KR830007515A - Method for preparing a new blood pressure lowering agent consisting of carboxyalkyl peptide, thioether peptide and ether peptide - Google Patents

Abstract

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Description

Method for preparing a new blood pressure lowering agent consisting of carboxyalkyl peptide, thioether peptide and ether peptide

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Claims (105)

x and y are 0 or 1, X is S, O or N—R ₉ (R ₉ is —H or —CH ₃ ), m is 0 or 1, R ₁₀ is H, CH ₃ , F, Cl, or Br, TR ₂ is COOH, CH ₂ COOH, CORH, CH ₂ COOSH, CH ₂ SH, CH ₂ CH ₂ SH or the physiologically obtained non-toxic salts of these, COOY, CH ₂ COOY, COZY, CH ₂ COSY, CH ₂ SY or CH ₂ CH ₂ SY (Y is a phenyl group, benzyl group or alkyl group of 1-5 carbons or A ₁ and A ₂ are H, phenyl group, benzyl group or 1-5 carbons) Can be an alkyl group R ₄ and R ₅ form a ring having the following structure as the nitrogen atom and carbon atom to which they are bonded, These structures include —OH, —OCH ₃ , F, , , , Cl, Br, i, phenyl group, hydroxyphenyl group, —SH, —SCH ₃ , , , -NHCH ₃ , -CH ₂ NH ₂ , -CH ₃ , -CH ₂ OH, trophyl group, guanidino group, nitroguanidino group or thioganidino group can be substituted with a single or hexagonal The ring may be disubstituted with —OH, F, Cl, Br, L, OCH ₃ or with two of these substituents. R ₆ is NH ₂ , —OM or —SM (-M is H, alkyl group of 1 to 3 carbon atoms, esters that can be hydrolyzed to —OH under conditions such as the body of a mammal in vitro, or physiological R ₇ is H ₁ -CH ₃ , halomethyl group, hydroxymethyl group, aminomethyl group or mercaptomethyl group, and R ₈ is -H, CH _3- , amino, halomethyl, hydroxymethyl, aminomethyl, methyldiomethyl, methoxycarbonylmethyl, cyanomethyl, benzyl, acetoxymethyl, CH ₂ = CH-CH ₂ , isobutyl, 2- Mercaptoalkyl group of 3 carbon atoms, hydroxyalkyl group of 2-3 carbon atoms, ethyl group, acetylthioethyl group, benzamido group, acetamido group, phthaloylaminoalkylene group of 1-4 carbon atoms , Alkyl group containing 1-6 carbon atoms Alkoxycarbonylisoalkylene groups containing 3 to 5 carbon atoms, benzoylamine groups, alkanoylamine groups having 1 to 6 carbon atoms, and alkylamide groups having 1 to 6 carbon atoms Groups or alkanoylamine groups of _{1 to} 6 carbon atoms, wherein R ₁ and R ₃ are as described below. R ₁ and R ₃ [1] R ₁ and R ₂ may be the same as or different from each other in the following cases. (1) an alkylene group of 2 to 4 carbon atoms substituted once with an N-substituent which is a benzoyl group, Boc, Cbo, Tos, formyl group or acetyl group, (2) a hydroxyphenyl- (1-6c) -alkylene hydroxyalkylene group or a thiol analog thereof, wherein the hydroxyphenyl group or alkylene group is 1-4 carbon atoms, (3) mercaptoalkylene groups of 1 to 6 carbon atoms, (4) Phenylalkylenes having 1 to 6 carbon atoms, alkyl or phenyl groups having linear or branched chains with 1 to 5 carbon atoms, (5) a phenylthioalkylene group, a phenoxyalkylene group, a benzyloxyalkylene group, or a benzylthioalkylene group, wherein the alkylene group has 1-6 carbon atoms; (6) alkylthioalkylene groups in which the alkyl group and the alkylene group have 1-6 carbon atoms, (7) alkoxyphenyl groups having 1 to 6 carbon atoms, alkoxybenzyl groups, phenoxyphenyl groups, phenoxybenzyl groups, benzyloxybenzyl groups or benzyloxyphenyl groups, or thioether analogs thereof; (8) — (CH ₂ ) _n —CH—CH ₃ or —SB analog thereof, wherein n is 0-4 and B is an alkyl group of H or 1-6 carbon atoms, (9) Anions of (CH ₂ ) _p COOZ or (CH ₂ ) _p COSZ or a physiologically acceptable salt wherein p is 0-3 and Z is H, a phenyl group, a benzyl group or an alkyl group of 1-6 carbon atoms 10 Where n and z are as defined above. (11) n is 0-4 and D is a phenyl group, thienyl group or an alkyl group of 1 to 3 carbon atoms or (12) n is the HO-, as defined earlier _{(CH 2) n -X (CH} 3) 2 -, HS- (CH 2) n -C (CH 3) -p- -hydroxyphenyl - (CH _{2) n-} C (CH ₃ ) ₂ -or p-mercaptophenyl- (CH ₂ ) _n -C (CH ₃ ) _2- (13) D- mercapto-phenyl such as phenyl, and the ring has 1 or 2 nitrogen substituent or amino substituents n are as defined above - (CH _{2) n} -CH ₂ - or p- hydroxyphenyl - (CH _{2) n-} CH _2- (14) CH ₃ (CH ₂ ), wherein n is as previously defined Or CH ₃ (CH ₂ ) _n (15) NO ₂ -alkylene groups or NH ₂ -alkylene groups containing 1-6 carbon atoms, containing a hydroxy group or a mercapto group; (16) hydroxy group or mercapto-phenoxybenzyl group (17) q is 1-5 and z and n are defined as (18) z, q and n are as defined above (19) Phenyl alkoxyl or phenylalka, wherein G is an alkoxyl or alkyloxy group, a benzoyl or benzoyloxy group, an alkyl or alkyloxy group having 1 to 6 carbon atoms containing 2 to 6 carbon atoms. Is real and q and n are (20) n is as defined above, k is a carboxyphenyl group, aminophenyl group, nitrophenyl group, halophenyl group, hydroxyphenyl group, alkylthiophenyl group, alkylphenyl group, mercaptophenyl group, cyanophenyl group, mercapto-carbonylphenyl group, Alkylcarbonylphenyl group, alkylcarbonyloxyphenyl group, hydrazinophenyl group, ureidophenyl group, alkylcarbonylaminophenyl group, alkylcarbonylthiophenyl group, alkyloxyphenyl group and hydroxyaminophenyl group (all alkyl groups have 1-6 carbon atoms I choose it.) (21) n is as defined above, L is a carboxyl group, amino group, nitro group, halo group, hydroxy group, mercapto group, mercaptocarbonyl group, hydroxyamino group, alkyl group, alkylcarbonyl group, alkylcarbonyloxy group, alkyl Thio group, alkylcarbonylamino group, alkylcarbonylthio group, cyano group, hydrazino group, ureido group and alkyloxy group (all alkyl groups contain 1-6 carbon atoms) From cycloalkyl groups of 3 to 7 carbon atoms (22) Guanidinoalkylene group, thioguanidinoalkylene group, or nitroguanidinoalkylene group in which the alkylene group contains 1-6 carbon atoms (23) —NH ₂ , —OZ, —SZ, halogen, —CN, —NO ₂ , —COOZ, COSZ, CONH ₂ , —NHNH ₂ , alkyl group, alkylcarbonyl group, alkylcarbonyloxy group, alkylcarbonylamino group, Haloalkyl group, dihaloalkyl group, trihalomethyl group, hydroxyamino group, alkylcarbonylthio group, phenoxy group and benzyloxy group (all alkyl groups contain 1-6 carbon atoms and Z is as defined above) An aryl group in which a ring is substituted by selecting up to five substituents per ring among ring substituents among the same or different ring substituents. (24) Amidoalkylene groups or alkylcarbonyl-aminoalkylene groups in which the alkyl group and the alkylene group contain 1-6 carbon atoms. (25) Hydroxyaminoalkylene groups of 1 to 6 carbon atoms (26) Vinyl groups substituted with vinyl groups and substituents such as alkyl groups, aryl groups, cycloalkyl groups or heterocyclic groups (27) Phenothiazinyl group, pyrrolidinyl group, pyrrolyl group, quinolinine group, imidazolyl group, pyridyl group, riminyl group, benzothiazinyl group, indolyl group thienyl group, furinyl group, piperidinyl group, morpholinyl group , Unsubstituted heterocyclic groups selected from azaindolyl group, pyrazinyl group, pyrimidyl group, piperonyl group, piperazinyl group, furanyl group, thiazolyl group and thiazolidinyl group, cytonyl group, etc. (28) Alkyl or alkenyl groups having 1 to 6 carbon atoms substituted by one of the heterocyclic groups of (27). (29) Heterocyclic —OZ, —SZ, —COOZ, —NO ₂ , —NH ₂ , —COSZ, halogen, haloalkyl group, dihaloalkyl group, trihalomethyl group, cyano group, —CONH ₂ , alkyl group, alkyl Carbonyloxy group, alkylcarbonylamino group, alkylcarbonylthio group, spent hydroxy group, benzoxyoxy group, The groups described in (27) or (38) substituted with up to four ring substituents, such as —NHNH ₂ and HONH — where Z is as defined above. (30) groups described in (27), (28) or (29) bound to one branch of an ethereal —O— or —S (31) A mono-, di- or tri-alkyl group, an alkenyl group or a phenylsilyl group or serenyl group, wherein the alkyl group or alkenyl group contains 1-6 carbon atoms. [2] When R ₁ belongs to the group (11) to (31) described above, R ₃ is H, a linear or branched alkyl group of 1-5 carbon atoms, a phenyl group, -OH, 1-5 Benzyloxyalkylene or phenoxyalkylene groups containing 1 to 5 carbon atoms, alkoxy, benzyloxy and alkylene groups of carbon atoms, 1-6 carbon atoms of 1 to 5 carbon atoms with alkoxy and alkylene groups Amino alkylene groups of atoms, alkenyl groups of 1-6 carbon atoms, benzyl groups, hydroxyalkyl groups of 1-6 carbon atoms, mercaptoalkyl groups of 1-6 carbon atoms, hisridinyl groups, 1-6 carbons Haloalkyl groups, 4-aminoethyl-benzyl groups, acetamidoalkyl groups of 5-5 carbon atoms, benzylthio methylene groups, or dimethylaminoalkyl groups of 1-5 carbon atoms. [3] When R ₃ is a group belonging to the aforementioned (1)-(31) branches, R ₁ is H, C ₁ -C ₈ linear or branched alkyl group, phenyl group, benzyl group, unsubstituted 2-6 Aminoalkylene groups having 1 to 6 carbon atoms, hydroxyalkylene groups having 1 to 6 carbon atoms, hydroxyphenyl groups or phenoxyalkylene groups or benzyloxyalkylene groups having 1 to 6 carbon atoms, or 3 to 6 carbon atoms Cycloalkyl group, cycloalkylmethyl group, 3-indolyl-phenylethyl group, methylthioethyl group, 3-indolylalkyl group, imidazolyl group, alkyl group having 1-5 carbon atoms, alkyl group containing 1-5 carbon atoms Imidazolylalkyl group, phenoxymethyl group, phenylthiomethyl group, 4-aminomethylbenzyl group, 2-aminophenethyl group, naphthylethyl group, 4-halophenethyl group, 3,4-dihalophenethyl group, or phenoxyphenethyl group And the like. [4] When R ₁ and R ₂ together with —CH form a lactone ring of the following structural formula or form a similar hexagonal ring, R ₃ is necessarily selected from (1) to (31) described above. [5] NR | wherein at least one of R ₇ and R ₈ is not hydrogen or X is R ₉ is a methyl group; _{When 9,} R ₁ is as defined in [2] or belongs to (1)-(10) groups and R ₃ is as defined in [3]. [6] When both R ₄ and R ₅ are disubstituted or monosubstituted with a group other than -OH or R ₄ and R ₅ are In addition, in the structure described above, R ₁ is as defined in [2] or belongs to groups (1) to (10) and R ₃ is as defined in [3]. The compound of claim 1, wherein X is —NR ₉ . The compound of claim 1, wherein X is NH. The compound according to claim 2, wherein R ₁ and R ₃ , which are the same as each other, are selected from the groups of (1) to (31). The compound according to claim 2, wherein R ₁ and R ₃ , which are the same as each other, are selected from the groups of (1) to (31). The compound according to claim 2, wherein R ₁ belongs to the group described in (1). The compound according to claim 2, wherein R ₁ belongs to the group described in (2). The compound according to claim 2, wherein R ₁ belongs to the group described in (3). The compound according to claim 2, wherein R ₁ belongs to the group described in (4). The compound according to claim 2, wherein R ₁ belongs to the group described in (5). The compound according to claim 2, wherein R ₁ belongs to the group described in (6). The compound according to claim 2, wherein R ₁ belongs to the group described in (7). The compound according to claim 2, wherein R ₁ belongs to the group described in (8). The compound according to claim 2, wherein R ₁ belongs to the group described in (9). The compound of claim 2, wherein R ₁ belongs to the group described in (10). The compound according to claim 2, wherein R ₁ belongs to the group described in (11). The compound of claim 2, wherein R ₁ belongs to the group described in (12). The compound according to claim 2, wherein R ₁ belongs to the group described in (13). The compound of claim 2, wherein R ₁ belongs to the group described in (14). The compound according to claim 2, wherein R ₁ belongs to the group described in (15). The compound of claim 2, wherein R ₁ belongs to the group described in (16). The compound of claim 2, wherein R ₁ belongs to the group described in (17). The compound of claim 2, wherein R ₁ belongs to the group described in (18). The compound of claim 2, wherein R ₁ belongs to the group described in (19). The compound of claim 2, wherein R ₁ belongs to the group described in (20). The compound of claim 2, wherein R ₁ belongs to the group described in (21). The compound of claim 2, wherein R ₁ belongs to the group described in (22). The compound of claim 2, wherein R ₁ belongs to the group described in (23). The compound of claim 2, wherein R ₁ belongs to the group described in (24). The compound of claim 2, wherein R ₁ belongs to the group described in (25). The compound of claim 2, wherein R ₁ belongs to the group described in (26). The compound of claim 2, wherein R ₁ belongs to the group described in (27). The compound of claim 2, wherein R ₁ belongs to the group described in (28). The compound of claim 2, wherein R ₁ belongs to the group described in (29). The compound of claim 2, wherein R ₁ belongs to the group described in (30). The compound of claim 2, wherein R ₁ belongs to the group described in (31). The compound according to claim 2, wherein R ₃ belongs to the group described in (1). The compound according to claim 2, wherein R ₃ belongs to the group described in (2). The compound according to claim 2, wherein R ₃ belongs to the group described in (3). The compound according to claim 2, wherein R ₃ belongs to the group described in (4). The compound according to claim 2, wherein R ₃ belongs to the group described in (5). The compound according to claim 2, wherein R ₃ belongs to the group described in (6). The compound according to claim 2, wherein R ₃ belongs to the group described in (7). The compound according to claim 2, wherein R ₃ belongs to the group described in (8). The compound of claim 2, wherein R ₃ belongs to the group described in (9). The compound of claim 2, wherein R ₃ belongs to the group described in (10). The compound of claim 2, wherein R ₃ belongs to the group described in (11). The compound of claim 2, wherein R ₃ belongs to the group described in (12). The compound of claim 2, wherein R ₃ belongs to the group described in (13). The compound of claim 2, wherein R ₃ belongs to the group described in (14). The compound of claim 2, wherein R ₃ belongs to the group described in (15). The compound of claim 2, wherein R ₃ belongs to the group described in (16). The compound of claim 2, wherein R ₃ belongs to the group described in (17). The compound of claim 2, wherein R ₃ belongs to the group described in (18). The compound of claim 2, wherein R ₃ belongs to the group described in (19). The compound of claim 2, wherein R ₃ belongs to the group described in (20). The compound of claim 2, wherein R ₃ belongs to the group described in (21). The compound of claim 2, wherein R ₃ belongs to the group described in (22). The compound of claim 2, wherein R ₃ belongs to the group described in (23). The compound of claim 2, wherein R ₃ belongs to the group described in (24). The compound of claim 2, wherein R ₃ belongs to the group described in (25). The compound of claim 2, wherein R ₃ belongs to the group described in (26). The compound of claim 2, wherein R ₃ belongs to the group described in (27). The compound of claim 2, wherein R ₃ belongs to the group described in (28). The compound of claim 2, wherein R ₃ belongs to the group described in (29). The compound of claim 2, wherein R ₃ belongs to the group described in (30). The compound of claim 2, wherein R ₃ belongs to the group described in (31). The compound of claim 2, wherein R ₁ is selected from the groups (11)-(31) and R ₃ is the same as defined in [2] of claim ₁ . The compound according to claim 1, wherein R ₃ is selected from the groups (1) to (31) and R ₁ is the same as defined in [3] of claim ₁ . A compound according to claim 1, wherein R ₃ is selected from the groups (1) to (31) and R ₁ is R ₂ to form -CH and a lactone ring as defined in [4] of claim 1. The compound of claim 1, wherein R ₇ is not hydrogen. The compound of claim 1, wherein R ₈ is not hydrogen and y is 1. The compound of claim 2, wherein R ₉ is a methyl group. The compound of claim 2, wherein R ₇ is not hydrogen. The compound of claim 2, wherein R ₈ is not hydrogen. R ₄ and R ₅ and Compounds that form proline. The compound of claim 2, wherein R ₆ is a group other than hydrogen. The compound of claim 2, wherein R ₄ and R ₅ form this substituted structure as described in detail in claim 1, wherein R ₁ is selected from the groups (1)-(10) or As defined herein. 3. A compound according to claim 2, wherein R ₄ and R ₅ form a monosubstituted structure with groups other than OH as described in claim 1 and R ₁ is selected from groups (1)-(10) or A compound as defined in [2] and R ₃ is as defined in [1] of claim 1. The compound of claim 2 wherein R ₄ and R ₅ are To form a structure other than R ₁ is selected from groups (1) to (10) or as defined in paragraph [2] of claim ₁ , and R ₃ is defined in paragraph [3] of claim 1; The compound of claim 1, wherein X is —S—. The compound of claim 1, wherein X is —O—. The compound of claim 1, wherein R ₆ is —OH or a physiologically acceptable nontoxic salt thereof. The compound of claim 1, wherein R ₆ is —SH or a physiologically acceptable nontoxic salt thereof. The compound of claim 1, wherein R ₁ is CH ₃ —, R ₂ is —COOH, R ₃ is a methyl group, X is S, R ₄ and R ₅ are , R ₆ is —OH, m is 1. The compound of claim 1, wherein R ₁ is a 2-hydroxypropyl group, R ₂ is —COOH, R ₃ is CH ₃ , X is S, R ₄ and R ₅ are , R ₆ is OH and m is 0. The compound of claim ₁ wherein R ₁ and R ₂ are Form a structure, R ₃ is CH ₃ , X is S, R ₄ and R ₅ are , Structure, R ₆ is OH, m is 0. The compound of claim 1, wherein R ₁ is CH ₃ —, R ₂ is —COOC ₂ H ₅ , X is —NH—, R ₃ is CH ₃ —, R ₄ and R ₅ are And R ₆ is —OH and m is 0. R ₁ is CH ₃ —, R ₂ is —COOH, R ₃ is CH ₃ , X is S, R ₄ and R ₅ are And R ₆ is —OH and m is 0. The compound of claim 1, wherein R ₁ is a benzyl group, R ₂ is COOH, R ₃ is H, X is 0 and R ₄ and R ₅ are And R ₆ is OH and m is zero. A composition of matter comprising a therapeutically effective amount of the compound of claim 1 as an active ingredient and effective in inhibiting angiotensin converting elements in the cytoplasm. A composition of matter containing a therapeutically effective amount of the compound of claim 2 as an active ingredient and effective to inhibit angiotensin converting elements in the cytoplasm. A composition of matter comprising a therapeutically effective amount of the compound of claim 3 as an active ingredient and effective in inhibiting angiotensin converting elements in the cytoplasm. A composition of matter comprising a therapeutically effective amount of the compound of claim 4 as an active ingredient and effective in inhibiting angiotensin converting elements in the cytoplasm. A composition of matter comprising a therapeutically effective amount of the compound of claim 5 as an active ingredient and effective in inhibiting angiotensin converting elements in the cytoplasm. A method for inhibiting angiotensin converting enzyme in the cytoplasm by administering a compound of claim 1 to a mammal showing an abnormal serum concentration of angiotensin II. A method for inhibiting angiotensin converting enzyme in the cytoplasm by administering a compound of claim 2 to a mammal showing an abnormal serum concentration of angiotensin II. A method for inhibiting angiotensin converting enzyme in the cytoplasm by administering a compound of claim 3 to a mammal exhibiting an abnormal serum concentration of angiotensin II. A method for inhibiting angiotensin converting enzyme in the cytoplasm by administering a compound of claim 4 to a mammal showing an abnormal serum concentration of angiotensin II. A method for inhibiting angiotensin converting enzyme in the cytoplasm by administering a compound of claim 5 to a mammal showing an abnormal serum concentration of angiotensin II. A method of reducing blood pressure in a mammal by administering a compound of claim 1 to a mammal in hypertension with a therapeutically effective amount. A method of reducing mammalian blood pressure by administering a compound of claim 2 to a mammal in hypertension with a therapeutically effective amount. A method of reducing blood pressure in a mammal by administering a compound of claim 3 to a mammal in high blood pressure. A method of reducing mammalian blood pressure by administering a compound of claim 4 to a mammal in hypertension with a therapeutically effective amount. A method of reducing mammalian blood pressure by administering a compound of claim 5 to a mammal in hypertension with a therapeutically effective amount. ※ Note: The disclosure is based on the initial application.