IE903422A1 - Amino acid derivatives - Google Patents

Amino acid derivatives

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Publication number
IE903422A1
IE903422A1 IE342290A IE342290A IE903422A1 IE 903422 A1 IE903422 A1 IE 903422A1 IE 342290 A IE342290 A IE 342290A IE 342290 A IE342290 A IE 342290A IE 903422 A1 IE903422 A1 IE 903422A1
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Ireland
Prior art keywords
phe
ahcp
isoser
amino
ampa
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IE342290A
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Merck Patent Gmbh
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Publication of IE903422A1 publication Critical patent/IE903422A1/en

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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Abstract

Amino-acid derivatives of the formula I R1-CpH2p-(NH)q-CO-NH-CHR<2>-CO-Z-CmH2m-CHWR<3>-CO-NH-CHR3-CR<4>-(CHR<5>)n- CO-E-Q-Y 1 in which R<1> to R<5>, p, q, Z, m, n, E, Q, W and Y have the meanings given in Claim 1, and the salts thereof inhibit the activity of human plasma renin.

Description

Amino acid derivatives The invention relates to new amino acid derivatives of the formula I R1-CpH2p-(NH)q-CO-NH-CHR2-CO-Z-CmH2m-CHWR3-CONH-CHR3-CR4-(CHR5)n-CO-E-Q-Y 1 in which R1 is R®R7N-, R6-NH-C(=NH)-NH-, NC-NH-C ( =NH)-NH-, RSOOC-, R5O3S- or Rs-0-(CH2CH2O) r-, Z is -0-, -CH2-, -CH=CH-, -C=C-, -NR3-, -CH2-O-, -CH2-NRa- or -CH2-S-, E is 0 to 2 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ala, Cal, His, lie, Leu, Met, Nle, Nva, Phe, Trp, Tyr and Val, Q is 0 or NR10, Y is -CtH2t-Rn, -CtH2t-R12 or -C^- (CR13) s-CtH2t-Ru, WR3 is -OR3 or -NHR3, R2, R3 and R11 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R4 and R13 are each (H, OH), (H, NH2) or =0, R5, R3 and R10 are each H or A, Rs and R7 are each H, A or Ar-alkyl, R7 is also R3-O-CIH2l-CO-, R9-CxH2x-O-CO- or Ac, R9 is A or Ar-alkyl, R6R7N is also a pyrrolidinyl, piperidinyl, morpholinyl or PAT LOG 19-B 130989 - 2 piperazinyl group which is unsubstituted or substituted by A, OH, NH2, NHA, NA2, NHAc, NH-CO-C^^-O-R9, NH-CO-O-CJi^-R9, NH-SO2-A, hydroxyalkyl, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N®alkyl An®, NH-CO-NH2, NH-CO-NHA, NH-CO-NA2, guanidinyl or guanidinyl-alkyl, R12 is -SO3H, -SO2NH2, -SO2NHA, -SO2NA2, -NH2, -NHA, -NA2, -NH-C(=NH)-NH-, -NH-C(=NH)-NHCN, -NH-CO-NH2, -NH-CO-NHA, -NH-CO-NA2, -NH-CS-NH2, -NH-CS-NHA, -NH10 CS-NA2, -COOH, -COOA, -COO-alkyl-Ar, -CONH2, -CONHA or -CONA2, q is 0 or 1, n is 0, 1 or 2, s is 1 or 2, m, p, t, w and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, r is 1, 2 or 3, Ar is phenyl which is unsubstituted or singly or multiply substituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NAj, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONHZ, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N®alkyl An® and/or guanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, 0 and/or S atoms andean be fused with a benzene ring and/or can be singly or multiply substituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NAj, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, NH-SO2-A, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl, and/or whose N and/or S hetero atoms can also be oxidized, Hal is F, Cl, Br or I, Ac is H-CO-, A-CO-, CF3-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, An® is an anion, which can also be absent if, in its stead, a carboxyl group contained in the compound of PAT LOG 19-B 130989 the formula I is in the form of a carboxylate anion, -alkyl- is an alkylene group having 1-8 C atoms, and A is alkyl having 1-8 C atoms, in which, furthermore, it is also possible for one or 5 more -NH-CO- groups to be replaced by one or more -NA-COgroups, as well as the salts thereof.
The invention had the object of finding new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and the salts thereof have very valuable properties. In particular, they inhibit the activity of human plasma renin. This action can be detected, for example, by the method of F. Fyhrquist et al., Clin.
Chem. 22., 250-256 ( 1976). The noteworthy point is that these compounds are very specific inhibitors of renin; as a rule, the concentrations of these compounds necessary for the inhibition of other aspartyl proteinases (for example pepsin and cathepsin D) are about 100 to 1000 times as high as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate, as well as the inhibition of renin activity in blood plasma can furthermore be determined in conscious monkeys, for example female monkeys, (Macaca f ascicularis); it is possible in this for the blood pressure and heart rate to be measured by a modification of the method of M.J. Wood et al., J. Hypertension 4., 251-254 (1985). In order to stimulate renin activity in this, the animals are preferably pretreated with a saluretic. Blood samples for the determination of the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be used as pharmaceutically active substances in human and veterinary medicine, in particular for the prophylaxis and for the treatment of diseases of the heart, circulation and vessels, especially of hypertension, cardiac insufficiency and PAT LOG 19-B 130989 - 4 hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in orer to determine, in patients with hypertension or hyperaldosteronism, the possible contribution of the renin activity to maintain5 ing the pathological state. The procedure for such diagnostic tests can be similar to that indicated in EP-A-77 028.
The abbreviations quoted hereinbefore and hereinafter for amino acid residues represent the radicals -NR'-R-CO-, as a rule -NH-CHR-CO- (in which R, R' and R have the specific meaning known for each amino acid), of the following amino acids: Abu 2-Aminobutyric acid AHCH 4S-Amino-3S-hydroxy-6-cyclohexyl-hexanoic acid AHCP 4S-Amino-3S-hydroxy-5-cyclohexyl-pentanoic acid AHPP 4S-Amino-3S-hydroxy-5-phenyl-pentanoic acid Ala Alanine £Ala β-Alanine Cal 3-Cyclohexylalanine DACH 3S,4S-Diamino-6-cyclohexyl-hexanoic acid DACP 3S,4S-Diamino-5-cyclohexyl-pentanoic acid DAMH 3S,4S-Diamino-6-methyl-heptanoic acid DAPP 3S,4S-Diamino-5-phenyl-pentanoic acid Gly Glycine His Histidine lie Isoleucine Isoser Isoserine Leu Leucine Lys Lys ine Mai 3-(p-Methoxyphenyl)-alanine Met Methionine ctNal 3-(α-Naphthyl)-alanine £Nal 3-(^-Naphthyl)-alanine Nle Norleucine N-Me-His N-Methyl-histidine N-Me-Phe N-Methyl-phenylalanine Nva Norvaline PAT LOG 19-B 130989 Orn Ornithine Phe Phenylalanine Pia 3-(Piperidyl)-alanine [e.g. 2-pia = 3-(2- piperidyl)-alanine] 5 Pya 3-(Pyridyl)-alanine [e.g. 3-pya = 3-(3- pyridyl)-alanine] Sta Statine Tia 3-(Thienyl)-alanine [e.g. 2-tia = 3-(2- thienyl)-alanine] 10 Trp Tryptophan Tyr Tyrosine Val Valine. Further meanings hereinafter are: ADPA N-2-Amino-5,6-dimethyl-3-pyrazinylmethyl-amide 15 AMPA N-4-Amino-2-methyl-5-pyrimidinylmethyl-amide BOC tert.-Butoxycarbonyl BOM Benzyloxymethyl imi-BOM Benzyloxymethyl in the 1 position of the imidazole ring 20 CBZ Benzyloxycarbonyl DCCI Dicyclohexylcarbodiimide DMF Dimethylformamide DNP 2,4-Dinitrophenyl imi-DNP 2,4-Dinitrophenyl in the 1 position of the 25 ETOC imidazole ring E t ho xyc a r bo ny 1 FMOC 9 -F luor eny line t ho xyc arbony 1 HOBt 1-Hydroxybenzotriazole IPOC Isopropoxycarbonyl 30 OMe Methyl ester OEt Ethyl ester POA Phenoxyacetyl THF Tetrahydrofuran. If the abovementioned amino acids can occur in 35 more than one enantiomeric form, then all these forms, as well as mixtures thereof (for example the DL forms), are included hereinbefore and hereinafter, for example as PAT LOG 19-B 130989 - β constituent of the compounds of the formula I. The L forms are preferred. Where individual compounds are mentioned hereinafter, then the abbreviations of these amino acids each relate to the L form unless expressly indicated otherwise.
The invention furthermore relates to a process for the preparation of an amino acid derivative of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional deriv10 atives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II iC-CpHjp-iNHJq-CO-G^OH II in which G1 is (a) absent, (b) -NH-CHR2-CO-, (c) -NH-CHR2-CO-Z-CinH2m-CHWR3-CO-, (d) -NH-CHR2-CO-Z-CarH2m-CHWR3-CO-K-, ( e) -NH-CHR2-CO-Z-CiaH2m-CHWR3-CO-K-E1-, (f) -NH-CHR2-CO-Z-CDH2ffl-CHWR3-CO-K-E- and K is -NH-CHR3-CR4-(CHR5)n-CO20 or one of the reactive derivatives thereof, is reacted with an amino compound of the formula III H-G2 III in which G2 is (a) -NH-CHR^CO-Z-CJi^-CKWR^CO-K-E-Q-Y, (b) -Z-CoH2m-CHWR3-C0-K-E-Q-Y, (c) -K-E-Q-Y, (d) -E-Q-Y, (e) -E2-Q-Y, (f) -NR10-Y and E1 + E2 are together E, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenolyzing agents, and/or for the preparation of a compound PAT LOG 19-B 130989 - 7 of the formula I, R4 = (H, OH) or (H, NH2) , an amino keto acid derivative of the formula I, R4 = 0, is reduced or reductively aminated, and/or a radical R1 is converted into another radical R1 and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof.
Hereinbefore and hereinafter the radicals and parameters R1 to R13, Z, E, Q, Y, m, n, p, r, s, t, w, x, q, Ar, W, Het, Hal, Ac, An, A, G1, G2, E1, E2 and K have the meanings indicated for the formulae I, II or III unless expressly indicated otherwise.
The two radicals R3 in the formulae I, II and III can be identical or different.
A in the formulae mentioned hereinbefore has 1-8, 15 preferably 1, 2, 3 or 4, C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, as well as pentyl, 1-, 2- or 3- methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2ethylbutyl, 1-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl or octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but is also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or 4- methylcyclohexyl.
Correspondingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2- cyclobutylethyl,cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but is also, for example, 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-, 3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-decalyl, 2bicyclo[2.2.1]heptyl or 6,6-dimethyl-2-bicyclo[3.1.1]35 heptyl.
Tricycloalkyl is preferably 1-adamantyl.
Hal is preferably F, Cl or Br, but is also I.
PAT LOG 19-B 130989 Ac is preferably A-CO-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, ο-, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-CO- such as Nmethyl- or N-ethylcarbamoyl.
Ar is preferably phenyl and is furthermore preferably ο-, m- or p-tolyl, ο-, m- or p-ethylphenyl, o—, m- or p-methoxyphenyl, ο-, m- or p-fluorophenyl, ο-, m- or p-chlorophenyl, ο-, m- or p-bromophenyl, ο-, m- or p-iodophenyl, ο-, m- or p-trifluoromethylphenyl, ο-, m10 or p-hydroxypheny1, ο-, m- or p-sulfamoylphenyl, 2,3-, 2.4- , 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5trimethoxyphenyl, ο-, m- or p-aminophenyl, ο-, m or paminomethylphenyl, ο-, m- or p-dimethylaminomethylphenyl, o-, m- or p-guanidinomethylphenyl, or 1- or 2-naphthyl.
Correspondingly, Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl, ο-, m- or p-methylbenzyl, 1- or 2o-, -m- or -p-tolylethyl, ο-, m- or p-ethylbenzyl, 1- or 2- 0-, -m- or -p-ethylphenylethyl, ο-, m- or p-methoxybenzyl, 1- or 2-o-, -m- or -p-methoxyphenylethyl, ο-, m20 or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, o—, m- or p-chlorobenzyl, 1- or 2-ο-, -m- or -pchlorophenylethyl, ο-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, ο-, m- or p-iodobenzyl, 1- or 2-0-, -m- or -p-iodophenylethyl, ο-, m- or p-trifluoro25 methylbenzyl, ο-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2.5- , 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyi, ο-, m- or p-aminobenzyl, ο-, m- or p-aminomethylbenzyl, ο-, m- or p-dimethylaminomethylbenzyl, ο-, m- or p-guanidinomethylbenzyl, or 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-l-, -4- or -5-yl, 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, PAT LOG 19-B 130989 -91.3.4- thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or 6-2Hthiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1- , 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, -, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzo10 thiazolyl, 2-, 4-, 5-, 6- or 7- 2-, 4-, 5-, 6- or 7benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2- , 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl.
The heterocyclic radicals can also be partially or completely hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -320 furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,425 dihydro-Ι-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro1- -2-, -3- or -4-, -5- or -6-pyridyl, 1,2,3,6-tetrahydro-Ι-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-Ι-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1.2.3.4- tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The heterocyclic radicals can also be substituted as indicated. Het can also preferably be, for example, 2amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl-2PAT LOG 19-B 130989 - 10 thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4-carbamoyl-piperidino, furthermore, for example, 3-, 4or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,45 dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4- or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl, 3- methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, 5phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2-pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimethyl10 4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 5-methyl-3isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or 4-methyl-5thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 6methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2-pyridyl, 2-, 4- , 5- or 6-chloro-3-pyridyl, 2- or 3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-, 4-, 5- or -6-pyridyl, (= lH-2-pyridon-3-, -4-, -5- or -6-yl), 5-phenyl-1H-2pyridon-3-yl, 5-p-methoxyphenyl-lH-2-pyridon-3-yl, 220 methyl-3-hydroxy-4-hydroxymethyl-5-pyridyl, 2-hydroxy-4amino-6-methyl-3-pyridyl, 3-N'-methylureido-lH-4-pyridon5- yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2- , 5- or 6-methyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrimidinyl, 5-chloro-2-methyl-425 pyrimidinyl, 3-methyl-2-benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl3- indolyl, l-methyl-5- or -6-benzimidazolyl, l-ethyl-5or -6-benzimidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2quinolyl, 2-oxo-pyrrolidino, 2-oxo-piperidino, 2,530 dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
R1 is preferably R6R7N or R5OOC.
Z is preferably -NR3-, in particular -NH- or -N(CH3)-, furthermore preferably -CH2-, -CH2-O-, -CH2-NRa(in particular -CH2-NH-) or -CH2-S-. WR3 is preferably -OR3, in particular preferably -OH or -0A, furthermore preferably -NHR3, in particular -NHA. Correspondingly, -Z-CnH2ia-CHWR3-CO- is preferably Isoser, Lys or Orn, in PAT LOG 19-B 130989 - 11 particular preferably Isoser.
The parameter q is preferably 0; n and s are preferably each 1; m is preferably 1 or 2, furthermore preferably 3,4 or 5; p is preferably 1, 2, 3, 4 or 5, furthermore 6 or 7; r is preferably 1 or 2. The groups and CpH2p are preferably -(CH2)m-, in particular -CH2-, ~ (CH2) 2—, -(CH2)3—, — (CH2)4 or -(CH2)5—, or -(CH2)p-, in particular -CH2-, -(CH2)2-, -((ΖΗ2)Α- or -(CH2)5-. The groups CtH2t and C.^H2w are preferably each -CH2-, -(CH2)2-, -CH(CH3)-, -CH( isobutyl) - or -CH( sec .-butyl)-; it is also possible and preferable for the group CtH2fc to be absent (t = 0). The parameter x is preferably 1, furthermore 0 or 2 .
R2 is preferably Ar-alkyl, in particular benzyl, 1- or 2-naphthylmethyl, furthermore preferably cycloalkylalkyl, in particular eyelohexyImethyl, as well as Het-alkyl, in particular 2-, 3- or 4-piperidylmethyl, 2-, 3-, or 4-pyridylmethyl, 2- or 3-thienylmethyl. Accordingly, the group -NH-CHR2-CO- is preferably Phe, and is furthermore preferably Mai, aNal, £Nal, Cal, Pia, Pya or Tia.
R3 is preferably eyelohexylmethy1, furthermore preferably H or A, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, (3-methylbutyl) or 2-methylbutyl, phenyl, benzyl, pchlorobenzyl, 2-eyelohexylethy1, bicyclo[2.2.l]heptyl-2methyl or 6,6-dimethylbicyclo[3.1.1]heptyl-2-methyl.
R* and R13 are each preferably (H, OH) .
R5, R6, R7, R3 and R10 are each preferably H or methyl, furthermore ethyl, propyl, isopropyl, butyl or isobutyl, and R7 is also preferably benzyl, alkoxycarbonyl such as ETOC, IPOC or BOC or Ar-alkoxycarbonyl such as CBZ, and R6R7N is also preferably pyrrolidino, piperidino or 4-methylpiperidino.
Accordingly, the group R^CpH^-iNHJq-CO- is preferably R1-CpH2p-CO-, in particular R1-(CH2)p-CO-, specifically and in particular R8R7N-CpH2p-CO-, preferably R6R7NPAT LOG 19-B 130989 - 12 (CH2)p-CO-, especially H2N-CpH2p-CO-, such as aminocarbonyl, aminoacetyl (H-Gly-), 3-aminopropionyl (H-ySAla-), 4aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoylz -aminodecanoyl, 11-aminoundecanoyl, but also, for example, 2-amino-propionyl (Ala), 2-amino-2-methylpropionyl; ANH-CpH2p-C0- such as methylaminocarbonyl, raethylaminoacetyl, (sarcosyl), 3-methylaminopropionyl, 4methylaminobutyryl, 5-methylaminopentanoyl, 6-methyl10 aminohexanoyl, 6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methylaminooctanoyl, 9-methylaminononanoyl, 10-methylaminodecanoyl, 11-methylaminoundecanoyl; A^NCpH2p-CO- such as dimethylaminoc arbonyl, dimethylaminoacetyl, 3-dimethylaminopropionyl, 4-dimethylaminobutyryl, -dimethylaminopentanoyl, 6-dimethylaminohexanoyl, 6diethylaminohexanoyl,7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11-dimethylaminoundecanoyl; A-O-CONH-CpH2p-CO- such as BOC-Gly, ETOC-Gly-, IPOC-Gly, BOC2 0 /9Ala, ETOC-£Ala, IPOC-^Ala-, 4-BOC-amino-butyryl, 5-BOCamino-pentanoyl, 6-BOC-amino-hexanoyl, 7-BOC-aminoheptanoyl, 8-BOC-amino-octanoyl, 9-BOC-amino-nonanoyl, 10-BOC-amino-decanoyl, 11-BOC-amino-undecanoyl; ArCH2-OCO-NH-CpH2p-CO- such as CBZ-Gly-, CBZ-/3Ala, 4-CBZ-amino25 butyryl, 5-CBZ-amino-hexanoyl, 7-CBZ-amino-heptanoyl, 8CBZ-amino-octanoyl, 9-CBZ-amino-nonanoyl, 10-CBZ-aminodecanoyl, 11-CBZ-amino-undecanoyl; pyrrolidino-CpH2p-COsuch as pyrrolidinocarbonyl, pyrrolidino-acetyl, 3pyrrolidino-propionyl, 4-pyrrolidino-butyryl, 5-pyr30 rolidino-pentanoyl, 6-pyrrolidino-hexanoyl, 4-pyrrolidino-heptanoyl, 8-pyrrolidino-octanoyl, 9-pyrrolidinononanoyl, 10-pyrrolidino-decanoyl; piperidino-CpH2p-COsuch as piperidinocarbonyl, piperidinoacetyl, 3-piperidinopropionyl, 4-piperidino-butyryl, 5-piperidino-penta35 noyl, 6-piperidino-hexanoyl, 7-piperidinoheptanoyl, 8piperidino-octanoyl, 9-piperidino-nonanoyl, 10-piperidino-decanoyl; morpholino-CpH2p-CO- such as morpholinoPAT LOG 19-B 130989 carbonyl, morpholinoacetyl, 3-morpholino-propionyl, 4morpholino-butyryl,5-morpholino-pentanoyl, 6-morpholinohexanoyl, 7-morpholino-heptanoyl, 8-morpholino-octanoyl, 9-morpholino-nonanoyl, 10-morpholino-decanoyl; 4-amino5 piperidino-CpH2p-CO- such as 4-amino-piperidino-carbonyl, 4-amino-piperidino-acetyl, 3-(4-amino-piperidino)-propionyl, 4-(4-amino-piperidino)-butyryl, 5-(4-aminopiperidino )-pentanoyl, 6-(4-amino-piperidino)-hexanoyl, 7-(4-amino-piperidino)-heptanoyl, 8-(4-amino-piperidino) 10 octanoyl, 9-(4-amino-piperidino)-nonanoyl, 10-(4-aminopiperidino )-decanoyl; 4-dialkylamino-piperidino-CpH2p-COsuch as 4-dimethylamino-piperidinocarbonyl, 4-dimethylaminopiperidino-acetyl; 4-guanidino-piperidino-CpH2p-COsuch as 4-guanidino-piperidino-carbonyl, 4-guanidino15 piperidino-acetyl; 4-carboxy-piperidino-CpH2p-CO- such as 4- carboxy-piperidino-carbonyl, 4-carboxy-piperidinoacetyl; 4-alkoxycarbonyl-piperidino-CpH2p-CO- such as 4methoxycarbonyl-piperidino-carbonyl, 4-ethoxycarbonylpiperidino-carbonyl; 4-methoxycarbonyl-piperidino-acetyl, 4-ethoxycarbonyl-piperidino-acetyl; 4-AcNH-piperidinoCpH2p-CO- such as 4-acetamido-piperidino-carbonyl, 4acetamido-piperidino-acetyl; H2N-C (=NH)-NH-CpH2p-CO- such as guanidinoacetyl, 3-guanidinopropionyl, 4-guanidinobutyryl, 5-guanidino-pentanoyl, 6-guanidino-hexanoyl, 725 guanidino-heptanoyl, 8-guanidino-octanoyl; NC-NH-C(=NH)NH-CpH2p-CO- such as N' -cyanoguanidino-acetyl, 3-(N'cyanoguanidino)-propionyl, 4-(N'-cyanoguanidino)-butyryl; - (N'-cyanoguanidino)-pentanoyl, 6-(N'-cyanoguanidino)hexanoyl, 7-(N'-cyanoguanidino)-heptanoyl, 8-(N'-cyano30 guanidino)-octanoyl; HOOC-CpH2p-CO- such as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carboxynonanoyl, 10c ar boxy-dec anoyl, 11-carboxyundecanoyl; AOOC-CpH2p-COsuch as methoxycarbonyl-acetyl, 3-methoxycarbonyl-pro35 pionyl, 4-methoxycarbonyl-butyryl, 5-methoxycarbonylpentanoyl, 6-methoxycarbonyl-hexanoyl, 7-methoxycarbonylheptanoyl, 8-methoxycarbonyl-octanoyl, 9-met ho xyc arbony 1PAT LOG 19-B 130989 - 14 nonanoyl, 10-methoxycarbonyl-decanoyl, ethoxycarbonylacetyl, 3-ethoxycarbonyl-propionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonyl-pentanoyl, hexanoyl, 7-ethoxycarbonyl-heptanoyl, 6-ethoxycarbonyl8-ethoxycarbonyl10 octanoyl, 9-ethoxycarbonyl-nonanoyl, 10-ethoxycarbonyldecanoyl; H-SO3-CpH2p-CO- such as sulfo-acetyl, 3-sulfopropionyl, 4-sulfo-butyryl, 5-sulfo-pentanoyl, 6-sulfohexanoyl, 7-sulfo-heptanoyl, 8-sulfo-octanoyl, 9-sulfononanoyl, 10-sulfo-decanoyl; A-SO3-CpH2p-CO- such as methoxysulfonyl-acetyl, 3-methoxysulfonyl-propionyl, 4-methoxysulfonyl-butyryl, 5-methoxysulfonyl-pentanoyl, 6-methoxysulfonyl-hexanoyl, 7-methoxysulfonyl-heptanoyl, 8methoxysulfonyl-octanoyl, 9-methoxysulfonyl-nonanoyl, 10methoxysulfonyl-decanoyl, ethoxysulfonyl-acetyl, 3-ethoxysulfonyl-propionyl, 4-ethoxysulfonyl-butyryl, 5-ethoxysulfonyl-pentanoyl, 6-ethoxysulfonyl-hexanoyl, 7-ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyl-octanoyl, 9-ethoxysulfonyl-nonanoyl, 10-ethoxysulfonyl-decanoyl; A-O(CH2CH2O)r-CpH2p-CO- such as 3,6-dioxa-heptanoyl, 3,6- or 4,7-dioxa-octanoyl, 3,6-, 4,7- or 5,8-dioxa-nonanoyl, 3.6.9- trioxa-decanoyl,3,6,9-or 4,7,10-trioxa-undecanoyl, 3.6.9- , 4,7,10- or 5,8,11-trioxa-dodecanoyl.
If n is 2, the two radicals R5 can be identical to or different from one another; in the latter case, preferably one radical R5 is H and the other is A, in particular isopropyl, and the group -(CHR5)n- is preferably -CH2-CHA-, in particular -CH2-CH(isopropyl)-. n can also be 0.
R9 is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl or benzyl.
The group K is preferably -NH-CHR3-CHOH-CH2-CO-, in particular AHCP, AHCH, Sta or AHPP. The group K is furthermore preferably -NH-CHR3-CH(NH2)-CH2-CO-, in particular DACP, DACH, DAMH or DAPP.
The group K has at least one chiral centre. Further chiral centres may be present in the groups R1 to R5 CpH2p, CJH^-CHWR3, Z, E, Q and Y. The compounds of the PAT LOG 19-B 130989 formula I can therefore occur in various, optically inactive or optically active, forms. The formula I embraces all these forms. If K is -NH-CHR3-CR4-CH2-COwith R4 being (H, OH) or (H, NH2), the 3S-hydroxy-4S-amino enantiomers and 3S,4S-diamino enantiomers are preferred.
The abbreviations AHCP, AHCH, Sta, AHPP, DACP, DACH, DAMH and DAPP always relate to the 3S,4S forms.
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably have 1 to 3, in particular 1 or 2, substituents.
E is preferably one of the said amino acid residues, in particular lie or Leu; furthermore, E is preferably absent or is preferably Abu, Cal, Met, Nle, Nva, Phe or Val.
Q is preferably NR10, in particular NH or N(CH3).
Y is preferably -CtH2t -R11 or -CtH2t-R12, in particular -CH2Rn, -CH2R12 or -CH2CH2R12. In these, R11 is preferably H, A, Ar or Het, specifically and preferably H, alkyl having 3-5 C atoms, phenyl, ο-, m- or p-amino20 methylphenyl, ο-, m- or p-guanidinomethylphenyl, ο-, mor p-dialkylaminomethylphenyl, such as ο-, m- or pdimethylaminomethylphenyl, 2-, 3- or 4-pyridyl, 2-hydroxy-4 ,6-dimethyl-3-pyridyl, 4-amino-2-methyl-5-pyrimidinyl or 2-amino-5,6-dimethyl-3-pyrazinyl. R12 is prefer2 5 ably -SO3H, -SO2NH2, -NA2, -NA3+An, -NH-C( =NH) -NH2, -NH-CONHA or -NH-CS-NHA, wherein A is preferably CH3.
Some particularly preferred meanings of the group Q-Y are -NH-CH2-(4-amino-2-methyl-5-pyrimidinyl) ( AMPA), -NH-CH2-( 2-amino-5,6-dimethyl-3-pyrazinyl) (ADPA) and -NH-CH2-( 3-pyridyl), furthermore -NH-A.
Accordingly, the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated hereinbefore. Some preferred groups of cora35 pounds can be represented by the following partformulae la to Ii which correspond to the formula I but in which PAT LOG 19-B 130989 - 16 10 in la R1 is R6R7N- ; in lb R1 is R6-NH-C(=NH)-NH or NC-NH- in Ic R1 is R6OOC-; in Id R1 is R6O3S-; in Ie R1 is R6-0-(CH2CH2O) r-; in If R1 is R6R7N-; R6 is H or A, R7 is H, A, BOC or CBZ, R5R7N is also 4-aminopiperidino, q is 0 and P is 0, 1, 2, 3, 4, 5, 6 or 7 in ig R1 is R5OOC, R5 is H or A and q is 0; in Ih R1 is R6O3S; Rs is H or A and q is 0; in Ii r5r7n is 4-aminopiperidino and q and p are ϊ each 0.
Particularly preferred compounds are those of the part-formulae: (a) Iaa to Iia, which correspond to the formulae la to Ii but in which additionally R2 is phenyl or p-methoxyphenyl; (b) lab to lib as well as Iaab to Iiab, which correspond to the formulae la to Ii and Iaa to Iia but in which additionally -Z-CJi^-CHWR3- is -NH-CH2-CHOR3, or -NH-CH2-CHOH-, or -NH-(CH2) 3-CHNH3- or -NH-(CH2)ACHNH2- ; (c) lac to lie, Iaac to Iiac, Iabc to Iibc and Iaabc to Iiabc, which correspond to the formulae la to Ii, Iaa to Iia, lab to lib and Iaab to Iiab but in which additionally -NH-CHR3-CR4-(CHR5)Q-CO- (=K) is AHCP; (d) lad to lid, Iaad to Iiad, Iabd to Iibd, Iacd to lied, Iaabd to Iiabd, Iaacd to Iiacd, Iabcd to Iibcd and Iaabcd to Iiabcd, which correspond to the formulae la to Ii, Iaa to Iia, lab to lib, lac PAT LOG 19-B 130989 - 17 to lie, Iaab to Iiab, Iaac to Iiac, Iabc to Iibc and Iaabc to Iiabc but in which additionally E is lie or Leu; Particularly preferred compounds are those of the part5 formulae: I* and la* to Ii*, which correspond to the formulae I and la to Ii, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Q is NH, Y is H, A or -CH2Ru and R11 is o—, m- or p-aminomethylbenzyl, ο-, m- or pguanidinomethylbenzyl, 3-pyridyl, 4-amino-2-methyl5-pyrimidinyl or 2-amino-5,6-dimethyl-3-pyrazinyl; I' and la' to Ii', which correspond to the formulae I and la to Ii, as well as those compounds which correspond to the other abovementioned part-formulae but in which additionally Q is NH and Y is H, A, 4-amino-2-methyl-5-pyrimidinyImethyl or 2amino-5,6-dimethyl-3-pyrazinyImethyl.
The compounds of the formula I, as well as the starting materials for the preparation thereof, are furthermore prepared by methods which are known per se and as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie, (Methods of Organic Chemistry), published by Georg Thieme, Stuttgart; as well as EP-A-45665, EP-A-77028, EP-A 77029, EP-A-81783, EP-A30 249096) specifically under reaction conditions which are known and suitable for the said reactions. In this connection it is also possible to make use of variants which are known per se and which are not mentioned in detail herein.
It is also possible, if desired, to form the starting materials in situ so that they are not isolated from the reaction mixture but are immediately reacted PAT LOG 19-B 130989 - 18 further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis.
Preferred starting materials for the solvolysis or hydrogenolysis are those which correspond to the formula I apart from containing, in place of one or more free amino and/or hydroxyl groups, corresponding protect10 ed amino and/or hydroxyl groups, preferably those which carry an amino protective group in place of an H atom bonded to an N atom, for example those which correspond to the formula I but contain in place of a His group an N(im)-R'-His group (in which R' is an amino protective group, for example BOM or DNP), or those of the formula R1-CpH2p- ( NH ) q-CO-NH-CHRz-CO-Z-CmH2B1-CHNHR ' -CO-NH-CHR3CH(NHR')-(CHR5) n-CO-E-Q-Y.
Further preferred starting materials are those which carry, in place of the H atom of a hydroxyl group, a hydroxyl protective group, for example those of the formula R1-CpH2p-(NH)q-CO-NH-CHRz-CO-Z-C!nH2m-CHOR-CO-NHCHR3-CHOR-(CHR5)n-CO-E-Q-Y, in which R is a hydroxyl protective group.
It is also possible for more than one - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups which are present differ from one another it is possible in many cases to eliminate them selectively.
The term amino protective group is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl PAT LOG 19-B 130989 - 19 groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size are not otherwise critical; however, those which are preferred have 1-20, in particular 1-8 C atoms. The term acyl group in connection with the present process is to be interpreted in the widest sense. It embraces acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryl15 oxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbony1; aralkyloxycarbonyl such as CBZ, 4methoxybenzyloxycarbonyl, FMOC. Preferred amino protective groups are BOC, DNP and BOM, as well as CBZ, FMOC, benzyl and acetyl.
The term hydroxyl protective group is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemi2 5 cal reaction has been carried out elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, as well as alkyl groups. The nature and size of the hydroxyl protective groups are not critical because they are removed again after the desired chemical reaction or reaction sequence; preferred groups have 1-20, in particular 1-10, C atoms. Examples of hydroxyl protective groups are, inter alia, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulphonyl and acetyl, with benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I which are to be used as starting materials PAT LOG 19-B 130989 - 20 can be prepared by customary methods of amino acid and peptide synthesis as are described, for example, in the said standard works and patent applications, for example also by the solid-phase method of Merrifield.
The liberation of the compounds of the formula I from their functional derivatives is effected - depending on the protective group used - for example with strong acids, preferably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable and preferred inert solvents are organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, as well as alcohols such as methanol, ethanol or isopropanol, and water.
Furthermore suitable are mixtures of the abovementioned solvents. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, and perchloric acid in the form of a mixture of acetic acid and 70 % perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are preferably between about 0 and about 50°, preferably between 15 and 30° (room temperature).
The BOC group can be eliminated, for example, preferably with 40 % trifluoroacetic acid in dichloro30 methane or with about 3 to 5 N HCl in dioxane at 15-30°, and the FMOC group with an approximately 5-20 % solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°. Elimination of the DNP group is effected, for example, also with an approximately 3-10 % solution of 235 mercaptoethanol in DMF/water at 15-30°.
Protective groups which can be removed by hydrogenolysis (for example BOM, CBZ or benzyl) can be PAT LOG 19-B 130989 - 21 10 eliminated, for example by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, preferably on a support such as carbon). Solvents suitable for this are those mentioned above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is, as a rule, carried out at temperatures between about 0 and 100° under pressures between about 1 and 200 bar, preferably at 20-30° and under 1-10 bar. Hydrogenolysis of the CBZ group is effected satisfactorily, for example, on 5-10 % Pd-C in methanol at 20-30°.
Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid component (formula II) and an amine component (formula III). Examples of suitable carboxylic acid components are those of the part-formulae (a) R1-CpH2p(NH)q-COOH, (b) R1-CpH2p-(NH)q-CO-NH-CHR2-COOH, (c) R1CpH2p- (NH)q-CO-NH-CHR2-CO-Z-CmH2m-CHWR3-COOH, (d) rLc^(NH) q-CO-NH-CHR2-CO-Z-CniH2m-CHWR3-CO-K-OH or (f) R^CpH^(NH)q-CO—NH-CHR2—CO-Z-CDH2m-CHWR3-CO-K-E-OH, and of amine components are those of the part-formulae (a) H2N-CHR2CO-Z-CinH2ni-CHWR3-CO-K-E-Q-Y, (b) H-Z-Ca]H2ni-CHWR3-CO-K-E-QY, (c) H-K-E-Q-Y, (d) H-E-Q-Y or (f) H-NR10-Y. The peptide linkage can, however, also be formed within the group E; this entails a carboxylic acid of the formula (e) R1CpH2p-(NH)q-CO-NH-CHR2-CO-Z-CBH2m-CHWR3-CO-K-E1-OH being reacted with an amino compound of the formula H-K-E2-Q-Y, where E1 + E2 = E. The methods preferably used for this are those customary in peptide synthesis, as are described, for example, in Houben-Weyl, 1. c., Volume 15/11, pages 1-806 (1974).
The reaction is preferably effected in the presence of a dehydrating agent, for example a carbodiimide such as DCCI or dimethylaminopropylethyl-carbodiimide, or else propanephosphonic anhydride (compare Angew. Chem. 92., 129 ( 1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-l,2-dihydroquinoline, in an PAT LOG 19-B 130989 - 22 inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, or a nitrile such as acetonitrile, at temperatures between about -10 and 40, preferably between 0 and 30°.
It is also possible, in place of II or III, to use suitable reactive derivatives of these substances in the reaction, for example those in which reactive groups have undergone intermediate blocking with protective groups. The acid derivatives II can be used, for example, in the form of their activated esters which are preferably formed in situ, for example by addition of HOBt or Nhydroxysuccinimide.
Urea derivatives of the formula I (y = 1) can be obtained, for example, by reacting an isocyanate of the formula R1-CpH2p-NCO (can be prepared from an amine of the formula R1-CpH2p-NH2 and phosgene) with an amine of the formula H2N-CHR2-CO-Z-C!nH2m-CHWR:}-CO-K-E-Q-Y (Ila), preferably in an inert solvent such as THF, at temperatures between about -10 and 40°, preferably between 10 and 30°.
The starting materials of formulae II and III are mostly known. Those which are unknown can be prepared by known methods, for example the abovementioned methods of peptide synthesis and of elimination of protective groups.
If desired, it is possible for a functionally modified amino and/or hydroxyl group in a compound of the formula I to be liberated by solvolysis or hydrogenolysis by one of the methods described above.
Thus, for example, a compound of the formula I which contains an R9-CrH2x-O-CO-NH-, an AcNH-, an ArCH2-SO3- or an AOOC-group can be converted into the corresponding compound of the formula I which contains in its stead an H2N-, an HSO3- or an HOOC- group, preferably by selective solvolysis by one of the methods indicated above. AOOC-groups can, for example, be hydrolyzed with NaOH or KOH in water/dioxane at temperatures between 0 PAT LOG 19-B 130989 - 23 10 and 40°, preferably 10 and 30”.
Furthermore, for example, keto compounds of the formula I (R4 = 0) can be reduced to compounds of the formula I (R4 = (H, OH) ) , for example with a complex metal hydride such as NaBH4 which does not simultaneously reduce the peptide carbonyl groups, in an inert solvent such as methanol at temperatures between about -10 and +30°.
Keto compounds of the formula I (R4 = 0) can also be converted into compounds of the formula I (R4 = H, NH2) by reductive amination. The reductive amination can be carried out in one or more stages. Thus, for example, the keto compound can be treated with ammonium salts, for example ammonium acetate and NaCNBH3, preferably in an inert solvent, for example an alcohol such as methanol, at temperatures between about 0 and 50°, in particular between 15 and 30°. It is furthermore possible initially to convert the keto compound into the oxime, using hydroxylamine, in a customary manner, and to reduce the oxime to the amine, for example by catalytic hydrogenation on Raney nickel.
A base of the formula I can be converted into the relevant acid addition salt using an acid. Particularly suitable acids for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, as well as organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, PAT LOG 19-B 130989 - 24 benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids, and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify 5 the compounds of the formula I.
The new compounds of the formula I and the physiologically acceptable salts thereof can be used to prepare pharmaceutical products by converting them, together with at least one vehicle or auxiliary and, if 10 desired, together with one or more other active substance^), into a suitable dosage form. The compositions obtained in this way can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (for 15 example oral or rectal) or parenteral administration or for administration in the form of a spray for inhalation and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty 20 acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose. Used orally are, in particular, tablets, capsules, syrups, elixirs or drops; interest are lacquered tablets and capsules with enteric coatings or capsule shells. Used rectally are suppositories, and for parenteral administration are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. For administration by spray for inhalation, it is pos30 sible to use sprays which contain the active substance either dissolved or suspended in a propellant gas mixture (for example chlorofluorohydrocarbons). The active substance is preferably used for this in micronized form, with one or more additional physiologically tolerated 35 solvents possibly being present, for example ethanol.
Solutions for inhalation can be administered with the aid of customary inhalers. The new compounds can also be coated tablets, specifically of PAT LOG 19-B 130989 - 25 freeze-dried and the resulting lyophilisates used, for example, to prepare products for injection. The stated compositions can be sterilized and/or contain auxiliaries such as preservatives , stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colourants and/or flavourings. They can, if desired, also contain one or more other active substances, for example one or more vitamins.
The substances according to the invention are, as 10 a rule, administered in analogy to other known, commercially available peptides, but especially in analogy to the compounds described in EP-A-249096, preferably in dosages between about 10 mg and 1 g, in particular between 50 mg and 500 mg, per dosage unit. The daily dosage is preferably between about 0.2 and 20 mg/kg, in particular 1 and 10 mg/kg, of body weight. The specific dose for each particular patient depends, however, on a wide variety of factors, for example on the activity of the specific compound used, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration and on the rate of excretion, medicinal substance combination and severity of the particular disease for which the therapy is applied. Parenteral administration is preferred.
Renin-dependent hypertension and hyperaldosteronism can be effectively treated by administration of dosages between, in particular, about 1 and 300, preferably between 5 and 50, mg/kg of body weight. For diagnostic purposes, it is possible and preferable for the new compounds to be administered in single doses, particularly in about 0.1 and 10 mg/kg of body weight.
All temperatures stated hereinbefore and hereinafter are in °C. In the examples which follow, usual working up means: if necessary, water is added, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, extraction is carried out with ethyl acetate or dichloromethane, the organic phase PAT LOG 19-B 130989 - 26 is separated off, dried over sodium sulfate, filtered and concentrated, and purification is carried out by chrc-atography on silica gel and/or crystallization.
In the examples the 2 stereoisomers of each 5 compound are obtained in each case.
Example 1 A mixture of 890 mg of 3S-hydroxy-4S-(4-dimethylaminobutyryl-L-phenylalanyl-isoseryl-amino) -5-cyclohexylpentanoyl-N-imi-(2,4-dinitrophenyl)-L-histidine N-butyl10 amide [4-dimethylaminobutyryl-Phe-Isoser-AHCP-(imi-DNPHis) N-butylamide; obtainable by reaction of 4-dimethylaminobutyric acid with H-Phe-Isoser-AHCP- ( imi-DNP-His ) Nbutylamide], 2 g of 2-mercaptoethanol, 20 ml of DMF and 2 0 ml of water is adjusted to pH 8 with aqueous Na2CO3 solution while stirring at 20° and is stirred at 20° for hours. The usual working up results in 4-dimethylaminobutyryl-Phe-Isoser-AHCP-His N-butylamide.
Example 2 gof 3S-CBZ-amino-4S-(4-dimethylamino-butyryl20 Phe-Isoser-amino)-5-cyclohexyl-pentanoyl-Ile AMPA (obtainable by reaction of 4-dimethylaminobutyryl-Phe-OH with 3S-CBZ-amino-4S-Isoser-amino-5-cyclohexyl-pentanoylIle AMPA) are dissolved in 150 ml of ethanol and hydrogenated on 5 g of 10 % Pd-C at 20° and under 1 bar until H2 uptake ceases, the mixture is filtered, the filtrate is evaporated, and purification by chromatography results in 3S-amino-4S-( 4-dimethylamino-butyryl-Phe-Isoser-amino) 5-cyclohexyl-pentanoyl-Ile AMPA ( 4-dimethylaminobutyrylPhe-Isoser-DACP-Ile AMPA).
The following are obtained analogously from the corresponding CBZ derivatives: 4-Morpholino-butyryl-Phe-Isoser-DACH-Ile-OMe 4-Pyrrolidino-butyryl-Phe-Isoser-DAMH-Ile-NH2 4-Piperidino-butyryl-Phe-Isoser-DAPP-Ile-OEt. 4-BOC-Amino-piperidinocarbonyl-Phe-Isoser-AHCPHis-NH2 is obtained analogously by hydrogenolysis of 4BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-(imi-BOMPAT LOG 19-B 130989 - 27 His) amide.
BOC-^Ala-Phe-Lys-AHCP-Ile ΑΚΡΑ BOC-^3Ala-Phe-Lys-AHCP-Ile AD PA BOC-jAla-Phe-Orn-AHCP-Leu ΑΚΡΑ BOC-3Ala-Phe-Orn-AHCP-Leu ADPA Example 3 A solution of 1 g of the di-BOC derivative of 4guanidino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile ΑΚΡΑ [obtainable by reaction of N,N'-di-BOC-S-methyl-isothiourea (m.p. 121°) with 4-aminopiperidinocarbonyl-Phe benzyl ester to give 4-(N,N'-di-BOC-guanidino)-piperidinocarbonyl-Phe benzyl ester, hydrogenolysis to give 4(N,N'-di-BOC-guanidino)-piperidinocarbonyl-Phe-OH and condensation with H-Isoser-AHCP-Ile ΑΚΡΑ] in 20 ml of 4 N HC1 in dioxane is stirred at 20° for 30 min and then evaporated. 4-Guanidino-piperidinocarbonyl-Phe-IsoserAHCP-Ile ΑΚΡΑ is obtained in the form of the dihydrochloride .
The following are obtained analogously from the corresponding di-BOC or tri-BOC derivatives: 4-Guanidino-piperidinocarbonyl-Phe-0rn-AHCP-Ile ΑΚΡΑ 4-Guanidino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile ADPA 4-Guanidino-piperidinocarbonyl-Phe-Isoser-AHCP-Leu ΑΚΡΑ 4-Guanidino-piperidinocarbonyl-Phe-Isoser-AHCP-Leu ADPA 4-Guanidino-piperidinocarbonyl-Phe-Lys-AHCP-Ile ADPA 4-Guanidino-piperidinocarbonyl-Phe-Lys-AHCP-Leu AMPA 4-Guanidino-piperidinocarbonyl-Phe-0rn-AHCP-Leu ADPA 4-Guanidino-piperidinocarbonyl-Phe-Lys-AHCP-Ile-ADPA 6-Guanidino-hexanoyl-Phe-Isoser-AHCP-Ile ΑΚΡΑ 30 6-Guanidino-hexanoyl-Phe-Isoser-AHCP-Ile ADPA 6-Guanidino-hexanoyl-Phe-Isoser-AHCP-Leu ΑΚΡΑ 6-Guanidino-hexanoyl-Phe-Isoser-AHCP-Leu ADPA 6-Guanidino-hexanoyl-Phe-Lys-AHCP-Ile ΑΚΡΑ 6-Guanidino-hexanoyl-Kal-Isoser-AHCP-Ile ΑΚΡΑ 6-Guanidino-hexanoyl-Mal-Isoser-AHCP-Ile ADPA PAT LOG 19-B 130989 - 28 6-Amino-hexanoyl-Phe-1 soser-AHCP-He N-6-aminohexyl-amide 6-Amino-hexanoyl-Phe-Isoser-AHCP-lie N-6-guanidinohexylamide 6-Amino-hexanoyl-Phe-Orn-AHCP-Ile N-6-guanidinohexyl5 amide.
Example 4 1.01 g of N-methylmorpholine are added to a solution of 6.52 g of H-Phe-Isoser-AHCP-Ile AMPA (obtainable by condensation of BOC-Phe-Isoser-AHCP-Ile-OH with 4-araino-5-aminomethyl-2-methyl-pyrimidine to give BOCPhe-Isoser-AHCP-Ile AMPA and subsequent elimination of the BOC group) in 160 ml of DMF. While stirring, 2.31 g of 6-BOC-amino-hexanoic acid, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of CH2C12 are added, the mixture is stirred at 4° for 12 hours, the precipitated dicyclohexylurea is filtered off, and the filtrate is evaporated. The usual working up results in 6-BOCaminohexanoyl-Phe-Isoser-AHCP-Ile AMPA.
The following are obtained analogously: BOC-/9Ala-Phe-Isoser-AHCP-Ile-NH2 BOC-^Ala-Phe-Isoser-AHCP-He N-butylamide BOC-^9Ala-Phe-1 soser-AHCP-He N-pentylamide BOC-^Ala-Phe-Isoser-AHCP-Ile N,N-diethylamide BOC-^Ala-Phe-Isoser-AHCP-Ile AMPA 25 BOC-^Ala-Phe-Isoser-AHCP-Ile ADPA BOC-^Ala-Phe-Isoser-AHCP-Leu AMPA BOC-j3Ala-Phe-1 soser-AHCP-Leu ADPA 4-BOC-aminobutyryl-Phe-Isoser-AHCP-lie AMPA 4-BOC-aminobutyryl-Phe-Isoser-AHCP-Ile ADPA 4-BOC-aminobutyryl-Phe-Isoser-AHCP-Leu AMPA 4-BOC-aminobutyryl-Phe-Isoser-AHCP-Leu ADPA 4-BOC-aminobutyry1-Mai-Isoser-AHCP-Ile AMPA PAT LOG 19-B 130989 -294-BOC-aminobutyryl-Mai-Isoser-AHCP-lie ADPA -BOC-aminopentanoyl-Phe-Isoser-AHCP-lie AMPA -BOC-aminopentanoyl-Phe-Isoser-AHCP-lie ADPA 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-lie amide 5 6-BOC-aminohexanoyl-^Ala-Isoser-AHCP-Ile amide 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-lie ADPA 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-Leu AMPA 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-Leu ADPA 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-lie AMPA 6-BOC-aminohexanoyl-Mal-Isoser-AHCP-Ile AMPA 6-BOC-aminohexanoyl-Mal-Isoser-AHCP-Ile ADPA 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-lie N-3-pyridyl methylamide 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-lie N-m-aminomethyl benzylamide 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-lie N-p-dimethyl aminomethyl-benzylamide 6-BOC-aminohexanoyl-Phe-1 soser-AHCP-lie N-5-tetrazolyl methylamide 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-Ile N-3-dimethyl aminopropylamide 6-BOC-aminohexanoyl-Phe-1 soser-AHCP-lie N-2-sulfoethyl amide 7-BOC-aminoheptanoyl-Phe-Isoser-AHCP-lie AMPA 25 7-BOC-aminoheptanoyl-Phe-Isoser-AHCP-Ile ADPA 8-BOC-aminooctanoyl-Phe-Isoser-AHCP-lie AMPA 8-BOC-aminooctanoyl-Phe-Isoser-AHCP-lie ADPA Dimethylaminoacetyl-Phe-Isoser-.JiCP-Ile AMPA 3-Dimethylamino-propionyl-Phe-Isoser-AHCP-Ile AMPA PAT LOG 19-B 130989 -304-Dimethylamino-butyryl-Phe-Isoser-AHCP-lie AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-lie ADPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-lie p-sulfamoyl anilide 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Leu AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Leu ADPA 4-Dimethylaminobutyryl-Mai-Isoser-AHCP-lie AMPA 4- Dimethylaminobutyryl-Mai-Isoser-AHCP-lie ADPA - Dimethylamino-pentanoyl-Phe-Isoser-AHCP-lie AMPA -Dimethylamino-pentanoyl-Phe-Isoser-AHCP-ILE ADPA -Dimethylamino-pentanoyl-Phe-Isoser-AHCP-Leu AMPA - Dimethylamino-pentanoyl-Phe-Isoser-AHCP-Leu ADPA 6- Dimethylamino-hexanoyl-Phe-Isoser-AHCP-lie AMPA 6-Dimethylamino-hexanoyl-Phe-Isoser-AHCP-Ile ADPA 6-Dimethylamino-hexanoyl-Phe-Isoser-AHCP-Leu AMPA 6-Dimethylamino-hexanoyl-Phe-Isoser-AHCP-Leu ADPA 6-Dimethylamino-hexanoyl-Mai-Isoser-AHCP-lie AMPA 6- Dimethylamino-hexanoyl-Mai-Isoser-AHCP-lie ADPA 7- Dimethylamino-heptanoyl-Phe-Isoser-AHCP-lie AMPA 8-Dimethylamino-octanoyl-Phe-Isoser-AHCP-Ile AMPA (4-Piperidyl)-acetyl-Phe-Isoser-AHCP-Ile AMPA, dihydro chloride (4-Piperidyl)-acetyl-Phe-Isoser-AHCP-Ile ADPA Piperidinoacetyl-Phe-Isoser-AHCP-He AMPA Piperidinoacetyl-Phe-Isoser-AHCP-Ile ADPA 3-Piperidino-propionyl-Phe-Isoser-AHCP-lie AMPA 3- Piperidino-propionyl-Phe-Isoser-AHCP-lie ADPA 4- Pyrrolidino-butyryl-Phe-Isoser-AHCP-Ile AMPA, dihydro chloride PAT LOG 19-B 130989 -314-Pyrrolidino-butyryl-Phe-Isoser-AHCP-lie ADPA 4-Piperidino-butyryl-Phe-Isoser-AHCP-Ile AMPA, dihydrochloride 4- Piperidino-butyryl-Phe-Isoser-AHCP-Ile ADPA -Pyrrolidino-pentanoyl-Phe-Isoser-AHCP-Ile AMPA, dihydrochloride - Pyrrolidino-pentanoyl-Phe-Isoser-AHCP-Ile ADPA -Pyrrolidino-pentanoyl-Phe-Isoser-AHCP-Ile AMPA -Piperidino-pentanoyl-Phe-Isoser-AHCP-Ile AMPA, dihydro10 chloride -Piperidino-pentanoyl-Phe-Isoser-AHCP-Ile ADPA - Piperidino-pentanoyl-Phe-Isoser-AHCP-lie AMPA 6- CBZ-amino-hexanoyl-Phe-Isoser-AHCP-lie AMPA 6-CBZ-amino-hexanoyl-Phe-Isoser-AHCP-lie ADPA 2-CBZ-amino-2-methyl-propionyl-Phe-Isoser-AHCP-Ile ADPA 2-CBZ-amino-2-methyl-propionyl-Phe-Isoser-AHCP-lie AMPA 2-CBZ-amino-2-methyl-propionyl-Mal-Isoser-AHCP-lie AMPA 2-CBZ-amino-2-methyl-propionyl-Mai-Isoser-AHCP-lie ADPA Example 5 The two stereoisomers 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA m.p. 142-150’ and m.p. 146-151’are obtained in analogy to Example 4 from 4BOC-amino-piperidinocarbonyl-Phe-OH (m.p. 158-159’) and H-Isoser-AHCP-Ile AMPA (obtainable from BOC-Isoser-AHCP25 lie AMPA (two stereoisomers with m.p. 102-109’ and 105114’)).
The following are obtained analogously 3,6-Dioxaheptanoyl-Phe-Isoser-AHCP-Ile AMPA, [obtainable via BOC-Isoser-AHCP-Ile AMPA and H-Gly-AHCP30 lie AMPA] 3,6-Dioxaheptanoyl-Phe-Isoser-AHCP-Ile ADPA PAT LOG 19-B 130989 - 32 3,6,9-Trioxadecanoyl-Phe-Isoser-AHCP-Ile AMPA 3,6,9-Trioxadecanoyl-Phe-Isoser-AHCP-Ile ADPA 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Leu AMPA 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Leu ADPA 4-BOC-araino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile N-2pyridylmethylamide 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-lie N-3pyridylmethylamide 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCH-Ile AMPA 10 4-Dimethylamino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA 4-Dimethylamino-piperidinocarbonyl-Phe-Isoser-AHCP-lie ADPA -Ethoxycarbonyl-piper idinocarbonyl-Phe-1 soser-AHCP-lie 15 AMPA 4-Ethoxycarbonyl-piper idinocarbonyl-Phe-1 soser-AHCP-lie ADPA N-(Ethoxycarbonylmethyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA N-(Ethoxycarbonylmethyl)-carbamoyl-Phe-Isoser-AHCP-lie ADPA N-(4-Methoxycarbonylbutyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA N- ( 4-Methoxycarbonylbutyl)-carbamoyl-Phe-Isoser-AHCP-Ile 25 ADPA N- (6-Methoxycarbonylhexyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA N—(6-Methoxycarbonylhexyl)-carbamoyl-Phe-Isoser-AHCP-Ile ADPA Example 6 6-Methoxycarbonyl-hexanoyl-Phe-Isoser-AHCP-lie ADPA is obtained in analogy to Example 4 by condensation of 6-methoxycarbonyl-hexanoyl-Phe-Isoser-OH with H-AHCPPAT LOG 19-B 130989 - 33 lie ADPA.
The following are obtained analogously 3-Methoxycarbonyl-propionyl-Phe-Isoser-AHCP-lie AMPA 3- Methoxycarbonyl-propionyl-Phe-Isoser-AHCP-lie ADPA 4-Ethoxycarbonyl-butyryl-Phe-Isoser-AHCP-Ile AMPA 4- Ethoxycarbony1-butyryl-Phe-Isoser-AHCP-lie ADPA - Ethoxycarbonyl-pentanoyl-Phe-Isoser-AHCP-Ile AMPA - Ethoxycarbonyl-pentanoyl-Phe-Isoser-AHCP-lie ADPA 6- Methoxycarbonyl-hexanoy1-Phe-Isoser-AHCP-Ile AMPA 6-Methoxycarbonyl-hexanoyl-Phe-Isoser-AHCP-Ile ADPA 6-Methoxycarbonyl-hexanoyl-Phe-Isoser-AHCP-Leu ADPA 4-CBZ-amino-butyryl-Phe-Isoser-AHCP-lie AMPA 4- CBZ-amino-butyryl-Phe-Isoser-AHCP-lie ADPA - CBZ-amino-pentanoyl-Phe-Isoser-AHCP-lie AMPA -CBZ-amino-pentanoyl-Phe-Isoser-AHCP-Ile ADPA 6- CBZ-amino-hexanoyl-Mai-Isoser-AHCP-lie AMPA 6-CBZ-amino-hexanoyl-Mal-Isoser-AHCP-lie ADPA 6-N'-Cyanoguanidino-hexanoyl-Phe-Isoser-AHCP-lie AMPA 6-N'-Cyanoguanidino-hexanoyl-Phe-Isoser-AHCP-Ile ADPA 3-Benzyloxysulfonyl-propionyl-Phe-Isoser-AHCP-Ile AMPA 3-Benzyloxysulfonyl-propionyl-Phe-Isoser-AHCP-Ile ADPA 2S-Isopropyl-4S-hydroxy-5S-(4-BOC-amino-piperidino carbonyl-Phe-Isoser-amino)-7-methyl-octanoyl-lie AMPA 2S-Isopropyl-4S-hydroxy-5S-(4-BOC-amino-piperidino carbonyl-Phe-Isoser-amino)-7-methyl-octanoyl-Ile ADPA.
Example 7 8-BOC-amino-octanoyl-Phe-I so ser-AHCP-11 PAT LOG 19-B 130989 - 34 p-sulfamoylanilide is obtained in analogy to Example 4 by condensation of 8-BOC-amino-octanoyl-Phe-Isoser-AHCP-OH with H-Ile p-sulfamoylanilide.
The following are obtained analogously 5 4-BOC-amino-butyryl-Phe-Isoser-AHCP-Ile p-sulfamoylanilide 4-BOC-amino-butyryl-Phe-Isoser-AHCP-Leu p-sulfamoylanilide ΣΟ -BOC-amino-pentanoyl-Phe-Isoser-AHCP-lie anilide -BOC-amino-pentanoyl-Phe-Isoser-AHCP-Leu anilide 6-BOC-amino-hexanoyl-Phe-Isoser-AHCP-lie anilide 6-BOC-amino-hexanoyl-Phe-Isoser-AHCP-Leu anilide 7-BOC-amino-heptanoyl-Phe-Isoser-AHCP-lie anilide 7-BOC-amino-heptanoyl-Phe-Isoser-AHCP-Leu anilide p-sulfamoylp-sulfamoylp-sulfamoylp-sulfamoyΙp-sulfamoylp-sulfamoyl8-BOC-amino-octanoyl-Phe-Isoser-AHCP-Leu p-sulfamoylanilide 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Abu AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Ala AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Cal AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Met AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Nle AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Nva AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Phe AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Trp AMPA 4-Dimethylamino-butyry 1-Phe-Isoser-AHCP-Tyr AMPA 4-Dimethylamino-butyryl-Phe-Isoser-AHCP-Val AMPA.
PAT LOG 19-B 130989 - 35 Example 8 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-Ile-Ala AMPA is obtained in analogy to Example 4 from 6-BOC-aminohexanoyl-Phe-Isoser-AHCP-Ile-OH and Η-Ala AMPA.
Example 9 6-CBZ-amino-hexanoyl-Phe-Isoser-AHCP-Ile AMPA is obtained in analogy to Example 4 from 6-CBZ-amino-hexanoyl-Phe-Isoser-AHCP-Ile-OH and 4-amino-5-aminomethyl-2methylpyrimidine.
The following are obtained analogously: 4-Methyl-piperidino-carbonyl-Phe-Isoser-AHCP-Ile AMPA 4-Hydroxy-piperidino-carbonyl-Phe-Isoser-AHCP-Ile AMPA, hydrochloride 4-Methyl amino-piper idino-carbonyl-Phe-1 soser-AHCP-lie 15 AMPA 4-Acetamido-piperidino-carbonyl-Phe-Isoser-AHCP-lie AMPA 4-POA-amino-piperidino-carbonyl-Phe-Isoser-AHCP-lie AMPA 4- ( 2-Hydroxyethyl) -piperazino-carbonyl-Phe-Isoser-AHCPIle AMPA 4-Carbamoyl-piperidino-carbonyl-Phe-Isoser-AHCP-Ile AMPA 4-( 2-Trimethylammonio-ethyl) -piperidino-carbonyl-PheIsoser-AHCP-Ile AMPA chloride.
Example 10 A solution of 1.56 g of 5-dimethylaminopentyl isocyanate in 16 ml of THF is added dropwise at 20 to a stirred solution of 6.52 g of H-Phe-Isoser-AHCP-Ile AMPA in 65 ml of THF. The mixture is stirred at 20 for 3 hours, and the usual working out results in N-(5dimethylaminopentyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA.
The following are obtained analogously with the corresponding isocyanates : N-(2-Dimethylaminoethyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA PAT LOG 19-B 130989 - 36 N- ( 3-Dimethylaminopropyl) -carbamoyl-Phe-Isoser-AHCP-Ile AMPA N- ( 5-Dimethylaminopentyl) -carbamoyl-Mal-Isoser-AHCP-Ile AMPA Example 11 A solution of 1 g of 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA [obtainable by reaction of BOC-AHCP-Ile AMPA (m.p. 218-220°) with HCl/dioxane to give H-AHCP-lie AMPA and reaction with 4-BOC-amino10 piperidinocarbonyl-Phe-Isoser-OH] in 20 ml of 4 N HCl in dioxane is stirred at 20° for 30 min and then evaporated. Two stereoisomers 4-amino-piperidinocarbonyl-Phe-IsoserAHCP-Ile AMPA m.p. 203-210° and m.p. 205-214’ are obtained.
The following are obtained analogously from the corresponding BOC derivatives : H-^Ala-Phe-Isoser-AHCP-Ile AMPA H-^Ala-Phe-Isoser-AHCP-Ile ADPA H-^Ala-Phe-Isoser-AHCP-Leu AMPA H-^Ala-Phe-Isoser-AHCP-Leu ADPA 4-Aminobutyryl-Phe-Isoser-AHCP-lie AMPA 4-Aminobutyryl-Phe-Isoser-AHCP-lie ADPA 4-Aminobutyryl-Phe-Isoser-AHCP-Leu AMPA 4-Aminobutyryl-Phe-Isoser-AHCP-Leu ADPA 4-Aminobutyryl-Mai-Isoser-AHCP-lie AMPA 4- Aminobutyryl-Mai-Isoser-AHCP-lie ADPA - Aminopentanoy1-Phe-Isoser-AHCP-lie AMPA - Aminopentanoy1-Phe-Isoser-AHCP-lie ADPA 6- Aminohexanoyl-Phe-Isoser-AHCP-Ile amide 6-Aminohexanoyl-Phe-Isoser-AHCP-Ile AMPA 6-Aminohexanoyl-Phe-Isoser-AHCP-lie ADPA PAT LOG 19-B 130989 - 37 6-Aminohexanoyl-Phe-Isoser-AHCP-Leu AMPA 6-Aminohexanoyl-Phe-Isoser-AHCP-Leu ADPA 6-Aminohexanoyl-Mai-Isoser-AHCP-lie AMPA, dihydrochloride 6-Aminohexanoyl-Mal-Isoser-AHCP-Ile ADPA, dihydrochloride 6-Aminohexanoyl-Mal-Isoser-AHCP-Ile ADPA 6-Aminohexanoyl-Phe-Isoser-AHCP-lie N-3-pyridylmethylamide 6-Aminohexanoyl-Phe-Isoser-AHCP-lie N-m-aminomethylbenzylamide 6-Aminohexanoyl-Phe-Isoser-Ile N-p-dimethylaminomethylbenzylamide 6-Aminohexanoyl-Phe-Isoser-AHCP-Ile N-5-tetrazolylmethylamide 6-Aminohexanoyl-Phe-Isoser-AHCP-lie N-3-dimethylamino15 propylamide 6- Aminohexanoyl-Phe-Isoser-AHCP-lie N-2-sulfo-ethylamide 7- Aminoheptanoyl-Phe-Isoser-AHCP-lie AMPA 7- Aminoheptanoy1-Phe-1soser-AHCP-1le ADPA 8- Aminooctanoyl-Phe-Isoser-AHCP-lie AMPA 8-Aminooctanoyl-Phe-Isoser-AHCP-Ile ADPA 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-lie AMPA, dihydrochloride 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-lie ADPA 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-Leu AMPA 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-Leu ADPA 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-lie AMPA 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-lie N-2-pyridyl -me thy lamide 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-lie N-330 pyridyl-methylamide 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCH-Ile AMPA 4-Amino-piperidinocarbonyl-Phe-Isoser-Sta-lie AMPA 4-Amino-piperidinocarbonyl-Phe-Isoser-AHPP-lie AMPA PAT LOG 19-B 130989 - 38 2S-Isopropyl-4S-hydroxy-5S-(4-amino-piperidino-carbonylPhe-Isoser-amino)-7-methyl-octanoyl-lie AMPA 2S-Isopropyl-4S-hydroxy-5S-(4-amino-piperidino-carbonylPhe-Isoser-amino)-7-methyl-octanoyl-Ile ADPA 4-Amino-butyryl-Phe-Isoser-AHCP-Ile p-sulfamoylanilide 4- Amino-butyryl-Phe-Isoser-AHCP-Leu p-sulfamoylanilide - Amino-pentanoyl-Phe-Isoser-AHCP-lie p-sulfamoylanilide - Amino-pentanoyl-Phe-1 soser-AHCP-Leu p-sulfamoylanilide 6- Amino-hexanoyl-Phe-Isoser-AHCP-He p-sulfamoylanilide 6-Amino-hexanoyl-Phe-Isoser-AHCP-Leu p-sulfamoylanilide 7- Amino-heptanoyl-Phe-Isoser-AHCP-Ile p-sulfamoylanilide 7- Amino-heptanoyl-Phe-Isoser-AHCP-Leu p-sulfamoylanilide 8- Amino-octanoyl-Phe-Isoser-AHCP-Ile p-sulfamoylanilide 8-Amino-octanoyl-Phe-Isoser-AHCP-Leu p-sulfamoylanilide Example 12 A mixture of 1 g of 6-methoxycarbonyl-hexanoylPhe-Isoser-AHCP-Ile ADPA, 50 ml of dioxane and 20 ml of 2 N NaOH (aqueous) is stirred at 20° for 3 hours. The usual working up results in 6-carboxy-hexanoyl-Phe20 Isoser-AHCP-Ile ADPA.
The following are obtained analogously by hydrolysis : 3-Carboxy-propionyl-Phe-Isoser-AHCP-He AMPA 3- Carboxy-propionyl-Phe-Isoser-AHCP-He ADPA 4-Carboxy-butyryl-Phe-Isoser-AHCP-Ile AMPA 4- Carboxy-butyryl-Phe-Isoser-AHCP-He ADPA - Carboxy-pentanoyl-Phe-Isoser-AHCP-He AMPA -Carboxy-pentanoyl-Phe-Isoser-AHCP-Ile ADPA PAT LOG 19-B 130989 - 39 6-Carboxy-hexanoyl-Phe-Isoser-AHCP-lie AMPA 6-Carboxy-hexanoyl-Phe-Isoser-AHCP-Leu AMPA 6-Carboxy-hexanoyl-Phe-Isoser-AHCP-Leu ADPA 6-Carboxy-hexanoyl-Phe-Lys-AHCP-Ile AMPA 6-Carboxy-hexanoyl-Phe-Lys-AHCP-Ile ADPA 6-Carboxy-hexanoyl-Phe-Orn-AHCP-Leu AMPA 6-Carboxy-hexanoyl-Phe-Orn-AHCP-Leu ADPA 4-Carboxy-piperidinocarbonyl-Phe-isoser-AHCP-lie AMPA 4-Carboxy-piperidinocarbonyl-Phe-isoser-AHCP-lie ADPA N-(Carboxymethyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA N-(Carboxymethyl)-carbamoyl-Phe-Isoser-AHCP-Ile ADPA N-(4-Carboxybutyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA N-(4-Carboxybutyl)-carbamoyl-Phe-Isoser-AHCP-Ile ADPA N-(4-Carboxybutyl)-carbamoyl-Phe-Lys-AHCP-Ile AMPA N-(4-Carboxybutyl)-carbamoyl-Phe-Lys-AHCP-Ile ADPA N-(6-Carboxyhexyl)-carbamoyl-Phe-Isoser-AHCP-Ile AMPA N-(6-Carboxyhexyl)-carbamoyl-Phe-Isoser-AHCP-Ile ADPA N—(6-Carboxyhexyl)-carbamoyl-Phe-Orn-AHCP-lie AMPA N-(6-Carboxyhexyl)-carbamoyl-Phe-Orn-AHCP-Ile ADPA.
Example 13 6-Amino-hexanoyl-Phe-Isoser-AHCP-Ile AMPA is obtained in analogy to Example 2 from 6-CBZ-amino-hexanoyl-Phe-Isoser-AHCP-Ile AMPA by hydrogenolysis.
The following are obtained analogously by hydro25 genolysis of the corresponding CBZ derivatives: 2-Amino-2-methyl-propionyl-Phe-Isoser-AHCP-lie AMPA 2-Amino-2-methyl-propionyl-Phe-Isoser-AHCP-lie ADPA 2-Amino-2-methyl-propionyl-Mai-Isoser-AHCP-lie AMPA 2-Amino-2-methyl-propionyl-Mai-Isoser-AHCP-lie ADPA Example 14 3-Sulfo-propionyl-Phe-Isoser-AHCP-lie AMPA is obtained in analogy to Example 2 from 3-benzyloxysulfonyl-propionyl-Phe-Isoser-AHCP-Ile AMPA by PAT LOG 19-B 130989 - 40 hydrogenolysis .
The following are obtained analogously by hydrogenolysis of the corresponding benzyl esters: 3-Sulfo-propionyl-Phe-Isoser-AHCP-lie ADPA 5 3-Sulfo-propionyl-Phe-Lys-AHCP-Ile AMPA 3-Sulfo-propionyl-Phe-Lys-AHCP-lie ADPA.
Example 15 a) 3-Oxo-4S- ( 4-dimethylaminobutyryl-Phe-Isoser-amino) 5-cyclohexyl-pentanoyl-Ile AMPA is obtained in analogy to Example 4 from 4-dimethylaminobutyrylPhe-Isoser-OH and 3-oxo-4S-amino-5-cyclohexylpentanoyl-Ile AMPA. b) A solution of 1 g of the abovementioned keto amide in 25 ml of CH30H is hydrogenated on 0.1 g of 10 % Pd-C at 20° and under 1 bar until H2 uptake ceases.
Filtration and evaporation result in a mixture of 3R- and 3S-hydroxy-4S-(4-dimethylaminobutyryl-PheIsoser-amino)-5-cyclohexyl-pentanoyl-Ile AMPA.
Example 16 70 mg of hydroxylamine hydrochloride are added to a solution of 763 mg of 3-oxo-4S-(4-dimethylaminobutyrylPhe-Isoser-amino)-5-cyclohexylpentanoyl-Ile AMPA and 1.43 g of Na2CO310 H20 in 5 ml of methanol and 5 ml of water, and the mixture is stirred at 20’ for 14 hours.
The precipitated oxime is filtered off, dried, dissolved in 10 ml of methanol and hydrogenated on 0.5 g of Raney Ni at 20“ and under 5 bar. The catalyst is filtered off, the filtrate is evaporated, the resulting mixture is separated on silica gel, and 3S-amino-4S-(4-dimethyl30 amino-butyryl-Phe-1 soser-amino) -5-cyclohexylpentanoyl-Ile AMPA (4-dimethylaminobutyryl-Phe-Isoser-DACP-Ile AMPA) is obtained; the 3R-amino epimer is also obtained.
PAT LOG 19-B 130989 - 41 Example 17 The following are obtained in analogy to Example 4: 1-Methyl-4-piperidinyl-carbonyl-Phe-Isoser-AHCP-lie AMPA 5 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-Sta-Ile AMPA 6-BOC-amino-hexanoyl-N-Me-Mal-Isoser-AHCP-He AMPA 4-BOC-amino-piperidino-carbonyl-Phe-Isoser-AHCP-Isoser AMPA 3-(l-Methyl-2-piperidyl)-propionyl-Phe-Isoser-AHCP-Ile AMPA 3- (1-Methy1-2-piperidyl)-propionyl-Phe-1soser-AHCP-lie AMPA 4- (l-Methyl-2-piperidyl)-butyryl-Phe-Isoser-AHCP-Ile AMPA 4-(l-Methyl-2-piperidyl)-butyryl-Phe-Isoser-AHCP-Ile AMPA 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ala AMPA Pyrrolidinocarbonyl-Phe-Isoser-AHCP-He AMPA Morpholinocarbonyl-Phe-Isoser-AHCP-lie AMPA 4-BOC-amino-piperidinocarbonyl-Mai-Isoser-AHCP-He AMPA Piperidinocarbonyl-Phe-Isoser-AHCP-lie AMPA 4-BOC-amino-piperidinoacetyl-Phe-Isoser-AHCP-Ile AMPA 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Nle AMPA 3- BOC-amino-3-methyl-butyryl-Phe-Isoser-AHCP-Ile AMPA 4- BOC-amino-piperidinocarbonyl-Leu-Isoser-AHCP-Ile AMPA 3- BOC-amino-3-methyl-butyryl-Phe-Isoser-AHCP-lie N-325 pyridylmethyl-amide 4- Methy lsulf onamido-piper idinocarbonyl-Phe-1 soser-AHCPIle AMPA 4-( 3-Hydroxypropyl) -piperazinocarbonyl-Phe-Isoser-AHCPIle AMPA 4-BOC-piperazinocarbonyl-Phe-Isoser-AHCP-Ile AMPA 4-BOC-amino-piper idinocarbonyl-Phe-1 soser-AHCP-1 le-aminoacetic acid benzyl ester 3-(4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-IlePAT LOG 19-B 130989 - 42 amino)-propionic acid benzyl ester 4- (4 -BOC-amino-piperidinocarbony1-Phe-1soser-AHCP-1leamino)-butyric acid benzyl ester - (4-BOC-amino-piperidinocarbony1-Phe-Isoser-AHCP-Ile5 amino)-pentanoic acid benzyl ester 6- (4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ileamino)-hexanoic acid benzyl ester 4-Formamido-piperidinocarbony1-Phe-Isoser-AHCP-lie AMPA 4-Trifluoroacetamido-piperidinocarbony1-Phe-Isoser-AHCP10 He AMPA 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-D-Ile AMPA 4-BOC-amino-piperidinocarbonyl-Mal-Isoser-AHCP-lie AMPA 4-BOC-amino-piperidinocarbonyl-D-Phe-Isoser-AHCP-Ile AMPA 4-B0C-amino-piperidinocarbonyl-Phe-Isoser-AHCP-0Me 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile OMe 4-BOC-amino-piperidinoacetyl-Phe-Isoser-AHCP-Ile AMPA 4-Cyano-piperidinocarbonyl-Phe-Isoser-AHCP-lie AMPA 4-Dimethylaminomethyl-piperidinocarbonyl-Phe-Isoser-AHCPIle AMPA 4-BOC-aminomethyl-piperidinocarbony1-Phe-Isoser-AHCP-He AMPA 3- (2-Piperidyl)-propionyl-Phe-Isoser-AHCP-Ile AMPA, tris(trifluoroacetate) 4- (2-Piperidyl) -butyiryl-Phe-1 soser-AHCP-He AMPA, tri25 acetate Example 18 The following are obtained in analogy to Example 11 from the corresponding BOC compounds: -Amino-piperidinocarbony1-Phe-1soser-Sta-He AMPA, dihydrochloride 4-Ami no-piperidi nocarbonyl-Phe-1 soser-AHCP-1 soser-AMPA, dihydrochloride 4-Amino-piperidinocarbony1-Phe-Isoser-AHCP-Ala AMPA, dihydrochloride 4-Amino-piperidinocarbonyl-Mal-Isoser-AHCP-Ile AMPA, PAT LOG 19-B 130989 - 43 dihydrochloride 4-Amino-piperidinoacetyl-Phe-Isoser-AHCP-lie AMPA trihydrochloride 3- Amino-3-methy1-butyryl-Phe-1soser-AHCP-lie AMPA dihydrochloride 4- Amino-piperidinocarbonyl-Leu-Isoser-AHCP-lie AMPA dihydrochloride 3- Amino-3-methyl-butyryl-Phe-Isoser-AHCP-lie N-3-pyridyl methyl-amide 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-D-Ile AMPA dihydrochloride 4- Amino-piperidinocarbonyl-Mal-Isoser-AHCP-lie AMPA dihydrochloride 4-Amino-piperidinoc arbonyl-D-Phe-1soser-AHCP-1le AMPA dihydrochloride 4-Amino-piperidinoc arbonyl-Phe-Isoser-AHCP-OH hydrochloride 4-Amino-piperidinocarbonyl-Phe-1soser-AHCP-1le-OH hydrochloride Piperazinocarbonyl-Phe-Isoser-Ile AMPA, dihydrochloride 4-Amino-piperidinoacetyl-Phe-Isoser-AHCP-lie AMPA trihydrochloride 4-Amino-piperidinocarbonyl-Phe-1 soser-AHCP-1 le-amino· acetic acid 3-( 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile-amino) propionic acid 4- ( 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile-amino) butyric acid - ( 4-Amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile-amino) pentanoic acid 6- ( 4-Amino-piper idinoc arbonyl-Phe-1 soser-AHCP-1 le-amino) hexanoic acid 4-Aminomethyl-piperidinocarbonyl-Phe-Isoser-AHCP-I1< AMPA.
PAT LOG 19-B 130989 - 44 Example 19 The following are obtained in analogy to Example 2 by hydrogenolysis of the corresponding benzyl esters : 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile-aminoacetic acid 3- (4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ileamino)-propionic acid 4- (4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile10 amino)-butyric acid - (4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ileamino)-pentanoic acid 6- (4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ileamino)-hexanoic acid Example 20 The following are obtained in analogy to Example 12 by hydrolysis of the corresponding methyl esters : 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-OH 20 4-BOC-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile-OH Example 21 A mixture of 792 mg of 4-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA, 90 mg of S-methylisothiourea, 5 ml of ethanol and 5 ml of water is stirred at 50’ for 2 h. The usual working up results in 4-guanidinyl-piperidinocarbonyl-Phe-Isoser-AHCP-lie AMPA. Example 22 A mixture of 792 mg of 4-amino-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA, 115 mg (= 0.132 ml) of trimethylsilyl isocyanate and 10 ml of THF is stirred at ° for 16 h. The mixture is then stirred into water, and the usual working up results in 4-ureido-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA, hydrochloride.
PAT LOG 19-B 130989 - 45 The following are obtained analogously using the corresponding alkyl isocyanates: 4- (N ' -Ethylureido)-piperidinocarbonyl-Phe-Isoser-AHCP-Ile AMPA, hydrochloride 4 - (N ' -Isopropylureido) -piperidinocarbony 1-Phe -IsoserAHCP-Ile AMPA, hydrochloride The examples which follow relate to pharmaceutical compositions: Example A: Tablets A mixture of 1 kg of 4-aminopiperidinocarbonylPhe-Isoser-AHCP-Ile AMPA dihydrochioride, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is compressed in a customary manner to give tablets in such a way that each tablet contains 500 mg of active compound.
Example B: Coated tablets Tablets are compressed in analogy to Example A and are then coated in a customary manner with a coating composed of sucrose, maize starch, talc, tragacanth and colorant.
Example C: Capsules 500 g of 6-aminohexanoyl-Phe-Isoser-AHCP-Isoser AMPA dihydrochioride are dispensed in a customary manner into hard gelatin capsules so that each capsule contains 500 mg of active compound.
Example D: Injection ampoules A solution of 100 g of the Na salt of 6-carboxyhexanoyl -Phe- I soser-AHCP- lie ADPA in 4 1 of doubledistilled water is adjusted to pH 6.5 with 2 N hydro30 chloric acid, filtered sterile and dispensed into injection ampoules. These are lyophilized under sterile conditions and sealed sterile. Each injection ampoule contains 50 mg of active compound.
Example E: Suppositories A mixture of 50 g of 4-dimethylaminobutyryl-PheIsoser-AHCP-Ile AMPA dihydrochioride with 10 g of soya PAT LOG 19-B 130989 - 46 lecithin and 140 g of cocoa butter is melted, poured into moulds and left to cool. Each suppository contains 250 rag of active compound.
PAT LOG 19-B 130989 Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt

Claims (13)

1. Patent claims Amino acid derivatives of the formula I -CHWR 3 -COCpH2p-(NH)q-CO-NH-CHR 2 -CO-Z-CmH 2m NH-CHR 3 -CR 4 -(CHR 5 ) n ~CO-E-Q-Y in which R 1 is R 6 R 7 N-, R 6 -NH-C(=NH)-NH-, NC-NH-C ( =NH) -NH- , R 5 OOC-, R 6 O3S- or R s -O- (CH2CH 2 O) r -, Z is -0-, -CH 2 -, -CH=CH-, -OC-, -NR 3 -, -CH 2 -O-, -CH 2 -NR 3 - or -CH 2 -S-, E is 0 to 2 amino acid residues which are linked together in the manner of a peptide and are selected from the group comprising Abu, Ala, Cal, His, lie, Leu, Met, Nle, Nva, Phe, Trp, Tyr and Val, Q is 0 or NR 10 , Y is -C t H zt -R n , -C t H 2t -R 12 or -C^- (CR 13 ) .-CJ^-R 11 , WR 3 is -OR 3 or -NHR 3 , R 2 , R 3 and R 11 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, unsubstituted or singly or multiply, by A, AO and/or Hal, substituted cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R* and R 13 are each (H, OH), (H, NH 2 ) or =0, R 5 , R 3 and R 10 are each H or A, R 5 and R 7 are each H, A or Ar-alkyl, R 7 is also RLo-C^-CO-, R 9 -C x H 2x -O-CO- or Ac, R 9 is A or Ar-alkyl, R 6 R 7 N is also a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group which is unsubstituted or PAT LOG 19-A 130989 - 48 substituted by A, OH, NH 2 , NHA, NA2, NHAc, NH-CO-CJI^-O-R 9 , NH-CO-O-C^-R 9 , NH-SO2-A, hydroxyalkyl, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N®alkyl An 9 , NH-CO-NH2, NH-CO-NHA, NH-CONA 2 , guanidinyl or guanidinyl-alkyl, R 12 is -SO 3 H, -SO 2 NH 2 , -SO 2 NHA, -SO 2 NA 2 , -NH 2 , -NHA, -NA 2 , -NH-C(=NH)-NH 2 , -NH-C(=NH)-NHCN, -NH-CO-NH 2 , -NH-CO-NHA, -NH-CO-NA,, -NH-CS-NH 2 , -NH-CS-NHA, -NH- CS-NA 2 , -COOH, -COOA, -COO-alkyl-Ar, or -CONA 2 , -CONH 2 , -CONHA q is 0 or 1, n is 0, 1 or 2, s is 1 or 2, m, p, t, w and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, r is 1, 2 or 3, Ar is phenyl which is unsubstituted or singly or multiply substituted by A, OA, Hal, CF 3 , OH, NO Z , hydroxyalkyl, NH 2 , NHA, NA 2 , NHAc, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, aminoalkyl, HAN-alkyl, A 2 N-alkyl, A 3 N®alkyl An 9 and/or guanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical which has 1-4 N, 0 and/or S atoms andean be fused with 2 benzene ring and/or can be singly or multiply substituted by A, OA, Hal, CF 3 , OH, NO 2 , carbonyl oxygen, NH 2 , NHA, NA 2 , NHAc, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, NH-SO 2 -A, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl, and/or whose N and/or S hetero atoms can also be oxidized, Hal is F, Cl, Br or I, Ac is H-CO-, A-CO-, CF 3 -CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, An 9 is an anion, which can also be absent if, in its stead, a carboxyl group contained in the compound of the formula I is in the form of a carboxylate anion, PAT LOG 19-A 130989 - 49 -alkyl- is an alkylene group having 1-8 C atoms, and A is alkyl having 1-8 C atoms, in which, furthermore, it is also possible for one or more -NH-CO- groups to be replaced by one or more -NA-COgroups, as well as the salts thereof.
2. a) 6-(BOC-amino)-hexanoyl-Phe-Isoser-AHCP-Ile AMPA; b) 6-Amino-hexanoyl-Phe-Isoser-AHCP-Ile ADPA; c) 4-Dimethylamino-butyryl-Phe-1soser-AHCP-lie AMPA; d) 4-Aminopiperidinocarbonyl-Phe-Isoser-AHCP-lie AMPA; e) 6-Methoxycarbonyl-hexanoyl-Phe-Isoser-AHCP-Ile ADPA; f) 6-Carboxy-hexanoyl-Phe-Isoser-AHCP-lie ADPA.
3. Process for the preparation of an amino acid derivative of the formula I, and of the salts thereof, characterized in that it is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that a carboxylic acid of the formula II R 1 -C p H 2p -(NH) (I -C0-G 1 -0H II in which G 1 is (a) absent, (b) -NH-CHR 2 -CO-, (C) -NH-CHR 2 -CO-Z-C D H 2m -CHWR 3 -CO-, (d) -NH-CHR 2 -CO-Z-C m H 2m -CHWR 3 -CO-K-, ( e) -NH-CHR 2 -CO-Z-C D H 2m -CHWR 3 -CO-K-E 1 - , (f) -NH-CHR 2 -CO-Z-CeH2m-CHWR 3 -CO-K-E- and K is -NH-CHR 3 -CR*-(CHR 5 )n-COor one of the reactive derivatives thereof, is reacted with an amino compound of the formula III H-G 2 III in which G 2 is (a) -NH-CHR 2 -CO-Z-CnH2n-CHWR 3 -CO-K-E-Q-Y, (b) -Z-CnH 2ni -CHWR 3 -CO-K-E-Q-Y, PAT LOG 19-A 130989 - 50 (c) -K-E-Q-Y, (d) -E-Q-Y, (e) -E 2 -Q-Y, (f) -NR 10 -Y and E 1 + E 2 are together E, and in that a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated where appropriate by treatment with solvolyzing or hydrogenolyzing agents, and/or for the preparation of a compound of the formula I, R 4 = (H, OH) or (H, NH 2 ), an amino keto acid derivative of the formula I, R 4 = 0, is reduced or reductively aminated, and/or a radical R 1 is converted into another radical R 1 and/or a compound of the formula I is converted by treatment with an acid into one of the salts thereof.
4. Process for the preparation of pharmaceutical compositions, characterized in that a compound of the formula I and/or one of the physiologically acceptable salts thereof is converted together with at least one solid, liquid or semi-liquid vehicle or auxiliary, and, where appropriate, in combination with one or more other active compound(s) into a suitable dosage form.
5. Pharmaceutical composition characterized by containing at least one compound of the formula I and/or one of the physiologically acceptable salts thereof.
6. Use of compounds of the formula I or of physiologically acceptable salts thereof for the preparation of a medicament.
7. Use of compounds of the formula I or of physiologically acceptable salts thereof for controlling renindependent hypertension or hyperaldosteronism.
8. An amino acid derivative of the formula I given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified.
9. A process for the preparation of an amino acid derivative of the formula I given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified. PAT LOG 19-A 130989 - 51
10. An amino acid derivative of the formula I given and defined in claim 1, or a salt thereof, whenever prepared by a process claimed in claims 3 or 9.
11. A pharmaceutical composition according to claim 5, substantially as hereinbefore described and exemplified.
12. Use according to claim 6, substantially as hereinbefore described.
13. Use according to claim 7, substantially as hereinbefore described.
IE342290A 1989-09-22 1990-09-21 Amino acid derivatives IE903422A1 (en)

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US5034512A (en) * 1987-10-22 1991-07-23 Warner-Lambert Company Branched backbone renin inhibitors
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