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    Amino acid derivatives
    3.
    发明授权
    Amino acid derivatives 失效
    氨基酸衍生物

    公开(公告)号：US4113715A

    公开(公告)日：1978-09-12

    申请号：US759685

    申请日：1977-01-17

    申请人： Miguel Angel Ondetti ,  Michael Edward Condon

    发明人： Miguel Angel Ondetti ,  Michael Edward Condon

    IPC分类号： A61K31/19 ,  A61K31/195 ,  A61K31/215 ,  A61K31/22 ,  A61K31/395 ,  A61K31/40 ,  A61K31/403 ,  A61K31/404 ,  A61K38/00 ,  A61P9/12 ,  A61P43/00 ,  C07C67/00 ,  C07C313/00 ,  C07C323/60 ,  C07C327/20 ,  C07C327/22 ,  C07C327/34 ,  C07D207/08 ,  C07D207/10 ,  C07D207/16 ,  C07D207/46 ,  C07D209/20 ,  C07D211/60 ,  C07D211/86 ,  C07D233/64 ,  C07K5/02 ,  C07K5/06 ,  C07K5/062 ,  C07C103/52 ,  A61K37/00

    CPC分类号： C07K5/0606 ,  C07C327/00 ,  C07D207/16 ,  C07D207/46 ,  C07D209/20 ,  C07D211/60 ,  C07D211/86 ,  A61K38/00 ,  Y10S514/929 ,  Y10S530/80

    摘要： New substituted acyl derivatives of amino acids which have the general formula ##STR1## are useful as angiotensin converting enzyme inhibitors.SUMMARY OF THE INVENTIONThis invention relates to new substituted acyl derivatives of amino acids which have the general formula ##STR2## and salts thereof,WHEREIN R is hydroxy or lower alkoxy;R.sub.1 is hydrogen, lower alkanoyl or amino(imino)methyl;R.sub.2 is hydrogen, lower alkyl or phenyl-lower alkylene;R.sub.3 is hydrogen, lower alkanoyl, benzoyl or ##STR3##A is hydrogen, lower alkyl or hydroxy-lower alkylene;B is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, hydroxy-lower alkylene, hydroxyphenyl-lower alkylene, amino-lower alkylene, guanidino-lower alkylene, mercapto-lower alkylene, lower alkyl-thio-lower alkylene, imidazolyl-lower alkylene, indolyl-lower alkylene, carbamoyl-lower alkylene or carboxy-lower alkylene;OR A and B together form a (CH.sub.2).sub.p bridge which completes a ring of 5 or 6 atoms with the nitrogen and carbon to which they are joined, one carbon optionally bearing a hydroxy group;N IS 0 OR 1;M IS 0, 1, 2, 3 OR 4; AT LEAST ONE OF M AND N IS OTHER THAN 0; ANDP IS 3 OR 4.The asterisks denote centers of asymmetry.DETAILED DESCRIPTION OF THE INVENTION phenylglycineThe invention in its broad aspects includes substituted acyl derivatives of amino acids having formula I above. The substituted acyl groups refer to the side chains on the carbon beta to the nitrogen atom. The one side chain has one or two sulfur containing groups and the second side chain has one nitrogen containing group. Within the class defined by formula I, because of their properties, certain subgroups are preferred.Compounds in the group represented by formula I which are derived from or include the structure of the amino acids glycine, alanine, leucine, threonine, phenylalanine, lysine, arginine, glutamine, histidine, methionine, serine, cysteine, tyrosine, valine, asparagine, glutamic acid, proline, hydroxyproline, pheylglycine or tryptophane are broadly preferred. Preferred modifications are compounds of formula I wherein R is hydroxy; R.sub.1 is hydrogen, lower alkanoyl or amino(imino)-methyl [particularly hydrogen, methyl, acetyl or amino(imino)-methyl]; R.sub.2 is hydrogen, lower alkyl (particularly hydrogen or methyl) or phenyl-lower alkylene (particularly benzyl), most particularly R.sub.2 is hydrogen; R.sub.3 is hydrogen, lower alkanoyl or benzoyl (particularly hydrogen, or acetyl); A is hydrogen; B is lower alkyl, guanidino-lower alkylene (particularly guanidinopropyl), amino-lower alkylene (particularly amino-C.sub.3 -C.sub.4 -lower alkylene) or phenyl-lower alkylene (particularly phenylmethyl); or A and B complete a 5- or 6-membered ring; m is 0, 3 or 4 and n is 0 or 1, but not both m and n are 0.Especially preferred are those compounds of formula I which are derived from proline and have the formula ##STR4## The symbols have the same preferred meanings described above.The lower alkyl groups represented by any of the variables include straight and branched chain hydrocarbon radicals from methyl to heptyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl and the like. The lower alkylene groups are of the same kind also having 1 to 7 carbons. Similarly, the lower alkoxy groups are of the same kind with a link to oxygen, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like. The C.sub.1 -C.sub.4 members, especially C.sub.1 and C.sub.2 members, of all types are preferred. Phenylmethyl is the preferred phenyl-lower alkylene group and methoxy and t-butoxy the preferred lower alkoxy groups. The lower alkanoyl groups are the acyl radicals of the lower (up to 7 carbons) fatty acids, e.g., acetyl, propionyl, butyryl and the like, acetyl being preferred.The amino(imino)methyl group represented by R.sub.1 is the residue of the guanidino radical ##STR5##The products of formula I and the preferred subgroups can be produced by various methods of synthesis. According to a preferred method, the amino acid of the formula ##STR6## wherein A, B and R are defined as above, and R is hydroxy is acylated with an acid of the formula ##STR7## wherein R.sub.1 is an acyl group, and R.sub.2, R.sub.3, m and n have the meaning defined above, by one of the known procedures in which the acid IV is activated, prior to reaction with the amino acid III, involving formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester, Woodward reagent K, N,N'-carbonylbisimidazole, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) or the like. When R is lower alkoxy, this or other known methods of coupling such moieties can be used [For a review of these methods, see Methoden der Organischen Chemie (Houben-Weyl) Vol. XV, parts 1 and 2 (1974)].When the product obtained is an ester, e.g., R is t-butoxy, the ester can be converted to the free carboxy group (R is hydroxy) by cleavage with acids, e.g., trifluoroacetic acid. Conversely the free acid can be esterified by conventional procedures.Starting materials of formula IV wherein m is 0 are derivatives of the amino acid cysteine which can be produced by known procedures.The acids of formula IV wherein m is 2, 3 or 4 can be synthesized, according to a preferred method, by the addition of a thiol acid to the substituted acrylic acid of the formula ##STR8##The latter are obtained by hydrolysis, e.g., with 6N hydrochloric acid, of the methylene lactams of the formula ##STR9## [J. Org. Chem. 39, 893 (1974)]The compounds of formula I wherein m is 1 are obtained by the Curtius rearrangement of an acid of the formula ##STR10##The preferred method for producing compounds of formula I wherein n is 0 is by displacement of the halo derivative of the formula ##STR11## wherein X is halogen, preferably chlorine or bromine, with the thiol acid R.sub.3 --COSH.The disulfides of formula I, wherein R.sub.3 is ##STR12## are obtained by oxidation of the compound of the formula ##STR13## e.g., with an alcoholic solution of iodine.The compounds of formula I wherein R.sub.1 is amino(imino)-methyl are obtained by reacting a compound of formula I wherein R.sub.1 or R.sub.2 is hydrogen with a guanyl-forming reagent e.g., guanyl-3,5-dimethylpyrazole nitrate, S-methylisothiourea, or O-methylisourea.Products of formula I have two asymmetric carbon atoms. These carbon atoms are indicated by an asterisk in formula I. The compounds accordingly exist in diastereoisomeric forms or in racemic mixtures thereof. All of these are within the scope of the invention. The above described syntheses can utilize the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthetic procedure, the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. In general, the L-isomer with respect to the carbon of the amino acid constitutes the preferred isomeric form.The compounds of formula I form salts which are also part of this invention. The salts include acid-addition salts which are formed by reaction with a variety of inorganic and organic acids providing acid addition salts including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, benzenesulfonate, methanesulfonate, cyclohexanesulfamate and toluenesulfonateThe salts are formed in conventional manner by reacting the free form of the product with one or more equivalents of the appropriate acid or base providing the desired anion or cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freezing drying. By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen form [e.g., polystyrene sulfonic acid resin -- Dowex 50 (Mikes, Laboratory Handbook of Chromatographic Methods (Van Nostrand, 1961) page 256] eluting with a volatile buffer (e.g. pyridine-acetic acid) extraction with an organic solvent, the free form can be obtained, and if, desired, another salt formed.Additional experimental details are found in the examples which are preferred embodiments and also serve as models for the preparation of other members of the group.The compounds of this invention inhibit the conversion of the decapeptide angiotensin I to angiotensin II and therefore are useful in reducing or relieving angiotensin related 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. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats, dogs, etc. The compounds of this invention intervene in the angiotensingen .fwdarw. angiotensin I .fwdarw. angiotensin II sequence by inhibiting angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II.The inhibition of the angiotensin converting enzyme by compounds of formula I can be measured in vitro with isolated angiotensin converting enzyme from rabbit lungs following the procedure described by Cushman and Cheung [Biochem. Pharmacol., 20, 1637 (1971)], and with an excised smooth muscle assay [E. O'Keefe, et al., Federation Proc. 31, 511 (1972)] in which these compounds have been shown to be powerful inhibitors of the contractile activity of angiotensin I and potentiators of the contractile activity of bradykinin.The administration of a composition containing one or a combination of compounds of formula I or physiologically acceptable salt thereof to the species of hypertensive mammal alleviates or reduces hypertension. A single dose, or preferably two to four divided daily doses, provided on a basis of about 5 to 1000 mg. per kilogram per day, preferably about 10 to 500 mg. per kilogram per day is appropriate to reduce blood pressure. The animal model experiments described by S. L. Engel, T. R. SChaeffer, M. H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. 143, 483 (1973) serve as a useful guide.The substance is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intravenously or intraperitoneally can also be employed.The compounds of this invention can be utilized to achieve the reduction of blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solution or suspensions for parenteral administration. About 10 to 500 mg. of a compound or mixture of compounds of formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

    摘要翻译： 具有通式“IMAGE”的氨基酸的新取代的酰基衍生物可用作血管紧张素转换酶抑制剂。