HK1193602B - Oxy-cyclohexyl-4h,6h-5-oxa-2,3,10b-triaza-benzo[e]azulenes as v1a antagonists - Google Patents

Description

oxy-cyclohexyl-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulenes as V1a antagonists

The present invention provides 4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulenes, which are useful as Vla receptor modulators, and in particular as Vla receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The compounds of the invention are useful as therapeutic agents acting both peripherally and centrally in the following conditions: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.

Technical Field

The present invention provides a compound of formula I,

wherein the substituents and variables are as described below and in the claims, or pharmaceutically acceptable salts thereof.

The compounds of the invention are Vla receptor antagonists which are useful in the treatment of depression.

Background

Vasopressin is a 9 amino acid peptide that is produced mainly by the paraventricular nucleus of the hypothalamus. In the periphery, vasopressin acts as a neurohormone and stimulates vasoconstriction, glycogenolysis and antidiuresis.

Three vasopressin receptors are known, all of which belong to the class I G-protein coupled receptors. The Vla receptor is expressed in brain, liver, vascular smooth muscle, lung, uterus and testis, the Vlb or V3 receptor is expressed in brain and pituitary, the V2 receptor is expressed in kidney, where it regulates water reabsorption and mediates the antidiuretic action of vasopressin (Robben et al (2006), Amjphysiol RenalPhysiol.291, F257-70, "Cellbiogica spectorfthevasopressin-2 receptor and daquaponin 2 Watermannelinnen diagnostically encapsulating species"). Thus, compounds active at the V2 receptor may cause side effects on blood homeostasis.

Oxytocin receptors are involved in the vasopressin receptor family and mediate the role of the neurohormone oxytocin in the brain and periphery. Oxytocin is believed to have a central anxiolytic effect (Neumann (2008), JNeuroendocrinol.20, 858-65, "Brainoxyocin: anereglato of exotionand coccalebais of human being healthcare with human being and human being). Central oxytocin receptor antagonism may therefore lead to anxiogenic effects, which are considered to be undesirable side effects.

In the brain, vasopressin acts as a neuromodulator and is elevated in the tonsils during stress (Ebner et al (2002), EurJNeurosci.15, 384-8, "forcedswimmingtriggersversopressin expression with intrinsic molecular dynamics"). It is known that stressful life events can cause major depression and anxiety (Kendler et al (2003), ArchGenpsychiatry.60, 789-96, "Life EventTimentionssof Loss, Humiliation, Entrap, and Dangerin the predictionof Onsetsof major Depression and GeneralizeddAnxitence") and that both have very high complex lesions, with anxiety often preceding major depression (Regier et al (1998), BrPsychiatry Suppl.24-8, "prevalence of anxiety disorders and great sympathology of major depression and anxiety disorders"). Vla receptors are widely expressed in the brain and especially in the limbic regions such as the tonsils, lateral spaces and hippocampus, where they play an important role in regulating anxiety. In fact, Vla knockout mice show reduced anxiety behavior in the plus maze, open field, and light and dark boxes (Bielsky et al (2004), neuropsychopharmacology.29, 483-93, "Profundamentmanagementassociated reduction efficacy-likebehavorinnvasepression Vlareceptoutment"). Downregulation of Vla receptors by antisense oligonucleotide injection in the septum also causes a reduction in anxiety behavior (landgrafgraff et al (1995), regulpept.59, 229-39, "V1 vasopressin receptor oligodynamics associated with anxiety binding, social crismationin abilities, and anddanxiety-related anxiety"). Vasopressin or Vla receptors are also involved in other neuropsychological diseases: genetic studies have recently linked sequence polymorphisms in the promoter of the human Vla receptor to autism spectrum disorders (Yirmiya et al (2006), 11, 488-94, "Association between genetic and systemic expression analyzer (AVPRla)), intranasal administration of vasopressin was shown to affect the aggressiveness of human males (Thompson et al (2004), Psychoeurocorinology.29, 35-48," infection of human male responsiveness and vascular hypertension syndrome "), and elevated levels of vasopressin were found in schizophrenic patients (Raskind et al (1987), Biolzyme et al (22, 22-62," antibiotic therapy, "infection of human male relationship) and patients suffering from autism spectrum (Alicyclothymic analysis"), and patients suffering from autism spectrum disorder (Alirnonia-20), Adhesis spectrum disorder (Alirnisation et al (Alirmiana et al, Psidium fractogenes), and Adhesis strain infection.

The Vla receptor also mediates the cardiovascular effects of vasopressin in the brain by centrally modulating blood pressure and heart rate in the solitary nucleus (Michelini and Morris (1999), AnnNYAcadSci.897, 198-211, "endogenesis vastus modestus cardiac vasopression restonaceae"). In the periphery, it induces contraction of vascular smooth muscle and chronic inhibition of the Vla receptor improves the hemodynamic parameters in myocardial infarcted rats (VanKerckhoven et al (2002), eurjpharmacol.449, 135-41, "chronovasopressin v (1A) butnotV (2) rectonantronisma depressor shearthictureincarcalinfatdrates"). Therefore, Vla antagonists with improved penetration through the blood-brain barrier are expected to be advantageous.

Vasopressin Vla receptor antagonists have been shown to be effective in reducing dysmenorrhea in the clinic (Brouard et al (2000), bjog.107, 614-9, "EffectofSR 49059, anorallyactivevlavassopressin receptor agonist, inlanderitionation of dyssenorrhea"). Vla receptor antagonism has also been implicated in the treatment of female sexual dysfunction (Aughton et al (2008), BrJPharmacol. doi: 10.1038/bjp.2008.253, "Pharmacological profiling of neuropepetide in plunger tissue in vivo"). In a recent study, Vla receptor antagonists have been shown to have a therapeutic effect in erectile dysfunction and premature ejaculation (Gupta et al (2008), brjpharmacol.155, 118-26, "oxyglobin-induced linkage switching and abortive jaculation of tissue and liver disorders v (1A) receptors and nonoxyytococci").

Detailed Description

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the therapeutic and/or prophylactic treatment of diseases and conditions associated with the modulation of, and in particular antagonism of, Vla receptors. It is a further object of the present invention to provide selective inhibitors of the Vla receptor, as selectivity for the Vla receptor is expected to provide a low likelihood of causing undesirable off-target related side effects as discussed above.

The compounds of the invention are useful as therapeutic agents acting both peripherally and centrally in the following conditions: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior. Specific indications for the present invention are the treatment of anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.

The following definitions of general terms as used in the present specification apply irrespective of whether the term in question appears alone or in combination with other groups.

The term "C_1-6-alkyl ", alone or in combination with other groups, represents a branched hydrocarbon group which may be linear or with single or multiple branches, wherein the alkyl group generally comprises from 1 to 6 carbon atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, isobutyl (i-butyl), 2-butyl (sec-butyl), tert-butyl (tert-butyl), isopentyl, 2-ethyl-propyl, 1, 2-dimethyl-propyl, etc. In particular "C_1-6Alkyl "has 1 to 4 carbon atoms. Specific groups are isopropyl and sec-butyl.

The term "halogen-C_1-6-alkyl ", alone or in combination with other groups, means substituted by one or more halogens, in particular 1 to 5 halogens, more particularly 1 to 3 halogens (" halogen-C)_1-3-alkyl "), in particular 1 halogen or 3 halogen substituted C as defined herein_1-6-an alkyl group. A particular halogen is fluorine. Particular "halogen-C_1-6-alkyl "is fluoro-C_1-6-an alkyl group.

The term "hydroxy-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein substituted by one or more-OH, in particular 1-2-OH, more particularly 1-OH_1-6-an alkyl group.

The term "C_1-6-alkoxy-C_1-6-alkyl ", alone or in combination with other groups, refers to one or more C as defined herein_1-6Alkoxy, especially 1-2C_1-6Alkoxy, more particularly 1C_1-6-alkoxy substituted C as defined herein_1-6-an alkyl group.

The term "cyano", alone or in combination with other groups, refers to N tri C- (NC-).

The term "hydroxy", alone or in combination with other groups, refers to-OH.

The term "halogen", alone or in combination with other groups, denotes chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). Particular "halogens" are Cl and F. In particular Cl.

The term "aryl", alone or in combination with other groups, refers to an aromatic carbocyclic group containing from 6 to 14, especially from 6 to 10, carbon atoms and having at least one aromatic ring or multiple fused rings wherein at least one ring is aromatic. Examples of "aryl" groups include benzyl, biphenyl, indanyl, naphthyl, phenyl (Ph), and the like. A particular "aryl" group is phenyl.

The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group having a single 4 to 8 membered ring or multiple condensed rings containing 6 to 14, especially 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms independently selected from N, O and S, especially N and O, in which group at least one heterocyclic ring is aromatic. Examples of "heteroaryl" groups include benzofuranyl, benzimidazolyl, 1H-benzimidazolyl, benzoAzinyl radical, benzoOxazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolyl, isothiazolylThe group of azolyl groups,azolyl, pyrazinyl, pyrazolyl (pyrazinyl), 1H-pyrazolyl, pyrazolo [1, 5-a ]]Pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6, 7-dihydro-5H- [1]Azoindenyl, and the like. Particular "heteroaryl" groups are pyridyl and pyrazinyl, especially pyridin-2-yl and pyrazin-2-yl.

The term "C_1-6-alkoxy ", alone or in combination with other groups, signifies-O-C which may be linear or branched, with a single or multiple branching_1-6An alkyl group, wherein the alkyl group typically contains 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (isobutoxy), 2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy), and the like. In particular "C_1-6The alkoxy radical having from 1 to 4 carbon atoms ("C)_1-4-alkoxy ").

The term "halogen-C_1-6-alkoxy ", alone or in combination with other groups, means C as defined herein substituted by one or more halogens, in particular fluorine_1-6-alkoxy groups. Particular "halogen-C_1-6The radical-alkoxy "being fluoro-C_1-6-alkoxy groups.

The term "C_3-7-Cycloalkyl "refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 6 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. In particular C_3-6-Cycloalkyl groups are monocyclic. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. An example for bicycloalkyl is bicyclo [2.2.1]Heptyl or bicyclo [2.2.2]And (4) octyl. "C_3-7-A particular example of a cycloalkyl "group is cyclopropyl.

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but not limited to, acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. In particular hydrochloric acid, trifluoroacetic acid and fumaric acid.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. In particular, it encompasses products comprising one or more active ingredients and optionally a carrier (including inert ingredients), as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The term "half maximal inhibitory concentration" (IC)_s0) Represents the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted to pIC₅₀Value (-logIC)₅₀) Where higher values indicate greater efficacy of the exponential law. IC (integrated circuit)₅₀The value is not an absolute value but depends on the experimental conditions used, such as concentration. IC (integrated circuit)_s0Values can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (biochem. Pharmacol. (1973) 22: 3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competitive binding assay and is equal to the concentration where a particular inhibitor would occupy 50% of the receptors if no competitive ligand (e.g., radioligand) were present. Ki values can be converted logarithmically to pKi values (-logKi), with higher values indicating greater potency of the exponential law.

The term "antagonist" refers to a compound that reduces or prevents the action of another compound as defined, for example, in "the pharmacological basis of therapeutics, 7 th edition", page 35, macmillan publication company, canada, 1985, by Goodman and Gilman. In particular, antagonists refer to compounds that impair the effect of agonists. A "competitive antagonist" binds to the same site of a receptor as an agonist but does not activate the receptor, thus blocking the action of the agonist. A "noncompetitive antagonist" binds to an allosteric (non-agonistic) site on the receptor to prevent activation of the receptor. The "reversible antagonist" binds non-covalently to the receptor and can thus be "washed away". An "irreversible antagonist" binds covalently to the receptor and cannot be displaced by competing ligands or washes.

By "therapeutically effective amount" is meant the amount of a compound that, when administered to a subject for the treatment of a disease state, is sufficient to effect such treatment for that disease state. The "therapeutically effective amount" will vary according to: the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the practitioner involved in the medical or veterinary medicine, and other factors.

When referring to a variable, the terms "as defined herein" and "as described herein" are incorporated by reference into the broad definition of the variable as well as the preferred, more preferred and most preferred definitions, if any.

The terms "treating", "contacting", and "reacting" when referring to a chemical reaction refer to the addition or mixing of two or more reagents under appropriate conditions to produce the specified and/or desired product. It will be appreciated that the reaction which produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates produced in the mixture which ultimately results in the formation of the specified and/or desired product.

The term "aromatic" denotes the general concept of aromaticity as defined in the literature, in particular in IUPAC-Compenditum of chemical technology, 2nd, A.D.McNaught & A.Wilkinson (Eds.) Blackwell scientific publications, Oxford (1997).

The term "pharmaceutically acceptable excipient" refers to any ingredient used in formulating pharmaceutical products that is not therapeutically active and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, bulking agents, stabilizers, antioxidants, surfactants, or lubricants.

In detail, the present invention provides compounds of formula I

Wherein

R¹Is halogen, and

R²selected from the group consisting of:

i) heteroaryl unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: OH, halogen, cyano, C_1-6-alkyl radical, C_1-6Alkoxy, halogen-C_1-6Alkyl, halogen-C_1-6-alkoxy radical, C_1-6-alkoxy-C_1-6-alkyl and hydroxy-C_1-6-an alkyl group;

ii) aryl unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: OH, halogen, cyano, C_1-6-alkyl radical, C_1-6Alkoxy, halogen-C_1-6Alkyl, halogen-C_1-6-alkoxy radical, C_1-6-alkoxy-C_1-6-alkyl and hydroxy-C_1-6-an alkyl group;

iii) C unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of_3-7-a cycloalkyl group: OH, halogen, cyano, C_1-6-alkyl radical, C_1-6Alkoxy, halogen-C_1-6Alkyl, halogen-C_1-6-alkoxy radical, C_1-6-alkoxy-C_1-6-alkyl and hydroxy-C_1-6-an alkyl group; and

iv) unsubstituted or individually selected from the group consisting ofC substituted by 1 to 3 substituents of_1-6-an alkyl group: OH, halogen, cyano, C_1-6Alkoxy and halogen-C_1-6-an alkoxy group;

or a pharmaceutically acceptable salt thereof.

An embodiment of the invention are compounds of formula I, wherein R¹Is chlorine.

An embodiment of the invention are compounds of formula I, wherein R²Selected from the group consisting of: unsubstituted heteroaryl, unsubstituted aryl, unsubstituted C_3-7Cycloalkyl and unsubstituted C_1-6-an alkyl group.

An embodiment of the invention are compounds of formula I, wherein R²Selected from the group consisting of pyridyl, pyrazinyl, phenyl, cyclopentyl, isopropyl, and sec-butyl.

An embodiment of the invention are compounds of formula I, wherein R²Selected from pyridin-2-yl, pyrazin-2-yl, phenyl, cyclopentyl, isopropyl and sec-butyl.

An embodiment of the invention are compounds of formula I, wherein R²Is a heteroaryl group.

An embodiment of the invention are compounds of formula I, wherein R²Is a pyridyl group.

An embodiment of the invention are compounds of formula I, wherein R²Is a pyrazinyl group.

An embodiment of the invention are compounds of formula I, wherein R²Is an aryl group.

An embodiment of the invention are compounds of formula I, wherein R²Is phenyl

An embodiment of the invention are compounds of formula I, wherein R²Is C_3-7-a cycloalkyl group.

An embodiment of the invention are compounds of formula I, wherein R²Is cyclopentyl.

An embodiment of the invention are compounds of formula I, wherein R²Is C_1-6-an alkyl group.

An embodiment of the invention are compounds of formula I, wherein R²Is isopropyl.

An embodiment of the invention are compounds of formula I, wherein R²Is sec-butyl.

One embodiment of the invention is a compound of formula I selected from the group consisting of: 8-chloro-1- (4-isopropoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene, 1- (4-sec-butoxy-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene, 8-chloro-1- (4-cyclopentyloxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene, 8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene, 8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene, and

8-chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention is a compound of formula I which is 8-chloro-1- (4-isopropoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

One embodiment of the present invention is a compound of formula I which is 1- (4-sec-butoxy-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

One embodiment of the present invention is a compound of formula I which is 8-chloro-1- (4-cyclopentyloxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

One embodiment of the present invention is a compound of formula I, which is 8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

One embodiment of the present invention is a compound of formula I, which is 8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

One embodiment of the present invention is a compound of formula I which is 8-chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

One embodiment of the present invention is a process for the synthesis of a compound of formula I as described herein, said process comprising reacting a compound of formula II with a compound of formula III to form a compound of formula I

Wherein R is¹And R²As defined herein.

One embodiment of the invention is a compound of formula I prepared by a process as defined herein.

One embodiment of the present invention is a compound of formula I for use as therapeutically active substance.

One embodiment of the present invention are compounds of formula I for use as therapeutically active substances for the therapeutic and/or prophylactic treatment of diseases and disorders which are associated with Vla receptor antagonism.

One embodiment of the present invention are compounds of the formula I for use as therapeutically active substances which act peripherally and centrally in the context of the following diseases: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.

One embodiment of the present invention is a pharmaceutical composition comprising a compound of formula I as described herein and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

One embodiment of the present invention provides the use of a compound of formula I as described herein for the preparation of a medicament for acting peripherally and centrally in the context of the following diseases: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.

One embodiment of the present invention provides a method for using a compound as described herein, which functions peripherally and centrally in the context of the following diseases: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia and aggression, the method comprising administering to a human or animal a compound of formula I.

Furthermore, the present invention includes all optical isomers, i.e. diastereoisomers, mixtures of diastereomers, racemic mixtures of the compounds of formula I, all their corresponding enantiomers and/or tautomers and also their solvates.

The compounds of formula I may contain one or more asymmetric centers and may thus occur as racemates, racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may exist depending on the nature of the different substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended that all possible optical isomers and diastereomers, both in mixtures and as pure or partially purified compounds, are encompassed by the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation may be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates derivatized, if desired, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated so as to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

This applies in particular to the alkylcyclohexyl ether-Headgroups (HG) of the compounds of the formula I, i.e.

Wherein at least carbon atoms 1 and 4 are asymmetric carbon atoms and R²May further comprise asymmetric carbon atoms. It is to be understood that the present invention includes all individual stereoisomers of the head group and mixtures thereof.

Examples of these head bases HG are described below, with a particular example being HG-4.

It is also to be understood that all embodiments of the invention as described herein may be combined with each other.

In embodiments where an optically pure enantiomer is provided, an optically pure enantiomer means that the compound contains > 90% by weight of the desired isomer, particularly > 95% by weight of the desired isomer, or more particularly > 99% by weight of the desired isomer, the weight% based on the total weight of the isomer or isomers of the compound. Chirally pure or chirally enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. The separation of the enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

The compounds of formula I may be prepared according to the following scheme. The starting materials are commercially available or can be prepared according to known methods. Unless otherwise indicated, any pre-defined residues and variables will continue to have the previously defined meanings.

The compounds of formula I may be prepared by a number of synthetic routes such as those shown in the schemes below. The preparation of the compounds of formula I according to the invention can be carried out sequentially or by convergent routes. The synthesis of the compounds of the invention is given in the scheme below. The techniques required for carrying out the reaction and purification of the resulting product are those known to those skilled in the art. Unless indicated to the contrary, the substituents and indices used in the following description of the process have the meanings given herein before.

In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the one shown in the scheme described below, however, the order of the reaction steps may be freely changed depending on the raw materials and their respective reactivities. The starting materials are either commercially available or can be prepared by methods analogous to those given below, by methods described in the references cited in the specification or in the examples, or by methods known in the art.

In a particular embodiment, the compounds of formula (I) of the present invention may be prepared according to a process comprising the steps of: reacting a compound of formula (II)

With a compound of the formula (III),

to obtain a compound of formula (I), wherein R¹And R²As defined herein for formula I.

The methods are described in more detail with the following general schemes and procedures a through G.

Scheme 1: general scheme A

The compounds of formula (I) can be prepared by thermal condensation of hydrazide derivatives of formula (II) and thiolactam derivatives of formula (III). The synthesis of the compounds of formula (II) is outlined in the general schemes C-G below. The compounds of formula (III) may be prepared according to general scheme B as described below. General scheme a is further illustrated below by general procedure V.

Scheme 2: general scheme B

The thiolactone derivative of the formula (III-1) can be obtained as follows: acylation of 2-aminobenzyl alcohol of formula (a) to bromoacetamide of formula (b) (BrCOCH2Br) can be carried out in Schotten-Baumann conditions (biphasic basic aqueous conditions such as aqueous sodium carbonate (Na) solution₂CO₃Aqueous solution)) in quantitative yield. Cyclization of the compound of formula (b) with potassium tert-butoxide i (KOtBu) n 2-propanol (2-PrOH) at low temperatures gives the compound of formula (c). Thiolactone derivatives of the formula (III) by reacting compounds of the formula (c) with Laoweisen's reagent (2, 4-bis- (4-methoxyphenyl) -1, 3, 2, 4-diPhosphodiepise-2, 4-disulfide) or phosphorus pentasulfide at elevated temperature in a suitable solvent, such as Tetrahydrofuran (THF).

Scheme 3: general scheme C

The 4-alkoxy-cyclohexanecarboxylic acid ester derivative of the formula (VII-1) can be obtained by reductive etherification as follows: the 4-hydroxy-cyclohexanecarboxylic acid ester (IV) is converted to 4-trimethylsiloxy-cyclohexanecarboxylic acid ester (V) by O-silylation methods known in the art, for example by using a silylating agent such as trimethylsilyl chloride (TMSCl) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the presence of a base such as imidazole or 2, 6-lutidine in a suitable solvent such as N, N-Dimethylformamide (DMF) or dichloromethane (CH)₂l₂) And (4) treating. 4-trimethylsilyloxy-cyclohexanecarboxylic acid ester (V) and ketones or aldehydes of the formula (VI) are prepared with trimethylsilyl trifluoromethanesulfonate in dichloromethane and a reducing agent such as triethylsilane (Et)₃SiH) at Room Temperature (RT) to give the 4-alkoxy-cyclohexanecarboxylic acid ester derivative of formula (VII-1). The compound of formula (VII-1) is typically obtained as a mixture of cis-and trans-isomers, which in some cases can be chromatographed to give pure trans-4-alkoxy-cyclohexanecarboxylic acid ester of formula (VII-1a) and cis-4-alkoxy-cyclohexanecarboxylic acid ester of formula (VII-1 b). General scheme C is further exemplified below by general step I.

Scheme 4: general scheme D

Alternatively, the 4-alkoxy-cyclohexanecarboxylic acid ester derivative of the formula (VII-1) can be obtained by reductive etherification as follows: the alkoxy-trimethyl-silanes of formula (IX) and ethyl 4-cyclohexanecarboxylate (X) are treated continuously with trimethylsilyl trifluoromethanesulfonate in methylene chloride and a reducing agent such as triethylsilane to give the 4-alkoxy-cyclohexanecarboxylate derivatives of formula (VII-1). The compound of formula (VII-1) is typically obtained as a mixture of cis-and trans-isomers, which in some cases can be chromatographed to give pure trans-4-alkoxy-cyclohexanecarboxylate of formula (VII-1a) and cis-4-alkoxy-cyclohexanecarboxylate of formula (VII-1 b). Alkoxy-trimethyl-silane derivatives of formula (IX) are either commercially available or prepared using O-silylation methods known in the art, for example by treating the alcohol of general formula (VIII) with a silylating agent such as trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate in the presence of a base such as imidazole or 2, 6-lutidine in a suitable solvent such as N, N-dimethylformamide or dichloromethane. Alternatively, the alkoxy-trimethyl-silane derivative of formula (IX) may be prepared in situ without isolation by treating the alcohol of general formula (VIII) with trimethylsilyl trifluoromethanesulfonate and 2, 6-lutidine in dichloromethane prior to the reductive etherification step with ethyl 4-cyclohexanecarboxylate (X). General scheme D is further exemplified below by general steps IIA and IIB.

Scheme 5: general scheme E

4-hydroxy-cyclohexanecarboxylic acid esters of the formula (IV) are prepared with phenol derivatives of the formula (XI) under Mitsunobu conditions (diethyl azodicarboxylate (DEAD)) and triphenylphosphine (PPh)₃) Etherification under (VII) to give 4-aryloxy-cyclohexanecarboxylic acid esters of the formula (VII-2) in the inverted configuration. Thus, formula (VII-2) is obtained from cis-4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV-a)_a) And trans-4-aryloxy-cyclohexanecarboxylic acid ester of the formula (VII-2b) from trans-4-hydroxy-cyclohexanecarboxylic acid ester of the formula (IV-b). General scheme E is further exemplified below by general procedure IIIA.

Scheme 6: general scheme F

A compound of formula (VII-3) (a compound of formula (VII) wherein R²Is heteroaryl) can be prepared from 4-hydroxy-cyclohexanecarboxylic acid ester of the formula (IV) and heteroaryl chloride of the formula (XII) in catalytic or stoichiometric amounts of sodium methanesulfinate and a base such as potassium carbonate (K)₂CO₃) In Dimethylformamide (DMF) at 120 ℃ or in a mixture of copper iodide (CuI) and 1, 10-phenanthroline and a base such as cesium carbonate (Cs)₂CO₃) Prepared in toluene at reflux in the presence of the catalyst system formed. General scheme F is further exemplified below by general steps IIIB and IIIC.

Scheme 7: general scheme G

The 4-alkoxy-or aryloxycyclohexanecarboxylic acid esters of formula (VII) can be converted into hydrazide derivatives of formula (II) by heating with hydrazine hydrate in a suitable solvent such as n-butanol (n-BuOH). Alternatively, the ester derivative of formula (VII) may be used with aqueous sodium or potassium hydroxide (NaOH or KOH) and an ether solvent such as diThe biphasic mixture of alkanes is hydrolyzed to the carboxylic acid derivative of formula (XIII). The hydrazide derivatives of formula (II) can be prepared by coupling an acid intermediate of formula (XIII), for example with ethyl chloroformate, thionyl chloride, oxalyl chloride or an amide coupling agent such as triethylamine (Et)₃N)) and then coupled with hydrazine. General scheme G is further exemplified below by general procedure IV.

The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to those skilled in the art, for example by dissolving a compound of formula I in a suitable solvent such as diAlkane or THF and adding an appropriate amount of the corresponding acid. The product can usually be isolated by filtration or by chromatography. The conversion of a compound of formula I to a pharmaceutically acceptable salt with a base can be achieved by treating the compound with such a base. One possible method for forming such salts is, for example, by reacting 1/n equivalent of a basic salt such as M (OH)_nAdded to a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and the solvent is removed by evaporation or lyophilization, where M = metal or ammonium cation and n = number of hydroxide anions. Particular salts are the hydrochloride, formate and trifluoroacetate salts.

As long as their preparation is not described in the examples, the compounds of formula I as well as all intermediates can be prepared according to analogous methods or according to the methods set forth herein. The starting materials are commercially available, known in the art, or can be prepared by methods known in the art or similar methods.

It will be appreciated that the compounds of general formula I in the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

Pharmacological testing

The human Vla receptor was cloned from total human liver RNA by RT-PCR. The coding sequences were subcloned into expression vectors after sequencing to confirm the identity of the amplified sequences. To confirm the affinity of the compounds from the present invention for the human Vla receptor, binding studies were performed. Cell membranes were prepared from HEK293 cells transiently transfected with the expression vector and grown in 20 liter fermentors using the following protocol.

50g cells were resuspended in 30ml of freshly prepared ice-cold lysis buffer (50mM HEPES, 1 mM)EDTA，10mMMgCl₂Adjusted to pH =7.4+ complete mixture of protease inhibitors (Roche diagnostics)). Homogenized for 1min with Polytron and sonicated at 80% intensity on ice for 2x2 minutes (Vibracell sonicator). The preparation was centrifuged at 500g for 20min at 4 ℃, the pellet discarded and the supernatant centrifuged at 43 '000 g (19' 000rpm) for 1 hour at 4 ℃. The pellet was resuspended in 12.5ml lysis buffer +12.5ml sucrose 20% and homogenized using Polytron for 1-2 min. Protein concentration was determined by Bradford method and aliquots were stored at-80 ℃ until use. For binding studies, 60mg of yttrium silicate SPA beads (Amersham) were combined with an aliquot of the membrane in binding buffer (50mM Tris, 120mM NaCl, 5mM KCl, 2mM CaCl)₂，10mMMgCl₂) Mixed and mixed for 15 minutes. Then 50. mu.l of the bead/membrane mixture was added to each well of a 96-well plate followed by 50. mu.l of 4nM 3H-vasopressin (American RadiolabeledCchemicals). For the total binding measurements, 100 μ l of binding buffer was added to each well, 100 μ l of 8.4mM cold vasopressin was added for non-specific binding and 100 μ l of serial dilutions of each compound in 2% DMSO were added for compound testing. The plate was incubated at room temperature for 1h, centrifuged at 1000g for 1min and counted on a Packardtop-Count. Non-specific binding counts were subtracted from each well and the data were normalized to set at 100% of the maximum specific binding. To calculate the IC_s0The curve was fitted using a non-linear regression model (XLFit) and Ki calculated using the Cheng-Prussoff equation.

The following representative data show the antagonistic activity of the compounds according to the invention against the human Vla receptor.

Table 1: the pKi value of the selected embodiment.

Pharmaceutical composition

The compounds of formula I and the pharmaceutically acceptable salts can be used as therapeutically active substances, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the manufacture of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Also provided by the present invention are medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, as well as processes for their preparation, which comprise bringing one or more compounds of formula I and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and must of course be adjusted in each particular case to suit the individual needs. In the case of oral administration, the dosage for adults may vary from a corresponding amount of about 0.01mg to about 1000mg of the compound of formula I or a pharmaceutically acceptable salt thereof per day. The daily dose may be administered as a single dose or in divided doses and, in addition, the upper limit may also be exceeded when this is found to be necessary.

The following examples illustrate the invention without limiting it, but merely serve as a representative thereof. The pharmaceutical preparation conveniently contains from about 1 to 500mg, especially from 1 to 100mg, of a compound of formula I. Examples of compositions according to the invention are:

example A

Tablets of the following composition were manufactured in a conventional manner:

table 2: possible tablet compositions

Manufacturing process

1. Ingredients 1, 2,3 and 4 were mixed and granulated with purified water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Add ingredient 5 and mix for 3 minutes; pressing on a suitable press.

Example B-1

Capsules of the following composition were made:

table 3: possible capsule ingredient composition

Manufacturing process

1. Ingredients 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Encapsulating into suitable capsule.

The compound of formula I, lactose and corn starch are first mixed in a mixer and then mixed in a mill. Returning the mixture to the mixer; talc was added thereto and mixed well. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

Example B-2

Soft gelatin capsules of the following composition were made:

composition (I)	mg/capsule
		A compound of formula I	5
Yellow wax	8
		Hydrogenated soybean oil	8
Partially hydrogenated vegetable oils	34
		Soybean oil	110
Total of	165

Table 4: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		karion83	8 (dry matter) 18->
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Total of	116.5

Table 5: possible soft gelatin capsule compositions

Manufacturing process

The compound of formula I is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to conventional procedures.

Example C

Suppositories of the following composition were made:

composition (I)	mg/suppository
		A compound of formula I	15
Suppository bolus	1285
		Total of	1300

Table 6: possible suppository composition

Manufacturing process

The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ℃. Thereafter, the finely powdered compound of formula I is added thereto and stirred until it is completely dispersed. Pouring the mixture into a suppository mold with a proper size, and keeping the mixture stand for cooling; the suppositories are then removed from the moulds and individually packaged in waxed paper or metal foil.

Example D

An injection of the following composition was made:

composition (I)	mg/injection
		A compound of formula I	3
Polyethylene glycol 400	150
		Acetic acid	Adding into a container with a pH of 5.0
Water for injection	Adding to 1.0ml

Table 7: possible injection compositions

Manufacturing process

The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0ml by adding the remaining amount of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Example E

Sachets of the following composition were made:

composition (I)	mg/sachet
		A compound of formula I	50
Lactose, fine powder	1015
		Microcrystalline cellulose (AVICEL PH102)	140019 -->
Sodium carboxymethylcellulose	14
		Polyvinylpyrrolidone K30	10
Magnesium stearate	10
		Flavoring additive	1
Total of	2500

Table 8: possible sachet composition

Manufacturing process

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Experimental part

The following examples are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

An intermediate of formula (V)

Cis/trans-4-trimethylsilyloxy-cyclohexanecarboxylic acid ethyl ester (2: 1)

To a solution of cis/trans-4-hydroxycyclohexanecarboxylic acid ethyl ester (2: 1) (5.0g, 29mmol) and imidazole (4.4g, 64mmol) in N, N-dimethylformamide (90ml) was added trimethylsilyl chloride (4.0ml, 32mmol) at 0-5 ℃. Stir at room temperature for 1h before partitioning between tert-butyl methyl ether (300ml) and water (150 ml). The layers were separated. The organic layer was washed with two 150-ml parts of water and one 50-ml part of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.7g, 94%) as colorless oil. MSm/e: 245([ M + H)]⁺)。

4-alkoxy-cyclohexanecarboxylic acid ester intermediate of formula (VII-1)

Reduction etherification

General procedure I:

to a solution of cis/trans-4-trimethylsilyloxy-cyclohexanecarboxylic acid ethyl ester (2: 1) in dichloromethane (0.1M) were added successively at-78 ℃ the ketone or aldehyde of formula (VI) (0.85 eq) and trimethylsilyl trifluoromethanesulfonate (0.10 eq). The reaction mixture was stirred for 1 h. After addition of triethylsilane (1 eq), the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued overnight. The mixture was quenched with saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave the 4-alkoxy-cyclohexanecarboxylic acid ester intermediate of formula (VII-1).

General procedure IIA:

the alkoxy-trimethyl-silane intermediate of formula (IX) is formed in situ by adding trimethylsilyl trifluoromethanesulfonate (1 equivalent) to a solution of the alcohol derivative of formula (VIII) (1 equivalent) and 2, 6-lutidine (1 equivalent) in dichloromethane (0.1M) at-78 ℃. After 1h, 4-Cyclohexanone formate of formula (X) (0.85 equiv.) and trimethylsilyl trifluoromethanesulfonate (0.1 equiv.) were added continuously. The reaction mixture was stirred for 1 h. After addition of triethylsilane (2 equivalents), the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued overnight. The mixture was quenched with saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave the 4-alkoxy-cyclohexanecarboxylic acid ester intermediate of formula (VII-1).

General procedure IIB:

the trimethylsilyloxy intermediate of formula (IX), which is commercially available or which can be prepared according to methods known in the art, is dissolved in dichloromethane (0.1M). 4-Cyclohexanone formate of formula (X) (0.85 equiv.) and trimethylsilyl trifluoromethanesulfonate (0.1 equiv.) were added continuously at-78 ℃. The reaction mixture was stirred for 1 h. After addition of triethylsilane (2 equivalents), the cold bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued overnight. The mixture was quenched with saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave the 4-alkoxy-cyclohexanecarboxylic acid ester intermediate of formula (VII-1).

4-alkoxy-cyclohexanecarboxylic acid esters 1

Trans-4-isopropoxy-cyclohexanecarboxylic acid ethyl ester

Trans-4-isopropoxy-cyclohexanecarboxylic acid ethyl ester was obtained as colorless oil from acetone after purification by flash column chromatography according to general procedure I,the yield was 23%. MSm/e: 214 (M)⁺)

4-alkoxy-cyclohexanecarboxylic acid esters 2

(RS) -trans-4-sec-butoxy-cyclohexanecarboxylic acid ethyl ester

From 2-butanone according to general procedure I (RS) -trans-4-sec-butoxy-cyclohexanecarboxylic acid ethyl ester was obtained as colorless oil in 22% yield after purification by flash column chromatography. MS (EI) m/e: 228 (M)⁺，1％)，199([M-C₂H₅]⁺，6％)，155([M-C₄H₉O]⁺，100％)

4-alkoxy-cyclohexanecarboxylic acid esters 3

Trans-4-cyclopentyloxy-cyclohexanecarboxylic acid ethyl ester

From cyclopentanone, trans-4-cyclopentyloxy-cyclohexanecarboxylic acid ethyl ester was obtained as colorless oil in 22% yield after purification by flash column chromatography according to general procedure I. MS (EI) m/e: 240 (M)⁺’1％)，155[M-C_sH₉O]⁺，30％)

4-aryloxy-cyclohexanecarboxylic acid ester intermediates of formulae (VII-2) and (VII-3)

General procedure IIIA: etherification under Mitsunobu conditions

To a solution of triphenylphosphine (1.2 equiv.) in anhydrous tetrahydrofuran (0.1M) was added diethyl azodicarboxylate (1.2 equiv.) at 0 deg.C. After 20 minutes, a solution of the phenol derivative of formula (XI) (1.2 equivalents) and the 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) in tetrahydrofuran (1-3M) was added successively at 5 ℃. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 3-18 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with one to two portions of 1M aqueous sodium hydroxide solution. The aqueous layer was extracted with one to two portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave the 4-aryloxy-cyclohexanecarboxylic acid ester of formula (V11-2).

General procedure IIIB: sodium methanesulfinate mediated arylation

To a solution of 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 eq) and heteroaryl chloride derivative of formula (XII) (1 eq) in anhydrous N, N-monomethylformamide (1M) were added sodium methanesulfinate (85%, 0.25-1 eq) and potassium carbonate (1.5 eq) sequentially. After the addition was complete, the reaction mixture was stirred at 120 ℃ for 3-18 h. After cooling to room temperature, the reaction mixture was partitioned between tert-butyl methyl ether and water. The layers were separated and the aqueous layer was extracted with one to two portions of tert-butyl methyl ether. The combined organic layers were washed with one to two portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave the 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (V11-3).

General procedure IIIC: copper catalyzed arylation

To a mixture of cuprous iodide (0.1 equivalent), 1, 10-phenanthroline (0.2 equivalent), and the heteroaryl chloride derivative of formula (XII) (1 equivalent) in toluene (2M) was added 4-hydroxy-cyclohexanecarboxylic acid ester of formula (IV) (1 equivalent) and cesium carbonate (2 equivalents). The reaction mixture was heated at reflux for 20 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with one to two portions of ethyl acetate. The combined organic layers were washed with one to two portions of 0.5 aqueous hydrogen chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography gave the 4-heteroaryloxy-cyclohexanecarboxylic acid ester of formula (VII-3).

4-aryloxy-cyclohexanecarboxylic acid ester 1

Trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester

The title compound was obtained as colorless oil in 23% yield from phenol and trans-4-hydroxy-cyclohexanecarboxylic acid methyl ester according to general procedure IIIA. MSm/e: 234 (M)⁺)。

4-aryloxy-cyclohexanecarboxylic acid ester 2

Trans-4- (pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as light red solid in 36% yield from 2-hydroxypyridine and trans-4-hydroxy-cyclohexanecarboxylic acid methyl ester according to general procedure IIIA. MSm/e: 236([ M + H)]⁺)。

4-aryloxy-cyclohexanecarboxylic acid ester 3

Cis/trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylic acid ethyl ester (1: 1)

The title compound was obtained as white solid in 15% yield from 2-chloropyrazine and cis/trans-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (2: 1) according to general procedure IIIB. MSm/e: 251([ M + H)]⁺)。

Hydrazide intermediates of formula (II)

General procedure IV: formation of hydrazides from 4-alkoxy-or 4-aryloxy-cyclohexanecarboxylic acid esters

4-alkoxy-or 4-aryloxy-cyclohexanecarboxylates of the formula (VII) (1 equivalent) and hydrazine hydrate (2-6 equivalents) in n-butanol (0)_-2-1M) is heated at reflux for 16-72 h. After cooling to room temperature, the reaction mixture is partitioned between an organic solvent such as ethyl acetate or dichloromethane and water. The layers were separated and the aqueous layer was extracted with two portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude hydrazide derivative of formula (II), which can generally be used in the next step without further purification.

Hydrazide 1

Trans-4-isopropoxy-cyclohexanecarboxhydrazide

The title compound was obtained as off-white solid in 70% yield from trans-4-isopropoxy-cyclohexanecarboxylic acid ethyl ester according to general procedure IV. MSm/e: 201([ M + H ]]⁺)

Hydrazide 2

(RS) -trans-4-sec-butoxy-cyclohexanecarboxhydrazide

The title compound was obtained as white solid in 93% yield from (RS) -trans-4-sec-butoxy-cyclohexanecarboxylic acid ethyl ester according to general procedure IV. MS (EI) m/e: 214 (M)⁺)

Hydrazide 3

Trans-4-cyclopentyloxy-cyclohexanecarboxhydrazide

The title compound was obtained as white solid in 80% yield from trans-4-cyclopentyloxy-cyclohexanecarboxylic acid ethyl ester according to general procedure IV.

MS(EI)m/e：226(M⁺)

Hydrazide 4

Trans-4-phenoxy-cyclohexanecarboxhydrazide

The title compound was obtained as white solid in quantitative yield from trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester according to general procedure IV.

MSm/e：235([M+H]⁺)

Hydrazide 5

Trans-4- (pyridin-2-yloxy) -cyclohexanecarboxylhydrazides

The title compound was obtained as white solid in 96% yield from trans-4- (pyridin-2-yloxy) -cyclohexanecarboxylic acid methyl ester according to general procedure IV.

MSn/e：236([M+H]⁺)

Hydrazide 6

Trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylhydrazides

A mixture of cis/trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylic acid ethyl ester (1.11g, 4.41mmo1) and hydrazine hydrate (0442g, 8.83mmol) was heated at 120 ℃ for 72 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50ml) and water (30ml)And (4) preparing. The organic layer was separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were washed with brine (30ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude cis/trans-hydrazide was triturated in ethyl acetate (5 ml). The precipitate was collected by filtration and dried in vacuo to afford the crude title compound (0.236g, 23%) as a white solid, which was used in the next step without further purification. MSm/e: 237([ M + H)]⁺)。

Thiolactone intermediates of formula (III)

7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem -2(1H) -thiones

a) 2-bromo-N- (4-chloro-2- (hydroxymethyl) phenyl) acetamide

To a solution of (2-amino-5-chlorophenyl) methanol (4.30g, 27.3mmol) in dichloromethane (220ml) was added 2-bromoacetyl bromide (6.06g, 2.61ml, 30.0mmol) at 0-5 ℃. After stirring for 5 minutes, a 2M aqueous sodium carbonate solution (130ml) was added dropwise over the course of approximately 10 minutes. The cooling bath was removed and stirring was continued for 2 h. The solvent was removed in vacuo. The aqueous residue was extracted with three 100-ml portions of ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (7.30g, 96%) as a pale gray solid, which was used in the next step without further purification. MSm/e: 276([ M + H)]⁺)。

b) 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem -2(1H) -one

To a suspension of 2-bromo-N- (4-chloro-2- (hydroxymethyl) phenyl) acetamide (3.60g, 12.9mmol) in 2-propanol (129ml)The supernatant was added in small portions to potassium tert-butoxide (3.77g, 33.6mmol) at 0-5 ℃. The reaction mixture was stirred for 90 minutes and then poured onto ice/water (500 ml). The precipitate was collected by filtration and washed with water. The residual water was removed by successive evaporation with two 50-ml portions of toluene to give the title compound (2.34g, 92%) as a light yellow solid. MSm/e: 196([ M-H)]^-)。

c) 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem -2(1H) -thiones

To 7-chloro-3, 5-dihydrobenzo [ e ]][1，4]OxazazemSuspension of (E) -2(1H) -one (3.01g, 15.2mmol) in tetrahydrofuran (102ml) 2, 4-bis- (4-methoxyphenyl) -1, 3, 2, 4-dithiodiphosphetane-2, 4-disulfide (3.45g, 8.53mmol) was added at room temperature. The reaction mixture was heated at reflux for 4 h. After cooling to room temperature, the solvent was evaporated and the residue was crystallized from hot ethanol to give the title compound (1.96g, 60%) as a light yellow solid. MSm/e: 211.6([ M-H)]^-)。

General procedure V: condensation of hydrazides and thiolactones to triazoles

A mixture of the hydrazide derivative of formula (II) (1-1.5 equivalents) and the thiolactone of formula (III) (1 equivalent) in n-butanol (0.1-0.2M) was heated at reflux for 16-72 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography to give the compound of formula (I).

Example 1

Trans-8-chloro-1- (4-isopropoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 57% yield using general procedure V.

Hydrazide: trans-4-isopropoxy-cyclohexanecarboxhydrazide

Thiolactones: 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem-2(1H) -thiones

MSm/e：362([M+H]⁺)

Example 2

Trans-1- (4-sec-butoxy-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

The title compound was obtained as an off-white solid in 63% yield using general procedure V.

Hydrazide: (RS) -trans-4-sec-butoxy-cyclohexanecarboxhydrazide

Thiolactones: 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem-2(1H) -thiones

MSm/e：376([M+H]⁺)

Example 3

Trans-8-chloro-1- (4-cyclopentyloxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

The title compound was obtained as an off-white solid in 72% yield using general procedure V.

Hydrazide: trans-4-cyclopentyloxy-cyclohexanecarboxhydrazide

Thiolactones: 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem-2(1H) -thiones

MSm/e：388([M+H]⁺)

Example 4

Trans-8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 75% yield using general procedure V.

Hydrazide: trans-4-phenoxy-cyclohexanecarboxhydrazide

Thiolactones: 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem-2(1H) -thiones

MSm/e：396([M+H]⁺)

Example 5

Trans-8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

The title compound was obtained as an off-white solid in 71% yield using general procedure V.

Hydrazide: trans-4- (pyridin-2-yloxy) -cyclohexanecarboxylhydrazides

Thiolactones: 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem-2(1H) -thiones

MSm/e：397([M+H]⁺)

Example 6

Trans-8-chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

The title compound was obtained as an off-white solid in 37% yield using general procedure V.

Hydrazide: trans-4- (pyrazin-2-yloxy) -cyclohexanecarboxylhydrazides

Thiolactones: 7-chloro-3, 5-dihydrobenzo [ e][1，4]Oxazazem-2(1H) -thiones

MSm/e：398([M+H]⁺)。

Claims (6)

1. A compound of the formula I,

wherein

R¹Is halogen, and

R²selected from the group consisting of pyridyl, pyrazinyl, phenyl, cyclopentyl, isopropyl, and sec-butyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R¹Is chlorine.

3. The compound according to any one of claims 1 or 2, selected from the group consisting of:

8-chloro-1- (4-isopropoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

1- (4-sec-butoxy-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

8-chloro-1- (4-cyclopentyloxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

8-chloro-1- (4-phenoxy-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

8-chloro-1- [4- (pyridin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene, and

8-chloro-1- [4- (pyrazin-2-yloxy) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

or a pharmaceutically acceptable salt thereof.

4. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 3, which process comprises reacting a compound of formula II with a compound of formula III to form a compound of formula I

Wherein R is¹And R²As defined in any one of claims 1 to 2.

5. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

6. The use of a compound of formula I according to any one of claims 1 to 3 for the preparation of a medicament for acting peripherally and centrally in the context of the following diseases: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.