IE921995A1 - Compounds with renin-inhibiting properties, a process for¹the preparation thereof and the use thereof - Google Patents
Compounds with renin-inhibiting properties, a process for¹the preparation thereof and the use thereofInfo
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- IE921995A1 IE921995A1 IE199592A IE921995A IE921995A1 IE 921995 A1 IE921995 A1 IE 921995A1 IE 199592 A IE199592 A IE 199592A IE 921995 A IE921995 A IE 921995A IE 921995 A1 IE921995 A1 IE 921995A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
Compounds of the formula (I) in which X and Y are, for example, N, R<1>, R<2> and R<3> are, for example, hydrogen, A and L are, for example, CH2 or CO, Z is, for example, hydrogen, R<4> is, for example, cyclohexylmethyl, R<5> is, for example, hydroxyl, R<6> is, for example, n is, for example, zero or 1, are active renin-inhibiting compounds which have a high in-vitro and in-vivo activity.
Description
COMPOUNDS WITH RENIN-INHIBITING PROPERTIES, A PROCESS FOR THE PREPARATION THEREOF AND THE USE THEREOF
APPLICATION No-SPECIFICATION FILED—β
HOECHST AKTIENGESELLSCHAFT, a Joint Stock Company organised and existing under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany.
ΙΑ
HOECHST AKTIENGESELLSCHAFT HOE 91/F 186
Dr. JA/Le
Description
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 heterocyclically substituted amino diol derivatives with renin-inhibitory action. EP-A 365 992 describes alkyl alcohol and statin derivatives with a fixed conformation at the N terminus.
It has now been found that compounds which have a preferably saturated, heterocyclic group at the N terminus and a heterocyclic substituent at the C terminus of the molecule are exceptionally active and highly specific renin inhibitors which have a substantially improved action in vivo and a considerably increased absorption.
The invention therefore relates to a compound of the formula (I)
in which
X is N, 0 or CH;
R1 is absent, hydrogen, an N protective group, aryl, heterocyclic or R7-Q with
1) R7 equal to short-chain alkyl, amino, alkylamino, dialkylamino, (alkoxyalkyl)(alkyl)amino, (alkoxyalkoxyalkyl) (alkyl) amino, aryl, arylalkyl, amino25 alkyl, N-protected aminoalkyl, alkoxy, substituted short-chain alkyl with a substituent from the group comprising alkoxy, alkylthio, halogen, alkylamino, N-protected (alkyl)amino and dialkylamino,
R
with m equal to 1-5 and R8 hydrogen, hydroxyl, alkoxy, alkylthio, alkoxyalkoxy, polyalkoxy, amino, N-protected amino, alkylamino, N-protected alkylamino or dialkylamino,
with R9 equal to 0, S, S02, 0=C or R10N with R10 equal to hydrogen, short-chain alkyl or an N protective group,
2) Q is C=0 or CH2 where X equals N when R1 is an N protective group,
R11 S(0)2 with R11 equal to amino, alkylamino, dialkylamino, short-chain alkyl, halogenoalkyl, aryl, p-biphenylyl, heterocyclic or (R12)2P(O) with R12 equal to alkoxy, alkylamino or dialkylamino,
A and L are, independently of one another, either absent, C=0, S02 or CH2;
Y is N or CH;
R2 is hydrogen, short-chain alkyl, cycloalkylalkyi, -CH2-R13- (CH2) q-R14 where q equals 0, 1 or 2;
R13 is absent or is 0, NH or S when q equals 1 or 2; R14 is alkyl or a heterocycle;
Z is hydrogen or -R15C(O)R16, -R15S(O)2R16 or -R15-C(S)R16, where R15 equals NH, -N(R17)- with R17 equal to shortchain alkyl or benzyl, or CH2 and R16 is alkoxy, benzyloxy, alkylamino, dialkylamino, aryl or heterocyclic;
R3 is hydrogen, short-chain alkyl, short-chain alkenyl, cycloalkylalkyl, cycloalkenylalkyl, alkoxyalkyl, alkythioalkyl, (alkoxyalkoxy)alkyl, (polyalkoxy)alkyl, arylalkyl or heterocyclically substituted alkyl;
n is 0 or 1
R4 is hydrogen, (Ci-Cu,)-alkyl, (C3-C6)-cycloaikyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (C6-C12) -aryl or (C6-C12) -aryl- (Cx-C4) -alkyl
R5 is hydrogen, (Cj-Cn,) -alkyl, (C6-C12)-aryl, 15 (C6-C12) -aryl-(Cx-C4)-alkyl, hydroxyl or amino;
R6 is a radical of the formula (II) (CH2)„-CHR18-Het (II) where
R18 is hydrogen, (Cx-C7) -alkyl, (Cx-C4) -alkoxy, 20 (Cj-CJ-alkylthio, (Cx-C4) -alkylamino, hydroxyl, azido or halogen, and Het is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydrogenated or completely hydrogenated, which can contain as hetero atoms one or two identical or different radicals from the group comprising N, O, S, NO, SO, S02, and which can be substituted by one or two identical or different radicals from the series comprising (Cx-C4)-alkyl, allyl, (Cx-C4)-alkoxy, hydroxyl, halogen, amino, mono- or di-(Cx-C4)-alkylamino and CF3; and s is 0, 1, 2, 3 or 4, and the physiologically tolerated salts thereof.
Preferred in this connection is a heterocyclic compound of the formula (I) or a salt of this compound, in which the symbols have the following meanings:
R4 isobutyl, benzyl or eyelohexylmethyl;
R5 hydrogen, (Ci-C5) -alkyl, (C6-C10)-aryl, (C5-C10)-aryl(Ci-CJ-alkyl or hydroxyl;
R6 a radical of the formula (II) in which R18 is hydrogen, (Ci-Ci)-alkyl, (Ci-C4)-alkoxy, (Ci-C4)-alkylthio, (Ci-C4)-alkylamino, hydroxyl, azido or halogen, s 0, 1 or 2.
Likewise preferred are the following meanings for the symbols:
X N or CH,
R1 absent, hydrogen, benzyl, 2-pyridyl, 1-piperazinyl, (4-OMe)phenyl, tert.-butyloxycarbonyl, isobutyl, benzyloxycarbonyl, Me2NC(0)-, 4-methyl-l-piperazinylcarbonyl, 1-morpholinylcarbonyl, p-toluenesulfonyl or 4-methyl-l-piperazinylsulfonyl;
A and L independently of one another either absent or CH2,
D C=0 or CH2;
Y equal to N
R2 hydrogen or benzyl;
Z hydrogen, BOC-NH, CbZ-NH, p-toluenesulfonylamino,
4-methyl-1-piperaz inylsulfonyl amino, 4-methyl1-piperazinyl, N-methyl-N-(4-methyl-l-piperazinylIE 921995 sulfonyl)amino;
R3 hydrogen, methyl, n-butyl, 4-imidazolylraethyl,
4-thiazolylmethyl or N-B0C-4-(imidazolyImethyl); and n zero.
The invention particularly relates to a heterocyclic compound of the formula (I) in which the symbols have the following meanings:
R4 isobutyl, benzyl or cyclohexylmethyl;
R5 hydrogen or hydroxyl;
R6 a radical of the formula (II) in which R18 is hydrogen or fluorine,
Het is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or
-imidazolyl radical or a 2-oxazolinyl radical, where the said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, alkyl, fluorine, chlorine, bromine, CF3 and methoxy, and s 0, 1 or 2;
and the other radicals and variables are as defined above, and the physiologically tolerated salts thereof.
The centers of chirality in the compounds of the formula (I) can have the R or S configuration.
The term N protective group means those groups suitable for protecting nitrogen atoms during synthetic processes from unwanted reactions, for preventing attack of exopeptidases on the final products or for contributing to increasing the solubility. The term means groups such as, for example, acyl, acetyl, pivaloyl, t-butylacetyl, trichloroethoxycarbonyl, t-butyloxycarbonyl (BOC), benzyloxycarbonyl (CbZ) or benzoyl groups or an L- or D-aminoacyl radical which is itself in turn N-protected in the same way.
The term short-chain alkyl means unbranched or branched alkyl radicals with 1 to 7 carbon atoms such as, for example, methyl, n-propyl, iso-propyl, n-butyl, iso5 butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl or n-hexyl.
The term short-chain alkenyl means short-chain alkyl radicals which contain at least one C-C double bond.
The term alkylamino means -NH linked to a short-chain alkyl radical.
The term aminoalkyl means -NH2 linked to a short-chain alkyl radical.
The term cycloalkyl means an aliphatic ring of 3-7 carbon atoms.
The term aryl means mono- or bicyclic carbon ring systems with one or more aromatic rings such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. The term aryl likewise means heterocyclic, aromatic ring systems. Aryl radicals can moreover be unsubstituted or substituted by 1, 2 or 3 substituents which can be, independently of one another, short-chain alkyl, halogenoalkyl, alkoxy, alkylthio, amino, alkylamino, hydroxyl, halogen, mercapto, nitro, formyl, carboxyl and carbamoyl.
The term polyalkoxy means -OR19 with R19 equal to a branched or unbranched alkyl chain with 1-5 C^-O-C* linkages in which w and x can be, independently of one another, 1-3.
The term heterocyclic alkyl means a heteroeycle sub30 stituted by a short-chain alkyl radical, such as, for example, imidazolyImethyl or thiazolyImethyl.
Halogen is fluorine, chlorine, bromine or iodine.
(ci-C10) -alkyl preferably means an alkyl radical or a corresponding unsaturated radical with 1-10 carbon atoms. The radical can be straight-chain or branched. Corres5 ponding statements 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 contain more than one substituent, the latter can be both cis and trans to one another.
The heteroaromatic radical means, in particular, a radical which contains a six-membered aromatic ring derived from benzene, in which one or more CH groups are replaced by N, or which contain a five-membered aromatic ring derived from benzene, in which one or two CH groups are replaced by 0, S, NH or N and in which other CH groups are optionally replaced by N. This heteroaryl radical is preferably monocyclic or bicyclic, and in the latter case it is fused to a benzene or a five- or sixmembered ring defined as above. Corresponding statements apply to radicals derived therefrom such as the heteroaromatic-aliphatic radicals heteroaralkyl, hetero25 aroyl or heteroaryloxy.
A Het radical within the meaning of the above definition is, for example, a heteroaryl radical such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quino30 lyl, isoquinolyl, quinoxalinyl, β-carbolinyl or a benzofused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocycle can be substituted on a nitrogen atom by oxide, (Cx-C6)-alkyl, for example methyl or ethyl, phenyl or phenyl-(Ci-C4)IE 921995 alkyl, for example benzyl and/or on one or more carbon atoms by (^-ΰ4) -alkyl, for example methyl, phenyl, phenyl-(Ci-C^-alkyl, for example benzyl, halogen, for example chlorine, hydroxyl, (Ci-Ci)-alkoxy, for example methoxy, phenyl-(Cx-C4)-alkoxy, for example benzyloxy, or oxo, up to three times, and be partially saturated.
Examples are: 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl,
4-imidazolyl, methylimidazolyl, for example 1-methyl-2-,
-4- or -5-imidazolyl, l,3-thiazol-2-yl, 2-, 3- or
4-pyridyl, 2-, 3- or 4-pyridyl 1-oxide, 2-pyrazinyl, 2-,
4- or 5-pyrimidyl, 2-, 3- or 5-indolyl, substituted
2-indolyl, for example Ι-methyl-, 5-methyl-, 5-methoxy-,
- benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, l-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl,
4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1,2-dihydro-3-isoquinolyl 1-oxide, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzothiazolyl, benzo[c]indol20 2-yl 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, thiomorpholino, tetrahydrothienyl.
The term optionally substituted which is used means that the relevant radical can be substituted by one, two or three, preferably one or two, identical or different radicals from the series comprising (Cx-C6)-alkyl, (Cx-C6)30 alkoxy, hydroxyl, halogen, (Cx-C6)-alkanoyl, CF3, amino, (Cx-C6)-alkylamino, di-(Cx-C6)-alkylamino, carbamoyl, (Cx-C6)-alkoxycarbonyl and sulfamoyl.
Salts of compounds of the formula (I) mean, in particular, pharmaceutically utilizable and non-toxic salts.
- 9 Salts of this type are formed, for example, by compounds of the formula (I) which contain acid 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, hydro10 chloric 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 β-toluenesulfonic acid.
The invention furthermore relates to a process for the preparation of compounds of the formula (I), which comprises coupling a fragment with terminal carboxyl group or its reactive derivative to a corresponding fragment with free amino group, where appropriate elimi20 nating (a) protective group(s) temporarily introduced to protect other functional groups, and converting the compound obtained in this way, where appropriate, into its physiologically tolerated salt.
Fragments of a compound of the formula (I) with a ter25 minal carboxyl group have the following formula (III)
COOH
Ί »3 (III)
Fragments of a compound of the formula (I) with a ter minal amino group have the following formula (IV) (IV) r r
H-N-CH-CH-CH-R’
I
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 employed: active ester method with N-hydroxysuccinimide or 1-hydroxybenzotriazole as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propanephosphonic anhydride or methylethylphosphinic anhydride and the mixed anhydride method with pivaloyl chloride (M. Zaoral, Coll. Czech. Chem. Commun., 1962,
27, 1273). The reactions are preferably carried out in an inert solvent or mixtures of solvents at a temperature between -20 °C and the boiling point of the reaction mixture.
The carboxylic acids of the formula (III) are prepared, for example, by the method of EP-A 365 992. The optically active amines of the formula (IV) in which R4, R5 and R6 are as defined above, which are used as starting compounds, are prepared starting from optically active α-amino acids with retention of their center of asym25 metry. For this purpose, an N-protected amino aldehyde is prepared in a known manner and is coupled in an aldolanalogous addition to a corresponding heteroarylalkyl building block and, after elimination of the N protective groups, yields amino alcohols of the formula (IV). When
R5 = OH, an N-protected amino aldehyde is likewise used as starting material and is converted, for example, by aldol-analogous addition of unsaturated compounds.
introduction of suitable protective groups and subsequent epoxidation into the required intermediates. Mixtures of diastereomers with respect to the OH-carrying center are obtained and are separated in a manner known per se, for example by fractional crystallization or by chromatography. Diastereomeric purity is checked 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 cimino 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 components 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-butyllithium, methyllithium or phenyllithium, sodamide and alkali metal salts of organic nitrogen bases such as lithium diisopropylamide.
The preliminary and subsequent operations necessary to prepare compounds of the formula (I), such as introduction and elimination of protective groups, are known from the literature and described, for example, in
D.W. Greene, Protective Groups in Organic Synthesis.
Salts of compounds of the formula (I) with salt-forming groups are prepared in a manner known per se, by reacting, for example, 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 via the juxtaglumerular cells of the kidney into the bloodstream as a consequence of various stimuli (volume depletion, sodium deficiency, β-receptor stimulation). There it eliminates the decapeptide angiotensin I from 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 blood pressure by vasoconstriction. In addition, it stimulates the sec20 retion of aldosterone from the adrenal and, in this way, via inhibition of sodium excretion, increases the extracellular fluid volume, which in turn contributes to increasing the blood pressure. Inhibitors of the enzymatic activity of renin bring about a reduced formation of angiotensin I, which is followed by 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 in vitro tests. These entail the reduction in the formation of angiotensin I being measured in various systems (human plasma, purified human renin).
1. Principle of the test
For example human plasma which contains both renin and angiotensinogen is incubated at 37°C with the compound to be tested. During this, angiotensin I is liberated from angiotensinogen due to the action of renin and is subsequently 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 cooled in ice. Coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifugation (rotor HS 4 (Sorvall), 3500 rpm, 0-4eC, 15 min; repeat if necessary), the plasma is cautiously removed by pipette and frozen in suitable portions 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 (-4°C, 3 days).
3. Test procedure
Angiotensin I is determined using the renin Maia* kit (Sereno Diagnostics S.A., Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given therein.
Incubation mixture: 25 1,000 μί of plasma (thawed at 0-4°C) 100 μί of phosphate buffer (pH 7.4) (addition of 10‘4 M ramiprilat) 10 μί of PMSF solution 10 μί of 0.1% Genapol PFIC 30 12 μί of DMSO or test product In general, 10 '2 M solutions of the test products
dimethyl sulfoxide (DMSO) are prepared and appropriately diluted with DMSO; the incubation mixture contains a maximum of 1% DMSO.
- 14 The mixtures are mixed in ice and placed in a water bath (37°C) for incubation for 1 hour. A total of 6 samples (100 μί each) are taken from an additional mixture without inhibitor and without further incubation for determination of the initial angiotensin I content in 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, 100 μί samples from each mixture are frozen in precooled Eppendorf tubes on dry ice and stored at about -25C 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, 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 reported as % remaining activity. The
IC50 is read off a plot of % remaining activity against 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 10_1° 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 vitro test of renin inhibitors. Primate renin and human renin are substantially homologous in their sequence. Endogenous renin secretion is stimulated by i.v. injection of furosemide.
The test compounds are then administered, and their action on blood pressure and heart rate is measured. In this test the compounds of the present invention are active in the i.v. dose range of about 0.1-5 mg/kg, and in the dose range of about 1-50 mg/kg on intraduodenal administration by gastroscope. 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.
It has emerged from biological tests that the compounds according to the invention have enzyme inhibitory action and also inhibit viral enzymes such as HIV protease. The action inhibiting HIV protease is particularly important 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 at concentrations of about 10-4 to 108 mol/1 in the in vitro tests used.
The invention furthermore 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, especially of diseases caused by HIV, and to the said pharmaceuticals.
Pharmaceutical products contain an effective amount of the active substance of the formula (I) together with an inorganic or organic pharmaceutically utilizable excipient. Intranasal, intravenous, subcutaneous or oral administration is possible. The dosage of 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 excipients, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or 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, especially corn starch. This preparation can take place both as dry and wet granules. Examples of suitable oily excipients or solvents are plant 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 salt 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-butyllithium
- 17 10
DCC dicyclohexylcarbodiimide DC I desorption chemical ionization 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 triphenyImethyl
The following examples illustrate the invention.
Example 1
N-[2S-(3R-Benzyl-4-(1-morpholinylcarbonyl)-1-pipera20 zinyl)hexanoyl]-(2S,3R, 4S)-1-cyclohexyl-3,4-dihydroxy6-(2-pyridyl)-2-hexylamine
a) (2S,3R,4S)-2-tert-Butoxycarbonylamino-l-cyclohexyl3,4-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. The mixture is warmed to room temperature, stirred for 30 min and then cooled to -40eC. 2 mmol of (2RS,3R,4S)-3-tert.-butyldimethylsilyloxy-4-tert. -butyloxycarbonylamino-5-cyclohexy 1-1,2-epoxypentane (disclosed in EP-A 189 203,
Example 6) are added (dissolved in 10 ml of THF). Stirring at room temperature for 10 h is followed by dilution with water and extraction 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 tetrabutyl35 ammonium 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 chromatographic separation on silica gel.
b) N-[2S-(3R-Benzyl-4-(1-morpholinylcarbonyl)-1-piperazinyl )hexanoyl]-(2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy6-(2-pyridyl)-2-hexylamine
200 mg of (2S,3R,4S)-2-tert.-butyloxycarbonylaminol-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane (compound from Example la) are stirred with 3 ml of trifluoroacetic acid in 3 ml of abs. methylene chloride at room temperature for 2 h. The residue resulting after concentration is taken up in 1 M NaHCO3 solution, the mixture is extracted three times with EA, and the EA phases are dried over Na2SO4. The residue after concentration is dissolved in 2 ml of abs. DMF, 205.8 mg of 2-[3R-benzyl-4-(1-morpholinylcarbonyl) -1-piperazinyl ]hexanoic acid (disclosed in EP-A 365 992, Example 38), 104.2 mg of Ν,Ν'-dicyclohexylcarbodiimide and 103.4 mg of 1-hydroxybenzotriazole are added, the pH of the solution is adjusted to 9 with N-ethylmorpholine, and the mixture is stirred at room temperature for 48 h. Filtration is followed by dilution with EA and washing once each with saturated NaHCO3 solution, water and saturated sodium chloride solution, drying over Na2SO4 and concentration. Chromatography on silica gel (with a CH2Cl2/MeOH mixture as mobile phase) yields 93.7 mg of the title compound.
MS (FAB): 678 (M + H)
Example 2
N- [ 2S - (3R-Benzyl-4-tert.-butyloxycarbonyl-2-keto1 -piperazinyl) hexanoyl ] - (2S, 3R, 4S) -l-cyclohexyl-3,4 -dihydroxy-6- (2-pyridyl)-2-hexylamine
The title compound is prepared by the process described in Example lb from 2-(3R-benzyl-4-tert.-butyloxycarbonyl35 2-keto-1-piperazinyl)hexanoic acid (disclosed in
- 19 EP-A 365 992, Example 43) and the compound from Example la.
MS (FAB): 679 (M + H)
Example 3
N-[3-(4-Imidazolyl)-2S-(3R-benzyl-4-tert.-butyloxycarbonyl-2-keto-1-piperazinyl) propionyl ]-(2S,3R,4S) -1-cyclohexyl-3 ,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound results from reaction of 3-(4-imidazolyl) -2S- (3R-benzyl-4-tert. -butyloxycarbonyl-2-keto10 1-piperazinyl)propionic acid (prepared as described in
EP-A 365 992, Example 45) and the compound from Example la by the process described in Example lb.
MS (FAB): 703 (M + H)
Example 4
N- [ 2S- (3-Benzyloxycarbonylamino-3-phenylmethyl-2-oxol-pyrrolidinyl)-3-(4-imidazolyl)propionyl]-(2S,3R,4S) l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared by the process described in Example lb from (2S)-((3R,S)-benzyloxycarbonylamino20 3-phenylmethyl-2-oxo-l-pyrrolidinyl)-3-(4-imidazolyl)propionic acid (disclosed in EP-A 365 992, Example 62) and the compound from Example la.
MS (FAB): 737 (M + H)
Example 5
N-[2S-(3S-Benzyloxycarbonylamino-3-phenylmethyl-2-oxo1-piperidinyl )-3-( 4-imidazolyl Jpropionyl ] - (2S, 3R, 4S) l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
This compound is prepared from lithium (2S)-2-(l-tert.butyloxycarbonyl-4-imidazolylmethyl )-3-( (3S) -benzyloxy30 carbonylamino-3-phenylmethyl-2-oxo-l-piperidinyl) acetate (disclosed in EP-A 365 992, Example 84) and the compound from Example la by the process described in Example lb and subsequent elimination of protective groups in THF (1 ml), acetic acid (3 ml) and water (1 ml).
MS (FAB)s 753 (M + H)
Example 6
N-[3-(4-Thiazolyl)-2-(3R-benzyl-4-(1-morpholinylcar5 bonyl)-2-keto-l-piperazinyl)propionylJ-(2S,3R,4S)1- cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 3-(4-thiazolyl)2- ( 3R-benzyl-4-(1-morpholinylcarbonyl)-2-keto-l-piperazinyl)propionic acid (disclosed in EP-A 365 992, Example
129) and the compound from Example la by the process described in Example lb.
MS (FAB): 733 (M + H)
Example 7
N- [ 3-(4-Thiazolyl)-2-(3R-benzyl-4-p-toluenesulfonyl15 2-keto-l-piperazinyl)propionyl]-(2S,3R,4S)-1-eyelohexy13,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 3-(4-thiazolyl)2-( 3R-benzyl-4-p-toluenesulfonyl-2-keto-l-piperazinyl)propionic acid (disclosed in EP-A 365 992, Example 130) and the compound from Example la by the process indicated in Example lb.
MS (FAB): 774 (M + H)
Example 8
N-[3-(4-Thiazolyl)-2-(3R-benzyl-4-(N-methylpiperazine25 sulfonyl) -2-keto-l-piperazinyl) propionyl ]-(2S,3R,4S) 1- cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 3-(4-thiazolyl)2- (3R-benzyl-4-(N-methylpiperazinesulfonyl)-2-ketol-piperazinyl) propionic acid (disclosed in EP-A 365 992,
Example 141) and the compound from Example la by the process of Example lb.
MS (FAB): 782 (M + H)
Example 9
N- [ 3- (4-Imidazolyl )-2-( 3R-benzyl-4- (N-methylpiperazinesulf onyl ) -2-keto-l-piperazinyl) propionyl ]-(2S,3R,4S)1- cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)-2-hexylamine
The title compound is prepared from 3-(1-tert.-butyloxycarbonyl-4-imidazolyl)-2-(3R-benzyl-4-(N-methylpiperazinesulfonyl)-2-keto-l-piperazinyl)propionic acid (disclosed in EP-A 365 992, Examples 1 and 2) and the compound from Example la by the process indicated in
Example lb with subsequent elimination of protective groups with CF3COOH in CH2C12 and working up by extraction.
MS (FAB): 765 (M + H)
Example 10
N- [ (2S) - ((3S) -N-methylpiperazinesulfonylamino-3-phenylmethyl-2-oxo-l-piperidinyl)-3-(4-thiazolyl) propionyl]( 2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)2- hexylamine
The title compound is prepared from (2S)-((3S)-N-methyl20 piperazinesulfonylamino-3-phenylmethyl-2-oxo-l-piperidinyl)-3-(4-thiazolyl)propionic acid (disclosed in EP-A 365 992, Example 151) and the compound from Example la by the process from Example lb.
MS (FAB): 796 (M + H)
Example 11
N— [ (2S)-3-(4-Imidazolyl)-3-((3S)-4-methylphenylsulfonylamino-3-phenylmethyl-2-oxo-l-piperidinyl)propionyl]( 2S,3R,4S)-l-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)2-hexylamine
The title compound is prepared from (2S)-2-(1-tert.butyloxycarbonyl-4-imidazolylmethyl)-3-((3S)-4-methylphenylsulf onylamino-3-phenylmethyl-2-oxo-l-piperidinyl)acetic acid (disclosed in EP-A 365 992, Example 155) and the compound from Example la by the process of Example lb
- 22 and subsequent elimination of protective groups in THF/acetic acid/water.
MS (FAB): 771 (M + H)
Claims (12)
1. A compound of the formula (I) R i H —CH.-CH-R 1 OH 0) in which X is N, 0 or CH; R 1 is absent, hydrogen, an N protective group, aryl, heterocyclic or R 7 -Q with
2. A compound of the formula (I) as claimed in claim 1, wherein the symbols have the following meanings: 25 R 4 isobutyl, benzyl or eyelohexylmethyl; R 5 hydrogen, (C x -C 5 )-alkyl, (C 6 -C X0 )-aryl, (C 6 -C x0 )aryl-(C x -C 4 )-alkyl or hydroxyl; R 6 a radical of the formula (II) in which R 18 is hydrogen, (C x -C 4 )-alkyl, (C x -C 4 )-alkoxy, (C x -C 4 )30 alkylthio, (C x -C 4 )-alkylamino, hydroxyl, azido or halogen, s 0, 1 or 2; X N or CH, R 1 absent, hydrogen, benzyl, 2-pyridyl, 1-piperazinyl, (4-OMe)phenyl, tert.-butyloxycarbonyl, isobutyl, benzyloxycarbonyl, Me 2 NC (0)-, 4-methyl1-piperazinylcarbonyl, 1-morpholinylcarbonyl, p-toluenesulfonyl or 4-methyl-l-piperazinylsulfonyl; A and L independently of one another either absent or CH 2 , D C=O or CH 2 ; Y equal to N R 2 hydrogen or benzyl; Z hydrogen, BOC-NH, CbZ-NH, p-toluenesulfonylamino, 2) Q is C=0 or CH 2 where X equals N when R 1 is an N protective group,
3. A compound of the formula (I) as claimed in claim 1 25 or 2, wherein the symbols have the following meanings: R 4 isobutyl, benzyl or eyelohexyImethyl; R 5 hydrogen or hydroxyl; R 6 a radical of the formula (II) in which R 18 is hydrogen or fluorine, Het is a 2-, 3- or 4-pyridyl radical, a 2-, 4- or
4. -thiazolyImethyl or N-BOC-4-(imidazolyImethyl); n zero. and the other radicals are as defined in claim 1, and the physiologically tolerated salts thereof. 4-methyl-1-piperazinylsulfonylamino, 4-methyl1-piperazinyl, N-methyl-N-(4-methyl-1-piperazinyl sulf onyl ) amino; R 3 hydrogen, methyl, n-butyl, 4-imidazolyImethyl, 5. Claims l.to 3 for use as medicine for the treatment of high blood pressure.
5. A compound of the formula (I) as claimed in any of claims 1 to 3 for use as medicine. 5 5-imidazolyl radical or a 2-oxazolinyl radical, where the said heterocycles can each be substituted by one or two identical or different radicals from the series comprising methyl, ethyl, propyl, alkyl, fluorine, chlorine, bromine, CF 3 and 5 R 6 is a radical of the formula (II) (CH Z ) B -CHR 18 -Het (11) where R 18 is hydrogen, (Cj-Cy)-alkyl, (C x -C 4 )-alkoxy, (C x -C 4 ) -alkylthio, (C x -C 4 ) -alkylamino, hydroxyl, 5 R 11 S(0)2 with R 11 equal to amino, alkylamino, dialkylamino, short-chain alkyl, halogenoalkyl, aryl, p-biphenylyl, heterocyclic or (R 12 )2P(O) with R 12 equal to alkoxy, alkylamino or dialkylamino,
6. A compound of the formula (I) as claimed in any of
7. A pharmaceutical composition containing an active substance and, where appropriate, excipients and other additives, which contains as active substance
8. A process for the production of a pharmaceutical composition as claimed in claim 7, which comprises converting the active substance or substances to15 gether with a physiologically acceptable vehicle and, where apropriate, other additives into a suitable dosage form.
9. A compound according to claim 1, substantially as hereinbefore described and exemplified.
10. A process for the preparation of a compound according to claim 1, substantially as hereinbefore described and exemplified. 10 at least one compound of the formula (I) as claimed in claim 1. 10 methoxy, and s 0, 1 or 2; and the other radicals and variables are as defined in claim 1 or 2, and the physiologically tolerated salts thereof. 15 4. Process for the preparation of a compound of the formula (I) as claimed in claim 1, wherein a fragment of the formula (III) with terminal carboxyl group or its reactive derivative is coupled to a fragment of the formula (IV) with free amino group COOH (III) R' I N-CH-CH-CH-R (IV) OH where appropriate (a) protective group(s) temporarily introduced to protect other functional groups is (are) eliminated, and the compound obtained in this way is converted, where appropriate, into a - 28 physiologically tolerated salt. 10 azido or halogen, and Het is a 5- to 7-membered heterocyclic ring which can be benzo-fused, aromatic, partially hydrogenated or completely hydrogenated, which can contain as hetero atoms one or two identical or different radicals from 15 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, (C x -C 4 )-alkoxy, hydroxyl, halogen, amino, mono- or di-(C x -C 4 )-alkylamino 20 and CF 3 ; and s is 0, 1, 2, 3 or 4, and the physiologically tolerated salts thereof. 10 A and L are, independently of one another, either absent, C=0, S0 2 or CH 2 ; D is C=0, S0 2 or CH 2 , Y is N or CH; R 2 is hydrogen, short-chain alkyl, cycloalkylalkyl, 15 -CH2-R 13 -(CH2) q -R 14 where q equals 0, 1 or 2; R 13 is absent or is O, NH or S when q equals 1 or 2; R 14 is alkyl or a heterocycle; 20 Z is hydrogen or -R 15 C(O)R 16 , -R 15 S(O) 2 R 16 or -R 15 -C(S)R 16 , where R 15 equals NH, -N(R 17 )- with R 17 equal to short-chain alkyl or benzyl, or CH 2 and R 16 is alkoxy, benzyloxy, alkylamino, dialkylamino, aryl or heterocyclic; 25 R 3 is hydrogen, short-chain alkyl, short-chain alkenyl, cycloalkylalkyl, cycloalkenylalkyl, alkoxyalkyl, alkylthioalkyl, (alkoxyalkoxy)alkyl, (polyalkoxy)alkyl, arylalkyl or heterocyclically substituted alkyl; 30 n is 0 or 1 R 4 is hydrogen, (C x -C 10 )-alkyl, (C 3 -C 6 )-cycloalkyl, (C 3 -C 8 )-cycloaikyl-(C x -C 4 )-alkyl, (C 6 -C x2 )-aryl or (C 6 -C 12 ) -aryl- (C x -C 4 ) -alkyl R 5 is hydrogen, (C x -C xo )-alkyl, (C 6 -C 12 )-aryl, (C 6 -C X2 )-aryl-(C x -C 4 )-alkyl, hydroxyl or amino;
11. A compound according to claim 1, whenever prepared by a process claimed in claim 4 or 10.
12. A pharmaceutical composition according to claim 7, substantially as hereinbefore described.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4120510 | 1991-06-21 |
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| IE921995A1 true IE921995A1 (en) | 1992-12-30 |
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| EP (1) | EP0519433A1 (en) |
| JP (1) | JPH05186461A (en) |
| KR (1) | KR930000506A (en) |
| CN (1) | CN1068112A (en) |
| BR (1) | BR9202325A (en) |
| CA (1) | CA2071744A1 (en) |
| CZ (1) | CZ190692A3 (en) |
| FI (1) | FI922875A (en) |
| HU (1) | HUT61744A (en) |
| IE (1) | IE921995A1 (en) |
| MX (1) | MX9203070A (en) |
| NO (1) | NO922426L (en) |
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| US6071895A (en) | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
| DE69333270T2 (en) | 1992-03-11 | 2004-08-05 | Narhex Ltd. | AMINE DERIVATIVES OF OXO AND HYDROXY SUBSTITUTED CARBON HYDROGEN |
| US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
| RU2126794C1 (en) | 1992-03-11 | 1999-02-27 | Нархекс Лимитед | Amino-derivatives of oxo- or hydroxy-substituted hydrazines, method of their synthesis and pharmaceutical compositions for inhibition of retrovirus protease |
| IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
| US6063794A (en) | 1996-10-11 | 2000-05-16 | Cor Therapeutics Inc. | Selective factor Xa inhibitors |
| US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
| US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| WO1998046628A1 (en) * | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
| EP0977772A1 (en) | 1997-04-14 | 2000-02-09 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
| AU6896398A (en) | 1997-04-14 | 1998-11-11 | Cor Therapeutics, Inc. | Selective factor xa inhibitors |
| US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
| US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
| ECSP003707A (en) * | 1999-10-13 | 2002-05-23 | Novartis Ag | DIAZEPANES |
| US6399599B1 (en) | 1999-10-13 | 2002-06-04 | Novartis Ag | Substituted 2-oxo-1,4-diazacycloalkanes |
| WO2002060894A2 (en) | 2001-01-30 | 2002-08-08 | Bristol-Myers Squibb Company | Sulfonamide lactam inhibitors of factor xa |
| BRPI0506490A (en) * | 2004-01-23 | 2007-02-13 | Speedel Experimenta Ag | organic compounds |
| EP1756037B1 (en) | 2004-01-23 | 2010-12-15 | Novartis AG | Amino alcohol derivatives and their activity as renin inhibitors |
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| IL81234A (en) * | 1986-01-16 | 1992-09-06 | Abbott Lab | Peptidylaminodiols,process for their preparation and pharmaceutical compositions comprising them |
| GB8707412D0 (en) * | 1987-03-27 | 1987-04-29 | Fujisawa Pharmaceutical Co | Peptide compounds |
| IL87614A0 (en) * | 1987-09-16 | 1989-01-31 | Abbott Lab | Peptidylheterocycles |
| EP0309766B1 (en) * | 1987-09-29 | 1998-04-15 | Banyu Pharmaceutical Co., Ltd. | N-acylamino acid derivatives and their use |
| IL92011A0 (en) * | 1988-10-19 | 1990-07-12 | Abbott Lab | Heterocyclic peptide renin inhibitors |
| DE3839559A1 (en) * | 1988-11-24 | 1990-05-31 | Hoechst Ag | RENIN-INHIBITING AMINODIOL 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 PL29487092A patent/PL294870A1/xx unknown
- 1992-06-17 EP EP92110244A patent/EP0519433A1/en not_active Withdrawn
- 1992-06-18 FI FI922875A patent/FI922875A/en unknown
- 1992-06-19 CZ CS921906A patent/CZ190692A3/en unknown
- 1992-06-19 KR KR1019920010653A patent/KR930000506A/en not_active Application Discontinuation
- 1992-06-19 MX MX9203070A patent/MX9203070A/en unknown
- 1992-06-19 JP JP4160476A patent/JPH05186461A/en active Pending
- 1992-06-19 CA CA002071744A patent/CA2071744A1/en not_active Abandoned
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- 1992-06-19 BR BR929202325A patent/BR9202325A/en not_active Application Discontinuation
- 1992-06-20 CN CN92104887A patent/CN1068112A/en active Pending
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| NO922426D0 (en) | 1992-06-19 |
| BR9202325A (en) | 1993-01-19 |
| CN1068112A (en) | 1993-01-20 |
| KR930000506A (en) | 1993-01-15 |
| PL294870A1 (en) | 1993-02-08 |
| HUT61744A (en) | 1993-03-01 |
| HU9202062D0 (en) | 1992-10-28 |
| FI922875A (en) | 1992-12-22 |
| NO922426L (en) | 1992-12-22 |
| MX9203070A (en) | 1992-12-01 |
| CZ190692A3 (en) | 1993-01-13 |
| EP0519433A1 (en) | 1992-12-23 |
| CA2071744A1 (en) | 1992-12-22 |
| JPH05186461A (en) | 1993-07-27 |
| FI922875A0 (en) | 1992-06-18 |
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