PL233938B1 - Derivatives of 3-phenyl-4-hexynoic acid as GPR40 agonists - Google Patents

Description

Description of the invention

Technical field

The invention relates to novel compounds, 3-phenyl-4-hexinoic acid derivatives having agonist activity at the GPR40 receptor, pharmaceutical compositions containing them and their use in the treatment of GPR40 mediated diseases, in particular type 2 diabetes.

State of the art

G-protein coupled receptors (GPRs) are membrane proteins responsible for signaling through the lipid bilayer to effector sites inside the cell. They participate in signaling cascades, mediating the transmission of information by numerous extracellular signaling molecules: hormones, neuronal messengers, small proteins, short peptide chains, amines, lipids, nucleotides or derivatives of amino acids and fatty acids. For each signaling molecule, there is a receptor or a group of receptors that can bind a given molecule and initiate signal transmission across the cell membrane. GP receptors play a key role in many physiological processes regulating cell function, metabolism, growth and immune defense.

The GP40 receptor (GPR40), also known as the free fatty acid receptor 1 (FFA1), is a G protein-coupled receptor expressed in beta islets and, to a lesser extent, in the brain. It is a receptor activated by fatty acids and mediates the insulinotropic action of fatty acids exerted directly on the beta cells of the pancreas. The insulinotropic effect exerted by GPR40 is glucose concentration dependent. Its activation leads to an increase in insulin secretion by beta cells only in the presence of elevated glucose levels, thus reducing the risk of hypoglycaemia.

Intensive research is underway to find small-molecule GPR40 ligands and their pharmacological use in the treatment of primarily type 2 diabetes (Takafumi Hara, Ligands at Free Fatty Acid Receptor 1, Handbook of Experimental Pharmacology, Springer International Publishing AG 2016). Such ligands may potentially be anti-diabetic agents regulating glucose homeostasis, having antihyperglycaemic effects and not at risk of causing hypoglycaemia. Certain compounds were brought to the clinical trial phase, however, despite their agonistic activity against GPR40, in clinical trials the compounds were shown to be potentially hepatotoxic or had other side effects, or increased insulin levels without lowering glucose levels. Since GPR40 is not expressed in the liver, the molecular mechanism of hepatotoxicity is probably not related to the direct activation of GPR40, but may occur in a signaling cascade triggered upon activation by ligand binding. This mechanism is presumed to be associated with an inhibitory effect on bile acid transport and a disturbance of bile acid homeostasis.

Hitherto known compounds typically contain as common structural elements an acid head group, usually a carboxyl group in the phenylpropanoic acid backbone believed to be responsible for binding to the receptor, and a hydrophobic tail group, usually an aromatic fragment, linked to the head moiety by a linker, typically 2 to 2 in length. 4 carbon atoms, and preferably with an ether linkage. In this way, synthetic modulators mimic the structure of the fatty acids, natural GPR40 ligands. In the known compounds, the tail group can be a monocyclic or a bicyclic group.

WO2004 / 041266 discloses as regulators of GPR40 functions compounds generally very broadly defined solely by the presence of an aromatic ring group and a group capable of releasing a cation, particularly a carboxyl group.

WO2004 / 106276 discloses as regulators of GPR40 function carboxylic acids in which the head group is a bicyclic group of formula

D B) Xd-COR 'where A may be a benzene ring, Xc may be an oxygen atom, D may be a phenyl, thienyl or thiazole ring, B is a 5-7 membered non-aromatic ring, Xd may be a bond, CH or CH2.

PL 233 938 Β1

WO2005 / 086661 discloses GPR40 modulators, inter alia, carboxylic acids based on the phenylpropanoic acid skeleton with an ethynyl substituent in the beta position relative to the carboxyl group, with the formula

wherein R ²⁵ is a hydrogen atom or an alkyl, oxyalkyl, aryl or heteroaryl group, especially methyl, and R ^{28 is} a phenyl or benzyl group optionally substituted with various substituents or with a pyridyl or pyridyl group. One of the compounds described is (3S) -1-propyn-1-yl-4 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -3-yl] methoxy] benzenepropanoic acid (AMG-837) with the following structural formula

It was reported that this compound in Phase I clinical trials increased plasma insulin levels, but did not lower glucose levels ("Free Fatty Acid Receptors" Handbook of Experimental Pharmacology, vol. 236, ISBN 978-3-319-50692-0, DOI 10.1007 / 978-3-319-50693-7, Springer International Publishing AG 2017, page 11). Further development research was discontinued.

WO2005 / 063729 discloses non-cyclic head compounds of formula as GPR40 modulators

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

PL 233 938 Β1

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

with a bicyclic head group in which R ¹ is an alkylsulfonyl group, R is a hydroxyl group and B is preferably a tetrahydropyran ring. One of the compounds described is 2 - [(3S) -6 - [[3- [2,6-dimethyl-4- (3-methylsulfonylpropoxy) phenyl] phenyl] methoxy] -2,3-dihydro-1-benzofuran- 3-yl] acetic (fasiglypham, TAK-875) with the following structural formula

YES-875 (Takeda)

C ₂₉ H _J2 O ₇ S = 524.63

This compound in phase 3 clinical trials showed the ability to lower glucose levels in patients with type 2 diabetes. However, further development of the compound was discontinued due to side effects on the liver related to the inhibitory effect on bile acid transport and disturbance of bile acid homeostasis (A. Mancini et al. ., "GPR40 agonists forthe treatment of type 2 diabetes: life after" TAKing "a hit", Diabetes Obesity and Metabolism 2015 vol. 17 pp. 622-629).

WO2013 / 128378 discloses as modulators of GPR40 function compounds based on a phenylpropanoic acid skeleton having a heterocyclic, e.g. oxetanyl substituent, beta to the carboxyl group.

WO2011 / 046851 discloses as GPR40 activators carboxylic acid compounds based on a phenylpropanoic acid skeleton having an ethynyl substituent in the beta position to the carboxyl group and a spiropiperidine substituent on the aromatic tail fragment,

WO2013 / 025424 discloses GPR40 activators based on a phenylpropanoic acid skeleton having an ethynyl substituent in the beta position to the carboxyl group and 1- (thiophen-2-ylmethyl) -1,2,3,4-tetrahydroquinoline as an aromatic moiety.

WO2015 / 105786 discloses GPR40 activators based on a phenylpropanoic acid skeleton containing an ethynyl substituent at the beta position to the carboxyl group and a bicyclic triazolopyridine moiety as an aromatic moiety.

WO2012 / 011125 discloses GPR40 activators based on a phenylpropanoic acid skeleton having a cyano substituent beta to the carboxyl group and an aromatic moiety with oxime functionality.

PL 233 938 Β1

WO2010 / 143733 discloses GPR40 activators of formula

wherein the ether is replaced by a linker amino linker, Y is CH2, NH or O, Z is CH or N and X is CH 2, or together with R ¹ may form an alicyclic ring.

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

US2009 / 0111859 discloses compounds of formula as GPR40 inhibitors

US2008 / 0090840 discloses compounds of formula as GPR40 inhibitors

R '' * R ⁵

PL 233 938 Β1

US2008 / 0176912 discloses compounds of formula as GPR40 inhibitors

wherein Q is a phenyl or a 5-membered heteroaromatic ring.

WO2012 / 136221 discloses compounds of formula as GPR40 inhibitors

US2012 / 004166 discloses aryloxyalkylene substituted hydroxyphenylhexinoic acid derivatives of the formula below, wherein A is (C6-C10) aryl, (C3-C1O) cycloalkyl or a 4 to 12 membered heterocycle, namely phenyl or pyridyl.

HI

OH

KJ. '

They act to activate the GPR40 receptor, lower blood glucose levels and may be useful in the treatment of diabetes.

There is a need for new compounds with the ability to activate the GPR40 receptor with potential utility in the treatment of metabolic diseases, in particular type 2 diabetes, preferably without exerting hepatic effects, in particular without inhibiting bile acid secretion. Solving these problems is the object of the present invention.

Summary of the invention

The present invention relates to a compound of general formula (I)

(l) in which:

- R stands for:

A C3-C15 straight or branched primary or secondary acyclic hydrocarbon group which may be saturated or unsaturated, or a straight or branched C3-C15 primary or secondary acyclic hydrocarbon group which may be saturated or unsaturated and in which one or both more than one of the hydrogen atoms is replaced with a fluorine atom;

- X is hydrogen or halogen and its salts, especially pharmaceutically acceptable salts, with the exception of 3- (4 - {[(2E, 3Z) -2-propylidene-pent-3-en-1-yl] oxy} phenyl) hex-4-yn.

3- (4 - {[(2E, 3Z) -2-propylidene-pent-3-en-1-yl] oxy} phenyl) hex-4-ynoic acid is a compound listed in the National Center for Biotechnology Information database. PubChem Substance Database; SID = 344303732, https://pubchem.ncbi.nlm.nih.gov/substance/344303732 (accessed October 20, 2017). No information was given about its biological activity or use.

Unlike the compounds known in the art GPR40 modulators, the compounds of the invention do not possess an aromatic or (hetero) cyclic ring in the tail group and are capable of interacting with the GPR40 receptor. The compounds according to the invention do not have the ability to inhibit bile acid transporters and therefore may be free from hepatotoxic activity.

The compounds according to the invention may be, as compounds with a free carboxyl group, liquids (syrups, oils) under normal conditions, therefore there is no risk of their crystallization in hepatocytes, as is the case with the previously known GPR40 activators with a high molecular weight, as in the case of TAK-875: (Wolenski F, S., 2017, “Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Injury”, TOXICOLOGICAL SCIENCES, 157 (1), 2017, 50-61).

At the same time, the same compounds can be converted into the corresponding, pharmaceutically acceptable solid salts which, due to their physical state, are a more convenient and practical form for the preparation and purification of the compounds according to the invention into the active ingredient of a pharmaceutical composition.

The compounds according to the invention have a reduced molecular weight (molar, MW) compared to the reference compound (fasiglypham, TAK-875), often achieving comparable or higher activity (EC50 value) than the same compound. This means better "molecular efficiency" (the LE parameter - ligand efficiency). In other words, by using fewer atoms for the construction of the GPR40 agonist ligand molecule than in the reference compound, a comparable or better biological effect can be obtained with the compounds of the invention. This also means, on the one hand, a better production economy and, on the other hand, a potentially lower number of possible side effects due to the simultaneous decrease in the lipophilicity of the compounds obtained due to the associated decrease in molecular weight.

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

The invention also includes in a further aspect a compound of formula (I) as defined above for use as a medicament.

The invention in a further aspect also comprises a pharmaceutical composition which comprises a compound of formula (I) as defined above.

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

The invention also includes in a further aspect a method of treating a GPR40 mediated disease in a subject comprising administering an effective amount of a compound of formula (I) as defined above.

The invention also includes, in a further aspect, a compound of formula (I) as defined above for use in a method of treating a GPR40 mediated disease in a subject.

GPR40 mediated diseases include neoplastic diseases and metabolic diseases, including diseases such as diabetes, type 2 diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolaemia, and metabolic syndrome.

Detailed description of the invention

Preferred embodiments of the invention are disclosed in the detailed description below and in the appended claims. Various aspects of the invention are defined in more detail herein. Anyone with yes

EN 233 938 Β1 of the defined aspects may be combined with any other aspect or aspects unless otherwise expressly indicated. In particular, any of the features indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or preferred.

Reference throughout the specification to "one embodiment" or "an embodiment" means that the particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, occurrences of the phrases "in one embodiment" or "in an embodiment" in various places in this specification do not necessarily refer to the same embodiment, but may. Moreover, particular features, structures or characteristics may be combined in any appropriate manner, as will be apparent to one skilled in the art of this disclosure, in one or more embodiments. Moreover, while some of the embodiments described herein include some but not other features included in other embodiments, combinations of features from the different embodiments are intended to be within the scope of the invention and form different embodiments as will be understood by those skilled in the art. For example, in the following claims, any of the claimed embodiments may be used in any combination.

The invention relates in a first aspect to a compound of general formula (I)

(0 where

R means:

a C3-C15 straight or branched primary or secondary acyclic hydrocarbon group which may be saturated or unsaturated, or a straight or branched C3-C15 primary or secondary acyclic hydrocarbon group which may be saturated or unsaturated and in which one or more of the hydrogen atoms on a saturated or unsaturated carbon atom are replaced by a fluorine atom;

- X represents a hydrogen atom or a halogen atom, and its salts, especially pharmaceutically acceptable salts.

In formula (I), * represents the pro-chiral center.

In one embodiment, R is a C4-C12 straight or branched acyclic hydrocarbon group, which may be saturated or unsaturated.

In one embodiment, R is a C3-C15 straight or branched saturated acyclic hydrocarbon group, especially C4-C12.

A preferred straight saturated alkyl group is n-butyl.

A preferred branched saturated alkyl group is 3-methylbutyl.

Another preferred straight saturated alkyl group is n-pentyl.

Another preferred straight saturated alkyl group is n-hexyl.

Another preferred straight saturated alkyl group is n-heptyl.

Another preferred branched saturated alkyl group is the isobutyl group.

Another preferred branched saturated alkyl group is sec-butyl.

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

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

Another preferred branched saturated alkyl group is the 2-pentyl group.

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

In one embodiment, R is a C3-C15 linear or branched unsaturated acyclic hydrocarbon group, especially C4-C12.

A straight or branched C3-C15 unsaturated acyclic hydrocarbon group, especially C4-C12, may contain one double bond or more than one double bond in the system

PL 233 938 Β1 conjugated or unconjugated in the E or Z stereochemical configuration. Preferably, said C3-C15 hydrocarbon group contains two double bonds in an uncoupled or conjugated system. A straight or branched C3-C15 unsaturated acyclic hydrocarbon group, especially C4-C12, may contain one or more triple bonds, preferably one triple bond.

Preferred C3-C15 unsaturated acyclic hydrocarbon 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 of the hydrogen atoms on a saturated or unsaturated carbon atom of the C3-C15 hydrocarbon group may be replaced by one or more fluorine atoms, for example, one, two or three hydrogen atoms on the same carbon atom may be replaced with one, two or three fluorine atoms to form a CH2F, CHF2 or CF3 group, respectively.

Examples of partially fluorinated and perfluorinated commercially available compounds (alcohols and alkyl halides) which can be used as a source to obtain the acyclic, partially fluorinated or perfluorinated R group of the compound of general formula (I) are shown in Table 1. It is obvious to the skilled person that the structural motifs partial substitution by fluorine or atoms for the shorter fragments as shown in Table 1 may be repeated analogously for any structural element of a C3-C15 acyclic hydrocarbon group.

TABLE 1:

Structure CAS number or supplier Name Sigma - Aldrich 3-Fluoro-1-propanol F. I ^ F F 76-37-9 2,2,3,3-Tetraf luoro-1-propanol r * F F. Sigma - Aldrich 3,3,3-Trifluoro-1-propanol F F. i F. 422-05-9 2,2,3,3,3-Pentafluoro-1-propanol F F.l F Γτ T F F 754-34-7 Perfluoropropyl iodide IN Sigma - Aldrich 4,4,4-Trifluoro-2-butanol F. χ - OH I ^ F F. 461-18-7 4,4,4-Trifluoro-1-butanol OH Γ-f F ' Sigma - Aldrich 4,4,4-Trifluoro-2-methyl-1-butanol

PL 233 938 Β1 cont. table 1

F F. I PF F '' 'OH Sigma - Aldrich 3,3,4,4,4-Pentafluoro-1-butanol FF 1 ^F xi F ' ^X T ^S <' f Pr F F sL · - ¹ F 423-39-2 Nonafluoro-1-iodobutane ^F 's _i X ^F F <T "F Pf F ^ OH Sigma - Aldrich 3,4,4,4-Tetrafluoro-3- (trifluoromethyl) butan-1-ol F. F.1 F Pf T F F '' OH 375-01-9 2,2,3> 3,4,4,4-Heptafluoro-1-butanol F J F Pf T F F ^ OH 382-31-0 2,2,3,4,4,4-Hexafluoro-1-butanol 1 F ^ Tpi ^ 'F L-F Ρ' - '^ ρ OH 102710-48-5 4,4,4-Trifluoro-3- (trifluoromethyl) -2-buten-1-ol F Ρ'Τ'-γί ^ · '' ·· F LF F - '' \ _F OH 656-80-4 5,5,5-Trifluoro-4- trifluoromethyl-3-penten-2-ol F. "OH 123028-48-8 (Z) -3-Methyl-2,3-difluoroallyl alcohol F. F. "OH 123028-47-7 (F) -3-Methyl-2,3-difluoroallyl alcohol AND F. \ x- ^OH 123028-51-3 (E) -3-Butyl-2,3-difluoroallyl alcohol F. OH ^ F 123028-52-4 (Z) -3-Butyl-2,3-difluoroallyl alohol _F Ύ T ^ F F 'OH 91600-37-2 2,4,4,4-Tetrafluoro-2-buten-1-ol ^F V ^F F <T 'OH 59867-95-7 4,4,4-Trifluoro-3-methyl-2-buten-1-ol

PL 233 938 Β1 cont. table 1

104715-02-8 (Z) -1-Bromo-3- (difluoromethyl) - 2-butene F. Br F. 104715-03-9 (f) -1-Bromo-3- (difluoromethyl) - 2-butene F F F X Γ-F] F F F 72990-82-0 trans-1 -Bromoheptafluoro-2-buten F. Br F. 31450-13-2 1,1,1-Trifluoro-4-bromo-2-butene F. 113439-92-2 4,4,4-Trifluoro-2-butyne-1-ol F JL F DF F. 103245-51-8 6,6,7,7,7-Pentafluoro-2,2- dimethyl-4-heptyn-3-ol Fri. F. 27611-20-7 5,5,5-Trifluoro-3-pentyn-1-ol

In one embodiment, X is hydrogen.

In another embodiment, X is halogen, in particular preferably fluoro. Definitions

The term "alkyl" as used herein by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group connected by single carbon-carbon bonds having the number of carbon atoms indicated in the definition. The number following the carbon symbol refers to the number of carbon atoms that the group may contain. Thus, for example, C1-C4 alkyl is an alkyl of 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and sec-butyl. C3-C15 alkyl is alkyl of 3 to 15 carbon atoms and C4-C10 alkyl is alkyl of 4 to 10 carbon atoms.

The C3-C15 saturated alkyl groups are propyl, isopropyl, 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, 2,2-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, 3,3-dimethylbut-1-yl, 3,3-dimethylbut-2-yl, 2-ethylbut-1-yl, and analogous possible C7-C15 isomers excluding tertiary groups.

C3-C15 unsaturated alkyl 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-butyne-1-yl, 2-butyne-1-yl, 3-butyne-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-methylidenebutan-1-yl, 4-penten-2-yl, ( 3E) -3-penten-2-yl, (3Z) -3-penten-2-yl, 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-butyne-1-yl, 2-methylidene-3-butyn-1-yl , 4-pentyn-2-yl, 3-pentyn-2-yl, 1-pentyn-3-yl, 1,4-pentadin-3-yl, 5-hexen-1-yl, (4E) -4-hexene -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, (2 E, 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-hexene-312

PL 233 938 B1

-yl, (4E) -4-hexen-3-yl, (4Z) -4-hexen-3-yl, 1-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, (2Z) -2-methyl-2-penten-1-yl, 2-methylidenepentan-1-yl, (2E) -2-methyl -2,4-pentadien-1-yl, (2Z) -2-methyl-2,4-pentadien-1-yl, 2-methylidene-4-penten-1-yl, (3E) -2-methylidene-3 -penten-1-yl, (3Z) -2-methylidene-3-penten-1-yl, 3-methyl-4-penten-1-yl, (3E) -3-methyl-3-penten-1-yl , (3Z) -3-methyl-3-penten-1-yl, (2E) -3-methyl-2-penten-1-yl, (2Z) -3-methyl-2-penten-1-yl, 3 -methylidenepentan-1-yl, 3-methylidene-4-penten-1-yl, (2E) -3-methyl-2,4-pentadien-1-yl, (2Z) -3-methyl-2,4-pentadiene -1-yl, 4-methyl-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-methylidene-pentan-2-yl, 3 -methylidene-4-penten-2-yl, 4-methyl-4-penten-2-yl, 4-methyl-3-penten-2-yl, 4-methyl-1-penten-3-yl, 2-methyl-1-penten-3-yl, 2- methyl-1,4-pentadien-3-yl, 2,2-dimethyl-3-buten-1-yl, 2,3-dimethyl-3-buten-1-yl, 2,3-dimethyl-2-butene- 1-yl, 3-methyl-2-methylidenebutan-1-yl, 3-methyl-2-methylidene-3-buten-1-yl, 2-ethyl-3-buten-1-yl, (2E) -2- ethyl-2-buten-1-yl, (2Z) -2-ethyl-2-buten-1-yl, (2E) -2-ethylidene-3-buten-1-yl, (2Z) -2-ethylidene- 3-buten-1-yl, 2-ethenyl-3-buten-1-yl, 5-hexin-1-yl, 4-hexin-1-yl, 3-hexin-1-yl, 2-hexyn-1- yl, 3,5-hexadin-1-yl, 2,5-hexadin-1-yl, 2,4-hexadin-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-hexin-2-yl, 4-hexyn-2- yl, 3-hexyn-2-yl, 3,5-hexadin-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-hexin-3-yl, 4-hexin-3-yl, 1-hexin-3-yl, 1,5-hexadin- 3-yl, 1,4-hexadyn-3 -yl, hex-1-en-5-yn-3-yl, hex-5-en-1-yn-3-yl, (4E) -hex-4-en-1-yn-3-yl, ( 4Z) -hex-4-en-1-yn-3-yl, hex-1-en-4-yn-3-yl, 2-methyl-4-pentin-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-methylidene-4-pentin-1-yl, 2-methylidene-3-pentin-1-yl, 3-methyl-4-pentin-1-yl, 3-methylidene-4-pentin-1-yl, (2E ) -3-methylpent-2-en-4-yn-1-yl, (2Z) -3-methylpent-2-en-4-yn-1-yl, 4-methyl-2-pentin-1-yl,

4-methylpent-4-en-2-yn-1-yl, 3-methyl-4-pentin-2-yl, 3-methylidene-pent-4-yn-2-yl, 4-methyl-1-pentin-3- yl, 2-methylpent-1-en-4-yn-3-yl, 2,2-dimethyl-3-butin-1-yl, 2-ethyl-3-butin-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 analogous possible C7-C15 isomers excluding tertiary groups.

Halogen is fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), especially fluorine.

Compounds of formula (I) containing a carboxyl group can form metal salts, ammonium salts, and organic base salts, including, but not limited to, pharmaceutically acceptable salts and alkaline ion-exchange resin salts (e.g., cholestyramine). Metal salts include in particular alkali metal salts including sodium, potassium and lithium salt, alkaline earth metal salts including but not limited to calcium salt, magnesium salt and barium salt. Salts with organic bases include salts with amines, in particular aliphatic amines, such as the salt with trimethylamine, triethylamine, cyclohexylamine, te (β) butylamine, L-arginine, W- (phenylmethyl) benzeneethylamine, W, W-dibenzylethylenediamine, choline, 2- (dimethylamino) ethanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, L-lysine, morpholine, 4- (2-hydroxyethyl) morpholine, piperazine, 1- (2-hydroxyethyl) pyrrolidine, triethanolamine, 2-amino-2- (hydroxymethyl) propane-1,3-diol, aromatic amines, such as salt with aniline, methylaniline, naphthylamine, or with heterocyclic amines, such as, for example, 1H-imidazole or pyridine. It should be understood that other than pharmaceutically acceptable salts, which may be useful especially as intermediates in the processes for preparing, isolating and purifying the compounds of the invention, are within the scope of the invention. Salts of compounds of formula (I) can be prepared by directly combining compounds of formula (I) with an organic amine (aliphatic, aromatic, heterocyclic) in a protic or aprotic solvent or solvent mixture, e.g. acetone, acetonitrile, toluene. In the case of self-crystallization under such conditions, the precipitate of salt is filtered off and dried. In the absence of spontaneous crystallization, the salt solution can be concentrated or completely evaporated. It is also possible to carry out such a solvent-free process by directly grinding the appropriate ingredients. Inorganic salts of the compounds of formula (I) can additionally be obtained by dissolving the starting acid in an aqueous or water-containing solution of a suitable hydroxide, e.g. sodium, potassium or in the presence of ammonia, and also in the presence of the corresponding unstable alkali metal carbonates and bicarbonates. From such a solution, as in the case of organic amines, the desired salt can be obtained, or it can be combined with another salt (inorganic or organic), which in the exchange reaction will lead to the formation of the desired salt. In the case of reactive metals such as sodium and potassium, there is a possibility of obtaining

A suitable salt by reacting a compound of formula (I) directly with the metal, with or without an inert solvent. Salts of compounds of formula (I) can be converted to compounds of formula (I) with a free carboxyl group by acidifying the salt solution with an acid, e.g. hydrochloric, sulfuric, phosphoric, citric acid; combined with extraction with a suitable organic solvent, e.g. diethyl ether, ethyl acetate, chloroform, methylene chloride. In this process, the salt of the compound of formula (I) is transferred to the organic phase, which is then separated, dried and concentrated.

The compound of the invention contains a pro-chiral center at a carbon atom to which a propy-1-yl (methylacetylene) substituent is attached. Thus, a compound may exist in the form of enantiomers, mixtures of enantiomers of various ratios, in particular racemic mixtures (racemates). It is understood that the enantiomer of the compound of formula (I) will be substantially optically pure, but typically will contain some percentage of the opposite enantiomer, such as up to 10%, 5%, 3%, 2%, 1% or 0.5% of the enantiomer. the opposite.

The compound of the invention may also contain further prochiral centers present in the C3-C15 alkyl group and may therefore exist in the form of enantiomers, mixtures of enantiomers with various ratios, in particular racemic mixtures (racemates), and also in the form of diastereoisomers and mixtures thereof.

The enantiomers of the compound of formula (I) can be obtained by asymmetric synthesis starting from the appropriate chiral starting material. Alternatively, enantiomers of a compound of formula (I) may be obtained by resolving a racemic mixture using methods known to those skilled in the art, including preparative liquid HPLC chromatography, HPLC chromatographic separation using a chiral stationary phase, or by formation of optically active diastereomeric derivatives with chiral aids and vapor fractionated crystallization. diastereoisomerics and removal of chiral aids. For example, a racemic mixture may be separated by chiral HPLC into two enantiomers, enantiomer A with a shorter retention time and enantiomer B with a longer retention time. The retention time of a chiral chromatography process in a defined stationary-eluent system is a physical parameter that identifies the enantiomer. The absolute stereochemistry of the enantiomer can then be determined using known methods.

Particular compounds according to the invention are selected from the group consisting of the following compounds and their salts, especially 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-dimethylocta-2,6-dien-1-yl] oxy} phenyl) hex-4-ynoic acid

12) (3R) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4-ynoic acid

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

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

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

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

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

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

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

20) (3S) -3- (4 - {[(2E, 6E) -3,7,11-trimethyldodeca-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-methylbutan-2-yl] oxy} phenyl) hex-4-ynoic acid

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

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

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

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

PL 233 938 B1

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

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

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

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

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

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

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

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

36) (3R) -3- [4- (pentan-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) -hexa-2,4-dien-1-yloxy] phenyl} hex-4-ynoic acid

40) (3R) -3- {4 - [(2E, 4E) -hexa-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 - [(2R) -2-methylbutoxy] phenyl} hex-4-ynoic acid

64) (3R) -3- {4 - [(2R) -2-methylbutoxy] phenyl} hex-4-ynoic acid

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

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

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

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

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

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

71) (3S) -3- (4 - {[(3R) -3-methylpentyl] oxy} phenyl) hex-4-ynoic acid

72) (3R) -3- (4 - {[(3R) -3-methylpentyl] oxy} phenyl) hex-4-ynoic acid

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

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

75) (3S) -3- [4- (4,4,4-trifluorobutoxy) phenyl] hex-4-ynoic acid

76) (3R) -3- [4- (4,4,4-trifluorobutoxy) phenyl] hex-4-ynoic acid

77) (3S) -3- {4 - [(5,5,5-trifluoropentyl) oxy] phenyl} hex-4-ynoic acid, and

78) (3R) -3- {4 - [(5,5,5-trifluoropentyl) oxy] phenyl} hex-4-ynoic acid.

In a further aspect the invention therefore provides a compound of formula (I) as defined above according to any of the illustrated embodiments for use as a medicament.

In a further aspect, the invention also relates to a pharmaceutical composition containing as active ingredient a compound of general formula (I) as defined above according to any of the illustrated embodiments, in admixture with pharmaceutically acceptable excipients.

PL 233 938 Β1

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

The invention therefore provides a compound of formula (I) as defined above for use in a method of treating GPR40 mediated diseases in mammals, including humans.

The invention also relates to the use of a compound of formula (I) as defined above for the preparation of a medicament for the treatment of GPR40 mediated diseases in mammals, including humans.

The invention also relates to a method of treating GPR40 mediated diseases in mammals, including humans, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined above or a pharmaceutical composition containing a compound of formula (I) as defined above. above.

Compounds of the invention can be prepared by the method outlined in Scheme 1.

Scheme 1

PL 233 938 Β1

A compound of formula (I), wherein R is as previously defined, can be prepared by hydrolyzing an ester group on a compound of formula (II), shown as step (S10) in scheme 1.

COOG

In the compound of formula (II), G, together with the oxygen through which it is linked, represents a synthetically useful alcohol residue on an ester group. Especially preferred are esters with a low molecular weight, e.g. alkyl groups with a chain length of C1-C4, because they have a low molecular weight and are economically viable, and those which, due to their favorable physicochemical properties, e.g. crystallization ability, can be used in manufacturing process and at the same time facilitate the isolation or cleaning process

The hydrolysis product may, depending on the conditions used, be a compound of formula (I) with 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, i-propanol, often with the addition of water and other solubilizing solvents such as e.g. tetrahydrofuran, acetonitrile, Ν, Ν-dimethylformamide, dioxane, in an alkaline environment against e.g. metal hydroxides, such as e.g. LiOH, NaOH, KOH, over a wide temperature range depending on the solvents used; typically between 0 and 100 ° C. In such a medium, the corresponding salt of compound (I) is formed, which may be the final form of the compound or may be converted to the free acid or may also be converted, by exchange (shown as step (S11) in Scheme 1), into another salt, e.g. magnesium or calcium. If the free acid is obtained, the reaction in step (S11) is a process for the preparation of the corresponding salt directly from the free acid using any suitable method known from the literature. For example, a salt of compound (I) can be obtained directly from the free acid by combining it with an appropriate amine, hydroxide, hydride, metal salt, or the metal itself, e.g. sodium.

A compound of formula (II) in which G, together with the oxygen atom through which it is linked, represents a synthetically useful alcohol residue of an ester group, can be prepared by an etherification reaction, shown as step (S9) in Scheme 1, between the compound (III) and the compound R-LG (IV), wherein R is as previously defined for a compound of general formula (I) and LG is a leaving group. The leaving group may be a halogen atom, e.g. chlorine, bromine, iodine, or an ester group such as e.g. methanesulfone, p-toluenesulfone, trifluoromethanesulfone. In such cases, the reaction is carried out in an aprotic organic solvent such as, for example, acetone, acetonitrile, dimethylformamide, in the presence of a compound capable of neutralizing the LG-H side acid formally formed in the reaction. Such compounds can be, for example, potassium carbonate, cesium carbonate, organic amines or organometallic compounds, such as, for example, n-butyl lithium or sodium hydride. The leaving group (LG) may also be a hydroxyl group. In such cases, the compound of formula (II) can be efficiently obtained, for example, under the conditions of a Mitsunobu reaction. The reactions for producing compound (II) can be carried out over a wide temperature range depending on the solvent used; typically between 0 and 100 ° C. Thus, preferably the compound R-LG is a C3-C15 alcohol or a C3-C15 alkyl halide, for which compounds R is as previously defined for a compound of general formula (I) and LG is a hydroxyl group or a halogen atom, respectively. At the same time, the compound of general formula (II) can be obtained according to any other suitable method for producing ethers known from the literature. Due to the fact that the same reactions that are used to form the ether bond can also be used to form esters, it is possible to obtain compound (II) directly from compound (V), wherein PG is

A hydrogen atom by the reaction depicted in step (S9a) in Scheme 1. Such a process may be economically advantageous and then G is identical to R.

The reaction depicted as step (S8) in Scheme 1 shows the method of obtaining compound (III) from compound (V). First of all, it is associated with the formation of an ester in which G, together with the oxygen atom through which it is linked, represents a synthetically useful alcohol residue of the ester group. Especially preferred are esters with a low molecular weight, e.g. with a chain length of C1-C4, because they have a low molecular weight and are economically viable, and those which, due to their favorable physicochemical properties, e.g. crystallization ability, can be used in the production process. and at the same time facilitate the isolation or purification process. Compound (III) can be prepared by conventional methods for the preparation of esters from the free acid, e.g. directly - by an equilibrium reaction in the presence of an excess of alcohol, preferably with simultaneous removal of water, or by any other method of ester preparation known from the literature by selecting appropriate conditions. and synthetic equivalents of the above alcohols which will result in the desired ester. The second aspect of the reaction of step (S8) is the recovery of a free phenolic group in compound (III). As long as this process, depending on the PG protecting group used, has not taken place earlier, it must be carried out at this stage at the latest, as it is necessary to carry out the process of step (S9). Advantageously, the removal of the PG protecting group and the corresponding ester formation process can be carried out simultaneously. For example, it is known that tetrahydropyranyl or silyl ethers which can be used as PG protecting group in the production process are hydrolyzed, for example, in methanol in an acidic environment, for example in the presence of hydrogen chloride. These conditions, on the other hand, may be sufficient to generate the methyl ester.

The process of step (S7) is related to chiral resolution of the racemate (VI) and obtaining one of the active optical antipodes, represented by the formula (V). This process can be carried out advantageously at the stage in which the free carboxyl group of the compound (VI) makes it possible, using optically pure amines, to obtain diastereoisomeric salts, then purify them by fractional crystallization and then, after acidification, to obtain the compound (V) in enriched in the desired optical isomer. It is a classic method known from professional literature. Another way to prepare compound (V) is by chromatographic separation using chiral stationary phases. Such separations can be performed for both analytical and preparative purposes. It should be emphasized that in order to produce the compound (I), the optical antipode separation step can be, as a synthetic element, performed analogously at any of the steps (S4) - (S11) from the moment of the chiral carbon atom marked with an asterisk ( *). It should also be assumed that, according to the methods known from the professional literature, it is possible, by means of an appropriate chemical or enzymatic reaction, to racemize the mixture enriched in pharmacologically inactive optical isomer and thus increase the yield of the desired isomer. If it is found that each of the two optical antipodes has the desired pharmacological effect, the practice of the invention envisages that optical resolution will not be accomplished and compound (I) will be used as a racemate or, with appropriate enrichment in one optical isomer, used as a mixture of optical isomers, with whereby the actual final proportion can be controlled by adding an appropriate amount of one of the isomers or a mixture of optical isomers in a predetermined proportion.

The less active optical isomers of the compounds according to the invention of formula (I) are also important due to the fact that at the time of selecting the optimal production method and the final composition of the active pharmaceutical ingredients composition, they also become analytical standards of this process, allowing control of optical purity in terms of qualitative and quantitative.

Compound (VI) is produced by the decarboxylation reaction, shown in step (S6) in Scheme 1, of one of the carboxyl groups of compound (VII). This process usually requires an elevated temperature, ranging from 50 to 200 ° C, and can be carried out in a variety of protic and aprotic organic solvents, with the addition of water, and also solvent-free. It can be catalyzed by acids or bases as well as by the presence of metal salts and reduced pressure.

The production step (S5) is related to the hydrolysis of the Zi and Z2 fragments in the compound (VIII) and the preparation of the dicarboxylic compound (VII). It can be carried out under conditions like those already described for step (S10).

PL 233 938 B1

The essence of the process of step (S4) is the removal of the PG protecting group in the compound (IX) and the preparation of the compound (VIII). Depending on the type of protecting group used, it can be carried out under conditions known from the literature suitable for the reactivity of the PG group introduced. For example, ester protection to remove requires protic basic conditions, tetrahydropyranyl protection to protic acid conditions, silyl ether protection to protic acid conditions or in the presence of a compound that is a source of F ^- fluoride anions. It should be noted that the removal of the protecting group, depending on the economy of the production process, can also be performed at any later stage from (S4) to (S8) or it may not be removed at all if PG forms an ether bond with compound (IX) and PG is identical to the substituent R. In this particular situation, compound (V) may be identical to compound (I) or may become, formally, by changes from step (S9a) / (S10) / (S11).

Step (S3) of producing a compound (IX) comprises the addition reaction of an organometallic compound (X) to a compound (XI). This process is highly exothermic and requires cooling to a temperature of -76 to + 50 ° C. Due to the instability of the compound (X), step (S3) should be performed under anhydrous conditions in an aprotic solvent, e.g. tetrahydrofuran, preferably under an inert gas atmosphere, e.g. argon or nitrogen. The organometallic compound (X) is commercially available as 1-propynylmagnesium bromide. However, other types of organometallic compounds are also possible that could be used to prepare compound (IX), e.g. 1-propynyl lithium. Organometallic compounds can be prepared in advance and stored as solutions, or prepared in situ, immediately prior to the reaction. The addition reaction of the organometallic compound (X) to the compound (XI) produces a chiral carbon atom in the product (IX) marked with an asterisk (*). From that moment on, it is possible to perform the separation into optical antipodes, which was described earlier. It is also possible to obtain the compound (IX) by an enantioselective addition reaction of an organometallic compound and thus obtain a mixture enriched in the desired optical isomer at once. Such a process can be carried out through the intermediate (XII) (where Z together with the oxygen atom represents an alcohol residue of the ester group) which can be obtained according to the decarboxylation process (S6a), described e.g. in Mohite, AR, Mete, TB, Bhat, RG, An Expedient Stereoselective Synthesis of (Ε) -α, β-Unsaturated Esters and Thioesters Using FeCl3.6H2O, Tetrahedron Letters (2017), and then subjected to one of the reactions described e.g. in PATAl's Chemistry of Functional Groups in 2009 by John Wiley & Sons, Ltd. pp. 772-800; DOT. 10.1002 / 9780470682531.pat0416.

The production of compound (XI) from compound (XIII) involves the step (S2) of protecting the phenolic group (PG = H). There is a wide range of PG protecting groups that can be used in this process, e.g. acyl groups (esters), tetrahydropyranyl (acetal) protection, silyl ethers, or ethers (e.g. methoxy, ethoxy), often used to protect systems phenolic. Since in compound (I) R, together with the oxygen atom through which it is linked, also formally forms an ether bond, it may happen that PG in compound (XI) will be identical to R in compound (I) and in this case the deprotection step phenolic function will not be necessary. In other words, the R fragment in compound (I), together with the oxygen atom, will form an ether protecting bond already in step (S2), although it will not belong to the group of typical protecting ethers known from the literature. Due to the different nature of the possible protecting groups, the manner of obtaining them and the recovery of the free phenolic function is different, albeit well described in the literature, e.g., P.J. Kocienski, Protecting Groups, 3rd Edition, Hydroxyl Protecting Groups, p. 187. A PG protecting group may be introduced into the preparation step of compound (I) in this step as well as it may already be present, e.g. in compound (XV) as a reaction starting material. from step (S1). The PG protecting group can be deprotected at various synthetic steps of the present scheme for producing compound (I). It is essential that it is present in intermediate (XI) before carrying out the organometallic reaction in step (S3) and that it is removed from the compound (V) before carrying out the etherification reaction in step (S9). Therefore, Scheme 1 mentions when the PG protecting group must or may not be present in the intermediate at a given production step (PG = H).

Step (S1) relates to a method for producing compound (XIII) from commercially available compounds (XIV) and (XV) by a Knovenagel condensation reaction known from the literature. Compound (XV) is an aldehyde where X is hydrogen or a halogen atom in the 2 (ortho) position. Moreover, at the 4-position, this aldehyde contains a phenolic function (para-OH), which from the beginning of the synthesis may be protected with an appropriate protecting group (PG) or may remain unprotected at this synthetic stage (PG = H). Compound (XIV) is a classic C-H acid where Zi and Z2 together

And the oxygen atoms to which they are attached represent alcohol residues of the ester groups formed. Zi and Z2 may be the same or different, preferably the same. In particular, Zi and Z2 can combine with each other to form a cyclic relationship. Examples of the compound (XIV) may be diethyl malonate or Meldrum's acid. Step (S1) may be self-catalyzed or base catalyzed in a suitable protic or aprotic organic solvent. Since the Knovenagel reaction can proceed in an equilibrium manner, it is preferable to select the solvents that cause the product to self-crystallize, thereby purifying and simultaneously removing the product from equilibrium.

The method for producing compound (I), shown in Scheme 1, involves the production of one chiral center marked with an asterisk (*). Therefore, compound (I) can be obtained as a racemate, pure enantiomer, or a mixture of enantiomers. However, in the case of the preparation of salts which require more than one anion derived from compound (I) to form, more than one chiral center will also be present in the final compound and the compound should then be regarded as a pure diastereoisomer or diastereomeric mixture. The same situation may arise 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 preparation, since the same purification methods for diastereomeric mixtures as for the enantiomeric mixtures described earlier can be used.

It should be noted that the method for producing compound (I) shown in Scheme 1 is an exemplary embodiment of the present invention. If there is an economic justification, the steps presented may be changed accordingly and combined, omitting the steps of isolating intermediates.

The invention also relates to a pharmaceutical composition containing, as an active ingredient, a compound of general formula (I) as defined above in a mixture with pharmaceutically acceptable excipients.

Where a therapeutically favorable pharmacological rationale exists, the practice of the present invention also does not preclude the use of more than one active compound of general formula (I) in the pharmaceutical composition.

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

In the treatment of the aforementioned diseases, the compounds of formula (I) according to the invention may be administered as a chemical compound, but will usually be used in the form of pharmaceutical compositions containing a compound according to the invention or a pharmaceutically acceptable salt thereof as defined above as an active ingredient, in combination with acceptable compounds. pharmaceutical carriers and excipients.

For the treatment of the aforementioned disorders, the pharmaceutical compositions according to the invention may be administered by any route, preferably orally, parenterally or by inhalation, and will be in the form of a preparation intended for use in medicine, depending on the intended route of administration.

Compositions for administration by the oral route may take the form of solid or liquid preparations. Solid preparations may take the form of, for example, tablets or capsules prepared in a conventional manner from pharmaceutically acceptable inactive ingredients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); bulking agents (e.g., lactose, sucrose, carboxymethylcellulose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., crospovidone, corn starch or sodium starch glycolate); wetting agents (e.g. sodium lauryl sulfate). Tablets may be coated by methods well known in the art with plain coatings, delaying / controlling release coatings, or enteric coatings. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means from pharmaceutically acceptable inactive ingredients such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oil esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain suitable buffering systems, flavoring, coloring and sweetening agents.

PL 233 938 B1

Formulations for oral administration can be formulated appropriately by methods known to those skilled in the art to provide controlled-release of the active compound.

The parenteral route of administration includes administration by intramuscular and intravenous injection, and intravenous infusion (infusion). Compositions for parenteral administration may be in unit dosage form, for example, in ampoules or 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 contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

Compositions for administration by the inhalation route may be in the form of inhalation and be administered by nebulization. Such preparations contain the active compound and excipients administered in the form of an aerosol, i.e. a system of fine particles suspended in a gas, a liquid or a solid, finely divided. The excipients used in nebulization may be sodium chloride as an isotonic agent, inorganic acids and hydroxides as pH regulators and stabilizers, benzalkonium chloride as a preservative, sodium citrate as a buffering agent, polysorbate 80 as a surfactant, ethanol and propylene glycol as a cosolvent and sulphates (VI) as antioxidants. Formulations for administration by inhalation may take the form of a pressurized inhaler or an inhaler delivering the substance in powder form.

The method of treatment using the compounds of this invention will involve administering a therapeutically effective amount of a compound of the invention, preferably in the form of a pharmaceutical composition, to a subject in need of such treatment.

A proposed dose of the compounds of the invention is from 0.1 to about 1000 mg per day, in a single dose or in divided doses. It will be appreciated by those skilled in the art that the selection of the dose necessary to achieve the desired biological effect will depend on a number of factors, for example the specific compound, application, mode of administration, age and condition of the patient, and that the precise dose will ultimately be determined at the discretion of the attending physician.

Examples

The following examples are illustrative and represent the generally used methods of synthesizing the intermediates used to prepare the compounds of the invention.

The examples below use the following abbreviations with the following meanings:

NMR - the result of nuclear magnetic resonance spectroscopy (δ is the value of the shift of a given signal, expressed in ppm). For the 1H NMR spectra, tetramethylsilane (TMS) was used as an internal standard. For the ¹³ C NMR spectra, the solvent shift value was used as a reference, which is 77.16 ppm for deuterochloroform (CDCl 3) and 39.52 mmp for hexadeuterodimethylsulfoxide (DMSO-d6).

MS is the result of the mass spectrometry expressed as m / z ratio. Measurements were made in the electrospray ionization technique (ESI) and the produced ions were observed as positive ions (ESI +) or negative ions (ESI ^- ). The symbol M for each compound is marked with the molecular ion obtained for the tested molecule without fragmentation.

HPLC stands for High Performance Liquid Chromatography.

TLC stands for Thin Layer Plate Chromatography.

Reference compounds:

Two compounds were used as reference compounds: TAK-875 (Fasiglypham, Example R1) and AMG837 (Example R2). TAK-875 is a compound that among the known GPR40 receptor agonists advanced to the 3rd phase of clinical trials, therefore it is an example often discussed in the literature and is a good background for comparative experiments. On the other hand, AMG-837 shows the greatest similarity to the compounds of the invention with regard to the structure of the head fragment.

Compound R1: 2 - [(3S) -6 - ({3- [4- (3-methanesulfonylpropoxy) -2,6-dimethylphenyl] phenyl} methoxy) -2,3-dihydro-1-benzofuran-3-yl acid ] acetic (TAK-875, fasiglypham)

PL 233 938 Β1

TAK-875 (fasiglifarn)

C _J9 H _3I O ₇ S = 524.63

It was obtained according to the method described in "Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonisf", ACS Medicinal Chemistry Letters, 2010, 1, pp. 290-294. The spectral analysis of the obtained compound was fully consistent with the literature data:

¹ H NMR (300 MHz, CDCl) δ: 7.50 - 7.30 (m, 2H), 7.16 (s, 1 H), 7.12 - 6.98 (m, 2H), 6.64 (s, 2H), 6.51 -6.46 (m, 2H ), 5.06 (s, 2H), 4.76 (t, J = 9.1 Hz, 1H), 4.29 (dd, J = 9.2, 6.1 Hz, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.90 - 3.65 (m, 1H), 3.40 - 3.14 (m, 2H), 2.97 (s, 3H), 2.81 (dd, J = 16.9, 5.3 Hz, 1H), 2.61 (dd, J = 16.9, 9.3 Hz, 1H), 2.41-2.29 (m, 2H), 1.99 (s, 6H).

¹³ C NMR (75 MHz, CDCb) δ: 177.45, 161.08, 159.95, 157.09, 140.93, 137.63, 137.12, 134.82, 129.16, 128.70, 128.59, 125.65, 124.35, 121.25, 113.21, 107.41, 97.52, 77.50, 70.28, 65.35 , 51.85, 40.85, 39.42, 37.52, 22.72, 21.18.

MS (ESI +): m / z = 547.2 [M + Na] ⁺ . MS (ESI -): m / z = 523.1 [MH] ^- , 559.1 [M + CI] -.

Compound R2: (3S) -3- [4 - ({3- [4- (trifluoromethyl) phenyl] phenyl} methoxy) phenyl] hex-4-ynoic acid (AMG-837)

AMG-837

II

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (0.733 g, 3.36 mmol, Example 115), 1- [3- (chloromethyl) ) phenyl] -4- (trifluoromethyl) benzene (1.0 g, 3.69 mmol, Example 11) and the remaining reagents and solvents used in the correct proportion. The conditions of Example F1, the obtained product (1.4 g) and the remaining reagents and solvents in the correct ratio were then applied. 1.35 g (91.8% of total yield) of product was obtained as an amorphous solid.

Spectral data consistent with literature data: James Y. Hamilton, "Iridium-Catalyzed Enantioselective Allylic Alkynylation, Angewandte Chemie Int. Ed. Eng. 52 (9) (2013), pp. 7532-7535:

¹ H NMR (300 MHz, CDCl) δ: 7.68 (s, 4H), 7.65 (s, 1H), 7.55 (dt, J = 6.8, 2.2 Hz, 1 H), 7.51 - 7.44 (m, 2H), 7.34 - 7.28 (m, 2H), 6.98 - 6.92 (m, 2H), 5.10 (s, 2H), 4.10 - 4.00 (m, 1H), 2.76 (ddd, J = 22.5, 15.7, 7.6 Hz, 2H), 1.83 ( d, J = 2.4 Hz, 3H).

Intermediate compounds:

The intermediates for the preparation of compounds of the invention were prepared as described below.

The intermediate examples whose number is preceded by the letter I refer to synthetic fragments related to the synthesis of the head portion or the tail portion of the compounds according to the invention.

The intermediate examples, the number of which is preceded by the letter E, relate to ester compounds which are the direct precursors of the corresponding final compounds.

Example 11: 1- [3- (Chloromethyl) phenyl] -4- (trifluoromethyl) benzene

PL 233 938 Β1 {3- [4- (Trifluoromethyl) phenyl] phenyl} methanol, prepared in Example I2 (1.5 g, 5.95 mmol), was dissolved under argon in 10 ml of anhydrous dichloromethane, to which, while stirring, 1.29 ml (17.8 mmol) of thionyl chloride were slowly added dropwise. After stirring was continued overnight, the solvents and excess thionyl chloride were distilled off under reduced pressure. Purification by chromatography (silica gel 60, particle size 230-400 mesh, phase: n-hexane 100% to n-hexane-dichloromethane 4: 1) gave a colorless solid (1.04 g, 65% yield).

¹ H NMR (300 MHz, CDCl) δ: 7.69 (s, 4H), 7.61 (s, 1H), 7.55 (dt, J = 7.3, 1.8 Hz, 1 H), 7.50 - 7.40 (m, 2H), 4.65 ( s, 2H).

Example I2: {3- [4- (trifluoromethyl) phenyl] phenyl} methanol

It was obtained according to the method described in J. B. Houze et al. "AMG 837: A potent, orally bioavailable

GPR40 agonisf; Bioorganic and Medicinal Chemistry Letters. 22 (2012) pp. 1267-1270. Compound spectral data as reported in the literature, e.g. WO 2005/118542 A1, example 11 on p. 50:

¹ H NMR (300 MHz, CDCl) δ: 7.68 (s, 4H), 7.60 (s, 1H), 7.51 (dt, J = 7.5, 1.6 Hz, 1 H), 7.48 - 7.36 (m, 2H), 4.76 ( s, 2H).

Example I3: 5 - [(4-hydroxyphenyl) methylidene] -2,2-dimethyl-1,3-dioxane-4,6-dione

HO

C ₁₃ H _tl O ₅ = 248.23

5.0 L of water, commercially available 4-hydroxybenzaldehyde (500.0 g, 3.89 mol, CAS [128-08-0]) and commercially available 2,2-dimethyl-1,3 were placed in a 10 L reactor. -Dioxane-4,6-dione (700 g, 4.76 mol, CAS [2033-24-1]), 700 ml of toluene was added and stirred at 20 to 33 ° C for 6 hours. During this time an intense yellow precipitate is formed which, after cooling the reactor to room temperature, is filtered off, washed with water and then dried in a vacuum oven (+ 50 ° C, 5 mbar) until constant weight. The end of the reaction is determined by TLC analysis (heptane-ethyl acetate 3: 1) showing no starting material (4-hydroxybenzaldehyde). Yield: 960 g (97.4%).

Melting point: 192.5-193.4 ° C (with decomposition).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 10.95 (s, 1H); 8.26 (s. 1H); 8.23 - 8.13 (m, 2H); 6.97-6.86 (m, 2H); 1.73 (s, 6H).

¹³ C NMR (75 MHz, DMSO-d ₆ )?: 163.67; 163.39; 160.27; 157.03; 137.94; 123.06; 115.84; 109.89; 103.94; 26.87.

Example I4: 5 - [(2-fluoro-4-hydroxyphenyl) methylidene] -2,2-dimethyl-1,3-dioxane-4,6-dione

^c i3 ^H nFO _s = 266.22

The product, 18.2 g (98% yield), was obtained from commercially available 2-Fluoro-4-hydroxybenzaldehyde (10.0 g, 70 mmol, CAS [348-27-6]) and commercially available 2,2-dimethyl1, 3-Dioxane-4,6-dione (12.1 g, 82.5 mmol, CAS [2033-24-1]) in an analogous manner to Example I3.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 11.23 (s, 1H), 8.35 (s, 1H), 8.21 (t, J = 8.9 Hz, 1H), 6.73 (ddd, J = 15.1, 10.8, 2.4 Hz, 2H), 1.75 (s, 6H).

¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ: -106.10 (dd, J = 12.7, 9.0 Hz).

¹³ C NMR (75 MHz, DMSO-d ₆ , DEPT 135 °) δ: 147.32 (d, Jc-f = 5.9 Hz), 134.68, 112.38, 102.67 (d, Jc-f = 24.6 Hz), 26.87 (s) .

PL 233 938 Β1

Example I5: 5- [1 (R / S) - (4-hydroxyphenyl) but-2-yn-1-yl] -2,2-dimethyl-1,3-dioxane-4,6-dione

5 - [(4-Hydroxyphenyl) methylidene] -2,2-dimethyl-1,3-dioxane-4,6-dione, prepared in Example 13, (2.5 g, 10.1 mmol) was dissolved in dry tetrahydrofuran ( 40 ml), under argon. While stirring and cooling to 0 ° C, 4-methylmorpholine (1.23 g, 12.2 mmol) was added and acetyl chloride (0.8 ml, 11.1 mmol) was slowly added dropwise. Then, after 30 min. After stirring at room temperature, the formed 4-methylmorpholine hydrochloride was filtered on a Buchner funnel and washed with 10 ml of dry tetrahydrofuran. The obtained filtrate was cooled back to 0 ° C and 22.0 ml of commercially available 1-propynylmagnesium bromide (0.5M tetrahydrofuran solution, 22.0 ml, 11.0 mmol, CAS [16466-97-0]) was added dropwise under argon. ) and then stirred for 30 min. in room temperature. At this time, 20 mL of 2M aqueous sodium hydroxide solution was added to the reaction mixture and the reaction mixture was heated for another 30 min. up to a temperature of 60 ° C. The reaction mixture was then re-cooled to 0 ° C and acidified by adding 10 ml of 5M aqueous hydrochloric acid. The reaction product was isolated by adding water (50 ml) and extracting with toluene containing (10% v / v) ethyl acetate. The organic layer was washed with 1% hydrochloric acid solution, brine, dried and evaporated. 3.0 g of product were obtained in the form of an amber oil (quantitative yield).

MS (ESI +): m / z = 311.1 [M + Na] -. MS (ESI -): m / z = 287.1 [M-H] -.

Example I6: 5- [1 (R / S) - (2-fluoro-4-hydroxyphenyl) but-2-yn-1-yl] -2,2-dimethyl-1,3-dioxane-4,6-dione

C ₁₆ H ₁₅ FO _s = 306.29

The reaction product was obtained under the conditions as in Example I5 from 5 - [(2-fluoro-4-hydroxyphenyl) methylidene] -2,2-dimethyl-1,3-dioxane-4,6-dione (8, 2 g, 30.8 mmol), 4-methylmorpholine (4.6 g, 45.5 mmol), acetyl chloride (3.0 ml, 41.8 mmol), commercially available 1-propynylmagnesium bromide (0.5M solution in tetrahydrofuran, 67.1 mL, 33.5 mmol, CAS [16466-97-0]).

MS (ESI +): m / z = 329.1 [M + Na] -. MS (ESI -): m / z = 305.1 [M-H] -.

Example I7: (3R / S) -3- (4-hydroxyphenyl) hex-4-ynoic acid

5- [1 (R / S) - (4-hydroxyphenyl) but-2-yn-1-yl] -2,2-dimethyl-1,3-dioxane-4,6-dione, prepared in Example I5, ( 64.0 g, 222 mmol) was dissolved in a mixture of (V,) dimethylformamide (300 ml) and water (30 ml) and heated at 90 ° C for 18 hours. During this time, the decarboxylation process can be observed through the carbon dioxide bubbles emerging from the reaction solution. After cooling the product, diluting with water (1 L), brine (0.5 L) and acidifying (100 ml of a 5% aqueous solution)

PL 233 938 µl hydrochloric acid), the reaction product was extracted with t-butyl methyl ether (4 x 0.5 L). The organic phase was separated, washed with brine, dried, concentrated and the resulting residue was purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 10: 1 to 1: 3). 33.2 g of a light syrup (73% yield) was obtained.

MS (ESI -): m / z = 203.1 [M-H] -, 239.0 [M + Cl] -.

Example I8: (3R / S) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid

HO '

ΌΗ

C ₁₂ H _tl FO ₃ = 222.21

The reaction product was obtained under the conditions as in Example 17 from 5- [1 (R / S) - (2-fluoro-4-hydroxyphenyl) but-2-yn-1-yl] -2,2-dimethyl-1,3 -dioxane-4,6-dione, obtained in Example I6, (6.0 g, 19.6 mmol). Yield: 4.3 g of syrup (99% yield).

MS (ESI -): m / z = 221.1 [M-H] -, 257.1 [M + Cl] -.

Example I9: (1S, 2R) -1-Amino-2,3-dihydro-1H-inden-2-ol salt of (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid

HO '

HO

C ₂₁ H "NO ₄ = 353.41

Racemic (3R / S) -3- (4-hydroxyphenyl) hex-4-ynoic acid, prepared in Example 17, (187.4 g, 0.918 mol) was dissolved in 2.0 L acetonitrile and with stirring and heating to 70 ° C was added commercially available (1S, 2R) - (-) - cis-1-aminoindan-2-ol (69.8 g, 0.467 mol, CAS [126456-43-7]). Stirring and heating to the same temperature was continued for a further 4 hours and the salt slurry of the product was allowed to cool to room temperature. Before filtering, the suspension was cooled to + 5 ° C, the precipitate was filtered off and washed with 2 x200 ml of cold (0 ° C) acetonitrile. The obtained precipitate was quenched with 1.1 L of 10: 1 acetonitrile / water and stirred and heated at 70 ° C, then cooled and filtered, washing with cold acetonitrile to give a crystal of higher optical purity. The last process was repeated analogously two more times, recrystallizing the product obtained successively from 0.8 and 0.6 L of a 10: 1 acetonitrile-water mixture. The salt was finally obtained with an optical purity of> 98% diastereomeric excess as a colorless solid, in an amount of 102.4 g (63% yield). The optical purity was determined by chiral HPLC (Chiralpak Daicel IB-U 100 x 3.0 mm column; 1.6 µm; isocratic phase 92: 8 (hexane + 0.2% TFA: ethanol + 0.2% TFA); this dominant isomer Rt = 5.67 min. (content 99.2%); opposite isomer Rt = 4.94 min. (content 0.8%)). Based on literature data: Shawn D. Walker "Development of a Scalable Synthesis ofa GPR40 Receptor Agonisf, Organic Process Research and Development, 15, (2011), pp. 570-580 and the in vitro activity of its derivatives at the GPR40 receptor, configuration of this the optical isomer of 3- (4-hydroxyphenyl) hex-4-ynoic acid was designated as the S isomer.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 7.45 - 7.35 (m, 1H), 7.28 - 7.17 (m, 3H), 7.17 - 7.06 (m, 2H), 6.73 - 6.62 (m, 2H), 4.41 (td, J = 5.6, 3.2 Hz, 1H), 4.27 (d, J = 5.4 Hz, 1H), 3.90 (td, J = 7.4, 2.5 Hz, 1H), 3.03 (dd, J = 16.2, 5.8 Hz , 1H), 2.84 (dd, J = 16.2, 3.1 Hz, 1H), 2.39 (ddd, J = 22.0, 14.9, 7.1 Hz, 2H), 1.76 (d, J = 2.4 Hz, 3H).

¹³ C NMR (75 MHz, DMSO-d ₆ )?: 174.32, 155.94, 141.28, 140.83, 132.55, 128.16, 128.03, 126.41, 124.90, 114.98 (x2), 82.18, 77.05, 71.30, 57.52, 45.69, 39.07, 33.42 , 3.35.

Example 110: (1R, 2S) -1-Amino-2,3-dihydro-1H-inden-2-ol salt of (3R) -3- (4-hydroxyphenyl) hex-4-ynoic acid

PL 233 938 Β1

C ₂₁ H ₁₃ NO ₄ = 353.41

The compound was prepared analogously to Example 19 using racemic (3R / S) -3- (4-hydroxyphenyl) hex-4-ynoic acid obtained in Example 17, (120.0 g, 0.588 mol) commercially available (1R, 2S) -cis-1-aminoindan-2-ol (43.8 g, 0.294 mol, CAS [136030-00-7]) and the proportions of the solvents are proportional to the reagents used. Yield: 57.2 g (55% yield) of a colorless solid with optical purity> 98% diastereomeric excess. Since the compounds of Example I9 and Example 110 are enantiomers of each other, their spectral data is identical. On the same basis, the configuration of the present 3- (4-hydroxyphenyl) hex-4-ynoic acid optical isomer is designated as the R isomer.

Example 111: (3S) -3- (4-Hydroxyphenyl) hex-4-ynoic acid

(1S, 2R) -1-Amino-2,3-dihydro-1H-inden-2-ol salt of (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid, prepared in Example I9, (35 , 3 g, 0.1 mol), while stirring, were poured at room temperature with 200 ml of 1M hydrochloric acid solution and 100 ml of tert-butyl methyl ether. After 30 minutes, the substrate salt is dissolved, with the amine hydrochloride remaining dissolved in the aqueous phase and the free acid of the product passing into the organic phase. The aqueous and organic phases were separated. The aqueous phase was extracted with an additional 3 x 50 ml of methyl t-butyl ether. The organic phases were combined, washed with brine, dried and concentrated to give a quantitatively (20.4 g) product with spectral data identical to Example I7. The absence of secondary racemization was confirmed by repeating the HPLC analysis on a chiral resin as in Example I9. Optical purity> 98% e.e.

Example 112: (3R) -3- (4-Hydroxyphenyl) hex-4-ynoic acid

C _n HiA = 204.22

The product was obtained quantitatively from (1R, 2S) -1-amino-2,3-dihydro-1H-inden-2-ol salt of (3R) -3- (4-hydroxyphenyl) hex-4-ynoic acid obtained from Example 110 using the conditions and methods of Example 111.

Example 113: (3R) -3- (2-Fluoro-4-hydroxyphenyl) hex-4-ynoic acid

C ₁₂ H _u FOj = 222.21

PL 233 938 Β1

Racemic (3R / S) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid, obtained in Example I8, was separated into optical enantiomers by HPLC separation on a chiral bed using a semi-preparative Chiralpak Daicel IG 250 column x 30 mm; 5.0 gm and the isocratic phase 92: 8 (hexane + 0.2% TFA: ethanol + 0.2% TFA). The control of the separation was carried out using analogous conditions for the mobile phase used and the analytical Chiralpak Daicel IG-3 250 x 2.1 mm column; 3.0 μΠΊ. Retention time for the present isomer Rt = 3.551 min. Based on the in vitro activity of the derivatives of this compound at the GPR40 receptor, the configuration of the present optical isomer of 3- (4-hydroxyphenyl) hex-4-ynoic acid was designated as the R isomer. 50 mg of compound with optical purity> 98% e.e. were obtained with spectral data identical to Example I8.

Example 114: (3S) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid

Product in the amount of 45 mg, purity> 98% e.e. prepared as in Example 113. Retention time for the present isomer Rt = 3.118 min. (analytical column Chiralpak Daicel IG-3 250 x 2.1 mm; 3.0 μπι, isocratic phase 92: 8 (hexane + 0.2% TFA: ethanol + 0.2% TFA). Based on the activity of the derivatives of this compound against GPR40 receptor in vitro, the configuration of the present 3- (4-hydroxyphenyl) hex-4-ynoic acid optical isomer is designated as the S isomer.

Example 115: (3S) -3- (4-Hydroxyphenyl) hex-4-ynoic acid methyl ester

_I3 C ₁₄ O H = 218.25

(1S, 2R) -1-Amino-2,3-dihydro-1H-inden-2-ol salt of (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid, prepared in Example I9, (25 , 1 g, 71 mmol), quenched with 125 ml of a cold (+ 4 ° C) solution of hydrogen chloride gas in methanol (58 g of HCl gas / 865 ml of methanol) and stirred for 18 hours at 25 ° C. During this time, all the substrate is dissolved. The reaction solution was evaporated until a white precipitate appeared, which was flooded with 200 ml of methyl t-butyl ether. The resulting amine hydrochloride precipitate was filtered off and washed with t-butyl methyl ether (50 ml) and heptane (50 ml). The filtrate was transferred to a separatory funnel and washed with water (2 x 100 mL), 6% aqueous sodium bicarbonate, brine, dried and concentrated. The product was obtained quantitatively in the form of a light yellow syrup in an amount of 15.5 g.

The same product can be obtained using the above conditions and the (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid from Example 111 as a substrate.

¹ H NMR (300 MHz, CDCl) δ: 7.25 - 7.18 (m, 2H), 6.81 - 6.73 (m, 2H), 5.73 (s (br), 1H), 4.04 (ddd, J = 8.2, 4.9, 2.4 Hz, 1H), 3.67 (s, 3H), 2.71 (qd, J = 15.2, 7.7 Hz, 2H), 1.82 (d, J = 2.4 Hz, 3H).

¹³ C NMR (75 MHz, CDCl) δ 172.21,154.90, 133.12, 128.60, 115.56, 79.70, 79.02, 52.01,43.58, 33.58, 3.76.

MS (ESI +): m / z = 241.1 [M + Na] ⁺ .

Example 116: (3R) -3- (4-Hydroxyphenyl) hex-4-ynoic acid methyl ester

= 218.25

PL 233 938 Β1

The product was prepared using (1R, 2S) -1-amino-2,3-dihydro-1H-inden-2-ol salt of (3R) -3- (4-hydroxyphenyl) hex-4-ynoic acid as a substrate, prepared in Example 110, and the conditions of Example 115. Spectral data identical to Example 115.

Example 117: (3R) -3- (2-Fluoro-4-hydroxyphenyl) hex-4-ynoic acid methyl ester

The product was prepared using (3R) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid, prepared in Example 113, and the conditions of Example 115 as a substrate.

MS (ESI +): m / z = 259.1 [M + Na] ⁺ .

Example 118: (3S) -3- (2-Fluoro-4-hydroxyphenyl) hex-4-ynoic acid methyl ester

^c i3 ^H i3 ^FO 3- 236.24

The product was prepared using (3S) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid, prepared in Example 114, and the conditions of Example 115 as a starting material.

MS (ESI +): m / z = 259.1 [M + Na] -.

Example 119: 2,3-Dimethyl-but-2-enoic acid ethyl ester

C ₈ H ₁₄ O ₂ - 142.20

Commercially available triethyl 2-phosphonopropionate (22.5 ml, 103 mmol, CAS [3699-66-9]) was placed in dry tetrahydrofuran (65 ml) under argon, cooled to -76 ° C, and 2 was slowly added dropwise with stirring. 5M solution in n-butyllithium hexanes (39.2 mL, 98 mmol). After a colorless precipitate formed, the reaction mixture was allowed to warm to 0 ° C. Acetone (14.4 mL, 196 mmol) was added dropwise to the reaction mixture, and the contents of the reaction vessel were stirred at room temperature for 24 hours. The reaction product was isolated by adding 100 ml of a 3% aqueous solution of sulfuric acid and extraction with diethyl ether. The organic layer was separated, washed twice with water, 6% aqueous sodium bicarbonate, brine, dried and concentrated by evaporation at 30 ° C and 400 mbar pressure. The residue was distilled under reduced pressure to collect the product fraction distilling in the temperature range 59-62 ° C and pressure range 5.3-5.6 mbar. 11.2 g of a colorless liquid (80% yield) were obtained.

¹ H NMR (300 MHz, CDCl) δ: 4.19 (q, J = 7.1 Hz, 2H), 2.00 (d, J = 1.3 Hz, 3H), 1.85 (s, 3H), 1.80 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H.

¹³ C NMR (75 MHz, CDCb) δ: 169.90, 142.77, 122.76, 60.09, 22.92, 22.45, 15.75, 14.43.

Example I20: 2,3-dimethylbut-2-en-1-ol

C ₆ H ₁₂ O = 100.16

PL 233 938 Β1

Lithium aluminum hydride (5.69 g, 142 mmol) was placed in 10 ml of dry tetrahydrofuran under a blanket of argon, 200 ml of tert-butyl methyl ether were added and a solution of 2,3-dimethylbut-2-enoic acid ethyl ester prepared in Example 2 was slowly added dropwise. 119, (18.4 g, 129 mmol), dissolved in 30 mL of tert-butyl methyl ether at such a rate as to keep the reaction mixture just below reflux. After completion of the dropwise addition, the contents of the reaction vessel were stirred for an additional 10 minutes, then cooled to 0 ° C and the excess lithium aluminum hydride was decomposed by the gradual addition of ice (10 g). The reaction mixture was diluted with another portion of tert-butyl methyl ether (200 ml) and the insoluble aluminum salts were taken up by adding 0.5 L of 50% aqueous sodium hydroxide solution. The reaction mixture was transferred to a separating funnel. The organic layer was separated, washed with 50% aqueous sodium hydroxide (100 ml), 6% aqueous potassium bisulfate, brine and dried. The product was isolated by distillation under reduced pressure. The obtained was 8.2 g of a colorless liquid (63% yield), distilling in the temperature range 48-49 ° C at a pressure of 2.9 mbar.

¹ H NMR (300 MHz, CDCl 2) δ: 4.12 (s, 2H), 1.74 (s, 6H), 1.69 (s, 3H).

¹³ C NMR (75 MHz, CDCl b) δ: 129.16, 127.47, 63.89, 20.88, 20.00, 16.60.

Example 121: (2R / S) -2,3-dimethylbutan-1-ol

C ₆ H ₁₄ O = 102.18

Commercially available 2,3-dimethyl-1-butene (6 mL, 4.08 g, 47 mmol, CAS [56378-0]) was dissolved in dry tetrahydrofuran (10 mL) and added 100 portions while cooling to 0 ° C and stirring. ml of a 0.5M solution in tetrahydrofuran of 9-Borabicyclo [3.3.1] nonane (9-BBN, 50 mmol). The contents of the reaction vessel were then stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0 ° C again and 60 ml of a 3M aqueous sodium hydroxide solution and 60 ml of a 30% aqueous hydrogen peroxide solution were carefully added dropwise, and stirring was continued for another 1.5 hours at ambient temperature. The reaction product was isolated by extraction with diethyl ether (100 ml). The organic layer was separated, washed with 5% aqueous sodium sulfite solution, brine, dried and concentrated at 40 ° C and 100 mbar. The residue was distilled under reduced pressure. The product, a colorless liquid in an amount of 2.0 g (42% yield), was collected as the distillation fraction at 50 ° C and 3 mbar.

¹ H NMR (300 MHz, CDCl) δ: 3.59 (dd, J = 10.6, 5.9 Hz, 1H), 3.44 (dd, J = 10.6, 7.0 Hz, 1H), 1.70 (dtd, J = 13.7, 6.8, 5.1 Hz, 1H), 1.59 - 1.42 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 66.64, 41.56, 28.99, 20.73, 18.12, 12.65.

Example I22: 1-Bromo-4- (2,2-dimethylpropoxy) benzene

Neopentyl alcohol (2,2-dimethyl-1-propanol, 2.93 ml, 27 mmol) was dissolved in 50 ml of dry (V) V-dimethylformamide, cooled to 0 ° C and triethylamine (3.78 ml, 27 mmol) and methanesulfonic chloride (1.94 ml, 25 mmol) was slowly added dropwise. After a precipitate of triethylamine hydrochloride had formed, the contents of the reaction vessel were stirred for an additional 30 min. without cooling, then commercially available 4-Bromophenol (3.53 g, 20 mmol, CAS [106-41-2]), tetrabutylammonium iodide (0.923 g, 2.5 mmol) cesium carbonate (18.5 g, 56 , 2 mmol) and heating the reaction to 80 ° C while purging with argon for 15 minutes. The temperature of the reaction mixture was then increased to 130 ° C and stirred for 18 hours. After cooling, the reaction product was isolated by adding water (150 ml) and extracting with diethyl ether. The organic layer was separated, washed with water (2 x 50 ml), brine (50 ml), dried, concentrated and purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 20: 1 to 8: 1) ). 3.66 g of a colorless oil (75% yield) was obtained.

¹ H NMR (300 MHz, CDCl 2) δ: 7.37 - 7.30 (m, 2H), 6.79 - 6.72 (m, 2H), 3.53 (s, 2H), 1.01 (s, 9H).

¹³ C NMR (75 MHz, CDCl) δ: 158.86, 132.26, 116.46, 112.58, 78.27, 32.03, 26.71.

PL 233 938 Β1

Example I23: 4- (2,2-Dimethylpropoxy) benzaldehyde o

C _ia H _u O ₂ = 192.25

The 1-Bromo-4- (2,2-dimethylpropoxy) benzene obtained in Example 122 (4.54 g, 18.7 mmol) was dissolved in 15 ml of dry tetrahydrofuran under argon and cooled to 0 ° C. At this temperature, a 1.3M solution in tetrahydrofuran of lithium chloride isopropylmagnesium chloride complex (1.64 ml, 6.91 mmol) was added, and after 20 minutes 2.5M n-butyl lithium hexanes solution (1.7 ml, 13.8 mmol) and stirred for 1 hour at the same temperature. After this time, 4 ml of dry N-dimethylformamide was added and the temperature was stirred for another hour at the same temperature. The reaction was terminated by adding water (50 mL). The reaction product was isolated by extraction with a 1: 1 mixture of ethyl acetate and diethyl ether. The organic layer was separated, washed with water (2 x 50 ml), brine (50 ml), dried, concentrated and purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 20: 1 to 4: 1) . 3.40 g of a colorless oil were obtained (95% yield).

¹ H NMR (300 MHz, CDCl 2) δ: 9.87 (s, 1H), 7.86 - 7.78 (m, 2H), 7.05 - 6.96 (m, 2H), 3.67 (s, 2H), 1.05 (s, 9H).

¹³ C NMR (75 MHz, CDCl b) δ: 190.75, 164.66, 131.97, 129.81, 114.83, 78.19, 31.91.26.55.

Example I24: 2 - {[4- (2,2-Dimethyl-propoxy) phenyl] methylidene} propanedioic acid, 1,3-methyl diester ^C 17 ^H 21 ° s = 306.35

The 4- (2,2-dimethylpropoxy) benzaldehyde (3.59 g, 18.7 mmol) obtained in Example I23 was dissolved in benzene (25 ml), added dimethyl malonate (2.24 ml, 19.6 mmol), piperidine ( 0.184 mL, 1.87 mmol), acetic acid (0.101 mL, 1.77 mmol), and the mixture was stirred and refluxed while removing water that formed from the reaction (Dean-Stark trap) for 18 hours. The reaction mixture was then evaporated and purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 20: 1 to 4: 1). 1.86 g of a colorless syrup was obtained (31% yield).

¹ H NMR (300 MHz, CDCl 2) δ: 7.71 (s, 1H), 7.40-7.34 (m, 2H), 6.92-6.86 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.61 (s, 2H), 1.03 (s, 9H).

¹³ C NMR (75 MHz, CDCl) δ: 167.70, 164.93, 161.85, 142.81, 131.60, 125.10, 122.67, 114.99, 78.05, 52.63, 52.53, 31.93, 26.61.

Example I25: 2 - [(1R / S) -1- [4- (2,2-dimethyl-propoxy) phenyl] but-2-yn-1-yl] propanedioic acid methyl diester

C _I0 H _1S O _S = 346.42

The reaction product in an amount of 850 mg (91% yield) was obtained from 2 - {[4- (2,2-dimethylpropoxy) phenyl] methylidene} propanedioic acid 1,3-methyl diester, prepared in Example I24, (830 mg, 2 71 mmol) and the conditions used in Example I5, omitting the first acetylation step and using the remaining reagents in proportion to the starting material used.

PL 233 938 Β1

MS (ESI +): m / z = 715.3 [2M + Na] ⁺ .

Example I26: 2 - [(1 R / S) -1 - [4- (2,2-dimethylpropoxy) phenyl] but-2-yn-1-yl] propanedioic acid

2 - [(1R / S) -1- [4- (2,2-dimethyl-propoxy) phenyl] but-2-yn-1-yl] propanedioic acid 1,3-methyl diester obtained in Example I25 (850 mg, 2 , 45 mmol) was dissolved in a mixture of tetrahydrofuran (20 ml) and methanol (10 ml) and 1.03 g (24.5 mmol) of lithium hydroxide monohydrate dissolved in 10 ml water was added and the contents of the reaction vessel were stirred at 25 ° C for 18 hours. The formation of the product was monitored by TLC (100% ethyl acetate - starting material disappeared (Rf = 0.8) and a new product of much greater polarity (Rf = 0.05) was formed). The reaction product was isolated after acidifying the reaction mixture with 3% aqueous sulfuric acid and exhaustive extraction with ethyl acetate with the addition of 5% vol. methanol. The combined organic phases were washed with brine, dried and concentrated. The obtained crude product was a yellow oil and an amount of 730 mg (94% yield) was used for the next reaction step without purification.

Example E1: (3S) -3- (4-propoxyphenyl) hex-4-ynoic acid methyl ester

Prepared in Example 115 (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (125 mg, 0.573 mmol), commercially available 1-bromopropane (0.52 ml, 5.73 mmol, CAS [106 -94-5]) was dissolved in dry Λ /, Λ / '- dimethylformamide (10 mL), cesium carbonate (377 mg, 1.15 mmol) was added and stirred at 50 ° C for 18 hours. The reaction was quenched by adding water (50 mL). The product was extracted with diethyl ether and ethyl acetate 1: 1 (50 ml). The organic layer was washed with 3% aqueous sulfuric acid, water, brine, dried and concentrated. The product was purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 100: 1 to 20: 1). 130 mg of a colorless syrup (87% yield) was obtained.

¹ H NMR (300 MHz, CDCl) δ: 7.32 - 7.21 (m, 2H), 6.90 - 6.77 (m, 2H), 4.11 - 3.99 (m, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.66 (s, 3H), 2.82 - 2.58 (m, 2H), 1.82 (d, J = 2.4 Hz, 3H), 1.85 - 1.72 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

¹³ C NMR (75 MHz, CDCl) δ: 171.66, 158.30, 133.12, 128.36, 114.67, 79.82, 78.78, 69.63, 51.74, 43.53, 33.57, 22.70, 10.61,3.72.

MS (ESI +): m / z = 283.1 [M + Na] ⁺ , 299.1 [M + K] ⁺ .

Example E2: (3S) -3- [4- (hexyloxy) phenyl] hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (125 mg, 0.573 mmol, Example 115), commercially

PL 233 938 µ1 of available 1-bromhexane (0.82 ml, 5.73 mmol, CAS [111-25-1] and the remaining reagents and solvents used in the correct proportion to give 132 mg (76% yield) of the product as a syrup.

¹ H NMR (300 MHz, CDCb) δ: 7.31 - 7.22 (m, 2H), 6.89 - 6.77 (m, 2H), 4.05 (ddq, J = 9.3, 7.2, 2.3 Hz, 1H), 3.92 (t, J = 6.6 Hz, 2H), 3.65 (s, 3H), 2.70 (qd, J = 15.2, 7.7 Hz, 2H), 1.82 (d, J = 2.4 Hz, 3H), 1.80 - 1.71 (m, 2H), 1.52 - 1.38 (m, 2H), 1.38 - 1.24 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 171.67, 158.32, 133.11, 128.36, 114.68, 79.83, 78.78.68.14, 51.74, 43.54, 33.58, 31.70, 29.38, 25.85, 22.71, 14.12, 3.73.

MS (ESI +): m / z = 325.2 [M + Na] ⁺ , 341.1 [M + K] ⁺ .

Example E3: (3S) -3- [4- (heptyloxy) phenyl] hex-4-ynoic acid methyl ester

The product was prepared under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (125 mg, 0.573 mmol, Example 115), commercially available 1-bromoheptane (0.9 ml, 5.73 mmol, CAS [629-04-9]) and the remaining reagents and solvents used in the correct ratio. 153 mg (84% yield) of the product were obtained in the form of a syrup.

¹ H NMR (300 MHz, CDCb) δ: 7.31 - 7.23 (m, 2H), 6.87 - 6.79 (m, 2H), 4.05 (ddq, J = 9.4, 4.8, 2.4 Hz, 1H), 3.92 (t, J = 6.6 Hz, 2H), 3.65 (s, 3H), 2.70 (qd, J = 15.2, 7.7 Hz, 2H), 1.82 (d, J = 2.4 Hz, 3H), 1.87 - 1.69 (m, 2H), 1.52 - 1.22 (m, 8H), 0.89 (t, J = 6.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 171.65, 158.31,133.09, 128.35, 114.66, 79.82, 78.76.68.12, 51.72, 43.53, 33.57, 31.89, 29.40, 29.16, 26.12, 22.70, 14.15, 3.71.

MS (ESI +): m / z = 317.2 [M + H] ⁺ , 339.2 [M + Na] ⁺ , 355.2 [M + K] ⁺ .

Example E4: (3S) -3- [4- (3-methylbutoxy) phenyl] hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (2.05 g, 9.39 mmol, Example 115), commercially available 1-bromo -3-methylbutane (1.58 mL, 13.1 mmol, CAS [107-82-4]) and the remaining reagents and solvents used in the correct ratio. 2.47 g (91% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 311.2 [M + Na] ⁺ .

Example E5: (3S) -3- {4 - [(3-methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester

PL 233 938 Β1

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (3.03 g, 13.9 mmol, Example 115), commercially available 1-bromo -3-methyl-2-butene (2.25 mL, 19.4 mmol, CAS [870-63-3]) and the remaining reagents and solvents used in the correct ratio. 3.93 g (99% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 309.1 [M + Na] ⁺ , 325.1 [M + K] ⁺ .

Example E6: (3R) -3- {4 - [(3-Methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester ^c 18 ^H 22 ° 3 = 286.37

The product was obtained under the conditions of Example E1 using (3R) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (0.303 g, 1.39 mmol, Example 116), commercially available 1-bromo-3 -methyl-2-butene (0.225 mL, 1.94 mmol, CAS [870-63-3]) and the remaining reagents and solvents used in the correct ratio. 0.331 g (83% yield) of the product was obtained as a syrup.

MS (ESI +): m / z = 309.1 [M + Na] ⁺ , 325.1 [M + K] ⁺ .

Example E7: (3 /?) - 3- {2-fluoro-4 - [(3-methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester

C _in H _m FO, = 304.36

The product was obtained under the conditions of Example E1 using (3R) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid methyl ester (50 mg, 0.212 mmol, Example 117), commercially available 1-bromo -3-methyl-2-butene (0.25 mL, 2.2 mmol, CAS [870-63-3]) and the remaining reagents and solvents used in the correct ratio. 32 mg (49% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 327.1 [M + Na] ⁺ .

Example E8: (3S) -3- {2-fluoro-4 - [(3-methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester

C _le H ₂₁ FO ₃ = 304.36

The product was obtained under the conditions of Example E1 using (3S) -3- (2-fluoro-4-hydroxyphenyl) hex-4-ynoic acid methyl ester (45 mg, 0.191 mmol, Example 118), commercially available 1-bromo -3-methyl-2-butene (0.25 mL, 2.2 mmol, CAS [870-63-3]) and the remaining reagents and solvents used in the correct ratio. 44 mg (76% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 327.1 [M + Na] ⁺ .

PL 233 938 Β1

Example E9: (3S) -3- [4- (2-ethylbutoxy) phenyl] hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (0.30 g, 1.37 mmol, Example 115), commercially available 1-bromo -2-ethylbutane (0.397 mL, 2.75 mmol, CAS [3814-34-4]) and the remaining reagents and solvents used in the correct ratio. 0.37 g (89% yield) of the product was obtained as an oil.

MS (ESI +): m / z = 325.2 [M + Na] ⁺ .

Example E10: (3S) -3- [4- (4,4,4-trifluorobutoxy) phenyl] -hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available 1-bromo-4 , 4,4-trifluorobutane (0.431 mL, 3.44 mmol, CAS [406-81-5]) and the remaining reagents and solvents used in the correct ratio. 451 mg (100% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 351.1 [M + Na] ⁺ .

Example E11: (3S) -3- {4 - [(5,5,5-trifluoropentyl) oxy] phenyl} hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available 5-bromo-1 , 1,1-trifluoro pentane (0.488 mL, 3.44 mmol, CAS [54932-74-0]) and the remaining reagents and solvents used in the correct ratio. 470 mg (100% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 365.1 [M + Na] ⁺ .

PL 233 938 Β1

Example E12: (3S) -3- [4- (2-methyl-propoxy) phenyl] hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E1 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 115), commercially available 1-bromo-2 -methylpropane (1.01 g, 7.36 mmol, CAS [78-77-3]) and the remaining reagents and solvents used in the correct ratio. 460 mg (92% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.30 - 7.22 (m, 2H), 6.87 - 6.79 (m, 2H), 4.09 - 4.00 (m, 1H), 3.69 (d, J = 6.5 Hz, 2H), 3.66 (s, 3H), 2.70 (qd, J = 15.2, 7.7 Hz, 2H), 2.14-1.99 (m, 1H), 1.82 (d, J = 2.4 Hz, 3H), 1.01 (d, J = 6.7 Hz , 6H).

¹³ C NMR (75 MHz, CDCb) δ: 171.70, 158.45, 133.11, 131.02, 128.36, 114.72, 79.84, 78.79, 74.61.51.76, 43.54, 33.59, 28.39, 19.37, 3.73.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ .

Example E13: (3S) -3- {4 - [(2R / S) -2-methylbutoxy] phenyl} hex-4-ynoic acid methyl ester

The (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol) obtained in Example 115 was dissolved in 10 ml of dry tetrahydrofuran under argon, and triphenylphosphine (728 mg, 2 75mmol), commercially available 2-methyl-1-butanol (0.754ml, 6.87mmol, CAS [137-32-6]) and diisopropyl azodicarboxylate (0.674ml, 3.44mmol) was added with stirring at this rate to keep the reaction mixture just below reflux. After completion of the dropwise addition, the reaction mixture was heated for an additional 30 minutes at 50 ° C, then the reaction was terminated by adding 30 ml of water. The product was extracted with diethyl ether and ethyl acetate 1: 1 (50 ml). The organic layer was washed with water, brine, dried, and concentrated. The product was purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 100: 1 to 20: 1). 312 mg of a light yellow syrup was obtained (79% yield).

MS (ESI +): m / z = 311.1 [M + Na] ⁺ .

Example E14: (3S) -3- {4 - [(2S) -2-methylbutoxy] phenyl} hex-4-ynoic acid methyl ester

PL 233 938 Β1

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 115), commercially available (S) -2 -methyl-1-butanol (1.0 mL, 9.12 mmol, CAS [1565-80-6]) and the rest of the reagents and solvents used in the correct ratio. 150 mg (29% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 311.1 [M + Na] ⁺ .

Example E15: (3S) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester

The product was prepared under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 115), commercially available trans-3.7 -dimethyl-2,6-octadien-1-ol (geraniol, 0.566 g, 3.67 mmol, CAS [1565-80-6]) and the remaining reagents and solvents used in the correct ratio. 364 mg (56% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 377.2 [M + Na] ⁺ .

Example E16: (3R) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester

C "H _J0 O ₃ = 354.48

The product was prepared under the conditions of Example E13 using (3R) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 116), commercially available trans-3.7 -dimethyl-2,6-octadien-1-ol (geraniol, 0.566 g, 3.67 mmol, CAS [1565-80-6]) and the remaining reagents and solvents used in the correct ratio. 292 mg (45% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 377.2 [M + Na] ⁺ .

Example E17: (3S) -3- (4 - {[(2Z) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 115), commercially available (Z) -3 , 7-dimethyl-2,6-octadien-1-ol (nerol, 0.874 g, 5.5 mmol, CAS [106-25-2] and the remaining reagents and solvents used in the correct ratio. 364 mg (56% yield) were obtained. ) of the oil product.

MS (ESI +): m / z = 377.2 [M + Na] ⁺ .

PL 233 938 Β1

Example E18: (3S) -3- (4 - {[(3R) -3,7-dimethylocta-6-en-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 115), commercially available (R) - ( +) - citronellol (0.584 g, 3.67 mmol, CAS [1117-61-9]) and the remaining reagents and solvents used in the correct ratio. 330 mg (51% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 379.2 [M + Na] ⁺ .

Example E19: (3S) -3- (4 - {[(3S) -3,7-dimethylocta-6-en-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (400 mg, 1.83 mmol, Example 115), commercially available (S) - ( -) - citronellol (0.877 g, 5.5 mmol, CAS [7540-51-4]) and the remaining reagents and solvents used in the correct ratio. 395 mg (61% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 379.2 [M + Na] ⁺ .

Example E20: (3R / S) -3- (4 - {[(2E, 6E) -3,7,11-trimethyl-dodeca-2,6,10-trien-1-yl] oxy} phenyl) hexyl ester -4-yoke

The product was obtained under the conditions of Example E13 using the esterified under the conditions of Example 115 (3R / S) -3- (4-hydroxyphenyl) hex-4-ynoic acid (150 mg, 0.687 mmol), commercially available trans, trans- farnesol (0.271 g, 1.17 mmol, CAS 106-28-5]) and the remaining reagents and solvents used in the correct ratio. 204 mg (70% yield) of the racemic product were obtained as an oil.

MS (ESI +): m / z = 445.3 [M + Na] ⁺ .

PL 233 938 Β1

Example E21: (3S) -3- {4 - [(2,3-dimethyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester

^C is ^h m ° s = 300.39

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (1.6 g, 7.33 mmol, Example 115), 2,3-dimethylbut -2-en-1-ol (1.47 g, 14.7 mmol, prepared in Example I20) and the remaining reagents and solvents used in the correct proportion. 850 mg (39% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 323.2 [M + Na] ⁺ , 623.3 [2M + Na] ⁺ .

Example E22: (3S) -3- [4- (pent-3-yn-1-yloxy) phenyl] hex-4-ynoic acid methyl ester

C _la H ₂₀ O ₃ = 284.35

The product was prepared under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (140 mg, 0.641 mmol, Example 115), a commercially available 3-pentyn-1-ol (0.540 g, 6.41 mmol, CAS [10229-10-4]) and the remaining reagents and solvents used in the correct ratio. 109 mg (60% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 307.1 [M + Na] ⁺ .

Example E23: (3S) -3- [4- (pent-2-yn-1-yloxy) phenyl] hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available 2-pentyn-1 -ol (0.590 g, 6.87 mmol, CAS [6261-22-9]) and the remaining reagents and solvents used in the correct ratio. 139 mg (36% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 307.1 [M + Na] ⁺ .

Example E24: (3S) -3- {4 - [(2E) -hex-2-en-1-yloxy] phenyl} hex-4-ynoic acid methyl ester

PL 233 938 Β1

The product was prepared under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available trans-2-hexene -1-ol (0.725 g, 6.87 mmol, CAS [928-95-0]) and the remaining reagents and solvents used in the correct ratio. 256 mg (62% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 323.2 [M + Na] ⁺ .

Example E25: (3S) -3- [4- (pent-4-en-1-yloxy) phenyl] hex-4-ynoic acid methyl ester

C _te H “O ₃ = 286.37

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available 4-pentene-1 -ol (0.237 g, 2.75 mmol, CAS [821-09-0]) and the remaining reagents and solvents used in the correct ratio. 291 mg (74% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 309.1 [M + Na] ⁺ .

Example E26: (3S) -3- {4 - [(2E, 4E) -hexa-2,4-diene-1-yloxy] phenyl} hex-4-ynoic acid methyl ester

C _in H "O ₃ = 298.38

The product was prepared under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available trans, trans-2 , 4-hexadien-1-ol (0.167 g, 1.65 mmol, CAS [17102-64-6]) and the remaining reagents and solvents used in the correct ratio. 342 mg (83% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 321.1 [M + Na] ⁺ .

Example E27: (3S) -3- {4 - [(2R / S) -pentan-2-yloxy] phenyl} hex-4-ynoic acid methyl ester

(* racemate) C and _E H _M 0 ₃ = 288.38

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available 2-pentanol (0.148 g, 1.65 mmol, CAS [6032-29-7]) and the remaining reagents and solvents used in the correct ratio. 312 mg (79% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 311.1 [M + Na] ⁺ .

PL 233 938 Β1

Example E28: (3S) -3- {4 - [(2R / S) -3-methylpentyl] oxy} phenyl) hex-4-ynoic acid methyl ester (»racemate) C ₁₉ H ₂₆ O ₃ = 302.41

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (300 mg, 1.37 mmol, Example 115), commercially available 3-methyl-1 -pentanol (0.248 g, 2.75 mmol, CAS [589-35-5]) and the remaining reagents and solvents used in the correct ratio. 332 mg (80% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 325.2 [M + Na] ⁺ .

Example E29: (3S) -3- [4- (pentan-3-yloxy) phenyl] hex-4-ynoic acid methyl ester

C _1B H 2 O 3 = ²⁸⁸³⁸

The product was prepared under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (140 mg, 0.641 mmol, Example 115), commercially available 3-pentanol (0.577 g, 6.41 mmol, CAS [584-02-1]) and the remaining reagents and solvents used in the correct proportion. 100 mg (54% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 311.1 [M + Na] ⁺ .

Example E30: (3S) -3- [4- (3,3-dimethylbutoxy) phenyl] hex-4-ynoic acid methyl ester ^c 19 ^H J6 ° 3 = 302.41

The product was prepared under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (178 mg, 0.816 mmol, Example 115), commercially available 3,3-dimethyl-1 -butanol (0.344 g, 3.26 mmol, CAS [624-95-3]) and the remaining reagents and solvents used in the correct ratio. 120 mg (49% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 325.2 [M + Na] ⁺ .

PL 233 938 Β1

Example E31: (3S) -3- {4 - [(2R / S) -2,3-dimethylbutoxy] phenyl} hex-4-ynoic acid methyl ester

(* racemate) 0 ₁₉ Η _Ζ6 0, = 302.41

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (1.4 g, 6.41 mmol, Example 115), (2R / S) -2,3-dimethylbutan-1-ol (1.30 g, 12.7 mmol, prepared in Example 121) and the rest of the reagents and solvents used in the correct proportion. 1200 mg (62% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 325.2 [M + Na] ⁺ .

Example E32: (3S) -3- {4 - [(3-methyl-but-3-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (450 mg, 2.06 mmol, Example 115), commercially available 3-methyl-3 -buten-1-ol (0.512 g, 5.94 mmol, CAS [763-32-6]) and the remaining reagents and solvents used in the correct ratio. 370 mg (63% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 309.1 [M + Na] ⁺ .

Example E33: (3S) -3- (4 - {[(2R / S) -3-methylbutan-2-yl] oxy} phenyl) hex-4-ynoic acid methyl ester

(* Racemate) C ₁₈ H _2l O ₃ = 288.38

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (500 mg, 2.29 mmol, Example 115), commercially available 3-methyl-2 -butanol (0.453 g, 5.04 mmol, CAS [598-75-4]) and the remaining reagents and solvents used in the correct ratio. 407 mg (62% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 311.2 [M + Na] ⁺ .

PL 233 938 Β1

Example E34: (3S) -3- {4 - [(2R) -butan-2-yloxy] phenyl} hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (500 mg, 2.29 mmol, Example 115), commercially available (S) - ( +) - 2-butanol (0.401 g, 5.36 mmol, CAS [4221-99-2]) and the remaining reagents and solvents used in the correct ratio. 415 mg (66% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ .

Example E35: (3S) -3- {4 - [(2S) -butan-2-yloxy] phenyl} hex-4-ynoic acid methyl ester

The product was obtained under the conditions of Example E13 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid methyl ester (500 mg, 2.29 mmol, Example 115), commercially available (R) - ( -) - 2-butanol (0.401 g, 5.36 mmol, CAS [14898-79-4]) and the remaining reagents and solvents used in the correct ratio. 369 mg (59% yield) of the product were obtained in the form of a syrup.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ .

Example E36: (3S) -3- (4-butoxyphenyl) hex-4-ynoic acid butyl ester

Prepared in Example 111 (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid (244 mg, 1.19 mmol), commercially available 1-bromobutane (0.9 mL, 8.36 mmol, CAS [109 -65-9]) was dissolved in dry Λ /, Λ / '-dimethylformamide (10 ml), cesium carbonate (1.0 g, 3.04 mmol) was added and stirred at 50 ° C for 18 hours. The reaction was quenched by adding water (50 mL). The product was extracted with diethyl ether and ethyl acetate 1: 1 (50 ml). The organic layer was washed with 3% aqueous sulfuric acid, water, brine, dried and concentrated. The product was purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 100: 1 to 20: 1). 275 mg of a light yellow syrup (73% yield) was obtained.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.22 (m, 2H), 6.87 - 6.79 (m, 2H), 4.18 - 3.99 (m, 1H), 4.07 (t, J = 6.6 Hz, 2H), 3.94 (t, J = 6.6 Hz, 2H), 2.69 (qd, J = 15.0, 7.7 Hz, 2H), 1.82 (d, J = 2.4 Hz, 3H), 1.81 - 1.69 (m, 2H), 1.62 - 1.42 (m, 4H), 1.41-1.23 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 171.42, 158.29, 133.13, 128.40, 114.64, 79.89, 78.76, 67.81.64.53, 43.81.33.69, 31.47, 30.78, 19.38, 19.19, 13.97, 13.82, 3.77.

MS (ESI +): m / z = 339.1 [M + Na] ⁺ , 355.2 [M + K] ⁺ , 655.4 [2M + Na] ⁺ .

Example E37: (3S) -3- [4- (pentyloxy) phenyl] hex-4-ynoic acid pentyl ester

PL 233 938 Β1

The product was prepared under the conditions of Example E36 using (3S) -3- (4-hydroxyphenyl) hex-4-ynoic acid, (142 mg, 0.697 mmol, Example 111), commercially available 1-bromopentane (615 mg, 4 , 07 mmol, CAS [110-53-2]) and the remaining reagents and solvents used in the correct proportion. 225 mg (94% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.31 - 7.22 (m, 2H), 6.87 - 6.79 (m, 2H), 4.06 (t, J = 6.7 Hz, 2H), 4.10-3.99 (m, 1H), 3.92 (t, J = 6.3 Hz, 2H), 2.69 (qd, J = 15.0, 7.7 Hz, 2H), 1.82 (d, J = 2.4 Hz, 3H), 1.80 - 1.71 (m, 2H), 1.66 - 1.52 (m, 2H), 1.51-1.21 (m, 8H), 0.98 - 0.82 (m, 6H).

¹³ C NMR (75 MHz, CDCb) δ: 171.42, 158.28, 133.13, 128.40, 114.63, 79.90, 78.75, 68.11.64.84, 43.80, 33.68, 29.11.28.44, 28.34, 28.13, 22.59, 22.44, 14.15, 08.14, 3.78 .

MS (ESI +): m / z = 367.2 [M + Na] ⁺ .

Example E38: (3R / S) -3- [4- (3-methylbutoxy) phenyl] hex-4-ynoic acid 3-methyl-butyl ester

(* racemate) C ₂₂ H ₃₂ O ₃ = 344.49

The product was obtained under the conditions of Example E36 using (3R / S) -3- (4-hydroxyphenyl) hex-4-ynoic acid, (200 mg, 0.979 mmol, Example I7), commercially available 1-bromo-3- methylbutane (0.3 mL, 2.45 mmol, CAS [107-82-4]) and the remaining reagents and solvents used in the correct ratio. 327 mg of product was obtained quantitatively as an oil.

MS (ESI +): m / z = 367.2 [M + Na] ⁺ , 711.5 [2M + Na] ⁺ .

Final relationships:

Selected examples for the preparation of the final compounds of the invention are shown below.

The examples of the final compounds, the number of which is preceded by the letter F, relate to the compounds of the invention in the form of free acids.

The examples of the final compounds, the number of which is preceded by the letter S, relate to the compounds of the invention in salt form.

Example F1: (3S) -3- (4-propoxyphenyl) hex-4-ynoic acid

The (3S) -3- (4-propoxyphenyl) hex-4-ynoic acid methyl ester (130 mg, 0.499 mmol) obtained in Example E1 was dissolved in 20 ml of tetrahydrofuran, 10 ml of methanol, and 120 mg (2.86 mmol) were added with stirring. ) lithium hydroxide monohydrate, then the reaction mixture was heated to 40 ° C and stirred 18 hours. The reaction was quenched with diethyl ether (20 mL) and acidification with 3% aqueous sulfuric acid (20 mL) and the product was extracted with ethyl acetate (2 x 20 mL). The organic layer was separated, washed with brine, and dried. After evaporation, the residue was purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 5: 1 to 1: 1). 73 mg of product (59% yield) was obtained as an amorphous solid.

PL 233 938 Β1 ¹ H NMR (300 MHz, CDCb) δ: 7.32 - 7.26 (m, 2H), 6.89 - 6.81 (m, 2H), 4.04 (ddq, J = 8.8, 4.7, 2.2 Hz, 1H), 3.89 (t, J = 6.6 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.86 - 1.72 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

¹³ C NMR (75 MHz, CDCl b) δ: 177.38, 158.36, 132.87, 128.41, 114.74, 79.61, 79.11, 69.67, 43.46, 33.26, 22.71, 10.65, 3.79.

MS (ESI +): m / z = 269.1 [M + Na] ⁺ , 285.1 [M + K] ⁺ , 515.2 [2M + Na] ⁺ . MS (ESI -): m / z = 281.1 [M + Cl] -, 491.2 [2M-H] -.

Example F2: (3S) -3- (4-butoxyphenyl) hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- (4-butoxyphenyl) hex-4-ynoic acid butyl ester obtained in Example E36, (245 mg, 0.774 mmol) and the remaining reagents and solvents used in the appropriate proportion . 178 mg (88% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.33 - 7.22 (m, 2H), 6.89 - 6.80 (m, 2H), 4.10 - 3.98 (m, 1H), 3.94 (t, J = 6.5 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.81 - 1.69 (m, 2H), 1.56 1.40 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

¹³ C NMR (75 MHz, CDCl) δ: 177.42, 158.36, 132.83, 128.40, 114.71,79.60, 79.10, 67.83, 43.46, 33.25, 31.45, 19.38, 13.97, 3.78.

MS (ESI +): m / z = 283.1 [M + Na] ⁺ , 299.1 [M + K] ⁺ , 543.3 [2M + Na] ⁺ . MS (ESI -): m / z = 259.1 [MH] -,

295.1 [M + CI] -, 519.3 [2M-H] -.

Example F3: (3S) -3- [4- (pentyloxy) phenyl] hex-4-ynoic acid

The product was prepared using the conditions of Example F1, (3S) -3- [4- (pentyloxy) phenyl] hex-4-ynoic acid pentyl ester obtained in Example E37, (210 mg, 0.61 mmol) and the remaining reagents and solvents used in the correct proportion. 130 mg (78% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.25 (m, 2H), 6.88 - 6.81 (m, 2H), 4.09 - 3.99 (m, 1H), 3.93 (t, J = 6.0 Hz, 2H), 2.75 (qd, J = 15.6, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.80 - 1.72 (m, 2H), 1.49 1.30 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.23, 158.36, 132.85, 128.41, 114.72, 79.62, 79.10, 79.12, 68.15, 43.45, 33.27, 29.11, 28.34, 22.60, 14.16, 3.80.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ , 313.1 [M + K] ⁺ , 571.3 [2M + Na] ⁺ . MS (ESI -): m / z = 273.1 [MH] -,

309.1 [M + CI] -, 547.3 [2M-H] -.

Example F4: (3S) -3- [4- (hexyloxy) phenyl] hex-4-ynoic acid

PL 233 938 Β1

The product was obtained using the conditions of Example F1, (3S) -3- [4- (hexyloxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E2, (140 mg, 0.463 mmol) and the remaining reagents and solvents used in the right proportion. 75 mg (56% yield) of the product were obtained in the form of an amorphous solid.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.24 (m, 2H), 6.89 - 6.79 (m, 2H), 4.09 - 3.99 (m, 1H), 3.93 (t, J = 6.6 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.82 - 1.70 (m, 2H), 1.51 1.37 (m, 2H), 1.38 - 1.23 (m, 4H ), 0.90 (t, J = 7.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.20, 158.39, 132.85, 128.41, 114.74, 79.62, 68.18, 43.45, 33.28, 31.73, 29.39, 25.87, 22.75, 14.17, 3.80.

MS (ESI +): m / z = 311.2 [M + Na] ⁺ , 327.1 [M + K] ⁺ , 599.3 [2M + Na] ⁺ . MS (ESI -): m / z = 287.2 [M-Hp,

323.1 [M + CI] -, 575.3 [2M-H] -.

Example F5: (3S) -3- [4- (heptyloxy) phenyl] hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- [4- (heptyloxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E3, (142 mg, 0.449 mmol) and the remaining reagents and solvents used in the right proportion. 108 mg (80% yield) of the product were obtained in the form of an amorphous solid.

¹ H NMR (300 MHz, CDCl) δ: 7.32 - 7.24 (m, 2H), 6.89 - 6.80 (m, 2H), 4.04 (ddd, J = 8.7, 5.6, 2.4 Hz, 1H), 3.93 (t, J = 6.6 Hz, 2H), 2.75 (ddd, J = 22.4, 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.87 1.69 (m, 2H), 1.50 - 1.22 (m, 8H ), 0.89 (t, J = 6.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.22, 158.39, 132.85, 128.41, 114.74, 79.62, 79.12, 68.17, 43.45, 33.28, 31.93, 29.42, 29.20, 26.16, 22.75, 14.22, 3.80.

MS (ESI +): m / z = 325.2 [M + Na] ⁺ , 341.2 [M + K] ⁺ , 627.4 [2M + Na] ⁺ . MS (ESI -): m / z = 337.2 [M + Cl] -, 603.4 [2M-H] -.

Example F6: (3S) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4-ynoic acid

C _la H _J8 O ₃ = 340.46

The product was obtained using the conditions of Example F1, (3S) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4 acid methyl ester sine obtained in Example E15 (350 mg, 0.987 mmol) and the remaining reagents and solvents used in the correct proportion. 246 mg (73% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.33 - 7.24 (m, 2H), 6.91 - 6.83 (m, 2H), 5.48 (td, J = 6.5, 1.1 Hz, 1 H), 5.14 - 5.04 (m, 1H ), 4.51 (d, J = 6.5 Hz, 2H), 4.05 (ddd, J = 8.6, 6.6, 2.4 Hz, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 2.20 - 2.02 (m, 4H), 1.83 (d, J = 2.4 Hz, 3H), 1.73 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 176.96, 158.12, 141.31, 132.97, 131.94, 128.41, 123.95, 119.65, 114.92, 79.61.79.13, 65.03, 43.41, 39.69, 33.28, 26.44, 25.82, 17.84, 16.78, 3.81 .

MS (ESI +): m / z = 363.2 [M + Na] ⁺ . MS (ESI -): m / z = 375.2 [M + Cl] -.

PL 233 938 Β1

Example F7: (3R) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) -hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3R) -3- (4 - {[(2E) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4 acid methyl ester sine, obtained in Example E16, (280 mg, 0.790 mmol) and the remaining reagents and solvents used in the correct proportion. 169 mg (63% yield) of the product were obtained as an oil. Spectral data identical to Example F6.

Example F8: (3S) -3- (4 - {[(3R) -3,7-dimethylocta-6-en-1-yl] oxy} phenyl) hex-4-ynoic acid

The product was obtained using the conditions in Example F1, (3S) -3- (4 - {[(3R) -3,7-dimethylocta-6-en-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester , obtained in Example E18, (300 mg, 0.842 mmol) and the remaining reagents and solvents used in the correct proportion. 190 mg (66% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.32 - 7.23 (m, 2H), 6.88 - 6.80 (m, 2H), 5.15 - 5.06 (m, 1H), 4.10 3.92 (m, 3H), 2.75 (ddd, J = 22.4, 15.7, 7.6 Hz, 2H), 2.10 - 1.91 (m, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.88 - 1.75 (m, 1H), 1.68 (d, J = 1.1 Hz , 3H), 1.60 (d, J = 0.8 Hz, 3H), 1.74 - 1.50 (m, 2H), 1.46 - 1.32 (m, 1H), 1.28 - 1.14 (m, 1H), 0.94 (d, J = 6.5 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.23, 158.38, 132.89, 131.40, 128.41, 124.84, 114.77, 79.63, 79.12, 66.46, 43.46, 37.28, 36.30, 33.29, 29.69, 25.84, 25.60, 19.69, 17.80, 3.78 .

MS (ESI +): m / z = 365.2 [M + Na] ⁺ . MS (ESI -): m / z = 377.2 [M + Cl] -.

Example F9: (3S) -3- (4 - {[(3S) -3,7-dimethylocta-6-en-1-yl] oxy} phenyl) hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- (4 - {[(3S) -3,7-dimethylocta-6-en-1-yl] oxy} phenyl) hex-4-ynoic acid methyl ester , obtained in Example E19, (300 mg, 0.842 mmol) and the remaining reagents and solvents used in the correct proportion. 170 mg (59% yield) of the product were obtained as an oil. Spectral data identical to Example F8.

PL 233 938 Β1

Example F10: (3S) -3- (4 - {[(2Z) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) -hex-4-yanoic acid 'OH

C _i2 H ₁₈ O ₃ = 340.46

The product was obtained using the conditions of Example F1, (3S) -3- (4 - {[(2Z) -3,7-dimethylocta-2,6-diene-1-yl] oxy} phenyl) hex-4 acid methyl ester sine, obtained in Example E17, (350 mg, 0.987 mmol) and the remaining reagents and solvents used in the correct proportion. 231 mg (69% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.25 (m, 2H), 6.89 - 6.82 (m, 2H), 5.49 (td, J = 6.7, 1.4 Hz, 1 H), 5.16 - 5.05 (m, 1H ), 4.48 (dd, J = 6.7, 1.0 Hz, 2H), 4.05 (ddq, J = 8.8, 4.7, 2.3 Hz, 1H), 2.75 (ddd, J = 22.4, 15.7, 7.6 Hz, 2H), 2.17- 2.07 (m, 4H), 1.83 (d, J = 2.4 Hz, 3H), 1.79 (dd, J = 2.3, 1.0 Hz, 3H), 1.68 (d, J = 0.9 Hz, 3H), 1.60 (d, J = 1.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.08, 158.10, 141.71, 132.99, 132.29, 128.41, 123.80, 120.55, 114.91.79.62, 79.13, 64.67, 43.43, 33.28, 32.56, 26.73, 25.83, 23.62, 17.80, 3.76 .

MS (ESI +): m / z = 363.2 [M + Na] ⁺ . MS (ESI -): m / z = 375.2 [M + Cl] -.

Example F11: (3R / S) -3- (4 - {[(2E, 6E) -3,7,11-trimethyldodeca-2,6,10-trien-1-yl] oxy} phenyl) hex-4 acid -new

ΌΗ (* racemate) C _I7 H ₃₆ O ₃ = 408.57

The product was obtained using the conditions of Example F1, (3R / S) -3- (4 - {[(2E, 6E) -3,7,11-trimethyl-dodeca-2,6,10-trien-1-yl) acid methyl ester ] oxy} phenyl) hex-4-yno, obtained in Example E20, (198 mg, 0.469 mmol) and the remaining reagents and solvents used in the correct proportion. 42 mg (22% yield) of the racemic product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.34 - 7.23 (m, 2H), 6.93 - 6.81 (m, 2H), 5.48 (dt, J = 6.5, 3.3 Hz, 1 H), 5.17 - 5.04 (m, 2H ), 4.51 (d, J = 6.5 Hz, 2H), 4.10 - 4.00 (m, 1H), 2.75 (ddd, J = 22.4, 15.7, 7.6 Hz, 2H), 2.20 - 1.93 (m, 8H), 1.83 ( d, J = 2.4 Hz, 3H), 1.73 (d, J = 1.1 Hz, 3H), 1.68 (d, J = 1.1 Hz, 3H), 1.60 (s, 6H).

¹³ C NMR (75 MHz, CDCb) δ: 176.85, 158.12, 141.34, 135.55, 132.98, 131.45, 128.40, 124.46, 123.83, 119.64, 114.91, 79.61, 79.12, 65.02, 43.40, 39.83, 39.69, 33.28, 26.85, 26.36 , 25.83, 17.83, 16.80, 16.16, 3.80.

MS (ESI +): m / z = 431.3 [M + Na] ⁺ . MS (ESI -): m / z = 443.2 [M + Cl] -.

Example F12: (3S) -3- [4- (2-methylpropoxy) phenyl] hex-4-ynoic acid

OH

C ₁₆ H _m O ₃ = 260.33

PL 233 938 Β1

The product was obtained using the conditions of Example F1, (3S) -3- [4- (2-methylpropoxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E12, (430 mg, 1.57 mmol) and others reagents and solvents used in the correct proportion. 356 mg (87% yield) of the product were obtained as an amorphous solid.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.25 (m, 2H), 6.88 - 6.80 (m, 2H), 4.04 (DDQ, J = 9.0, 7.0, 2.3 Hz, 1H), 3.69 (d, J = 6.5 Hz, 2H), 2.75 (ddd, J = 22.4, 15.7, 7.6 Hz, 2H), 2.07 (tq, J = 13.3, 6.6 Hz, 1H), 1.82 (d, J = 2.4 Hz, 3H), 1.01 (d, J = 6.7 Hz, 6H).

¹³ C NMR (75 MHz, CDCl b) δ: 177.30, 158.52, 132.86, 128.40, 114.79, 79.64, 79.10, 74.64, 43.45, 33.29, 28.40, 19.39, 3.78.

MS (ESI +): m / z = 283.1 [M + Na] ⁺ . MS (ESI -): m / z = 295.1 [M + Cl] -.

Example F13: (3S) -3- (4 - {[(2R / S) -3-methylbutan-2-yl] oxy} phenyl) hex-4-ynoic acid (* _racemate ) C ₁₇ H ₁₂ O ₃ = 274.36

The product was obtained using the conditions of Example F1, (3S) -3- (4 - {[(2R / S) -3-methylbutan-2-yl] oxy} phenyl) hex-4-ynoic acid methyl ester obtained in Example E33, (360 mg, 1.248 mmol) and the remaining reagents and solvents used in the correct ratio. 266 mg (78% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.31 - 7.22 (m, 2H), 6.87 - 6.79 (m, 2H), 4.12 - 4.07 (m, 1H), 4.10 (t, J = 6.0, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.91 (qd, J = 12.5, 6.8 Hz, 1H), 1.83 (d, J = 2.4, 3H), 1.21 (d, J = 6.2 Hz, 3H), 0.96 (dd, J = 8.7, 6.8 Hz, 6H).

¹³ C NMR (75 MHz, CDCl) δ: 177.18, 157.69, 132.78, 128.44, 116.17, 79.68, 79.08, 78.71,43.48, 33.31,33.14, 18.64, 17.89, 16.19, 3.77.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ . MS (ESI -): m / z = 309.1 [M + Cl] -.

Example F14: (3S) -3- {4 - [(2R) -butan-2-yloxy] phenyl} hex-4-ynoic acid

OH

C H _{M e} O ₃ = 260.33

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2R) -butan-2-yloxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E34, (400mg, 1.458 mmol) and the remaining reagents and solvents used in the correct proportion. 345 mg (91% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.30 - 7.22 (m, 2H), 6.87 - 6.79 (m, 2H), 4.26 (h, J = 6.1 Hz, 1H), 4.04 (ddq, J = 8.8, 4.7 , 2.2 Hz, 1H), 2.75 (qd, J = 15.6, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.81-1.52 (m, 2H), 1.27 (d, J = 6.1 Hz , 3H), 0.96 (t, J = 7.4 Hz, 3H).

¹³ C NMR (75 MHz, CDClb) δ: 177.13, 157.51,132.87, 128.45, 116.16, 79.67, 79.09, 75.31, 43.47, 33.31, 29.35, 19.43, 9.91, 3.76.

MS (ESI +): m / z = 283.1 [M + Na] ⁺ . MS (ESI -): m / z = 395.1 [M + Cl] -.

PL 233 938 Β1

Example F15: (3S) -3- {4 - [(2S) -butan-2-yloxy] phenyl} hex-4-ynoic acid

ΌΗ ^C 16 ^H 20 ° ₃ = “0.33

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2S) -butan-2-yloxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E35, (345mg, 1.262 mmol) and the remaining reagents and solvents used in the correct proportion. 278 mg (85% yield) of the product were obtained as an oil. Spectral analysis identical to Example F14.

Example F16: (3S) -3- {4 - [(2R / S) -pentan-2-yloxy] phenyl} hex-4-ynoic acid with

OH (* racemate) C ₁₂ H ₂₂ O ₃ = 274.36

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2R / S) -pentan-2-yloxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E27, (250 mg , 0.867 mmol) and the remaining reagents and solvents used in the correct proportion. 124 mg (52% yield) of the product were obtained as an oil.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ . MS (ESI -): m / z = 309.1 [M + Cl] -.

Example F17: (3S) -3- [4- (pentan-3-yloxy) phenyl] hex-4-ynoic acid

ΌΗ

C ₁₇ H ₂₂ O ₃ = 274.36

The product was obtained using the conditions of Example F1, (3S) -3- [4- (pentan-3-yloxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E29, (185 mg, 0.641 mmol) and others reagents and solvents used in the correct proportion. 75 mg (43% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.23 (m, 2H), 6.88 - 6.80 (m, 2H), 4.12 - 3.99 (m, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H ), 1.83 (d, J = 2.4 Hz, 3H), 1.72 - 1.60 (m, 4H), 0.94 (t, J = 7.4 Hz, 6H).

¹³ C NMR (75 MHz, CDCl) δ: 176.84, 157.98, 132.73, 128.44, 116.16, 80.40, 79.66, 79.10, 43.41, 33.28, 26.21, 9.75, 3.81.

MS (ESI +): m / z = 397.1 [M + Na] ⁺ . MS (ESI -): m / z = 309.1 [M + Cl] -.

Example F18: (3S) -3- {4 - [(2E) -hex-2-en-1-yloxy] phenyl} hex-4-ynoic acid with

ΌΗ

C _le H "O ₃ = 286.37

PL 233 938 Β1

The product was obtained using the conditions of Example u F1, (3S) -3- {4 - [(2E) -hex-2-en-1-yloxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E24 , (240 mg, 0.799 mmol) and the remaining reagents and solvents used in the correct ratio. 149 mg (65% yield) of the product were obtained in the form of an amorphous solid.

¹ H NMR (300 MHz, CDCb) δ: 7.31 - 7.24 (m, 2H), 6.90 - 6.83 (m, 2H), 5.89 - 5.77 (m, 1H), 5.74 5.62 (m, 1H), 4.45 (dd, J = 5.8, 1.0 Hz, 2H), 4.04 (ddd, J = 8.7, 6.6, 2.4 Hz, 1H), 2.75 (qd, J = 15.6, 7.6 Hz, 2H), 2.12 - 2.01 (m, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.50 - 1.36 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.17, 157.98, 135.67, 133.06, 128.41, 125.03, 114.99, 79.57, 79.16, 69.03, 43.44, 34.54, 33.27, 22.27, 13.81, 3.80.

MS (ESI +): m / z = 309.1 [M + Na] ⁺ . MS (ESI -): m / z = 321.1 [M + Cl] -.

Example F19: (3S) -3- {4 - [(2E, 4E) -hexa-2,4-dien-1-yloxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2E, 4E) -hexa-2,4-diene-1-yloxy] phenyl} hex-4-ynoic acid methyl ester, obtained from Example E26, (6.44 g, 21.6 mmol) and the remaining reagents and solvents used in the correct proportion. 3.3 g (54% yield) of a solid precipitate were obtained.

¹ H NMR (300 MHz, CDCb) δ: 7.35 - 7.21 (m, 2H), 6.94 - 6.78 (m, 2H), 6.31 (dd, J = 15.2, 10.6 Hz, 1H), 6.08 (ddd, J = 14.7 , 10.5, 1.4 Hz, 1H), 5.86 - 5.65 (m, 2H), 4.52 (d, J = 6.0 Hz, 2H), 4.10 - 3.97 (m, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.77 (d, J = 6.7 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 176.87, 157.95, 133.93, 133.17, 130.87, 130.77, 128.45, 125.09, 115.03, 79.58, 79.19, 68.67, 43.40, 33.30, 18.24, 3.79.

MS (ESI +): m / z = 307.1 [M + Na] ⁺ . MS (ESI -): m / z = 319.1 [M + Cl] -.

Example F20: (3S) -3- [4- (pent-4-en-1-yloxy) phenyl] hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- [4- (pent-4-en-1-yloxy) phenyl] hex-4-ynoic acid methyl ester, obtained in Example E25, (250mg, 0.783 mmol) and the remaining reagents and solvents used in the correct proportion. 191 mg (80% yield) of the product were obtained in the form of an amorphous solid.

¹³ C NMR (75 MHz, CDCb) δ: 176.49, 158.26, 137.94, 133.01, 128.42, 115.30, 114.74, 79.65, 79.07, 67.32, 43.38, 33.28, 30.24, 28.56, 3.79.

MS (ESI +): m / z = 295.1 [M + Na] ⁺ . MS (ESI -): m / z = 307.1 [M + Cl] -.

Example F21: (3S) -3- [4- (pent-3-yn-1-yloxy) phenyl] hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- [4- (pent-3-yn-1-yloxy) phenyl] hex-4-ynoic acid methyl ester, obtained in Example E22, (90mg, 0.317 mmoles) and

PL 233 938 Β1 other reagents and solvents used in the correct proportion. 25 mg (29% yield) of the product were obtained in the form of an amorphous solid.

¹ H NMR (300 MHz, CDCl) δ: 7.28 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.09 - 3.99 (m, 3H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 2.60 (td, J = 7.2, 2.7 Hz, 2H), 1.83 (d, J = 2.3 Hz, 3H), 1.79 (t, J = 2.5 Hz, 3H).

¹³ C NMR (75 MHz, CDCl) δ: 176.64, 157.83, 133.41,128.50, 114.95, 79.57, 79.21,77.47, 75.18, 66.85, 43.34, 33.32, 19.95, 3.78, 3.64.

MS (ESI +): m / z = 293.1 [M + Na] ⁺ . MS (ESI -): m / z = 305.1 [M + Cl] -.

Example F22: (3S) -3- [4- (pent-2-yn-1-yloxy) phenyl] hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- [4- (pent-2-yn-1-yloxy) phenyl] hex-4-ynoic acid methyl ester, obtained in Example E23, (130mg, 0.458 mmol) and the remaining reagents and solvents used in the correct proportion. 70 mg (60% yield) of the product were obtained as a solid.

¹ H NMR (300 MHz, CDCl) δ: 7.34 - 7.27 (m, 2H), 6.96 - 6.88 (m, 2H), 4.64 (t, J = 2.1 Hz, 2H), 4.05 (ddd, J = 8.6, 6.6 , 2.4 Hz, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 2.23 (qt, J = 7.4, 2.1 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.14 (t , J = 7.5 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.27, 157.12, 133.62, 128.41,115.13, 89.66, 79.49, 79.23, 74.32, 56.68, 43.42, 33.26, 13.72, 12.63, 3.78.

MS (ESI +): m / z = 293.1 [M + Na] ⁺ . MS (ESI -): m / z = 305.1 [M + Cl] -.

Example F23: (3R / S) -3- [4- (3-methylbutoxy) phenyl] hex-4-ynoic acid

(* racemate) C ₁₇ H ₂₂ O., e 274.36

The product was prepared using the conditions of Example F1, (3R / S) -3- [4- (3-methylbutoxy) phenyl] hex-4-ynoic acid 3-methylbutyl ester, obtained in Example E38, (327mg, 0.949mmol) and the remaining reagents and solvents used in the proper proportion. 210 mg (81% yield) of the racemic solid product were obtained. Spectral analysis identical to Example F24.

Example F24: (3S) -3- [4- (3-methylbutoxy) phenyl] hex-4-ynoic acid

The product was prepared using the conditions of Example F1, (3S) -3- [4- (3-methylbutoxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E4, (2.47 g, 8.56 mmol) and the remaining reagents and solvents used in the proper proportion. 1.8 g (77% yield) of the product were obtained in the form of a crystalline solid (temp, mp: 26.4-27.1 ° C, after recrystallization from n-pentane).

PL 233 938 Β1 ¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.27 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.13 - 4.00 (m, 1H), 3.96 (t, J = 6.6 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.3 Hz, 3H), 1.97 - 1.74 (m, 1H), 1.66 (q, J = 6.7 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H).

¹³ C NMR (75 MHz, CDCl3) δ: 177.44, 158.35, 132.84, 128.40, 114.72, 79.61, 79.11,66.50, 43.47,

38.13, 33.25, 25.17, 22.71, 3.79.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ , 571.3 [2M + Na] ⁺ . MS (ESI -): m / z = 309.1 [M + Cl], 547.3 [2M-H] '.

Example F25: (3S) -3- [4- (2-ethylbutoxy) phenyl] hex-4-ynoic acid

OH

The product was obtained using the conditions of Example F1, (3S) -3- [4- (2-ethylbutoxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E9, (350 mg, 1.15 mmol) and others reagents and solvents used in the correct proportion. 290 mg (87% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl 3) δ: 7.32 - 7.23 (m, 2H), 6.89 - 6.81 (m, 2H), 4.09 - 3.99 (m, 1H), 3.82 (d, J = 5.7 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.71 - 1.58 (m, 1H), 1.55 1.36 (m, 4H), 0.92 (t, J = 7.4 Hz, 6H).

¹³ C NMR (75 MHz, CDCl 3) δ: 176.92, 158.64, 132.77, 128.39, 114.75, 79.65, 79.10, 70.28, 43.40, 41.04, 33.29, 23.51, 11.27, 3.81.

MS (ESI +): m / z = 311.2 [M + Na] ⁺ . MS (ESI -): m / z = 323.1 [M + Cl] -.

Example F26: (3R / S) -3- [4- (2,2-dimethylpropoxy) phenyl] hex-4-ynoic acid

OH (* racemate) C ₁₇ H ₂₂ O ₃ = 274.36

2 - [(1R / S) -1- [4- (2,2-dimethyl-propoxy) phenyl] but-2-yn-1-yl] propanedioic acid, 1,3-methyl diester obtained in Example I25 (730 mg, 2 , 29 mmol) was dissolved in 40 ml of toluene and stirred and heated at 100 ° C for 18 hours. After evaporation, the residue was purified by chromatography (silica gel 60, particle size 230-400 mesh, phase: heptane-ethyl acetate from 5: 1 to 1: 1). 195 mg of the racemic product (30% yield) was obtained in the form of a colorless wax.

¹ H NMR (300 MHz, CDCl 3) δ: 7.34 - 7.22 (m, 2H), 6.90 - 6.80 (m, 2H), 4.10 - 3.98 (m, 1H), 3.56 (s, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.02 (s, 9H).

¹³ C NMR (75 MHz, CDCl 3) δ: 177.30, 158.87, 132.76, 128.37, 114.75, 79.65, 79.08, 78.04, 43.43, 33.28, 32.01.26.75, 3.80.

MS (ESI +): m / z = 297.2 [M + Na] ⁺ , 571.3 [2M + Na] ⁺ . MS (ESI -): m / z = 273.1 [MH] -, 309.1 [M + CI] -, 547.3 [2M-H] -.

PL 233 938 Β1

Example F27: (3S) -3- [4- (3,3-dimethylbutoxy) phenyl] hex-4-ynoic acid

Ε, .Η ,, Ο, = ²⁸ 8-38

The product was obtained using the conditions of Example F1, (3S) -3- [4- (3,3-dimethylbutoxy) phenyl] hex-4-ynoic acid methyl ester obtained in Example E30, (120 mg, 0.397 mmol) and others reagents and solvents used in the correct proportion. 60 mg (53% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.34 - 7.23 (m, 2H), 6.92 - 6.80 (m, 2H), 4.09 - 3.95 (m, 1H), 4.00 (t, J = 9.0 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.71 (t, J = 7.3 Hz, 2H), 0.98 (s, 9H).

¹³ C NMR (75 MHz, CDCl) δ: 176.94, 158.31,132.87, 128.43, 114.77, 79.64, 79.13, 65.51,43.42, 42.55, 33.31,29.94, 29.89, 3.79.

MS (ESI +): m / z = 311.2 [M + Na] ⁺ . MS (ESI -): m / z = 323.1 [M + Cl] -.

Example F28: (3S) -3- {4 - [(3-methylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid

C ₁₇ H _F O ₃ = 272.34

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(3-methylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E5, (3.93 g, 13.7 mmol) and the remaining reagents and solvents used in the correct ratio. 1.65 g (44% yield) of the product were obtained in the form of a crystalline solid (temp, mp: 52.1-53.1 ° C, after recrystallization from n-pentane).

¹ H NMR (300 MHz, CDCl) δ: 7.33 - 7.26 (m, 2H), 6.90 - 6.82 (m, 2H), 5.55 - 5.42 (m, 1H), 4.49 (d, J = 6.7 Hz, 2H), 4.10 - 3.98 (m, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.79 (s, 3H), 1.73 (s, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 176.49, 158.16, 138.19, 133.06, 128.43, 119.93, 114.96, 79.66,

79.14, 65.00, 43.37, 33.34, 25.93, 18.31, 3.77.

MS (ESI +): m / z = 295.1 [M + Na] ⁺ , 567.2 [2M + Na] ⁺ . MS (ESI -): m / z = 307.1 [M + Cl] -.

Example F29: (3R) -3- {4 - [(3-methylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3R) -3- {4 - [(3-methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester obtained in Example E6, (300 mg, 1.05 mmol) and the remaining reagents and solvents used in the correct ratio. 198 mg (69% yield) of the product were obtained as a solid. Spectral analysis identical to Example F28.

PL 233 938 Β1

Example F30: (3S) -3- {4 - [(3-methylbut-3-en-1-yl) oxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(3-methyl-but-3-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester, obtained from Example E32, (370 mg, 1.29 mmol) and the remaining reagents and solvents used in the correct ratio. 275 mg (78% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.32 - 7.25 (m, 2H), 6.89 - 6.81 (m, 2H), 4.86 - 4.75 (m, 2H), 4.06 (t, J = 9.0 Hz, 2H), 4.10 - 4.00 (m, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.81-1.78 (m, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.18, 158.15, 142.33, 133.10, 128.44, 114.85, 112.10, 79.60,

79.15, 66.68, 43.44, 37.34, 33.29, 22.96, 3.79.

MS (ESI +): m / z = 295.1 [M + Na] ⁺ . MS (ESI -): m / z = 307.1 [M + Cl] -.

Example F31: (3R) -3- {2-fluoro-4 - [(3-methylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid

C ₁₇ H ₁₉ FO ₃ = 290.33

The product was obtained using the conditions of Example F1, (3R) -3- {2-fluoro-4 - [(3-methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester obtained in Example E7, (32 mg, 0.105 mmol) and the remaining reagents and solvents used in the correct proportion. 25 mg (80% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.41 (t, J = 8.8 Hz, 1H), 6.69 (dd, J = 8.6, 2.5 Hz, 1H), 6.60 (dd, J = 12.2, 2.5 Hz, 1H) , 5.52 - 5.41 (m, 1H), 4.47 (d, J = 6.7 Hz, 2H), 4.31 (ddd, J = 8.6, 6.2, 2.4 Hz, 1H), 2.84 - 2.68 (m, 2H), 1.84 (d , J = 2.4 Hz, 3H), 1.80 (s, 3H), 1.74 (s, 3H).

¹⁹ F NMR (282 MHz, CDCb) δ: -121.21 (dd, J = 12.2, 9.0 Hz).

¹³ C NMR (75 MHz, CDCb) δ: 176.98, 160.50 (d, Jc-f = 244.5 Hz), 159.43 (d, Jc-f = 10.9 Hz), 138.79, 129.72 (d, Jc-f = 5.9 Hz) , 119.45 (d, Jc-f = 14.3 Hz), 119.31, 110.81 (d, Jc-f = 2.8 Hz), 102.43 (d, Jc-f = 25.1 Hz), 79.15, 78.33, 65.25, 41.62, 27.39, 27.37 (d, Jc-f = 2.7 Hz), 18.33, 3.77.

MS (ESI +): m / z = 313.1 [M + Na] ⁺ . MS (ESI -): m / z = 325.1 [M + Cl] -.

Example F32: (3S) -3- {2-fluoro-4 - [(3-methylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- {2-fluoro-4 - [(3-methyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester obtained in Example E8, (44mg, 0.145mmol) and the remaining reagents and solvents used in the correct ratio. 32 mg (78% yield) of the product were obtained as an oil. Spectral analysis identical to Example F31.

PL 233 938 Β1

Example F33: (3S) -3- {4 - [(2,3-dimethylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid

^ε ι. ^Η 22θ3 = 286.37

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2,3-dimethyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E21, (1.0 g, 3.33 mmol) and the remaining reagents and solvents used in the correct ratio. 766 mg (80% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.36 - 7.22 (m, 2H), 6.91 - 6.80 (m, 2H), 4.47 (s, 2H), 4.14 - 3.94 (m, 1H), 2.75 (qd, J = 15.6, 7.5 Hz, 2H), 1.82 (d, J = 2.4 Hz, 3H), 1.77 (s, 6H), 1.74 (s, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 176.28, 158.64, 133.07, 131.04, 128.41, 124.16, 115.07, 79.72, 79.14, 69.49, 43.35, 33.40, 21.09, 20.37, 16.79, 3.74.

MS (ESI +): m / z = 309.1 [M + Na] ⁺ . MS (ESI -): m / z = 321.1 [M + Cl] -.

Example F34: (3S) -3- {4 - [(2R / S) -2-methylbutoxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2R / S) -2-methylbutoxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E13, (250mg, 0.867 mmol) and the remaining reagents and solvents used in the correct proportion. 156 mg (66% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCb) δ: 7.31 - 7.24 (m, 2H), 6.88 - 6.81 (m, 2H), 4.10 - 3.99 (m, 1H), 3.75 (ddd, J = 26.8, 9.0, 6.3 Hz , 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.92 - 1.77 (m, 1H), 1.83 (d, J = 2.4 Hz, 3H), 1.64-148 (m, 1H), 1.33- 1.17 (m, 1H), 1.00 (d, J = 6.7 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.13, 158.56, 132.80, 128.40, 114.76, 79.63, 79.10, 73.05, 43.43, 34.85, 33.28, 26.28, 16.68, 11.45, 3.80.

MS (ESI +): m / z = 297.1 [M + Na] ⁺ , 313.1 [M + K] ⁺ , 571.3 [2M + Na] ⁺ . MS (ESI -): m / z = 273.1 [MH] -, 309.1 [M + CI] -, 547.3 [2M-H] -.

Example F35: (3S) -3- {4 - [(2S) -2-methylbutoxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2S) -2-methylbutoxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E14, (130 mg, 0.451 mmol) and the remaining reagents and solvents used in the proper proportion. 93 mg (75% yield) of the product were obtained as an oil. Spectral data identical to Example F34.

PL 233 938 Β1

Example F36: (3S) -3- {4 - [(2R / S) -2,3-dimethylbutoxy] phenyl} hex-4-ynoic acid

(* racemate) C _Ig H "O ₃ = 288.38

The product was obtained using the conditions of Example F1, (3S) -3- {4 - [(2R / S) -2,3-dimethylbutoxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E31, (1200 mg 3.97 mmol) and the remaining reagents and solvents used in the correct ratio. 923 mg (81% yield) of the product were obtained as an oil.

¹ H NMR (300 MHz, CDCl) δ: 7.31 - 7.25 (m, 2H), 6.88 - 6.81 (m, 2H), 4.04 (DDQ, J = 8.9, 4.7, 2.3 Hz, 1 H), 3.92 - 3.83 (m , 1H), 3.78 - 3.68 (m, 1H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 1.83 (d, J = 2.4 Hz, 3H), 1.88 - 1.73 (m, 2H), 0.95 ( dd, J = 6.6, 2.0 Hz, 6H), 0.88 (d, J = 6.6 Hz, 3H).

¹³ C NMR (75 MHz, CDCb) δ: 177.19, 158.57, 132.83, 128.40, 114.79, 79.65, 79.10, 71.72, 43.44, 38.80, 33.30, 29.44, 20.63, 18.38, 13.22, 3.79.

MS (ESI +): m / z = 311.1 [M + Na] ⁺ . MS (ESI -): m / z = 323.1 [M + Cl] -.

Example F37: (3S) -3- (4 - {[(3R / S) -3-methylpentyl] oxy} phenyl) hex-4-ynoic acid

(* racemate) C _1B H _I4 O ₃ = 288.38

The product was obtained using the conditions of Example F1, (3S) -3- (4 - {[(3R / S) -3-methylpentyl] oxy} phenyl) hex-4-ynoic acid methyl ester, obtained in Example E28, (300 mg, 0.992 mmol) and the remaining reagents and solvents used in the correct ratio. 228 mg (80% yield) of the product were obtained as an oil.

¹³ C NMR (75 MHz, CDCb) δ: 176.84, 158.37, 132.87, 128.41, 114.74, 79.64, 79.10, 66.50, 43.41, 35.96, 33.29, 31.54, 29.65, 19.27, 11.40, 3.80.

MS (ESI +): m / z = 311.1 [M + Na] ⁺ . MS (ESI -): m / z = 323.1 [M + Cl] -.

Example F38: (3S) -3- [4- (4,4,4-trifluorobutoxy) phenyl] hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- [4- (4,4,4-trifluorobutoxy) phenyl] hex-4-ynoic acid methyl ester, obtained in Example E10, (300 mg, 0.914 mmol) and the remaining reagents and solvents used in the proper proportion. 203 mg (71% yield) of the product were obtained as a solid.

MS (ESI +): m / z = 337.1 [M + Na] ⁺ . MS (ESI -): m / z = 349.1 [M + Cl] -.

PL 233 938 Β1

Example F39: (3S) -3- {4 - [(5,5,5-trifluoropentyl) oxy] phenyl} hex-4-ynoic acid

The product was obtained using the conditions of Example F1, (3S) -3- {4- (5,5,5-trifluoropentyl) oxy] phenyl} hex-4-ynoic acid methyl ester, obtained in Example E11, (450mg, 1.314 mmol) and the remaining reagents and solvents used in the correct proportion. 380 mg (88% yield) of the product were obtained in the form of an amorphous solid.

¹ H NMR (300 MHz, CDCl) δ: 7.29 (t, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.11 - 4.00 (m, 1H), 3.96 (t, J = 5.8 Hz, 2H), 2.75 (qd, J = 15.7, 7.6 Hz, 2H), 2.26 - 2.06 (m, 2H), 1.83 (d, J = 2.3 Hz, 3H), 1.93-167 (m, 4H).

¹⁹ F NMR (282 MHz, CDCb) δ: -66.36 (t, J = 10.9 Hz).

¹³ C NMR (75 MHz, CDCb) δ: 177.10, 158.06, 133.24, 128.51,127.24 (q, Jc-f = 274.5 Hz), 114.70, 79.54, 79.20, 67.30, 43.30, 33.46 (q, Jc-f = 27.5 Hz), 33.27, 28.45, 19.05 (q, Jc-f = 3.1 Hz), 3.79.

MS (ESI +): m / z = 351.1 [M + Na] ⁺ . 367.1 [M + K] ⁺ . MS (ESI -): m / z = 327.1 [MH] ^- . 363.1 [M + CI] -, 655.2 [2M-H] -.

Example S1: (3S) -3- {4 - [(2,3-dimethylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid, calcium salt

C »H" CaO ₆ = 610.79

(3S) -3- {4 - [(2,3-dimethylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid, obtained in Example 33, under normal conditions as an oil, (3, 52 g, 12.3 mmol) was dissolved in water (49 ml) while stirring at room temperature and adding lithium hydroxide monohydrate (0.54 g, 12.9 mmol). The lithium salt solution was cooled to 15 ° C and a cold (0 ° C) solution of calcium chloride (0.72 g, 6.51 mmol) in 14 mL of water was added with vigorous stirring. The formed precipitate was filtered off, washed with ice water and dried in vacuo. Quantitatively (3.179 g) a colorless precipitate was obtained which melts with a decomposition in the range of 220-240 ° C.

Example S2: (3S) -3- {4 - [(2,3-dimethyl-but-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid (3S) -butylammonium salt

C ₂₁ H, NO ₃ = 359.50

(3S) -3- {4 - [(2,3-dimethylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid, obtained in Example 33, under standard conditions as an oil, (300 mg , 1.05 mmol) was dissolved in 5 ml of toluene and while stirring at room temperature, te / N-Butylamine solution (0.111 ml, 1.05 mol) was added

PL 233 938 Β1 in 5 ml of acetone. The precipitate is allowed to shape for 18 hours (seasoning), then it is filtered on a glass frit, washed with a cold mixture of toluene and acetone in the proportion 1: 1, n-pentane and dried in vacuo. 321 mg (85% yield) of a colorless crystal was obtained, the melting point of which is 151.6-152.9 ° C (with decomposition).

Example S3: (1R, 2S) -1-Amino-2-indanol salt (3S) -3- {4 - [(2,3-dimethylbut-2-en-1-yl) oxy] phenyl} hex-4 -new

C 'H ₃₃ NO ₄ = 435.56

(3S) -3- {4 - [(2,3-dimethylbut-2-en-1-yl) oxy] phenyl} hex-4-ynoic acid, obtained in Example 33, under standard conditions as an oil, (300 mg , 1.05 mmol) was dissolved in 10 mL acetonitrile and warm (50 ° C) (1R, 2S) -1-amino-2-indanol (150 mg, 0.985 mmol) in 5 mL acetonitrile was added with stirring. After stirring for 5 minutes, as the reaction mixture reaches ambient temperature, a precipitate forms which is filtered off on a glass frit, washed with cold acetonitrile, n-pentane and dried in vacuo. 252 mg (55% yield) of a colorless crystal was obtained, the melting point of which is 137.8-139.1 ° C (with decomposition).

Biological action of compounds:

Experiment B1: Analysis of receptor activation - measurement of calcium ion concentration

The study of GPR40 receptor agonist activity was carried out on the commercial CHO-K1 cell line overexpressing the human GPR40 receptor and the luminescent protein aquorin (Perkin Elmer), the luminescence of which increases significantly after binding calcium ions. Cells collected from the passage in the amount of 2x10 ^{6 were} incubated for 3 h in HBSS (GIBCO) solution with 0.015% BSA and 5 µΜ of coelenterazine (Promega), which is a prosthetic group of aquorin, necessary for the bioluminescence reaction. Then, the cells were dispensed using a dispenser in the amount of 5x10 ³ cells / well to a multiwell plate placed in the luminometer measuring chamber, where previously 2 x concentrated solutions of the test chemicals were prepared in HBSS reaction buffer in the concentration range of 0.01-10 μΜ. As a result of the measurement, curves of changes in the luminescence of cells over time are obtained, the integration of which allows to calculate the relative amount of calcium ions that have been released into the cytosol. Compounds that strongly activate the receptor cause the release of large amounts of calcium ions into the cytosol and strong luminescence of cells. From the obtained results, curves were determined that allow to determine the EC50 values. The test results are expressed as a percentage of the test system activation induced by a high concentration of the positive control alpha-linolenic acid.

Thus, on the basis of the determined EC50 values, the compounds of the invention can be directly compared and the reference compounds, e.g. presented in Table 2:

PL 233 938 Β1

TABLE 2:

Number For example Structure Value EC50 [nM] R1 YES-875 (fasiglifam) o ^{x X} O \ _Λ ^ -COOH C „H„ O ₇ S = 524.63 320 R2 AMG-837 COOH 438.44 141 S1 ||| o γχτ ¹ · C _J6 H CaO ₆ = 610.79 Ca ² '2 77

Due to the changing environmental conditions of the repeatedly performed Experiment B1 and to avoid the constant tabular reference to the reference compounds, the activity of the compounds according to the invention was expressed according to the following equation as% Ptak-87s value:

EC50 YES - 875% PtAK-875 ~ rr ---- 7--7 - J ------ ^X 1θθ%

EC50 Test Compound

The above equation therefore represents the percentage of increase or decrease in activity of the compound of the invention with respect to the reference compound TAK-875 (Fasiglypham, Compound R1).

Table 3 below shows the% Ptak-875 values obtained for the compounds of the invention where the (A), (B), (C), (D), (E) values used are the following ranges for the% Pt-87s values:

(A):> 120% Bird-875 (B): 81-120% Bird-875 (C): 51-80% Bird-875 (D): 21-50% Bird-875 (E): <20% Bird-875

Table 3 simultaneously shows the percent decrease in molecular weight (molar, MW) of the compounds of the invention with respect to the reference compound TAK-875 (Fasiglypham, Compound R1).

PL 233 938 Β1

PL 233 938 Β1 cont. table 3

F6 C ₂₂ H _IS O ₃ = 340.46 1 0 La" AND -35.1% n ^c 12 ^H 2B ° 3 = 340.46 0 'Ks ^ Loh E. -35.1% F8 C _m H ₃₀ O, = 342.4 1 o ^ A _o " B -34.7% F9 ^C 22 ^H _M ° 3 = 3 ⁴² « and 0 7 B -34.7% F10 ^C 22 ^H _Ie ^O 3 = 341 ' ^Χ ^ · ΟΗ 3.46 C. -35.1% F11 H o .. JE * ϋ 1 1 1 ίι oh {* racemat) C ₂₇ H _3S O ₃ = 408.57 D -22.1% F12 lithium C, ₆ H _I0 O ₃ = 260.33 AND -50.4%

PL 233 938 Β1 cont. table 3

F13 AND (* racemate ' And. ^ '-'Χ'ΌΗ C ₁₇ H ₂ jO ₃ = 274.36 AND -47.7% F14 I UJU C _ls H _{2 O} 2 0 ₃ = 0 .60.33 AND -50.4% F15 I _Cl6 H ₂₀ O ₃ = 2 0 ί 60.33 AND -50.4% F16 Jt * \ (* racemate) C. "H" ( And 0> ₃ = 274.36 AND -47.7% F17 c "h ₂₂ at ₃ = 0 ' ^X ^ ^S OH 274.36 E. -47.7% F18 I C ₁₈ H "O ₃ = 2 And 0 86.37 AND -45.4% F19 I C ₁₈ H ₂₀ O ₃ = 284 And Fr. 35 AND -45.8%

PL 233 938 Β1

PL 233 938 Β1

PL 233 938 Β1

Experiment B2: Glucose-dependent insulin secretion on MIN6 murine insulinoma cells.

MIN6 cells (mouse insulinoma) were plated on a PDL (poly-D-lysine) coated plate at 5x10 ⁵ / well and cultured for 48 hours. After 48 h, cells were washed twice with KRBH buffer (119 mM NaCl, 4.7 mM KOI, 1.2 mM KH2PO4, 1.1.16 mM MgCl2, 10 mM HEPES, 2.5 mM CaCl ₂ , 25.5 mM NaHCO _3). 0.1% BSA, pH 7.4) and incubated in KRBH buffer with the addition of 2 mM glucose for 2 h so as to lower intracellular glucose concentration. Test compounds were diluted to a concentration of 10-40 µM in KRBH buffer supplemented with 20 mM glucose and then added to the cells and incubated for 1 h to induce insulin secretion. KRBH buffer is the negative control of the experiment

PL 233 938 Β1 with 2 mM glucose. The concentration of secreted insulin was determined using an ELISA kit (Mercodia). The results of the experiment are presented in Table 4.

Table 4 shows the MIN6insuiin @ 10uM value for selected compounds of the invention. The MIN6insuiin @ 10uM value represents the fold of the favorable increase in insulin surge with respect to the control experiment after the addition of a 10 µM aliquot of the test compound.

Experiment B3: In vivo glucose tolerance test in rats.

A glucose tolerance test (TTG) was performed to evaluate the effect of compounds on lowering glycemia in vivo. The study was carried out on male rats from the Wistar HAN Crl: WI (HAN) outbreeding herd from Charles River culture, body weight approx. 250-300 g, age 8-10 weeks. Rats were fasted for 12 hours (with free access to water).

At time t = 0, they received a single dose of compound administered orally (gastric tube) followed by an immediate (t = 0) and 6 h (t = 6 h) glucose bolus at 2 mg / kg after 6 h (t = 6 h). At subsequent time points t = 0 (immediately before the oral administration of preparations and before the intraperitoneal administration of glucose, 0.25; 0.5; 1.2, 2.5; 3; 6; 6.25; 6.5; 7; 8 9 hours each

PL 233 938 Β1 rat blood was collected from the tail vein for the determination of glucose concentration using an Accu-chek glucometer (Roche Diagnost) and additionally at t = 0.25; 0.5; 1.2, 2.5; 3 h blood from the tail vein for determination of insulin concentration by ELISA test (Mercodia).

Compounds were prepared in 5% DMSO / 40% PEG300 / 55% PBS vehicle and administered at a dose of 10 mg / kg bw. in a volume of 0.5 ml / 100 g b.w. rat. 4 h after compound administration, animals received standard cage food. The reduction in AUC for blood glucose was measured and the results for selected compounds of the invention are shown in Table 5. Analyzes were performed in GraphPad prism.

TABLE 5:

Number An example Structure Glucose AUC values (0-540 min.) Insulin AUC values (0-180 min.) - Carrier 44,940.4 37.8 R1 YES-875 (fastglifam) ^{0 0} * —COOH C _2g H ₃₂ O ₇ S = 524.63 30,950.6 210.5 F6 II 0 and JL ij ^ ⁰ C _ai H _2B O ₃ = 25184.1 492.5 F24 I ^ 17 ^ 22θ3 ⁼ And 0 274.36 24,289.7 329.0 F28 1 ^C 1, ^H 2 O ° 3 = 27 And 0 2.34 28377.4 499.2 F33 AND And 0 La" 286.37 19393.1 519.1

PL 233 938 Β1

Experiment B4: Inhibition of bile acid transporters in the liver.

To check the influence of the lead compound on the inhibition of bile acid and bilirubin transporters in the liver and to compare the results with the TAK-875 compound, which is known for its hepatotoxic properties, including the inhibition of bile acid transporters at low concentrations was performed by SOLVO Biotechnology. The lead compound was tested on a panel of 10 transporters: BSEP, MRP2, MRP3, MRP4 with the vesicular transport inhibition assay and NTCP, OAT1, OAT2v1, OATP1A2, OATP1B1, OATP1B3 with the transporter assay inhibitor uptake inhibition assay.

An alveolar transport inhibition assay was performed on membrane vesicles isolated from mammalian HEK293 cells overexpressing human ABC transporters. Compounds were incubated with vesicles and substrates for the test transporters. Incubation was performed in the presence of 4 mM ATP or AMP to differentiate between transporter-mediated uptake and passive diffusion into vesicles. In the case of MRP2 and MRP3, the reactions were performed in the presence of 2 mM glutathione. Compounds were added to the reaction mixture in 0.75 µΙ of solvent (1% final incubation volume). Reaction mixtures were preincubated for 15 minutes at 37 ± 1 ° C. Reactions were started by the addition of 25 µl12 mM MgATP (or 12 mM AMP in assay buffer, as background control), pre-incubated separately. Reactions were stopped by adding 200 µL of ice cold washing buffer and immediately filtering through glass fiber filters mounted on a 96-well filter plate. The filters were rinsed (5 x 200 µL ice-cold wash buffer), dried and the amount of substrate inside the filtrate vesicles was determined by liquid scintillation counting.

A transporter uptake inhibition assay was performed on mammalian HEK293 cells that overexpressed the transporter in question. Cells were grown at 37 ± 1 ° C and seeded in standard 96-well tissue culture plates at 1x10 ⁵ / well. Before the experiment, the medium was removed and the cells were washed twice with 100 µL of the appropriate buffer (HK pH 7.4 for OATP1B1 and HBSS pH 7.4 for NTCP, OAT1, OAT2v1, OATP1A2, OATP1B3). Capture experiments were performed at 37 ± 1 ° C in 50 µΙ of an appropriate buffer containing labeled substrate and test compound or solvent. The concentration of the organic solvent was the same in all wells and did not exceed 1.5% (v / v). After the experiment, cells were washed twice with 100 µL of cold appropriate buffer and lysed with 50 µL 0.1 M NaOH. Transport of radiolabeled substrate was determined by measuring on a scintillation counter. The results of the experiment are presented in Table 6.

TABLE 6:

Transporter IC50 Example S1: II 0 L ^Ca2 LJ 2 C ^ H.jCaO * = 610.79 Compound R1: ΤΑΚ-Β75 (fasiglypham) ° COOH Cj ₉ H "O, S = S24.63 MRP2 n / a * 48.1 μΜ MRP3 n / a * 31.8 μΜ MRP4 131 μΜ 6.9 μΜ BSEP > 100 µM 30 µM OAT1 245 μΜ 34.8 μΜ OAT2v1 > 300 μΜ 62.8 μΜ OATP1A2 118 μΜ 10.6 μΜ OATP1B1 17.9 μΜ 0.49 μΜ OATP1B3 42.9 μΜ 3.44 μΜ NTCP 46.8 μΜ 53.1 μΜ

* Value n.a. denotes no inhibition of a specific receptor up to a concentration of 100 μΜ of the test compound.

Claims (14)

Patent claims 1. A compound of general formula (I) (l) in which: - R stands for: a C3-C15 straight or branched primary or secondary acyclic hydrocarbon group which may be saturated or unsaturated, or a straight or branched C3-C15 primary or secondary acyclic hydrocarbon group which may be saturated or unsaturated and wherein one or more of the hydrogen atoms are replaced by a fluorine atom; - X represents a hydrogen atom or a halogen atom and its salts, especially pharmaceutically acceptable salts, with the exception of 3- (4 - {[(2E, 3Z) -2-propylidene-pent-3-en-1-yl] oxy} phenyl) -hex-4-yne. 2. A compound according to claim 3. The process of claim 1 wherein R is a C3-C15 straight or branched saturated acyclic hydrocarbon group, especially C4-C12, which may be saturated or unsaturated. 3. The compound of claim 1 Is a simple C3-C15 saturated acyclic hydrocarbon group, especially C4-C12. 4. The compound of claim 1 2. The compound of claim 2, wherein R is a branched C3-C15 saturated acyclic hydrocarbon, especially C4-C12. 5. The compound according to p. Is a simple C3-C15, especially C4-C12, unsaturated acyclic hydrocarbon group. 6. The compound according to p. Is a branched C3-C15, especially C4-C12, unsaturated acyclic hydrocarbon group. 7. The compound of claim 1 3. The process of claim 1 wherein R is a straight or branched C3-C15 primary or secondary acyclic hydrocarbon group, especially C4-C12, which may be saturated or unsaturated and in which one or more of the hydrogen atoms is replaced by a fluorine atom. 8. The compound of claim 1 Is a simple C3-C15 saturated acyclic hydrocarbon group, especially C4-C12. 9. The compound of claim 1 The process of claim 7, wherein R is a branched C3-C15 saturated acyclic hydrocarbon, especially C4-C12. 10. The compound of claim 1 Is a simple C3-C15, especially C4-C12, unsaturated acyclic hydrocarbon group. 11. The compound of claim 1 Is a branched C3-C15, especially C4-C12, unsaturated acyclic hydrocarbon group. 12. A compound according to any one of claims 1 to 12 1 to 11, wherein X is hydrogen. 13. A compound according to any one of claims 1 to 13 Is a halogen atom, in particular a fluorine atom. 14. A compound of formula (I) according to any one of the preceding claims 1 for use as a medicine.