HK1190399A

HK1190399A - Substituted n-phenethyltriazoloneacetamides and use thereof

Info

Publication number: HK1190399A
Application number: HK14103614.4A
Authority: HK
Inventors: Chantal FÜRSTNER; Jörg Keldenich; Martina Delbeck; Peter Kolkhof; Axel Kretschmer; Elisabeth Pook; Carsten Schmeck; Hubert TRÜBEL
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2010-09-02
Filing date: 2011-08-31
Publication date: 2014-07-04

Description

Substituted N-phenylethyl triazolone acetamides and uses thereof

The present application relates to novel substitutedN-phenethyltriazolone acetamides, to processes for their preparation, to their use alone or in combination for the treatment and/or prophylaxis of diseases and to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, more particularly for the treatment and/or prophylaxis of cardiovascular disorders.

The fluid content of the human body is determined by different physiological control mechanisms, the aim of which is to keep it constant (volume homeostasis). Here, the volume filling of the vascular system (Volumenf ü llung) and the permeability of the plasma are continuously recorded by corresponding receptors (baroreceptors and osmoreceptors). The information transmitted by these receptors to the central host of the brain regulates drinking behavior and controls fluid excretion via the kidneys by means of humoral and neural signals. The peptide hormone vasopressin plays an important role therein [ schrie r.w., Abraham, w.t.,New Engl. J. Med. 341, 577-585（1999）]。

vasopressin is produced by specialized endocrine neurons in the suprafascial and paraventricular nuclei in the wall of the third ventricle (hypothalamus) and is sent from there along the neurites of said neurons into the posterior lobe of the pituitary (the neuropituitary). There, the hormone is released into the blood circulation system in response to the stimulus. Volume loss (e.g. due to acute bleeding, profuse sweating, prolonged thirst or diarrhea) is a stimulus for a large outflow of this hormone. Conversely, an increase in intravascular volume (e.g., due to an increase in fluid intake) inhibits the secretion of vasopressin.

Vasopressin exerts its effects mainly through binding to 3 receptors, which are classified as V1a-, V1 b-and V2-receptors and belong to the family of G-protein coupled receptors. The V1a receptor is located primarily on cells of vascular smooth muscle tissue. Their activation leads to vasoconstriction, thereby increasing peripheral resistance and blood pressure. In addition, the V1a receptor was also detected in the liver. The V1b receptor (also known as the V3 receptor) is detectable in the central nervous system. Together with corticotropin-releasing hormone (CRH), vasopressin regulates both basal and stress-induced secretion of adrenocorticotropic hormone (ACTH) via the V1b receptor. The V2 receptor is located in the distal tubular epithelium and epithelium of the renal collecting duct. Their activation renders these epithelia permeable to water. This phenomenon is due to the insertion of aquaporins (special water channels) in the luminal membrane of epithelial cells.

What importance the vasopressin has on the reabsorption of water from the urine in the kidneys becomes evident by the symptoms of diabetes insipidus due to hormone deficiency (for example due to pituitary damage). Patients suffering from this condition excrete up to 20 litres of urine every 24 hours if they are not administered a replacement hormone. This volume corresponds to about 10% of the original urine. Because of its great importance for the reabsorption of water from urine, vasopressin is also synonymously referred to as antidiuretic hormone (ADH). It is logical that pharmacological inhibition of the vasopressin/ADH action at the V2 receptor results in increased urinary excretion. However, in contrast to the effects of other diuretics (thiazides and loop diuretics), the V2 receptor antagonist causes increased water excretion without significantly increasing electrolyte excretion. This means that by V2 antagonising the drug, volume homeostasis can be restored without here affecting electrolyte homeostasis. Thus, drugs that antagonize V2 appear to be particularly suitable for use in treating all disease states associated with water overload of the body without a corresponding increase in electrolytes at the same time. In clinical chemistry, significant electrolyte abnormalities can be measured as hyponatremia (sodium concentration < 135 mmol/L); it is the most important electrolyte abnormality in hospitalized patients, with a frequency of about 5% in the united states alone or 250000 cases per year. Coma and death are encountered when plasma sodium concentration drops below 115 mmol/L.

Based on the root cause, hyponatremia with hypovolemia, normvolemia and hypervolemia are distinguished. Clinically important is the form of hypervolemia with edema formation. Typical examples for this are the syndrome of inappropriate ADH/vasopressin Secretion (SIAD), for example following craniocerebral injury, or as a tumor-associated symptom of cancer, and hypervolemic hyponatremia in liver cirrhosis, various renal diseases and heart failure [ De Luca L., et al,Am. J. Cardiol. 96(supplement), 19L-23L (2005)]. In particular, despite their relative hyponatremia and hypervolemia, patients with heart failure often exhibit elevated vasopressin levels, which are considered as a consequence of neurohumoral regulation that is commonly disturbed in heart failure [ Francis g.s. et al,Circulation 82, 1724-1729（1990）]。

disturbed regulation of neurological humoral status is mainly manifested in an increase in sympathetic tone and inappropriate activation of the renin-angiotensin-aldosterone system. The intrinsic part of pharmacological treatment of heart failure is now the inhibition of these components by beta-blockers on the one hand and ACE inhibitors or angiotensin-receptor blockers on the other hand, but at present, inappropriate elevation of vasopressin secretion in advanced heart failure remains inadequately treatable. In addition to the unfavorable hemodynamic consequences of water retention mediated by the V2 receptor and the afterload increase associated therewith (nachlastith banding), the emptying of the left ventricle, the pressure in the pulmonary vessels and the cardiac power are also adversely affected by V1 a-mediated vasoconstriction. Furthermore, based on animal experimental data, the direct hypertrophy-promoting effect on cardiac muscle is also attributed to vasopressin. Unlike the effects of renal volume expansion, which is mediated by activation of the V2 receptor, this direct effect on the myocardium is triggered by activation of the V1a receptor.

For these reasons, substances inhibiting the action of vasopressin at the V2 and/or at the V1a receptor appear to be suitable for the treatment of heart failure. First, compounds having a combination of activities at two vasopressin receptors (V1 a and V2) should be expected to work both with renal and hemodynamic effects and thus provide properties that are particularly desirable for treatment of heart failure patients. It also appears reasonable to provide such a combination of vasopressin antagonists in this regard, since the separately mediated decrease in capacity via V2 receptor blockade causes stimulation of osmo-photoreceptors and thus a further compensatory increase in vasopressin release. As a result, the deleterious effects of vasopressin, such as vasoconstriction and myocardial hypertrophy, are further potentiated in the absence of a component that simultaneously blocks the V1a receptor [ Saghi p. et al,Europ. Heart J. 26, 538-543（2005）]。

it is therefore an object of the present invention to provide novel compounds which act as potent and selective V1a-, V2-or dual V1 a/V2-receptor antagonists and thus as those suitable for the treatment and/or prophylaxis of diseases, more particularly of cardiovascular disorders.

Different classes of substituted 1,2, 4-triazolones are disclosed in WO 99/31099-a1 as therapeutically useful integrin receptor antagonists. The use of 5-aryl-1, 2, 4-triazolones as medicaments with neuroprotective effect is claimed in WO 99/54315-a2, and 4, 5-diaryltriazolone derivatives as anti-inflammatory agents are described in WO 2006/117657-a 1. 3-heterocyclyl-4-phenyltriazoles are known from WO 2005/105779-A1 as inhibitors of the vasopressin-V1A-receptor, while amide-linked 5-aryl-1, 2, 4-triazolones are disclosed in WO 2007/134862-A1 as dual vasopressin antagonists.

The invention provides compounds of general formula (I) and salts, solvates and solvates of said salts

Wherein

R¹Is represented by (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl or (C)₂-C₆) -alkynyl groups, each of which may be mono-or disubstituted by identical or different residues selected from: fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, oxo, hydroxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, (C)₃-C₆) -a cycloalkyl group and a phenyl group,

wherein (C)₃-C₆) -cycloalkyl can be substituted up to 2 times by identical or different residues selected from: fluorine, trifluoromethyl and (C)₁-C₄) -alkyl, oxo, hydroxy, trifluoromethoxy and (C)₁-C₄) -alkoxy radical

And is

Wherein the phenyl group may be substituted up to 3 times by the same or different residues selected from: halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, hydroxy, hydroxymethyl, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, (C)₁-C₄) Alkoxymethyl, hydroxycarbonyl, (C)₁-C₄) Alkoxycarbonyl, aminocarbonyl, mono- (C)₁-C₄) -alkylaminocarbonyl and di- (C)₁-C₄) -an alkyl-amino-carbonyl group,

or

Represents(C₃-C₆) -cycloalkyl, which may be mono-or disubstituted by identical or different residues selected from: fluorine, trifluoromethyl and (C)₁-C₄) -alkyl, oxo, hydroxy, trifluoromethoxy and (C)₁-C₄) -an alkoxy group,

R²represents phenyl or thienyl, which may be mono-or disubstituted by identical or different residues selected from: halogen, cyano, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, hydroxy, trifluoromethoxy and (C)₁-C₄) -an alkoxy group,

R^3A、R^3Band R^3CIndependently of one another, represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl, (C)₁-C₄) -alkyl, difluoromethoxy, trifluoromethoxy or (C)₁-C₄) -an alkoxy group,

but wherein the residue R^3A、R^3B、R^3CAt least one of which is different from hydrogen,

and is

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0, 1 or 2,

R⁴represents hydrogen or a methyl group,

R⁵represents a group of formula: -O-C (= O) -NR^7AR^7B、-NR⁸-C(=O)-NR^7AR^7B、-NR⁸-SO₂-NR^7AR^7B、-NR⁸-C(=O)-R⁹、-NR⁸-SO₂-R¹⁰or-NR⁸-C(=O)-OR¹⁰Wherein

R^7AAnd R^7BIndependently of one another, represents hydrogen, (C)₁-C₆) -alkyl or (C)₃-C₆) -cycloalkyl, or together with the nitrogen atom to which they are both attached, form a 4-6 membered heterocyclic ring which may contain another heteroatom from the ring of N, O and S, and which may be mono-or di-substituted by the same or different residues selected from: fluorine, trifluoromethyl and (C)₁-C₄) -alkyl, hydroxy and oxo,

R⁸represents hydrogen or (C)₁-C₄) -an alkyl group,

R⁹represents hydrogen, (C)₁-C₆) -alkyl or (C)₃-C₆) -a cycloalkyl group,

and is

R¹⁰Is represented by (C)₁-C₆) -alkyl or (C)₃-C₆) -a cycloalkyl group,

and is

R⁶Having R as given above⁵Or represents hydroxy.

The compounds according to the invention are compounds of formula (I) and salts, solvates and solvates of said salts; compounds of the formula (la) and salts, solvates and solvates of said salts encompassed by formula (I); and the compounds covered by formula (I) mentioned below as examples, as well as salts, solvates and solvates of said salts; provided that the compounds covered by formula (I) mentioned below are not already salts, solvates and solvates of said salts.

AsSalt (salt)Preferred within the scope of the present invention are the physiologically acceptable salts of the compounds according to the invention. Also included are compounds which, although not suitable for pharmaceutical use per se, may be used, for example, for isolation,Purifying or storing the salt of the compound according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example the following acid salts: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16C atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine,N,N-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine,N-methylpiperidine, N-acetylsalicylic acid,N-methylmorpholine, arginine, lysine and 1, 2-ethylenediamine.

Solvates within the scope of the present invention denote such forms of the compounds according to the invention: which form complexes in solid or liquid state by coordination with solvent molecules. Hydrates are a particular form of solvates in which the complexation is with water. Hydrates are preferred as solvates within the scope of the invention.

Depending on their structure, the compounds according to the invention may exist in different stereoisomeric forms, i.e. in the form of configurational isomers, or also possibly as conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers). The present invention thus includes enantiomers and diastereomers and each mixture thereof. The stereoisomerically identical components can be separated from such mixtures of enantiomers and/or diastereomers in a known manner; preference is given to using chromatography, especially HPLC chromatography on the achiral or chiral phase, for this purpose.

If the compounds according to the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.

The invention also includes all suitable isotopic variations of the compounds according to the invention. Isotopic variations of the compounds according to the invention are understood herein to mean compounds which: wherein at least one atom has been replaced by another atom of the same atomic number within a compound according to the invention, but which atom has an atomic mass different from the atomic mass usually found or predominant in nature. Examples of isotopes that can be incorporated into the compounds according to the invention are: isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. certain isotopic variations of the compounds according to the present invention (such as, inter alia, those into which one or more radioactive isotopes have been incorporated) can be useful, for example, for examining the mechanism of action or the distribution of active species in vivo; due to comparatively easy manufacturability and detectability, use³H-or¹⁴C-isotopically labelled specific compounds are suitable for this purpose. In addition, due to the greater metabolic stability of the compounds, the incorporation of isotopes (e.g., deuterium) can result in certain therapeutic benefits, such as increased in vivo half-life or reduced requisite active dosages; thus, such modifications of the compounds according to the invention may also optionally constitute preferred embodiments of the invention. The preparation according to the invention can be carried out by general methods known to the person skilled in the art, for example by using the respective reagents and/or the corresponding isotopic modifications of the starting compounds according to the methods described below and in the working examplesIsotopic variations of the compounds of the invention.

Furthermore, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrug" herein denotes a compound that: which may be biologically active or inactive per se, but which are converted to the compounds according to the invention via, for example, metabolic or hydrolytic pathways during their residence time in the body.

Within the scope of the present invention, unless otherwise indicated, the substituents have the following definitions:

within the scope of the present invention is, ₁ ₆(C-C)- alkyl radicalAnd ₁ ₄(C-C)- alkyl radicalRepresent straight-chain or branched alkyl residues having 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is given to linear or branched alkyl residues having 1 to 4 carbon atoms. For example and preferably, mention may be made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.

Within the scope of the present invention is, ₂ ₆(C-C)- alkenyl radicalAnd ₂ ₄(C-C)- alkenyl radicalRepresents a straight-chain or branched alkenyl residue having 2 to 6 and 2 to 4 carbon atoms containing 1 double bond, respectively. Preferably, the alkenyl residue is a straight chain alkenyl residue having 2 to 4 carbon atoms. For example and preferably, mention may be made of: vinyl, n-prop-1-en-1-yl, allyl, isopropenyl, 2-methyl-2-propen-1-yl, n-but-1-en-1-yl, n-but-2-en-1-yl, n-but-3-en-1-yl, n-pent-1-en-1-yl, n-pent-2-en-1-yl, n-pent-3-en-1-yl, n-pent-4-en-1-yl, 3-methylbut-2-en-1-yl and 4-methylpent-3-en-1-yl.

Within the scope of the present invention is, ₂ ₆(C-C)- alkynyl radicalRepresents a straight-chain or branched alkynyl residue having 2 to 6 carbon atoms and a triple bond. Straight-chain or branched alkynyl residues having 3 to 6 carbon atoms are preferred. For example and preferably, mention may be made of: ethynyl, n-prop-1-yn-1-ylN-prop-2-yn-1-yl, n-butyl-3-yn-1-yl, n-pent-2-yn-1-yl, n-pent-3-yn-1-yl and n-pent-4-yn-1-yl.

Within the scope of the present invention is, ₁ ₄(C-C)- alkoxy radicalRepresents a linear or branched alkoxy residue having 1 to 4 carbon atoms. For example and preferably, mention may be made of: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

Within the scope of the present invention is, ₁ ₄(C-C)- alkoxymethyl groupRepresents a linear or branched alkoxy residue having 1 to 4 carbon atoms, said alkoxy residue being linked via a methylene [ -CH ] group to an oxygen atom₂-]Attached to the remainder of the molecule. For example and preferably, mention may be made of: methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl and tert-butoxymethyl.

Within the scope of the present invention is, ₁ ₄(C-C)- alkoxycarbonyl radicalRepresents a linear or branched alkoxy residue having 1 to 4 carbon atoms via a carbonyl [ -C (= O) -]Attached to the remainder of the molecule. For example and preferably, mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

Within the scope of the present invention is,sheet ₁ ₄-(C-C)- Alkylamino radicalRepresents such an amino group: having a linear or branched alkyl substituent containing 1 to 4 carbon atoms. For example and preferably, mention may be made of: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.

Within the scope of the present invention is,II ₁ ₄-(C-C)- Alkylamino radicalRepresents an amino group having 2 identical or different linear or branched alkyl substituents each of whichHaving 1-4 carbon atoms. For example and preferably, mention may be made of:N,N-dimethylamino group,N,N-diethylamino,N-ethyl-N-methylamino radical,N-methyl-N-n-propylamino group,N-isopropyl-N-methylamino radical,N-isopropyl-N-n-propylamino group,N,N-diisopropylamino group,N-n-butyl-N-methylamino radical,N,N-di-n-butylamino andN-tert-butyl-N-methylamino radical.

Within the scope of the present invention is,sheet - And two ₁ ₄-(C-C)- Alkyl amino carbonylRepresents such an amino group: via carbonyl [ -C (= O) -]Linked to the remainder of the molecule and having 1 linear or branched and 2 identical or different linear or branchedN-an alkyl substituent, saidNThe alkyl substituents each have 1 to 4 carbon atoms. For example and preferably, mention may be made of: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl,N,N-dimethylaminocarbonyl group,N,N-diethylaminocarbonyl,N-ethyl-N-methylaminocarbonyl group,N-methyl-N-n-propylaminocarbonyl group,N,N-diisopropylaminocarbonyl group,N-n-butyl-N-methylaminocarbonyl andN-tert-butyl-N-methylaminocarbonyl.

Within the scope of the present invention is, ₃ ₆(C-C)- cycloalkyl radicalsAnd ₃ ₅(C-C)- cycloalkyl radicalsRepresent monocyclic saturated cycloalkyl groups having 3 to 6 and 3 to 5 carbon atoms, respectively. For example and preferably, mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Within the scope of the present invention is,4-6 membered heterocyclic ringRepresents a monocyclic saturated heterocyclic ring having a total of 4 to 6 ring atoms, which ring contains a nitrogen atom via which the heterocyclic ring is linked to the rest of the molecule, and which may furthermore contain another heteroatom in the ring selected from N, O and S. For example and preferably, mention may be made of: azacyclobutyl, pyrroleAlkyl, pyrazolidinyl, 1, 3-oxazolidinyl, 1, 3-thiazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Preference is given to azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.

Within the scope of the present invention is,halogen elementIncluding fluorine, chlorine, bromine, and iodine. Chlorine, fluorine or bromine is preferred, and fluorine or chlorine is particularly preferred.

Within the scope of the present invention is,oxo-substituted radicalRepresents an oxygen atom linked to a carbon atom by a double bond.

Within the scope of the present invention, all residues occurring in multiple instances are meant independently of one another. If a residue in a compound according to the invention is substituted, said residue may be mono-or polysubstituted, unless otherwise specified. Preference is given to substitution with 1 or with 2 or 3 identical or different substituents. Particular preference is given to substitution with 1 or with 2 identical or different substituents. Substitution with 1 substituent is most particularly preferred.

A preferred embodiment of the present invention comprises compounds of formula (I) and salts, solvates and solvates of said salts, wherein

R¹Is represented by (C)₁-C₄) -alkyl or (C)₂-C₄) -alkenyl, each of which may be mono-or di-substituted by the same or different residues selected from: fluoro, trifluoromethyl, hydroxy, trifluoromethoxy and (C)₁-C₄) -an alkoxy group,

or

Represents a benzyl group, which may be mono-or disubstituted in the phenyl ring by identical or different residues selected from: fluorine, chlorine, trifluoromethyl, (C)₁-C₄) -alkyl, trifluoromethoxy and (C)₁-C₄) -an alkoxy group,

or

Is represented by (C)₃-C₅) -a cycloalkyl group.

An equally preferred embodiment of the invention comprises compounds of formula (I) and salts, solvates and solvates of said salts, wherein

R²Represents phenyl or thienyl, which may be substituted by a residue selected from: fluoro, chloro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy and trifluoromethoxy.

Another preferred embodiment of the invention comprises compounds of formula (I) and salts, solvates and solvates of said salts, wherein

R^3A、R^3BAnd R^3CIndependently of one another, represents hydrogen, fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy or trifluoromethoxy,

but wherein the residue R^3A、R^3B、R^3CAt least one of which is different from hydrogen.

R^3CRepresents hydrogen.

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0 or 1 and,

R⁴representsHydrogen or a methyl group, or a mixture thereof,

and is

R⁵Represents a group of formula: -O-C (= O) -NR^7AR^7B、-NH-C(=O)-NR^7AR^7B、-NH-C(=O)-R⁹、-NH-SO₂-R¹⁰OR-NH-C (= O) -OR¹⁰Wherein

R^7AAnd R^7BIndependently of one another, represents hydrogen or (C)₁-C₄) -an alkyl group,

R⁹represents hydrogen or (C)₁-C₄) -an alkyl group,

and is

R¹⁰Is represented by (C)₁-C₄) -an alkyl group.

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

and is

R⁶Represents hydroxy or a group of the formula-O-C (= O) -NR^7AR^7BA group of (1), wherein

R^7AAnd R^7BIndependently of one another, represents hydrogen or (C)₁-C₄) -an alkyl group.

Particularly preferred within the scope of the present invention are compounds of the formula (I) and salts, solvates and solvates of said salts, wherein

R¹Is represented by (C)₁-C₄) -alkyl or (C)₂-C₄) -alkenyl, each of which may be mono-or di-substituted by the same or different residues selected from: fluorine, trifluoromethyl, hydroxyl, methoxy and ethoxy,

or

Represents a benzyl group which may be substituted in the phenyl ring by a residue selected from: fluorine, chlorine, methyl, trifluoromethyl and methoxy,

or

Represents a cyclopropyl group, and the like,

R²represents phenyl or thienyl, which may be substituted by residues selected from fluorine and chlorine,

R^3Aand R^3BIndependently of one another, represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,

but wherein the residue R^3AAnd R^3BAt least one of which is different from hydrogen,

R^3Crepresents hydrogen, and is selected from the group consisting of,

and is

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0 or 1 and,

and is

R⁵Represents a group of formula: -O-C (= O) -NHR^7B、-NH-C(=O)-NHR^7B、-NH-C(=O)-R⁹、-NH-SO₂-R¹⁰OR-NH-C (= O) -OR¹⁰Wherein

R^7BRepresents hydrogen or (C)₁-C₄) -an alkyl group,

R⁹represents hydrogen or (C)₁-C₄) -an alkyl group,

and is

R¹⁰Is represented by (C)₁-C₄) -an alkyl group.

Within the scope of the present invention, very particular preference is given to compounds of the formula (I) and the salts, solvates and solvates of said salts, where

R¹Represents 3,3, 3-trifluoro-2-hydroxypropyl, 3,3, 3-trifluoropropyl or 3,3, 3-trifluoroprop-1-en-1-yl,

R²represents a p-chlorophenyl group, and a pharmaceutically acceptable salt thereof,

R^3Aand R^3BIndependently of one another, represents hydrogen, chlorine or trifluoromethyl,

R^3Crepresents hydrogen, and is selected from the group consisting of,

and is

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0 or 1 and,

and is

R⁵Represents a group of formula: -O-C (= O) -NH₂、-NH-C(=O)-NH₂or-NH-SO₂-R¹⁰Wherein

R¹⁰Represents methyl or ethyl.

Independent of the combinations of residues given individually, the definitions of residues given in detail in each combination or preferred combination of residues are also arbitrarily replaced by the definitions of residues in other combinations. Combinations of 2 or more of the above preferred ranges are particularly preferred.

The invention further provides a process for the preparation of a compound of formula (I) according to the invention, characterized in that,

coupling a compound of formula (II) with a compound of formula (III) in an inert solvent under conditions that activate the carboxylic acid function

Wherein R is¹And R²Having the meaning given above, it is preferred that,

l, R therein^3A、R^3BAnd R^3CHaving the meaning given above, it is preferred that,

and the resulting compounds of formula (I) are optionally separated into their enantiomers and/or diastereomers and/or converted into their solvates, salts and/or solvates of said salts with a suitable (I) solvent and/or (ii) base or acid.

Inert solvents for process step (II) + (III) → (I) are, for example, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane or bis- (2-Methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethylene or chlorobenzene, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide (DMSO),N,N-Dimethylformamide (DMF),N,N-Dimethylacetamide (DMA),N,N'-Dimethylpropyleneurea (DMPU) orN-methylpyrrolidone (NMP). Mixtures of such solvents may also be used. Preference is given to acetonitrile, dichloromethane, dimethylformamide or mixtures of these solvents.

Suitable activators/condensing agents for the coupling reaction (II) + (III) → (I) are, for example, carbodiimides such asN,N'-diethyl-,N,N'-dipropyl-,N,N'-diisopropyl-,N,N'dicyclohexylcarbodiimide (DCC) orN- (3-dimethylaminoisopropyl) -N'Ethyl carbodiimide hydrochloride (EDC), phosgene derivatives such asN,N'Carbonyldiimidazole (CDI) or isobutyl chloroformate, 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, amido compounds such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, alpha-chloroalkenamines such as 1-chloro-2-methyl-1-dimethylamino-1-propene, phosphorus compounds such as propanephosphonic anhydride, diethyl cyanophosphonate, bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, mixtures thereof, and mixtures thereof, Benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or uronium compounds such asO- (benzotriazol-1-yl) -N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU),O- (benzotriazol-1-yl) -N,N,N',N'Tetramethyluronium Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2)H) -pyridyl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TPTU),O- (7-azabenzotriazol-1-yl) -N,N,N',N'Tetramethyluronium Hexafluorophosphate (HATU) orO-(1H6-chlorobenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TCTU), optionally with other promotersCombinations of agents, the auxiliaries being, for example, 1-hydroxybenzotriazole (HOBt) orN-hydroxysuccinimide (HOSu), and as base, an alkali metal carbonate, for example sodium or potassium carbonate, or a tertiary amine base such as triethylamine,N-methylmorpholine,N-methylpiperidine, N-acetylsalicylic acid,N 、 NDiisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine. Preferably, HOBt andN,N-diisopropylethylamine in combination with EDC.

The coupling (II) + (III) → (I) is usually carried out at a temperature in the range from-20 ℃ to +60 ℃, preferably at 0 ℃ to +40 ℃. The reaction can be carried out at atmospheric pressure, at elevated pressure or at reduced pressure (e.g. 0.5-5 bar). It is usually operated at atmospheric pressure.

The preparation of the compounds according to the invention can be illustrated by the following synthetic schemes:

scheme(s) 1

For their part, alkylation of 2, 4-dihydro-3 of formula (IV) with a haloacetate of formula (V) induced by a baseH-1,2, 4-triazol-3-one to give N²-substituted compounds of formula (VI) and subsequent ester hydrolysis, to obtain compounds of formula (II) (see scheme 2):

scheme(s) 2

[ Alk = alkyl, Hal = halogen ].

Compounds of formula (VI) can also be of formula (VIII) known from the literature in an alternative routeN- (alkanes)Oxycarbonyl) arylthioamides [ see, e.g., m. Arnswald, w.p. Neumann,J. Org. Chem. 58 (25), 7022-7028 (1993)；E.P. Papadopoulos, J. Org. Chem. 41 (6), 962-965 (1976)]prepared by reaction with a hydrazino acetate of formula (VII) and subsequent derivatization at N-4 of triazolone (IX) (see scheme 3):

scheme(s) 3

Starting from the carboxylic acid hydrazide of formula (XI), the compound of formula (IV) can be prepared by reaction with an isocyanate of formula (XII) or a nitrophenylcarbamate of formula (XIII), and subsequent cyclization of the intermediate (XIV) of the hydrazoamide (hydrazinocarboxamide) with base (see scheme 4):

scheme(s) 4

According to one particular process variant, the compounds of the formula (VI) can optionally also be prepared as follows: in the methods described in schemes 2 and 4, the group R is first replaced with a temporary Protecting Group (PG), such as allyl or 4-methoxybenzyl¹(ii) a After its dissociation into the compound of formula (IX), it may then be passed through the appropriate N⁴Alkylation to give the desired compound of formula (VI) (see scheme 5):

scheme(s) 5

[ PG = protecting group such as allyl or 4-methoxybenzyl ].

Here, according to the conventional methods in the literature [ see, for example, t.w. Greene and p.g.m. Wuts,Protective Groups in Organic Synthesis, Wiley, New York, 1999]the introduction and removal of the protecting group PG are performed. The allyl group is thus preferably removed by means of formic acid in the presence of tetrakis (triphenylphosphine) palladium (0) -catalyst and an amine base such as triethylamine. The cleavage of the methoxybenzyl protecting group is preferably carried out with the aid of strong acids, such as trifluoroacetic acid, or in an oxidative route, for example by treatment with 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) or cerium (IV) ammonium nitrate.

Analogous transformation PG → R¹And may optionally also be carried out in a further process stage.

It is also possible, if appropriate, to start from other compounds of the formula (I) obtained by the abovementioned process or their precursors, by converting the functional groups of the respective residues and substituents, in particular at R¹、R²、R⁵And R⁶Those listed below to prepare other compounds of formula (I) according to the invention. These transformations are carried out according to conventional methods well known to the person skilled in the art and include, for example, the following reactions: such as nucleophilic or electrophilic substitution reactions, nucleophilic or electrophilic addition reactions, elimination reactions, oxidations, reductions, hydrogenations, alkylations, acylations, sulfonylations, aminations, hydroxylations, etherifications, esterifications, ether cleavage and hydrolyzations, in particular to form carboxamides, sulfonamides, carbamates, ureas and sulphamides, and also the introduction and removal of temporary protecting groups [ see also the preparation of the working examples described in detail in the experimental section below for]。

Depending on the practical application, the compounds according to the invention may also already be separated into the corresponding enantiomers and/or diastereomers at the respective intermediate stages as listed above, whereby they are reacted further in isolated form according to the above-described process steps. The separation of such stereoisomers may be carried out according to conventional methods known to those skilled in the art; preferably, chromatographic methods are used, especially HPLC chromatography on achiral or chiral phases.

The compounds of formulae (III), (V), (VII), (VIII), (X), (XI), (XII) and (XIII) are commercially available, or as those described in the literature, or they may be prepared from commercially available compounds according to common conventional methods known from the literature. Numerous detailed procedures and literature references for the preparation of these materials are also found in the experimental section below for the preparation of the starting compounds and intermediates.

The compounds according to the invention have valuable pharmacological properties and can be used universally for the prophylaxis and/or treatment of various diseases and disease-causing states in humans and in mammals.

The compounds according to the invention are potent and selective V1a-, V2-or dual V1 a/V2-receptor antagonists that inhibit vasopressin activity in vitro and in vivo. In addition, the compounds according to the invention also act as antagonists of the relevant oxytocin receptors.

The compounds according to the invention are particularly suitable for the prophylaxis and/or treatment of cardiovascular diseases. In this respect, mention may be made, by way of example and preferably, as target indications: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory disorders, arterial pulmonary hypertension, spasms of the coronary and peripheral arteries, thrombosis, thromboembolic diseases, edema formation (e.g. pulmonary edema, cerebral edema, renal edema or edema associated with heart failure) and restenosis (e.g. after thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery).

Within the scope of the present invention, the term heart failure also includes more specific or related forms of disease, such as right heart failure, left heart failure, global failure (globalintufzenz), ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defects, heart failure with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary insufficiency, complex heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic toxic cardiomyopathy, heart storage diseases, diastolic heart failure and systolic heart failure.

Furthermore, the compounds according to the invention are suitable for use as diuretics for the treatment of edema and electrolyte disorders, especially in the case of hypervolemic and normovolemic hyponatremia.

The compounds according to the invention are also suitable for the prophylaxis and/or treatment of polycystic kidney disease (PCKD) and ADH hyposecretion Syndrome (SIADH).

In addition, the compounds according to the invention can be used for the prophylaxis and/or treatment of cirrhosis of the liver, ascites, diabetes and diabetic complications, such as neuropathy and nephropathy, acute and chronic renal failure and chronic renal insufficiency.

Furthermore, the compounds according to the invention are suitable for the prophylaxis and/or treatment of central nervous disorders (such as anxiety states and depression), glaucoma and cancer, in particular lung tumors.

Furthermore, the compounds according to the invention may be used for the prevention and/or treatment of inflammatory diseases, asthma diseases, chronic obstructive respiratory disease (COPD), pain states, prostatic hypertrophy, incontinence, bladder inflammation, bladder hyperactivity, adrenal disorders (e.g. pheochromocytoma and adrenal stroke), bowel diseases (e.g. crohn's disease and diarrhea) or menstrual disorders (e.g. dysmenorrhea) or endometriosis.

Because of their activity profile, the compounds according to the invention are particularly suitable for the treatment and/or prophylaxis of acute and chronic heart failure, hypervolemic and normovolemic hyponatremia, cirrhosis of the liver, ascites, oedema and ADH hyposecretion Syndrome (SIADH).

A further subject of the present invention is the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further subject of the present invention is the use of the compounds according to the invention for the production of medicaments for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

Another subject of the present invention is the use of the compounds according to the invention in a method for the treatment and/or prevention of diseases, in particular of the diseases mentioned above.

A further subject of the present invention is a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, using an effective amount of at least one compound according to the invention.

The compounds according to the invention can be used alone or, if desired, in combination with other active substances. The invention further relates to medicaments containing at least one compound according to the invention and one or more further active substances, which are used, inter alia, for the treatment and/or prophylaxis of the abovementioned diseases. The following may be mentioned by way of example and preferably as combined active substances suitable for this purpose:

● organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 and inhaled NO;

● diuretics, especially loop diuretics and thiazide analog diuretics;

● positive inotropic active compounds such as cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine, and dobutamine;

● compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), for example inhibitors of Phosphodiesterase (PDE) 1,2, 3, 4 and/or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil and PDE 3 inhibitors such as amrinone and milrinone;

● natriuretic peptides such as "atrial natriuretic peptide" (ANP, Anaeritide), "B-type natriuretic peptide" or "brain natriuretic peptide" (BNP, Neiritide), "C-type natriuretic peptide" (CNP) and vasodilator;

● calcium sensitizers such as, and preferably, levosimendan;

● guanylate cyclase activators which are independent of NO and heme, such as, inter alia, Cinaciguat and the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

● NO-independent, but heme-dependent guanylate cyclase stimulators, such as, inter alia, Riociguat and the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

● inhibitors of Human Neutrophil Elastase (HNE), such as cevelsitol or DX-890 (Reltran);

● inhibit signal transduction cascades, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib;

● affecting the energy metabolism of the heart, such as and preferably cetuximab, dichloroacetate, ranolazine or trimetazidine;

● has an antithrombotic effect, for example and preferably selected from thrombocyte aggregation inhibitors, anticoagulants or fibrinolytic (profibrinolytische) substances;

● blood pressure lowering active substances, for example and preferably selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and Rho-kinase inhibitors; and/or

● active substances altering fat metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors (for example and preferably HMG-CoA-reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists), cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as, and preferably, furosemide, bumetanide, torasemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorofinamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

An agent having an antithrombotic effect is preferably understood to mean a compound selected from thrombocyte aggregation inhibitors, anticoagulants or fibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombocyte aggregation inhibitor, such as, and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, and preferably, ximelagatran, melagatran, dabigatran, bivalirudin or cricetrin.

In a preferred embodiment of the invention, the compound according to the invention is administered in combination with a GPIIb/IIIa antagonist, such as and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban, DU-176b, apixaban, omixaban, Feedxaban, Razaxaban, fondaparinux, epidoparin, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a Low Molecular Weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, and preferably, coumarin.

Hypotensive agents are preferably understood to mean compounds selected from the group consisting of: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, neutral endopeptidase inhibitors, endothelin peptide antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, Rho-kinase inhibitors and diuretics.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist such as, and preferably, nifedipine, amlodipine, verapamil or diltiazem。

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan or embsartan.

In a preferred embodiment of the present invention, the compounds according to the present invention are administered in combination with an ACE inhibitor, such as, and preferably, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril (Quinopril), perindopril or trandolapril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vasopeptidase inhibitor or neutral endopeptidase inhibitor (NEP), such as, and preferably, omatrala or AVE-7688.

In a preferred embodiment of the invention, the compound according to the invention is administered in combination with an endothelin peptide antagonist such as, and preferably, bosentan, darussan, ambrisentan or sitaxentan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as, and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, such as, and preferably, prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-blocker, such as, and preferably, propranolol, atenolol, timolol, pindolol, oxprenolol, penbutolol, bucanolol, metipranolol, nadolol, mepindolol, carabronolol (Carazalol), sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, eparnolol or bucindolol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, and preferably, spironolactone, eplerenone, canrenone or potassium canrenoate.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with Rho-kinase inhibitors such as, and preferably, fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

Fat metabolism altering agents are preferably understood to mean compounds selected from the following: CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors (such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists), cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, and preferably, Tochester, Dasartrapib, Anacetrapib, BAY 60-5521 or CETP-vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as, and preferably, D-thyroxine, 3,5,3' -triiodothyronine (T3), CGS 23425 or acitiro (CGS 26214).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor selected from the group of statins, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as, and preferably, BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, and preferably, avasimibe, melinamide, petibobu, Eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as, and preferably, inpitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, and preferably, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as, and preferably, GW-501516 or BAY 68-5042.

In a preferred embodiment of the present invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as, and preferably, ezetimibe, tiquinan or pamoside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, and preferably, orlistat.

In a preferred embodiment of the invention, the compound according to the invention is administered in combination with a polymeric bile acid adsorbent, such as and preferably cholestyramine, colestipol, Colesolvam, Colestimide or Colestimide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as, and preferably, an ASBT (= IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, and preferably, Gemcabene calcium (CI-1027) or niacin.

Another subject of the invention is a medicament and its use for the aforementioned purposes: the medicament contains at least one compound according to the invention, usually accompanied by one or more inert, non-toxic, pharmaceutically suitable excipients.

The compounds according to the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic routes, or as implants or stents.

For these administration routes, the compounds according to the invention can be administered in a suitable administration form.

For oral administration, such administration forms are suitable: said administration forms function according to the prior art, releasing rapidly and/or with a limited degree of release the compounds according to the invention, containing the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example coatings which are resistant to gastric juice or dissolve with a delay or are insoluble and which control the release of the compounds according to the invention), tablets which disintegrate rapidly in the oral cavity or film/starch papers, film/lyophilized powders, capsules (for example hard or soft gelatin capsules), sugar-coated pills, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be achieved by bypassing an absorption step (e.g., intravenous, intra-arterial, intracardiac, intravertebral or intravertebral administration), or by including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Administration forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilized powders or sterile powders.

For other routes of administration, suitable are, for example, inhalation forms (in particular powder inhalers and nebulizers), nasal drops, -solutions or-sprays, tablets for lingual, sublingual or buccal administration, films/starch papers or capsules, suppositories, ear-or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), emulsions, pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration is preferred, especially oral and intravenous administration.

The compounds according to the invention can be converted into the administration forms described. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, inter alia, carrier substances (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxide) and taste-and/or odor-correctors.

In general, it has proven advantageous to administer amounts of about 0.001 to 10 mg/kg, preferably about 0.01 to 1 mg/kg, of body weight for effective results when administered parenterally. In oral administration, the dose is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and most particularly preferably 0.1 to 10 mg/kg of body weight.

Nevertheless, it may sometimes be necessary to deviate from the stated amounts, i.e. depending on the body weight, the route of administration, the individual response to the active substance, the type of formulation and the time or interval over which the administration is carried out. Thus, in some cases less than the aforementioned minimum amount may be sufficient, while in other cases the upper limit must be exceeded. In the case of administering larger amounts, it may be appropriate to divide these amounts into separate administrations over multiple times of the day.

The following working examples illustrate the invention. The invention is not limited to the embodiments described.

Unless otherwise indicated, the percentage data set forth in the experiments and examples described below are percentages by weight and parts are parts by weight. The solvent ratio, dilution ratio, and concentration data for the liquid/liquid solution are each based on volume.

A. Examples of the embodiments

Abbreviations and acronyms:

ac acetyl group

Alk alkyl group

Boc tert-butoxycarbonyl

Bsp. e.g.

ca. about

CI chemical ionization (in MS)

DCI direct chemical ionization (in MS)

DME 1, 2-dimethoxyethane

DMF N,N-dimethylformamide

DMPU 1, 3-dimethyltetrahydro-2 (1)H) -pyrimidinones

DMSO dimethyl sulfoxide

d. Th. theoretical value (yield)

EDC N'- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride

ee enantiomeric excess

eq. equivalent

ESI electrospray ionization (in MS)

Es. saturated

h hours

Hal halogen

HOBt 1-hydroxy-1H-benzotriazole hydrate

HPLC high pressure-high performance liquid chromatography

Concentrated by konz

LC/MS liquid chromatography-mass spectrometry combination

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide

min for

MS mass spectrometry

MTBE methyl tert-butyl ether

NMR nuclear magnetic resonance spectroscopy

OAc acetate

p To pair

Ph phenyl

quantitive (yield)

rac racemic/racemic

RT Room temperature

R_tWhen reservedIn HPLC

THF tetrahydrofuran

UV ultraviolet spectrometry

v/v volume to volume ratio (solution)

zus. co

LC/MS-and HPLC-methods:

method of producing a composite material 1 (LC/MS) ：

MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Synergi 2.5 mu MAX-RP 100A Mercury 20 mm x 4 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; flow rate: 2 ml/min; a constant temperature box: 50 ℃; ultraviolet detection: 210 nm.

Method of producing a composite material 2 (LC/MS) ：

The instrument comprises the following steps: micromass Quattro Micro MS with HPLC Agilent Series 1100; column: thermo Hypersil GOLD 3 μm 20 mm x 4 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow rate 2.5 ml/min) → 5.00 min 100% A; a constant temperature box: 50 ℃; flow rate: 2 ml/min; ultraviolet detection: 210 nm.

Method of producing a composite material 3 (LC/MS) ：

The instrument comprises the following steps: micromass Quattro Premier with Waters UPLC Acquity; column: thermo Hypersil GOLD 1.9 μm 50 mm x 1 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; flow rate: 0.33 ml/min; a constant temperature box: 50 ℃; ultraviolet detection: 210 nm.

Method of producing a composite material 4 (LC/MS) ：

The instrument comprises the following steps: waters Acquity SQD UPLC System; column: waters Acquity UPLC HSS T31.8 mu 50 mm x 1 mm; eluent A: 1 liter of water + 0.25 ml of 99% formic acid, eluent B: 1 liter acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; flow rate: 0.40 ml/min; a constant temperature box: 50 ℃; ultraviolet detection: 210-400 nm.

Method of producing a composite material 5 ( Chiral preparation HPLC) ：

Based on the selection agent poly (N-methacryloyl-L-leucine- (+) -3-pinane methylamide) on a chiral silica gel stationary phase; column: 600 mm x 30 mm; temperature: 24 ℃; ultraviolet detection: 265 nm; flow rate: 80 ml/min; eluent:

method of producing a composite material 5a0-13.1 min isohexane/ethyl acetate 25:75 (v/v), 13.11-19.1 min 100% ethyl acetate, 19.11-23.5 min isohexane/ethyl acetate 25:75 (v/v);

method of producing a composite material 5b100% ethyl acetate.

Method of producing a composite material 6 ( Chiral analysis type HPLC) ：

A chiral silica gel stationary phase based on the selector poly (N-methacryloyl-L-leucine- (+) -3-pinane methylamide); column: 250 mm x 4.6 mm; temperature: 24 ℃; ultraviolet detection: 265 nm; flow rate: 2 ml/min; eluent:

method of producing a composite material 6aIsohexane/ethyl acetate 1:4 (v/v);

method of producing a composite material 6b100% ethyl acetate.

Method of producing a composite material 7 ( Preparation type HPLC) ：

Column: YMC ODS C18, 10 μm, 250 mm x 30 mm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-6 min to 10% B, 6-27 min to 95% B, 27-43 min to 95% B, 43-45 min to 10% B, 45-50 min to 10% B.

Method of producing a composite material 8 ( Preparation type HPLC) ：

Column: the Grom-Sil 120 ODS-4HE is 10 mu m and 250 mm x 30 mm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-3 min to 10% B, 3-27 min to 95% B, 27-34 min to 95% B, 34-38 min to 10% B.

Method of producing a composite material 9 ( Preparation type HPLC) ：

Column: the Grom-Sil 120 ODS-4HE is 10 mu m and 250 mm x 30 mm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-6 min 5% B, 6-34 min to 95% B, 34-38 min 95% B, 38-45 min 5% B.

Method of producing a composite material 10 ( Chiral preparation HPLC) ：

Based on the selection agent poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide) on a chiral silica gel stationary phase; column: 670 mm x 40 mm; flow rate: 80 ml/min; temperature: 24 ℃; ultraviolet detection: 260 nm; eluent:

method of producing a composite material 10aIsohexane/ethyl acetate 20:80 (v/v);

method of producing a composite material 10bIsohexane/ethyl acetate 15:85 (v/v).

Method of producing a composite material 11 ( Chiral analysis type HPLC) ：

Based on the selection agent poly (N-methacryloyl-D-leucine-dicyclopropylmethylamide) on a chiral silica gel stationary phase; column: 250 mm x 4.6 mm; eluent: 100% ethyl acetate; flow rate: 2 ml/min; temperature: 24 ℃; ultraviolet detection: 265 nm.

Method of producing a composite material 12 ( Preparation type HPLC) ：

Column: the Grom-Sil 120 ODS-4HE is 10 mu m and 250 mm x 30 mm; eluent A: 0.1% formic acid in water, eluent B: methanol; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-6 min to 20% B, from 6-27 min to 98% B, from 27-53 min to 98% B, from 53-54 min to 20% B, from 54-61 min to 20% B.

Method of producing a composite material 13 ( Chiral preparation HPLC) ：

Stationary phase: daicel Chiralpak AS-H, 5 μm; column: 250 mm x 20 mm; eluent: isohexane/methanol/n-propanol 95:2.5:2.5 (v/v/v); flow rate: 20 ml/min; temperature: RT; ultraviolet detection: 230 nm.

Method of producing a composite material 14 ( Chiral analysis type HPLC) ：

Stationary phase: daicel Chiralpak AS-H, 5 μm; column: 250 mm x 4 mm; eluent: isohexane/methanol/ethanol 92:4:4 (v/v/v); the flow rate is 1 ml/min; ultraviolet detection: 220 nm.

Method of producing a composite material 15 ( Chiral preparation HPLC) ：

Based on the selection agent poly (N-methacryloyl-L-isoleucine-3-pentylamide) on a chiral mercaptosilica gel stationary phase; column: 430 mm x 40 mm; eluent: 100% ethyl acetate; flow rate: 80 ml/min; temperature:24 ℃; ultraviolet detection: 265 nm.

Method of producing a composite material 16 ( Chiral analysis type HPLC) ：

Based on the selection agent poly (N-methacryloyl-L-isoleucine-3-pentylamide) on a chiral mercaptosilica gel stationary phase; column: 250 mm x 4.6 mm; eluent: 100% ethyl acetate; flow rate: 2 ml/min; temperature: 24 ℃; ultraviolet detection: 265 nm.

Method of producing a composite material 17 ( Chiral preparation HPLC) ：

Stationary phase: daicel Chiralpak AD-H, 10 μm; column: 250 mm x 20 mm; temperature: RT; ultraviolet detection: 230 nm; flow rate: 20 ml/min; eluent:

method of producing a composite material 17aIsohexane/isopropanol 60:40 (v/v);

method of producing a composite material 17bIsohexane/isopropanol 70:30 (v/v);

method of producing a composite material 17cIsohexane/ethanol 75:25 (v/v).

Method of producing a composite material 18 ( Chiral analysis type HPLC) ：

Stationary phase: daicel Chiralpak AD-H, 5 μm; column: 250 mm x 4.6 mm; temperature: 30 ℃; ultraviolet detection: 230 nm; flow rate: 1.0 ml/min; eluent:

method of producing a composite material 18aIsohexane/isopropanol 50:50 (v/v);

method of producing a composite material 18bIsohexane/ethanol 70:30 (v/v).

Method of producing a composite material 19 ( Preparation type HPLC) ：

Column: rerosil C18, 10 μm, 250 mm x 30 mm; eluent A: 0.1% formic acid in water, eluent B: methanol; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-6 min to 30% B, from 6-33 min to 95% B, from 33-42 min to 95% B, from 42-43 min to 30% B, from 43-50 min to 30% B.

Method of producing a composite material 20 ( Preparation type HPLC) ：

Column: rerosil C18, 10 μm, 250 mm x 40 mm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-6 min to 10% B, 6-40 min to 95% B, 40-53 min to 95% B, 53-54 min to 10% B, and 54-57 min to 10% B.

Method of producing a composite material 21 (LC/MS) ：

MS instrument type: waters ZQ; HPLC instrument type: waters Alliance 2795; column: phenomenex Onyx Monolithic C18, 100 mm x 3 mm; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; flow rate: 2 ml/min; a constant temperature box: 40 ℃; ultraviolet detection: 210 nm.

Method of producing a composite material 22 (LC/MS) ：

MS instrument type: micromass ZQ; HPLC instrument type: HP 1100 Series, UV DAD; column: phenomenex Gemini 3 is 30 mm x 3.00 mm in mu and mu; eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; flow rate: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; a constant temperature box: 50 ℃; ultraviolet detection: 210 nm.

Method of producing a composite material 23 ( Preparation type HPLC) ：

Column: rerosil C18, 10 μm, 250 mm x 30 mm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; flow rate: 50 ml/min; the procedure is as follows: gradient from 0-6 min to 10% B, 6-27 min to 95% B, 27-38 min to 95% B, 38-39 min to 10% B, and 39-40 min to 10% B.

Starting compounds and intermediates:

example 1A

N- ({2- [ (4-chlorophenyl) carbonyl ] hydrazino } carbonyl) glycine ethyl ester

A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzoyl hydrazine in 50 ml of dry THF is initially added at 50 ℃ and a solution of 10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF is added dropwise. First a solution is formed and then a precipitate is precipitated. After the addition was complete, the mixture was stirred at 50 ℃ for an additional 2 h, then allowed to stand at room temperature overnight. The crystals were isolated by filtration, washed with a small amount of diethyl ether and dried under high vacuum. This gives 21.43 g (89% of theory) of the title compound.

Example 2A

[3- (4-chlorophenyl) -5-oxo-1, 5-dihydro-4-carboxylic acidH-1,2, 4-triazol-4-yl]Acetic acid

91 ml of 3N aqueous sodium hydroxide solution were added to 21.43 g (67.9 mmol) of the compound of example 1A and the mixture was heated at reflux overnight. After cooling to room temperature, the mixture was adjusted to pH 1 by slowly adding about 20% hydrochloric acid. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 60 ℃. This gives 17.55 g of the title compound in a purity of about 88% (90% of theory).

Example 3A

5- (4-chlorophenyl) -4- (3,3, 3-trifluoro-2-oxopropyl) -2, 4-dihydro-3H-1,2, 4-triazol-3-one(s) ((iii))Ketone forms) Or 5- (4-chlorophenyl) -4- (3,3, 3-trifluoro-2, 2-dihydroxypropyl) -2, 4-dihydro-3H-1,2, 4-triazol-3-one(s) ((iii))Hydrate form)

5.0 g (16.36 mmol) of the compound from example 2A are dissolved in 200 ml of pyridine under argon, and 17.18 g (81.8 mmol) of trifluoroacetic anhydride are added. During the addition, the temperature rose to about 35 ℃. After 30 min, the pyridine was removed on a rotary evaporator and 1.5 l of 0.5N hydrochloric acid were added to the residue. The mixture was heated to 70 ℃ and then filtered while hot. The solid was washed with a small amount of water. The whole filtrate was extracted 3 times with ethyl acetate. The combined organic phases were washed successively with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dried under high vacuum. This gives 3.56 g (68% of theory) of the title compound in the form of a hydrate.

Example 4A

5- (4-chlorophenyl) -4- (3,3, 3-trifluoro-2-hydroxypropyl) -2, 4-dihydro-3H-1,2, 4-triazol-3-ones

3.56 g (11.0 mmol) of the compound of example 3A were dissolved in 100 ml of methanol, and 3.75 g (99.5 mmol) of sodium borohydride were added under ice cooling. After 1.5 h, 200 ml of 1M hydrochloric acid were slowly added. The methanol was removed on a rotary evaporator and the residue was diluted with 500 ml of water and extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dried under high vacuum. This gives 3.04 g (90% of theory) of the title compound.

Example 5A

{3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoro-2-hydroxypropyl) -4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid methyl ester(s) (iii)Racemic modification)

3.04 g (9.9 mmol) of the compound from example 4A are dissolved in 100 ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and potassium iodide in the 1-bit tip are added. The reaction mixture was heated at reflux for 1 h, then cooled to room temperature and filtered. The filtrate was freed of volatile constituents on a rotary evaporator and the residue was dried under high vacuum. This gives 3.70 g of the title compound in a purity of about 90% (89% of theory).

The racemic compound of example 5A was separated into enantiomers by preparative HPLC on chiral phase [ sample preparation: 3.6 g of the racemate was dissolved in 54 ml of ethyl acetate/isohexane (1:1 v/v), and separated on a column in 3 portions; column: based on the selection agent poly (N-methacryloyl-L-isoleucine-3-pentylamide), 430 mm x 40 mm; eluent: stepwise gradient isohexane/ethyl acetate 1:1 → ethyl acetate → isohexane/ethyl acetate 1: 1; flow rate: 50 ml/min; temperature: 24 ℃; ultraviolet detection: 260 nm]. In this way, 1.6 g of enantiomer 1 eluting first (example 6A) and 1.6 g of enantiomer 2 eluting later (example 7A) were obtained:

example 6A

{3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid methyl ester)( Enantiomers 1)

The enantiomer eluting first from the racemate separation of example 5A.

R_t= 3.21 min [ column: based on the selection agent poly (N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm x 4.6 mm; eluent: different from each otherHexane/ethyl acetate 1: 1; flow rate: 1 ml/min; ultraviolet detection: 260 nm]。

Example 7A

{3- (4-chlorophenyl) -5-oxo-4- [ (2R) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid methyl ester( Enantiomers 2)

The enantiomer eluting after separation from the racemate of example 5A.

R_t= 4.48 min [ column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-isoleucine-3-pentylamide), 250 mm x 4.6 mm; eluent: isohexane/ethyl acetate 1: 1; flow rate: 1 ml/min; ultraviolet detection: 260 nm]。

Example 8A

{3- (4-chlorophenyl) -5-oxo-4- [ (2S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid

The enantiomerically pure compound from example 6A (1.6 g, 4.21 mmol) was dissolved in 77 ml of methanol and 17 ml of a 1M solution of lithium hydroxide in water was added. The mixture was stirred at room temperature for 1 h and then concentrated on a rotary evaporator. The residue is diluted with 100 ml of water and acidified to pH 1-2 with 1N hydrochloric acid. The precipitated product is filtered off, washed successively with water and cyclohexane and dried by suction filtration. After further drying under high vacuum, 1.1 g (71% of theory) of the title compound are obtained.

Example 9A

{3- (4-chlorophenyl) -5-oxo-4- [ (2)R) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid

Starting from example 7A, the title compound is obtained in analogy to example 8A.

Example 10A

3-amino-2- [2- (trifluoromethyl) phenyl ] propanoic acid ethyl ester

1.035 g (2.54 mmol) of ethyl 3- { [ (benzyloxy) carbonyl ] amino } -2- [2- (trifluoromethyl) phenyl ] propionate [ see example 193A in WO 2007/134862 for preparation ] were dissolved in 24 ml of ethanol and hydrogenated under atmospheric pressure in the presence of 100 mg of 10% palladium on carbon for 3 h. The catalyst was then filtered off and the solvent of the filtrate was removed on a rotary evaporator. The residue corresponds to the title compound.

Yield: 700 mg (96% of theory, 91% purity according to LC/MS)

。

Example 11A

3-amino-2- [2- (trifluoromethyl) phenyl ] propane-1-ol hydrochloride

A solution of 700 mg (2.44 mmol) of ethyl 3-amino-2- [2- (trifluoromethyl) phenyl ] propionate (example 10A) in 10 ml of diethyl ether is added slowly dropwise to a solution of lithium aluminium hydride (1M solution in diethyl ether, 3.9 ml, 3.9 mmol) which has been cooled beforehand to 0 ℃. After the end of the addition, the reaction mixture was heated at reflux for 1 h and then cooled again to 0 ℃. A few drops of water were added until no more hydrogen generation was observed. The reaction mixture was then filtered and 1 ml of a 4N solution of hydrogen chloride in dioxane was added to the filtrate. The precipitated solid was isolated by filtration, washed with a small amount of diethyl ether and dried under high vacuum. This gives 390 mg (63% of theory) of the title compound.

Example 12A

{ 3-hydroxy-2- [2- (trifluoromethyl) phenyl ] propyl } carbamic acid tert-butyl ester

265 mg (1.21 mmol) of di-tert-butyl dicarbonate are added to a mixture of 310 mg (1.21 mmol) of the compound from example 11A in 9.3 ml of dioxane and 9.3 ml of 5% aqueous sodium bicarbonate solution, and the solution is stirred at room temperature until the reaction is complete. The mixture was then extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue (440 mg) corresponded to the title compound and was used in the next reaction without further purification.

Example 13A

3-amino-2- [2- (trifluoromethyl) phenyl ] propyl ] carbamate hydrochloride

A solution of 387 mg (1.21 mmol) of the compound from example 12A in 19.3 ml of acetonitrile is cooled to-15 ℃ and 148. mu.l (1.70 mmol) of chlorosulfonyl isocyanate are added. After 5 min, 10 ml of water were added and the reaction mixture was continued to be stirred at 60 ℃ overnight. After cooling to room temperature, 10 ml of saturated aqueous sodium bicarbonate solution were added. The mixture was extracted 4 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. 5 ml of a 4N solution of hydrogen chloride in dioxane were added to the residue and the mixture was stirred for 5 min. The volatile components are then removed again on a rotary evaporator. The residue (300 mg, purity about 90%) corresponded to the title compound and was reacted further without further purification.

Example 14A

[2- (2-chlorophenyl) -3-hydroxypropyl ] carbamic acid tert-butyl ester

705 mg (3.23 mmol) of di-tert-butyl dicarbonate are added to 300 mg (1.62 mmol) of 3-amino-2- (2-chlorophenyl) propan-1-ol [ for preparation, seeArch. Pharm1968, 301 (10), 750-]In 14 ml of dichloromethane and the mixture is stirred at room temperature for 3 h. The mixture was then diluted with 100 ml of ethyl acetate and washed successively with 1M hydrochloric acid (2 times), saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue was purified by preparative HPLC (method 7). This gives 382 mg (83% of theory) of the title compound as a colorless oil.

Example 15A

Carbamic acid 3-amino-2- (2-chlorophenyl) propyl ester

A solution of 344 mg (1.20 mmol) of the compound of example 14A in 86 ml acetonitrile was cooled to-15 ℃ and 314 μ l (3.61 mmol) chlorosulfonyl isocyanate was added. After 5 min, 10 ml of water were added and the reaction mixture was continued to be stirred at 60 ℃ overnight. After cooling to room temperature, 10 ml of saturated aqueous sodium bicarbonate solution were added. The mixture was extracted 4 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue (118 mg, purity about 85%, about 37% of theory) corresponded to the title compound and was reacted further without further purification.

Example 16A

3- (1, 3-dioxo-1, 3-dihydro-2)H-isoindol-2-yl) -2- [3- (trifluoromethyl) phenyl]Propionic acid methyl ester

A solution of n-butyllithium (1.6M in hexane, 18.75 ml, 30 mmol) was added dropwise over about 5 min to a solution of 4.91 ml (35 mmol) of diisopropylamine in 50 ml of THF, previously cooled to-20 ℃. The LDA solution thus obtained was cooled to-78 ℃ and 15.1 ml of DMPU (1, 3-dimethyltetrahydro-2 (1)H) -pyrimidinone, 125 mmol). After a hold at-78 ℃ for 20 min, 5.45 g (25 mmol) of [3- (trifluoromethyl) phenyl ] are slowly added dropwise]A solution of methyl acetate in 35 ml THF. After a further 20 min at-78 deg.C, 7.20 g (30 mmol) were added dropwiseN-a solution of bromomethylphthalimide in 50 ml THF. The reaction mixture was first stirred at-78 ℃ for 1 h and then at room temperature overnight without a cooling bath. After addition of 100 ml of 1N hydrochloric acid, the mixture is extracted 3 times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and with sulfuric acidThe sodium was dried and the solvent was removed on a rotary evaporator. The residue was dissolved in 50 ml DMSO and fractionated by preparative HPLC [ method 8]]And (5) purifying. This gives 2.20 g (22% of theory) of the title compound.

Example 17A

{ 3-hydroxy-2- [3- (trifluoromethyl) phenyl ] propyl } carbamic acid tert-butyl ester

550 mg (1.46 mmol) of the compound from example 16A are initially added to a mixture of 19 ml of 2-propanol and water (6:1 v/v), and 276 mg (7.29 mmol) of sodium borohydride are added. The reaction mixture was stirred at room temperature overnight and then adjusted to pH 5 by the addition of glacial acetic acid. The resulting mixture was heated to 80 ℃ and stirring was continued overnight at this temperature. Analysis of the sample by LC/MS showed free 3-amino-2- [3- (trifluoromethyl) phenyl]Propane-1-ol as the major component [ LC/MS (method 3): R)_t = 1.02 min, m/z = 220 (M+H)⁺]. After slight cooling, the volatile constituents of the reaction mixture were removed on a rotary evaporator. After 2 coevaporations with methanol and with toluene, respectively, the residue was dried under high vacuum. It was then dissolved in a 1:1 mixture of 6 ml acetonitrile and sodium bicarbonate solution (5% in water) and 402. mu.l (1.75 mmol) of di-tert-butyl dicarbonate was added. The solution was stirred at room temperature overnight and then extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. By preparative HPLC [ method 8]]The residue was purified. This gives 351 mg (75% of theory) of the title compound.

Example 18A

3-amino-2- [3- (trifluoromethyl) phenyl ] propylcarbamate hydrochloride

A solution of 350 mg (1.10 mmol) of the compound of example 17A in 50 ml of acetonitrile is cooled to-15 ℃ and a solution of 191 μ l (2.19 mmol) of chlorosulfonyl isocyanate in 10 ml of acetonitrile is added dropwise. After 5 min, 50 ml of water were added and the mixture was heated at 60 ℃ for 4 h. After cooling to room temperature, 50 ml of saturated aqueous sodium bicarbonate solution were added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the volatile components were removed on a rotary evaporator. 5 ml of a 4N solution of hydrogen chloride in dioxane were added to the residue and the mixture was stirred for 5 min. The volatile components are then removed again on a rotary evaporator. The residue (385 mg) corresponded to the crude title compound, with a purity of about 60% (about 70% of theory) according to LC/MS; this material was reacted further without purification.

Example 19A

3- [ (tert-Butoxycarbonyl) amino ] -2- [3- (trifluoromethyl) phenyl ] propyl ethylcarbamate

5 mg (42 mu mol) 4-N,NDimethylaminopyridine and 66 μ l (0.84 mmol) of ethyl isocyanate were added to a solution of 134 mg (0.42 mmol) of the compound of example 17A in 2.5 ml of pyridine. The mixture was stirred at room temperature overnight. Then another 66 μ l of ethyl isocyanate was added and the mixture was heated at 50 ℃ for 24 h. After cooling to room temperature, 0.5 ml ammonia solution (35% in water) was added. The volatile components are removed on a rotary evaporator. A small amount of acetonitrile and 1N hydrochloric acid was added to the residue and purified by preparative HPLC [ method 9]]The solution was separated. This gives 110 mg (67% of theory) of the title compound.

Example 20A

3-amino-2- [3- (trifluoromethyl) phenyl ] propyl ethylcarbamate hydrochloride

105 mg (0.27 mmol) of the compound of example 19A were dissolved in 2 ml of a 4N solution of hydrogen chloride in dioxane and the mixture was stirred at 60 ℃ until the reaction was complete (about 2 h). The volatile components are then removed on a rotary evaporator and the residue is dried under high vacuum. This gave 91 mg of the title compound in a purity of about 83% (about 86% of theory) according to LC/MS; this material was reacted further without further purification.

Example 21A

[ (2, 3-dichlorophenyl) (phenylsulfonyl) methyl ] carbamic acid tert-butyl ester

2.23 g (19.0 mmol) of tert-butyl carbamate and 6.25 g (38.1 mmol) of the sodium salt of benzenesulfinic acid are initially introduced into 55 ml of methanol/water (1:2) at room temperature, and 5.00 g (28.6 mmol) of 2, 3-dichlorobenzaldehyde are added, followed by 1.43 ml (37.9 mmol) of formic acid. The reaction mixture was stirred at room temperature for 2 days. The precipitated solid is filtered off with suction and washed with water and 2 times with diethyl ether. After removal of the solvent on a rotary evaporator, 3.47 g of 2, 3-dichlorobenzaldehyde are recovered from the ether-containing filtrate. The suction-filtered solid was dried under high vacuum. This gives 2.22 g (19% of theory) of the title compound.

Example 22A

[(E) - (2, 3-dichlorophenyl) methylene]Carbamic acid tert-butyl ester

4.42 g (32.0 mmol) of potassium carbonate are dried thermally under high vacuum and then cooled to room temperature under an argon atmosphere. 52 ml of anhydrous THF and 2.22 g (5.33 mmol) of the compound from example 21A are added. The reaction mixture was then stirred at reflux temperature for 16 h. After cooling to room temperature, the reaction mixture was filtered through Celite. The solid was washed with a small amount of THF. The solvent of the combined filtrates was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 1.38 g (94% of theory) of the title compound.

Example 23A

[1- (2, 3-dichlorophenyl) -2-nitroethyl ] carbamic acid tert-butyl ester

263 mu l (1.51 mmol)N,NDiisopropylethylamine was added to 10.1 ml (186 mmol) of nitromethane and the yellow solution was stirred at room temperature for 1 h. Then 1.38 g (5.03 mmol) of the compound of example 22A were added and the mixture was stirred at room temperature overnight. All volatile components were removed on a rotary evaporator. By preparative HPLC [ method 12 ]]The residue was purified. This gives 865 mg (51% of theory) of the title compound.

Example 24A

[ 2-amino-1- (2, 3-dichlorophenyl) ethyl ] carbamic acid tert-butyl ester

A solution of 440 mg (1.31 mmol) of the compound of example 23A in 100 ml of methanol was hydrogenated in a continuous flow hydrogenation apparatus (H-Cube, Model HC-2-SS from Budapest Thales Nano) equipped with a Raney-Nickel cartridge (Raney-Nickel-Kartusche) at a flow of 1 ml/min, a temperature of 40 ℃ and standard pressure. After the reaction was complete, the methanol of the solution was removed on a rotary evaporator and the residue was dried briefly under high vacuum. This gives 370 mg (91% of theory) of the title compound.

Example 25A

1- (2-chlorophenyl) -2-nitroethylamine hydrochloride

10 ml of a 4N solution of hydrogen chloride in dioxane were added to 1.037 g (3.45 mmol) of [1- (2-chlorophenyl) -2-nitroethyl]Tert-butyl carbamate [ see, for example,Tetrahedron Lett. 2009, 50 (9), 1016]in a solution in 10 ml of dichloromethane and the mixture is stirred at room temperature for 2 h. The volatile components are then removed on a rotary evaporator. 5 ml of dichloromethane are added to the residue and the solvent of the mixture is removed again on a rotary evaporator and then dried under high vacuum. This gave 898 mg of the title compound (quantitative, according to¹H NMR, still containing about 8% dioxane).

Example 26A

N- [1- (2-chlorophenyl) -2-nitroethyl group]Methanesulphonamides

182 μ l (2.35 mmol) of methanesulfonyl chloride was added to a solution of 300 mg (purity about 93%, 1.18 mmol) of the compound of example 25A in 7.2 ml of pyridine at room temperature, and the mixture was stirred for 1 h. Pyridine was removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 20 ]. This gives 221 mg (65% of theory) of the title compound.

Example 27A

N- [ 2-amino-1- (2-chlorophenyl) ethyl group]Methanesulphonamides

A solution of 221 mg (0.79 mmol) of the compound of example 26A in 45 ml of methanol is hydrogenated in a continuous flow hydrogenation apparatus (H-Cube, Model HC-2-SS from Budapest Thales Nano) equipped with a Raney nickel cartridge at a flow rate of 1 ml/min, a temperature of 45 ℃ and standard pressure. After the reaction had ended, the methanol of the solution was removed on a rotary evaporator and the residue was dried briefly under high vacuum. This gives 186 mg (94% of theory) of the title compound.

Example 28A

N- [1- (2-chlorophenyl) -2-nitroethyl group]Ethanesulfonamides

219 μ l (2.31 mmol) of ethanesulfonyl chloride was added to a solution of 295 mg (purity about 93%, 1.16 mmol) of the compound of example 25A in 7.0 ml of pyridine at room temperature, and the mixture was stirred for 1 h. The pyridine was then removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 20 ]. This gives 230 mg (purity approx. 90% according to LC/MS, 61% of theory) of the title compound.

Example 29A

N- [ 2-amino-1- (2-chlorophenyl) ethyl group]Ethanesulfonamides

Analogously to example 27A, from 230 mg (0.79 mmol) of the compound of example 28A 190 mg (purity approx. 90% according to LC/MS, 83% of theory) of the title compound are obtained.

Example 30A

1- [1- (2-chlorophenyl) -2-nitroethyl ] urea

300 mg (purity: about 93%, 1.18 mmol) of the compound from example 25A are initially taken in 12 ml of water/methanol (1:1 v/v) and 287 mg (3.53 mmol) of potassium cyanate are added at room temperature. The reaction mixture was warmed to 40 ℃ for 1 h. After cooling to room temperature, the mixture was directly separated into its components by preparative HPLC [ method 8 ]. This gives 120 mg (41% of theory) of the title compound.

Example 31A

1- [ 2-amino-1- (2-chlorophenyl) ethyl ] urea

In analogy to example 27A, from 120 mg (0.49 mmol) of the compound of example 30A 94 mg (72% of theory) of the title compound are obtained.

Example 32A

{3- (4-chlorophenyl) -5-oxo-4- [ (1)E) -3,3, 3-trifluoroprop-1-en-1-yl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid methyl ester

280 mg (0.74 mmol) of the compound from example 7A and 108 mg (0.89 mmol) of 4-one at room temperatureN,NDimethylaminopyridine was initially introduced together into 5.3 ml of pyridine and 0.31 ml (1.84 mmol) of trifluoromethanesulfonic anhydride was added in portions and the mixture was stirred for 12 h. The pyridine was then removed on a rotary evaporator. The residue was dissolved in acetonitrile and 1N hydrochloric acid and passed through preparative HLPC [ method 9]]And (5) purifying. This gives 230 mg (86% of theory) of the title compound.

Example 33A

{3- (4-chlorophenyl) -5-oxo-4- [ (1)E) -3,3, 3-trifluoroprop-1-en-1-yl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetic acid

260 mg (0.72 mmol) of the compound from example 32A are dissolved in 5 ml of methanol and 2.87 ml (2.87 mmol) of a 1M solution of lithium hydroxide in water are added. The mixture was stirred at room temperature for 1 h, then acidified with 1N hydrochloric acid and diluted with DMSO. The solution was then directly purified by preparative HLPC [ method 9 ]. This gives 215 mg (86% of theory) of the title compound.

Example 34A

2-amino-2- [3- (trifluoromethyl) phenyl ] propanamide

138 ml of water, 108 ml of a 25% aqueous ammonia solution and 173 ml of ethanol were placed in advance. To the mixture were added 108 g (574 mmol) of 1- [3- (trifluoromethyl) phenyl ] ethanone, 30 g (574 mmol) of sodium cyanide and 31 g (631 mmol) of ammonium chloride. The mixture was stirred in an autoclave at 70 ℃ for 20 h. The ethanol is then removed on a rotary evaporator and the residue is extracted 4 times with 500 ml of diethyl ether each time. Magnesium sulfate and activated carbon were added to the combined organic phases and the mixture was filtered off with suction over celite. The filtrate is concentrated on a rotary evaporator and the residue is purified by chromatography on 2 kg of silica gel 60 (eluent: cyclohexane/ethyl acetate 3:1-1: 1).

500 ml of concentrated hydrochloric acid was slowly added to the intermediate 2-amino-2- [3- (trifluoromethyl) phenyl thus obtained under ice-cooling]Propionitrile [56 g, 46% of theory;¹H NMR (400 MHz, CDCl₃): δ [ppm] = 1.78 (s, 3H), 2.14 (br. s, 2H), 7.55 (t, 1H), 7.63 (d, 1H), 7.88 (d, 1H), 7.96 (s, 1H)]in (1). The suspension was stirred at room temperature overnight. The volume was then reduced to about 150 ml on a rotary evaporator. 250 ml of acetone are added and then all volatile constituents are removed on a rotary evaporator. 125 ml of concentrated ammonia solution was added to the remaining solid paste under ice cooling. The mixture was stirred in an ice bath for 30 min. The crystals formed are suction-filtered off, compacted and washed 2 times with 50 ml of ice-water each time and then with pentane. The product was dried under high vacuum. This gives 43 g (32% of theory) of the title compound.

Example 35A

2- [3- (trifluoromethyl) phenyl ] propane-1, 2-diamine dihydrochloride

A suspension of 500 mg (2.15 mmol) of the compound from example 34A in 20 ml of diethyl ether is cooled to 0 ℃ and 3.72 ml of lithium aluminium hydride solution (1M in diethyl ether, 3.72 mmol) are slowly added. After 15 min, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Under ice-cooling, 5 ml of a 5% aqueous solution of potassium sodium tartrate was slowly added dropwise. The mixture was diluted with 40 ml of diethyl ether and 40 ml of 5% potassium sodium tartrate solution and extracted with shaking. The aqueous phase was extracted with diethyl ether an additional 2 times. The combined organic phases were dried over sodium sulfate, 3 ml of a 4N solution of hydrogen chloride in dioxane were added, and the volatile components of the mixture were then removed on a rotary evaporator. The residue (153 mg) containing about 35% of the title compound was reacted further as such without further purification according to LC/MS.

Example 36A

{ 2-hydroxy-2- [2- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

963 μ l (4.19 mmol) of di-tert-butyl dicarbonate are added to a solution of 430 mg (2.1 mmol) of 2-hydroxy-2- [ (2-trifluoromethyl) phenyl ] ethylamine in 20 ml of dichloromethane at room temperature and the mixture is stirred for 3 h. The reaction mixture was then diluted with 100 ml of ethyl acetate and washed 2 times with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution each. The organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue was purified by preparative HPLC [ method 9 ]. This gives 470 mg (73% of theory) of the title compound.

Example 37A

Carbamic acid 2-amino-1- [2- (trifluoromethyl) phenyl ] ethyl ester

A solution of 420 mg (1.38 mmol) of the compound from example 36A in 100 ml of acetonitrile is cooled to-15 ℃ and a solution of 168 μ l (1.93 mmol) of chlorosulfonyl isocyanate in 10 ml of acetonitrile is added dropwise. After 5 min, 50 ml of water were added and the reaction mixture was further stirred at 60 ℃ overnight. After cooling to room temperature, 50 ml of saturated aqueous sodium bicarbonate solution were added. The mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue (321 mg, purity about 90%, 85% of theory) corresponded to the title compound and was reacted further without additional purification.

Example 38A

{ 2-hydroxy-2- [3- (trifluoromethyl) phenyl ] ethyl } carbamic acid tert-butyl ester

3.2 ml of a 5% aqueous sodium hydrogencarbonate solution and 91 mg (0.41 mmol) of di-tert-butyl dicarbonate were added at room temperature to 85 mg (0.41 mmol) of 2-hydroxy-2- [ (3-trifluoromethyl) phenyl]Ethylamine [ for preparation, seeJ. Med. Chem. 1968, 11, 1258-1262]In a solution in 3.2 ml dioxane and the mixture was stirred until the reaction was complete. The reaction mixture was then extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue (88 mg, 70% of theory) corresponds to the title compound.

Example 39A

Carbamic acid 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl ester hydrochloride

In analogy to example 37A, 85 mg (0.28 mmol) of the compound of example 38A are reacted. The carbamic acid 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl ester thus obtained was stirred for 5 min with 2 ml of a 4N solution of hydrogen chloride in dioxane. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. This gives 73 mg (85% of theory) of the title compound.

Example 40A

Carbamic acid 2-amino-1- (2-chlorophenyl) ethyl ester

In analogy to example 37A, from 114 mg (0.42 mmol) of tert-butyl [2- (2-chlorophenyl) -2-hydroxyethyl ] carbamate are obtained 46 mg (51% of theory) of the title compound.

Example 41A

2-amino-1- (2, 3-dichlorophenyl) ethanone hydrochloride

411 mg (4.33 mmol) of diformylaminocodium are added at room temperature to a solution of 1.0 g (3.73 mmol) of 2-bromo-1- (2, 3-dichlorophenyl) ethanone [ for preparation see, for example, U.S. Pat. No. 5,831,132] in 4 ml of acetonitrile and the mixture is stirred at room temperature overnight. The mixture was then heated to 70 ℃ and filtered hot. The remaining solid was washed with 2 ml of hot acetonitrile. The solvent of the combined filtrates was removed on a rotary evaporator. 10 ml of a 5% ethanolic solution of hydrogen chloride were added to the dark brown oily residue and the mixture was stirred at room temperature overnight. Volatile components were removed on a rotary evaporator and the remaining yellow solid was stirred in 20 ml of boiling ether. After cooling to room temperature, the solid was isolated by filtration, washed with diethyl ether and dried under high vacuum. This gives 410 mg (46% of theory) of the title compound.

Example 42A

2-amino-1- (2, 3-dichlorophenyl) ethanol

300 mg (1.25 mmol) of the compound from example 41A are placed in advance in 2 ml of methanol under argon. 189 mg (5.0 mmol) of sodium borohydride was added and the mixture was stirred overnight. 1N hydrochloric acid was added slowly until after the end of gas formation, methanol was removed on a rotary evaporator. The aqueous residue was made basic by addition of sodium bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue (189 mg, 74% of theory) corresponds to the title compound.

Example 43A

[2- (2, 3-dichlorophenyl) -2-hydroxyethyl ] carbamic acid tert-butyl ester

281 μ l (1.22 mmol) of di-tert-butyl dicarbonate are added to a solution of 126 mg (0.61 mmol) of the compound of example 42A in 5 ml of acetonitrile and 5 ml of dichloromethane at room temperature, and the mixture is stirred overnight. Volatile components were removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 9 ]. This gives 117 mg (62% of theory) of the title compound.

Example 44A

Carbamic acid 2-amino-1- (2, 3-dichlorophenyl) ethyl ester

Analogously to example 37A, from 117 mg (0.38 mmol) of the compound of example 43A 62 mg (63% of theory) of the title compound are obtained.

Example 45A

(2R) -2-amino-3- [3- (trifluoromethyl) phenyl]Propane-1-ol hydrochloride

4.29 ml of lithium aluminium hydride solution (1M in diethyl ether, 4.29 mmol) are added at 0 DEG.CSlowly add to 500 mg (2.14 mmol) (2)R) -2-amino-3- [ (3-trifluoromethyl) phenyl]Propionic acid in 20 ml of diethyl ether. The reaction mixture was stirred at 0 ℃ for 15 min and then heated at reflux overnight. After cooling to 0 ℃,5 ml of a 5% aqueous solution of sodium aluminum tartrate was added dropwise. The mixture was diluted with 40 ml of diethyl ether and 40 ml of 5% sodium aluminium tartrate solution and extracted with shaking. The aqueous phase was extracted with diethyl ether an additional 2 times. The combined organic phases were dried over sodium sulfate, 3 ml of a 4N solution of hydrogen chloride in dioxane were added and the volatile components of the mixture were removed on a rotary evaporator. The residue was dried under high vacuum. This gives 410 mg (67% of theory, purity approx. 90% according to LC/MS) of the title compound.

Example 46A

(2S) -2-amino-3- [3- (trifluoromethyl) phenyl]Propane-1-ol hydrochloride

Analogously to example 45A, 500 mg (2)S) -2-amino-3- [ (3-trifluoromethyl) phenyl]And (4) carrying out propionic acid reaction. This gives 517 mg (89% of theory) of the title compound.

Example 47A

Carbamic acid- (2)R) -2-amino-3- [3- (trifluoromethyl) phenyl]Propyl ester hydrochloride

Mu.l (0.44 mmol) of chlorosulfonyl isocyanate was slowly added to 100 mg (0.31 mmol) { 1-hydroxy-3- [3- (trifluoromethyl) phenyl ] at-15 ℃]Propan-2-yl carbamic acid- (2)R) Tert-butyl ester (for preparation, see U.S. patent application 2008/0242694, example [0440 ]]) In a solution in 2 ml of acetonitrile. The reaction mixture was stirred at room temperature for 1 h, then 3 ml water was added and the mixture was heated under reflux overnight. After cooling to room temperature, by preparative HPLC [ method 9]]And (4) directly purifying the mixture. This gave a first fraction (21 mg) of the title compound (partly as formate) and a corresponding fraction of the compound still protected by Boc-protection (17 mg). The latter stage was stirred with 3 ml of a 4N solution of hydrogen chloride in dioxane for 30 min, and then the volatile components were removed on a rotary evaporator and subsequently under high vacuum. The residue (16 mg) corresponded to the pure title compound. 2 fractions of the title compound were combined and used to prepare the following compound.

Example 48A

Carbamic acid- (2)S) -2-amino-3- [3- (trifluoromethyl) phenyl]Propyl ester hydrochloride

Mu.l (0.70 mmol) of chlorosulfonyl isocyanate was slowly added to 160 mg (0.50 mmol) { 1-hydroxy-3- [3- (trifluoromethyl) phenyl ] at-15 ℃]Propan-2-yl carbamic acid- (2)S) -tert-butyl ester (as regardsPreparation, see U.S. patent application 2008/0242694, example [0464 ]]) In a solution in 7.6 ml of acetonitrile. The reaction mixture was stirred at room temperature for 1 h, then 1 ml water was added and the mixture was heated at 60 ℃ overnight. Analysis of the sample by LC/MS indicated complete conversion to the desired product. After cooling to room temperature, the volatile constituents are removed on a rotary evaporator and finally under high vacuum. The residue (80 mg, 53% of theory) corresponds to the title compound.

Example 49A

2- [ (5-chloro-2-thienyl) carbonyl]-N- (2-methoxyethyl) hydrazinecarboxamide

3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide are essentially suspended in 30 ml of dry THF at 50 ℃. 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane dissolved in 30 ml of THF are then added dropwise. The mixture was stirred at 50 ℃ for 2.5 h. After cooling to room temperature, the solvent was removed on a rotary evaporator and the residue was stirred with diethyl ether. The crystals are filtered off with suction, washed with diethyl ether and dried under high vacuum. This gives 4.87 g (100% of theory) of the title compound.

Example 50A

5- (5-chloro-2-thienyl) -4- (C-chloro-5-thienyl)2-methoxyethyl) -2, 4-dihydro-3H-1,2, 4-triazol-3-ones

4.85 g (17.46 mmol) of the compound from example 49A are dissolved in 17 ml (52.39 mmol) of 3M aqueous sodium hydroxide solution and heated at reflux for 168 h. After 16, 40, 64 and 88 h, respectively, a further 1.05 g (26.19 mmol, total 104.76 mmol) of solid sodium hydroxide are added. The batch is then adjusted to pH 10 with 1M hydrochloric acid and the mixture is extracted 2 times with 30 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue was dried under high vacuum. This gives 2.44 g (54% of theory) of the title compound.

Example 51A

[3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Ethyl acetate

2.4 g (9.24 mmol) of the compound from example 50A and 2.55 g (18.48 mmol) of potassium carbonate are suspended in 48 ml of acetonitrile. 1.08 ml (10.17 mmol) ethyl chloroacetate are then added and the mixture is heated at 80 ℃ under reflux for 4.5 h. 113 mg (0.92 mmol) of ethyl chloroacetate are then added again and the mixture is stirred at 80 ℃ for a further 2 h. The suspension is then filtered over a layer of silica gel and washed with ethyl acetate, the filtrate is evaporated on a rotary evaporator and the residue is dried under high vacuum. This gives 3.24 g (100% of theory) of the title compound.

Example 52A

[3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetic acid

3.2 g (9.25 mmol) of the compound from example 51A are dissolved in 28 ml of methanol. Then 2.82 ml of a 20% aqueous solution of potassium hydroxide was added. The mixture was stirred at room temperature for 2 h. The methanol fraction was then reduced by half on a rotary evaporator. The mixture was then diluted with water and extracted 1 time with 15 ml of ethyl acetate. The aqueous phase was acidified with 920 μ l concentrated hydrochloric acid and extracted 2 times with 15 ml ethyl acetate each time. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue is dried under high vacuum to yield 2.34 g (80% of theory) of the title compound.

Example 53A

N- { 2-amino-2- [3- (trifluoromethyl) phenyl]Propyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide formate (CMixtures of diastereomers)

A mixture of 166 mg (0.45 mmol) of the compound from example 8A, 131 mg (0.68 mmol) of EDC and 92 mg (0.68 mmol) of HOBt in 4 ml of DMF is initially stirred at room temperature for 10 min and then added dropwise to 152 mg of the compound from example 35A (purity approx. 35%) and 158. mu.l (0.91 mmol)N,N-diisopropylethylamine in 2 ml of DMF. The reaction mixture was stirred at room temperature for 5 min, then 2 ml of 1N hydrochloric acid were added and subjected to preparative HPLC [ method 9]]And (4) directly separating. This gives 84 mg (30% of theory) of the pure title compound.

Example 54A

N- [ 2-amino-2- (2, 3-dichlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide hydrochloride (A)Diastereoisomers 1)

5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 147 mg (0.23 mmol) of the compound of example 19 in 5 ml of dichloromethane and the mixture was stirred at room temperature for 2 h. The volatile components are then removed on a rotary evaporator. An additional 5 ml of dichloromethane were added to the residue and the solvent of the mixture was removed again on a rotary evaporator and then purified by preparative HPLC [ method 8 ]. 10 ml of 1M hydrochloric acid were added to the product-containing fractions, and all volatile constituents of the mixture were then removed on a rotary evaporator. The residue was dried under high vacuum. This gives 127 mg (96% of theory) of the title compound.

Example 55A

N- [ 2-amino-2- (2, 3-dichlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide hydrochloride (A)Diastereoisomers 2)

Analogously to example 54A, from 147 mg (0.23 mmol) of the compound of example 20, 115 mg (87% of theory) of the title compound are obtained.

Example 56A

N- { 2-amino-2- [2- (trifluoromethyl) phenyl]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide hydrochloride (A)Diastereoisomers 1)

5 ml of a 4N solution of hydrogen chloride in dioxane were added145 mg (0.22 mmol) of the compound from example 14 in 5 ml of dichloromethane and the mixture is stirred at room temperature for 2 h. The volatile components are then removed on a rotary evaporator. An additional 5 ml of dichloromethane were added to the residue and the solvent of the mixture was removed again on a rotary evaporator and then dried under high vacuum. This gives 130 mg (91% of theory) of the title compound (according to¹H NMR, still containing about 7% dioxane).

Example 57A

N- { 2-amino-2- [2- (trifluoromethyl) phenyl]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide hydrochloride (A)Diastereoisomers 2)

Analogously to example 56A, from 117 mg (0.18 mmol) of the compound of example 15 there are obtained 104 mg (93% of theory) of the title compound (according to¹H NMR, still containing about 5% dioxane).

Example 58A

N- { 2-amino-2- [3- (trifluoromethyl) phenyl]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide hydrochloride (A)Mixtures of diastereomers)

Analogously to example 56A, from 235 mg (0.36 mmol) of the compound of example 34 there are obtained 220 mg (99% of theory) of the title compound (according to¹H NMR, still containing about 5% dioxane).

Example 59A

N- { 2-amino-2- [2- (trifluoromethyl) phenyl]Ethyl } -2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetamide hydrochloride (A)Racemic modification)

Analogously to example 56A, 40 mg (99% of theory) of the title compound (according to example 56A) were obtained from 44 mg (62 μmol) of the compound of example 65¹H NMR, still containing about 22% dioxane).

Example 60A

N- { 2-amino-2- [2- (trifluoromethyl) phenyl]Ethyl } -2- [3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo4, 5-dihydro-1-oxoH-1,2, 4-triazol-1-yl]Acetamide hydrochloride (A)Racemic modification)

Analogously to example 56A, 40 mg (99% of theory) of the title compound (according to example 56A) were obtained from 44 mg (60 μmol) of the compound of example 66¹H NMR, still containing about 20% dioxane).

Example 61A

N- { 2-amino-2- [2- (trifluoromethyl) phenyl]Ethyl } -2- [3- (5-chloro-2-thienyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetamide hydrochloride (A)Racemic modification)

Similar to example 56A, 47 mg (99% of theory) of the title compound (according to example 56A) were produced from 49 mg (60 μmol) of the compound of example 67¹H NMR, still containing about 30% dioxane).

Working examples are as follows:

example 1

Carbamic acid-3- [ ({3- (4-chloro)Phenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [2- (trifluoromethyl) phenyl]Propyl ester (C)Mixtures of diastereomers)

366 mg (1.00 mmol) of the compound of example 8A, 299 mg (1.00 mmol) of the compound of example 13A, 288 mg (1.50 mmol) of EDC, 203 mg (1.50 mmol) of HOBt and 348. mu.l (2.0 mmol)N,NA mixture of diisopropylethylamine in 25 ml of DMF was stirred at room temperature overnight. 1 ml of 1M hydrochloric acid is then added to the mixture and subjected to preparative HPLC [ method 8]]The mixture is separated directly into its components. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 340 mg (56% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 10a ], see example 2 and example 3.

Example 2

Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [2- (trifluoromethyl) phenyl]Propyl ester (C)Diastereoisomers 1)

340 mg of the compound of example 1, the diastereomer eluting first, are chromatographed according to method 10 a. The material thus obtained (170 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 160 mg of the pure title compound.

Chiral analytical HPLC [ method 11]: R_t = 2.30 min。

Example 3

Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [2- (trifluoromethyl) phenyl]Propyl ester (C)Diastereoisomers 2)

340 mg of the compound of example 1 are chromatographed according to method 10a, followed by the eluted diastereomer. The material thus obtained (185 mg) was again purified finely by preparative HPLC [ method 8 ]. This gave 160 mg of the pure title compound.

Chiral analytical HPLC [ method 11]: R_t = 2.98 min。

Example 4

Carbamic acid 2- (2-chlorophenyl) -3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-trisOxazol-1-yl } acetyl) amino]Propyl ester (C)Mixtures of diastereomers)

185 mg (0.51 mmol) of the compound from example 8A, 146 mg (0.76 mmol) of EDC and 108 mg (0.76 mmol) of HOBt in 5 ml of DMF are stirred at room temperature for 20 min. The resulting solution was then added dropwise to a solution of 116 mg (0.51 mmol) of the compound of example 15A in 15 ml of acetonitrile. After 30 min at room temperature, the acetonitrile was removed on a rotary evaporator. 1 ml of 1M hydrochloric acid was added to the remaining solution and the mixture was separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 150 mg (49% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 5b ], see example 5 and example 6.

Example 5

Carbamic acid 2- (2-chlorophenyl) -3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Propyl ester (C)Diastereoisomers 1)

According to method 5b, 150 mg of the compound of example 4 are chromatographed, the diastereomer eluting first. The material thus obtained (58 mg) was again purified by preparative HPLC [ method 8 ]. This gave 46 mg of the pure title compound.

Chiral analytical HPLC [ method 6b ]]: R_t = 2.51 min。

Example 6

Carbamic acid 2- (2-chlorophenyl) -3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Propyl ester (C)Diastereoisomers 2)

According to method 5b, 150 mg of the compound of example 4 are chromatographed, the diastereomer eluting thereafter. The material thus obtained (63 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 59 mg of the pure title compound.

Chiral analytical HPLC [ method 6b ]]: R_t = 2.92 min。

Example 7

Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [3- (trifluoromethyl) phenyl]Propyl ester (C)Mixtures of diastereomers)

236 mg (0.64 mmol) of the compound of example 8A, 385 mg (0.77 mmol) of the compound of example 18A, 148 mg (0.77 mmol) of EDC, 110 mg (0.77 mmol) of HOBt and 225 μ l (1.29 mmol)N,NA mixture of diisopropylethylamine in 10 ml of DMF was stirred at room temperature overnight. 2 ml of 1M hydrochloric acid are then added to the mixture and subjected to preparative HPLC [ method 8]]The mixture is separated directly into its components. Then by another preparative HPLC [ method 9]]And the resulting product was purified again. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 140 mg (35% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 5a ], see example 8 and example 9.

Example 8

Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [3- (trifluoromethyl) phenyl]Propyl ester (C)Diastereoisomers 1)

According to method 5a, 140 mg of the compound of example 7 are chromatographed, the diastereomer eluting first. The material thus obtained (82 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 69 mg of the pure title compound.

Chiral analytical HPLC [ method 6a ]]: R_t = 3.54 min。

Example 9

Carbamic acid 3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [3- (trifluoromethyl) phenyl]Propyl ester (C)Diastereoisomers 2)

140 mg of the compound of example 7 are chromatographed according to method 5a, followed by the eluted diastereomer. The product thus obtained (83 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 67 mg of the pure title compound.

Chiral analytical HPLC [ method 6a ]]: R_t = 4.29 min。

Example 10

Ethylcarbamic acid-3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [3- (trifluoromethyl) phenyl]Propyl ester (C)Mixtures of diastereomers)

95 mg (0.26 mmol) of the compound from example 8A, 75 mg (0.39 mmol) of EDC and 56 mg (0.39 mmol) of HOBt are stirred in 2.5 ml of DMF for 5 min at room temperature. The resulting solution was then added dropwise to a solution of 102 mg (0.26 mmol) of the compound of example 20A in 7.5 ml of acetonitrile. After 30 min at room temperature, the acetonitrile was removed on a rotary evaporator. 1 ml of 1M hydrochloric acid was added to the remaining solution and the mixture was separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 123 mg (73% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 10b ], see example 11 and example 12.

Example 11

Ethylcarbamic acid-3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [3- (trifluoromethyl) phenyl]Propyl ester (C)Diastereoisomers 1)

According to method 10b, 120 mg of the compound of example 10, the first eluting diastereomer, are chromatographically separated. The material thus obtained (62 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 50 mg of the pure title compound.

Chiral analytical HPLC [ method 11]: R_t = 1.77 min。

Example 12

Ethylcarbamic acid-3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-2- [3- (trifluoromethyl) phenyl]Propyl ester (C)Diastereoisomers 2)

According to method 10b, 120 mg of the compound of example 10 are chromatographed, the diastereomer eluting thereafter. The material thus obtained (about 60 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 52 mg of the pure title compound.

Chiral analytical HPLC [ method 11]: R_t = 2.28 min。

Example 13

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Mixtures of diastereomers)

A mixture of 295 mg (0.81 mmol) of the compound from example 8A, 270 mg (0.89 mmol) of tert-butyl { 2-amino-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamate, 216 mg (1.13 mmol) of EDC and 153 mg (1.13 mmol) of HOBt in 7 ml of DMF is stirred at room temperature for 1 h. 1 ml of 1M hydrochloric acid was added to the mixture and the mixture was separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 494 mg (94% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 13a ], see example 14 and example 15.

Example 14

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Diastereoisomers 1)

490 mg of the compound from example 13, the diastereomer eluting first (145 mg) were chromatographed according to method 13 a.

Chiral analytical HPLC [ method 14 ]]: R_t = 5.25 min。

Example 15

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Diastereoisomers 2)

490 mg of the compound from example 13 were chromatographed according to method 13a, followed by the eluted diastereomer (117 mg).

Chiral analytical HPLC [ method 14 ]]: R_t = 5.94 min。

Example 16

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- {2- [ (methylsulfonyl) amino group]-2- [2- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Diastereoisomers 1)

13 μ l of methanesulfonyl chloride was added to a solution of 90 mg (0.15 mmol) of the compound of example 56A in 1.5 ml of pyridine at room temperature. The mixture was stirred at room temperature for 1 h, and then 12 μ l methanesulfonyl chloride (total 0.32 mmol, 2.1 equivalents) was added again. After 1 h, the volatile components are removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC [ method 8 ]. This gives 59 mg (61% of theory) of the title compound.

Example 17

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- {2- [ (methylsulfonyl) amino group]-2- [2- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Diastereoisomers 2)

In analogy to example 16, 67 mg (0.114 mmol) of the compound from example 57A are treated with methanesulfonyl chloride to give 40 mg (56% of theory) of the title compound.

Example 18

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-tert-butyl 1- (2, 3-dichlorophenyl) ethyl } carbamate ((iii))Mixtures of diastereomers)

In analogy to example 13, 185 mg (0.51 mmol) of the compound of example 8A and 170 mg (0.56 mmol) of the compound of example 24A are reacted. This gives 300 mg (88% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be isolated by preparative HPLC on chiral phase [ method 15a ], see example 19 and example 20.

Example 19

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-tert-butyl 1- (2, 3-dichlorophenyl) ethyl } carbamate ((iii))Diastereoisomers 1)

According to method 15a, 300 mg of the compound of example 18 was chromatographed, the diastereomer eluting first (150 mg).

Chiral analytical HPLC [ method 16 ]]: R_t = 2.15 min。

Example 20

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-tert-butyl 1- (2, 3-dichlorophenyl) ethyl } carbamate ((iii))Diastereoisomers 2)

According to method 15a, 300 mg of the compound of example 18 was chromatographed, followed by the eluted diastereomer (150 mg).

Chiral analytical HPLC [ method 16 ]]: R_t = 5.33 min。

Example 21

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- {2- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino group]Ethyl } acetamide (C)Diastereoisomers 1)

Analogously to example 16, by treating 77 mg (0.131 mmol) of the compound from example 54A with methanesulfonyl chloride, 55 mg (67% of theory) of the title compound are obtained.

Example 22

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- {2- (2, 3-dichlorophenyl) -2- [ (methylsulfonyl) amino group]Ethyl } acetamide (C)Diastereoisomers 2)

Analogously to example 16, by treating 76 mg (0.13 mmol) of the compound from example 55A with methanesulfonyl chloride, 59 mg (73% of theory) of the title compound are obtained.

Example 23

N- [2- (carbamoylamino) -2- (2, 3-dichlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 1)

12 mg (153. mu. mol) of potassium cyanate was added to a mixture of 30 mg (51. mu. mol) of the compound of example 54A, 1 ml of water and 1 ml of methanol, and the mixture was stirred at 40 ℃ for 1.5 h. An additional 6 mg (75 μmol) of potassium cyanate was added and stirring of the reaction mixture was continued at room temperature overnight. Several ml of DMSO were added and the whole solution was separated by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 17 mg (56% of theory) of the title compound.

Example 24

N- [2- (carbamoylamino) -2- (2, 3-dichlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 2)

In analogy to example 23, 19 mg (63% of theory) of the title compound were obtained from 30 mg (51 μmol) of the compound of example 55A and potassium cyanate.

Example 25

N- {2- (2-chlorophenyl) -2- [ (methylsulfonyl) amino group]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Mixtures of diastereomers)

A mixture of 249 mg (0.68 mmol) of the compound from example 8A, 186 mg (0.75 mmol) of the compound from example 27A, 195 mg (1.02 mmol) of EDC and 138 mg (1.02 mmol) of HOBt in 6.5 ml of DMF is stirred at room temperature for 2 h. The mixture was then separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 356 mg (83% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be isolated by preparative HPLC on chiral phase [ method 17a ], see example 26 and example 27.

Example 26

N- {2- (2-chlorophenyl) -2- [ (methylsulfonyl) amino group]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 1)

356 mg of the compound of example 25, the first eluting diastereomer, were chromatographed according to method 17 a. The material thus obtained (150 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 100 mg of the pure title compound.

Chiral analytical HPLC [ method 18a ]]: R_t = 4.10 min。

Example 27

N- {2- (2-chlorophenyl) -2- [ (methylsulfonyl) amino group]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 2)

356 mg of the diastereomer eluted after the compound of example 25 were chromatographed according to method 17 a. The material thus obtained (160 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 120 mg of the pure title compound.

Chiral analytical HPLC [ method 18a ]]: R_t = 4.94 min。

Example 28

N- {2- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Mixtures of diastereomers)

In analogy to example 25, 216 mg (0.59 mmol) of the compound of example 8A and 190 mg (90% pure, 0.65 mmol) of the compound of example 29A yield 274 mg (73% of theory) of the title compound.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 17b ], see example 29 and example 30.

Example 29

N- {2- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 1)

According to method 17b, 274 mg of the compound of example 28, the first eluting diastereomer, are chromatographically separated. The material thus obtained (123 mg) was again finely purified by preparative HPLC [ method 19 ]. This gave 92 mg of the pure title compound.

Chiral analytical HPLC [ method 18a ]]: R_t = 4.27 min。

Example 30

N- {2- (2-chlorophenyl) -2- [ (ethylsulfonyl) amino]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 2)

274 mg of the compound according to example 28 are chromatographed according to method 17b, the diastereomer eluting thereafter. The thus-obtained substance (109 mg) was again subjected to fine purification by preparative HPLC [ method 19 ]. This gave 82 mg of the pure title compound.

Chiral analytical HPLC [ method 18a ]]: R_t = 5.02 min。

Example 31

N- [2- (carbamoylamino) -2- (2-chlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Mixtures of diastereomers)

Analogously to example 25, from 118 mg (0.32 mmol) of the compound of example 8A and 94 mg (81% pure, 0.36 mmol) of the compound of example 31A 138 mg (73% of theory) of the title compound are obtained.

The 2 diastereomers can be separated by preparative HPLC on chiral phase [ method 17c ], see example 32 and example 33.

Example 32

N- [2- (carbamoylamino) -2- (2-chlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 1)

According to method 17c, 138 mg of the compound of example 31, the first eluting diastereomer, are chromatographed. The material thus obtained (31 mg) was again finely purified by preparative HPLC [ method 19 ]. This gave 21 mg of the pure title compound.

Chiral analytical HPLC [ method 18b]: R_t = 6.80 min。

Example 33

N- [2- (carbamoylamino) -2- (2-chlorophenyl) ethyl]-2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 2)

138 mg of the compound according to example 31 are chromatographed according to method 17c, the diastereomer eluting thereafter. The material thus obtained (40 mg) was again finely purified by preparative HPLC [ method 19 ]. This gave 24 mg of the pure title compound.

Chiral analytical HPLC [ method 18b]: R_t = 8.50 min。

Example 34

{2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [3- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Mixtures of diastereomers )

Analogously to example 25, from 152 mg (0.42 mmol) of the compound from example 8A and 150 mg (0.46 mmol) of tert-butyl { 2-amino-1- [3- (trifluoromethyl) phenyl ] ethyl } carbamate there are obtained 240 mg (88% of theory) of the title compound.

Example 35

N- { 2-acetylamino-2- [3- (trifluoromethyl) phenyl]Ethyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Mixtures of diastereomers)

20 μ l (0.11 mmol)N,NDiisopropylethylamine was added to a solution of 60 mg (0.10 mmol) of the compound from example 58A in 1 ml of dichloromethane. The mixture was cooled to 0 ℃, then 10 μ l (0.10 mmol) acetic anhydride was added and stirring continued at 0 ℃ for 1 h. The volatile components are then removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and subjected to preparative HPLC [ method 8]]And (5) separating. The solvent of the fractions containing the product was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 50 mg (83% of theory) of the title compound.

Example 36

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- { 2-carboxamido-2- [3- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Mixtures of diastereomers)

20 mul (112 mul)N,NDiisopropylethylamine was added to a solution of 60 mg (102 μmol) of the compound of example 58A in 1 ml THF. The mixture was cooled to 0 ℃, then 18 mg (107 μmol) of 4-nitrophenyl formate was added in portions and stirring was continued at 0 ℃ for 1 h. As a result of LC/MS analysis of the reaction mixture, it was shown thatOBy-product of the formylation, 408 μ l of 1N lithium hydroxide solution in water was added to the reaction mixture. The mixture was then continued to stir at room temperature overnight. The volatile components are then removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and subjected to preparative HPLC [ method 8]]Separation is carried out. On a rotary evaporatorThe solvent of the product-containing fractions is removed and the residue is dried under high vacuum. This gives 35 mg (59% of theory) of the title compound.

Example 37

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- {2- [ (methylsulfonyl) amino group]-2- [3- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Mixtures of diastereomers)

4 μ l (56 μmol) of methanesulfonyl chloride was added to a solution of 30 mg (51 μmol) of the compound of example 58A in 0.5 ml of pyridine, and the mixture was stirred at room temperature overnight. Since HPLC analysis indicated that a large amount of starting material remained, additional equivalents of methanesulfonyl chloride (3.1 equivalents total) were added in portions until complete reaction. Then 100 mul each of water and methanol was added. After stirring for 5 min, the reaction mixture was diluted with about 3 ml DMSO and separated by preparative HPLC [ method 8 ]. The solvent of the fractions containing the product was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 22 mg (68% of theory) of the title compound.

Example 38

N- { 2-acetylamino-2- [3- (trifluoromethyl)) Phenyl radical]Propyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 1)

At room temperature, 12 μ l (68 μmol)N,NDiisopropylethylamine, then 6 μ l (62 μmol) of acetic anhydride was added to a solution of 38 mg (62 μmol) of the compound of example 53A in 0.96 ml dichloromethane, and the mixture was stirred for 1 h. The volatile components are then removed on a rotary evaporator. Since LC/MS analysis of the crude product indicated additional formationOAcetylated by-products, the residue was dissolved in 2 ml methanol and 800 μ l of 2N aqueous sodium hydroxide solution was added. After 72 h, the mixture was acidified with 1N hydrochloric acid and subjected to preparative HPLC [ method 8]]Separation is carried out. In this step, 2 product diastereomers were obtained in isolated form. This gives 6 mg (16% of theory) of the title compound (diastereomer 1) and 7 mg (19% of theory) of the second diastereomer (cf. example 39).

Example 39

N- { 2-acetylamino-2- [3- (trifluoromethyl) phenyl]Propyl } -2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetamide (C)Diastereoisomers 2)

From the reaction of the compound of example 53A with acetic anhydride (cf. example 38), the second diastereomer (7 mg, 19% of theory) was isolated.

Example 40

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N- { 2-carboxamido-2- [3- (trifluoromethyl) phenyl]Propyl } acetamide (C)Mixtures of diastereomers)

At room temperature, 12 μ l (68 μmol)N,NDiisopropylethylamine, then 11 mg (65 μmol) of 4-nitrophenyl formate were added to a solution of 38 mg (62 μmol) of the compound of example 53A in 1 ml of THF, and the mixture was stirred at room temperature. After 1 h, 10 mg (62. mu. mol) of 4-nitrophenyl formate were added again and the reaction mixture was stirred further overnight. Due to LC/MS analysis indicating additional formationO-by-product of formylation, 248 μ l of 1N lithium hydroxide solution in water was added to the reaction mixture. After 1 h, the mixture was acidified with 1N hydrochloric acid and subjected to preparative HPLC [ method 8]]Separation is carried out. This gives 30 mg (81% of theory) of the title compound as a mixture of diastereomers.

EXAMPLE 41

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Mixtures of diastereomers)

371 mg (1.02 mmol) of the compound from example 8A, 292 mg (1.52 mmol) of EDC and 206 mg (1.52 mmol) of HOBt are stirred in 10 ml of DMF for 5 min at room temperature. The resulting solution was then added dropwise to a solution of 280 mg (90% pure, 1.02 mmol) of the compound of example 37A in 40 ml of acetonitrile. After 30 min at room temperature, the acetonitrile was removed on a rotary evaporator. 1 ml of 1M hydrochloric acid was added to the remaining solution and the mixture was separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gave 481 mg (80% of theory) of the title compound as a diastereoisomeric mixture.

The 2 diastereomers can be isolated by preparative HPLC on chiral phase [ method 15a ], see example 42 and example 43.

Example 42

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Diastereoisomers 1)

480 mg of the compound of example 41, the first eluting diastereomer, were chromatographed according to method 15 a. The material thus obtained (254 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 220 mg of pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 2.26 min。

Example 43

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Diastereoisomers 2)

480 mg of the compound of example 41 were chromatographed according to method 15a, followed by the eluted diastereomer. The material thus obtained (258 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 220 mg of pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 4.33 min。

Example 44

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [3- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Mixtures of diastereomers)

78 mg (0.21 mmol) of the compound of example 8A, 73 mg (0.26 mmol) of the compound of example 39A, 43 mg (0.26 mmol) of EDC, 36 mg (0.26 mmol) of HOBt and 56. mu.l (0.32 mmol) were mixed at room temperatureN,NDiisopropylethylamine was stirred in 2 ml DMF for 30 min. 1 ml of 1M hydrochloric acid was then added to the solution and subjected to preparative HPLC [ method 8]]The mixture is separated directly into its components. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 95 mg (75% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be isolated by preparative HPLC on chiral phase [ method 15a ], see example 45 and example 46.

Example 45

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [3- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Diastereoisomers 1)

According to method 15a, 95 mg of the compound of example 44, the first eluting diastereomer, are chromatographically separated. The material thus obtained (44 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 33 mg of pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 2.27 min。

Example 46

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [3- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Diastereoisomers 2)

The diastereomer eluted after 95 mg of the compound of example 44 was chromatographed according to method 15 a. The material thus obtained (44 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 35 mg of the pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 4.33 min。

Example 47

Carbamic acid 1- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trisFluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Ethyl ester (A), (B) to (C)Mixtures of diastereomers)

78 mg (0.21 mmol) of the compound from example 8A, 61 mg (0.32 mmol) of EDC and 46 mg (0.32 mmol) of HOBt are stirred in 2 ml of DMF for 20 min at room temperature. The resulting solution was then added dropwise to a solution of 46 mg (0.21 mmol) of the compound of example 40A in 8 ml of acetonitrile. After 30 min at room temperature, the acetonitrile was removed on a rotary evaporator. 1 ml of 1M hydrochloric acid was added to the remaining solution and the mixture was separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 59 mg (49% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be isolated by preparative HPLC on chiral phase [ method 15a ], see example 48 and example 49.

Example 48

Carbamic acid 1- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Ethyl ester (A), (B) to (C)Diastereoisomers 1)

59 mg of the compound of example 47, the first eluting diastereomer, are chromatographed according to method 15 a. The material thus obtained (28 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 22 mg of the pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 2.75 min。

Example 49

Carbamic acid 1- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Ethyl ester (A), (B) to (C)Diastereoisomers 2)

According to method 15a, 59 mg of the later eluted diastereomer of the compound of example 47 were chromatographed. The material thus obtained (30 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 19 mg of the pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 5.11 min。

Example 50

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- (2, 3-bis)Chlorophenyl) ethyl ester (Mixtures of diastereomers)

73 mg (0.20 mmol) of the compound from example 8A, 60 mg (0.24 mmol) of the compound from example 44A, 46 mg (0.24 mmol) of EDC and 34 mg (0.24 mmol) of HOBt are stirred at room temperature in 2 ml of DMF overnight. 1 ml of 1M hydrochloric acid was then added to this solution and the mixture was separated directly into its components by preparative HPLC [ method 8 ]. The solvent of the product fractions was removed on a rotary evaporator and the residue was dried under high vacuum. This gives 100 mg (83% of theory) of the title compound as a mixture of diastereomers.

The 2 diastereomers can be isolated by preparative HPLC on chiral phase [ method 15a ], see example 51 and example 52.

Example 51

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- (2, 3-dichlorophenyl) ethyl ester(s) (iii)Diastereoisomers 1)

100 mg of the compound of example 50, the first eluting diastereomer, are chromatographed according to method 15 a. The material thus obtained (47 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 32 mg of the pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 3.20 min。

Example 52

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- (2, 3-dichlorophenyl) ethyl ester(s) (iii)Diastereoisomers 2)

100 mg of the compound of example 50 were chromatographed according to method 15a, followed by the eluted diastereomer. The material thus obtained (50 mg) was again finely purified by preparative HPLC [ method 8 ]. This gave 39 mg of the pure title compound.

Chiral analytical HPLC [ method 16 ]]: R_t = 6.05 min。

Example 53

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N-{(2R) -1-hydroxy-3- [3- (trifluoromethyl) phenyl]Propan-2-yl acetamide

48 mu l ofN,NDiisopropylethylamine was added to a mixture of 50 mg (137. mu. mol) of the compound of example 8A, 42 mg (164. mu. mol) of the compound of example 45A, 39 mg (205. mu. mol) EDC and 28 mg (205. mu. mol) HOBt in 1.36 ml DMF. The resulting mixture was stirred at room temperature overnight and then subjected to preparative HPLC [ method 9]]Directly separated into its components. This gives 61 mg (79% of theory) of the title compound.

Example 54

2- {3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl-N-{(2S) -1-hydroxy-3- [3- (trifluoromethyl) phenyl]Propan-2-yl acetamide

In analogy to example 53, 53 mg (68% of theory) of the title compound were obtained from 50 mg (137 μmol) of the compound of example 8A and 42 mg (164 μmol) of the compound of example 46A.

Example 55

Carbamic acid- (2)R) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } ethaneAcyl) amino]-3- [3- (trifluoromethyl) phenyl]Propyl ester

37 mul (210 mul mol)N,NDiisopropylethylamine was added to a mixture of 38 mg (105 μmol) of the compound of example 8A, 42 mg (115 μmol) of the compound of example 47A, 28 mg (147 μmol) EDC and 21 mg (147 μmol) HOBt in 1.39 ml DMF. The resulting mixture was stirred at room temperature for 2 h, then 1 ml of 1M hydrochloric acid was added and prepared by preparative HPLC [ method 9]]The mixture is separated directly into its components. This gives 61 mg (79% of theory) of the title compound.

Example 56

Carbamic acid- (2)S) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (2)S) -3,3, 3-trifluoro-2-hydroxypropyl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-3- [3- (trifluoromethyl) phenyl]Propyl ester

67 μ l (383 μmol)N,NDiisopropylethylamine was added to a mixture of 70 mg (191 μmol) of the compound of example 8A, 79 mg (264 μmol) of the compound of example 48A, 44 mg (230 μmol) EDC and 33 mg (230 μmol) HOBt in 3 ml DMF. The resulting mixture was stirred at room temperature overnight, then 1 ml 1M hydrochloric acid was added and prepared by preparative HPLC [ method 9]]The mixture is separated directly into its components. This gives 64 mg (55% of theory) of the title compound.

Example 57

Carbamic acid 1- (2-chlorophenyl) -2- ({ [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl amino ethyl esterRacemic modification)

66 mg (182 μmol) [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1 ] was added at room temperatureH-1,2, 4-triazol-1-yl]Acetic acid [ for preparation see example 156A in WO 2007/134862]47 mg (219 μmol) of the compound of example 40A, 42 mg (219 μmol) EDC and 35 mg (219 μmol) HOBt in 4 ml DMF were stirred overnight, then 1 ml 1M hydrochloric acid was added and purified by preparative HPLC [ method 23 [ ]]The mixture is separated directly into its components. This gives 64 mg (63% of theory) of the title compound.

Example 58

Carbamic acid 1- (2-chlorophenyl) -2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1)E) -3,3, 3-trifluoroprop-1-en-1-yl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Ethyl ester (A), (B) to (C)Racemic modification)

A mixture of 128 mg (369 μmol) of the compound of example 33A, 95 mg (443 μmol) of the compound of example 40A, 85 mg (443 μmol) EDC and 71 mg (443 μmol) HOBt in 4 ml DMF was stirred overnight at room temperature, then 1 ml 1M hydrochloric acid was added and the mixture was directly separated into its components by preparative HPLC [ method 23 ]. This gives 130 mg (65% of theory) of the title compound.

Example 59

Carbamic acid 1- (2-chlorophenyl) -2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl amino ethyl esterRacemic modification)

A solution of 50 mg (92. mu. mol) of the compound of example 58 in 20 ml of methanol was hydrogenated in a continuous flow hydrogenation apparatus (H-Cube, Model HC-2-SS from Budapest Thales Nano) equipped with a 5% Pt/C cartridge at a flow rate of 1 ml/min, a temperature of 60 ℃ and under standard pressure. After the reaction had ended, the methanol of the solution was removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 23 ]. This gives 22 mg (44% of theory) of the title compound.

Example 60

Carbamic acid 2- ({ [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl } amino) -1- [2- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Racemic modification)

40 mg (111. mu. mol) [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1 ] are added at room temperatureH-1,2, 4-triazol-1-yl]Acetic acid [ for preparation see example 156A in WO 2007/134862]A mixture of 33 mg (133. mu. mol) of the compound of example 37A, 25 mg (133. mu. mol) EDC and 21 mg (133. mu. mol) HOBt in 2.4 ml DMF was stirred overnight, then 1 ml 1M hydrochloric acid was added and purified by preparative HPLC [ method 20]The mixture is separated directly into its components. This gives 53 mg (81% of theory) of the title compound.

Example 61

Carbamic acid 2- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1)E) -3,3, 3-trifluoroprop-1-en-1-yl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]-1- [2- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Racemic modification)

A mixture of 39 mg (111 μmol) of the compound of example 33A, 33 mg (133 μmol) of the compound of example 37A, 25 mg (133 μmol) EDC and 21 mg (133 μmol) HOBt in 1.2 ml DMF was stirred overnight at room temperature, then 1 ml 1M hydrochloric acid was added and the mixture was directly separated into its components by preparative HPLC [ method 20 ]. This gives 52 mg (81% of theory) of the title compound.

Example 62

Carbamic acid 2- ({ [3- (4-chlorophenyl) -5-oxo-4- (3,3, 3-trifluoropropyl) -4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl } amino) -1- [2- (trifluoromethyl) phenyl]Ethyl ester (A), (B) to (C)Racemic modification)

A solution of 30 mg (52. mu. mol) of the compound of example 61 in 15 ml of methanol was hydrogenated in a continuous flow hydrogenation apparatus (H-Cube, Model HC-2-SS from Budapest Thales Nano) equipped with a 5% Pt/C cartridge at a flow rate of 1 ml/min, a temperature of 60 ℃ and under standard pressure. After the reaction had ended, the methanol of the solution was removed on a rotary evaporator and the residue was purified by preparative HPLC [ method 23 ]. This gives 15 mg (50% of theory) of the title compound.

Example 63

Carbamic acid 2- (2-chlorophenyl) -3- [ ({3- (4-chlorophenyl) -5-oxo-4- [ (1)E) -3,3, 3-trifluoroprop-1-en-1-yl]-4, 5-dihydro-1H-1,2, 4-triazol-1-yl } acetyl) amino]Propyl ester (C)Racemic modification)

A mixture of 47 mg (135 μmol) of the compound of example 33A, 34 mg (176 μmol) EDC and 24 mg (176 μmol) HOBt in 1 ml DMF was stirred at room temperature for 1 h, then 34 mg (149 μmol) of the compound of example 15A was added. The mixture was stirred at room temperature for 16 h and then separated directly into its components by preparative HPLC [ method 9 ]. This gives 28 mg (37% of theory) of the title compound.

Example 64

Carbamic acid 2- (2-chlorophenyl) -3- ({ [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl amino propyl esterRacemic modification)

In analogy to the procedure of example 63, 49 mg (135. mu. mol) [3- (4-chlorophenyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetic acid [ for preparation see example 156A in WO 2007/134862]Reacted with 34 mg (149. mu. mol) of the compound of example 15A. This gives 27 mg (35% of theory) of the title compound.

Example 65

{2- ({ [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl } amino) -1- [2- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Racemic modification)

In analogy to the procedure of example 63, 43 mg (146. mu. mol) [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetic acid [ for preparation see example 88A in WO 2007/134862]And 49 mg (161. mu. mol) { 2-amino-1- [2- (trifluoromethyl) phenyl ]]Ethyl } carbamic acid tert-butyl ester. This gives 59 mg (69% of theory) of the title compound.

Example 66

{2- ({ [3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl } amino) -1- [2- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Racemic modification)

In analogy to the procedure of example 63, 47 mg (146 μmol) of the compound of example 52A were reacted with 49 mg (161 μmol) of tert-butyl { 2-amino-1- [2- (trifluoromethyl) phenyl ] ethyl } carbamate. This gives 60 mg (68% of theory) of the title compound.

Example 67

{2- ({ [3- (5-chloro-2-thienyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetyl } amino) -1- [2- (trifluoromethyl) phenyl]Ethyl } carbamic acid tert-butyl ester(s) (iii)Racemic modification)

In analogy to the procedure of example 63, 54 mg (146. mu. mol) [3- (5-chloro-2-thienyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]Acetic acid [ for preparation, see example 154A in WO 2007/134862]And 49 mg (161. mu. mol) { 2-amino-1- [2- (trifluoromethyl) phenyl ]]Ethyl carbamate is reacted with tert-butyl. This gives 64 mg (67% of theory) of the title compound.

Example 68

2- [3- (4-chlorophenyl) -4-cyclopropyl-5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]-N- {2- [ (methylsulfonyl) amino group]-2- [2- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Racemic modification)

4.1 μ l methanesulfonyl chloride was added to a solution of 29 mg (48 μmol) of the compound of example 59A in 0.5 ml pyridine at room temperature. The mixture was stirred at room temperature for 1 h and 4.1 μ l methanesulfonyl chloride was added again. The mixture was stirred at room temperature for an additional 18 h, and then an additional 12.3 μ l of methanesulfonyl chloride (total 265 μmol, 5.5 equivalents) was added over a period of 3 h. After 1 h, the volatile components are removed on a rotary evaporator. The residue was dissolved in a small amount of DMSO and purified by preparative HPLC [ method 9 ]. This gives 17 mg (65% of theory) of the title compound.

Example 69

2- [3- (5-chloro-2-thienyl) -4- (2-methoxyethyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]-N- {2- [ (methylsulfonyl) amino group]-2- [2- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Racemic modification)

In analogy to the procedure of example 68, 29 mg (46 μmol) of the compound of example 60A were reacted with methanesulfonyl chloride. This gives 25 mg (92% of theory) of the title compound.

Example 70

2- [3- (5-chloro-2-thienyl) -4- (2-fluorobenzyl) -5-oxo-4, 5-dihydro-1H-1,2, 4-triazol-1-yl]-N- {2- [ (methylsulfonyl) amino group]-2- [2- (trifluoromethyl) phenyl]Ethyl } acetamide (C)Racemic modification)

In analogy to the procedure of example 68, 35 mg (52 μmol) of the compound of example 61A was reacted with methanesulfonyl chloride. This gives 14 mg (41% of theory) of the title compound.

B. Evaluation of pharmacological Activity

The pharmacological effects of the compounds according to the invention can be demonstrated in the following tests:

abbreviations:

EDTA ethylene diamine tetraacetic acid

DMEM Dulbecco's modified Eagle Medium

FCS fetal calf serum

HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

SmGM smooth muscle cell growth medium

Tris-HCl 2-amino-2- (hydroxymethyl) -1, 3-propanediol hydrochloride.

Cell in vitro assay for determining the activity of the vasopressin receptor

The identification of agonists and antagonists of the V1 a-and V2-vasopressin receptors in humans and in rats, as well as the quantification of the activity of the compounds according to the invention, is carried out with the aid of recombinant cell lines. These cells were originally derived from hamster ovary epithelial cells (Chinese hamster ovary, CHO K1, ATCC: American type culture Collection, Manassas, VA 20108, USA). The experimental cell line deterministically expresses a modified form of the calcium sensitive photoprotein aequorinUpon reconstitution with Coelenterazine (Coelenterazine), light was emitted as the concentration of free calcium increased [ RizzutoR, Simpson AW, Brini M, Pozzan T,Nature 358, 325-327 (1992)]. In addition, the cells were stably transfected with human or rat V1 a-or V2-receptors. In the case of a Gs-coupled V2-receptor, the cell is stably transfected with another gene encoding a heterologous G, either independently or as a fusion gene_α ₁₆Proteins [ Amatruda TT, Steele DA, Slepak VZ, Simon MI,Proceedings in the National Academy of Science USA 88, 5587-5591 (1991)]. The resulting experimental cells of vasopressin receptors respond to stimulation by recombinantly expressed vasopressin receptors by intracellular release of calcium ions, which can be quantified by luminescence of the resulting aequorin using a suitable luminometer [ Milligan G, Marshall F, Rees S,Trends in Pharmacological Sciences 17, 235-237 (1996)]。

the experimental process comprises the following steps:

1 day before the assay, the cells were plated in 384-well microtiter plates in medium (DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES) and kept in a cell culture chamber (96% air humidity, 5% v/v CO)₂37 ℃ C.). On the day of the experiment, the test was carried out by Tyrode solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl)₂、2 mM CaCl₂20 mM glucose, 20 mM HEPES) and the Tyrode solution additionally contains the cofactor coelenterazine (50 μm), and then incubating the microtiter plate for an additional 3-4 hours. The assay was placed in the wells of a microtiter plate at various concentrations for 10-20 minutes, followed by addition of the agonist [ Arg ]⁸]Vasopressin and the resulting light signal is immediately measured in a photometer. IC was calculated using the computer program GraphPad PRISM (version 3.02)₅₀The value is obtained.

The following table shows representative IC's of the compounds according to the invention for cell lines transfected with the human V1 a-or V2-receptor₅₀The value:

watch (A)

Cell in vitro assay for the modulation of the profibrotic Gene by vasopressin V1a receptor antagonists

Cell line H9C2, which was isolated from rat heart tissue and described as a cardiomyocyte type (American type culture Collection ATCC No. CRL-1446), endogenously expressed vasopressin V1A receptor AVPR1A at high copy number, whereas AVPR2 expression could not be detected. Cellular assays for AVPR1A receptor-dependent modulation of gene expression by receptor antagonist inhibition were performed as follows:

in a 12-well microtiter plate for cell culture, H9C2 cells were seeded with a cell density of 100000 cells/well in 1.0 ml Opti-MEM medium (Invitrogen Corp., Carlsbad CA, USA, catalog # 11058-. After 24 hours, 3 wells per group (in triplicate) were added vehicle solution (negative control), vasopressin solution ([ Arg ] s)⁸]Vasopressin acetate, Sigma, catalogue No. V9879) or experimental material (dissolved in aqueous vehicle solution containing 20% by volume of ethanol) and vasopressin solution. In cell culture, the final vasopressin concentration was 0.05. mu.M. The test substance solution is added to the cell culture in such small volumes that a final ethanol concentration of 0.1% is not exceeded in the cell assay. After an incubation time of 6 hours, culture supernatant was aspirated, adherent cells were lysed in 250 μ l RLT buffer (Qiagen, Ratingen, cat # 79216), and RNA was isolated from the lysate using RNeasy kit (Qiagen, cat # 74104). This was followed by DNase digestion (Invitrogen, Cat. No. 18068-015), cDNA synthesis (ImProm-II Reverse Transcription System, Promega, Cat. No. A3800) and RTPCR (pPCR standard mix RT-QP2X-03-075 from Eurogentec, Seraing, Belgium). According toManufacturer's protocol for experimental reagents, all manipulations were performed. The Primer set for the RTPCR was selected by means of the program Primer3Plus, using 6-FAM TAMRA-labeled probes, based on the mRNA gene sequence (NCBI Genbank Entrez nucleotide database). RTPCR for determining relative mRNA expression in cells of different test batches was performed in a 96-well-or 384-well microtiter plate format using an Applied Biosystems ABI Prism 7700 sequence detector according to the instrument instructions. Reference to the expression intensity of ribosomal protein L-32 (Genbank accession NM-013226) and Ct threshold with Ct = 35, using delta-delta Ct value [ Applied Biosystems, user bulletin No. 2, ABI Prism 7700 SDS, 1997, 12/11 (10/2001 updated)]Indicates relative gene expression.

B-3. in vivo assay for cardiovascular efficacy: blood pressure measurement in anesthetized rats (vasopressin)'challenge'Model)

Ketamine/xylazine/pentobarbital injection anesthesia was performed, male Sprague-Dawley rats (250-350 g body weight) were fitted with polyethylene tubes (PE-50; Intramedic) preloaded with isotonic sodium chloride solution containing heparin (500 I.E./ml) into the jugular and femoral veins, and then fixed. Injecting Arg-vasopressin via a venous access with a syringe; the test substance is administered via a second intravenous access. To measure systolic blood pressure, a pressure catheter (Millar SPR-3202F) was fixed in the carotid artery. The arterial catheter is connected to a baroreceptor which transmits its signal to a measurement computer equipped with suitable recording software. In a typical experiment, 3-4 consecutive bolus injections containing a defined amount of Arg-vasopressin (30 ng/kg) in isotonic sodium chloride solution were administered to the experimental animals at intervals of 10-15 min, and when the blood pressure again reached the initial value, the experimental substance was administered as a bolus injection in a suitable solvent, followed by continuous infusion. Thereafter, at defined intervals (10-15 min), the same amount of Arg-vasopressin as the beginning was administered again. Based on the blood pressure values, the extent to which the test substance counteracts the blood pressure-raising effect of Arg-vasopressin was determined. Control animals received only solvent instead of experimental.

After intravenous administration, the compound according to the present invention acts to inhibit the increase in blood pressure caused by Arg-vasopressin, compared to the solvent control.

B-4. in vivo assay for cardiovascular efficacy: diuresis study in metabolism cages on conscious rats

Wistar rats (300-. During the experiment, animals were individually maintained free access to drinking water for 4-8 hours in metabolic cages suitable for this weight class of rats (Techniplast Deutschland GmbH, D-82383 Hohenpei beta. enberg). At the start of the experiment, the substance to be detected is administered into the stomach of the animal by means of gavage in a suitable solvent volume of 1-3 ml/kg body weight. Control animals received solvent only. On the same day, control and experimental experiments were performed in parallel. The control group and the substance dose group each consisted of 4-8 animals. During the experiment, urine excreted by the animals was continuously collected in a receiver located at the bottom of the cage. The urine volume per unit time was determined separately for each animal, and the concentration of sodium-and potassium ions excreted in the urine was measured by a standard method of flame photometry. To obtain a sufficient urine volume, a determined amount of water (typically 10 ml/kg body weight) is administered to the animals by gavage at the beginning of the experiment. The body weight of each animal was measured before the start of the experiment and after the end of the experiment.

After oral administration, the compounds according to the invention lead to an increase in urinary excretion, based mainly on increased water excretion (diuresis), compared to solvent control administration.

B-5. in vivo assay for cardiovascular efficacy: hemodynamic Studies on anesthetized dogs

Male or female hybrid dogs (Mongrels, Marshall BioResources, USA) weighing between 20-30 kg were anesthetized with pentobarbital (30 mg/kg intravenous, Narcoren, Merial, Germany), respectively, for surgical and hemodynamic and functional research purposes. Acrochloride (3 mg/animal, intravenous, Alloferin ®, ICN Pharmaceuticals, Germany) was additionally used here as muscle relaxant. The dogs were intubated and ventilated with an oxygen/ambient air mixture (40/60%, approximately 5-6L/min). Ventilation was performed using a ventilator from Draeger (Sulla 808) and monitoring was performed using a carbon dioxide analyzer (ensstr m). Anaesthesia was maintained by continuous infusion of pentobarbital (50 mug/kg/min); fentanyl was used as analgesic (10 μ g/kg/h). An alternative to pentobarbital is the use of isoflurane (1-2 vol%).

In a preparatory intervention, the dog was fitted with a cardiac pacemaker. At a time 21 days prior to the first drug trial (= start of experiment), cardiac pacemakers (Biotronik, gloos) were implanted in subcutaneous skin capsules and connected to the heart via pacemaker electrodes extending through the external jugular vein into the right ventricle.

Injury to the mitral valve was determined under cardiography and fluoroscopy monitoring by retrograde movement of a cannula inserter (Avanti +; Cordis) in the femoral artery with 7F biopsy forceps (Cordis) and after non-invasive penetration through the aortic valve, while the pacemaker was implanted. Thereafter, all the ports were removed and the dog was naturally awake from anesthesia. After another 7 days (= 14 days before the first drug trial), the pacemaker as described above was activated and the heart was stimulated at a rate of 220 beats/min.

At 14 and 28 days after the start of pacemaker stimulation, actual drug testing experiments were started using the following instruments:

● inserting a bladder catheter for bladder relief and for measuring urine flow;

● connecting Electrocardiogram (EKG) leads to the extremities for EKG measurements;

● FluidMedic containing sodium chloride solution^®The PE-300 tube was inserted into the femoral artery, the tube was connected to baroreceptors (Braun Melsungen, germany) for measuring systemic blood pressure;

● A Millar Tip catheter (model 350 PC, Millar Instruments, Houston, USA) was inserted through the left atrium or through a port fitted in the carotid artery for measurement of cardiac hemodynamics

● Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine, USA) was inserted into the pulmonary artery via the jugular vein for measurement of cardiac output, oxygen saturation, pulmonary artery pressure and central venous pressure

● placing an intravenous catheter in the cephalic vein for infusion of pentobarbital, for fluid replacement and for blood sampling (for determining plasma levels or other clinical blood values of substances)

● placing an intravenous catheter into the saphenous vein for fentanyl infusion and for administering substances

● vasopressin (Sigma) was infused in increasing doses until a dose of 4 mU/kg/min. The pharmacological substance is then tested at this dose.

The primary signal is amplified if necessary (Gould amplifiers, Gould Instrument Systems, Valley View, USA or Edwards-Visilance-Monitor, Edwards, Irvine, USA) and subsequently fed to the Ponemah system (DataSciences Inc, Minneapolis, USA) for evaluation. The signals were recorded continuously throughout the experimental period and further processed digitally by the software, taking an average over 30 seconds.

C. Examples of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations in the following manner:

and (3) tablet preparation:

consists of the following components:

100 mg of a compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany), and 2 mg of magnesium stearate.

The tablet had a weight of 212 mg, a diameter of 8 mm and a radius of curvature of 12 mm.

Production:

the mixture of compound according to the invention, lactose and starch was granulated using a 5% solution of PVP in water (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture is compressed with a conventional tablet press (see above for tablet forms). The standard value for pressing used a pressure of 15 kN.

Suspension that can be administered orally:

consists of the following components:

1000 mg of a compound according to the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ® xanthan gum from FMC, Pennsylvania, USA), and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of a compound according to the invention.

Production:

rhodigel is suspended in ethanol and the compound according to the invention is added to the suspension. Water was added with stirring. The mixture was stirred for about 6 h until the swelling of the Rhodigel was complete.

Solutions that can be administered orally:

consists of the following components:

500 mg of a compound according to the invention, 2.5 g of polysorbate, and 97 g of polyethylene glycol 400. 20 g of oral liquid correspond to a single dose of 100 mg of the compound according to the invention.

Production:

the compound according to the invention is suspended in a mixture of polyethylene glycol and polysorbate under stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

Intravenous solution:

the compounds according to the invention are dissolved at a concentration below the saturation solubility in physiologically tolerated solvents (e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution). The solution was sterile filtered by filtration and filled into sterile and pyrogen-free injection containers.

Claims

1. A compound of formula (I) and salts, solvates and solvates of said salts

Wherein

R¹Is represented by (C)₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl or (C)₂-C₆) Alkynyl, each of which may be the same or different, and is selected from the following residuesMono-or di-substitution: fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, oxo, hydroxy, difluoromethoxy, trifluoromethoxy, (C)₁-C₄) -alkoxy, (C)₃-C₆) -a cycloalkyl group and a phenyl group,

And is

or

Is represented by (C)₃-C₆) -cycloalkyl, which may be mono-or disubstituted by identical or different residues selected from: fluorine, trifluoromethyl and (C)₁-C₄) -alkyl, oxo, hydroxy, trifluoromethoxy and (C)₁-C₄) -an alkoxy group,

and is

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0, 1 or 2,

R⁴represents hydrogen or a methyl group,

R^7AAnd R^7BIndependently of one another, represents hydrogen, (C)₁-C₆) -alkyl or (C)₃-C₆) -cycloalkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring which may contain another heteroatom in the ring selected from N, O or S, and which may be mono-or di-substituted by the same or different residues selected from: fluorine, trifluoromethyl and (C)₁-C₄) -alkyl, hydroxy and oxo,

R⁸represents hydrogen or (C)₁-C₄) -an alkyl group,

and is

R⁶Having R as given above⁵Or represents hydroxy.

2. A compound of formula (I) as claimed in claim 1 and salts, solvates and solvates of said salts, wherein

or

Represents a cyclopropyl group, and the like,

R^3Crepresents hydrogen, and is selected from the group consisting of,

and is

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0 or 1 and,

and is

R^7BRepresents hydrogen or (C)₁-C₄) -an alkyl group,

R⁹represents hydrogen or (C)₁-C₄) -an alkyl group,

and is

R¹⁰Is represented by (C)₁-C₄) -an alkyl group.

3. A compound of formula (I) as claimed in claim 1 or 2 and salts, solvates and solvates of said salts, wherein

R^3Crepresents hydrogen, and is selected from the group consisting of,

and is

L represents a group of formula:

represents the point of attachment to the adjacent nitrogen atom

And is

Represents the point of attachment to the phenyl ring,

n represents the number 0 or 1 and,

and is

R¹⁰Represents methyl or ethyl.

4. Process for the preparation of a compound of formula (I) as defined in claims 1 to 3,

coupling a compound of formula (II) with a compound of formula (III) in an inert solvent with activation of the carboxylic acid function

Wherein R is¹And R²Having the meanings given in claims 1 to 3,

l, R therein^3A、R^3BAnd R^3CHaving the meanings given in claims 1 to 3,

and optionally separating the compounds of formula (I) thus obtained into their enantiomers and/or diastereomers, and/or converting them into their solvates, salts and/or solvates of said salts with a suitable (I) solvent and/or (ii) base or acid.

5. A compound of formula (I) as defined in any one of claims 1 to 3 for use in the treatment and/or prevention of a disease.

6. A compound of formula (I) as defined in any one of claims 1 to 3 for use in a method for the treatment and/or prophylaxis of acute and chronic heart failure, hypervolemic and normovolemic hyponatremia, cirrhosis of the liver, ascites, oedema and syndrome of dysregulation of the antidiuretic hormone (SIADH).

7. The use of a compound of formula (I) as defined in any one of claims 1 to 3 for the preparation of medicaments for the treatment and/or prophylaxis of acute and chronic heart failure, hypervolemic and normovolemic hyponatremia, cirrhosis, ascites, oedema and syndrome of antidiuretic hormone secretion disorder (SIADH).

8. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 3 in combination with one or more inert, non-toxic pharmaceutically suitable auxiliaries.

9. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 3 in combination with one or more further active substances selected from: diuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors and active substances that enhance contractility.

10. The medicament according to claim 8 or 9 for the treatment and/or prevention of acute and chronic heart failure, hypervolemic and normovolemic hyponatremia, cirrhosis, ascites, oedema and the syndrome of antidiuretic hormone Secretion (SIADH).