阅读说明：本技术 作为gpr40激动剂的3-苯基-4-己炔酸衍生物 (3-phenyl-4-hexynoic acid derivatives as GPR40 agonists ) 是由 马特乌什·马赫 拉多斯劳·吉达 达米安·斯穆加 菲利普·史迪玛 米科拉伊·马特洛克 卡塔日 于 2019-01-07 设计创作，主要内容包括：式(I)的化合物及其盐,其中R表示直链或支化的、伯或仲非环烃基C3-C15基团,其可以是饱和或不饱和的,或者直链或支化的、伯或仲非环烃基C3-C15基团,其可以是饱和或不饱和的且其中一个或多个氢原子被氟原子取代；X表示氢原子或卤素原子,*表示手性中心。该化合物可用于治疗由GPR40介导的疾病,尤其是II型糖尿病。<Image he="610" wi="687" file="DDA0002653133940000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Compounds of formula (I) and salts thereof, wherein R represents a linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group, which may be saturated or unsaturated, or a linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group, which may be saturated or unsaturated, and salts thereofWherein one or more hydrogen atoms are replaced by fluorine atoms; x represents a hydrogen atom or a halogen atom, and X represents a chiral center. The compounds are useful for the treatment of diseases mediated by GPR40, in particular type II diabetes.)

1. a compound of formula (I)

Wherein:

-R represents:

a linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group which may be saturated or unsaturated, or

A linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group, which may be saturated or unsaturated and in which one or more hydrogen atoms are replaced by fluorine atoms;

x represents a hydrogen atom or a halogen atom, and

-,

and salts thereof, particularly pharmaceutically acceptable salts,

with the proviso that formula (I) excludes 3- (4- { [ (2E,3Z) -2-propyliden-3-en-1-yl ] oxy } phenyl) hex-4-ynoic acid and (3R/S) -3- [4- (prop-2-yn-1-yloxy) phenyl ] hex-4-ynoic acid.

2. A compound of formula (I)

Wherein:

-R represents:

a linear or branched, primary or secondary acyclic hydrocarbyl C4-C15 group which may be saturated or unsaturated, or

A linear or branched, primary or secondary acyclic hydrocarbyl C4-C15 group, which may be saturated or unsaturated and in which one or more hydrogen atoms are replaced by fluorine atoms;

x represents a hydrogen atom or a halogen atom, and

-,

and salts thereof, particularly pharmaceutically acceptable salts,

with the proviso that formula (I) excludes 3- (4- { [ (2E,3Z) -2-propylidene-pent-3-en-1-yl ] oxy } phenyl) hex-4-ynoic acid.

3. The compound according to claim 1 or 2, wherein R represents a linear or branched acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group, which may be saturated or unsaturated.

4. A compound according to claim 3, wherein R represents a linear saturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

5. A compound according to claim 3, wherein R represents a branched saturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

6. A compound according to claim 3, wherein R represents a linear unsaturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

7. A compound according to claim 3, wherein R represents a branched unsaturated acyclic hydrocarbyl C4-C15 group, particularly a C4-C12 group.

8. The compound of claim 6 or 7, wherein unsaturated acyclic hydrocarbyl comprises only double bonds as unsaturated bonds.

9. A compound according to claim 1 or 2, wherein R represents a linear or branched, primary or secondary acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group, which may be saturated or unsaturated and in which one or more hydrogen atoms are substituted by fluorine atoms.

10. The compound according to claim 9, wherein R represents a linear saturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

11. The compound according to claim 9, wherein R represents a branched saturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

12. The compound according to claim 9, wherein R represents a linear unsaturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

13. The compound according to claim 9, wherein R represents a branched unsaturated acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

14. The compound of claim 12 or 13, wherein unsaturated acyclic hydrocarbyl comprises only a double bond as an unsaturated bond.

15. A compound according to any one of claims 1 to 14, wherein X represents a hydrogen atom.

16. A compound according to any one of claims 1 to 14, wherein X represents a halogen atom, preferably a fluorine atom.

17. A compound according to any one of claims 1 to 16, wherein one, two or three hydrogen atoms on the same carbon atom are substituted by one, two or three fluorine atoms, respectively forming CH₂F、CHF₂Or CF₃A group.

18. A compound according to any one of claims 1 to 17 in the form of a single enantiomer, a single diastereomer, a racemate, or a mixture of enantiomers or diastereomer.

19. A compound according to any one of claims 1 to 18 in the form of a single enantiomer or diastereomer having structure (Ia)

20. A compound according to claim 1 or 2 which is (3S) -3- {4- [ (2, 3-dimethylbut-2-en-1-yl) oxy ] phenyl } hex-4-ynoic acid and pharmaceutically acceptable salts thereof.

21. A compound of formula (I) according to any one of claims 1 to 18 for use as a medicament.

22. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 18 and a pharmaceutical excipient.

23. A method of treating a GPR 40-mediated disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 18, wherein the subject is a mammal, particularly a human.

24. The method of claim 21, wherein the disease is type II diabetes.

25. The method of claim 21, wherein the disease is diabetic neuropathy.

Technical Field

The present invention relates to novel 3-phenyl-4-hexynoic acid derivatives exhibiting GPR40 receptor agonist activity, pharmaceutical compositions comprising said derivatives and their use in the treatment of GPR40 mediated diseases, in particular type 2 diabetes.

Background

G protein-coupled receptors (GPCRs) are integral membrane proteins responsible for transmitting signals through the double lipid layer to effector sites within the cell. They participate in the signaling cascade through a number of signaling molecules: hormones, neurotransmitters, small proteins, short peptide chains, amines, lipids, nucleotides or amino acids and fatty acid derivatives. For each signaling molecule, there is a receptor or group of receptors that is capable of binding a particular molecule, thereby initiating signal transduction through the cell membrane. GPCRs play an important role in regulating physiological processes involved in cellular work, metabolism, growth and immune defense.

The G protein-coupled receptor 40(GPR40), also known as free fatty acid receptor 1(FFA1), is a protein that is expressed in pancreatic β islet cells to a lesser extent in the brain. This receptor is activated by fatty acids and mediates the direct action of fatty acids on the insulinotropic activity of pancreatic beta cells. The insulinotropic effect of GPR40 is insulin dependent. Only in the presence of elevated glucose levels, its activation leads to enhanced beta cell insulin secretion, thereby reducing the risk of hypoglycemia.

Intensive research work is underway to find small molecule GPR40 Ligands and use them in drug therapy, mainly for type 2diabetes (Takafumi Hara, Ligands at Free Fatty Acid Receptor 1, Handbook of Experimental Pharmacology, Springer International Publishing AG 2016). These ligands may be potential antidiabetic agents as antihyperglycemic agents without the risk of hypoglycemia. Some compounds have entered the clinical trial phase, but whatever their activity relative to GPR40, they were found to have potential hepatotoxicity or to produce other side effects, or to cause elevated insulin levels without lowering glucose levels. Since GPR40 is not expressed in the liver, the molecular mechanism of hepatotoxicity may not be directly related to the activation of GPR40, but may occur down in the signaling cascade activated upon ligand binding. This mechanism is presumed to be associated with bile acid transport inhibitory activity and bile acid homeostasis disorders.

Compounds having GPR40 modulating activity typically include as a common moiety an acidic head group, usually a carboxyl group in the phenylpropionic backbone, which is believed to be responsible for receptor binding, and a hydrophobic tail group, usually an aromatic fragment, attached to the head group via a linker, usually having a length of 2 to 4 carbon atoms, and preferably having an ether linkage. Thus, the structure of the fatty acid, the natural GPR40 ligand, is mimicked by synthetic modulators. In previously known compounds, the tail group may be a monocyclic or bicyclic group.

WO2004/041266 discloses compounds as modulators of GPR40 function which are defined solely by the presence of aromatic ring moieties and groups capable of releasing cations, especially carboxyl groups.

WO2004/106276 discloses carboxylic acids as modulators of GPR40 function wherein the head group is a bicyclic group of the formula:

wherein A may be a benzene ring, Xc may represent an oxygen atom, D may represent a phenyl group, a thienyl group or a thiazole ring, B is a 5-7-membered non-aromatic ring, and Xd may represent a bond, CH or CH₂。

WO2005/086661 discloses GPR40 modulators for controlling insulin levels of the formula:

Q-L¹-P-L²-M-X-L³-A

specifically, WO2005/086661 discloses carboxylic acids based on a phenylpropionic acid backbone as one of the GPR40 modulators comprising an ethynyl substituent in the beta position relative to the carboxy group of the formula:

wherein R is²⁵Is hydrogen or an alkyl, oxyalkyl, aryl or heteroaryl radical, especially methyl, R²⁸Is phenyl or benzyl, or pyridyl or pyrrolyl (pyryl group), optionally substituted with various substituents. WO2005/086661 also discloses the compound (3R/S) -3- [4- (prop-2-yn-1-yloxy) phenyl]Hex-4-ynoic acid (compound No. 17.38), which is not included in the above formula and provides no information about its biological activity.

One of the compounds specifically disclosed in WO2005/086661 is (3S) -1-propyn-1-yl-4- [ [4'- (trifluoromethyl) [1,1' -biphenyl ] -3-yl ] methoxy ] phenylpropionic acid (also known as code AMG-837) of the following structural formula:

it was reported that this compound increased plasma levels of insulin in phase I clinical trials ("Free FattyAcid Receptors" Handbook of Experimental Pharmacology, vol.236, ISBN 978-3-319-. However, further studies were abandoned.

WO2005/063729 discloses compounds having non-bicyclic head groups of the formula:

WO2005/087710 discloses compounds having a bicyclic head group and a nitrogen linker of the formula:

WO2008/001931 discloses compounds as modulators of GPR40 function of the formula:

having a bicyclic head group, wherein R¹Is alkylsulfonyl, R is hydroxy and B is preferably tetrahydropyran ring. One of the compounds described is 2- [ (3S) -6 of the formula]- [ [3- [2, 6-dimethyl-4- (3-methylsulfonylpropoxy) phenyl group]Phenyl radical]Methoxy radical]-2, 3-dihydro-1-benzofuran-3-yl]Acetic acid (also known as fasiglifam or TAK-875):

in phase 3 clinical trials, the compound showed the ability to lower blood glucose levels in type 2 diabetic patients. However, further studies have been abandoned due to side effects on the liver (associated with inhibitory activity on bile acid transport and disturbed bile acid homeostasis) (A. Mancini et al, GPR40 agonists for the treatment of type 2Diabetes: life after-TAKing "a hit", Diabetes Obesity and Metabolism 2015.17p.622-629).

WO2013/128378 discloses compounds based on phenylpropionic acid backbone having a heterocyclic substituent in the β -position relative to the carboxyl group of formula:

WO2011/046851 discloses carboxylic acid compounds based on phenylpropionic acid backbones as GPR40 activators having an ethynyl substituent at the β position relative to the carboxy group and having a spiropiperidine substituent of an aromatic tail fragment:

WO2013/025424 discloses GPR40 activators based on a phenylpropionic acid backbone with an ethynyl substituent in the beta position relative to the carboxyl group and with 1- (thien-2-ylmethyl) -1,2,3, 4-tetrahydroquinoline as aromatic fragment.

WO2015/105786 discloses GPR40 activators based on a phenylpropionic backbone with an ethynyl substituent at the β position relative to the carboxyl group and with a bicyclic triazolopyridine moiety as aromatic fragment.

WO2012/011125 discloses GPR40 activators based on a phenylpropionic acid backbone with a cyano substituent in the beta position relative to the carboxyl group and having an aromatic fragment containing an oxime function.

WO2010/143733 discloses GPR40 activators of the formula:

wherein the ether-type linker is substituted with an amine-type linker and Y is CH₂NH orO, Z is CH or N, and X is CH₂Or with R¹Together may form a cycloaliphatic ring.

WO2013/0125732 discloses ghrelin O-acetyltransferase (GOAT) inhibitors of the formula:

US2009/0111859 discloses compounds of the formula:

US2008/0090840 discloses compounds of the formula:

US2008/0176912 discloses compounds of the formula:

wherein Q represents phenyl or a 5-membered heterocyclic ring.

WO2012/136221 discloses compounds of the formula:

US2012/004166 discloses aryloxyalkylene substituted hydroxyphenylhexynoic acid derivatives of the formula wherein a represents (C6-C10) -aryl, (C3-C10) cycloalkyl or a 4-12 membered heterocycle, in particular phenyl or pyridyl, have activity in activating GPR40 and lowering plasma glucose, and are of potential use in the treatment of diabetes.

There is a need for new compounds that exhibit GPR40 receptor agonist activity and are potentially useful for the treatment of metabolic disorders, particularly type 2diabetes, preferably without producing liver effects, particularly without inhibiting bile acid secretion.

Brief description of the invention

Objects of the present invention are compounds of formula (I):

wherein:

-R represents:

a linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group which may be saturated or unsaturated, or

A linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group, which may be saturated or unsaturated and in which one or more hydrogen atoms are replaced by fluorine atoms;

x represents a hydrogen atom or a halogen atom,

-,

and salts thereof, particularly pharmaceutically acceptable salts,

with the proviso that formula (I) excludes 3- (4- { [ (2E,3Z) -2-propylidene pent-3-en-1-yl ] oxy } phenyl) hex-4-ynoic acid and (3R/S) -3- [4- (prop-2-yn-1-yloxy) phenyl ] hex-4-ynoic acid.

3- (4- { [ (2E,3Z) -2-Propylenepent-3-en-1-yl)]Oxy } phenyl) hex-4-ynoic acid is a compound contained in the National Center for Biotechnology Information (NCBI) database. A PubChem substance database; the SID is 344303732, the sum of the SID,https:// pubchem. ncbi. nlm. nih. gov/substance/344303732(2017, 10)Month 20 visit). No information is provided about its biological activity or use.

(3R/S) -3- [4- (prop-2-yn-1-yloxy) phenyl ] hex-4-ynoic acid is disclosed in WO2005/086661, although its activity has not been reported.

Unlike GPR40 modulators known in the prior art, the compounds of the present invention do not have an aromatic or (hetero) ring in the tail moiety and show GPR40 receptor modulating activity. The compounds of the present invention do not exhibit bile acid transporter inhibitory activity and therefore do not have hepatotoxic effects.

The compounds of the invention are compounds with free carboxyl groups which can be present as liquids under normal conditions (slurries, oils) and therefore do not risk crystallization in hepatocytes, as has been the case with the previous high molecular weight GPR40 activators, as in the case of TAK-875(Wolenski f. s.,2017, — fastlifam (TAK-875) alternatives bit acid homespace in rates and logs: a patent house of Drug Induced Liver Injury, TOXICOLOGICAL SCIENCES,157(1),2017, 50-61).

At the same time, the same compound can be converted into a suitable, pharmaceutically acceptable solid salt, which is a more convenient and practical form for manufacturing and purifying the compound of the invention due to its physical state, to form the active ingredient (API) of the pharmaceutical composition.

The compounds of the invention have a reduced Molecular Weight (MW) relative to a reference compound (fasiglifam), TAK-875, while having an activity (EC50 value) comparable to or higher than that of the reference compound. This means a better-molecular yield (molecular yield) "(i.e. Ligand Efficiency (LE) value). In other words, the compounds of the invention may achieve comparable or better biological effects using a lower number of atoms to construct a GPR40agonist ligand than the reference compound. This also means, on the one hand, that the economy of manufacture is better and, on the other hand, that side effects may be lower due to the simultaneous reduction in lipophilicity associated with the reduction in molecular weight.

Compounds of formula (I) as GPR40 receptor ligands, have GPR40 receptor modulating activity (they are agonists) and may find use in the treatment of GPR40 mediated diseases.

In another aspect, the present invention also has for its object a compound of formula (I) as defined above for use as a medicament.

In another aspect, the invention also aims at a pharmaceutical composition comprising a compound of formula (I) as defined above, together with pharmaceutical excipients.

In a further aspect, the invention also resides in the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment of a GPR40 mediated disease.

In another aspect, the present invention also aims at a method of treating a disease mediated by GPR40 in an individual in need thereof, which method comprises administering to said individual an effective amount of a compound of formula (I) as defined above.

In another aspect, an object of the present invention is a compound of formula (I) as defined above for use in a method of treatment of a disease mediated by GPR40 in an individual in need thereof, which method comprises administering to said individual an effective amount of said compound.

GPR 40-mediated diseases include cancer and metabolic diseases, including diseases such as diabetes, type 2diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, neuropathy, and metabolic syndrome.

Detailed Description

Preferred embodiments of the present invention are described in the following detailed description and the appended claims. Various aspects of the invention are more precisely defined herein. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Reference throughout this specification to one embodiment "or an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as would be understood by one of ordinary skill in the art. In addition, although some embodiments described herein include some, but not other, features included in other embodiments, combinations of features of the various embodiments may be covered by the scope of the invention, and form various examples for implementing the invention, as understood by those skilled in the art. For example, in the following claims, any of the claimed embodiments may be used in any combination.

In a first aspect, objects of the present invention are compounds of formula (I)

Wherein:

-R represents:

a linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group which may be saturated or unsaturated, or

A linear or branched, primary or secondary acyclic hydrocarbyl C3-C15 group, which may be saturated or unsaturated and in which one or more hydrogen atoms are replaced by fluorine atoms;

x represents a hydrogen atom or a halogen atom,

-,

and salts thereof, particularly pharmaceutically acceptable salts,

with the proviso that formula (I) excludes 3- (4- { [ (2E,3Z) -2-propyliden-3-en-1-yl ] oxy } phenyl) hex-4-ynoic acid and (3R/S) -3- [4- (prop-2-yn-1-yloxy) phenyl ] hex-4-ynoic acid.

In another aspect, objects of the present invention are compounds of formula (I)

Wherein:

-R represents:

a linear or branched, primary or secondary acyclic hydrocarbyl C4-C15 group which may be saturated or unsaturated, or

A linear or branched, primary or secondary acyclic hydrocarbyl C4-C15 group, which may be saturated or unsaturated and in which one or more hydrogen atoms are replaced by fluorine atoms;

x represents a hydrogen atom or a halogen atom,

-,

and salts thereof, particularly pharmaceutically acceptable salts,

with the proviso that formula (I) excludes 3- (4- { [ (2E,3Z) -2-propylidene-pent-3-en-1-yl ] oxy } phenyl) hex-4-ynoic acid.

In one of the embodiments of both aspects of the compounds of formula (I), R represents a linear or branched acyclic hydrocarbyl C4-C15 group, particularly a C4-C12 group, which may be saturated or unsaturated.

In one of the embodiments of both aspects of the compounds of formula (I), R represents a linear or branched, saturated, acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

The preferred straight chain saturated hydrocarbon group is n-butyl.

Another preferred straight chain saturated hydrocarbon group is n-pentyl.

Another preferred straight chain saturated hydrocarbon group is n-hexyl.

Another preferred straight chain saturated hydrocarbon group is n-heptyl.

A preferred branched saturated hydrocarbon group is 3-methylbutyl.

Another preferred branched saturated hydrocarbon group is isobutyl.

Another preferred branched saturated hydrocarbyl group is sec-butyl.

Another preferred branched saturated hydrocarbon group is 2-methyl-1-butyl.

Another preferred branched saturated hydrocarbon group is 2-ethyl-1-butyl.

Another preferred branched saturated hydrocarbon group is 2-pentyl.

Another preferred branched saturated hydrocarbon group is 3-methyl-2-butyl.

In one of the embodiments of both aspects of the compounds of formula (I) according to the invention, R represents a linear or branched, unsaturated, acyclic hydrocarbyl C4-C15 group, in particular a C4-C12 group.

The linear or branched unsaturated acyclic hydrocarbon radicals C3-C15 or C4-C15, in particular C4-C12, may contain one double bond or more than one double bond in the conjugated or unconjugated system of stereochemical configuration E or Z. Preferably, the hydrocarbyl C3-C15 or C4-C15 groups, especially C4-C12 groups, contain two double bonds in the nonconjugated or conjugated system. The straight-chain or branched unsaturated acyclic hydrocarbyl C3-C15 or C4-C15 groups, in particular C4-C12 groups, may also contain one or more triple bonds, preferably one triple bond.

Preferably, in all of the groups, subgroups and embodiments above, said unsaturated acyclic hydrocarbon group comprises only double bonds as unsaturated bonds.

Preferred unsaturated acyclic hydrocarbyl C3-C15 and C4-C15 groups are (2E) -2-hexen-1-yl, (2E,4E) -2, 4-hexadien-1-yl, 3-methyl-2-buten-1-yl, 3-methyl-3-buten-1-yl, 2, 3-dimethyl-2-buten-1-yl and (2E) -3, 7-dimethyl-2, 6-octadien-1-yl.

In one embodiment, one or more hydrogen atoms at a saturated or unsaturated carbon atom of an acyclic hydrocarbyl C3-C15 or C4-C15 group (particularly a C4-C12 group) may be substituted with one or more than one fluorine atom, e.g., one, two or three hydrogen atoms at the same carbon atom may be substituted with one, two or three fluorine atoms to form CH, respectively₂F、CHF₂Or CF₃A group.

Examples of partially fluorinated and perfluorinated commercial compounds (alcohols and alkyl halides) that can be used as starting materials for the preparation of acyclic, partially fluorinated or perfluorinated R groups for compounds of formula (I) are given in Table 1. It will be appreciated by those skilled in the art that the structural motif (motif) substituted with one or more fluorine atom moieties of the smaller fragments shown in table 1 may be similarly repeated for any moiety of the acyclic hydrocarbyl C3-C15 or C4-C15 group.

TABLE 1

In one embodiment, X represents a hydrogen atom.

In another embodiment, X represents a halogen atom, with fluorine being particularly preferred.

The present invention encompasses compounds of formula (I) in the form of a single enantiomer, a single diastereomer, a racemate or a mixture of enantiomers or a mixture of diastereomers.

In a particular and preferred embodiment, said compound as defined above is a single enantiomer or diastereomer having structure (Ia)

Definition of

The term "straight-chain or branched acyclic hydrocarbon group" as used herein relates to a hydrocarbon group having a straight-chain or branched chain attached to a single carbon-carbon bond, the number of carbon atoms being as indicated in the respective definitions. The numbers or ranges of numbers given after the carbon atom symbol (C) relate to the number of carbon atoms that the group may contain. For example, C3-C15 hydrocarbyl means acyclic hydrocarbyl groups containing 3 to 15 carbon atoms, C4-C15 hydrocarbyl means acyclic hydrocarbyl groups containing 4 to 15 carbon atoms, C4-C12 hydrocarbyl means acyclic hydrocarbyl groups containing 4 to 12 carbon atoms, C4-C10 hydrocarbyl means acyclic hydrocarbyl groups containing 4 to 10 carbon atoms, and the like. The term does not include hydrocarbyl groups having a ring structure. It will be apparent to those skilled in the art that a primary acyclic hydrocarbyl group is one in which its attached carbon atom is attached to only one other carbon atom, and a secondary acyclic hydrocarbyl group is one in which its attached carbon atom is attached to only two other carbon atoms. In the case of saturated acyclic hydrocarbyl groups, the carbon atoms in the chain of the acyclic hydrocarbyl group are attached only to single carbon-carbon bonds, and in the case of unsaturated acyclic hydrocarbyl groups, may contain one or more double or triple carbon-carbon bonds. Tertiary acyclic hydrocarbyl groups are excluded wherein the carbon atom of its point of attachment is attached to three additional carbon atoms.

Exemplary saturated acyclic hydrocarbyl C3-C15 groups are propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 3-methylbut-1-yl, 2-methylbut-1-yl, pent-2-yl, pent-3-yl, 3-methyl-but-2-yl, 2-dimethylprop-1-yl (neopentyl), n-hexyl, hex-2-yl, hex-3-yl, 2-methylpent-1-yl, 3-methylpent-1-yl, 4-methylpent-1-yl, 3-methylpent-2-yl, 4-methylpent-2-yl, 2-methylpent-3-yl, 2, 2-dimethylbut-1-yl, 2, 3-dimethylbut-1-yl, 3-dimethylbut-2-yl, 2-ethylbut-1-yl, and the analogous viable C7-C15 isomers, excluding tertiary groups.

Exemplary unsaturated acyclic hydrocarbyl C3-C15 groups are allyl, 2-propyn-1-yl, 3-buten-1-yl, (2E) -2-buten-1-yl, (2Z) -2-buten-1-yl, 3-buten-2-yl, 3-butyn-1-yl, 2-butyn-1-yl, 3-butyn-2-yl, 4-penten-1-yl, (3E) -3-penten-1-yl, (3Z) -3-penten-1-yl, (2E) -2-penten-1-yl, (2Z) -2-penten-1-yl, (2E) -2, 4-pentadien-1-yl, (2Z) -2, 4-pentadien-1-yl, 3-methyl-3-buten-1-yl, 3-methyl-2-buten-1-yl, 2-methyl-3-buten-1-yl, (2E) -2-methyl-2-buten-1-yl, (2Z) -2-methyl-2-buten-1-yl, 2-methylenebuten-1-yl, 4-penten-2-yl, (3E) -3-penten-2-yl, (3Z) -3-penten-2-yl, and mixtures thereof, 3-methyl-3-buten-2-yl, 1-penten-3-yl, 1, 4-pentadien-3-yl, 4-pentyn-1-yl, 3-pentyn-1-yl, 2-pentyn-1-yl, (2E) -pent-2-en-4-yn-1-yl, (2Z) -pent-2-en-4-yn-1-yl, pent-4-en-2-yn-1-yl, 2-methyl-3-butyn-1-yl, 2-methylene-3-butyn-1-yl, 4-pentyn-2-yl, 2-penten-3-yl, 4-penten-2-yl, 1-penten-3-yl, 1-penten-yl, 4-penten-1-yl, 4-penten, 3-pentyn-2-yl, 1-pentyn-3-yl, 1, 4-pentadiyn-3-yl, 5-hexen-1-yl, (4E) -4-hexen-1-yl, (4Z) -4-hexen-1-yl, (3E) -3-hexen-1-yl, (3Z) -3-hexen-1-yl, (2E) -2-hexen-1-yl, (2Z) -2-hexen-1-yl, (3E) -3, 5-hexadien-1-yl, (3Z) -3, 5-hexadien-1-yl, (2E,4E) -2, 4-hexadien-1-yl, (2Z,4Z) -2, 4-hexadien-1-yl, (2E,4Z) -2, 4-hexadien-1-yl, (2Z,4E) -2, 4-hexadien-1-yl, (2E) -2, 5-hexadien-1-yl, (2Z) -2, 5-hexadien-1-yl, 5-hexen-2-yl, (4E) -4-hexen-2-yl, (4Z) -4-hexen-2-yl, (3E) -3-hexen-2-yl, (3Z) -3-hexen-2-yl, (3E) -3, 5-hexadien-2-yl, (3Z) -3, 5-hexadien-2-yl, 5-hexen-3-yl, (4E) -4-hexen-3-yl, (4Z) -4-hexen-3-yl, 1, 5-hexadien-3-yl, (4E) -1, 4-hexadien-3-yl, 2-methyl-4-penten-1-yl, (3E) -2-methyl-3-penten-1-yl, (3Z) -2-methyl-3-penten-1-yl, (2E) -2-methyl-2-penten-1-yl, and mixtures thereof, (2Z) -2-methyl-2-penten-1-yl, 2-methylenepenten-1-yl, (2E) -2-methyl-2, 4-pentadien-1-yl, (2Z) -2-methyl-2, 4-pentadien-1-yl, 2-methylene-4-penten-1-yl, (3E) -2-methylene-3-penten-1-yl, (3Z) -2-methylene-3-penten-1-yl, 3-methyl-4-penten-1-yl, (3E) -3-methyl-3-penten-1-yl, and mixtures thereof, (3Z) -3-methyl-3-penten-1-yl, (2E) -3-methyl-2-penten-1-yl, (2Z) -3-methyl-2-penten-1-yl, 3-methylenepenten-1-yl, 3-methylene-4-penten-1-yl, (2E) -3-methyl-2, 4-pentadien-1-yl, (2Z) -3-methyl-2, 4-penten-1-yl, 4-methyl-3-penten-1-yl, (2E) -4-methyl-2-penten-1-yl, (2Z) -4-methyl-2-penten-1-yl, (2E) -4-methyl-2, 4-pentadien-1-yl, (2Z) -4-methyl-2, 4-pentadien-1-yl, 3-methyl-4-penten-2-yl, (3E) -3-methyl-3-penten-2-yl, (3Z) -3-methyl-3-penten-2-yl, 3-methylenepenten-2-yl, 3-methylene-4-penten-2-yl, 4-methyl-3-penten-2-yl, 4-methyl-1-penten-3-yl, 2-methyl-1, 4-pentadien-3-yl, 2-dimethyl-3-buten-1-yl, 2, 3-dimethyl-2-buten-1-yl, 3-methyl-2-methylenebuten-1-yl, 3-methyl-2-methylene-3-buten-1-yl, 2-ethyl-3-buten-1-yl, (2E) -2-ethyl-2-buten-1-yl, 2-methyl-3-buten-1-yl, 2-methyl-2-buten-1-yl, 2-methyl, (2Z) -2-ethyl-2-buten-1-yl, (2E) -2-ethylene-3-buten-1-yl, (2Z) -2-ethylene-3-buten-1-yl, 2-vinyl-3-buten-1-yl, 5-hexyn-1-yl, 4-hexyn-1-yl, 3-hexyn-1-yl, 2-hexyn-1-yl, 3, 5-hexadiyn-1-yl, 2, 4-hexadiyn-1-yl, (3E) -hex-3-en-5-yn-1-yl, (3Z) -hex-3-en-5-yn-1-yl, (2E) -hex-2-en-5-yn-1-yl, (2Z) -hex-2-en-5-yn-1-yl, (2E) -hex-2-en-4-yn-1-yl, hex-5-en-3-yn-1-yl, hex-5-en-2-yn-1-yl, (4E) -hex-4-en-2-yn-1-yl, (4Z) -hex-4-en-2-yn-1-yl, 5-hexyn-2-yl, and mixtures thereof, 4-hexyn-2-yl, 3, 5-hexadiyn-2-yl, (3E) -hex-3-en-5-yn-2-yl, (3Z) -hex-3-en-5-yn-2-yl, hex-5-en-3-yn-2-yl, 5-hexyn-3-yl, 4-hexyn-3-yl, 1, 5-hexadiyn-3-yl, 1, 4-hexadiyn-3-yl, hex-1-en-5-yn-3-yl, hex-5-en-1-yn-3-yl, and mixtures thereof, (4E) -alkyne-4-en-1-yn-3-yl, (4Z) -hex-4-en-1-yn-3-yl, hex-1-en-4-yn-3-yl, 2-methyl-4-pentyn-1-yl, 2-methyl-3-pentyn-1-yl, (2E) -2-methylpent-2-en-4-yn-1-yl, (2Z) -2-methylpent-2-en-4-yn-1-yl, 2-methylene-4-pentyn-1-yl, 2-methylene-3-pentyn-1-yl, 2-methylene-4-pentyn-1-yl, 2-methyl-1-methyl-yl, 2-methyl-pentyn-1-yl, 2-methyl-, 3-methyl-4-pentyn-1-yl, 3-methylene-4-pentyn-1-yl, (2E) -3-methylpent-2-en-4-yn-1-yl, (2Z) -3-methylpent-2-en-4-yn-1-yl, 4-methyl-2-pentyn-1-yl, 4-methylpent-4-en-2-yn-1-yl, 3-methyl-4-pentyn-2-yl, 3-methylenepent-4-yn-2-yl, 4-methyl-1-pentyn-3-yl, 2-methylpent-1-en-4-yn-3-yl, and mixtures thereof, 2, 2-dimethyl-3-butyn-1-yl, 2-ethyl-3-butyn-1-yl, 2-ethynyl-3-butyn-1-yl, (2E) -2-ethynyl-2-buten-1-yl, (2Z) -2-ethynyl-2-buten-1-yl, 2-ethynyl-3-buten-1-yl, and similarly feasible C7-C15 isomers, but excluding the tertiary group.

Halogen means a fluorine (F), chlorine (Cl), bromine (Br) or iodine atom, in particular a fluorine atom.

The compounds of formula (I) contain a carboxyl group and may form salts with metals, ammonia and organic bases, including but not limited to pharmaceutically acceptable salts and salts with basic ion exchange resins (e.g., cholestyramine). In particular, the metal salts include alkali metal salts (which include sodium, potassium and lithium salts), alkaline earth metal salts (which include calcium, magnesium and barium salts, in particular). Salts with organic bases include salts with amines, in particular with aliphatic amines, such as trimethylamine, triethylamine, cyclohexylamine, tert-butylamine, N- (phenylmethyl) -phenyl-ethylamine, N' -dibenzylethylenediamine, choline, 2 (dimethylamino) ethanol, diethanolamine, diethylamine, 2 (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrazinophenyldiamine, morpholine, 4- (2-hydroxyethyl) morpholine, piperazine, 1- (2-hydroxyethyl) pyrrolidine, triethanolamine, 2-amino-2- (hydroxymethyl) propane-1, 3-diol, an amino acid (such as arginine, lysine, histidine or ornithine), an aromatic amine (such as aniline, methylaniline, naphthylamine), or a heterocyclic amine such as, for example, example 1H-imidazole or pyridine.

It will be understood that salts other than pharmaceutically acceptable salts are also included within the scope of the invention, and that such salts may be used inter alia as intermediates in the manufacture, isolation and purification of the compounds of the invention. Salts of the compounds of formula (I) may be obtained by direct combination of the compounds of formula (I) with amines (aliphatic, aromatic, heterocyclic) in a protic or aprotic solvent or solvent mixture, for example in acetone, acetonitrile or toluene. If spontaneous crystallization occurs under these conditions, the solid precipitate is filtered off and dried. Under such conditions the salt solution can be concentrated or evaporated to dryness if there is no spontaneous crystallization. This process can also be carried out without solvent by direct grinding of the individual components. The inorganic salts of the compounds of the formula (I) can also be obtained by dissolving the starting acids of the formula (I) in an aqueous or aqueous solution of the corresponding hydroxide, for example sodium or potassium hydroxide or ammonium hydroxide, or in an aqueous or aqueous solution of the corresponding labile alkali metal carbonate or bicarbonate. The desired salt can be obtained from such a solution in a manner similar to that in the case of an organic amine, or such a solution can be combined with another salt (inorganic or organic) to obtain the desired salt in an exchange reaction. For reactive metals, such as sodium or potassium, the corresponding salts can be obtained by direct reaction of the compounds of formula (I) with the metal in the presence or absence of an inert solvent. Salts of the compounds of formula (I) may be converted to compounds of formula (I) having free carboxyl groups by acidification of the salt solution with an acid, such as hydrochloric acid, sulfuric acid, phosphoric acid or citric acid, followed by extraction with a suitable organic solvent, such as diethyl ether, ethyl acetate, chloroform, or dichloromethane. During the extraction, the salt of the compound of formula (I) is neutralized to the free acid form, passed into the organic phase, then separated, dried and concentrated.

The compounds of the present invention include a chiral center attached to the carbon atom of a propyn-1-yl (methylacetylene) substituent. Thus, these compounds may exist as enantiomers or as mixtures of enantiomers in various ratios, in particular as racemic mixtures (racemates). It will be appreciated that the enantiomers of the compounds of formula (I) are substantially optically pure, but may typically contain a percentage of the opposite enantiomer, for example up to 10%, 5%, 3%, 2%, 1% or 0.5% of the opposite enantiomer.

The compounds of the invention also include prochiral centers present in the hydrocarbon radicals C3-C15 and may therefore be present as enantiomers, mixtures of enantiomers in various ratios, in particular racemic mixtures (racemates), and also as diastereomers and mixtures thereof.

Enantiomers of compounds of formula (I) can be obtained by asymmetric synthesis starting from suitable chiral starting materials. Alternatively, enantiomers of compounds of formula (I) may be obtained by resolution of racemic mixtures using methods well known to those skilled in the art, including preparative High Performance Liquid Chromatography (HPLC), HPLC chromatographic resolution on chiral stationary phases, or formation of optically active diastereomeric derivatives by chiral auxiliaries, and fractionation of the crystalline diastereomeric pairs and removal of the chiral auxiliaries. For example, a racemic mixture can be resolved into two enantiomers by chiral HPLC: enantiomer a with shorter retention time and enantiomer B with longer retention time. The retention time in chiral chromatography processes in a given stationary phase and eluent system is one physical parameter for identifying enantiomers. The absolute stereochemistry of enantiomers can then be determined using known methods.

Particular compounds of the invention are selected from the following compounds and salts thereof, in particular pharmaceutically acceptable salts:

1) (3S) -3- (4-propoxyphenyl) hex-4-ynoic acid

2) (3R) -3- (4-propoxyphenyl) hex-4-ynoic acid

3) (3S) -3- (4-butoxyphenyl) hex-4-ynoic acid

4) (3R) -3- (4-butoxyphenyl) hex-4-ynoic acid

5) (3S) -3- [4- (pentyloxy) phenyl ] hex-4-ynoic acid

6) (3R) -3- [4- (pentyloxy) phenyl ] hex-4-ynoic acid

7) (3S) -3- [4- (hexyloxy) phenyl ] hex-4-ynoic acid

8) (3R) -3- [4- (hexyloxy) phenyl ] hex-4-ynoic acid

9) (3S) -3- [4- (heptyloxy) phenyl ] hex-4-ynoic acid

10) (3R) -3- [4- (heptyloxy) phenyl ] hex-4-ynoic acid

11) (3S) -3- (4- { [ (2E) -3, 7-Dimethyloct-2, 6-dien-1-Yl ] oxy } phenyl) hex-4-ynoic acid

12) (3R) -3- (4- { [ (2E) -3, 7-Dimethyloct-2, 6-dien-1-Yl ] oxy } phenyl) hex-4-ynoic acid

13) (3S) -3- (4- { [ (3R) -3, 7-Dimethyloct-6-en-1-yl ] oxy } phenyl) hex-4-ynoic acid

14) (3R) -3- (4- { [ (3R) -3, 7-Dimethyloct-6-en-1-yl ] oxy } phenyl) hex-4-ynoic acid

15) (3S) -3- (4- { [ (3S) -3, 7-Dimethyloct-6-en-1-yl ] oxy } phenyl) hex-4-ynoic acid

16) (3R) -3- (4- { [ (3S) -3, 7-Dimethyloct-6-en-1-yl ] oxy } phenyl) hex-4-ynoic acid

17) (3S) -3- (4- { [ (2Z) -3, 7-Dimethyloct-2, 6-dien-1-Yl ] oxy } phenyl) hex-4-ynoic acid

18) (3R) -3- (4- { [ (2Z) -3, 7-Dimethyloct-2, 6-dien-1-Yl ] oxy } phenyl) hex-4-ynoic acid

19) (3R) -3- (4- { [ (2E,6E) -3,7, 11-trimethyldodecane-2, 6, 10-trien-1-yl ] oxy } phenyl) hex-4-ynoic acid

20) (3S) -3- (4- { [ (2E,6E) -3,7, 11-trimethyldodecane-2, 6, 10-trien-1-yl ] oxy } phenyl) hex-4-ynoic acid

21) (3S) -3- [4- (2-methylpropoxy) phenyl ] hex-4-ynoic acid

22) (3R) -3- [4- (2-methylpropoxy) phenyl ] hex-4-ynoic acid

23) (3S) -3- (4- { [ (2R) -3-methylbut-2-yl ] oxy } phenyl) hex-4-ynoic acid

24) (3R) -3- (4- { [ (2R) -3-methylbut-2-yl ] oxy } phenyl) hex-4-ynoic acid

25) (3S) -3- (4- { [ (2S) -3-methylbut-2-yl ] oxy } phenyl) hex-4-ynoic acid

26) (3R) -3- (4- { [ (2S) -3-methylbut-2-yl ] oxy } phenyl) hex-4-ynoic acid

27) (3S) -3- {4- [ (2R) -but-2-yloxy ] phenyl } hex-4-ynoic acid

28) (3R) -3- {4- [ (2R) -but-2-yloxy ] phenyl } hex-4-ynoic acid

29) (3S) -3- {4- [ (2S) -but-2-yloxy ] phenyl } hex-4-ynoic acid

30) (3R) -3- {4- [ (2S) -but-2-yloxy ] phenyl } hex-4-ynoic acid

31) (3S) -3- {4- [ (2S) -pent-2-yloxy ] phenyl } hex-4-ynoic acid

32) (3R) -3- {4- [ (2S) -pent-2-yloxy ] phenyl } hex-4-ynoic acid

33) (3S) -3- {4- [ (2R) -pent-2-yloxy ] phenyl } hex-4-ynoic acid

34) (3R) -3- {4- [ (2R) -pent-2-yloxy ] phenyl } hex-4-ynoic acid

35) (3S) -3- [4- (pent-3-yloxy) phenyl ] hex-4-ynoic acid

36) (3R) -3- [4- (pent-3-yloxy) phenyl ] hex-4-ynoic acid

37) (3S) -3- {4- [ (2E) -hex-2-en-1-yloxy ] phenyl } hex-4-ynoic acid

38) (3R) -3- {4- [ (2E) -hex-2-en-1-yloxy ] phenyl } hex-4-ynoic acid

39) (3S) -3- {4- [ (2E,4E) -hex-2, 4-dien-1-yloxy ] phenyl } hex-4-ynoic acid

40) (3R) -3- {4- [ (2E,4E) -hex-2, 4-dien-1-yloxy ] phenyl } hex-4-ynoic acid

41) (3S) -3- [4- (pent-4-en-1-yloxy) phenyl ] hex-4-ynoic acid

42) (3R) -3- [4- (pent-4-en-1-yloxy) phenyl ] hex-4-ynoic acid

43) (3S) -3- [4- (pent-3-yn-1-yloxy) phenyl ] hex-4-ynoic acid

44) (3R) -3- [4- (pent-3-yn-1-yloxy) phenyl ] hex-4-ynoic acid

45) (3S) -3- [4- (pent-2-yn-1-yloxy) phenyl ] hex-4-ynoic acid

46) (3R) -3- [4- (pent-2-yn-1-yloxy) phenyl ] hex-4-ynoic acid

47) (3R) -3- [4- (3-methylbutoxy) phenyl ] hex-4-ynoic acid

48) (3S) -3- [4- (3-methylbutoxy) phenyl ] hex-4-ynoic acid

49) (3S) -3- [4- (2-ethylbutoxy) phenyl ] hex-4-ynoic acid

50) (3R) -3- [4- (2-ethylbutoxy) phenyl ] hex-4-ynoic acid

51) (3R) -3- [4- (2, 2-Dimethylpropoxy) phenyl ] hex-4-ynoic acid

52) (3S) -3- [4- (2, 2-Dimethylpropoxy) phenyl ] hex-4-ynoic acid

53) (3S) -3- [4- (3, 3-dimethylbutoxy) phenyl ] hex-4-ynoic acid

54) (3R) -3- [4- (3, 3-dimethylbutoxy) phenyl ] hex-4-ynoic acid

55) (3S) -3- {4- [ (3-methylbut-2-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

56) (3R) -3- {4- [ (3-methylbut-2-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

57) (3S) -3- {4- [ (3-methylbut-3-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

58) (3R) -3- {4- [ (3-methylbut-3-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

59) (3R) -3- { 2-fluoro-4- [ (3-methylbut-2-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

60) (3S) -3- { 2-fluoro-4- [ (3-methylbut-2-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

61) (3S) -3- {4- [ (2, 3-dimethylbut-2-en-1-yl) oxy ] phenyl } hex-4-ynoic acid

62) (3R) -3- {4- [ (2, 3-dimethylbut-2-en-1-yl) oxy-phenyl } hex-4-ynoic acid

63) (3S) -3- (4- { [ (2E) -4-methylpenta-2, 4-dien-1-yl ] oxy } phenyl) hex-4-ynoic acid

64) (3R) -3- (4- { [ (2E) -4-methylpenta-2, 4-dien-1-yl ] oxy } phenyl) hex-4-ynoic acid

65) (3S) -3- {4- [ (2R) -2-Methylbutoxy ] phenyl } hex-4-ynoic acid

66) (3R) -3- {4- [ (2R) -2-Methylbutoxy ] phenyl } hex-4-ynoic acid

67) (3S) -3- {4- [ (2S) -2-Methylbutoxy ] phenyl } hex-4-ynoic acid

68) (3R) -3- {4- [ (2S) -2-Methylbutoxy ] phenyl } hex-4-ynoic acid

69) (3S) -3- {4- [ (2R) -2, 3-dimethylbutoxy ] phenyl } hex-4-ynoic acid

70) (3R) -3- {4- [ (2R) -2, 3-dimethylbutoxy ] phenyl } hex-4-ynoic acid

71) (3S) -3- {4- [ (2S) -2, 3-dimethylbutoxy ] phenyl } hex-4-ynoic acid

72) (3R) -3- {4- [ (2S) -2, 3-dimethylbutoxy ] phenyl } hex-4-ynoic acid

73) (3S) -3- (4- { [ (3R) -3-methylpentyl ] oxy } phenyl) hex-4-ynoic acid

74) (3R) -3- (4- { [ (3R) -3-methylpentyl ] oxy } phenyl) hex-4-ynoic acid

75) (3S) -3- (4- { [ (3S) -3-methylpentyl ] oxy } phenyl) hex-4-ynoic acid

76) (3R) -3- (4- { [ (3S) -3-methylpentyl ] oxy } phenyl) hex-4-ynoic acid

77) (3S) -3- [4- (4,4, 4-trifluorobutoxy) phenyl ] hex-4-ynoic acid

78) (3R) -3- [4- (4,4, 4-trifluorobutoxy) phenyl ] hex-4-ynoic acid

79) (3S) -3- {4- [ (5,5, 5-trifluoropentyl) oxy ] phenyl } hex-4-ynoic acid, and

80) (3R) -3- {4- [ (5,5, 5-trifluoropentyl) oxy ] phenyl } hex-4-ynoic acid.

In a further aspect, the present invention therefore also resides in a compound of formula (I) as defined above for use as a medicament according to any of the embodiments.

In a further aspect, the object of the present invention is therefore also a pharmaceutical composition comprising as active ingredient a compound of formula (I) as defined above according to any of the embodiments in combination with a pharmaceutically acceptable excipient.

Compounds of formula (I) as defined above may find use in the treatment of GPR40 mediated diseases.

An object of the present invention is therefore also a compound of formula (I) as defined above according to any of the embodiments for use in a method of treatment of a GPR40 mediated disease in a mammal, including a human.

The present invention also features the use of a compound of formula (I) as defined above according to any of the embodiments for the manufacture of a medicament for the treatment of GPR40 mediated diseases in mammals, including humans.

The present invention also has for its object a method of treatment of a GPR 40-mediated disease in a mammal, including a human, comprising administering a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutical composition comprising a compound as defined above according to any of the described embodiments.

The compounds of the present invention can be prepared using the methods described in scheme 1.

Compounds of formula (I) wherein R as defined above is obtainable by hydrolysis of the ester group in compounds of formula (II) as shown in step (S10) in scheme 1.

In the compounds of formula (I), G together with the oxygen atom to which it is attached represents a synthetically useful alcohol residue of an ester group. Esters having low molecular weights, such as alkyl C1-C4, are preferred because they have low molecular weights and are cost-effective economically and can be applied in manufacturing processes while facilitating isolation or purification processes due to their favorable physicochemical properties, such as crystallinity.

Depending on the hydrolysis conditions applied, the product may be a compound of formula (I) having a free carboxyl group or a compound in the form of a salt, for example a metal salt. Typically, the hydrolysis reaction is carried out in a protic solvent (e.g. an alcohol such as methanol, ethanol or isopropanol), in an alkaline environment, typically in the range of 0-100 ° over a wide temperature range depending on the solvent used, usually with the addition of water and other solubility enhancing solvents such as tetrahydrofuran, acetonitrile, N-dimethylformamide, dioxane. In this context, the corresponding salt of the compound of formula (I) is formed, which may be the final form of the compound, or may be converted to the free acid, or may be converted to another salt, such as a magnesium or calcium salt, by an exchange reaction (shown as step (S11) in scheme 1). If the free acid is obtained, the reaction of step (S11) is a process for preparing the corresponding salt directly from the free acid using any suitable method known in the art. For example, salts of compounds of formula (I) can be formed directly from the free acid after combination with the corresponding amine, hydroxide, hydride, metal salt or metal (e.g., sodium).

Compounds of formula (II) wherein G together with the oxygen atom to which it is attached represents a synthetically available alcohol residue of an ester group, may be obtained by etherification reaction between compound (III) with a compound R-LG (iv), wherein R is as defined above for compounds of formula (I) and LG is a leaving group, shown as step (S9) in scheme 1. The leaving group may be a halogen atom, such as a chlorine, bromine or iodine atom, or may also be an ester group, such as methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid. In this case, the reaction is carried out in an aprotic organic solvent such as, for example, acetone, acetonitrile or dimethylformamide, in the presence of a compound capable of neutralizing the by-acid (side acid) LG-H formed in the reaction. Such compounds can be, for example, potassium carbonate, cesium carbonate, organic amines, or metal-organic compounds, such as n-butyllithium, or also sodium hydride. The Leaving Group (LG) may also be a hydroxyl group. In this case, the compound of formula (II) can be efficiently obtained, for example, under the Mitsunobu reaction condition. The preparation reaction of the compound (II) can be carried out in a wide temperature range depending on the solvent used; usually from 0 to 100 deg.c. Preferred compounds R to LG are therefore, respectively, alcohols or halides, where R is as defined above for the compounds of formula (I) and LG is a hydroxyl group or a halogen atom. Furthermore, the compound of formula (II) may be obtained using any other method of synthesizing ethers known in the art. Since the same reaction conditions as those used for the preparation of ethers can also be used for the preparation of esters, compound (II) wherein PG represents a hydrogen atom can be directly obtained from compound (V) by the reaction shown in step (S9a) in scheme 1. This process is economically advantageous and the substituents G are identical to the substituents R.

The reaction shown in step (S8) in scheme 1 shows the procedure for preparing compound (III) from compound (V). It relates primarily to the preparation of esters, in which G together with the oxygen atom to which it is attached is a synthetically useful alcohol residue of an ester group. Esters having low molecular weights, such as those having chain lengths of C1-C4, are particularly advantageous because they are cost-effective, as well as those that can be used in manufacturing processes due to advantageous physicochemical properties, such as crystallizability, while facilitating isolation or purification. Compound (III) may be obtained by typical methods for preparing esters from the free acid, e.g. by equilibration directly in the presence of an excess of alcohol, preferably with removal of water, or using any other ester preparation method known in the art, and selecting suitable conditions and synthetic equivalents of the above-mentioned alcohol which will result in the desired ester being obtained. The second aspect of the reaction of step (S8) is to obtain a free phenol group in compound (III). Unless this process occurs in advance depending on the type of protecting group PG used, since the process of step (S9) must be performed, it must be performed at the latest in this step. Preferably, the removal of the protecting group PG and the ester formation process may be performed simultaneously. For example, tetrahydropyranyl and silyl ethers which may be used as protecting group PG in this process are known to undergo hydrolysis, for example in methanol, under acidic conditions. On the other hand, such conditions are sufficient to form methyl esters.

The process in step (S7) involves chiral resolution of the racemate (VI) and yields one of the active optical enantiomers shown in formula (V). The process can preferably be carried out at a stage where the free carboxylic group of compound (VI) allows the diastereomeric salts to be obtained using optically pure amines, then the salts are purified by fractional crystallization and then by acidification to obtain compound (V) in a form enriched in the desired optical isomer. This is a classical method known in the art. Another method for preparing the compound (V) is to carry out chromatographic resolution using a chiral stationary phase. This resolution can be done for analytical and synthetic purposes. It should be emphasized that, in order to obtain compound (I), the step of resolving into optical enantiomers may be carried out as a synthesis element at any one of steps (S4) - (S11) from the moment the chiral carbon atom marked with an asterisk (a) appears during the synthesis. It can also be hypothesized that there is the possibility of secondary racemization (secondary racemization) of a mixture rich in pharmacologically inactive optical isomers by appropriate chemical or enzymatic reactions according to methods known in the art, thereby increasing the yield of the preparation of the desired isomer. If both optical enantiomers have the desired pharmacological activity, optical resolution can be omitted and the compound of formula (I) used as a racemic mixture or, after enrichment of one of the optical isomers, as a mixture of optical isomers with the appropriate final ratio of the isomers, which can be controlled by adding the appropriate amount of one isomer or the appropriate mixture of both isomers in the predetermined ratio.

The less active optical isomers of the compounds of formula (I) of the present invention are also important because, in selecting the best production method and final composition of the active pharmaceutical ingredient, they simultaneously become the analytical criteria for this process, which allows qualitative and quantitative control of the optical purity.

Compound (VI) is prepared by decarboxylation of one carboxyl group of compound (VII), as shown in step (S6) in scheme 1. This process generally needs to be carried out at elevated temperatures, in the temperature range of 50 ℃ to 200 ℃, and not only in a solventless (pure) process, but also in a variety of protic and aprotic organic solvents with the addition of water. It can be catalyzed by acids or bases, or in the presence of metal salts and under reduced pressure.

During step (S5), it is involved to hydrolyze the fragments Z1 and Z2 in compound (VIII) to obtain the dicarboxy compound (VII). It may be performed under the conditions as in the aforementioned step (S10).

In step (S4), the protecting group PG in compound (IX) is removed to obtain compound (VIII). Depending on the type of protecting group, it may be carried out under conditions known in the art to be suitable for introducing the reactivity of the group PG. For example, removal of the ester protection requires protic basic conditions, removal of the tetrahydropyranyl protection requires protic acidic conditions, and the silyl ether protecting group may be under protic acidic conditions or the fluoroanion F^-The presence of the source is removed. It should be emphasized that depending on the economics of the preparation process, the removal of the protecting group may also be carried out in any of the following steps (S4) to (S8), or if PG forms an ether bond with compound (IX) and PG is the same as substituent R, the removal of the protecting agent may be omitted. In this particular case, compound (V) may be the same as compound (I), or compound (V) may be formally produced as a result of conversion by steps (S9 a)/(S10)/(S11).

The step (S3) of preparing the compound (IX) includes adding the organometallic compound (X) to the compound (XI). The process is a highly exothermic process requiring cooling to temperatures of-76 ℃ to +50 ℃. Due to the instability of compound (X), step (S3) should be carried out under anhydrous conditions in an aprotic solvent, for example in tetrahydrofuran, advantageously in an inert gas atmosphere, for example in argon or nitrogen. The organometallic compound (X) is commercially available 1-propynyl magnesium bromide. However, other types of organometallic compounds can also be used for the preparation of compound (IX), for example 1-propynyl lithium. The organometallic compound may be prepared in advance and stored in the form of a solution, or may be prepared in situ immediately before the reaction. In the reaction of adding the organometallic compound (X) to the compound (XI), a chiral carbon atom indicated by an asterisk (—) is formed in the compound (IX). Thus, as previously mentioned, from this point on, it can be resolved into optical enantiomers. The compound (IX) can also be prepared by enantioselectively adding the organometallic compound (X), so that a mixture which is already enriched in the desired optical isomer is obtained. This process can be carried out by intermediate compounds (XII) in which Z together with the oxygen atom represents the alcohol residue of the ester group, which can be obtained by decarboxylation (step S6a), such as described in Mohite, AR, Mete, TB, Bhat, RG, An Expedient Stereoselective Synthesis of (E) - α, β -unreacted Esters and Thioesters fecl3.6H2O, Tetrahedron Letters (2017), followed by one of the reactions (step S3a), such as PATAI' S chemistry of Functional Groups in 2009 by Wiley & Sons, Ltd. p.772-800; 10.1002/9780470682531.pat 0416.

Preparation of compound (XI) from compound (XIII) includes a step (S2) of protecting a phenol group (PG ═ H). There is a wide range (spectrum) of protecting groups PG that can be used in this process, such as acyl groups, tetrahydropyranyl (acetal protection), silyl ethers or ethers (e.g. methoxy or ethoxy), which are commonly used to protect phenolic groups. Since in compound (I) R also forms an ether bond with the oxygen atom to which it is formally attached, PG in compound (XI) may be the same as the R group in compound (I), in which case a phenol deprotection step is not required. In other words, the fragment R in compound (I) together with the oxygen atom may form the protective bond already present in step (S2), although it does not belong to the usual protective ether groups known in the art. The methods of their formation and the ultimate recovery of the free phenolic functionality vary due to the various chemical characteristics of the possible Protecting Groups, although well described in the literature, such as p.j.kocienski, Protecting Groups,3rd Edition, hydroxy Protecting Groups, p.187. The protecting group PG may be introduced into the preparation route of compound (I) at the present stage or earlier, for example as a starting material in compound (XV) in the step (S1) reaction. The protecting group PG may be deprotected in the respective synthetic steps of scheme 1 for the preparation of compound (I). It is essential that it should be present in the intermediate compound (XI) before the organometallic reaction of step (S3) is carried out and should be removed from the compound (V) before the etherification reaction of step (S9) is carried out. Thus, scheme 1 includes two variants in which the protecting group PG must be present in the intermediate compound in a given synthetic step and one variant in which the protecting group PG may be removed depending on the ease of synthesis (PG ═ H).

Step (S1) involves preparing compound (XIII) from commercially available compounds (XV) and (XIV) by Knovenagel condensation reaction known in the art. The compound (XV) is an aldehyde in which X in position 2 (ortho position) is a hydrogen or fluorine atom. Furthermore, the compounds have a phenolic function in the 4 position (para-OH), which may be protected from the start of the synthesis with a suitable Protecting Group (PG) or may remain unprotected during this synthetic step (PG ═ H). Compound (XIV) is a classical C-H acid, wherein Z₁And Z₂Together with the oxygen atom to which they are attached represent the alcohol residue of the ester group formed. Z₁And Z₂May be the same or different, preferably the same. In particular, Z₁And Z₂May be linked together to form a cyclic compound. Examples of compounds (XIV) are diethyl malonate or Meldrum's acid. Step (S1) may be carried out spontaneously or catalyzed with a base in a suitable protic or aprotic solvent. Since the Knovenagel reaction may be an equilibrium reaction, it is preferred to select such solvents that will result in crystallization of the product, thereby allowing its purification and simultaneous removal from equilibrium.

The preparation of compound (I) given in scheme 1 is believed to yield a chiral center, indicated by the asterisk. Thus, the compound (I) can be obtained as racemate, pure enantiomer or mixture of enantiomer. However, in case more than one compound (I) -derived anion is required for the preparation of the salt, more than one chiral center will also be present in the final compound of the invention. In this case, the compound (salt) should be regarded as a pure diastereomer or a mixture of diastereomers. The same may occur if the R moiety in compound (I) contains one or more chiral carbon atoms. However, the presence of more than one chiral center in compound (I) does not affect its manner of preparation, since in the case of mixtures of diastereomers, analogous purification procedures as described above for mixtures of enantiomers can be used.

It should be emphasized that the methods of preparing the compounds of formula (I) are exemplary ways of carrying out the present invention. The steps shown may be suitably interchanged, or combined with the omission of intermediate separation steps, if economically justified.

The present invention also has for its object a pharmaceutical composition comprising as active ingredient a compound of formula (I) as defined above, in combination with a pharmaceutically acceptable excipient.

The use of more than one compound of formula (I) in the pharmaceutical composition of the invention is not excluded if it is pharmacologically reasonable and advantageous for therapeutic reasons.

The compounds of formula (I) may be administered in the form of a pharmaceutical composition or a pharmaceutical preparation containing the same in therapy.

In the treatment of the above mentioned diseases, the compounds of formula (I) may be administered in the form of chemical compounds, but in general, they will be used as pharmaceutical compositions or pharmaceutical preparations containing the compounds of the present invention or pharmaceutically acceptable salts thereof in combination with pharmaceutically acceptable carriers and auxiliary substances.

In the treatment of the above-mentioned disorders, diseases and conditions, the pharmaceutical compositions of the present invention may be administered by any suitable route, preferably the oral, parenteral or inhalation route, or in the form of preparations for use in medicine according to the intended route of administration.

Compositions for oral administration may be in the form of solid or liquid preparations. The solid preparation may be in the form of a tablet or capsule prepared in a conventional manner from pharmaceutically acceptable inactive excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, sucrose, carboxymethylcellulose, microcrystalline cellulose, or dibasic calcium phosphate); disintegrants (e.g., crospovidone, corn starch or sodium carboxymethyl starch); lubricants (e.g., magnesium stearate, talc, or silica), wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated with coatings well known in the art, such as simple coatings, sustained/controlled release coatings or enteric coatings. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or may be presented as a dry solid product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared from pharmaceutically acceptable non-active excipients by conventional means, such as suspending agents (e.g. sorbitol syrup, vitamin derivatives or hydrogenated edible oils), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters, ethanol or fractionated vegetable oils), and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The formulations may also include suitable buffers, flavoring agents, coloring agents and sweetening agents.

Formulations for oral administration may be formulated using methods known to those skilled in the art to obtain controlled release of the active compound.

Parenteral routes of administration include administration by intramuscular and intravenous injection, as well as intravenous infusion. Compositions for parenteral administration may, for example, be in unit dosage form, for example in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may include excipients such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be formulated as a powder for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Compositions for administration by the inhalation route may have an inhaled form and be administered by nebulization. Such formulations include the active compound and the auxiliary substances administered in the form of an aerosol, i.e. a fine particle system of solid or liquid substances suspended in a gas. The auxiliary substances used in atomization may be, for example, sodium chloride as an isotonic agent, inorganic acids and hydroxides as pH regulators and stabilizers, benzalkonium chloride as a preservative, sodium citrate as a buffer, polysorbate 80 as a surfactant, ethanol and propylene glycol as co-solvents, and sulfur compounds as antioxidants. Formulations for administration by the inhalation route may be in the form of a pressurized inhaler or a dry powder inhaler.

Methods of treatment using the compounds of the present invention will comprise administering to an individual in need of such treatment a therapeutically effective amount of a compound of the present invention, preferably in the form of a pharmaceutical composition.

The recommended dosage of the compounds of the invention is from 0.1mg to about 1000mg per day, in single or divided doses. It will be apparent to those skilled in the art that the choice of the dosage required to achieve the desired biological effect will depend on a number of factors, such as the particular compound, the indication, the mode of administration, the age and condition of the patient, and the exact dosage will ultimately be determined by the attending physician.

Examples

The following examples are illustrative and provide general synthetic methods for synthesizing intermediate compounds (which are useful in preparing the compounds of the invention), final compounds (of the invention) and reference compounds.