IE920422A1 - Amino acid derivatives - Google Patents
Amino acid derivativesInfo
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- IE920422A1 IE920422A1 IE042292A IE920422A IE920422A1 IE 920422 A1 IE920422 A1 IE 920422A1 IE 042292 A IE042292 A IE 042292A IE 920422 A IE920422 A IE 920422A IE 920422 A1 IE920422 A1 IE 920422A1
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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
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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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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- 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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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/70—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a carbon skeleton substituted by carboxyl groups
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/10—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/56—Nitrogen atoms
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- C07C2601/14—The ring being saturated
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Abstract
Novel amino acid derivatives of the formula I X-W-CR<1>R<2>-CO-NH-CH2CH2-CO-NH-CHR<3>-(CHOH)2-R<4> in which R<1> to R<4>, X and W have the meanings given in Patent Claim 1, and their salts inhibit the activity of human plasma renin. -
Description
Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt
Amino acid derivatives
The invention relates to novel amino acid derivatives of the formula I
X-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2-R4 I
in which X W and Y is H, Ri-0-CmH2m-C0-, R'-C^-O-CO-, r’-C^-CO-, R5-SO2-, R6R7N-CoH2b-C0- , R6-NH-C(=NH)-NH- C^-CO-, R'OOC-CJI^-CO-, RBO3S-C[nH2ai-CO-, R6-O-(CH2CH2O) n-C[nH2m-CO-, AaN^C^-CO-An' or R6OOC-CH (NR8R9) -CpH2p-Y-CO-, are each CH2, 0 or NH, 15 Rl, R7 and Re R2, R3 are each H or A, and R5 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsub- 20 stituted or monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 411 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, 25 R4 is H, A, Ar-alkyl, cycloalkyl having 3-7 C atoms or cycloalkylalkyl having 4-11 C atoms, R6 and Rfl are each H, A or R5-CpH2p-Y-CO-, R6R7N is also an unsubstituted pyrrolidino, piperidino, morpholino or piperazino group or one 30 which is substituted by A, OH, NH2, NHA, NA2, NHAc, NH-CO-CJIax-O-R10, NH-CO-O-C^-R10, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A^-alkyl, AsN^alkyl An®, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, 35 R10 is H, A, Ar-alkyl or CN, m, p and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
- 2 10 n is 0, 1, 2 or 3,
Ar is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NAj, NHAc, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N*-alkyl An® and/or guanidinyl alkyl, or is unsubstituted naphthyl,
Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, 0 and/or S atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, NH-COOA, NHCOOAr, NHCOOCHjAr, NH-SO2-A, SA, SO-A, S02-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, AzN-alkyl and/or A3N*-alkyl An® and/or whose N and/or S heteroatoms can also be oxidised,
Hal is F, Cl, Br or I,
Ac is Α-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-,
An® is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present 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 in addition instead of one or more -NH-CO groups there can also be one or more -ΝΑ-CO groups, and their salts.
Similar compounds are disclosed in EP-A-332,008. The invention was based on the object of finding novel compounds having useful 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 their salts have very useful properties. In particular, they inhibit the activity of human plasma renin. This action can be detected, for example, by the
- 3 10 method of F. Fyhrquist et al., Clin. Chem. 22, 250-256 (1976). It is noteworthy that these compounds are very specific inhibitors of renin; as a rule about 100 to 1000 times as high concentrations of these compounds are necessary for the inhibition of other aspartylproteinases (for example pepsin and cathepsin D) as for renin inhibition. The actions of the compounds on the blood pressure and/or on the heart rate and the inhibition of the renin activity in the blood plasma can additionally be determined in conscious monkeys, for example female monkeys (Macaca fascicularis); in this connection blood pressure and heart rate can be measured following the method of M.J. Wood et al., J. Hypertension 4, 251-254 (1985). To stimulate renin activity, the animals are in this case expediently pretreated with a saluretic. Blood samples for determining the plasma renin activity can be obtained by puncture of the femoral vein.
The compounds can be employed as medicament active compounds in human and veterinary medicine, in particular for the prophylaxis and for the treatment of cardiac, circulatory and vascular diseases, in particular hypertension, cardiac insufficiency and hyperaldosteronism. In addition, the compounds can be used for diagnostic purposes in patients with hypertension or hyperaldosteronism in order to determine the possible contribution of the renin activity to the maintenance of the pathological condition. Such diagnostic tests can be carried out in a similar manner to that given in EP-A-77,028.
The abbreviations of amino acid radicals mentioned above and below are for the radicals -NR'-RC0-, 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:
Ada 3-(1-adamantyl) alanine
Ala alanine jSAla ^-alanine
Bia 3-(2-benzimidazolyl)alanine
Cal 3-cyclohexylalanine
- 4 - Gly glycine His histidine Hph homophenylalanine (2-amino-4-phenylbutyric acid) lie isoleucine Leu leucine Mai 3-(p-methoxyphenyl) alanine aNal 3-(o-naphthyl) alanine ySNal 3-(^-naphthyl) alanine Nle norleucine Nva Norvaline Phe phenylalanine Tia 3-(thienyl)alanine [for example 2-Tia = 3-(2-thienyl) alanine] Tiz 3-(thiazolyl) alanine [for example 2-Tiz = 3-(2-thiazolyl) alanine] Trp tryptophan Tyr tyrosine. In addition, the following have the meaning below: BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzyloxymethyl in the 1-position of the imidazole ring CBZ benzyloxycarbonyl DCCI dicyclohexylcarbodi imide DMF dimethylformamide DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring ETOC ethoxyc arbony1 FMOC 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole IPOC i s opropoxyc arbony1 Pla the radical of phenyllactic acid -0-CH(CH2C8H5)-C0- (S-form) POA phenoxyacetyl THF tetrahydrofuran.
- 5 several enantiomeric forms, all these forms and also their mixtures (for example the DL-forms) are included above and below, for example as constituents of the compounds of the formula I. The L-forms are preferred. If individual compounds are mentioned below, the abbreviations of these amino acids in each case relate to the L-form, if not expressly stated otherwise.
The invention further relates to a process for the preparation of an amino acid derivative of the formula I and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II
X-G^OH II
in which G1 (a) is absent, (b) is -W-CRhP-CO-, (c) is -W-CR1R2-CO-NH-CH2CH2-CO-,
or one of its reactive derivatives is reacted with a compound of the formula III
H-G2-NH-CHR3-(CHOH)2-R* III
in which G2 (a) is (b) is (c) is and in that
group is optionally set free in a compound of the formula I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or a compound of the formula I is converted into one of its salts by treating with an acid.
Above and below, the radicals or parameters R1 to R10, W, X, Y, m, n, p, x, Ar, Het, Hal, Ac, An, A, G1 and G2 have the meanings indicated in the formulae I, II or III unless expressly stated otherwise.
- 6 In the above formulae, A has 1-8, preferably 1, 2, 3 or 4 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, or tert.-butyl, additionally also pentyl, 1-, 2- or
3-methylbutyl, 1,1-, 1/2- or 2,2-dimethylpropyl,
1- ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,
1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or
2- ethylbutyl, 1-ethyl-l-methylpropyl, l-ethyl-2-raethylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl.
Cyeloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also, for example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or
4-methylcyclohexyl.
Accordingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl,
2- cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, but also, for example, 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-,
3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-decalyl,
2-bicyclo[2.2.1]heptyl or 6,6-dimethyl-2-bicyclo[3.1.1]heptyl.
Tricycloalkyl is preferably 1-adamantyl.
Hal is preferably F, Cl or Br, but also I.
Ac is preferably Α-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 N-methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl, in addition preferably ο-, m- or p-tolyl, ο-, m- or p-ethylphenyl, ο-, 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-, mor p-hydroxyphenyl, ο-, m- or p-sulfamoylphenyl, 2,3-,
2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, ο-, m-, or p-aminophenyl, ο-, mor p-aminomethylphenyl, ο-, m- or p-dimethy1aminomethylphenyl, ο-, m- or p-guanidinomethylphenyl, 1- or
2-naphthyl.
- 7 Accordingly, Ar-alkyl is preferably benzyl, 1- or
2- phenylethyl, ο-, m- or p-methylbenzyl, 1- or 2-o-, -mor -p-tolylethyl, ο-, m- or p-ethylbenzyl, 1- or 2-o-, -m- or -p-ethylphenylethyl, ο-, m- or p-methoxybenzyl, 15 or 2-0-, -m- or -p-methoxyphenylethyl, ο-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, o—, m- or p-chlorobenzyl, 1- or 2-0-, -m- or -p-chlorophenylethyl, 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-trifluoromethylbenzyl, ο-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-,
2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, ο-, m- or p-aminobenzyl ο-, m- or p-aminomethylbenzyl, ο-, m- or p-dimethylaminomethylbenzyl, ο-, m- or p-guanidinomethylbenzyl, 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
- isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothi20 azolyl, 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, l,2,4-oxadiazol-3- or -5-yl,
1.3.4- thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or
-5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or
6- 2H-thiopyranyl, 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-iso30 indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-,
6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3- , 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or
7- benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl,
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-,
- , 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
- 8 hydrogenated. Het can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4or -5-furyl, tetrahydro-2- or -3-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-, -2- or -4-imidazolyl,
2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -510 or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or
4- morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, l,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-l-, -2-, -3-,
-4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-l-, -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:
2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl2- thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyraz inyl,
4- carbamoylpiperidino, in addition, for example, 3-, 4or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di25 methyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl,
3- methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl,
- phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimeth30 yl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl,
-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or
-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or
4- methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-,
- or 6-methyl-2-pyr idyl, 2-, 4-, 5- or 6-methyl-335 pyridyl, 2- or 3-methyl-4-pyr idyl, 3-, 4-, 5- or 6chloro-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-lH-2-pyridon-3-yl, 5-p-methoxyphenyl-lHIE 920422
2-pyridon-3-y1, 2-methyl-3-hydroxy-4-hydroxymethyl-5pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'methylureido-lH-4-pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimid5 inyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrimidinyl , 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl,
1- methyl-5- or -6-benzimidazolyl, l-ethyl-5- or -6-benz10 imidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl,
2- oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.
X is generally preferably H; R^CJ^-O-CO- such as BOC; R5-CoHZm-C0- such as formyl or acetyl; R5-SO2-, in particular A-SO2- such as methylsulfonyl; R6R7N-CmH2fll-CO-, in particular 4-BOC-aminopiperidinocarbonyl, 4-aminopiperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4dimethylaminopiperidinocarbonyl, 4-ethoxycarbonylaminopiperidinocarbonyl, morpholinocarbonyl, piperazino20 carbonyl or 4-BOC-piperazinocarbonyl.
The groups W and Y are each preferably NH.
R1, R6, R7, R8 and R9 are each preferably H, in addition preferably methyl. R6R7N is preferably also pyrrolidino, piperidino, morpholino, aminopiperidino such as 4-aminopiperidino, hydroxypiper idino such as 4hydroxypiperidino, alkylaminopiperidino such as 4-methylaminopiperidino, dialky 1 aminopiperidino such as 4-dimethylaminopiperidino, ethoxycarbonylaminopiperidino such as 4-ethoxycarbonylaminopiperidino or BOC-aminopiperidino such as 4-BOC-aminopiperidino, morpholino or 4-BOCpiperazino.
R2 is preferably Ar-alkyl, in particular benzyl or p-methoxybenzyl; in addition preferably A, in particular n-butyl or isobutyl; cycloalkylalkyl, in particular eyelohexylmethyl; or Het-alkyl, in particular 2-thienylmethyl. The group -W-CR1R2-CO- is preferably one of the radicals Phe or Pla, in addition Ada, Bia, Cal, His, Hph, He, Leu, Mai, aNal, £Nal, Nle, Nva, Tia, Tiz, Trp or Tyr.
R3 is preferably cycloalkylalkyl, in particular cyclohexylmethyl, in addition preferably alkyl, in particular n-butyl or isobutyl; Ar-alkyl, in particular benzyl or p-methoxybenzyl; Het-alkyl, for example 25 thienylmethyl; or cycloalkyl, in particular cyclohexyl.
R<, is preferably A eg. ethyl, propyl, isopropyl, butyl or isobutyl, or cycloalkyl, eg. cyclopropyl, furthermore cyclobutyl or cyclopentyl.
R10 is preferably H, methyl or CN.
The parameter m is preferably 1, 2, 3, 4 or 5; p is preferably 2 or 3; n is preferably 1; x is preferably 1 or 2.
and CxH2x are preferably straight-chain, that is to say preferably -(0Η2)ω- or -(CH2)X-.
Accordingly, the group X is in particular preferably H; R7R8N- (CH2)d-CO- , in particular H2N-CmH2m-C0- such as aminocarbonyl, aminoacetyl (H-Gly-), 3-aminopropionyl (H-^Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-amino20 nonanoyl, 10-aminodecanoyl, 11-aminoundecanoyl, but also, for example, 2-aminopropionyl (Ala), 2-amino-2-methylpropionyl, 3-amino-3-methylbutyryl; ANH-C^H^-CO- such as methylaminocarbonyl, ethylaminocarbonyl, methylaminoacetyl (sarcosyl), 3-methylaminopropionyl, 4-methylamino25 butyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl,
6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methylaminooctanoyl, 9-methylaminononanoyl, 10-methylaminodecanoyl, 11-methylaminoundecanoyl; A^-C^H^-CO- such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethyl30 aminopropionyl, 4-dimethylaminobutyryl, 5-dimethylaminopentanoyl, 6-dimethylaminohexanoy1, 6-diethylaminohexanoyl, 7 -dimethylaminoheptanoyl, 8-diroethylaminooc tanoyl,
9-dimethylaminononanoyl, 10-dimethyl aminodec anoyl, 11dimethylaminoundecanoyl; pyrrol idino-CmH2m“c0 such as pyrrolidinocarbonyl, pyrrolidinoacetyl, 3-pyrrolidinopropionyl, 4-pyrrolidinobutyryl, 5-pyrrolidinopentanoyl, 6pyrrolidinohexanoyl, 4-pyrrolidinoheptanoyl, 8-pyrrolidinooctanoyl, 9-pyrrolidinononanoyl, 10-pyrrolidinodecanoyl; piperidino-C^H^-CO- such as piperidinocarbonyl,
- 11 piperidinoacetyl, 3-piperidinopropionyl, 4-piperidinobutyryl, 5-piperidinopentanoyl, 6-piperidinohexanoyl, 7piperidinoheptanoyl, 8-piperidinooctanoyl, 9-piperidinononanoyl, 10-piperidinodecanoyl; morpholino-CnH^-CO- such as morpholinocarbonyl, morpholinoacetyl, 3-morpholinopropionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl,
6-morpholinohexanoyl, 7-morpholinoheptanoyl, 8-morpholinooctanoyl, 9-morpholinononanoyl, 10-morpholinodecanoyl;
4-hydroxypiperidino-C^H^-CO- such as 4-hydroxypiperidino10 carbonyl, 4-hydroxypiperidinoacetyl; 4-aminopiperidinoCnHaa-CO- such as 4-aminopiperidinocarbonyl, 4-aminopiperidinoacetyl, 3-(4-aminopiperidino)propionyl, 4-(4aminopiperidino)butyryl, 5-(4-aminopiperidino)pentanoyl,
6-( 4-aminopiperidino)hexanoyl, 7-(4-aminopiperidino)hept15 anoyl, 8-(4-aminopiperidino)octanoyl, 9-(4-aminopiperidino)nonanoyl, 10-(4-aminopiperidino)decanoyl; 4-BOCaminopiperidino-CnH2ni-C0- such as 4-BOC-aminopiperidinocarbonyl, 4-BOC-aminopiperidinoacetyl; 4-dialkylaminopiperidino-CnHaa-CO- such as 4-dimethylaminopiperidino20 carbonyl, 4-dimethylaminopiperidinoacetyl; 4-alkoxycarbonylaminopiperidino-C^H^-CO- such as 4-ethoxycarbonylaminopiperidinocarbonyl, 4-methoxycarbonylaminopiperidinoacetyl; 4-guanidinopiperidino-CmH2n-CO~ such as 4guanidinopiper idinocarbony 1, 4 -guanidinopiperidinoacetyl;
4-carboxypiperidino-CmH2m-CO- such as 4-carboxypiperidinocarbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonylpiperidino-CnHaj-CO- such as 4-methoxycarbonylpiperidinocarbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxycarbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidino30 acetyl; 4-AcNH-piperidino-CmH2ni-CO- such as
4-acetamidopiperidinocaxbonyl, 4-acetamidopiper idinoacetyl; morpholino-CnH^-CO- such as morpholinocarbonyl or morpholinoacetyl; 4-BOC-piperazino-CIBH2BI-CO- such as 4BOC-piperazinocarbonyl or 4-BOC-piperazinoacetyl;
H2N-C(=NH)-NH-CoHaa-C0- such as guanidinoacetyl, 3-guanidinopropiony 1, 4-guanidinobutyryl, 5-guanidinopentanoyl,
6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidinooctanoyl; HOOC-CnHaj-CO- such as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxyheptanoyl,
- 12 7-ethoxycarbonyl9-ethoxycarbonyl5-sulfopentanoyl, 8-sulfooctanoyl,
7-sulfoheptanoyl, 10-sulfodecanoyl;
sulfonylacetyl, sulfonylbutyryl, sulfonylhexanoyl, sulfonyloctanoyl, sulfonyldecanoyl;
8-carboxyoctanoyl, 9-carboxynonanoyl,10-carboxydecanoyl,
11-carboxyundecanoyl; AOOC-C^H^-CO- such as methoxycarbonylacetyl, 3-methoxycarbonylpropionyl, 4-methoxycarbonylbutyryl, 5-methoxycarbonylpentanoyl, 6-methoxycar5 bonylhexanoyl, 7-methoxycarbonylheptanoyl, 8-methoxycarbonyloctanoyl, 9-methoxycarbonylnonanoyl, 10-methoxycarbonyldecanoyl, ethoxycarbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonylpentanoy1, 6-ethoxycarbonylhexanoyl, heptanoyl, 8-ethoxycarbonyloctanoyl, nonanoyl, 10-ethoxycarbonyldecanoyl; H-SOj-C^am-CO- such as sulfoacetyl, 3-sulfopropionyl, 4-sulfobutyryl,
6-sulfohexanoyl,
9-sulfononanoyl,
A-SOj-C^a^-CO- such as methoxysulfonylacetyl, 3-methoxysulfonylpropionyl, 4-methoxysulfonylbutyryl, 5-methoxysulfonylpentanoyl, 6-methoxysulfonylhexanoyl, 7-methoxysulfonylheptanoyl, 8-methoxysulfonyloctanoyl, 9-methoxysulfonylnonanoyl, 10-methoxysulfonyldecanoyl, ethoxy20 sulfonylacetvl, 3-ethoxysulfonylpropionyl, 4-ethoxy5-ethoxysulfonylpentanoyl, 6-ethoxy7-ethoxysulfonylheptanoyl, 8-ethoxy9-ethoxysulfonylnonanoy1, 10-ethoxyR’-CJi^-O-CO-, in particular A-O-CO25 such as ETOC, IPOC, BOC and also Ar-CJija-O-CO- such as
CBZ; R5-CmH2ni-CO-, in particular A-CO- such as acetyl, trimethylacetyl or 3,3-dimethylbutyryl, but also formyl; or R3-SO2- such as A-S02-, preferably methylsulf onyl, isopropylsulfonyl or tert.butylsulfonyl.
The compounds of the formula I have at least two chiral centres and therefore occur in different optically active or optically inactive - forms. The formula I includes all these forms. The compounds with 1S-, 2R- and/or 3S- configuration are preferred (the C atom which carries the radical R* being allocated the 1position and the C atom which carries the radicals X-WCR1R2-CO-CH2CH2-CO-NH and R3 being allocated the 3-position.
The abovementioned cycloalkyl and phenyl groups are preferably unsubstituted or preferably carry 1 to 3, in particular 1 or 2 substituents.
The invention accordingly relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following sub-formulae la to Ik:
la H-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2-R*;
lb R6-O-CB1H2ai-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2
-R*;
lc R6-CBH2ffl-O-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2 -R*;
Id R6-CmH2ffl-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2-R*; le R7R8N-CBH2B-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2
-R4;
I f R9-NH-C (=NH) -NH-CJi^-CO-NH-CHaC^-CO-NH-CHR3- (CHOH) 2
-R*?
Ig R7OOC-CBH2a-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2 -R*?
lh R7O3S-CmH2m-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2 -R4;
I i R7-0- ( CH2CH2O) n-CmH2m-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2
-R4;
I j R7R8N-CO-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3- (CHOH) 2-R* ?
Ik 4-Aminopiperidinocarbonyl-W-CR1R2-C0-NH-CH2CH2-C0-NHCHR3-(CH0H)2-R*.
Particularly preferred compounds are those of the sub-formulae:
(a) Iaa to Ika which correspond to the formulae Ia to
Ik, but in which additionally
-W-CR1R2-CO- is Phe, Pla, Mai or -CH2-CH (CH2C6H5) -CO-;
(b) lab to Ikb and also Iaab to Ikab, which correspond to the formulae Ia to Ik and also Iaa to Ika, but In which additionally R3 is cyclohexylmethyl;
(c) lac to Ike, Iaac to Ikac and also Iabc to Ikbc, which correspond to the formulae Ia to Ik, Iaa to
- 14 Ika and also lab to Ikb, but in which additionally R4 is A or cycloalkyl having 3-6 C atoms.
Particularly preferred compounds are those of the sub-formulae:
I* and la* to Ik*, which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally
R* is cyclopropyl;
I' and Ia' to Ik', which correspond to the formulae I and also Ia to Ik and those compounds which correspond to the other abovementioned sub-formulae, but in which additionally
R* is isobutyl.
a particularly preferred group of compounds corresponds to the formula I in which
X is 4-BOC-aminopiperidinocarbonyl or 4-aminopiperidinocarbonyl,
-W-CRXR2-CO- is Phe,
R3 is eyelohexylmethyl, and R* isobutyl or cyclopropyl.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (for example in the standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; and in addition EP-A-45,665, EP-A-77,028, EP-A-77,029,
EP-A-81,783, EP-A-249,096 and EP-A-332,008), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se but are not mentioned here in greater detail.
The starting substances, if desired, can also be formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula I can be obtained by
- 15 setting them free from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis .
Preferred starting substances for the solvolysis 5 or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxy groups contain correspondingly protected amino and/or hydroxy groupe, preferably those which instead of an H atom which is bonded to an N atom, carry an amino protective group, for example those of the formula I, but instead of an His group contain an N(im)-R'-His group (in which R' is an amino protective group, for example BOM or DNP).
In addition, starting substances are preferred which instead of the H atom of a hydroxy group carry a hydroxy protective group, for example those of the formula
X-W-CR1R2-CO-NH-CH2CH2-CO-NH-CHR3-(CHOR)2-R4, in which R is a hydroxy protective group.
Several - identical or different - protected amino and/or hydroxy groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, they can in many cases be removed selectively.
The expression 'amino protective group' is generally known and relates to groups which are suitable for protecting an amino group from chemical reactions (for blocking), but which are easily removable after the desired chemical reaction has been carried out at another site in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl (for example DNP), aralkoxymethyl (for example BOM) or aralkyl groups (for example benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protective groups are removed after the desired reaction (or reaction seguence), their nature and size is otherwise not critical; but those with 1-20 C atoms, in particular 1-8 C atoms, are preferred. The expression acyl group is to be interpreted in the widest sense in connection with the present process. It
- 16 includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also in particular alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl or butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxycarbonyl and FMOC. Preferred amino protective groups are BOC, DNP and BOM, and in addition CBZ, FMOC, benzyl and acetyl.
The expression 'hydroxy protective group' is likewise generally known and relates to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at another site in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and in addition also alkyl groups. The nature and size of the hydroxy protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20 C atoms, in particular 1-10 C atoms, are preferred.
Examples of hydroxy protective groups are, among others, tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.
The functional derivatives of the compounds of the formula I to be used as starting substances can be prepared by customary methods of amino acid and peptide synthesis, such as, for example, are described in the said standard works and patent applications, for example also by the solid phase method according to Merrifield.
The compounds of the formula I are set free from their functional derivatives - depending on the protective group used - for example with strong acids, expediently 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 inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are suitable. Trifluoroacetic acid is preferably used in excess without addition of a further solvent, 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 expediently between about 0 and about 50*; the reaction is preferably carried out between 15 and 30* (room tempera20 ture).
The BOC group can, for example, preferably be removed with 40 % trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30*C, the FMOC group with an about 5-20 % solution of dimethyl25 amine, diethylamine or piperidine in DMF at 15-30*. The
DNP group is also removed, for example, with an about
3-10 % solution of 2-mercaptoethanol in DMF/water at 15-30’.
Protective groups which can be removed by hydro30 genolysis (for example BOM, CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are the abovementioned, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100* and at pressures between about 1 and 200 bar, preferably at 20-30* and at 1-10 bar. The
CBZ group is easily hydrogenolysed, for example, on 510 % Pd-C in methanol at 20-30*.
Compounds of the formula I can also be obtained by direct condensation (peptide synthesis) from a car5 boxylic acid component (formula II) and a hydroxyl or amino component (formula III). Suitable carboxylic acid components are, for example, those of the sub-formulae (a) X-OH, (b) X-W-CR1R2-C00H or (c) X-W-CR^-CO-NH-CH^H^ -CO-OH, suitable hydroxyl or amino components are those of the sub-formulae (a) HW-CR1R2-CO-NH-CH2CH2-CO-NH3- (CHOH) 2-R*, (b) H-NH-CH2CH2-CO-NH-CHR3-(CHOH)2-R4 or (c) H2N-CHR3-(CHOH)2-R4.
The reaction is expediently carried out in this 15 case by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, loc.cit., Volume 15/11, pages 1-806 (1974); these methods can also be transferred, if W = 0, to the condensation according to (a), an ester bond being formed.
The reaction is preferably carried out in the presence of a dehydrating agent, for example of a carbodiimide such as DCCI or dimethylaminopropylethylcarbodiimide, and in addition propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-l,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as THF 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*.
Instead of II or III, suitable reactive derivatives of these substances can also be employed in the reaction, for example those in which reactive groups are intermediately blocked by protective groups. The acid derivatives II can be used, for example, in the form of their activated esters, which are expediently formed in situ, for example by addition of HOBt or N-hydroxysuccinimide.
The starting substances of the formulae II and
- 19 III are for the greatest part known. If they are not known, they can be prepared by known methods, for example the abovementioned methods of condensation and removal of protective groups.
If desired, a functionally modified amino and/or hydroxy group in a compound of the formula I can be set free by solvolysis or hydrogenolysis according to one of the methods described above.
Thus, for example, a compound of the formula I 10 which contains an Rs-CxH2i-O-CO-NH- , an AcNH- or an AOOCgroup can be converted into the corresponding compound of the formula I which instead of this contains an H2N- or an HOOC-group, expediently by selective solvolysis according to one of the abovementioned methods. A00C15 groups can be hydrolysed, for example, with NaOH or KOH in water-dioxane at temperatures between 0 and 40”, preferably 10 and 30°.
It is also possible to acylate a compound of the formula I which contains a free primary or secondary amino group. Thus, in particular, compounds of the formula I, in which X is H, can be reacted with acylating agents of the formula X-Cl or X-Br (in which X is different from H), expediently in the presence of an inert solvent such as THF and/or of a base such as pyridine or triethylamine at temperatures between -10 and +30*.
A base of the formula I can be converted into the respective acid addition salt using an acid. Suitable acids for this reaction are in particular those which give physiologically acceptable salts, thus inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic
- 20 acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.
The novel compounds of the formula I and their physiologically acceptable salts can be used for the production of the pharmaceutical preparations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more other active compound(s). The preparations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration or for administration in the form of an inhalation spray and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose. For oral administration, tablets, coated tablets, capsules, syrups, juices or drops are used in particular; especially of interest are coated tablets and capsules having enteric coatings or capsule shells. Suppositories are used for rectal administration, and solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used for parenteral administration. For administration as inhalation sprays, sprays can be used which contain the active compound either dissolved or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons) . The active compound in this case is expediently used in micronised form, it being possible for one or more additional physiologically tolerable solvents to be present, for example ethanol.
- 21 Inhalation solutions can be administered with the aid of customary inhalers. The novel compounds can also be lyophilised and the lyophilisates obtained used, for example, for the production of injection preparations.
The preparations mentioned can be sterilised and/or can contain auxiliaries such as preservatives, stabilisers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants and/or flavourings. If desired, they can also contain one or more other active compounds, for example one or more vitamins .
The substances according to the invention are as a rule administered in analogy to other known commercially available peptides, but in particular in analogy to the compounds described in EP-A-332,008, preferably in dosages between about 10 mg and 1 g, in particular between 50 and 500 mg per dosage unit. The daily dosage is preferably between about 0.2 and 20 mg/kg, in particular between 1 and 10 mg/kg of body weight. The specific dose for each specific patient, however, depends on a wide variety of factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, medicament combination and severity of the particular disease to which the treatment applies. Parenteral administration is preferred. Renin-dependent hypertension and hyperaldosteronism can be effectively treated by administration of dosages between, in particular, about
0.2 and 20, preferably between 1 and 10 mg/kg of body weight. For diagnostic purposes the novel compounds can expediently be administered in individual doses between about 0.1 and 10 mg/kg of body weight.
Above and below, all temperatures are indicated in °C. In the following examples customary working up means: water is added if necessary, the pH is adjusted to between 2 and 8, depending on the constitution of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is
- 22 separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallisation. TFA = trifluoroacetate. FAB = mass spectrum by the fast atom bombardment method.
Example 1 g of 3S-[tert.-butoxycarbonyl-L-(N-imi-benzyloxymethylhistidyl) -0-alanylamino]-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol [= 3S-(BOC-(imi-BOM-His)-0Ala10 amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol is dissolved; obtainable by reaction of N-BOC-3-cyclohexylL-alaninal with trimethylsilyl cyanide/KCN/18-crown-6 to give 3S-BOC-amino-4-cyclohexyl-2-hydroxybutyronitrile (mixture of diastereomers), hydrolysis using HC1/CH3COOH to give 3S-amino-4-cyclohexyl-2-hydroxybutyric acid (mixture), esterification and subsequent reaction with (BOC)2O to give methyl 3S-BOC-amino-4-cyclohexyl-2hydroxybutyrate, reaction with 2,2-dimethoxypropane to give methyl 3-BOC-4S-cyclohexylmethyl-2,220 dimethyloxazolidine-5R-carboxylate (FAB: M + 1 = 356), reduction using diisobutylaluminium hydride in toluene to give 3-BOC-4S-cyclohexylmethyl-5R-formyl-2,2dimethyloxazolidine, reaction with cyclopropylmagnesium bromide and subsequent hydrolyis to give 3-BOC-4S2 5 eyelohexy lmethyl-5R- (1-cyclopropyl-1-hydroxymethyl )-2,2dimethyloxazolidine (mixture; FAB: M + 1 = 368), ring cleavage with 4 n HCl/dioxane to give 3S-amino-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol (Ilia) and condensation with BOC-(imi-BOM-His)-^Ala-OH] is dissolved in 30 ml of ethanol, the mixture is hydrogenated on 0.3 g of 10% Pd-C at 20’ and 1 bar until absorption of H2 has ceased, filtered and evaporated, and 3S-BOC-His-0Alaamino-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol is obtained after chromatographic purification on silica gel.
- 23 Example 2
3S-( 4-amino-4-carboxybutyryl-Phe-£Ala-amino) -4cyclohexyl-1-cyclopropyl-butane-IS,2R-diol is obtained analogously to Example 1 by hydrogenolysis of 3S—(4— benzyloxycarbonyl-4-CBZ-aminobutyryl-Phe-^Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol (obtainable by condensation of 4-benzyloxycarbonyl-4-CBZ-aminobutyrylPhe-^Ala-OH with Ilia).
The following are obtained analogously by 10 hydrogenolysis of the corresponding benzyloxycarbonylCBZ-amino derivatives:
3S- (3-amino-3-carboxypropionyl)-Phe-^Ala-amino)-4-cyclohexyl-1-cyclopropylbutane-IS,2R-diol
3S-[N-( 3-amino-3-carboxypropyl)carbamoyl-Phe-/3 Ala-amino ]15 4-eyelohexy1-1-cyclopropylbutane-IS,2R-diol
3S- [N-(4-amino-3-carboxybutyl)carbamoyl-Phe-£Ala-amino]4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol
Example 3
A mixture of 1 mmol of 3S-BOC-(imi-DNP-His)-^Ala20 amino-4-cyclohexyl-1-cyclopropylbutane-IS, 2R-diol [obtainable by condensation of BOC-(imi-DNP-His)-0Ala-OH with Ilia], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water is adjusted to pH 8 using aqueous Na2CO3 solution while stirring at 20* and stirred for a further
2 hours at 20°. Customary working up gives 3S-BOC-His0Ala-amino-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol.
Example 4
1.01 g of N-methylmorpholine is added to a solution of 2.27 g of Ilia in 60 ml of dichloromethane.
4.5 g of 4-B0C-aminopiperidinocarbonyl-Phe-^Ala-0H,
1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of dichloromethane are added with stirring, the mixture is stirred at 0-5“ for 12 hours, the precipitated dicyclohexyl urea is filtered off and the filtrate is evaporated. Customary working up gives 3S-(4-BOC-aminopiper idinocarbonyl-Phe-^Ala-amino) -4-cyclohexyl-l-cycloIE 920422
- 24 propylbutane-lS,2R-diol, m.p. 107-108°; FAB: M + 1 = 672.
Example 5
The following are obtained from Ilia analogously to Example 4
3S- (B0C-Phe-/3Ala-amino) -4-cyclohexyl-l-cyclopropylbutanelS,2R-diol using BOC-Phe-/3Ala-OH;
3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol using 4-hydroxypiperidinocarbonyl-Phe-^Ala-OH;
3S- (4-dimethylaminopiperidinocarbonyl-Phe-/3Ala-amino) -4cyclohexyl-l-cyclopropylbutane-lS,2R-diol using 4-dimethylaminopiperidinocarbonyl-Phe-^Ala-OH;
3S-(morpholinocarbonyl-Phe->3Ala-amino)-4-cyclohexyl-lcyclopropylbutane-lS,2R-diol using morpholinocarbonyl15 Phe-/9Ala-OH;
3S- ( 4-ethoxycarbonylpiperidinocarbonyl-Phe-/3Ala-amino) 4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol using 4ethoxycarbonylpiperidinocarbonyl-Phe-^Ala-OH;
3S-(methylsulfonyl-Phe-^Ala-amino)-4-cyclohexyl-l-cyclo20 propylbutane-lS, 2R-diol usingmethylsulfonyl-Phe-^Ala-OH;
3S- ( isopropylsul fonyl-Phe-/9Ala-amino ) -4-cyclohexyl-1cyclopropylbutane-lS,2R-diolusing isopropylsulfonyl-Phe^Ala-OH;
3S-(3-BOC-amino-3-methylbutyryl-Phe-£Ala-amino)-4-cyclo25 hexyl-l-cyclopropylbutane-lS,2R-diol using 3-BOC-amino3-methylbutyryl-Phe-^Ala-OH;
3S- ( 6-B0C-aminohexanoyl-Phe-£Ala-amino) -4-cyclohexyl-lcyclopropylbutane-lS,2R-diol using 6-BOC-aminohexanoylPhe-^Ala-OH;
- 25 3S-(3,6,8-trioxanonanoyl-Phe-£Ala-amino)-4-cyclohexyl-1cyclopropylbutane-lS,2R-diol using 3,6,8-trioxanonanoylPhe-/?Ala-0H;
3S- ( 6-methoxycarbonylhexanoyl-Phe-^Ala-amino)-4-cyclo5 hexyl-1-cyclopropylbutane-IS,2R-diol using 6-methoxycarbonylhexanoyl-Phe-^Ala-OH?
3S - (N-ethylcarbamoyl-Phe-^Ala-amino)-4-cyclohexyl-lcyclopropylbutane-lS,2R-diol using N-ethylcarbamoyl-Phe£Ala-0H;
3S - (N-BOC-carbamoyl-Phe-)9Ala-amino) -4-cyclohexyl-lcyclopropylbutane-lS,2R-diol using N-BOC-carbamoyl-PheMAla-OH;
3S-[N- (5-dimethylaminopentyl)carbamoyl-Phe-0Ala-amino]4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol using N-(515 dimethyl aminopentyl) carbamoyl-Phe-^Ala-OH;
3S-(morpholinocarbonyl-Pla-0Ala-amino)-4-cyclohexyl-lcyclopropylbutane-lS,2R-diol using morpholinocarbonylPla-^Ala-OH;
3S- ( 4-BOC-aminopiperidinocarbonyl-Pla-£Ala-amino)-420 cyclohexyl-l-cyclopropylbutane-lS,2R-diol using 4-BOCaminopiperidinocarbonyl-Pla-0Ala-OH;
3S-(2-benzyl-3-tert.-butylsulfonylpropionyl-£Ala-amino)4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol using 2benzyl-3-tert. -butylsulfonylpropionyl-^Ala-OH;
using 4-B0C-aminopiperidinocarbonyl-Z-^Ala-0H (Z = Ada,
Cal, Leu, Mai aNal, 0Nal, Nle, NVA, 2-Tia, 2-Tiz or Trp):
3S- ( 4-BOC-aminopiperidinocarbonyl-Ada-j9Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol;
3S- ( 4-BOC-aminopiperidinocarbonyl-Cal-^Ala-amino)-430 eyelohexyl-1-cyclopropylbutane-IS,2R-diol;
- 26 3S- ( 4-BOC-aminopiperidinocarbonyl-Leu-^Ala-amino)-4cyclohexyl-1-cyclopropylbutane-IS,2R-diol;
3S- ( 4-B0C-aminopiperidinocarbonyl-Mal-£Ala-amino)-4cyclohexyl-1-cyclopropylbutane-IS, 2R-diol;
3S- ( 4-BOC-aminopiperidinocarbonyl-aNal-^Ala-amino) -4cyclohexyl-1-cyclopropylbutane-IS,2R-diol;
3S- ( 4-BOC-aminopiperidinocarbonyl-£Nal-£Ala-amino) -4cyclohexyl-1-cyclopropylbutane-IS,2R-diol;
3S- ( 4-BOC-aminopiperidinocarbonyl-Nle-^Ala-amino)-410 cyclohexyl-1-cyclopropylbutane-lS,2R-diol;
3S- ( 4-BOC-aminopiperidinocarbonyl-Nva-^Ala-amino)-4cyclohexyl-1-cyclopropylbutane-IS,2R-diol;
3S-(4-BOC-aminopiperidinocarbonyl-(2-Tia)-£Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol;
3S-(4-BOC-aminopiperidinocarbonyl-(2-Tiz)-^Ala-amino)-4cyclohexyl-1-cyclopropylbutane-IS,2R-diol;
3S- ( 4-BOC-aminopiperidinocarbonyl-Trp-£Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol;
3S- (H-Pla-/}Ala-amino) -4-eye lohexyl-1-cyc lopropylbutane20 lS,2R-diol using H-Pla-^Ala-OH.
Example 6
The following are obtained analogously to Example 4 from 4-BOC-aminopiperidinocarbonyl-Phe-^Ala-OH or 4hydroxypiper idinocarbonyl-Phe-j3Ala-OH:
using 2S-amino-l-cyclohexyl-6-methylheptane-3R,4S-diol:
2S- ( 4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-1cyclohexyl-6-methylheptane-3R,4S-diol, m.p. 91-92’; FAB: M + 1 = 688
2S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-1-cyclo30 hexyl-6-methylheptane-3R, 4S-diol;
using 2S-amino-l-cyclohexyloctane-3R,4S-diol:
2S- ( 4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-1cyclohexyloctane-3R,4S-diol
2S-(4-hydroxypiperidinocarbonyl-Phe-0Ala-amino)-1-cyclohexyloctane-3R,4S-diol;
using 2S-amino-l-cyclohexylhexane-3R,4S-diol:
2S- ( A-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-I5 cyclohexylhexane-3R,4S-diol
2S-( 4-hydroxypiperidinocarbonyl-Phe-/3Ala-amino) -1-cyclohexylhexane-3R,4S-diol;
using 3S-amino-4-cyclohexyl-l-cyclopentylbutane-lS,2Rdiol:
3S- ( 4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-4cyclohexy1-1-cyclopentylbutane-IS,2R-diol 3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-4-cyclohexyl-1-cyclopentylbutane-IS,2R-diol.
Example 7
3S-(4-BOC-aminopiperidinocarbonyl-Phe-^Alaamino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol, m.p. 107-108°, is obtained analogously to Example 4 from 4BOC-aminopiperidinocarbonyl-Phe-OH and 3S- (H-^Ala-amino) 4-cyclohexyl-l-cyclopropylbutane-IS,2R-diol.
Example 8
3S- (6-ethoxysulfonylhexanoyl-Phe-^Ala-amino) -1,4bis-cyclohexylbutane-lS,2R-diol is obtained analogously to Example 4 from 6-ethoxysulfonylhexanoic acid and 3S- (H-Phe-£Ala-amino )-1,4-bis-cyc lohexy lbutane- IS, 2R25 diol.
Example 9
A solution of 1 g of 2S-(4-BOC-aminopiperidinocarbonyl-Phe-0Ala-amino)-l-cyclohexyl-6-methylheptane3R,4S-diol in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at 20’ for 1 hour and then evaporated. 2S-(4-aminopiperidinocarbonyl-Phe-0Alaamino)-l-cyclohexyl-6-methylheptane-3R,4S-diol is
- 28 obtained, trifluoroacetate, m.p. 140-141’; 1/3-citrate,
m.p. 183-184’; FAB: M + 1 = 588.
The following are obtained analogously by cleavage of the corresponding BOC-amino derivatives with trifluoroacetic acid:
3S-(4-aminopiperidinocarbonyl-Phe-£Ala-amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol, trifluoroacetate, FAB: M + 1 = 572
3S- (H-Phe-^Ala-amino) -4-cyclohexyl-l-cyclopropylbutane10 lS,2R-diol
3S- ( 3-amino-3-methylbutyryl-Phe-£Ala-amino) -4-eyelohexy11-cyclopropylbutane-lS,2R-diol
3S - (6-aminohexanoyl-Phe-0Ala-amino)-4-eyelohexyl-1cyclopropylbutane-IS,2R-diol
3S-(carbamoyl-Phe-^Ala-amino) -4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol
3S-(4-aminopiperidinocarbonyl-Pla-^Ala-amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol
3S-(4-aminopiperidinocarbonyl-Ada-£Ala-amino)-4-cyclo20 hexyl-l-cyclopropylbutane-lS,2R-diol
3S-(4-aminopiperidinocarbonyl-Cal-£Ala-amino)-4-eyelohexy 1-1-cyc lopropylbutane- IS, 2R-diol
3S-(4-aminopiperidinocarbonyl-Leu-^Ala-amino)-4-cyclohexyl-1-eyelopropylbutane-IS,2 R-diol
3S-(4-aminopiperidinocarbonyl-Mal-0Ala-amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol
3S-( 4-aminopiperidinocarbonyl-aNal-^Ala-amino) -4-cyclohexyl-1-cyclopropylbutane-IS,2R-diol
3S-(4-aminopiperidinocarbonyl-j9Nal-0 Ala-amino)-4-cyclo30 hexyl-1-eyelopropylbutane-IS,2R-diol
3S-(4-aminopiperidinocarbonyl-Nle-^Ala-amino)-4-cyclohexyl-1-cyclopropylbutane-IS,2R-diol
3S-(4-aminopiperidinocarbonyl-Nva-^Ala-amino)-4-cyclohexy1-1-eyelopropylbutane-IS,2R-diol
3S-(4-aminopiperidinocarbonyl-(2-Tia)-^Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol 3S-(4-aminopiperidinocarbonyl-(2-Tiz)-^Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol
- 29 3S-( 4-aminopiper idinocarbonyl-Trp-jSAla-amino) -4-cyclohexyl- 1-cyclopropylbutane-IS,2R-diol
2S—(4-aminopiperidinocarbonyl-Phe-^Ala-amino)-1-cyclohexyloctane-3R,4S-diol
3S-(4-aminopiperidinocarbonyl-Phe-£Ala-amino)-4-cyclohexyl-1-cyclopropylbutane-IS,2R-diol
2S- (4-aminopiperidinocarbonyl-Phe-/9Ala-amino) -1-cyclohexylhexane-3R,4S-diol
Example 10
A mixture of 1 g of 3S-(4-ethoxycarbonylpiperidinocarbonyl-Phe-^Ala-amino) -4-cyclohexyl-1-cyclopropylbutane-lS,2R-diol, 50 ml of dioxane and 20 ml of 2N aqueous NaOH solution is stirred at 20* for 3 hours. Customary working up gives 3S-(4-carboxypiperidino15 carbonyl-Phe-^Ala-amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol.
The following are obtained analogously by hydrolysis of the corresponding methyl or ethyl esters:
3S- ( 6-carboxyhexanoyl-Phe-^Ala-amino) -4-cyclohexyl-120 cyclopropylbutane-lS,2R-diol.
Example 11
3S-(H-Phe-£Ala-amino)-4-cyclohexyl-l-cyclopropylbutane-lS,2R-diol is obtained analogously to Example 1 by hydrogenolysis of 3S-(CBZ-Phe-^Ala-amino)-4-cyclohexyl25 l-cyclopropylbutane-lS,2R-diol.
Example 12 (a) 455 mg of 3S-(H-Phe-£Ala-amino)-4-cyclohexyl-lcyclopropylbutane-lS,2R-diol is dissolved in 25 ml of THF. A solution of 117 g of CH3SO2C1 in 3 ml of
THF is added dropwise with stirring. Stirring for a further 3 hours at 20’ and customary working up gives 3S-(raethanesulfonyl-Phe-0Ala-amino)-4-cyclohexyl-1-cyclopropylbutane-IS,2R-diol.
(b) 3S-(acetyl-Phe-0Ala-amino) -4-cyclohexyl-1-cycloIE 920422
- 30 10 propylbutane-lS,2R-diol using acetyl chloride.
The examples below preparations .
is obtained analogously relate to pharmaceutical
Example A: Tablets
A mixture of 1 kg of 3S-(4-aminopiperidinocarbonyl-Phe-βAla-amino) -4-cyclohexyl-1-cyclopropylbutane-lS,2R-diol trifluoroacetate, 4 kg of lactose, 1.2 kg of maize starch, 200 g of talc and 100 g of magnesium stearate is compressed to give tablets in a customary manner in such a way that each tablet contains 100 mg of active compound.
Example B: Coated tablets
Tablets are pressed analogously to Example A, and are then coated in a customary manner with a coating of sucrose, maize starch, talc, tragacanth and colourant. Example C: Capsules
500 g of 2S-(4-aminopiperidinocarbonyl-Phe-3Alaamino)-l-cyclohexyl-6-methylheptane-3R,4S-diol 1/3citrate are filled into hard gelatine capsules in a customary manner in such a way that each capsule contains 500 mg of active compound.
Example D: Injection vials
A solution of 100 g of 3S-(4-aminopiperidinocarbonyl-Phe-^Ala-amino)-4-eyelohexy1-1-cyclopropylbutane- IS, 2R-diol trifluoroacetate in 41 of doubly distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and poured into injection vials. The solution is lyophilised under sterile conditions and the vials are sterile sealed. Each injection vial contains 100 mg of active compound.
Example E: Suppositories
A mixture of 50 g of 3S-(4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-4-cyclohexyl-1-cyclopropylbutane-lS,2R-diol is fused with 10 g of soya lecithin and 140 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 250 mg of active compound.
I
- 31 Merck Patent Gesellechaft mit beschrankter Haftung 6100 Darmstadt
Claims (13)
1. Patent Claims Amino acid derivatives of the formula I X-W-CR l R 2 -CO-NH-CH
2. CH2-CO-NH-CHR 3 - (CHOH) 2-R* in which X is H, R 5 -O-C ni H 2ai -CO-, R'-CJi^-O-CO-, R^C^-CO-, R 5 -SO2-, R 6 R 7 N-CmH 2ni -CO- , R 6 -NH-C ( =NH) -NHCJi^-CO-, r'OOC-C^-CO-, R^S-C^-CO-, R 6 -O-(CH2CH2O) n-CnH^-CO-, A3N + -CmH 2jI! -CO-An or R 6 OOC-CH(NR 8 R e ) -C p H 2p -Y-CO-, W and Y are each CH 2 , 0 or NH, R 1 , R 7 and R 8 are each H or A, R 2 , R 3 and R 5 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsubstituted or monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 411 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, R* is H, A, Ar-alkyl, cycloalkyl having 3-7 C atoms or cycloalkylalkyl having 4-11 C atoms, R 6 and R 9 are each H, A or R’-CpH^-Y-CO-, R e R 7 N is also an unsubstituted pyrrolidino, piperidino, morpholino or piperazino group or one which is substituted by A, OH, NH2, NHA, NA^ NHAc, NH-CO-CJi^-O-R 10 , NH-CO-O-C^-R 10 , hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, AgN-alkyl, A 3 N*alkyl An®, NH-CO-NH 2 , NH-CO-NHA, guanidinyl or guanidinylalkyl, R 10 is H, A, Ar-alkyl or CN m, p and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, n is 0, 1, 2 or 3, - 32 10 Ar Het is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CFj, OH, NO 2 , hydroxyalkyl, NH 2 , NHA, NA 2 , NHAc, NH-SO 2 -A, 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® and/or guanidinylalkyl, or is unsubstituted naphthyl, is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, 0 and/or S atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF 3 , OH, NO 2 , carbonyl oxygen, NH 2 , NHA, NA 2 , NHAc, NH-COOA, NHCOOAr, NHCOOCH^Ar, NH-SO 2 -A, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A 2 N-alkyl and/or A 3 N*-alkyl An® and/or whose N and/or S heteroatoms can also be oxidised, Hal is 20 Ac is An® is n anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present in the form of a carboxylate anion, 25 -alkyl is an alkylene group having 1-8 C atoms and A is alkyl having 1-8 C atoms, in which in addition instead of one or more -NH-CO groups there can also be one or more -ΝΑ-CO groups, and their salts . 30 2. a) 2S-(4-aminopiperidinocarbonyl-Phe-£Ala-amino)-lcyclohexyl-6-methylheptane-3R,4S-diol; b) 3S-(4-aminopiperidinocarbonyl-Phe-£Ala-amino)-4cyclohexyl-l-cyclopropylbutane-lS,2R-diol.
3. Process for the preparation of an amino acid 35 derivative of the formula I and of its salts, characterised in that it is set free from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent or in that a carboxylic acid of the formula II - 33 X-G 1 -OH II in which G 1 (a) (b) is is absent, -W-CR^-CO-, 5 (c) is -W-CR 1 R 2 -CO-NH-CH 2 CH 2 -CO-, or one of its reactive derivatives is reacted with a compound of the formula III H-G 2 -NH-CHR 3 -(CHOH) 2 -R* III in which G 2 (a) is -W-CR 1 R 2 -CO-NH-CH 2 CH 2 -CO-, (b) is -NH-CH 2 CH 2 -C0-, (c) is absent, and in that a functionally modified amino and/or hydroxy group is optionally set free in a compound of the formula 15 I by treating with solvolysing or hydrogenolysing agents and/or a free amino group is acylated by treating with an acylating agent and/or a compound of the formula I is converted into one of its salts by treating with an acid.
4. Process for the production of pharmaceutical 20 preparations, characterised in that a compound of the formula I and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary. 25
5. Pharmaceutical preparation, characterised in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.
6. Use of compounds of the formula I or of their physiologically acceptable salts for the production of a 30 medicament.
7. Use of compounds of the formula I or of their physiologically acceptable salts in the control of renindependent hypertension or hyperaldosteronism. - 34
8. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
9. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
10. A compound as claimed in claim 1, whenever prepared by a process claimed in claim 3 or 9.
11. A pharmaceutical preparation according to claim 5, substantially as hereinbefore described and exemplified.
12. Use hereinbefore
13. Use hereinbefore according to claim 6, described . according to claim 7, described . substantially as substantially as
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| DE4104024A DE4104024A1 (en) | 1991-02-09 | 1991-02-09 | AMINOSAEUREDERIVATE |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1328333C (en) * | 1988-03-04 | 1994-04-05 | Quirico Branca | Amino acid derivatives |
-
1991
- 1991-02-09 DE DE4104024A patent/DE4104024A1/en not_active Withdrawn
-
1992
- 1992-01-27 EP EP19920101268 patent/EP0499080A3/en not_active Withdrawn
- 1992-02-05 AU AU10743/92A patent/AU1074392A/en not_active Abandoned
- 1992-02-05 CS CS92323A patent/CS32392A3/en unknown
- 1992-02-07 PT PT100109A patent/PT100109A/en not_active Application Discontinuation
- 1992-02-07 ZA ZA92909A patent/ZA92909B/en unknown
- 1992-02-07 IE IE042292A patent/IE920422A1/en unknown
- 1992-02-07 JP JP4066566A patent/JPH05105656A/en active Pending
- 1992-02-07 HU HU9200391A patent/HUT62915A/en unknown
- 1992-02-07 CA CA002060856A patent/CA2060856A1/en not_active Abandoned
- 1992-02-07 MX MX9200524A patent/MX9200524A/en unknown
- 1992-02-08 KR KR1019920001826A patent/KR920016465A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0499080A2 (en) | 1992-08-19 |
| CA2060856A1 (en) | 1992-08-10 |
| AU1074392A (en) | 1992-08-13 |
| JPH05105656A (en) | 1993-04-27 |
| MX9200524A (en) | 1992-08-01 |
| HUT62915A (en) | 1993-06-28 |
| CS32392A3 (en) | 1992-10-14 |
| HU9200391D0 (en) | 1992-04-28 |
| EP0499080A3 (en) | 1993-01-20 |
| ZA92909B (en) | 1992-11-25 |
| DE4104024A1 (en) | 1992-08-13 |
| KR920016465A (en) | 1992-09-24 |
| PT100109A (en) | 1993-05-31 |
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