Angiotensin converting enzyme inhibitors

Details Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors

1992-12-10

1994-09-20

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

549 66, 560147, 514445, A61K 3125, A61K 3138, C07C32108, C07D33334

Patent

active

053489780

DESCRIPTION:

BRIEF SUMMARY
This invention relates to new compounds, methods for their preparation and compositions containing them.
A wide variety of angiotensin converting enzyme (ACE) inhibitors are known, e.g. from British Patent No: 2001963B.
According to the invention we provide compounds of formula I, ##STR2## or --NHCHR.sub.7 COOH, R.sub.4, R.sub.5, R.sub.6 and R.sub.7, which may the same or different, are each phenyl or alkylphenyl C.sub.7-12, R.sub.9, substituted by a saturated 5- or 6-membered carbocyclic or heterocyclic ring, alkylhalo C.sub.1-6, alkylcyano C.sub.1-6, or alkyl phenyl C.sub.7-12, the phenyl being optionally substituted by NO.sub.2 or NH.sub.2, C.sub.1-6 substituted by halogen, alkanoyl C.sub.1-6, S(O).sub.r R.sub.12, NR.sub.13 R.sub.14, phenyl, alkylphenyl C.sub.7-12, naphthalenyl or a 5-membered unsaturated heterocyclic ring, 6, OR.sub.16, or alkanoyl C.sub.1-6, the same or different, are each hydrogen or alkyl C.sub.1-6, C.sub.1-6, then R.sub.2 is not alkyl C.sub.1-6 or alkylphenyl C.sub.7-12,
According to the invention we also provide a process for the production of a compound of formula I, or a pharmaceutically acceptable salt thereof which comprises formula I in which one or more of the functional groups is protected, another salt thereof, to a pharmaceutically acceptable salt thereof or vice versa.
In process a) the good leaving group L.sub.a may be, for example, halogen and the reaction may be carried out in an inert solvent, e.g. dichloromethane at a temperature of from about 0.degree. to 100.degree.. When L.sub.a is halogen the reaction may be carried out in the presence of base, e.g. pyridine.
The reaction may comprise the formation of, optionally in situ, an activated derivative of an acid, e.g. an anhydride, a dicyclohexylcarbodiimide or a carbodiimidazole derivative. The reaction may be carried out in a solvent which is inert under the reaction conditions, e.g. dichloromethane or ethyl acetate, at a temperature of from -10.degree. C. to the boiling point of the solvent, preferably from 0.degree. C. to 30.degree. C. The reaction may be carried out in the presence of a base, e.g. triethylamine. When the reaction involves dicyclohexylcarbodiimide it may be carried out in the presence of an activating agent, e.g. hydroxybenzotriazole or 4-(dimethylamino)pyridine.
The reaction will of course vary with the particular activated derivative used.
In process b) the functional group which is protected may be an amino, thiol or carboxylic acid group. The protecting group can be any convenient protecting group conventionally used in peptide synthesis and may be removed using techniques conventionally used in peptide synthesis. Thus protecting groups which may be used are alkoxy C.sub.1-6, which may be a straight chain or branched alkoxy, e.g. 2-propenyloxy or t-butyloxy; phenylalkoxy C.sub.7-12, e.g. benzyloxy; or alkanoyl C.sub.2-7, e.g. acetyl. These groups can be removed by hydrolysis, for example basic hydrolysis, e.g. using aqueous methanolic sodium or potassium hydroxide or aqueous ammonia solution; or cleavage using, for example, trifluoroacetic acid; or by hydrogenation, e.g. using palladium on charcoal. Amino-protecting groups which may be mentioned include alkyloxycarbonyl C.sub.2-7, e.g. t-butyloxycarbonyl, or phenylalkyloxycarbonyl C.sub.8-13, e.g. benzyloxycarbonyl.
Salts of the compounds of formula I may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or derivative thereof, with one or more equivalents of the appropriate base or acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
Pharmaceutically acceptable salts of the compounds of formula I include ammonium salts, alkali metal salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. the calcium and magnesium s

REFERENCES:
patent: 4242265 (1980-12-01), Wade et al.
patent: 4611002 (1986-09-01), Ondetti
Carey et al. Advanced Organic Chemistry, Part B: Reactions & Synthesis, N.Y., Plenum Press, 1990 pp. 677-678.

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