent at the 4-position of the ring. The hydroxyalkyl group has a hydroxyl group on the alkyl chain described, preferably at the terminal carbon atom; it is, for example, hydroxymethyl or 2-hydroxyethyl. Amino (carboxy) alkyl groups have one amino group and one carboxy group on a characterized alkyl group, preferably both on one carbon atom, for example on a terminal carbon atom; for example, a 2-amino-2-carboxyeithyl group is preferred.

Compounds of formula (I) are prepared by acylating compounds of formula (III) with h-ch-cor (III) wherein R, R 5, m is as defined for formula (I) with an acid of formula (IV)

CH 2 C-COOH (IV) wherein R 1, R 1 is as defined in formula I, and the resulting product is treated with a thiol anion or an acid of formula VII

R2-SH, (VII) wherein R2 is as defined above.

Acrylic acid is first converted to the acid halide, then reacted with a compound of formula III to give a compound of formula XIII

Rit-Ri H ₂ C ~~~ (CHH) m. CH = C-CO-N-CH-COR (XIII) and to this intermediate is added the thiol or thioacid of general formula VII.

The acrylic acid of formula (IV) may also be reacted first with a thiocysiline of formula (VII) wherein R 2 is as defined above to give a compound of formula (XV),

Rt Ri

I I

I]

R2 - S - CH - CH - COOH, (XV) which is converted to its acid halide, for example thionyl chloride, then coupled to a compound of formula III.

The acid or ester of formula III may also be acylated with a protected form of ω-meercaptoalkanoic acid of formula XVI

Rt Ri

I and

R 5 -S-CH-CH-COOH, (XVI) wherein R 5 is a protecting group and R 1, R t. Such a protecting group is, for example, chlorine or thunder, iodine or tosyloxyisphupine or the like. After acylation, the protecting group is cleaved from the products in a known manner, such as treatment with hot trifluoroootic acid, cold trifluoromethanesulfonic acid, mercuric acetate, sodium in liquid ammonia, zinc and hydrochloric acid, and the like.

The products of formula I have one or more asymmetric atoms. If R 1, R 3 or R 1 are different from hydrogen, the atoim of the carbon to which they are attached is asymmetric.

The compounds are therefore stereoisomeric or in the form of racemic mixtures. All forms of the compounds of formula I are prepared according to the invention. In the process according to the invention, the starting material or the enantiomer can be used. When racemic starting materials are used in the process of the invention, the resulting stereoisome viruses can be separated by conventional chromatography or by fractional crystallization. In general, the L-isomer with respect to the amino acid carbon atom represents the preferred isomeric form. Also, the D-isomer with respect to the α-carbon atom in the acyl side chain (e.g., the carbon atom bearing R 1) is preferred.

The compounds of formula (I) prepared by the process of the invention form basic salts with various inorganic cyanilines or organic acids; these salts are also included in the invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium, which are suitable, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine salt, benziathiin, N-methyl-D-glucamine, hydrabaimine, salts with amino acids such as arginineim, lysine and the like. Non-toxic, physiologically acceptable salts are preferred, and any other salts are also useful, for example, in the isolation or purification of the product, as exemplified in the examples of the dicylclohexylamine salt.

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 catalysis, in a solvent or in an environment in which the salt is insoluble, in water or freeze-dried, . Treatment of the salt with an insoluble acid such as a cation exchange resin in a hydrogen form (for example, a resin based on polystyrene, linoleic acid such as Dowex 50) or an aqueous acid and extraction with an organic solvent such as ethyl acetate, dichloromethane or the like can be obtained from salt The acid in free form and optionally another salt may be prepared.

Examples of particularly preferred embodiments of the process according to the invention are described in the accompanying examples.

The compounds of formula (I) prepared by the process of the invention inhibit the conversion of declapeptidangiotensin I to angiotensin II and are therefore useful for reducing or eliminating angiotenisine-induced hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II is an active, pressure-reducing agent that is believed to be the cause of various forms of hypertension in various mammalian species, such as rats and dogs. The compounds prepared by the process of the invention are involved in the sequence of angiotensin (renin) -> angiotensin I -> angiotensin II by inhibiting the angiotensin-converting enzyme and by reducing or eliminating the formation of pressure-acting angiotensin II substances.

Thus, the administration of a pircistripe containing 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. One dose or preferably two to four divided daily doses of 0.1 to 100, preferably up to 50, mg / kg per day is suitable for lowering blood pressure, as shown in animal experiments described by SL Engl. TR Schaeffereim, MH W-aug-hem and B. Rubin in Pro-c. Soc. Exp. Biol. Copper. 143, 483 (1973). The agent is preferably administered orally, but a parenteral route such as subcutaneous, intraimuscular, intravenous or ihpperitrit-o-neural can also be used.

The compounds prepared by the process of the invention may be used to lower blood pressure when processed into tablets, capsules or elixirs for oral administration - or sterile solutions - or suspensions for pareniteral administration. Around. 10 to 500 mg of the compounds of the formula I or a mixture of the compounds of the formula I or their physiologically acceptable salts are treated with physiologically acceptable binders, carriers, excipients, pre-preservatives, stabilizers, fragrances etc. into 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, aciacia, corn starch or gelatin; excipients such as dicalciurophosphate; disintegrants such as cereal starch, potato crocodile, alginoic acid and the like; lubricants such as magnesium stearate; sweetening agents such as sucrose, lactose or saccharin; - fragrances such as peppermint, oil of wintergreen or cherry extract. If the dosage form is a capsule, it may contain, in addition to the aforementioned substances, liquid carriers such as sweetening oils.

Various other substances may also be used, such as coatings or other modifiers for the physical form of the unit dose. For example, tablets may be coated with shellac, sugar or both shellac and sugar. A syrup or elixir may contain the active compound, a-sucrose as a sweetener, methyl and propylparab as a preservative, a colorant, and a flavoring 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, injection powder, natural vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty binders such as ethyl oleate or the like. If desired, buffers, preservatives, antioxidants and the like can be added.

The process according to the invention is illustrated by the accompanying examples, which describe particularly advantageous embodiments of the invention.

He did

Metakiryloyl chloride (4.16 g) was added to a solution of L-proline (3.45 g) mixed with water (100 ml) and sodium bicarbonate (12 g), cooled in ice water with vigorous stirring. When the addition was complete, the mixture was stirred at room temperature for two hours and then extracted with ether. The aqueous phase was acidified with 1N-chloro-hydrochloric acid and extracted with ethyl acetate. The organic phase is evaporated to dryness in vacuo, the residue is mixed with thiol acetic acid (3.5 g), several crystals of azobiis isobuityironitrile are added and the mixture is heated on a steam bath for two hours. The reaction mixture was dissolved in a benzein acetic acid system (75:25), and loaded onto a silica gel column. Elution with the same solvent mixture gave 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proline.

Example 2

Methacryloyl-L-proline

L-proline (23.0 g, 0.2 mol) was dissolved in 100 mL of water and stirred in an ice bath. Methacryloyl chloride (19.6 mL, 0.2 mol) in 25 mL of methyl isobufyl ketone was added dropwise over three hours. 2N sodium hydroxide solution was added simultaneously to maintain the pH of the reaction mixture at 7.0. The base addition was continued for four hours after the acid chloride addition was complete. The reaction mixture was adjusted to pH 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The aqueous layer is then acidified to pH1

2.5 and extracted thoroughly with ethyl acetate. The acidic extracts were washed with brine and dried (magnesium sulfate). The ethyl acetate solution was treated with dicyclohexylamine (40 mL) and cooled overnight. The resulting white precipitate was filtered off and dried, yielding 29 g (39%) of a white solid, mp 202-210 DEG C. ^q Peviná was recrystallized from 1.5 L of 3: 1 aceitonitril / isopropanol to afford 19.7 g of methacryloyl-L-proline in the form of the dicycloehexylamine salt in the form of fine white needles, m.p. 202-210 ° C.

The salt was dissolved in water / ethyl acetate and acidified with concentrated hydrochloric acid. The resulting suspension was filtered to remove a fine white precipitate which was washed well with ethyl acetate. The filtrate was saturated with sodium chloride! and extracted thoroughly with ethyl acetate. The extracts were washed with brine, dried (magnesium sulfate) and evaporated to a clear oil which solidified. Crystallization from ethyl acetate / hexane gave 7.5 g (83%) of meitacryloyl-L-proline as a crystalline solid, m.p. 89-93 ° C. An analytical sample was obtained by recrystallization and had a melting point of 95-98 ° C.

Example 3

1- (3-Acetylthio-2-D-methylpropainoyl) -L-proline

Methacryloyl-L-proline (183 mg, 0.001 mol) was dissolved in thiol acetic acid (0.5 mL) and allowed to stand at room temperature for 16 hours. The solution was evaporated in vacuo to give a yellow residue. Thin-layer prepairalivine chiromatography (Silica Gel, Dichloromethane / methanol / acetic acid 90: 5: 5) allows the isolation of a clear oil (240 milligrams) as the main fraction. Thin layer chromatography (system dichloromethane / methanol / acetic acid 90: 5: 5) confirms that the material is 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proline.

R _f = 0.35; (system benzene / quote acid 75:25) R _f = 0.38.

The oil is dissolved in 3 ml of acetonitrile, treated with dicyclohexylamine until the reaction is complete and cooled. A white, crystalline precipitate (106 mg) is collected, m.p. 175-181 ° C. Crystallization from isopropanol afforded l- (3-naphthylthio iace ^{L-2-D-methylpropanoyl)} -L-proline as dlcyklohexylamínové salt, mp 187-188 ° C.

Claims (20)

fRedmít A process for the preparation of proline derivatives of the general formula I R% Rf S-CH-Ct-h CO-N-CH-COR (where n is R is hydroxy, NHa or C1-C7alkoxy, R @ 1 and R @ 4 are each hydrogen, C1 -C7 alkyl, phenyl SC1, or phenyl C1 -C7 alkyl in the alkyl moiety, R @ 2 is hydrogen, C1 -C7 alkyl, phenyl optionally substituted by halogen, C1 -C7 alkyl or alkoxy, furthermore, phenylalkyl, diphenylalkyl or triphenylalkyl having 1 to 7 carbon atoms each alkyl radical, alkylthiomethyl radical, phenylalkylmethyl radical having 1 to 7 carbon atoms in each alkyl radical, alkanoylanndomeithyl radical having 1 to 7 carbon atoms in the alkanoyl radical, a radical of the formula O II R5 — c—, M II R5__M —C—, Μ R 5 —NH — C—, or Re-S—, Ted means R 5 is C 1 -C 7 alkyl, phenyl, or phenylalkyloxy of 1 to 7 carbon atoms in the alkyl moiety, (C 1 -C 7) -alkyl, phenyl optionally substituted by halogen, C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy, furthermore, C 1 -C 7 -alkyl, (C 1 -C 7) -alkyloxy; of the general formula O II HzN-C-Y-, wherein Y represents an alkyl group having 1 to 7 carbon atoms, M oxygen or sulfur atom, R3 is a hydrogen atom, a hydroxyl group or an alkyl group having from 1 to 7 carbon atoms, n is 1, 2 or 3, and their basic salts, characterized in that the compound of formula III is acylated I ³ H ₂ C- (CH) 2 -h-ch-cor (III) wherein R, R 3 and m are as defined above, with acid of formula IV CH = C-COOH (IV) wherein R 1 and R 1 are as defined above, and the resulting product is treated with a thiol anion or a thioacid of Formula VII Rz-SH (Vlij, where Rz is as defined above). 2. The process of item 1 for preparing compounds of formula II o RS- (CH _Z) -CH-CO-N ^Lc0R wherein R is hydroxy or alkoxy having 1-7 carbon atoms, R is hydrogen or alkyl having 1-7 carbon atoms, R is hydrogen UEBO alikanoylovou 1 -C 4 carbon atoms and their physiologically acceptable salts, characterized in that a compound of formula V is reacted with an acid of formula VI Ri AND Ra-S-CH2-CH-COOH (VI), wherein R, R1 and R2 are as defined above. 3. The process of claim 2 wherein the compound of formula V is reacted with an acid of formula VI wherein R is hydroxyl and R1, Ra are as defined in point 2. 4. A process according to claim 2 wherein the compound of formula (V) is reacted with an acid of formula (VI) wherein R @ 2 is hydrogen or C1 -C7 alkanoyl and R @ 1 and R @ 1 are as defined in point 2. 5. A process according to claim 2 wherein the compound of formula (V) is reacted with an acid of formula (VI) wherein R2 is hydrogen and R and R1 are as defined in item 2. 6. A process according to claim 2 wherein the compound of formula V is reacted with an acid of formula VI wherein R @ a is an aceityl group and R and R @ 1 are as defined in point 2. 7. A process as claimed in claim 2, wherein the compound of formula (V) is reacted with the acid of formula (VI), wherein R1 is hydrogen or C1-C7alkyl and R1 and R2 are as defined in 2. 8. A process according to claim 2 wherein the compound of formula (V) is reacted with an acid of formula (VI) wherein R1 is hydrogen or methyl and R1 and R2 are as defined in 2. 9. A process according to claim 2, wherein a compound of formula V is reacted with an acid of formula VI wherein R is OH, R1 is hydrogen or methyl, and R2 is as defined in 2. 10. A process according to claim 2, wherein a compound of formula V is reacted with an acid of formula VI wherein R is OH, R1 is hydrogen or methyl, R2 is hydrogen or acetyl. 11. A process according to claim 2, wherein the compound of formula V is reacted with an acid of formula VI wherein R is OH, R1 and R2 are each hydrogen. 12. The process of claim 2 wherein the compound of formula V is reacted with an acid of formula VI wherein R is OH, R1 is hydrogen, and R2 is acetyl. 13. The process of claim 2 wherein the compound of formula V is reacted with an acid of formula; of formula VI, wherein R is a hydroxyl group, R 1 is a methyl group, and R 2 is an acetyl group. 14. A process according to claim 2, wherein the compound of formula V is reacted with an acid of formula VI wherein R is OH, R1 and R2 are hydrogen. 15. The process of claim 2 wherein the compound of formula V is reacted with an acid of formula VI wherein R is OH, R1 is methyl, and R2 is hydrogen. 16. The process of claim 2, wherein the acid of formula VI is reacted, wherein R1 and R2 are as defined in point 2 in the L-form. 17. The process of claim 15, wherein proline is reacted in the L-form. 18. A process according to claim 1, wherein the compound of formula III is reacted with a compound of formula IV wherein R is OH, R1 is hydrogen, R2 is C1 -C7 alkylthio. 19. The process of claim 14 wherein the proline is in the L-form. 20. The process of claim 13 wherein the proline is in the L-form.