HK1193601A - Cyclohexyl-4h,6h-5-oxa-2,3,10b-triaza-benzo[e]azulenes as v1a antagonists - Google Patents

Description

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 as V1a receptor modulators, and especially as V1a receptor antagonists, their manufacture, pharmaceutical compositions comprising 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 compounds of formula I or pharmaceutically acceptable salts thereof,

wherein the substituents and variables are as described below and in the claims.

The compounds of the present invention are V1a receptor antagonists and are useful for 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 couplingA receptor. The V1a receptor is expressed in the brain, liver, vascular smooth muscle, lung, uterus and testis, the V1b or V3 receptor is expressed in the brain and pituitary, and the V2 receptor is expressed in the kidney, where it regulates water reabsorption and mediates the antidiuretic action of vasopressin (Robben et al)¹). 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 thought to have a central anxiolytic effect (Neumann)²). 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)³). It is known that stressful life events can cause major depression and anxiety (Kendler et al⁴) And both have very high complex lesions, with anxiety often preceded major depression (Regier et al)⁵). The V1a receptor is widely expressed in the brain and especially in the limbic regions such as the tonsils, lateral septum and hippocampus, where it plays an important role in the regulation of anxiety. In fact, V1a knockout mice showed reduced anxiety behavior in the plus maze, open field and light and dark boxes (Bielsky et al)⁶). Down-regulation of the V1a receptor using antisense oligonucleotide injection in the septum also causes a reduction in anxiety behavior (Landgraf et al⁷). Vasopressin or the V1a receptor are also involved in other neuropsychological diseases: genetic Studies recently linked sequence polymorphisms in the promoter of the human V1a receptor to autism spectrum disorders (Yirmiya et al)⁸Intranasal administration of vasopressin has been shown to affect the aggressiveness of human males (Thompson et al)⁹) Also, vasopressin levels were found in schizophrenic patients (Raskind et al¹⁰) And patients with obsessive-compulsive disorder (Altemus et al)¹¹) Is increased.

The V1a receptor also mediates the cardiovascular effects of vasopressin in the brain by centrally modulating blood pressure and heart rate in the solitary bundle of nucleiBy (Michelini et al)¹²). In the periphery, it induces contraction of vascular smooth muscle and chronic inhibition of the V1a receptor improves hemodynamic parameters in myocardial infarction rats (VanKerckhaven et al¹³). Thus, V1a antagonists with improved penetration across the blood-brain barrier are expected to be advantageous.

Vasopressin V1a receptor antagonists have been shown to be effective in clinically reducing dysmenorrhea (Brouard et al¹⁴). V1a receptor antagonism has also been implicated in the treatment of female sexual dysfunction (Aughton et al¹⁵). In recent studies, V1a receptor antagonists have been shown to have therapeutic effects in erectile dysfunction and premature ejaculation (Gupta et al¹⁶)。

Detailed Description

The present invention provides 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 the V1a receptor, and in particular with the antagonism of the V1a receptor. It is a further object of the present invention to provide selective inhibitors of the V1a receptor, since selectivity for the V1a 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 withOther groups, representing branched chain hydrocarbon groups which may be linear or with single or multiple branches, wherein the alkyl group generally contains 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 and the like. In particular "C_1-6Alkyl "has 1 to 4 carbon atoms. Specific groups are methyl and isobutyl.

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 ") substituted C as defined herein_1-6-an alkyl group. Specific groups have 1 halogen or 3 halogens. 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_3-7-cycloalkyl-C_1-6-alkyl ", alone or in combination with other groups, means C as defined herein_1-6-alkyl, which is substituted by one or more C as defined herein_3-6Cycloalkyl, especially 1C_3-6-cycloalkyl substitution.

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 ≡ 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 chloro (C1), iodo (I), fluoro (F) and bromo (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" include benzyl, biphenyl, indanyl, naphthyl, phenyl (Ph), and the like. A particular "aryl" group is phenyl. The term "optionally substituted aryl", alone or in combination with other groups, refers to an aryl group, as defined herein, which is 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.

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" 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 (pyrazolyl), 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" is pyridyl, benzo [ d ]]Isothiazolyl, [1, 2, 4 ]]Oxadiazolyl, isoxazolylAzolyl, 4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzolyl, 4-benzo [ d ]]Different from each otherOxazolyl and 4, 5, 6, 7-tetrahydro-1H-indazolyl. Specific "heteroaryl" groups are pyridin-2-yl, 4-benzo [ d ]]Isothiazol-3-yl, [1, 2, 4 ]]Oxadiazol-3-yl, isoAzol-3-yl, 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherAzol-3-yl, 4-benzo [ d ]]Different from each otherOxazol-3-yl and 4, 5, 6, 7-tetrahydro-1H-indazol-3-yl. The term "optionally substituted heteroaryl", alone or in combination with other groups, refers to heteroaryl as defined herein, which is unsubstituted orSubstituted 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.

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_1-6-alkoxy "is a group having 1 to 4 carbon atoms.

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_1-6-alkoxy "is 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 is 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. A specific example is cyclopentyl.

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 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)₅₀) 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 (-log IC)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)₅₀Values 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 (-log Ki), with higher values indicating greater potency of the exponential law.

The term "antagonist" refers to, for example, Goodman and Gilman, "The pharmacological basis of Therapeutics, 7 th edition", page 35, Macmillan Publ company, Canada, 1985¹⁷A compound as defined in (1) which reduces or prevents the action of another compound.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 or 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 special, more special and most special 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, for example, the literature, especially in IUPAC¹⁸The general concept of aromaticity as defined in (1).

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) C unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of_1-6-an alkyl group: OH, halogen, cyano, C_3-7-RingAlkyl radical, C_1-6Alkoxy and halogen-C_1-6-an alkoxy group;

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a compound of formula I

Wherein

R¹Is halogen, and

R²selected from the group consisting of:

i) heteroaryl, which is 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) an aryl group which is 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_3-7-cycloalkyl, 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; and

iv)C_1-6-an alkyl group which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: OH, halogen, cyano, C_3-7-cycloalkyl radical, C_1-6Alkoxy and halogen-C_1-6-an alkoxy group;

or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention provides a compound as defined herein, wherein R is¹Is chlorine.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Selected from the group consisting of: unsubstituted heteroaryl, by halogen or C_1-6-alkyl-substituted heteroaryl, unsubstituted C_1-6Alkyl and by halogen and C_3-7-cycloalkyl-substituted C_1-6-an alkyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is unsubstituted heteroaryl.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is 4-benzo [ d ]]An isothiazolyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherAn azole group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is a 4, 5, 6, 7-tetrahydro-1H-indazolyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is 4-benzo [ d ]]Different from each otherOxazol-3-yl.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is heteroaryl substituted by halogen.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is a 3-fluoro-pyridyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is a quilt C_1-6-alkyl-substituted heteroaryl.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is 5-methyl-isoAn azole group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is 5-methyl- [1, 2, 4 ]]A diazolyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is unsubstituted C_1-6-an alkyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is an isobutyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is substituted by halogen and C_3-7-cycloalkyl-substituted C_1-6-an alkyl group.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Is cyclopentyl-difluoro-methyl.

A certain embodiment of the invention provides a compound as defined herein, wherein R is²Selected from the group consisting of: 3-fluoro-pyridinyl, 4-benzenesAnd [ d ]]Isothiazolyl, 5-methyl- [1, 2, 4 ]]Oxadiazolyl, 5-methyl-iso-methylAzolyl, 4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzolyl, 4, 5, 6, 7-tetrahydro-1H-indazolyl, isobutyl, cyclopentyl-difluoro-methyl and 4-benzo [ d]Different from each otherAn azole group.

A certain embodiment of the invention provides a compound as defined herein, selected from the group consisting of:

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

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

8-chloro-1- [4- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzol-3-yl) -ringsHexyl radical]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

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

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

1- (4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene derivatives

Or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention provides a compound as defined herein which is 8-chloro-1- [4- (3-fluoro-pyridin-2-yl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

A certain embodiment of the present invention provides a compound as defined herein, which is 1- (4-benzo [ d ] isothiazol-3-yl-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

A certain embodiment of the invention provides a compound as defined herein, which is 8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]And (2) azulene.

A certain embodiment of the invention provides a compound as defined herein, which is 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H，6H-5-oxa-2, 3,10 b-triaza-benzo [ e]And (2) azulene.

A certain embodiment of the invention provides a compound as defined herein, which is 8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]And (2) azulene.

8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

A certain embodiment of the present invention provides a compound as defined herein which is 8-chloro-1- (4-isobutyl-cyclohexyl) -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

A certain embodiment of the invention provides a compound as defined herein which is 8-chloro-1- [4- (cyclopentyl-difluoro-methyl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene.

A certain embodiment of the invention provides a compound as defined herein, which is 1- (4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]And (2) azulene.

One embodiment of the invention is a method of synthesizing a compound of formula I as described herein, the method comprising reacting a compound of formula II with a compound of formula III to 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 conditions associated with the antagonism of the V1a receptor.

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, single 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.

In which at least carbon atoms 1 and 4 are asymmetricCarbon atom 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 shown below, with specific examples being HG-3 and HG-4, most particularly 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.

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

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). General scheme a is further illustrated below by general procedure (XI). The synthesis of the compounds of formula (II) is outlined in the general schemes C-K below. The compounds of formula (III) may be prepared according to general scheme B as described below.

Scheme 2: general scheme B

The thiolactone derivative of the formula (III) can be obtained as follows: acylation of 2-aminobenzyl alcohol of formula (a) to bromoacetamide of formula (b) can be carried out under Schotten-Baumann conditions (e.g., 2-bromoacetyl bromide (BrCOCH)₂Br), sodium carbonate (Na)₂CO₃) In the dichloromethyl group (CH)₂Cl₂) At room temperature) in quantitative yield. Cyclization of the compound of formula (b) with potassium tert-butoxide (KOtBu) in 2-propanol (2-PrOH) at low temperatures gives the compound of formula (c). The thiolactone derivative of formula (III) is obtained by treatment of the compound of formula (c) with lawesson's reagent (2, 4-bis- (4-methoxyphenyl) -1, 3, 2, 4-dithiodiphosphetane-2, 4-disulfide) or phosphorus pentasulfide at elevated temperature in a suitable solvent, for example Tetrahydrofuran (THF).

Scheme 3: general scheme C

The 4-aryl-or 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula (V) may be prepared as follows: under the conditions of the Suzuki reaction, from 4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid esters of the formula (IV) and aryl-or heteroarylboronic acids, aryl-or heteroarylboronic acid esters or aryl-or heteroaryltrifluoroborate salts in suitable organic solvents, for example 1, 4-bisIn an alkane, 1, 2-dimethoxyethane, tetrahydrofuran or toluene in the presence of catalytic amounts of a 1: 2 mixture of palladium (II) acetate and triphenylphosphine or a 1: 1 mixture of palladium (II) acetate and a bisphosphine ligand or tetrakis (triphenylphosphine) palladium (0) and in the presence of a base such as an alkali metal salt of phosphoric or carbonic acid, which may be used without water or as an aqueous solution, at reaction temperatures from room temperature to reflux. Alternatively, the 4-aryl-or 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula (V) may be prepared as follows: under the conditions of the Negishi reaction, from 4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid esters of the formula (IV) and aryl-or heteroarylzinc halides in a suitable organic solvent, such as tetrahydrofuran, and Pd (PPh)₃Prepared at reaction temperatures ranging from room temperature to reflux. Alternatively, the compound of formula (V) may be prepared by reaction between a base such as potassium carbonate and a suitable palladium catalyst such as (1, 3-diisopropyl)(VII) Trifluoroborate Potassium salt of formula (VII) with an aryl or heteroaryl halide R in the presence of ylimidazol-2-ylidene) (3-chloropyridyl) Palladium (II) chloride in a suitable solvent such as an alcohol under reflux²-X coupling. The potassium trifluoroborate salt of formula (VII) can be prepared by treating (RS) -4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] of formula (VI) with potassium bifluoride in a mixture of acetone and water at room temperature]Dioxaborolan-2-yl) -cyclohex-3-enecarboxylate. The compound of formula (V [) can be prepared by reacting a compound of formula (V [) with a compound of formula (V [) in the presence of a 1: 1 mixture of a suitable base such as potassium acetate and a suitable palladium catalyst such as the adduct of 1, 1 '-bis (diphenylphosphino) ferrocene and dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane in a suitable solvent such as 1, 4-bis (diphenylphosphino) ferroceneIn an alkane, at 90 ℃ by coupling the compound of formula IV with bis (pinacolato) diboron. The compounds of formula (V) may alternatively be reacted under the conditions of a Suzuki reaction in a suitable organic solvent such as 1, 4-bisAlkane, 1, 2-dimethoxyethane, tetrahydrofuran or toluene, in the presence of catalytic amounts of a 1: 2 mixture of palladium (II) acetate and triphenylphosphine or a 1: 1 mixture of palladium (II) acetate and a bisphosphine ligand or tetrakis (triphenylphosphine) palladium (0), and in the presence of a base such as an alkali metal salt of phosphoric acid or carbonic acid, which can be used without admixture of water or as an aqueous solution, at reaction temperatures from room temperature to reflux, from a compound of the formula (VI) and an aryl or heteroaryl halide R²-X preparation. General scheme C is further illustrated below by general procedure (I).

Scheme 4: general scheme D

The 4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII) is typically asThe following are obtained as a mixture of cis and trans isomers: the 4-substituted cyclohex-3-enecarboxylate intermediate of formula (V) is reduced in a suitable solvent such as ethyl acetate or an alcohol in the presence of catalytic amounts of palladium or platinum on carbon or platinum (IV) oxide at room temperature under an atmosphere of hydrogen (1 bar). Compounds of formulae (V) and (VIII) (residue R thereof²Aryl substituted with one or more halide substituents rather than fluorine) may be partially or fully dehalogenated under these reaction conditions. The acid formed as a result of the dehalogenation reaction may be neutralized by adding a base, such as a trialkylamine, to the reaction mixture. Pretreatment of the palladium or platinum catalysts with zinc halides can in some cases prevent or reduce the compounds of the formulae (V) and (VIII) (the residue R thereof)²Aryl substituted with one or more halide substituents other than fluorine). The cis/trans mixture of the 4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII) may in some cases be separated into the pure cis-4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII-a) and trans-4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII-b) by conventional methods such as silica gel column or high performance chromatography or crystallization, under standard conditions (e.g., in aqueous sodium hydroxide and ether solvents such as 1, 4-bisA mixture of an alkane, tetrahydrofuran or diethyl ether with stirring at room temperature) to pure cis-4-substituted cyclohexanecarboxylic acid intermediate of formula (IX-a) and trans-4-substituted cyclohexanecarboxylic acid intermediate of formula (IX-b). Alternatively, the trans-4-substituted cyclohexanecarboxylic acid intermediate of formula (IX-b) may be obtained by: epimerising the cis-isomer of the cis/trans-mixture of the 4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII) at reflux using a suitable base, e.g. an alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, in a suitable solvent such as methanol, ethanol or toluene, followed by standard conditions (e.g. in aqueous sodium hydroxide and an ether solvent such as 1, 4-bisMixtures of alkanes, tetrahydrofuran or diethyl etherStirred at room temperature) saponifying a crude reaction mixture, which may consist of a mixture of the trans-4-substituted cyclohexanecarboxylic acid intermediate of formula (IX-b) and the trans-4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII-b). In case the epimerisation reaction is carried out in an alcohol as solvent, the crude reaction mixture may alternatively be acidified by addition of concentrated sulfuric acid and heated to reflux to obtain the trans-4-substituted cyclohexanecarboxylic acid ester intermediate of formula (VIII-b). General scheme D is further illustrated below by general procedures (V) and (VI).

Scheme 5: general scheme E

The 4-aroyl-cyclohexanecarboxylic acid ester intermediate of formula (XII) can be prepared by: the cyclohexane-1, 4-dicarboxylic acid monoester of formula (X) is coupled with an aryl or heteroaryl boronic acid of formula (d) in the presence of a mixture of a carboxylic anhydride, such as trimethylacetic anhydride, and a suitable palladium catalyst, such as palladium (II) acetate, and a phosphine ligand, such as tris (4-methoxyphenyl) phosphine, in tetrahydrofuran with a small amount of water at 60 ℃. Alternatively, the 4-aroyl-cyclohexanecarboxylic acid ester intermediate of formula (XII) can be synthesized by: the 4-chlorocarbonyl-cyclohexanecarboxylate of formula (XI), which may be obtained from the cyclohexane-1, 4-dicarboxylic acid monoester of formula (X), by methods known in the art for converting carboxylic acids to carboxylic acid chlorides, such as treatment with thionyl chloride or oxalyl chloride and catalytic amounts of N, N-dimethylformamide, is coupled with an aryl or heteroaryl zinc halide of formula (e) in the presence of a suitable palladium catalyst, such as tetrakis (triphenylphosphine) palladium (0), in tetrahydrofuran at room temperature. Treatment of the 4-aroyl-cyclohexanecarboxylic acid ester intermediate of formula (XII) with a mixture of hydroxylamine hydrochloride and sodium acetate in a suitable alcohol at room temperature gives the oxime intermediate of formula (XIII), which is typically obtained as an E/Z mixture. The oxime intermediate of formula (XIII) can be cyclized to the aryl or heteroaryl iso-derivatives of formula (VIII-1) by treatment with potassium alkoxide base in tetrahydrofuran at room temperatureAn azole intermediate. Alternatively, treatment of the 4-aroyl-cyclohexanecarboxylate intermediate of formula (XII) with benzylthiol and potassium tert-butoxide in tetrahydrofuran at room temperature yields a benzyl ether of formula (XIV), which can be cyclized to the aryl or heteroaryl isothiazole intermediate of formula (VIII-2) via sequential S-debenzylation with sulfonyl chloride in dichloromethane at room temperature and treatment with an ethanolic solution of ammonia in tetrahydrofuran at room temperature. General scheme E is further illustrated below by general procedures (II), (III), (IV), (VII) and (VIII).

Scheme 6: general scheme F

The 4-hydroxymethyl-cyclohexanecarboxylic acid ester of formula (XVI) can be prepared by: 4-hydroxymethyl-cyclohexanecarboxylic acid (XV) is esterified in an alcohol in the presence of a catalytic amount of an acid such as concentrated sulfuric acid at elevated temperature (usually reflux) or the cyclohexane-1, 4-dicarboxylic acid monoester of formula (X) is reduced using conventional methods known in the art, for example borane derivatives such as borane-dimethyl sulfide complex. The alcohol intermediate of formula (XVI) can be oxidized to the aldehyde intermediate of formula (XVII) using conventional methods known in the art for oxidizing primary alcohol groups, for example, treatment with oxalyl chloride, DMSO, and a base such as triethylamine. The hydroxamoyl chloride (hydroxamoyl chloride) intermediate of formula (XIX) can be prepared by: chlorinating the aldoxime intermediate of formula (XVIII), the aldoxime intermediate of formula (XVIII) can be obtained by treating the aldehyde intermediate of formula (XVII) with hydroxylamine hydrochloride in the presence of sodium acetate.

Scheme 7: general scheme G

A hetero group of the formula (VIII-3)The azole intermediate can be obtained by: the nitrile oxide formed in situ by elimination of hydrochloric acid from the hydroxamoyl chloride intermediate of formula (XIX) is 3+2 cyclized using the enol ester intermediate of formula (f) in the presence of a base such as triethylamine, followed by spontaneous removal of the carboxylic acid R' COOH under the reaction conditions.

Scheme 8: general scheme H

A hetero group of the formula (VIII-4)The oxazole intermediate can be obtained from the intermediate of formula (XX) by treatment with hydroxylamine hydrochloride and sodium acetate in succession in toluene in the presence of catalytic amounts of p-toluenesulfonic acid and heating at reflux. The compound of formula (XX) can be obtained by: the hydrazone of formula (h) is deprotonated at low temperature using a strong base such as lithium N, N-diisopropylamide, followed by acylation with a compound of formula (XI). The compounds of formula (h) may be prepared by conventional methods, for example by reaction of a hydrazine derivative NH in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid in a suitable solvent such as ethanol₂-NR 'R' treatment, obtained from a ketone of formula (g).

Scheme 9: general scheme I

Of formula (VIII-5)The oxadiazole intermediate may be obtained by: the hydroxamoyl chloride intermediate of formula (XIX) is treated with the imidoate salt of formula (i) in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane.

Scheme 10: general scheme J

The 4- (1, 1-difluoro-alkyl) -cyclohexanecarboxylic acid ester intermediate of formula (VIII-6) can be prepared by: the acid chloride of formula (XI) is coupled with an alkyl zinc halide of formula (j) in tetrahydrofuran in the presence of a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) at room temperature, followed by treatment of the resulting 4- (alkyl-carbonyl) -cyclohexanecarboxylate intermediate of formula (XXI) with a fluorinating agent such as DAST (in toluene at 80 ℃) or xtal fluor-E ((diethylamino) difluorosulfonium tetrafluoroborate) or xtal fluor-M (difluoro (morpholino) sulfonium tetrafluoroborate) (in dichloromethane or dichloroethane in the presence of an amine such as triethylamine and HF at a suitable reaction temperature).

Scheme 11: general scheme K

The 4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula (VIII) can be converted to the hydrazide of formula (II) by heating with hydrazine hydrate. Alternatively, aqueous solutions of sodium hydroxide or potassium hydroxide and ethereal solvents such as bis (R) may be usedA biphasic mixture of an alkane, tetrahydrofuran or diethyl ether hydrolyses the ester of formula (VIII) to formic acid of formula (IX). The hydrazide of formula (II) can be obtained by: for example by ethyl chloroformate, thionyl chloride, oxalyl chloride or peptide coupling reagents(IX) acid Intermediate of (IX), and subsequent coupling with hydrazine. General scheme F is further illustrated below by general procedures (VII) and (VIII).

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 l/n equivalents 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 V1a 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 V1a 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, 1mM EDTA, 10mM MgCl)₂Adjusted 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, an aliquot of 60mg of yttrium silicate SPA beads (Amersham) and membrane was incubated in binding buffer (50mM Tris, 120mM NaCl, 5mM KCl, 2mM CaCl)₂，10mM MgCl₂) 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 radio laboratory Chemicals). 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 Packard Top-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 IC₅₀The curve was fitted using a non-linear regression model (XLFit) and Ki calculated using the Cheng-Prussoff equation.

The following representative data show that the compounds according to the invention are useful for human V1_aAntagonistic activity of the 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)
		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 proper amount of the mixture to pH5.0
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)	1400
Sodium carboxymethylcellulose	14
		Polyvinyl pyrrolidoneKetone 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. A. the

Thiolactone intermediates of formula (III)

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

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

To a mixture 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 about 10 minutes. The cooling bath was removed and stirring was continued for 2 h. The solvent was concentrated 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. MS m/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) was added potassium tert-butoxide (3.77g, 33.6mmol) in small portions 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 evaporation of two 50ml portions of toluene to give the title compound (2.34g, 92%) as a pale yellow solid. MS m/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. The solvent was evaporated and the residue was crystallized from hot ethanol to give the title compound (1.96g, 60%) as a pale yellow solid. MS m/e: 211.6([ M-H)]-)。

Intermediates of formula (IV)

(RS) -4-Trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester

To a solution of 4-Cyclohexanone ethyl formate (25.0g, 147mmol) in tetrahydrofuran (580mL) was added a 1M solution of lithium bis (trimethylsilyl) amide (154mL, 154mmol) in tetrahydrofuran at-78 ℃. Stirring was carried out for 1h, then a solution of N-phenyl-bis (trifluoromethanesulphonimide) (55.1g, 154mmol) in tetrahydrofuran (80ml) was added. The cooling bath was removed after 30 minutes of complete addition and the reaction mixture was stirred at room temperature for 12 h. The mixture was quenched with 1M aqueous sodium hydrogen sulfate (154ml, 154 mmol). The solvent was removed by rotary evaporation (40 ℃ water bath). The residue was partitioned between tert-butyl methyl ether (500ml) and 0.5M aqueous sodium hydroxide (400 ml). The organic layer was washed with two 400-ml parts of 0.5M aqueous sodium hydroxide solutions, one 200-ml part of saturated ammonium chloride solution and one 100-ml part of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (41.8g, 94.2%) as a yellow oil, which was used in the next step without further purification. MS m/e: 273([ M-C)₂H₅]^-)。

An intermediate of formula (VI)

(RS) -4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -cyclohex-3-enecarboxylic acid ethyl ester

(RS) -4-Trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester (3.0g, 9.92mmol), potassium acetate (2.92g, 29.8mmol) and bis (pinacolato) diboron (3.78g, 14.9mmol) were added to 1, 4-bisThe mixture in an alkane (30ml) was purged with argon. 1, 1 '-bis (diphenylphosphino) ferrocene (0.17g, 0.30mmol) and dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct (0.22g, 0.30mmol) were added, followed by stirring at 90 ℃ for 18 h. The reaction mixture was partitioned between ethyl acetate (200ml) and water (150 ml). The layers were separated. The organic layer was washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash chromatography using n-heptane/ethyl acetate as eluent afforded the title compound (1.95g, 70%) as a pale yellow oil. MS m/e: 281([ M + H)]⁺)

An intermediate of formula (VII)

(RS) - (4- (ethoxycarbonyl) cyclohex-1-enyl) potassium trifluoroborate

To a solution of (RS) -ethyl 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -cyclohex-3-enecarboxylate (0.37g, 1.32mmol) in acetone (9ml) and water (3ml) was added potassium bifluoride (0.41g, 5.28 mmol). Stir at rt for 4h, then evaporate the solvent mixture. The residue was triturated in warm acetonitrile (20 ml). The solids were removed by filtration. The filtrate was concentrated to dryness to give the title compound (0.35g, quantitative) as a white solid, which was used in the next step without further purification.

4-aryl-and 4-heteroaryl-cyclohex-3-enecarboxylate intermediates of formula (V)

General procedure (I):

to a mixture of potassium (RS) - (4- (ethoxycarbonyl) cyclohex-1-enyl) trifluoroborate (1 equivalent), aryl or heteroaryl halide (1.2 equivalents) and potassium carbonate (3 equivalents) in an alcohol such as ethanol or methanol (0.2M) was added (1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride (0.02 equivalents). The mixture was stirred at reflux for 1-20 h. After cooling to room temperature, the solvent was evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrated to dryness. Purification by flash chromatography yields a 4-aryl-or 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula (V).

(RS) -4- (3-fluoro-pyridin-2-yl) -cyclohex-3-enecarboxylic acid ethyl ester

The title compound was obtained as colorless oil in 89% yield from 2-bromo-3-fluoropyridine according to general procedure (I). MS m/e: 250([ M + H ]]⁺).

An intermediate of formula (XI)

trans-4-Chlorocarbonyl-Cyclohexanecarboxylic acid methyl ester

To a solution of monomethyl trans-1, 4-cyclohexanedicarboxylate (2.0g, 11mmol) in dichloromethane (30ml) at 0-5 ℃ were added oxalyl chloride (1.1ml, 13mmol) and a catalytic amount of N, N-dimethylformamide. The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 h. After evaporation of the solvent, the residue was triturated in n-hexane (100 ml). The precipitate was removed by filtration. The filtrate was concentrated in vacuo to yield the title compound (2.2g, quantitative) as a colorless oil, which was used in the next step without further purification.

4-aroyl-cyclohexanecarboxylic acid ester intermediate of formula (XII)

General procedure (II): negishi coupling

To a solution of aryl or heteroaryl bromide (1 eq) in anhydrous tetrahydrofuran (0.2M) at 0-5 deg.C was added a 2M solution of isopropyl magnesium chloride (1.05 eq) in tetrahydrofuran. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. A solution of zinc chloride (2 equivalents) (previously melted by vacuum followed by cool drying under argon) in anhydrous tetrahydrofuran (1.0M) was added to the Grignard intermediate. Stirring was carried out for 1h, followed by addition of 4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (1 eq) and tetrakis (triphenylphosphine) palladium (0) (0.05 eq). After 18-24h the reaction mixture is quenched with saturated aqueous ammonium chloride solution and extracted with two or three portions of an organic solvent such as tert-butyl methyl ether or ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography yields a 4-aroyl-cyclohexanecarboxylic acid ester intermediate of formula (XII).

Trans-4- (2-fluoro-benzoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as colorless liquid in 32% yield from 1-bromo-2-fluorobenzene according to general procedure (II). MS m/e: 264(M +)

An oxime intermediate of formula (XIII)

General procedure (III): oxime formation

A mixture of 4-aroyl-cyclohexanecarboxylic acid ester of the formula XII (1 equivalent), sodium acetate (2.4 equivalents) and hydroxylamine hydrochloride (2.4 equivalents) in an alcohol such as methanol or ethanol (0.1-0.2M) is stirred at room temperature for 2-24 h. The reaction mixture is optionally concentrated to dryness or partitioned directly between an organic solvent such as ethyl acetate or tert-butyl methyl ether and 2M aqueous sodium carbonate solution. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography yields an oxime intermediate of formula (XIII).

Trans-4- { (2-fluoro-phenyl) - [ (E/Z) -hydroxyimino ] -methyl } -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in 98% yield from trans-4- (2-fluoro-benzoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (III). MS m/e: 280([ M + H)]⁺)

Thioether intermediates of formula (XIV)

General procedure (IV): formation of thioethers

A mixture of potassium tert-butoxide (1 eq) and benzylthiol (1.1 eq) in anhydrous tetrahydrofuran (0.3M) was stirred at room temperature under an inert atmosphere for 5 min. A solution (0.3M) of the 4-aroyl-cyclohexanecarboxylic acid ester intermediate of formula (XII) (1 eq) in tetrahydrofuran was added and the reaction mixture was stirred for 16-24 h. The reaction mixture is partitioned between an organic solvent such as ethyl acetate or tert-butyl methyl ether and water. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography yields the thioether intermediate of formula (XIV).

Trans-4- (2-benzylsulfanyl-benzoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as yellow oil in 92% yield from trans-4- (2-fluoro-benzoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (IV). MS m/e: 369([ M + H)]⁺)

An intermediate of formula (XVI)

Trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester

To a solution of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (10.0g, 53.7mmol) in tetrahydrofuran (540ml) at 0-5 ℃ was added borane-dimethylsulfide complex (6.80g, 80.6 mmol). After 15 minutes, the cooling bath was removed and the mixture was stirred for 4 h. The reaction mixture was quenched with methanol (17.2g, 537mmol), stirred for 20min and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (300ml) and filtered over a pad of Decalite. The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (300ml) and 1M aqueous sodium hydroxide (100 ml). The layers were separated. The organic layer was washed with one 100ml portion of water. The combined aqueous layers were extracted with a 150-ml portion of ethyl acetate. The combined organic layers were washed with one 50ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.75g, 94.6%) as a colorless oil, which was used without further purification. MS m/e: 172(M +)

Intermediates of formula (XVII)

Trans-4-formyl-cyclohexanecarboxylic acid methyl ester

To a solution of dimethyl sulfoxide (9.53g, 122mmol) in dry dichloromethane (400ml) at-78 deg.C was slowly added oxalyl chloride (7.74g, 61.0 mmol). The cooling bath was removed and the reaction mixture was stirred at-50 ℃ for 5 min. A solution of trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (8.75g, 50.8mmol) in dichloromethane (108ml) was added at-65 ℃. Stirring was carried out for 30 min, followed by addition of triethylamine (25.7g, 254 mmol). After 15 minutes of complete addition, the cooling bath was removed. The reaction mixture was quenched with 1M aqueous hydrochloric acid (152ml, 152mmol) at-10 ℃. The layers were separated. The organic layer was washed with two 250ml portions of water and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (9.3g, quantitative), which was used in the next step without further purification. MS m/e: 170 (M)⁺)

Intermediate of formula (XVIII)

Trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid methyl ester

To a solution of trans-4-formyl-cyclohexanecarboxylic acid methyl ester (8.65g, 50.8mmol) in methanol (250ml) at 0-5 ℃ was added sodium acetate (12.5g, 152mmol) followed by hydroxylamine hydrochloride (10.6g, 152 mmol). The cooling bath was removed 10 minutes after the addition was complete and the mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (300ml) and 0.5M aqueous sodium hydroxide solution. The layers were separated. The organic layer was washed with 150-ml portions of 0.5M aqueous sodium hydroxide solution. The combined aqueous layers were extracted with one 150ml portion of ethyl acetate. The combined organic layers were washed with one 150ml part of 0.5M aqueous hydrochloric acid and one 100-ml part of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.5g, 90%) as colorless oil, which was used in the next step without further purification. MS m/e: 185(M +)

An intermediate of formula (XIX)

Trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylic acid methyl ester

To a solution of methyl trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylate (5.0g, 27mmol) in N, N-dimethylformamide (135ml) was added N-chlorosuccinimide (3.78g, 28.3mmol) at 0-5 ℃. The cooling bath was removed and the mixture was stirred for 1 h. The reaction mixture was partitioned between diethyl ether (250ml) and ice-water mixture (200 ml). The organic layer was washed with two 200ml portions of water and one 100ml portion of brine. The combined aqueous layers were extracted with one 150-ml portion of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.1g, quantitative) as a colorless viscous oil, which was used in the next step without further purification.

An intermediate of formula (XX)

Trans-4- [2- (dimethyl-hydrazono) -cyclohexanecarbonyl ] -cyclohexanecarboxylic acid methyl ester

a) N' -cyclohexylidene-N, N-dimethyl-hydrazine

To cyclohexanone (2.00g, 20.4 m)mol) and N, N-dimethylhydrazine (1.50ml, 20.4mmol) in ethanol (20ml) was added with a catalytic amount of toluene-4-sulfonic acid monohydrate. The reaction mixture was stirred at 70 ℃ for 72 h. The solvent was evaporated and the residue was purified by Kugelrohr distillation (60-80 ℃, 5mbar) to yield the title compound (2.50g, 87%) as a colorless oil. MS m/e: 141([ M + H)]⁺)

b) Trans- (R5) -4- [2- (dimethyl-hydrazono) -cyclohexanecarbonyl]-Cyclohexanecarboxylic acid methyl ester

To a solution of N, N-diisopropylamine (1.59ml, 11.2mmol) in dry tetrahydrofuran (10ml) at 0-5 deg.C was added 1.6M N-butyllithium in N-hexane (7.00ml, 11.2 mm)_ol). After 15 min N' -cyclohexylidene-N, N-dimethyl-hydrazine (1.50g, 10.7mmol) was added followed by stirring for 90 min. The resulting solution was dropwise added to a solution of methyl trans-4-chlorocarbonyl-cyclohexanecarboxylate (2.19g, 10.7mmol) in anhydrous tetrahydrofuran (50ml) at-65 ℃ via a tube. The reaction mixture was stirred at-78 ℃ for 20 h. The cooling bath was removed and the reaction mixture was quenched by addition of acetic acid (0.65ml, 11mmol) at-5 ℃. The mixture was partitioned between ethyl acetate (150ml) and saturated ammonium chloride solution (100 ml). The layers were separated. The aqueous layer was extracted with a 100-ml portion of ethyl acetate. The combined organic layers were washed with a 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent yielded the title compound (0.98g, 30%) as a pale yellow oil with a purity of 60%. MS m/e: 309([ M + H ]]⁺)

4-alkylcarbonyl-cyclohexanecarboxylates of formula (XXI)

trans-4-Cyclopentanecarbonyl-Cyclohexanecarboxylic acid methyl ester

To a solution of cyclopentylmagnesium chloride (2M in diethyl ether, 6.4ml, 12.9mmol) in tetrahydrofuran (30ml) was added a solution of zinc chloride (2.9g, 21.5mmol) in anhydrous tetrahydrofuran (20ml) which was previously dried by melting in vacuo followed by cooling under argon. The mixture was stirred at room temperature for 45 minutes. Tetrakis (triphenylphosphine) palladium (0.25g, 2 mol%) was added followed by trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (2.20g, 10.7 mmol). The reaction mixture was heated at reflux for 1 h. The mixture was diluted with tert-butyl methyl ether (200ml) and washed with 50-ml parts of saturated aqueous ammonium chloride solution and 30-ml parts of 1M aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography using n-heptane/ethyl acetate as eluent yielded the title compound (2.36g, 92%) as a white solid. MS m/e: 239([ M + H ]]⁺)

4-substituted cyclohexanecarboxylic acid ester intermediates of formula (VIII)

General procedure (V): palladium on carbon catalyzed hydrogenation

A solution (0.1M) of the 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula V and optionally a base such as triethylamine (1 eq) in an organic solvent such as ethyl acetate or toluene is purged with argon. 10% activated carbon palladium (0.05 eq) was added and the flask was subsequently filled with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (1bar) for 20-72 h. By usingThe catalyst was removed by filtration. The filtrate was washed with one portion of water. The aqueous layer was extracted with one or two portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness to yield a cis/trans mixture of the crude 4-heteroaryl-cyclohexanecarboxylate intermediate of formula VIII, which can generally be used in the next step without further purification.

General procedure (VI): epimerization

A mixture of the cis/trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII and sodium ethyl (3-6 equivalents) in ethanol was heated at reflux for 20-72 h. Under these reaction conditions, partial saponification of the resulting trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b to the trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b may occur. Such trans-4-heteroaryl-cyclohexanecarboxylic acid intermediates of formula IX-b can be converted into trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediates of formula VIII-b by successively cooling the mixture to 0-5 ℃, adding concentrated sulfuric acid (7-9 equivalents) and heating the mixture at reflux for 1-2 h. After cooling to room temperature, the reaction mixture was partitioned between an organic solvent such as ethyl acetate or tert-butyl methyl ether and 2M aqueous sodium carbonate solution. The layers were separated. The aqueous layer is extracted with two or three portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography yields the trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b.

General procedure (VII): aryl isoOxazole formation

To a solution of the oxime intermediate of formula XV (1 equivalent) in tetrahydrofuran (0.1-0.2M) at 0 deg.C was added potassium tert-butoxide (1.3 equivalents). The cooling bath was removed after 15 minutes of complete addition and the reaction mixture was stirred at room temperature for 2-24 h. The reaction mixture is partitioned between an organic solvent such as ethyl acetate or tert-butyl methyl ether and water. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography gives 4-aryliso-forms of formula (XVI)An azole-cyclohexanecarboxylate intermediate.

General procedure (VIII): aryl isothiazole formation

To a solution of the thioether intermediate of formula (XIII) (1 eq) in dichloromethane (0.1M) was added sulfonyl chloride (1.05 eq) at 0 ℃. The reaction mixture was stirred for 1 h. After evaporation of the solvent, the residue was redissolved in tetrahydrofuran (0.1M), followed by addition of 2M ammonia in ethanol (10 eq) at room temperature and stirring for 2-3 h. The reaction mixture is partitioned between an organic solvent such as ethyl acetate or tert-butyl methyl ether and a saturated sodium bicarbonate solution. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography yields a 4-arylisothiazole-cyclohexanecarboxylic acid ester intermediate of formula (XIV).

Cis/trans-4- (3-fluoro-pyridin-2-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as colorless liquid in 97% yield from (RS) -4- (3-fluoro-pyridin-2-yl) -cyclohex-3-enecarboxylic acid ethyl ester according to general procedure (V). MS m/e: 252([ M + H ]]⁺)

Trans-4- (3-fluoro-pyridin-2-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as colorless oil in quantitative yield from cis/trans-4- (3-fluoro-pyridin-2-yl) -cyclohexanecarboxylic acid ethyl ester according to general procedure (VI). MS m/e: 252([ M + H ]]⁺)

Trans-4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexanesAlkanecarboxylic acid methyl ester

Prepared according to general procedure (VII) from trans-4- { (2-fluoro-phenyl) - [ (E/Z) -hydroxyimino]Methyl-methyl } -cyclohexanecarboxylate the title compound was obtained in 71% yield as a white solid. MS m/e: 260([ M + H)]⁺)

Trans-4-benzo [ d ] isothiazol-3-yl-cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in 72% yield from trans-4- (2-benzylsulfanyl-benzoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (VIII). MS m/e: 276([ M + H ] +)

Trans-4- (5-methyl-iso)Azol-3-yl) -cyclohexanecarboxylic acid methyl ester

To a solution of methyl trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylate (5.90g, 26.9mmol) and isopropenyl acetate (53.8g, 537mmol) in dichloromethane (134ml) was added triethylamine (5.44g, 53.7mmol) at 0-5 ℃. The cooling bath was removed after 15 minutes of complete addition and the mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (250ml) and 0.1M aqueous hydrochloric acid (200 ml). The organic layer was washed with 100ml portions of 0.1M aqueous hydrochloric acid. The combined aqueous layers were washed with 150ml portions ofAnd (5) extracting with ethyl acetate. The combined organic layers were washed with 200ml portions of 2M sodium carbonate and 100-ml portions of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent yielded the title compound (3.00g, 50%) as a milky white solid. MS m/e: 224([ M + H)]⁺)

Trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid methyl ester

Reacting trans-4- [2- (dimethyl-hydrazinoidene) -cyclohexanecarbonyl]A mixture of methyl cyclohexanecarboxylate (0.95g, 3.1mmol), sodium acetate (0.28g, 3.4mmol) and hydroxylamine hydrochloride (0.24g, 3.4mmol) in methanol (15ml) was stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate (l00ml) and water (50 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue (0.88g) was dissolved in toluene (15 ml). After addition of a catalytic amount of toluene-4-sulfonic acid monohydrate, the mixture was heated at reflux for 3 h. The solvent was evaporated. Purification using n-heptane/ethyl acetate as eluent gave the title compound (0.58g, 72%) according to¹³C-NMR, regioisomeric purity of about 90%. MS m/e: 264([ M + H)]⁺)

Trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester

To a suspension of methyl trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylate (2.46g, 11.2mmol) and ethyl acetimidate hydrochloride (2.77g, 22.4mmol) in dichloromethane (55ml) was added triethylamine (3.10ml, 22.4mmol) at 0-5 ℃. The cooling bath was removed after 15 minutes of complete addition. After stirring overnight, the solvent was evaporated. The residue was partitioned between 1M aqueous hydrochloric acid (50ml) and ethyl acetate (50 ml). The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo.

To the residue, trans-4- (5-methyl- [1, 2, 4 ] at 0-5 deg.C]A solution of a mixture of oxadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester and trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid methyl ester in N, N-dimethylformamide (33ml) was added N-chlorosuccinimide (1.59g, 11.9 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between tert-butyl methyl ether (150ml) and water (50 ml). The aqueous layer was separated. The organic layer was washed with two 50-ml parts of water and one 30-ml part of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylate and trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester.

To the mixture thus obtained and a suspension of ethyl acetimidate hydrochloride (2.77g, 22.4mmol) in dichloromethane (55ml) was added triethylamine (3.10ml, 22.4mmol) at 0-5 ℃. After 15 minutes the cooling bath was removed and the reaction mixture was stirred overnight. The solvent was evaporated. The residue was partitioned between 1M aqueous hydrochloric acid (50ml) and ethyl acetate (50 ml). The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. On silica gelFlash chromatography with n-heptane/ethyl acetate yielded the title compound (1.56g, 59%) as a colorless amorphous solid. MS m/e: 225([ M + H)]⁺)

Trans-4- (cyclopentyl-difluoro-methyl) -cyclohexanecarboxylic acid methyl ester

A solution of trans-4-cyclopentanecarbonyl-cyclohexanecarboxylic acid methyl ester (1.0g, 4.2mmol) and DAST (1.1ml, 8.4mmol) in dry toluene (2ml) was stirred at 80 ℃ overnight (16 h). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50m1) and tert-butyl methyl ether (100m 1). The layers were separated. The aqueous layer was extracted with two 100-ml portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography using n-heptane/ethyl acetate as eluent gave the title compound (0.13g, 12%) as a brown oil. MS m/e: 261 (M)⁺)

4-substituted cyclohexanecarboxylic acid intermediates of formula (IX)

Trans-4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexanecarboxylic acids

Reacting trans-4-benzo [ d]Different from each otherAzol-3-yl-cyclohexanecarboxylic acid methyl ester (6.77g, 26.1mmol) and 2M aqueous sodium hydroxide solution (131ml, 261mmol) in 1, 4-bisThe mixture in alkane (261ml) was stirred at room temperature for 20 h. The reaction mixture was cooled by addition of crushed ice (120g) and acidified with concentrated hydrochloric acid (21.8ml, 261 mmol). The reaction mixture was extracted with three 150-ml portions of ethyl acetate. The combined organic layers were washed with a 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude acid was crystallized from hot ethyl acetate to give the title compound (4.09g, 64%) as white crystals. MS m/e: 246([ M + H ]]+)。

Cis/trans-4-isobutyl-cyclohexanecarboxylic acid (15: 85)

a) Cis/trans-4-isobutyl-cyclohexanecarboxylic acid (7: 3)

A solution of 4-isobutylbenzoic acid (1.0g, 5.6mmol) in acetic acid (56ml) was purged with argon. After addition of platinum (IV) oxide (0.38g, 1.7mmol), the reaction flask was filled with hydrogen. The reaction mixture was stirred at RT under hydrogen atmosphere for 72 h. The flask was purged with argon and the catalyst was removed by filtration using Decalite. The filtrate was concentrated to dryness to give the title compound as a (7: 3) cis/trans mixture. MS m/e: 183([ M-H)]^-)

b) Cis/trans-4-isobutyl-cyclohexanecarboxylic acid methyl ester (7: 3)

To a solution of cis/trans-4-isobutyl-cyclohexanecarboxylic acid (7: 3) (1.0g, 5.4mmol) in methanol (54ml) was added a catalytic amount of sulfuric acid (2 drops). The reaction mixture was heated at reflux for 16 h. The solvent was evaporated. The residue was diluted with tert-butyl methyl ether (100ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound ((7: 3) cis/trans mixture) as a pale yellow oil. MS m/e: 198 (M)⁺)

c) Cis/trans-4-isobutyl-cyclohexanecarboxylic acid (15: 85)

A2-neck round-bottom flask, dried under argon and cooled, was charged with cis/trans-4-isobutyl-cyclohexanecarboxylic acid methyl ester (7: 3) (0.5g, 2.5mmol), anhydrous toluene (10ml) and sodium methoxide (0.41g, 7.6 mmol). The reaction mixture was heated at reflux for 96 h. After cooling to room temperature, the mixture was diluted with tert-butyl methyl ether (100ml) and washed with ice-cold aqueous hydrochloric acid (pH 1). The aqueous layer was extracted with a 50-ml portion of t-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a (15: 85) cis/trans mixture. MS m/e: 183([ M-H)]^-)

Hydrazide intermediates of formula (II)

General procedure (IX): formation of hydrazides from acids

To a solution of the 4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula (IX) (1 eq) and triethylamine (1.05 eq) in tetrahydrofuran (0.2M) was added ethyl chloroformate (1.05 eq) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 h. The ammonium salt was removed by filtration. The filtrate was added to a cold solution (0.2M) of hydrazine hydrate (2 eq) in methanol. The reaction mixture was stirred at room temperature for 2-16 h. The solvent was evaporated under reduced pressure and the residue partitioned between an organic solvent such as ethyl acetate or dichloromethane and water. The organic layer was separated. The aqueous layer is extracted with two or three portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the hydrazide intermediate of formula (II), which was typically used in the next step without further purification.

General procedure (X): formation of hydrazides from esters

A mixture (0.2-1M) of the 4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula (VIII) (1 eq) and hydrazine hydrate (2-6 eq) in n-butanol was 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 yield the hydrazide intermediate of formula (II), which was typically used in the next step without further purification.

Hydrazide 1

Trans-4- (3-fluoro-pyridin-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in quantitative yield from trans-4- (3-fluoro-pyridin-2-yl) -cyclohexanecarboxylic acid ethyl ester according to general procedure (X). MS m/e: 238([ M + H)]⁺)

Hydrazide 2

Trans-4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexanecarboxylic acid hydrazide

By trans-4-benzo [ d ] according to general procedure (IX)]Different from each otherOxazol-3-yl-cyclohexanecarboxylic acid the title compound was obtained in 78% yield as a white solid. MS m/e: 260([ M + H)]+)

Hydrazide 3

Trans-4-benzo [ d ] isothiazol-3-yl-cyclohexanecarboxylic acid hydrazide

From trans-4-benzo [ d ] according to general procedure (X)]Isothiazol-3-yl-cyclohexanecarboxylic acid methyl ester the title compound was obtained in 62% yield as a white solid. MS m/e: 275 (M)⁺)

Hydrazide 4

Trans-4- (5-methyl-iso)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

From trans-4- (5-methyl-iso) according to general procedure (X)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester the title compound was obtained in 91% yield as a white solid. MS m/e: 224([ M + H)]⁺)

Hydrazide 5

Trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

Prepared according to general procedure (X) from trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester is obtained in 60% yieldThe title compound was a white solid. MS m/e: 225([ M + H)]⁺)

Hydrazide 6

Trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

And

hydrazide 7

Trans-4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) cyclohexanecarboxhydrazide

According to general procedure (X), from trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid methyl ester to obtain trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid and trans-4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) cyclohexanecarboxhydrazide as a mixture, which was used in the next step without purification. MS m/e: 263, 264([ M + H)]⁺)

Hydrazide 8

Trans-4- (cyclopentyl-difluoro-methyl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as light yellow solid in 88% yield from trans-4- (cyclopentyl-difluoro-methyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (X). MS m/e: 261([ M + H)]⁺)

Hydrazide 9

Cis/trans-4-isobutyl-cyclohexanecarboxylic acid hydrazide (15: 85)

The title compound was obtained as milky white solid in 97% yield from cis/trans-4-isobutyl-cyclohexanecarboxylic acid (15: 85) according to general procedure (IX). MS m/e: 199([ M + H ] +)

Examples

General procedure (XI): 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

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

The title compound was obtained as white solid in 75% yield according to general procedure (XI).

Hydrazide: trans-4- (3-fluoro-pyridin-2-yl) -cyclohexanecarboxylic acid hydrazide

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

MS m/e：399([M+H]⁺)

Example 2

1- (4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene derivatives

The title compound was obtained as a cream solid in 82% yield according to general procedure (XI).

Hydrazide: trans-4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexanecarboxylic acid hydrazide

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

MS m/e：421([M+H]⁺)

Example 3

1- (4-benzo [ d ] isothiazol-3-yl-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e1 azulene

The title compound was obtained as a cream solid in 82% yield according to general procedure (XI).

Hydrazide: trans-4-benzo [ d ] isothiazol-3-yl-cyclohexanecarboxylic acid hydrazide

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

MS m/e：437([M+H]⁺)

Example 4

8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene derivatives

The title compound was obtained as white solid in 41% yield according to general procedure (XI).

Hydrazide: trans-4- (5-methyl-iso)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

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

MS m/e：385([M+H]⁺)

Example 5

8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene derivatives

Example 6

8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene

After chromatographic separation according to general procedure (XI), trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ] is obtained]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene and trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]And (2) azulene.

Hydrazide: trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherMixture of oxazol-3-yl) -cyclohexanecarboxylic acid hydrazide and trans-4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) cyclohexanecarboxhydrazide

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

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ] was obtained in 25% yield]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene as a milky white solid.

MS m/e：425([M+H]⁺)

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene was obtained in 11% yield as a cream solid.

MS m/e：424([M+H]⁺)

Example 7

8-chloro-1- [4- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]Azulene derivatives

The title compound was obtained as a cream solid in 18% yield according to general procedure (XI).

Hydrazide: trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

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

MS m/e：386([M+H]⁺)

Example 8

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

The title compound was obtained as a cream solid in 25% yield according to general procedure (XI).

Hydrazide: trans-4- (cyclopentyl-difluoro-methyl) -cyclohexanecarboxylic acid hydrazide

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

MS m/e：422([M+H]⁺)

Example 9

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

The title compound was obtained as a cream solid in 42% yield according to general procedure (XI).

Hydrazide: cis/trans-4-isobutyl-cyclohexanecarboxylic acid hydrazide (15: 85)

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

MS m/e：360([M+H]⁺)

¹Robben et al (2006) Am J Physiol Secondary Physio1.291, F257-70, "Cellbiogical aspects of the vasopressin type-2receptor and aquaporin2water channel in a new genetic reagents excipients

²Neumann(2008).J Neuroendocrinol.20，858-65，″Brain oxytocin∶a keyregulator of emotional and social behaviours in both females and males″

³Ebner et al (2002), Eur J Neurosci.15, 384-8, "formed shock suppressing enzyme with the amygdala to modulated stress-coding sequences inquiries

⁴Kendler et al (2003), Arch Gen psychological.60, 789-96, "Life events dimensions of Loss, Humiliation, Entrap, and Danger in the compression of events of Major and Generalized approximation

⁵Region et al (1998). Br J Psychiatry suppl.24-8, "Presence of antibiotic disorders and the human regulatory with motion and active disorders

⁶Bielsky et al (2004) neuropsychopharmacology.29, 483-93, "primer in social recognition and reproduction in affinity-like behavor in Vasopressin V l a receptor knock out die

⁷Landgraf et al (1995), Regul peptide.59, 229-39, "Vl Vasopressin receptor oligodeoxynucleotide inter-receptor heavy expression, social differentiation inhibitors, and affinity-related behavor in rates

⁸Yirmiya et al (2006), 11, 488-94, "Association between the imaging Vasopressin 1a receiver (AVPR1a) gene and automation in affinity-based study: diagnosis by Association study

⁹Thompson et al (2004) psychoneuroendocrinology.29, 35-48, "The effect vector vasopression on human facial responses related to social communication

¹⁰Raskind et al (1987), Biol Psychiatry.22, 453-62, "antibiotic drug and plasma Vasopressin in normals and acid schzopyrenic pathogens

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^{Heart with heart-shaped}Michelini and Morris (1999). Ann N Y Acad Sci.897, l98-211, "endogenesis Vasopressin models the cardiovasular valves to exercise

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Claims (14)

1. A compound of the formula I,

wherein

R¹Is halogen, and

R²selected from the group consisting of:

i) heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents which are independentlyIs 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) an aryl group which is 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_3-7-cycloalkyl, 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; and

iv)C_1-6-an alkyl group which is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: OH, halogen, cyano, C_3-7-cycloalkyl radical, C_1-6Alkoxy and halogen-C_1-6-an alkoxy group;

or a pharmaceutically acceptable salt thereof.

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

3. The compound of any one of claims 1 or 2, wherein R²Selected from the group consisting of: unsubstituted heteroaryl, by halogen or C_1-6-alkyl-substituted heteroaryl, unsubstituted C_1-6Alkyl and by halogen and C_3-7-cycloalkyl-substituted C_1-6-an alkyl group.

4. A compound according to any one of claims 1 to 3, wherein R²Selected from the group consisting of: 3-fluoro-pyridinyl, 4-benzo [ d ]]Isothiazolyl, 5-methyl- [1, 2, 4 ]]Oxadiazolyl, 5-methyl-iso-methylAzolyl, 4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzolyl, 4, 5, 6, 7-tetrahydro-1H-indazolyl, isobutyl, cyclopentyl-difluoro-methyl and 4-benzo [ d]Different from each otherAn azole group.

5. The compound according to any one of claims 1 to 4, selected from the group consisting of:

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

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

8-chloro-1- [4- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

8-chloro-1- [4- (4,5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-1H-indazol-3-yl) -cyclohexyl ] -4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e ] azulene,

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

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

1- (4-benzo [ d ]]Different from each otherAzol-3-yl-cyclohexyl) -8-chloro-4H, 6H-5-oxa-2, 3,10 b-triaza-benzo [ e]The feed additive comprises (A) azulene and (B),

or a pharmaceutically acceptable salt thereof.

6. A process for the preparation of a compound of formula I according to any one of claims 1 to 5, 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 4.

7. A compound of formula I according to any one of claims 1 to 5, when manufactured by a process as claimed in claim 6.

8. A compound of formula I according to any one of claims 1 to 5 for use as therapeutically active substance.

9. A compound of formula I according to claims 1 to 5 for use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diseases and disorders associated with Vla receptor antagonism.

10. Compounds of formula I according to claims 1 to 5 for use as therapeutically active substances which act peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia and aggressive behavior.

11. Pharmaceutical compositions comprising a compound of formula I according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

12. Use of a compound of formula I according to any one of claims 1 to 5 for the preparation of a medicament that acts peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia and aggressive behavior.

13. A method of using a compound according to any one of claims 1 to 5 to act peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior, said method comprising administering said compound of formula I to a human being or animal.

14. The invention as described above.