IE921996A1 - Heterocyclic compounds with renin-inhibiting properties, a¹process for the preparation thereof and the use thereof - Google Patents
Heterocyclic compounds with renin-inhibiting properties, a¹process for the preparation thereof and the use thereofInfo
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- IE921996A1 IE921996A1 IE199692A IE921996A IE921996A1 IE 921996 A1 IE921996 A1 IE 921996A1 IE 199692 A IE199692 A IE 199692A IE 921996 A IE921996 A IE 921996A IE 921996 A1 IE921996 A1 IE 921996A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
Heterocyclic compounds of the formula (I) in which the radicals have the following meanings: R<1> is, for example, propyl or isobutyl, R<2> is, for example, phenyl or pyridyl, R<3> is, for example, hydrogen, R<4> is, for example, cyclohexylmethyl, R<5> is, for example, hydrogen or hydroxyl, R<6> is, for example, a radical of the formula (II> (CH2)5-CHR<7>-Z (II> where R<7> is, for example, hydrogen, Z represents a 5- to 7-membered heterocyclic ring and s denotes 0, 1, 2, 3 or 4; are potent renin-inhibiting compounds.
Description
HOECHST AKTIENGESELLSCHAFT HOE 91/F 187 Dr.JA/fe
Description
Heterocyclic compounds with renin-inhibiting properties, a process for the preparation thereof and the use thereof
EP-A 370 454, EP-A 373 497, EP-A 394 853 and EP-A 417 698 disclose amino diol derivatives which have C-terminal heterocyclic substituents and a renin-inhibitory action. EP-A 369 743 and J. Med. Chem. 33 (1990), 2326-2334,
J. Med. Chem. 33 (1990), 2335-2342 and J. Med. Chem. 34 (1991), 151-157 describe alkyl alcohol and statin derivatives which contain two heterocyclic systems linked via an alkylamino bridge.
It has now been found, surprisingly, that compounds which contain two heterocyclic systems linked via an alkylamino bridge are exceptionally active and highly specific renin inhibitors which have a substantially improved action in vivo and a considerably enhanced absorption in the gastrointestinal tract.
The invention therefore relates to compounds of the formula I
in which the radicals have the following meanings:
R1 (Ci-Ce)-alkyl or phenyl;
R2 phenyl or pyridyl, where the pyridyl radical 25 optionally carries a (Ci-Ci)-alkyl substituent;
R3 hydrogen or a group of the formula Q-A in which Q is pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A
- 2 is methylene or ethylene,
R4 hydrogen, (C^-Cm)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)cycloalkyl-(C.-CJ -alkyl, (C6-C12)-aryl or (C6-C12)aryl- (Cx-C4) -alkyl;
R5 hydrogen, (Cx-Cx0)-alkyl, (C6-C12)-aryl, (C6-C12)-aryl(Cx-C4)-alkyl, hydroxyl or amino;
R6 a radical of the formula (II) (CH2)e-CHR7-Z (II) where
R7 is hydrogen, (Cx-C7)-alkyl, (Cx-C4)-alkoxy, (Cx-C4)alkylthio, (Cx-CJ-alkylamino, hydroxyl, azido or halogen, and
Z is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydrogenated or completely hydrogenated and which can contain as hetero atoms one or two identical or different radicals from the group comprising N, 0, S, NO, SO, S02 and which can be substituted by one or two identical or different radicals from the series comprising (0χ-04)-alkyl, allyl, (Cx-C4)-alkoxy, hydroxyl, halogen, amino, mono- or di-(0χ-04)-alkylamino and CF3; and where s is 0, 1, 2, 3 or 4; and the physiologially tolerated salts thereof.
Preferred in this connection are heterocyclic compounds in which the radicals in formula (I) have the following meanings:
R4 isobutyl, benzyl or eyelohexyImethyl;
R5 hydrogen, (Cx-C5)-alkyl, (C6-C10)-aryl, (C6-Cx0)-aryl(Cx-C4)-alkyl or hydroxyl;
R6 a radical of the formula (II) in which
R7 is hydrogen, (Cj-CJ-alkyl, (Cx-C4)-alkoxy, (Cx-C4)alkylthio, (Cx~C4)-alkylamino, hydroxyl, azido or halogen, s is 0, 1 or 2, and
Z is a heteroaryl radical from the group comprising pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, pyrazinyl, isoquinolyl, benzo-fused, quinoxalinyl, cyclopenta-, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolyl, β-carbolinyl or a cyclohexa- or eyelohepta-fused derivative from this group, and the other radicals are defined as in claim 1, and the physiologically tolerated salts thereof.
Very particularly preferred compounds of the formula (I) are those in which the radicals have the following meaning:
R1 methyl, ethyl, propyl, i-propyl, butyl, i-butyl or pentyl;
R2 phenyl or 3-pyridyl, where the pyridyl radical optionally carries a methyl or ethyl substituent;
R4 isobutyl, benzyl or cyclohexylmethyl;
R5 hydrogen or hydroxyl;
R6 a radical of the formula (II), in which R7 is hydrogen or fluorine,
Z is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or
-imidazolyl radical or a 2-oxazolinyl radical, where said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF3 and methoxy, and s is 0, 1 or 2.
The chirality centers in the compounds of the formula (I) can have the R or S configuration.
The term aryl means, for example, mono- or bicyclic hydrocarbon ring systems with one or more aromatic rings such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. Aryl radicals can moreover be unsubstituted or substituted by 1, 2 or 3 substituents which can be, independently of one another, (Cx-C7)-alkyl, halogenoalkyl, alkoxy, alkylthio, amino, alkylamino, hydroxyl, halogen, mercapto, nitro, formyl, carboxyl and carbamoyl.
- 4 Halogen is fluorine, chlorine, bromine or iodine.
(C^-Cio)-Alkyl means an alkyl radical or a corresponding unsaturated radical with 1-10 carbon atoms. The radical can be straight-chain or branched. Corresponding state5 ments apply to radicals derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, alkanoyl and aralkyl.
(C3-C8)-Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclo10 octyl. If these cyclic radicals carry more than one substituent, these can be both cis and trans with respect to one another.
The radical Z is, for example, a heteroaryl radical such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocycle can be up to trisubstituted on a nitrogen atom by oxide, (Cx-Cg)-alkyl, preferably methyl or ethyl, phenyl or phenyl-(C1-C4)-alkyl, for example benzyl, and/or on one or more carbon atoms by (C^—C4)-alkyl such as, for example, methyl, phenyl, phenyl-(Cx-C4)-alkyl such as, for example, benzyl, halogen such as, for example, chlorine, hydroxyl, (Cx-C4)-alkoxy such as, for example, methoxy, phenyl-(Cx-C*)-alkoxy such as, for example, benzyloxy, or oxo, and can be partially saturated. Z preferably means one of the following groupss 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl,
2-thienyl, 4-imidazolyl, methylimidazolyl, for example l-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl 1-oxide, 2pyrazinyl, 2-, 4- or 5-pyrimidyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example Ι-methyl-, 5-methyl-,
-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2indolyl, l-benzyl-2- or -3-indolyl,
4,5,6,7-tetrahydro-2-indolyl, cycloheptafb]-5-pyrrolyl,
2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or
4-isoquinolyl, 1-oxo-l,2-dihydro-3-isoquinolyl,
2-quinoxalinyl, 2-benzofuranyl, 2-benzoxalolyl, 2-benzo5 thiazolyl, benzo[e]-2-indolyl or P-carbolin-3-yl.
Partially hydrogenated or completely hydrogenated heterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl, for example 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino, thio10 morpholino or tetrahydrothienyl.
Salts of compounds of the formula (I) mean, in particular, pharmaceutically utilizable and non-toxic salts .
Salts of this type are formed, for example, by compounds of the formula (I) which contain acidic groups, for example carboxyl, with alkali metals or alkaline earth metals such as Na, K, Mg and Ca, and with physiologically tolerated organic amines such as, for example, triethylamine.
Compounds of the formula (I) which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid and with organic carboxylic or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid or p-toluenesulfonic acid.
The invention furthermore relates to a process for preparing compounds of the formula (I), wherein a fragment with a terminal carboxyl group or its reactive derivative is coupled to a corresponding fragment with a free amino group, where appropriate protective group(s) temporarily introduced to protect other functional groups are eliminated, and the compound obtained in this way is,
- 6 where appropriate, converted into a physiologically tolerated salt.
Fragments of a compound of the formula (I) with a terminal carboxyl group have the following formula (III)
Fragments of a compound of the formula (I) with a terminal amino group have the following formula (IV)
h2n-ch-ch—ch-r· (IV)
OH
Methods suitable for producing an amide linkage are described, for example, in Houben-Weyl (Methoden der organischen Chemie [Methods of Organic Chemistry], volume 15/2), Bodanszky et al. (Peptide Synthesis, 2nd ed. (Wiley & Sons; New York 1976)) or Gross, Meienhofer (The Peptides-Analysis, Synthesis, Biology (Academic Press,
New York 1979)).
The following methods are preferably used: active ester method with N-hydroxysuccinimide or 1-hydroxybenzotriazole as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propane20 phosphonic anhydride or methylethylphosphinic anhydride, and the mixed anhydride method with pivaloyl chloride (M. Zaoral, Coll. Czech. Chem. Commun., 1962, 27, 1273). The reaction is carried out in an inert solvent or mixture of solvents, preferably at a temperature between
-20°C and the boiling point of the reaction mixture.
Carboxylic acids of the formula (III) were prepared by the methods of R. H. Bradbury et al. (EP-A 369 743),
D. A. Roberts et al. (J. Med. Chem. 33 (1990), 23262334), R. H. Bradbury et al. (J. Med. Chem. 33 (1990),
2335-2342) and R. H. Bradbury et al. (J. Med. Chem. 34 (1991), 151-157).
The preparation of the optically active amines of the formula (IV) in which R4, R5 and R6 are as defined above and which are used as starting compounds starts from optically active α-amino acids, whose center of asymmetry is retained. For this purpose, an N-protected amino aldehyde is prepared in a known manner and is coupled in an aldol-analogous addition onto a corresponding heteroarylalkyl building block and, after elimination of the
N-protective groups, gives amino alcohols of the formula (IV). When R5 = OH, an N-protected amino aldehyde is likewise used as starting material and is converted into the required intermediates for example by aldol-analogous addition of unsaturated compounds, introduction of suitable protective groups and subsequent epoxidation.
Mixtures of diastereomers with regard to the OH-carrying center are obtained and are separated in a manner known per se, for example by fractional crystallization or by chromatography. The diastereomeric purity is checked, for example, by HPLC; the enantiomeric purity can be checked in a known manner by conversion into Mosher derivatives (H. S. Mosher et al., J. Org. Chem. 34 (1969) 2543).
N-Protected amino aldehydes are prepared by the method of B. Castro et al. (Synthesis 1983, 676).
The aldol-analogous addition onto N-protected amino aldehydes (preferably N-tert-butyloxycarbonyl and benzyloxycarbonyl protective groups) is carried out in a solvent which is inert to bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane.
Bases which can be used for the deprotonation of the heteroarylalkyl component are alkali metal alcoholates such as potassium tert-butylate, sodium methylate, alkali metal hydrides such as sodium or potassium hydride, organometallic bases such as n-butyllithium, s-butyl5 lithium, methyllithium or phenyllithium, sodamide and alkali metal salts of organic nitrogen bases such as lithium diisopropylamide.
The necessary operations preceding and following the preparation of compounds of the formula (I), such as introduction and elimination of protective groups, are known from the literature and are described, for example, in T. W. Greene, Protective Groups Synthesis. Salts of compounds of the formula (I) with salt-forming groups are prepared in a manner known per se by, for example, reacting a compound of the formula (I) with a basic group with a stoichiometric amount of a suitable acid.
Mixtures of stereoisomers, in particular mixtures of diastereomers, which are produced when racemic carboxylic acid derivatives are used, can be separated in a manner known per se by fractional crystallization or by chromatography.
The compounds of the formula (I) according to the invention have enzyme-inhibiting properties, in particular they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme from the class of aspartyl proteases which is secreted as a consequence of various stimuli (volume depletion, sodium deficiency, β-receptor stimulation) by the juxtaglomerular cells of the kidney into the bloodstream. There it cleaves the decapeptide angiotensin I off the angiotensinogen which is secreted by the liver. Angiotensin I is converted by angiotensin converting enzyme (ACE) into angiotensin II. Angiotensin II plays an essential part in the regulation of blood pressure because it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal and in this way increases, via inhibition of sodium excretion, the extracellular fluid volume, which in turn contributes to increasing the blood pressure. Inhibitors of the enzyme activity of renin bring about a reduced formation of angiotensin I, which results in a reduced formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the direct reason for the blood pressure-lowering action of renin inhibitors.
The activity of renin inhibitors can be checked by 10 in vitro tests. This entails measuring the reduction in the formation of angiotensin I in various systems (human plasma, purified human renin).
1. Principle of the test
For example, human plasma which contains both renin and 15 angiotensinogen is incubated with the compound to be tested at 37°C. During this, angiotensin I is liberated from angiotensinogen due to the action of renin and can subsequently be measured in a commercially available radioimmunoassay. This angiotensin release is inhibited by renin inhibitors.
2. Obtaining the plasma
The blood is obtained from volunteer subjects (about 0.5 1 per person; Bluko sampler (supplied by ASID Bonz und Sohn, UnterschleiBheim)) and collected in partially evacuated bottles while cooling in ice. Coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifugation (HS 4 rotor (Sorvall), 3,500 rpm, 0-4°C, 15 min; repeat if necessary), the plasma is carefully removed by pipette and frozen in suitable proportions at -30 °C. Only plasmas with sufficiently high renin activity are used for the test. Plasmas with low renin activity are activated (prorenin - renin) by a cold treatment (-4eC, 3 days).
Angiotensin I is determined using the Renin-Maia* kit (Serono Diagnostics S.A., Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given there with:
3. Test procedure
Incubation mixture
1000 μΐ of plasma (thawed at 0-4°C) 100 μΐ of phosphate buffer (PH 7-4) (addition of 10-4 M ramiprilat)
μί of PMSF solution 10 μί of 0.1% Genapol PFIC 12 μί of DMSO or test product
The test products are generally dissolved 10-2 M in 100% 15 dimethyl sulfoxide (DMSO) and appropriately diluted with
DMSO; the maximum content of DMSO in the incubation mixture is 1%.
The mixtures are mixed in ice and, for the incubation, placed in a waterbath (37°C) for 1 hour. A total of 6 samples (each 100 μΐ) are taken from an additional mixture without inhibitor and without further incubation for determination of the initial angiotensin I content of the plasma used.
The concentrations of the test products are chosen so that approximately the range of 10-90% enzyme inhibition is covered (at least five concentrations). At the end of the incubation time, three 100 μΐ samples from each mixture are frozen in precooled Eppendorf tubes on dry ice and stored at about -25 °C for the angiotensin I determination (mean of three single samples).
Angiotensin I radioimmunoassay (RIA)
The instructions for use of the RIA kit (Renin-Maia* kit,
- 11 Serono Diagnostics S.A., Coinsins, Switzerland) are followed exactly.
The calibration plot covers the range from 0.2 to 25.0 ng of angiotensin I per ml. The baseline angiotensin I content of the plasma is subtracted from all the measurements. The plasma renin activity (PRA) is reported as ng of ang I/ml x hour. PRA values in the presence of the test substances are related to a mixture without inhibitor (= 100%) and the IC50 is read off as % remaining activity against the concentration (M) of the test product (logarithmic scale).
The compounds of the formula (I) described in the present invention show inhibitory actions in the in vitro test at concentrations of about 10'5 to IO10 mol/1.
Renin inhibitors bring about a lowering of blood pressure in animals deprived of salt. Since human renin differs from the renin of other species, primates (marmosets, rhesus monkeys) are used for the in vivo test of renin inhibitors. Primate renin and human renin are substan20 tially homologous in their sequence. Endogenous renin secretion is stimulated by i.v. injection of furosemide. The test compounds are subsequently administered and their action on blood pressure and heart rate is measured. The compounds of the present invention are active in this test in an i.v. dose range of about 0.1-5 mg/kg and on intraduodenal administration by gastroscope in the dose range of about 1-50 mg/kg. The compounds of the formula (I) described in the present invention can be used as antihypertensives and for the treatment of heart failure.
HIV protease is cut autocatalytically out of the GAG-POL polypeptide and subsequently cleaves the precursor peptide p55 into the core antigens pl7, p24 and pl4. It is thus an essential enzyme whose inhibition interrupts the life cycle of the virus and suppresses its growth.
Biological tests showed that the compounds according to the invention have an enzyme inhibitory action and inhibit viral enzymes such as HIV protease too. The HIV protease inhibiting action has particular importance and qualifies the compounds according to the invention in particular for the therapy and prophylaxis of diseases caused by infection with HIV. The compounds of the formula (I) according to the invention show inhibitory actions in the in vitro tests used at concentrations of about 104 to 10‘8 mol/1.
The present invention also relates to the use of compounds of the formula (I) for producing pharmaceuticals for the therapy of high blood pressure and the treatment of congestive heart failure, and for the therapy and prophylaxis of viral diseases, in particular of diseases caused by HIV, and to said pharmaceuticals.
Pharmaceutical products contain an effective amount of the active substance of the formula (I), preferably together with an inorganic or organic pharmaceutically utilizable excipient. Administration can be intranasally, intravenously, subcutaneously or orally. The dosage of the active substance depends on the warm blooded species, the body weight, age and on the mode of administration.
The pharmaceutical products of the present invention are produced in dissolving, mixing, granulating or coating processes known per se.
For a form for oral administration, the active compounds are mixed with the additives customary for this purpose, such as excipient, stabilizers or inert diluents, and converted by conventional methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. This preparation can be carried out both as dry and wet granules. Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil and fish liver oil.
For subcutaneous or intravenous administration, the active compounds or the physiologically tolerated salts thereof are converted, if required with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, into solutions, suspensions or emulsions. Examples of suitable solvents are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
List of abbreviations used:
Boc tert.-Butoxycarbonyl BuLi n-Buty11ithium DCC Dicyclohexylcarbodiimide DC I Desorption Chemical Ionisation DNP 2,4-Dinitrophenyl DME Dimethoxyethane DMF Dimethylformamide EA Ethyl acetate FAB Fast atom bombardment h Hour HOBt 1-Hydroxybenzotriazole M Molecular peak MS Mass spectrum min Minutes NEM N-Ethylmorpholine RT Room temperature THF Tetrahydrofuran Trt Triphenylmethyl
The following examples illustrate the preparation of the 35 compounds according to the invention.
Example 1
N-[2-(8-Isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3yl) ethanoyl ] - (2S, 3R, 4S) -1-cyclohexyl-3,4-dihydroxy-6(2-pyridyl)-2-hexylamine la) (2S,3R,4S)-2-tert.-Butyloxycarbonylamino-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-hexane
2.8 ml of n-butyl lithium are added to 186 mg of 2-picoline in 20 ml of THF at -78°C. After the mixture has warmed up to room temperature it is stirred for 30 min and then cooled to -40°C. 2 mmol of (2RS,3R,4S)-3tert . - butyldimethylsilyloxy-4-tert . butyloxycarbonylamino-5-cyclohexyl-l,2-epoxypentane (disclosed in EP-A 189 203, Example 6) are added (dissolved in 10 ml of THF) . The mixture is stirred at room temperature for 10 h and then diluted with water and extracted with methyl tert.-butyl ether. The crude product after concentration is dissolved in THF and stirred with 10 ml of a 1 M solution of tetrabutylammonium fluoride in THF at 0°C for 1 h.
Dilution with water, extraction with EA and concentration result in 300 mg of the (2S,3R,4S) isomer (MS (FAB): 393 (M+H)) and 240 mg of the (2S,3S,4S) isomer (MS (FAB): 393 (M+H)) after separation by chromatography on silica gel.
lb) N- [ 2-(8-Isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]2 5 pyr a z in-3-y1)-ethanoyl]-(2S,3R,4S)-1-cyclohexyl-3,4dihydroxy-6-(2-pyridyl)-2-hexylamine
400 mg of (2S,3R,4S)-2-tert.-butyloxycarbonylamino-1cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane (compound from Example la) are dissolved in 5 ml of abs. CH2C12,
ml of trifluoroacetic acid are added and the resulting solution is stirred at room temperature for 3 h. The residue obtained after concentration is taken up in 1 M NaHCO3 solution, the mixture is extracted three times with EA, and the combined EA phases are dried over Na2SO4.
- 15 The residue after concentration is dissolved in 5 ml of absolute DMF, 316.6 mg of 2-(8-isobutyl-6-phenyl-l,2,4triazolo[4,3-a]pyrazin-3-yl) acetic acid (disclosed in EP-A 369,743, Example 1), 208.4 mg of N,N-dicyclohexyl5 carbodiimide and 206.8 mg of 1-hydroxybenzotriazole are added, the pH of the solution is adjusted to 9 with N-ethylmorpholine, and it is stirred at room temperature for 50 h. Filtration is followed by dilution with EA and washing once each with saturated NaHCO3 solution, water and saturated brine, and chromatography with a
CH2C12/CH3OH mixture as mobile phase yields 207.4 mg of the title compound.
MS(FAB):585 (M+H)
Example 2
N-[2-(8-Is obutyl - 6 -phenyl -1,2,4 -tr iazo lo [ 4,3 -a ] pyraz in- 3 yl) -3-(3-pyridyl)propionyl]-(2S,3R,4S)-1-cyclohexyl-3,4dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound results from reaction of 2-[8-isobutyl-6 -phenyl-1,2,4 -triazolo [ 4,3-a]pyrazin-3-yl ] -3- (320 pyridyl)propionic acid (disclosed in EP-A 369 743, Example 3) with the compound from Example la by the process of Example lb.
MS (FAB):676 (M+H)
Example 3
N-[2-(8-Propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)ethanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 8-propyl-6-(3pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl-acetic acid (disclosed in EP-A 369 743, Example 4) and the compound from Example la by the process detailed in Example lb.
MS (FAB): 572 (M+H)
Example 4
N- [2-(8-Propyl-6-(3-pyridyl)-1,2, 4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)-propionyl]-(2S,3R,4S)-1cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 2-[8-propyl-6-(3pyridyl)-l,2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3pyridyl)propionic acid (disclosed in EP-A 369 743, Example 6) and the compound from Example la by the process of Example lb.
MS (FAB): 663 (M+H)
Example 5
N-[3-Imidazol-4-yl) -(2RS)-2-(8-propyl-6-(3-pyridyl)1,2,4-triazolo [4,3-a)pyrazin-3-yl)-propionyl ]-(2S,3R,4S)l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 3-(1-triphenylmethylimidazol-4-yl)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-propionic acid (disclosed in EP-A 369 743, Example 27) and the compound from Example la by the process of Example lb and subsequent elimination of the Nim-Trt protective group with 90% strength trifluoroacetic acid and working up by extraction.
MS (FAB): 652 (M+H)
Claims (11)
1. A heterocyclic compound of the formula (I) HOE 91/F 187 in which the radicals have the following meanings: 5 R 1 (Cj-Cg)-alkyl or phenyl; R 2 phenyl or pyridyl, where the pyridyl radical optionally carries a (C x -C 4 )-alkyl substituent; R 3 hydrogen or a group of the formula Q-A in which Q is pyridyl, imidazolyl, thiazolyl and 10 pyrazolyl, and A is methylene or ethylene; R 4 hydrogen, (Ci-C 10 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(C 1 -C 4 )-alkyl, (C 6 -C 12 )-aryl or (C 6 -C 12 ) -aryl- (C x -C 4 ) -alkyl; R 5 hydrogen, ((^-0^)-alkyl, (C 6 -C 12 )-aryl, (C 6 -C 12 )15 aryl-(C x -C 4 )-alkyl, hydroxyl or amino; R 6 a radical of the formula (IX) (CH 2 ) B -CHR 7 -Z (II) where R 7 is hydrogen, (C x -C 7 )-alkyl, (C x -C 4 )-alkoxy, 20 (C x -C 4 )-alkylthio, (C x -C 4 ) -alkylamino, hydroxyl, azido or halogen, and Z is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydrogenated or completely hydrogenated and which can 25 contain as hetero atoms one or two identical or different radicals from the group comprising N, O, S, NO, SO, S0 2 and which can be substituted by one or two identical or different radicals from the series comprising (C x -C 4 )-alkyl, allyl, 30 (C x -C 4 )-alkoxy, hydroxyl, halogen, amino, monoor di-(C x -C 4 )-alkylamino and CF 3 ; and where s is Ο, 1, 2, 3 or 4; and the physiologially tolerated salts thereof.
2. A heterocyclic compound as claimed in claim 1, wherein the radicals in the formula (I) have the 5 following meanings: R 4 isobutyl, benzyl or eyelohexylmethyl; R 5 hydrogen, (Cx-Cg)-alkyl, (C 6 -C 10 )-aryl, (C 6 -C 10 )aryl-(C x -C 4 )-alkyl or hydroxyl; R 6 a radical of the formula (II) in which 10 R 7 is hydrogen, (C x -C 4 ) -alkyl, (C x -C 4 )-alkoxy, (C x -C 4 )-alkylthio, (C x -C 4 )-alkylamino, hydroxyl, azido or halogen, s is 0, 1 or 2, and Z is a heteroaryl radical from the group comprising 15 pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl or a benzo-fused, cyclopenta-, cyclohexa- or eyelohepta-fused 20 derivative from this group, and the other radicals are defined as in claim 1, and the physiologically tolerated salts thereof.
3. A heterocyclic compound as claim in claim 1, wherein the radicals in the formula (I) have the following 25 meanings: R 1 methyl, ethyl, propyl, i-propyl, butyl, i-butyl or pentyl; R 2 phenyl or 3-pyridyl, where the pyridyl radical optionally carries a methyl or ethyl substituent; 30 R 4 isobutyl, benzyl or eyelohexylmethyl; R 5 hydrogen or hydroxyl; R 6 a radical of the formula (II), in which R 7 is hydrogen or fluorine, Z is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or 35 5-imidazolyl radical or a 2-oxazolinyl radical, where said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF 3 and methoxy, and s is 0, 1 or 2; 5 and the other radicals are as defined in claim 1, and the physiologically tolerated salts thereof.
4. A process for preparing a heterocyclic compound of the formula (I) as claimed in claim 1, wherein a fragment of the formula (III) with a terminal 10 carboxyl group or its reactive derivative is coupled to a fragment of the formula (IV) with a free amino group, R 4 R I i h 2 n-ch-ch—ch-r 1 (IV) OH 15 where appropriate protective group(s) temporarily introduced to protect other functional groups are eliminated, and the compound obtained in this way is, where appropriate, converted into a physiologically tolerated salt. 20 5. A heterocyclic compound claimed in any of claims 1 of to the 3 for formula (I) as use as medicine. 6. A heterocyclic compound of the formula (I) as claimed in any of claims 1 to 3 for use as medicine for the treatment of high blood pressure. - 20 7. A pharmaceutical composition containing an active substance and, where appropriate, excipients and further additives, which contains as active substance at least one compound of the formula (I) as claimed in claim 1.
5. 8. A process for the production of a pharmaceutical composition as claimed in claim 7, which comprises converting the active substance or substances together with a physiologically acceptable vehicle and, where appropriate, other additives into a suitable dosage form.
6. 9. A heterocyclic compound of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, substantially as hereinbefore described and exemplified.
7. 10. A process for preparing a heterocyclic compound of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, substantially as hereinbefore described and exemplified.
8. 11. A heterocyclic compound of the formula (I) given and defined in claim 1, whenever prepared by a process claimed in claim 4 or 10.
9. 12. A pharmaceutical composition according to claim 7, substantially as hereinbefore described.
10. 13. A process for the production of a pharmaceutical composition according to claim 7, substantially as hereinbefore described.
11. 14. A pharmaceutical composition according to claim 7, whenever produced by a process claimed in claim 8 or 13.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4120494 | 1991-06-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
IE921996A1 true IE921996A1 (en) | 1992-12-30 |
Family
ID=6434438
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE199692A IE921996A1 (en) | 1991-06-21 | 1992-07-01 | Heterocyclic compounds with renin-inhibiting properties, a¹process for the preparation thereof and the use thereof |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0519434A3 (en) |
JP (1) | JPH05170768A (en) |
KR (1) | KR930000516A (en) |
CN (1) | CN1068117A (en) |
AU (1) | AU1835592A (en) |
BR (1) | BR9202327A (en) |
CA (1) | CA2071743A1 (en) |
CZ (1) | CZ187992A3 (en) |
FI (1) | FI922876A (en) |
HU (1) | HU9202064D0 (en) |
IE (1) | IE921996A1 (en) |
MX (1) | MX9203076A (en) |
NO (1) | NO922428L (en) |
PL (1) | PL294866A1 (en) |
ZA (1) | ZA924521B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR9306058A (en) * | 1992-03-11 | 1997-11-18 | Narhex Ltd | Amine derivatives of oxo- and hydroxy-substituted hydrocarbons |
US6071895A (en) * | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
MXPA93002392A (en) | 1992-03-11 | 2005-02-04 | Narhex Ltd | Amine derivatives of oxo- and hydroxy-substitued hydrocarbons. |
US5888992A (en) * | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
EP1622901A1 (en) * | 2003-04-30 | 2006-02-08 | Actelion Pharmaceuticals Ltd. | Tropane derivatives and their use as ace inhibitors |
AU2004234038A1 (en) * | 2003-04-30 | 2004-11-11 | Actelion Pharmaceuticals Ltd. | Azabicyclononene derivatives |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU629867B2 (en) * | 1988-11-17 | 1992-10-15 | Imperial Chemical Industries Plc | Triazolo (4,3a) pyrazine derivatives |
DE3841732A1 (en) * | 1988-12-10 | 1990-06-13 | Hoechst Ag | DIPEPTIDE DERIVATIVES WITH ENZYME-INHIBITOR EFFECT |
DE3913272A1 (en) * | 1989-04-22 | 1990-10-25 | Hoechst Ag | DIPEPTIDE DERIVATIVES WITH ENZYME-INHIBITOR EFFECT |
-
1992
- 1992-06-11 PL PL29486692A patent/PL294866A1/en unknown
- 1992-06-17 EP EP19920110245 patent/EP0519434A3/en not_active Withdrawn
- 1992-06-18 CZ CS921879A patent/CZ187992A3/en unknown
- 1992-06-18 FI FI922876A patent/FI922876A/en unknown
- 1992-06-19 NO NO92922428A patent/NO922428L/en unknown
- 1992-06-19 AU AU18355/92A patent/AU1835592A/en not_active Abandoned
- 1992-06-19 BR BR929202327A patent/BR9202327A/en not_active Application Discontinuation
- 1992-06-19 JP JP4160477A patent/JPH05170768A/en active Pending
- 1992-06-19 KR KR1019920010652A patent/KR930000516A/en not_active Application Discontinuation
- 1992-06-19 ZA ZA924521A patent/ZA924521B/en unknown
- 1992-06-19 MX MX9203076A patent/MX9203076A/en unknown
- 1992-06-19 CA CA002071743A patent/CA2071743A1/en not_active Abandoned
- 1992-06-19 HU HU9202064A patent/HU9202064D0/en unknown
- 1992-06-20 CN CN92104867A patent/CN1068117A/en active Pending
- 1992-07-01 IE IE199692A patent/IE921996A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
KR930000516A (en) | 1993-01-15 |
BR9202327A (en) | 1993-01-19 |
CA2071743A1 (en) | 1992-12-22 |
CN1068117A (en) | 1993-01-20 |
NO922428D0 (en) | 1992-06-19 |
JPH05170768A (en) | 1993-07-09 |
FI922876A (en) | 1992-12-22 |
NO922428L (en) | 1992-12-22 |
AU1835592A (en) | 1992-12-24 |
CZ187992A3 (en) | 1993-01-13 |
EP0519434A3 (en) | 1993-04-14 |
EP0519434A2 (en) | 1992-12-23 |
FI922876A0 (en) | 1992-06-18 |
MX9203076A (en) | 1992-12-01 |
ZA924521B (en) | 1993-02-24 |
PL294866A1 (en) | 1993-05-31 |
HU9202064D0 (en) | 1992-09-28 |
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Legal Events
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FC9A | Application refused sect. 31(1) |