CS237325B2 - Processing of carboxyalkyldipeptide - Google Patents
Processing of carboxyalkyldipeptide Download PDFInfo
- Publication number
- CS237325B2 CS237325B2 CS821339A CS133982A CS237325B2 CS 237325 B2 CS237325 B2 CS 237325B2 CS 821339 A CS821339 A CS 821339A CS 133982 A CS133982 A CS 133982A CS 237325 B2 CS237325 B2 CS 237325B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- carbon atoms
- alkyl
- radical
- substituted
- hydroxy
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 150000001413 amino acids Chemical class 0.000 claims abstract description 12
- 150000002576 ketones Chemical class 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 118
- -1 acyl radical Chemical class 0.000 claims description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 150000005840 aryl radicals Chemical class 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 7
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 6
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 238000001640 fractional crystallisation Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 4
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000001769 aryl amino group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
- 125000002015 acyclic group Chemical group 0.000 claims description 2
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims 1
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims 1
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- 239000003112 inhibitor Substances 0.000 abstract 1
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- WPWUFUBLGADILS-WDSKDSINSA-N Ala-Pro Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O WPWUFUBLGADILS-WDSKDSINSA-N 0.000 description 8
- 108010087924 alanylproline Proteins 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 7
- 239000005541 ACE inhibitor Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
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- 150000002431 hydrogen Chemical class 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
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- WSSSPWUEQFSQQG-UHFFFAOYSA-N 4-methyl-1-pentene Chemical compound CC(C)CC=C WSSSPWUEQFSQQG-UHFFFAOYSA-N 0.000 description 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 2
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Způsob přípravy karboxyalkyldipeptidů obecného vzorce 1 O Rl R3 Ri Rs 0 - II II I I II R—C—C—ΝΉ—CH—C—·N—C—C—Re (I) .1. II I. ....-v. Rž O R7 a jejích farmaceuticky vhodných solí a biologicky účinného isomeru, spočívající v reakci ketonu obecného vzorce II s aminokyselinou nebo chráněnou aminokyselinou obecného vzorce III. Látky vzorce I jsou použitelné jako inhibitory konvertujícího enzymu a jako antihypertensivaProcess for preparing carboxyalkyldipeptides of formula (1) R 1 R 3 R 1 R 5 is O - II II I II R — C — C — CH — C — N — C — C — Re (I) .1. II I. ....- v. Rz O R7 and pharmaceutically acceptable salts thereof and biologically of the active isomer in the reaction ketone of formula II with an amino acid or a protected amino acid of Formula III. The compounds of formula I are useful as inhibitors converting enzyme and as an antihypertensive agent
Description
Vynález se týká způsobu přípravy karboxyalkyldipeptidů obecného vzorce IThe invention relates to a process for the preparation of carboxyalkyldipeptides of the formula I
O Ri R3 Rd Rd OO Ri R3 Rd Rd
R—C—-C—NH—CH—C—N—C—C—Re (I)R — C — C — NH — CH — C — N — C — C — Re (I)
R2 O R7 kdeR2 O R7 where
R a Re jsou stejná nebo rozdílné a znamenají hydroxyskupinu, alkoxyskupinu s 1 až 6 atomy uhlíku, alkenoxyskupinu s 1 až 6 atomy uhlíku, dialkylaminoalkoxyskupinu s 1 až 6 atomy uhlíku v alkylovém zbytku, acylaminoalkoxyskupinu s 1 až 6 atomy uhlíku v alkylovém zbytku a 2 až 12 atomy uhlíku v acylovém zbytku, acyloxyalkoxyskupinu s 1 až 6 atomy uhlíku v alkylovém zbytku a 2 až 12 atomy uhlíku v acylovém zbytku, aryloxyskupinu s alespoň 6 atomy uhlíku, aralkyloxyskupinu s 1 až 4 atomy uhlíku s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku, substituovanou aryloxyskupinu s alespoň 6 atomy uhlíku nebo substituovanou aralkoxyskupinu s 1 až 3 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku, kde substituentem je methyl, halogen nebo methoxyskupina, aminoskupinu, alkylaminoskupinu s 1 až 6 atomy uhlíku, dialkylaminoskupinu s 1 až 6 atomy uhlíku, aralkylaminoskupinu s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku nebo hydroxyaminoskupinu,R and R e are the same or different and are hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkenoxy, C 1 -C 6 dialkylaminoalkoxy, C 1 -C 6 acylaminoalkoxy, and 2 up to 12 carbon atoms in the acyl radical, acyloxyalkoxy of 1 to 6 carbon atoms in the alkyl radical and 2 to 12 carbon atoms in the acyl radical, aryloxy of at least 6 carbon atoms, aralkyloxy of 1 to 4 carbon atoms in the C1 to 4 carbon atoms and at least 6 carbon atoms in the aryl radical, substituted aryloxy of at least 6 carbon atoms or substituted aralkoxy of 1 to 3 carbon atoms in the alkyl radical and at least 6 carbon atoms in the aryl radical wherein the substituent is methyl, halogen or methoxy, amino, alkylamino (C 1 -C 6), (C 1 -C 6) dialkylamino, (C 1 -C 4) aralkylamino u in the alkyl radical and at least 6 carbon atoms in the aryl radical or the hydroxyamino group,
Ri je vodík, alkyl s 1 až 20 atomy uhlíku, který zahrnuje rozvětvené acyklické skupiny, allyl, substituovaný alkyl s 1 až 4 atomy uhlíku, kde substituentem je halogen, hydroxyskupina, alkoxyskupina s 1 až 3 atomy uhlíku, aryloxyskupina s alespoň 6 atomy uhlíku, aminoskupina, alkylaminoskupina, dialkylaminoskupina s 1 až 3 atomy uhlíku v alkylovém zbytku, acylaminoskupina se 2 až 12 atomy uhlíku, arylaminoskupina s alespoň 6 atomy uhlíku, a guanidinoskupina, imidazolyl, indolyl, merkaptoskupina, alkylthioskupina s 1 až 3 atomy uhlíku, arylthioskupina s alespoň 6 atomy uhlíku, karboxyskupina, karboxamidoskupina, karboalkoxyskupina s 1 až 3 atomy uhlíku, fenyl, substituovaný fenyl, kde substituentem je alkyl s 1 až 3 atomy uhlíku, alkoxyskupina s 1 až 3 atomy uhlíku, nebo halogen, aralkyl s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku nebo indolylalkyl s 1 až 3 atomy uhlíku v alkylovém zbytku, aralkenyl s 1 až 4 atomy uhlíku v alkenylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku, substituovaný aralkyl s 1 až 3 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku, substituovaný indolylethyl, substituovaný aralkenyl s 1 až 3 atomy uhlíku v alkenylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku, kde substituentem je halogen nebo dihalogen, alkyl s 1 až 3 atomy uhlíku, hydroxyskupina, alkoxyskupina s 1 až 3 atomy uhlíku, aminoskupina, aminomethyl, acylaminoskupina se 2 až 12 atomy uhlíku, dialkylaminoskupina s 1 až 3 atomy uhlíku v alkylovém zbytku, alkylaminoskupina s 1 až 3 atomy uhlíku, karboxyl, halogenalkyl s 1 až 3 atomy uhlíku, kyanoskupina nebo sulfonamidoskupina, aralkyl s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku nebo indolylethyl, substituovaný na alkylové části aminoskupinou nebo acylaminoskupinou se 2 až 12 atomy uhlíku,R 1 is hydrogen, alkyl of 1 to 20 carbon atoms which includes branched acyclic groups, allyl, substituted alkyl of 1 to 4 carbon atoms wherein the substituent is halogen, hydroxy, alkoxy of 1 to 3 carbon atoms, aryloxy of at least 6 carbon atoms , amino, alkylamino, dialkylamino of 1 to 3 carbon atoms in the alkyl radical, acylamino of 2 to 12 carbon atoms, arylamino of at least 6 carbon atoms, and guanidino, imidazolyl, indolyl, mercapto, alkylthio of 1 to 3 carbon atoms, arylthio at least 6 carbon atoms, carboxy, carboxamido, carboalkoxy of 1 to 3 carbon atoms, phenyl, substituted phenyl wherein the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, or halogen, aralkyl of 1 to 4 atoms carbon in the alkyl radical and at least 6 carbon atoms in the aryl radical or indolylalkyl of 1 to 3 carbon atoms in the alkyl radical, aralkenyl of 1 to 3 4 carbon atoms in the alkenyl radical and at least 6 carbon atoms in the aryl radical, substituted aralkyl of 1 to 3 carbon atoms in the alkyl radical and at least 6 carbon atoms in the aryl radical, substituted indolylethyl, substituted aralkenyl of 1 to 3 carbon atoms in the alkenyl radical, and at least 6 carbon atoms in the aryl radical wherein the substituent is halogen or dihalogen, alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, amino, aminomethyl, acylamino of 2 to 12 carbon atoms, dialkylamino of 1 to 3 carbon atoms in the alkyl radical, C1 -C3 alkylamino, carboxyl, C1 -C3 haloalkyl, cyano or sulphonamido, C1 -C4 aralkyl and at least 6 aryl radicals or indolylethyl, substituted on the alkyl moiety with an amino or acylamino group having 2 to 12 carbon atoms,
Rz znamená vodík nebo alkyl s 1 až 6 atomy uhlíku,R2 is hydrogen or alkyl of 1 to 6 carbon atoms,
R2 je vodík,R2 is hydrogen,
R3 je vodík, alkyl s 1 až 6 atomy uhlíku, fenylalkyl s 1 až Θ atomy uhlíku, aminomethyl-fenylalkyl s 1 až 6 atomy uhlíku, hydroxyfenylalkyl s 1 až 6 atomy uhlíku, hydroxyalkyl s 1 až 6 atomy uhlíku, acetylaminoalkyl s 1 až 6 atomy uhlíku, acylaminoalkyl s 1 až 6 atomy uhlíku v alkylovém zbytku s 2 až 12 atomy uhlíku v acylovém zbytku, aminoalkyl s 1 až 6 atomy uhlíku, dimethylaminoalkyl s 1 až 6 atomy uhlíku, halogenalkyl s 1 až 6 atomy uhlíku, guanidinoalkyl s 1 až 6 atomy uhlíku, imidazolylalkyl s 1 až 6 atomy uhlíku, indolylalkyl s 1 až 6 atomy uhlíku, merkaptoalkyl s 1 až 6 atomy uhlíku a alkylthioalkyl s 1 až 6 atomy uhlíku v alkylovém zbytku,R 3 is hydrogen, alkyl of 1 to 6 carbon atoms, phenylalkyl of 1 to 6 carbon atoms, aminomethyl-phenylalkyl of 1 to 6 carbon atoms, hydroxyphenylalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, acetylaminoalkyl of 1 to 6 carbon atoms 6 carbon atoms, acylaminoalkyl of 1 to 6 carbon atoms in the alkyl radical of 2 to 12 carbon atoms in the acyl radical, aminoalkyl of 1 to 6 carbon atoms, dimethylaminoalkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, guanidinoalkyl of (C 1 -C 6), (C 1 -C 6) imidazolylalkyl, (C 1 -C 6) indolylalkyl, (C 1 -C 6) mercaptoalkyl and (C 1 -C 6) alkylthioalkyl,
Rt je vodík nebo alkyl s 1 až 6 atomy uhlíku,R 1 is hydrogen or alkyl of 1 to 6 carbon atoms,
Rg je vodík, alkyl s 1 až 6 atomy uhlíku, fenyl, fenylalkyl s 1 až 6 atomy uhlíku, hydroxyfenylalkyl s 1 až 6 atomy uhlíku, hydroxyalkyl s 1 až 6 atomy uhlíku, aminoalkyl s 1 až 6 atomy uhlíku, guanidinoalkyl s 1 až 6 atomy uhlíku, imidazolylalkyl s 1 až 6 atomy uhlíku, indolylalkyl s 1 až 6 atomy uhlíku, merkaptoalkyl s 1 až 6 atomy uhlíku nebo alkylthioalkyl s 1 až 6 atomy uhlíku v alkylovém zbytku,R 8 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 1 to 6 carbon atoms, hydroxyphenylalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, aminoalkyl of 1 to 6 carbon atoms, guanidinoalkyl of 1 to 6 carbon atoms (C atom-C,), (C až-C im im) imidazolylalkyl, (Coly-C ind) indolylalkyl, (C až-C mer) mercaptoalkyl or (C až-C 6) alkylthioalkyl,
Rra Rs jsou popřípadě spojeny dohromady k vytvoření alkylenového můstku se 2 až 4 atomy uhlíku, alkylenového můstku se 2 až 3 atomy uhlíku a jedním atomem síry, alkylenového můstku se 3 až 4 atomy uhlíku obsahujícího dvojnou vazbu nebo alkylenového můstku se 2 až 4 atomy uhlíku substituovaného hydroxy-, alkolxyskupinou s 1 až 6 atomy uhlíku nebo alkylem s 1 až 6 atomy uhlíku, a jejich farmaceuticky vhodných solí a biologicky účinného isomeru.R 8 and R 8 are optionally joined together to form a C 2 -C 4 alkylene bridge, a C 2 -C 3 alkylene bridge, a C 1 -C 4 alkylene bridge or a C 2 -C 4 alkylene bridge. substituted with hydroxy, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, and pharmaceutically acceptable salts and biologically active isomers thereof.
Alkylové skupiny s 1 až 6 atomy uhlíku nebo alkenylové skupiny s 1 až 6 atomy uhlíku zahrnují například methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terc.butyl, pentyl, isopentyl, hexyl nebo vinyl, allyl, butenyl apod. Aralkylové skupiny s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku zahrnují například benzyl, p-methoxybenzyl apod. Halo237325 gen znamená chlor, brom, jod nebo fluor. Aryl představuje fenyl nebo naftyl. Heteroarylové skupiny zahrnují například pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazolyl a thiazolyl.C 1 -C 6 alkyl or C 1 -C 6 alkenyl include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like. having 1 to 4 carbon atoms in the alkyl radical and at least 6 carbon atoms in the aryl radical include, for example, benzyl, p-methoxybenzyl, and the like. The halo237325 gene is chlorine, bromine, iodine or fluorine. Aryl represents phenyl or naphthyl. Heteroaryl groups include, for example, pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazolyl and thiazolyl.
Substituované alkylové zbytky substituentu Ri, R3 a Rs se znázorní skupinami jakoSubstituted alkyl radicals of R 1, R 3, and R 5 are represented as
HO-CH2-, HS-CH2-, H2N-[CH2)4-, CH3-S-ÍCH2]2-, H2N- (CH2 )3-,HO-CH 2 -, HS-CH 2 -, H 2 N- [CH 2] 4 -, CH 3 -S-CH 2] 2 -, H 2 N- (CH 2) 3 -,
NHNH
IIII
H2N—C—NH“(CH2)3— a podobně.H 2 N — C — NH — (CH 2) 3 - and the like.
R4 a Rs, když jsou spojeny atomem uhlíku a dusíku, ke kterému jsou připojeny, tvoří 4ař 6členný kruh, který může obsahovat jeden atom síry nebo dvojnou vazbu.R 4 and R 5, when connected by a carbon and nitrogen atom to which they are attached, form a 4-membered ring which may contain a single sulfur atom or a double bond.
Výhodné kruhy mají obecný vzorecPreferred rings have the general formula
COOH kdeCOOH where
Y je CH2, S nebo CHOCH3, nebo vzorecY is CH 2, S or CHOCH 3, or the formula
COOHCOOH
Výhodné jsou sloučeniny obecného vzorce I, kdePreferred are compounds of formula I wherein
R je hydroxyskupina, alkoxyskupina s 1 až 6 atomy uhlíku, alkenoxyskupina s í až 6 atomy uhlíku, aralkyloxyskupina s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 atomy uhlíku v arylovém zbytku, dialkylaminoskupína s 1 až 6 atomy uhlíku v alkylovém zbytku, alkoxyskupina s 1 až 6 atomy uhlíku, acy lamin oalkoxyskupina s 1 až 6 atomy uhlíku v alkylovém zbytku a 2 až 12 atomy uhlíku v acylovém zbytku, acy loxy skupina se 2 až 12 atomy uhlíku, alkoxyskupina s 1 až 6 atomy uhlíku, kde substituentem je methyl, halogen nebo methoxyskupina,R is hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkenoxy, C 1 -C 4 aralkyloxy and at least 6 carbon atoms in the aryl radical, C 1 -C 6 dialkylamino, (C 1 -C 6) alkoxy, (C 1 -C 6) acylamine o (C 1 -C 6) alkoxy group, (C 2 -C 12) acyl group, (C 2 -C 12) acyloxy, (C 1 -C 6) alkoxy group with substituent is methyl, halogen or methoxy,
R6 je hydroxy- nebo amínoskupina,R 6 is hydroxy or amino,
R2 a R7 je vodík,R2 and R7 are hydrogen,
R3 je alkyl s 1 až 6 atomy uhlíku nebo aminoalkyl s 1 až 6 atomy uhlíku,R 3 is alkyl of 1 to 6 carbon atoms or aminoalkyl of 1 to 6 carbon atoms,
R4 a Rs jsou spojeny a tvoří výhodné kruhy, jak uvedeno výše, kde Y je CH2, S neboR 4 and R 5 are joined to form preferred rings as above wherein Y is CH 2, S or
CH-OCHs,CH-OCHs,
Ri má výše uvedený význam.R1 is as defined above.
Výhodnější sloučeniny jsou takové výhodné sloučeniny obecného vzorce I, kdeMore preferred compounds are those preferred compounds of formula I wherein
Ri je alkyl s 1 až 8 atomy uhlíku, substituovaný alkyl s 1 až 4 atomy uhlíku, kde substituentem je amínoskupina s alespoň 6 atomy uhlíku, aryloxyskupina s alespoň 6 atomy uhlíku nebo arylaminoskupina s alespoň 6 atomy uhlíku, aralkyl s 1 až 4 atomy uhlíku v alkylovém zbytku a alespoň 6 torny uhlíku v arylovém zbytku nebo indolylalkyl s 1 až 3 atomy uhlíku v alkylovém zbytku nebo substituovaný aralkyl (fenylalkyl nebo nafty 1alkyl) s 1 až 4 atomy uhlíku v alkylovém zbytku a substituovaný indolylalkyl s 1 až 3 atomy uhlíku v alkylovém zbytku, kde substituentem (yj je halogen, dihalogen, aminoskupina, aminoalkyl s 1 až 6 atomy uhlíku, hydroxyskupina, alkoxyskupina s 1 až 6 atomy uhlíku nebo alkyl s 1 až 6 atomy uhlíku.R 1 is C 1 -C 8 alkyl, substituted C 1 -C 4 alkyl wherein the substituent is an amino group of at least 6 carbon atoms, aryloxy of at least 6 carbon atoms, or arylamino of at least 6 carbon atoms, aralkyl of 1 to 4 carbon atoms in the alkyl radical and at least 6 carbon atoms in the aryl radical or indolyl alkyl of 1 to 3 carbon atoms in the alkyl radical or substituted aralkyl (phenylalkyl or naphthyl alkyl) of 1 to 4 carbon atoms in the alkyl radical and substituted indolylalkyl of 1 to 3 carbon atoms in an alkyl radical wherein the substituent (yj is halogen, dihalogen, amino, C 1 -C 6 aminoalkyl, hydroxy, C 1 -C 6 alkoxy or C 1 -C 6 alkyl.
Nejvýhodnější jsou sloučeniny obecného vzorce I, kdeMost preferred are compounds of formula I wherein
R je hydroxyskupina nebo alkoxyskupina s 1 až 6 atomy uhlíku,R is a hydroxy or alkoxy group having 1 to 6 carbon atoms,
Rs je hydroxyskupina,R 5 is hydroxy,
R2 a R7 je vodík,R2 and R7 are hydrogen,
R3 je methyl nebo aminoalkyl s 1 až 6 atomy uhlíku,R3 is methyl or aminoalkyl of 1 to 6 carbon atoms,
R4 a Rs jsou spojeny atomem uhlíku a atomem dusíku a tvoří prolin, 4-thiaprolin nebo 4-methoxyprolin,R 4 and R 5 are joined by a carbon atom and a nitrogen atom to form proline, 4-thiaproline or 4-methoxyproline,
Ri je alkyl s 1 až 18 atomy uhlíku, substituovaný alkyl s 1 až 4 atomy uhlíku, kde substituentem je amínoskupina, arylthíoskupina s alespoň 6 atomy uhlíku nebo aryloxyskupina s alespoň 6 atomy uhlíku nebo indolylalkyl s 1 až 3 atomy uhlíku v alkylovém zbytku, jako indolylethyl, nebo substituovaný aralkyl (fenylalkyl nebo naftylalkyl) s 1 až 4 atomy uhlíku v alkylovém zbytku a substituovaný indolylethyl, kde substituentem (yj je halogen, dihalogen, amínoskupina, aminoalkyl s 1 až 6 atomy uhlíku, hydroxyskupina, alkoxyskupina s 1 až 6 atomy uhlíku nebo alkyl s 1 až 6 ato-my uhlíku.R 1 is alkyl of 1 to 18 carbon atoms, substituted alkyl of 1 to 4 carbon atoms, wherein the substituent is amino, arylthio of at least 6 carbon atoms or aryloxy of at least 6 carbon atoms or indolylalkyl of 1 to 3 carbon atoms in the alkyl radical such as indolylethyl, or substituted (C1-C4) -alkyl (phenylalkyl or naphthylalkyl) and substituted indolylethyl, wherein the substituent (yj is halogen, dihalogen, amino, (C1-C6) aminoalkyl, hydroxy, (C1-C6) alkoxy) or alkyl having 1 to 6 carbon atoms.
Výhodné, výhodnější a nejvýhodnější sloučeniny také zahrnují farmaceuticky vhodné soli.Preferred, more preferred and most preferred compounds also include pharmaceutically acceptable salts.
Sloučeniny podle vynálezu jsou použitelné jako inhibitory konvertujícího enzymu a jako anf hypertenstva.The compounds of the invention are useful as converting enzyme inhibitors and as hypertension.
Způsob přípravy sloučenin vzorce I se provádí tak, že se nechá reagovat keton obecného vzorce IIThe process for preparing the compounds of formula I is carried out by reacting a ketone of formula II
O RlO Rl
R—C—C = O (II) kdeR = C = C = O (II) wherein
R má výše uvedený význam kromě hydroxyskupiny aR is as defined above except for hydroxy and
Rl má výše uvedený význam, přičemž může obsahovat vhodnou ochranu jakékoliv reaktivní skupiny, s aminokyselinou nebo chráněnou aminokyselinou obecného vzorce IIIR1 is as defined above and may contain suitable protection of any reactive group with an amino acid or a protected amino acid of formula III
HžNCH—COOH (III) kdeHNCH-COOH (III) wherein
Rs má výše uvedený význom, přičemž může zahrnovat vhodnou ochranu jakékoliv reaktivní skupiny, v přítomnosti redukčního činidla za vzniku meziproduktu obecného vzorce IVR 5 is as defined above, and may include appropriate protection of any reactive group in the presence of a reducing agent to form an intermediate of formula (IV)
O Ri R3About R1 R3
R—C—CH—NHCHCOOH (IV) kdsR-C-CH-NHCHCOOH (IV) kds
R, Ri a R3 mají výše uvedený význam, a potom se tento meziprodukt kopuluje s aminokyselinou nebo chráněným derivátem aminokyseliny obecného vzorce VR, R1 and R3 are as defined above, and then the intermediate is coupled with an amino acid or a protected amino acid derivative of formula V
Rl RsRl Rs
I 1I 1
HN—C—CO—Rs (V)HN — C — CO — Rs (V)
R7 kdeR7 where
Rs má výše uvedený význam kromě hydroxyskupiny aR 5 is as defined above except for hydroxy and
Rs má výše uvedený význam, přičemž může zahrnovat vhodnou ochranu jakékoliv reaktivní skupiny aR 5 is as defined above, and may include appropriate protection of any reactive group a
R7 a Ri mají výše uvedený význam a získá se sloučenina obecného vzorce I, kde R a Rs mají výše uvedený význam kromě hydroxyskupiny a Ri, Rz, R3, Rá, Rs a R7 mají výše uvedený význam, potom se ochranné skupiny odstraní a popřípadě se přemění R a/nebo Rs hydrolýzou nebo hydrogenací vhodného meziproduktu na hydroxyskupinu a popřípadě se připraví její sůl a popřípadě se izoluje biologicky účinnější isomer chromatografií nebo frakční krystalizaci.R 7 and R 1 are as defined above to give a compound of formula I wherein R and R 5 are as defined above except hydroxy and R 1, R 2, R 3, R 6, R 5 and R 7 are as defined above, then protecting groups are removed and optionally converting R and / or R 5 by hydrolysis or hydrogenation of a suitable intermediate to a hydroxy group and optionally preparing a salt thereof and optionally isolating the more biologically active isomer by chromatography or fractional crystallization.
Ketokyselina (nebo ester, amid nebo hydroxamová kyselina] vzorce II se kondenzuje s aminokyselinou vzorce III ve vodném roztoku, s výhodou téměř neutrálním, nebo ve vhodném organickém rozpouštědle (například CH3CN) za přítomnosti kyanoborohydridu sodného a získá se sloučenina vzorce I (Rz=H).The keto acid (or ester, amide or hydroxamic acid) of formula II is condensed with the amino acid of formula III in an aqueous solution, preferably near neutral, or in a suitable organic solvent (e.g. CH 3 CN) in the presence of sodium cyanoborohydride. ).
Během kopulační reakce se reaktivní skupiny chrání například N-formylem, N-terc.butoxykarbonylem a N-karbobenzoylskupinou a potom se odstraní za vzniku sloučeniny vzorce I.During the coupling reaction, the reactive groups are protected with, for example, N-formyl, N-tert-butoxycarbonyl and N-carbobenzoyl, and then removed to give the compound of formula I.
Kondenzační činidla v tomto postupu jsou taková, jako se používají v chemii peptidů, jako dicyklohexylkarbodiimid nebo difenylfosforylazid nebo se může sloučenina vzorce IV aktivovat přes přechodně vytvořené aktivní estery, takové, jaké se odvozují od 1-hydroxybenzotriazolu.The condensing agents in this process are those used in peptide chemistry, such as dicyclohexylcarbodiimide or diphenylphosphoryl azide, or the compound of formula IV can be activated via transiently formed active esters such as those derived from 1-hydroxybenzotriazole.
Jestliže R a R6 je karboxylová ochranná skupina, jako alkoxy- nebo benzyloxyskupina nebo podobně, může se přeměnit známými způsoby, jako hydrolýzou nebo hydrogenací na sloučeninu vzorce I, kde R a/nebo R6 je hydroxyskupina.When R 6 and R 6 is a carboxyl protecting group, such as an alkoxy or benzyloxy group or the like, it can be converted by known methods, such as hydrolysis or hydrogenation, to a compound of formula I wherein R and / or R 6 is hydroxy.
Výchozí látky, které se požadují pro výše uvedený postup, jsou známé v literatuře nebo se mohou připravit známými způsoby ze známých výchozích materiálů.The starting materials required for the above process are known in the literature or can be prepared from known starting materials by known methods.
V produktech obecného vzorce I mohou být atomy uhlíku, ke kterým jsou Ri, R3 a Rs připojeny, asymetrické. Tudíž existují sloučeniny v diastereomerních formách nebo jejich směsích. Ve výše popsané syntéze se mohou použít racernáty, enantiomery nebo diastereomery jako výchozí látky. Když se získají při syntetických postupech diastereomerní produkty, mohou se tyto dělit běžnými chromatografickými metodami nebo metodami frakční krystalizace. Obecně jsou v S-konfiguraci výhodné částečné struktury, tj.In the products of formula I, the carbon atoms to which R 1, R 3 and R 5 are attached may be asymmetric. Thus, the compounds exist in diastereomeric forms or mixtures thereof. In the above-described synthesis, racernates, enantiomers or diastereomers may be used as starting materials. When diastereomeric products are obtained in synthetic processes, they can be separated by conventional chromatographic or fractional crystallization methods. In general, partial structures, ie.
O Ri R3 About Ri R 3
R—C—C—NH, —NH—CHCO—R — C — C — NH, —NH — CHCO—
R2 aR2 a
Rá Rs O —N—C—C —Rá Rs O — N — C — C -
R7 aminokyseliny vzorce I.R7 amino acids of formula I.
Sloučeniny podle vynálezu tvoří soli s různými anorganickými a organickými kyselinami a zásadami, které jsou také zahrnuty do rozsahu vynálezu. Tyto soli zahrnují amonné soli, soli alkalického kovu, jako sodné a draselné soli, které jsou výhodné, soli kovů alkalických zemin, jako vápenaté a horečnaté soli, soli s organickými zásadami, například dicyklohexylaminové soli, N-methyl-D-glukamin, soli s aminokyselinami, jako arginin, lysin apod. Také se mohou připravit soli s organickými a anorganickými kyselinami, například HCI, HBr, H2SO4, H3PO4, methansulfoncvou, toluensulfonovou, maleinovou, fumarovou, kafrsulfonovou kyselinou. Výhodné jsou netoxické fyziologicky vhodné soli, ačkoliv jsou také použitelné jiné soli, například při izolaci nebo čištění produktu,The compounds of the invention form salts with various inorganic and organic acids and bases, which are also included within the scope of the invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts, which are preferred, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids such as arginine, lysine and the like. Salts with organic and inorganic acids such as HCl, HBr, H2SO4, H3PO4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic acid can also be prepared. Preferred are non-toxic physiologically acceptable salts, although other salts are also useful, for example, in isolating or purifying the product,
37 3 2 S38 3 2 S
Soli se mohou vytvořit běžnými způsoby, jako reakcí volné kyseliny nebo volné báze produktu s jedním nebo více ekvivalenty vhodné báze nebo kyseliny v rozpouštědle nebo prostředí, ve kterém je sůl nerozpustná, nebo v rozpouštědle, jako vodě, které se potom odstraní ve vakuu nebo sublimačním sušením nebo výměnou kationtů přítomné soli za jiný katión na vhodném iontoměniči.Salts may be formed by conventional methods, such as by reacting the free acid or free base of the product with one or more equivalents of a suitable base or acid in a solvent or environment in which the salt is insoluble or in a solvent such as water, which is then removed under vacuum or sublimation. drying or exchanging the present salt cations with another cation on a suitable ion exchanger.
Sloučeniny podle vynálezu inhibují enzym konvertující angiotensin a tak blokují konverzi dekapeptidu angiotensinu I na angiotensin II. Angiotensin II je účinná látka zvyšující krevní tlak.The compounds of the invention inhibit angiotensin converting enzyme and thus block the conversion of the angiotensin I decapeptide to angiotensin II. Angiotensin II is an active substance that increases blood pressure.
Účinek snižující krevní tlak se může odvozovat od ihibice jeho biosyntézy, obzvláště u zvířat a lidí, jejichž hypertense je ovlivněna angiotensinem II. Dále odbourává konvertující enzym vasodepresorickou látku bradykinin. Proto inhibitory enzymu konvertujícího angíotensm mohou snižovat krevní tlak také potenciací bradykininu. Ačkoliv se musí relativní význam těchto a dalších možných mechanismů potvrdit, jsou inhibitory enzymu konvertujícího angiotensin účinné antihypertensní látky na různých modelech zvířat a jsou použitelné klinicky, například u mnohých pacientů v humánní terapii s renovaskulární, maligní a esenciální hypertensí. Viz například D. W. Cushman et al., Biochemistry 16, 5484 (1977).The blood pressure lowering effect may be derived from the inhibition of its biosynthesis, especially in animals and humans whose hypertension is affected by angiotensin II. Further, the converting enzyme breaks down the vasodepressor bradykinin. Therefore, angiotensin converting enzyme inhibitors may also lower blood pressure by potentiating bradykinin. Although the relative importance of these and other possible mechanisms must be confirmed, angiotensin converting enzyme inhibitors are effective antihypertensive agents in various animal models and are clinically useful, for example, in many patients in human therapy with renovascular, malignant and essential hypertension. See, for example, D. W. Cushman et al., Biochemistry 16, 5484 (1977).
Zhodnocení Inhibitorů konvertujícího enzymu je provedeno ve zkoušce in vitro inhibice enzymu. Například použitelnou metodu uvedl Y. Piquilloud, A. Reinharz a M. Roth, Biochem. Biophys. Acta, 206, 136 (1970), podle které se měří hydrolýza karbobenzyloxyfenylalanylhistidinylleucinu. Hodnocení in vivo se například provádějí u krys s normálním tlakem, kterým se podává angiotensin I, podle techniky J. R Weeks a J. A. Jonese, Proč. Soc. Exp. Biol. Med. 104, 646 (1960) nebo na modelu krys s vysokým obsahem reninu, jak uvádí S. Koletsky et al., Proč. Soc. Exp. Biol. Med. 125, 96 (1967).Evaluation of the converting enzyme inhibitors is performed in an in vitro enzyme inhibition assay. For example, a useful method is reported by Y. Piquilloud, A. Reinharz and M. Roth, Biochem. Biophys. Acta, 206, 136 (1970), which measures the hydrolysis of carbobenzyloxyphenylalanylhistidinylleucine. For example, in vivo evaluations are performed in normal pressure rats administered angiotensin I according to the technique of J. R Weeks and J. A. Jones, Proc. Soc. Exp. Biol. Copper. 104, 646 (1960) or in the high renin rat model, as reported by S. Koletsky et al., Proc. Soc. Exp. Biol. Copper. 125, 96 (1967).
Sloučeniny podle vynálezu jsou použitelné jako antihypertensiva při léčení hypertensních savců, včetně lidí, a mohou se podávat k dosažení snížení krevního tlaku formováním do směsí, jako tablet, kapslí nebo elixírů pro parenterální podání. Sloučeniny podle vynálezu se mohou podávat pacientům (zvířatům a lidem] při potřebě tohoto léčení v dávkovém rozmezí 5 až 500 mg na pacienta při podávání několikrát za den, celková denní dávka je v rozmezí 5 až 2000 mg. Dávka se mění v závislosti na závažnosti onemocnění, hmotnosti pacienta a dalších faktorech, které určí lékař.The compounds of the invention are useful as antihypertensives in the treatment of hypertensive mammals, including humans, and can be administered to achieve blood pressure lowering by forming into compositions such as tablets, capsules, or elixirs for parenteral administration. The compounds of the invention may be administered to patients (animals and humans) in need of such treatment in a dose range of 5 to 500 mg per patient when administered several times a day, the total daily dose being in the range of 5 to 2000 mg. , the weight of the patient, and other factors determined by the physician.
Také se mohou podávat sloučeniny podle vynálezu ve směsi s dalšími diuretiky nebo antibypertensivy. Typické jsou směsi, jejichž individuální denní dávky se pohybují od jedné pětiny minimálně doporučených klinických dávek do maximálně doporučených hladin pro stav, kdy jsou podávány jednotlivě. K ilustraci těchto směsí se může jedna anťhypertensní látka podle vynálezu klinicky účinná v rozmezí 15 až 200 mg na den účinně smísit při hladině v rozmezí 3 až 200 mg na den s následujícími antihypertensivy a diuretiky v daném rozmezí dávek na den:Compounds of the invention may also be administered in admixture with other diuretics or antibypertensives. Typical compositions are those whose individual daily doses range from one fifth of the minimally recommended clinical doses to the maximum recommended levels for a single administration condition. To illustrate these mixtures, one antihypertensive agent of the invention clinically effective in the range of 15 to 200 mg per day can be effectively mixed at a level in the range of 3 to 200 mg per day with the following antihypertensives and diuretics over a given dose range per day:
hydrochlorthiazid (15 až 200 mg), chlorthiazid (125 až 2G0 mg), ethakrynová kyselina (15 až 200 mg), amilorid (5 až 20 mg), furosemid (5 až 80 mg), propane lol (20 až 480 mg), timolol (5 až 50 mg) a metyldopa (65 až 2000 mgj. Kromě toho jsou směsi s třemi léky, jako hydrochlorthiazid (15 až 200 mgj plus amilorid (5 až 20 mg) + inhibitor konvertujícího enzymu podle vynálezu (3 až 200 mgj nebo hydrochlorthiazid (15 až 200 mgj + timolol (5 až 50 mgj + 4- inhibitor konvertujícího enzymu podle vynálezu (3 až 200 mg), účinné směsi při léčení vysokého krevního tlaku u hypertensních pacientů. Výše uvedené rozmezí dávek se adjustuje na jednotkovém základě podle potřeby k dosažení rozdělení denní dávky.hydrochlorothiazide (15 to 200 mg), chlorthiazide (125 to 2 mg), ethacrylic acid (15 to 200 mg), amiloride (5 to 20 mg), furosemide (5 to 80 mg), propane lol (20 to 480 mg), timolol (5 to 50 mg) and methyldopa (65 to 2000 mgj). In addition, there are mixtures with three drugs, such as hydrochlorothiazide (15 to 200 mgj plus amiloride (5 to 20 mg) + converting enzyme inhibitor of the invention (3 to 200 mgj or hydrochlorothiazide (15 to 200 mgj + timolol (5 to 50 mgj + 4-converting enzyme inhibitor of the invention (3 to 200 mg)), an effective composition for treating high blood pressure in hypertensive patients. The above dosage range is adjusted on a unit basis as needed. to achieve a daily dose distribution.
Dávka, se mění v závislosti na závažnosti onemocnění, hmotnosti pacienta a dalších faktorech, které zhodnotí lékař.The dose varies depending on the severity of the disease, the weight of the patient, and other factors that will be assessed by the physician.
Výše uvedené směsi se formují do farmaceutických přípravků, jak uvedeno dále.The above mixtures are formed into pharmaceutical preparations as described below.
Asi 10 až 500 mg sloučeniny nebo směsi sloučenm vzorce I nebo fyziologicky vhodné soii se smísí s fyziologicky vhodným vehikulcm, nosičem, pomocnou látkou, pojivém, konzervační látkou, stabilizátorem, aromatickou látkou, atd. v jednotkové dávkové formě podle přijaté farmaceutické praxe. Množství účinné látky v těchto směsích nebo přípravcích je takové, aby se dosáhlo vhodných dávek v daném rozmezí.About 10 to 500 mg of a compound or mixture of compounds of Formula I or a physiologically acceptable salt is admixed with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring, etc. in unit dosage form according to accepted pharmaceutical practice. The amount of active ingredient in such compositions or compositions is such that appropriate dosages within the range will be achieved.
Příkladem .adjuvantů, které se mohou včlenit do tablet, kapslí apod., jsou následující látky: pojivo, jako tragant, arabská guma, kukuřičný škrob nebo želatina, pomocná látka, jako nrkrokrystalická celulóza, rozvolíiovadlo, jako kukuřičný škrob, předem želaťnový škrob, kyselina alginová apod., kluzná látka, jako stearan horečnatý, sladidlo, jako sacharóza, laktóza nebo sacharin, aromatická látka, jako silice z máty peprné, libavková silice nebo třešňová silice. Když se použije jako jednotková dávková forma kapsle, může obsahovat kromě výše uvedených látek tekutý nos'č, jako mastný olej. Různé další materiály mohou být obsaženy jako povlak nebo mohou jiným způsobem modifikovat fyzikální formu dávkové jednotky. Například mohou být tablety potaženy šelakem, cukrem nebo obojím. Sirup nebo elixír může obsahovat účinnou sloučeninu, sacharózu jako sladidlo, methyl- a propylparaben jako konzervační látku, barvivo1 a aromatickou látku, jako třešňovou nebo pomerančovou silici.Examples of adjuvants that can be incorporated into tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin, an excipient such as crocrystalline cellulose, a disintegrant such as corn starch, pregelatinized starch, acid alginic and the like; a glidant such as magnesium stearate; a sweetener such as sucrose, lactose or saccharin; an aromatic agent such as peppermint oil, wintergreen oil or cherry oil. When used as a unit dosage form, a capsule may contain, in addition to the above, a liquid carrier such as a fatty oil. Various other materials may be included as a coating or may otherwise modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl- and propylparaben as a preservative, colorant 1, and flavoring such as cherry or orange essential oil.
Sterilní směs pro injekce se může formovat podle běžné farmaceutické praxe rozpuštěním nebo suspendováním účinné látky ve vehikulu, jako vodě pro injekci, přírodně se vyskytujícím rozstlinném oleji, jako sezamovém oleji, kokosovém oleji, podzemnicovém oleji, bavlníkovém oleji atd., nebo syntetickém mastném vehikuiu, jako ethyloleanu nebo podobně. Podle potřeby se mohou včlenit pufry, konzervační látky, antioxidační látky apod.A sterile injectable mixture may be formulated according to conventional pharmaceutical practice by dissolving or suspending the active ingredient in a vehicle, such as water for injection, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle such as ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as desired.
Způsob podle vynálezu objasňují následující příklady. Výhodné diastereomery těchto příkladů se izolují sloupcovou chromatografií nebo frakční krystalizaci.The following examples illustrate the process of the invention. Preferred diastereomers of these examples are isolated by column chromatography or fractional crystallization.
Příklad 1Example 1
N- (l-karboxy-3-f enylpropyl j-L-alanyl-L-prolinN- (1-carboxy-3-phenylpropyl) -1-alanyl-L-proline
Směs 4-fenyl-2-oxomáselné kyseliny (1,49 gramu) a L-alanyl-L-prolinu (0,31 g) ve vodě se upraví hydroxidem sodným na pH 7,5 a přes noc se nechá působit kyanoborohydrid sodný (0,32 g). Produkt se adsorbuje na silně kyselém iontoměniči a eluuje se 2% pyridinem ve vodě a získá se 0,36 g surového diastereomerního produktu, N- (1-karboxy-3-fenylpropyl)-L-alanyl-L-prolinu. Čistí se gelovou filtrací (LH-20) pno spektrografickou analýzu. NMR spektrum v DMSO ukazuje aromatický vodík při 7,20, široký siglet při 4,30, široké multiplety při 3,0-3,9, 2,67 a 1,94 a dublet při 1,23 a 1,15. Hmotové spektrum ukazuje molekulový iont při 492 m/e pro ditrimethylsilylovaný druh.A mixture of 4-phenyl-2-oxobutyric acid (1.49 g) and L-alanyl-L-proline (0.31 g) in water was adjusted to pH 7.5 with sodium hydroxide and treated with sodium cyanoborohydride (0) overnight. , 32 g). The product was adsorbed on a strongly acidic ion exchanger and eluted with 2% pyridine in water to give 0.36 g of crude diastereomeric product, N- (1-carboxy-3-phenylpropyl) -L-alanyl-L-proline. Purified by gel filtration (LH-20) for spectrographic analysis. The NMR spectrum in DMSO shows aromatic hydrogen at 7.20, broad siglet at 4.30, broad multiplets at 3.0-3.9, 2.67 and 1.94 and doublet at 1.23 and 1.15. The mass spectrum shows a molecular ion at 492 m / e for the ditrimethylsilylated species.
Příklad 2Example 2
N- [ l-karbo'xy-2- (S )-amino-3-f enylpropyl ] -D,L-alanyl-L-prolinN- [1-carboxy-2- (S) -amino-3-phenylpropyl] -D, L-alanyl-L-proline
2-amino-4-fenyl-3- (S) -f taloylaminobutanová kyselina se kondenzuje s pyruvoyl-L-prolinem pomocí kyanohorohyridu sodného v methanolu v neutrálním prostředí a získá se N-(l-karboxy-3-fenyl-2-f taloylamino )-D,L-alanyl-L-prolin jako směs isomerů. Tento materiál se zahřívá v ethanolu pod zpětným chladičem s jedním ekvivalentem hydrazinu po dobu 1,5 hodiny, ochladí se, ftalhydrazid se odfiltruje a žádaný produkt se Izoluje chromatografickými metodami a získá se žádaná sloučenina. Chromatografie v tenké vrstvě na silikagelu se směsí 10 EtoAc: 5 pyridin :2-Amino-4-phenyl-3- (S) -phthaloylaminobutanoic acid is condensed with pyruvoyl-L-proline using sodium cyanohorohyride in methanol in a neutral medium to give N- (1-carboxy-3-phenyl-2-f). taloylamino) -D, L-alanyl-L-proline as a mixture of isomers. This material was refluxed in ethanol with one equivalent of hydrazine for 1.5 hours, cooled, the phthalhydrazide was filtered off and the desired product isolated by chromatographic methods to give the title compound. Thin layer chromatography on silica gel with 10 EtoAc: 5 pyridine:
: 1 HOAc : 3 HzO dává skvrnu s Rf ~ 0,15.: 1 HOAc: HZO 3 gives a spot with an R f ~ 0.15.
Příklad 3Example 3
N- [ l-kaťboxy-2- (S) -benzoylamino-3-f enylpropyl ] -D,L-alanyl-L-prolinN- [1-carboxy-2- (S) -benzoylamino-3-phenylpropyl] -D, L-alanyl-L-proline
Roztok N-ftaloyl-3-amino-4-fenyl-2-hydroxybutyronitrilu v ethanolu nasyceném bezvodým amoniakem se nechá stát 3 dny při teplotě místnosti. Rozpouštědlo se odstraní ve vakuu a zbytek se zahřívá 6 hodin pod zpětným chladičem v koncentrované kyselině chlorovodíkové. Odpaří se do sucha a zbytek se čistí na koloně iontoměniče Dowex-50 (H+), eluuje se postupně směsí voda-methanol 10 :1, voda-pyrídin 50 :1 a konečně 0,5 M roztokem hydroxidu amonného. Žádaná 2,3-diamino-4-fenylpropionové kyselina se izoluje z tohoto posledního eluentu koncentrací do sucha. Připraví se roztok komplexu mědi této aminokyseliny a benzoyluje se 3-aminoskupina in šitu benzoylchloridem za zásaditých podmínek, metodou, kterou popsal R. Roeske et al., J. Am. Chem. Soc·, 78, 5883 (1956).A solution of N-phthaloyl-3-amino-4-phenyl-2-hydroxybutyronitrile in ethanol saturated with anhydrous ammonia was allowed to stand at room temperature for 3 days. The solvent was removed in vacuo and the residue was refluxed in concentrated hydrochloric acid for 6 hours. Evaporate to dryness and purify the residue on a Dowex-50 (H + ) ion exchange column, eluting sequentially with water-methanol 10: 1, water-pyridine 50: 1 and finally with 0.5 M ammonium hydroxide solution. The desired 2,3-diamino-4-phenylpropionic acid is isolated from this last eluent by concentration to dryness. A solution of the copper complex of this amino acid was prepared and benzoylated with the 3-amino group in situ with benzoyl chloride under basic conditions, according to the method of R. Roeske et al., J. Am. Chem. Soc., 78, 5883 (1956).
Komplex mědi se štěpí sirovodíkem a získá se 2-amlno-3-(S)-benz©ylamino-4-fenylmáselná kyselina. Tento meziprodukt se kondenzuje s pyruvoyl-2-prolinem pomocí kyanoborohydridu sodného v methanolu v neutrálním prostředí a získá se žádaný N-jl-karboxy-2- (S j-benzoylamino-3-fenyl-propyl j -D,L-alanyl-L-prolin jako směs izomerů, které se může dělit případně chromatografickými metodami.The copper complex was digested with hydrogen sulfide to give 2-amino-3- (S) -benzylamino-4-phenylbutyric acid. This intermediate is condensed with pyruvoyl-2-proline using sodium cyanoborohydride in methanol under neutral conditions to give the desired N-β-carboxy-2- (S-benzoylamino-3-phenylpropyl) -D, L-alanyl-L -proline as a mixture of isomers which may be separated, if appropriate, by chromatographic methods.
Hmotové spektrum ukazuje vrchol při 596 m/e pro disilylovaný molekulový ion minus 15. NMR spektrum ukazuje ahsorbanci pro dva fenyly při 7,0-7,5 <S a diastereomerní methyly při 1,1 8.The mass spectrum shows a peak at 596 m / e for the disilylated molecular ion minus 15. The NMR spectrum shows the ahsance for two phenyls at 7.0-7.5 ° S and diastereomeric methyls at 1.18.
Příklad 4Example 4
N-(2-amino-l-karboxy-4-methylpentyl)-D,L-alanyl-L-prolinN- (2-Amino-1-carboxy-4-methylpentyl) -D, L-alanyl-L-proline
K roztoku 0,731 g trans-3-amino-4-(2-methylpropyl j-2-azetidinonu {připravený adicí chlorsulfonylisokyanatanu na 4-methyl-l-penten, získaný ,6-laktam se chrání jako terc.butyldhnethylsílylový derivát a potom se přidá dilsopropylamid lithný, déle tosylazid a chlortrimethylsilan. Kysele se zpracuje a chromatografií na silikagelu se získá trans-3-azído-4- (2-methylpropyl j-2-azetidinon, který se hydrogenuje (10% Pd/ethanol) na aminoderívát] a 4,58 g benzylpyruvátu ve 20 ml absolutního ethanolu obsahujícím 10 g práškovitého 4A molekulárního síta se přidá po kapkách roztok kyanoborohydridu sodného (0,65 gj v 8 ml absolutního ethanolu, dokud není reakce úplná. Reakčni směs se filtruje a filtrát se koncentruje. Zbytek se rozpustí v 50 ml vody a okyselí se 1 N HC1 na pH = 3. Směs se upraví 10% roztokem uhlič:tanu sodného na pH = 9,5. Vodný roztok se nasytí chloridem sodným a extrahuje se ethylacetátem (5 X 40 ml).To a solution of 0.731 g of trans-3-amino-4- (2-methylpropyl) -2-azetidinone (prepared by adding chlorosulfonyl isocyanate to 4-methyl-1-pentene), the obtained 6-lactam is protected as a tert-butyldimethylsilyl derivative and then added Lithium dilsopropylamide, longer tosylazide and chlorotrimethylsilane The acid was worked up and chromatographed on silica gel to give trans-3-azido-4- (2-methylpropyl) -2-azetidinone, which was hydrogenated (10% Pd / ethanol) to the amino derivative] and 4 58 g of benzylpyruvate in 20 ml of absolute ethanol containing 10 g of powdered 4A molecular sieves was added dropwise a solution of sodium cyanoborohydride (0.65 gj in 8 ml of absolute ethanol until the reaction was complete.) The reaction mixture was filtered and the filtrate was concentrated. dissolved in 50 ml of water and acidified with 1 N HC1 to pH = 3. the mixture was adjusted with 10% sodium carbonates: sodium carbonate at pH 9.5. the aqueous solution was saturated with sodium chloride and extracted with ethyl acetate (5 X 40 mL).
Spojené organické vrstvy se suší síranem sodným a koncentrují se za vzniku oleje (4,94 g). Chromatografií na silikagelu (ethylacetát) se získá 1,11 g produktu. NMR spektrum a hmotové spektrum souhlasí se strukturou benzylesteru N-[trans-4-( 2-methylpropyl j -2-oxo-3-azetidinyl j -D,L-alaninu. Debenzylace se provádí katalytickou hydrogenaci [10% Pd/C, 2:1 — etanol: voda]. Ke studenému roztoku (0°C) kyseliny (428 mg) a terc.butýlesteru L-prolinu (377 mg) v 5 ml dimethylformamidu se přidá roztok difenyl237325 fosforylazidu (650 mg) v 5 ml dimethylformamidu a potom roztok triethylaminu (223 miligramů v 5 mg dimethylformamidu) během 20 minut. Po 3 hodinách se ledová lázeň odstraní a reakční směs se nechá míchat přes noc při teplotě okolí. Přidá se 100 mililitrů ethylacetátu a výsledný roztok se promyje 2 X 40 ml vody, 3 X 30 ml 5% roztoku uhličitanu sodného a 1 X 50 ml vody, načež se suší síranem sodným. Koncentrací se získá 0,78 g oleje, jehož NMR spektrum a hmotové spektrum souhlasí se strukturou terc.butylesteru N- [trans-4- (2-methylpropyl)-2-oxo-3-azetidinyl]-D,L-alanyl-L-prolinu. Surový produkt se rozpustí ve 25 ml kyseliny trifluoroctové při 0 °C. Reakční směs se míchá 20 minut při 0 °C a potom 2,5 hodiny při teplotě místnosti. Reakční směs se koncentruje do sucha a ke zbytku se přidá při teplotě místnosti 30 ml 1 N hydroxidu sodného a nechá se působit 4,5 hodiny. Zásaditá směs se přidá pomalu k silně kyselému iontoměniči a produkt se získá 2% pyridinem ve vodě. Lyofilizaci se získá 0,30 g N-[2-amino-l-karboxy-4-methylpentyl]-D,L-alanyl-L-prolín, který obsahuje 4-diastereomery (S, S, S, S; S, S, R, S; R, R, R, S; R, R, S, S,j oddělitelné chromatograficky. NMR spektrum a hmotové spektrum potvrzuje strukturu. NMR spektrum ukazuje multiplety při 4,5, 3,85, 2,3, 1,79 a 1,16 ppm. Hmotový spektrogram ukazuje vrchol při 458 (disilylovaný molekulový iont-15).The combined organic layers were dried over sodium sulfate and concentrated to give an oil (4.94 g). Silica gel chromatography (ethyl acetate) afforded 1.11 g of the product. The NMR and mass spectra were consistent with the structure of N- [trans-4- (2-methylpropyl) -2-oxo-3-azetidinyl] -D, L-alanine benzyl ester Debenzylation was carried out by catalytic hydrogenation [10% Pd / C, 2 To a cold solution (0 ° C) of acid (428 mg) and tert-butyl L-proline ester (377 mg) in 5 mL of dimethylformamide was added a solution of diphenyl237325 phosphoryl azide (650 mg) in 5 mL of dimethylformamide and then a solution of triethylamine (223 mg in 5 mg dimethylformamide) over 20 minutes After 3 hours, the ice bath was removed and the reaction was allowed to stir overnight at ambient temperature, 100 mL ethyl acetate was added and the resulting solution was washed with 2 X 40 mL water, 3 X 30 ml of 5% sodium carbonate solution and 1 X 50 ml of water are then dried over sodium sulfate to give 0.78 g of an oil whose NMR and mass spectra are consistent with the structure of N- [trans-4- tert -butyl ester. (2-methylpropyl) -2-oxo-3-azetidinyl] -D, L-alanyl-L-proline. Dissolve in 25 mL of trifluoroacetic acid at 0 ° C. The reaction mixture was stirred at 0 ° C for 20 minutes and then at room temperature for 2.5 hours. The reaction mixture was concentrated to dryness and 30 ml of 1 N sodium hydroxide was added to the residue at room temperature and allowed to react for 4.5 hours. The basic mixture was added slowly to the strongly acidic ion exchanger and the product was obtained with 2% pyridine in water. Lyophilization gave 0.30 g of N- [2-amino-1-carboxy-4-methylpentyl] -D, L-alanyl-L-proline containing 4-diastereomers (S, S, S, S; S, S). The R, S, R, R, R, S, R, R, S, S are separable chromatographically, the NMR and mass spectra confirm the structure, and the NMR spectrum shows multiplets at 4.5, 3.85, 2.3, 1.79 and 1.16 ppm The mass spectrogram shows a peak at 458 (disilylated molecular ion-15).
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS821339A CS237325B2 (en) | 1978-12-11 | 1982-02-26 | Processing of carboxyalkyldipeptide |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US96824978A | 1978-12-11 | 1978-12-11 | |
| CS798645A CS237311B2 (en) | 1978-12-11 | 1979-12-11 | Processing of carboxyalkyldipeptide |
| CS821339A CS237325B2 (en) | 1978-12-11 | 1982-02-26 | Processing of carboxyalkyldipeptide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS237325B2 true CS237325B2 (en) | 1985-07-16 |
Family
ID=25746598
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS821340A CS237326B2 (en) | 1978-12-11 | 1982-02-26 | Method of preparation of carboxyalkyldipeptide |
| CS821339A CS237325B2 (en) | 1978-12-11 | 1982-02-26 | Processing of carboxyalkyldipeptide |
| CS821342A CS237328B2 (en) | 1978-12-11 | 1982-02-26 | Method of preparation of carboxyalkyldipeptide |
| CS821341A CS237327B2 (en) | 1978-12-11 | 1982-02-26 | Method of preparation of carboxyalkyl dipeptide |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS821340A CS237326B2 (en) | 1978-12-11 | 1982-02-26 | Method of preparation of carboxyalkyldipeptide |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS821342A CS237328B2 (en) | 1978-12-11 | 1982-02-26 | Method of preparation of carboxyalkyldipeptide |
| CS821341A CS237327B2 (en) | 1978-12-11 | 1982-02-26 | Method of preparation of carboxyalkyl dipeptide |
Country Status (1)
| Country | Link |
|---|---|
| CS (4) | CS237326B2 (en) |
-
1982
- 1982-02-26 CS CS821340A patent/CS237326B2/en unknown
- 1982-02-26 CS CS821339A patent/CS237325B2/en unknown
- 1982-02-26 CS CS821342A patent/CS237328B2/en unknown
- 1982-02-26 CS CS821341A patent/CS237327B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS237328B2 (en) | 1985-07-16 |
| CS237326B2 (en) | 1985-07-16 |
| CS237327B2 (en) | 1985-07-16 |
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