UA73749C2 - Diarylenines - Google Patents

Abstract

Provided, among other things, is a compound of Formula (I), wherein, Ar1 and ??r2 are independently selected aryl groups, optionally substituted with up to five substituents independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloallsyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl, heterocycloalkyl-substituted alkoxy, heterocycloalkyloxy-substituted alkoxy, thioaryl, aralkylthio, thioarylalkyl, aralkylthioalkyl, halo, NO2, ??F3, CN, OH, alkylenedioxy, SO2NRR', NRR', CO2R (where R and R' are independently selected from the group consisting of H and alkyl), and a second aryl group, which m???? be substituted as above; R1 is selected from the group consisting of H and alkyl; R2 is selected from the group consisting of H, alkyl and benzyl; R3 is selected from me group consisting of CO2R, CONRR', CONH(OH), COSR, SO2NRR', PO(ORXOR') and tetrazolyl, wherein R and R' are independently selected from me group consisting of H and alkyl; and a salt,solvate or hydrate thereof. , (I)

Description

Description of the invention

This invention relates to the class of diaryl enines, pharmaceutical compositions containing these compounds, and methods of treating neurological and neuropsychiatric disorders using these compounds.

Synaptic transmission is a complex form of intercellular communication that involves a significant complex of specialized structures in presynaptic and postsynaptic terminal and surrounding glial cells

Kanner and Schuldiner - Kappeg apa Zspsiaipeg, SAS Styisai Kemiemuv ip Viospetivighu, 22, 1987: 1032).

Transporters isolate the neurotransmitter from the synapse, thereby regulating the concentration of the neurotransmitter in the 70 synapse, as well as the duration of its stay there, that is, factors that collectively affect the intensity of synaptic transmission. In addition, by preventing the spread of transmitter across neighboring synapses, transporters maintain the fidelity of synaptic transmission. Finally, by sequestering the released transmitter into the presynaptic terminal, transporters allow the transmitter to be reused.

Neurotransmitter transport depends on extracellular sodium and the potential difference on the membrane; in 72 conditions of intense neuronal excitation, such as during an epileptic seizure, the transporters can act in the opposite way, releasing the neurotransmitter in a calcium-independent, non-exocytotic mode | (Atwell et al. - Abmei! ei aiYi., Maygop, 11, 1993: 401-407). Thus, pharmacological modulation of neurotransmitter transporters is a means of modifying synaptic activity that provides effective therapy for neurological and psychiatric disorders.

The main neurotransmitter in the central nervous system of mammals, which acts on both inhibitory and excitatory synapses, is the amino acid glycine. The term "nervous system" covers both central and peripheral parts of the nervous system. These different functions of glycine are mediated by two different types of receptors, each associated with a distinct class of glycine transporters. In the inhibitory activity of glycine, the mediators are glycine receptors sensitive to the convulsant alkaloid - strychnine, therefore, they are called "strychnine--utlyvim". Such receptors contain their own chloride channel, which opens when He) glycine binds to the receptor; the increase in conductivity under the influence of chlorides causes an increase in the excitation threshold of the action potential. Strychnine-h-utilizing glycine receptors are found primarily in the spinal cord and brainstem, and pharmacological agents that increase the activation of these receptors thus intensify inhibitory neurotransmission in these regions. at

Glycine also functions in excitatory transmission by modulating the action of glutamate, the main excitatory neurotransmitter in the central nervous system. Fletcher et al. "Glycine Transmission," ed. Otterson and Storm-Mathiesen - Riieispeg ei in aI,, SiIusipe Tgapztizziop, Omegwop apa 5iogt-Maiizep, eav., 1990:193-219). In particular, glycine is an obligatory co-agonist of a class of glutamate receptors called the M-methyl-O-asparaginate (MMOA) receptor. Activation of 3o MMOA receptors increases sodium and calcium conductance, which contributes to neuron depolarization, thereby increasing the probability of generating an action potential.

MMOA receptors in the hippocampus region of the brain play an important role in the pattern of synaptic plasticity known as long-term potentiation (LTP), which is an element of some types of learning ability and memory (Heb, "Organization of behavior" - Ner 0.0. (1949 ), Tne Ogdapigainyop oi Wepamiog, MUyPeu, MU; Bliss et al. 50 Collingridge - Wiivv apa SoiIipogidde (1993), Mayte 361: 31-39; Morris et al. - Moitiv ei ai. (1986), Maishge p 319:774-776 ). Increased expression of certain subunits of MMOA receptors in transgenic mice leads to

Iz» increasing the strength of currents mediated by MMOA receptors, increasing I TR and improving performance in some tests of learning ability and memory |Tan et al - Tapo eyi ai. (1999), Makige 401: 63).

In contrast, reduced expression of certain MMOA receptor subunits in transgenic mice causes behavioral traits similar to pharmacologically induced animal models of schizophrenia, including increased immobility, increased stereotypy, and defects in social and sexual interactions | Mon et al. - Mopp et al. oz (1999), Se! 98: 427-436). These behavioral abnormalities can be corrected with the antipsychotic drugs haloperidol and clozapine. and MMOA receptors are widely distributed in the brain, their density is especially high in the cerebral cortex and in the hippocampus.

Molecular cloning revealed that there are two classes of glycine transporters in the brain of mammals, which were designated C1IUT-1 and SIuT-2. CIuUT-1 is found in all parts of the brain and in the spinal cord, and it is assumed that its distribution corresponds to the distribution of glutamatergic pathways and MMOA receptors (Smith et al.,

Metsygop, 8, 1992: 927-935). In addition, molecular cloning revealed the existence of three varieties of 29 SIUT-1, which are designated (IUT-Ta, SIUT-15 and SIuUT-1c. Two of these varieties (Ta and 15) were found in rodents, while

HF) each of them has a characteristic distribution in the brain and in peripheral tissues (Borovsky and others - VogomuzKi ei aiYi., Maygop, 10, 1993: 851-863; Adams and others - Adatv ei ai., U. Metsygossiepse, 15, 1995: o 2524-25321. The third variety, 1c, was found only in human tissues |Kim and others - Kit ei ai., MoiIesshag

RPpagtasiodu, 45, 1994: 6008-6171. These variants arise by differential splicing and use of 60 exons and differ in their M-terminal regions. On the contrary, SIuUT-2 is found mainly in the brainstem and in the spinal cord, and its distribution corresponds to the distribution of strychnine-h-utly receptors of glycine |/Liu et al., 9. Vioiodisa! Spetivigu, 268, 1993:22802-22808; Yurskyi and Nelson - digeKu apa Meivop, 9.

Meygospetiviga, 64, 1995:1026-1033). Another difference between C1IuT-2-mediated glycine transport is that it is not inhibited by sarcosine like SIUT-1-mediated glycine transport. These data are consistent with the opinion that SiUT-1 and SIuUT-2, regulating the synaptic levels of glycine, selectively affect the activity of MMOA receptors and strychnine-sensitive glycine receptors, respectively.

Compounds that inhibit or activate glycine transporters can be expected to alter receptor function and thus provide therapeutic effects in a variety of disorders.

For example, compounds that inhibit the transport of glycine, mediated by SIuUT-1, increase the concentration of glycine in MMOA receptors, which are located, in particular, in the forebrain. This increase in concentration increases the activity of MMOA receptors, thereby alleviating the schizophrenic state and improving cognitive function. On the other hand, compounds that directly interact with the glycine receptor component of the MMOA receptor may produce the same or similar effect, respectively facilitating or hindering the 7/0 availability of extracellular glycine caused by inhibition or enhancement of SIUT-1 activity. See, for example, Pitkänen et al. 9. Rpaptasoi., 253, 125-129 (1994)); Tills and others (TpieiYiv ei aiYi., Metsygovzsiepse, 46, 501-509 (1992); and (Krechmer and Schmidt Kgeivspteg apa Zsptidi u. Meishgovsi., 16, 1561-1569 (1996)).

The present invention provides compounds that affect glycine transport. The invention also offers compositions, 7/5 Useful in the treatment of painful conditions in which the use of glycine transport modulators and, in particular, glycine absorption inhibitors is indicated.

According to one aspect of the invention, there are provided compounds of Formula I:

Аг что пе и хх M.Ya 2 k 1

Formula I with where:

Ag and Ago are independently selected aryl groups, optionally substituted with up to five substituents i) independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy group, aryloxyalkyl, aryloxyalkyl group, alkyl substituted by cycloalkyl, alkyl substituted by He! with a cycloalkyloxy group, an alkoxy group substituted by a cycloalkyl, an alkoxy group substituted by a cycloalkyloxy group, an alkyl substituted by a heterocycloalkyl group, an alkyl substituted by a heterocycloalkyloxy group, an alkoxy group substituted by a heterocycloalkyl group, an alkoxy group substituted by a heterocycloalkyloxy group, thioaryl, an aralkylthio group, Kk. thioarylalkyl, aralkylthioalkyl, halide, MO", CEz, CM, OH, alkylenedioxy group, ZO2MKK, MKK, CO (where K and KK are independently selected from the group consisting of H and alkyl) and a second aryl group, which can be me) z5 Substituted as indicated above; Cha

Ku is selected from the group consisting of H and alkyl;

E" is selected from the group consisting of H, alkyl and benzyl;

Ez is selected from the group consisting of SOOK, SOMEK, SOMN(OH), CO5E, 502MKK, PO(OKHOK)) and tetrazolyl, where K and K' are independently selected from the group consisting of H and alkyl; " and salts, solvates or hydrates of such compounds. It was found that the compounds of Formula ! inhibit the transport (or reabsorption) of glycine with the participation of . transporter SIuUT-1 or are precursors (for example, prodrugs) of such compounds and, thus, are useful in treatment of schizophrenia, as well as other disorders related to the central nervous system, for example, disorders of cognitive function, dementia (including Alzheimer's disease), attention deficit

And depression. -I According to another aspect of the invention, there is provided a pharmaceutical composition containing a compound of Formula | in an amount effective to inhibit glycine transport, and a pharmaceutically acceptable carrier. According to another aspect of the invention, there are provided compositions containing the above-mentioned compounds in amounts suitable for pharmaceutical use in the treatment of disease states in which the use of glycine transport inhibitors is indicated. Preference is given to compositions containing compounds useful in the treatment of disease states in which inhibition of glycine transport mediated by (C1UT-1,

Ge) for example, in the treatment of schizophrenia or disorders of cognitive function.

The term "aryl" as used herein means a monocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, etc., or an aromatic group fused to a benzene ring, such as naphthyl, di-indanyl, quinolinyl, fluorenyl, etc.

The term "alkyl" as used in this description means an alkyl radical of normal or branched (F) structure, which contains from 1 to 6 carbon atoms, including methyl, ethyl, and the like. The term "cycloalkyl" as used herein means a carbocyclic group containing from 3 to 8 carbon atoms, including cyclopropyl, cyclohexyl, and the like. Similarly, the term "Cycloalkyloxy(group)" refers to a carbocyclic group that is attached to another group through an oxygen atom, including cyclohexyloxy groups and the like.

The term "heterocycloalkyl" as used herein means a 3- to 8-membered ring containing up to two heteroatoms selected from the group consisting of M, 5, and O, and includes piperidinyl, piperazinyl, thiopyranyl, and the like. Such rings attached to other groups through an oxygen atom, for example, 65 Piperidinyloxy group, etc., are called heterocycloalkyloxy groups.

The terms "aralkyl", "aryloxyalkyl", "aralkyloxy(group)" and "aryloxyalkyl(group)" in the meanings,

as used herein refer to alkyl or alkyl radicals substituted with aryl or aryloxy, and include benzyl, phenethyl, benzyloxy, 2-phenoxyethyl, and the like. Similarly, the terms "cycloalkyl-substituted alkyl", "cycloalkyl-substituted alkoxy", "heterocycloalkyl-substituted alkyl" and "heterocycloalkyl-substituted alkoxy" refer to groups of the 2-cyclohexylethyl type and the like. Further, substituents in which the alkyl or alkoxy group is substituted by other groups through an oxygen bridge are referred to herein as "alkyl substituted by cycloalkyloxy", "alkyl substituted by cycloalkyloxy", "alkyl substituted by heterocycloalkyloxy" and "alkyloxy substituted by heterocycloalkyloxy".

The terms "alkylene" (e.g., -CHo-CNeo-), "alkenylene" (e.g., -"SNACIN-) and "alkynylene" (e.g., 7/0 7b-C-) as used herein mean divalent radicals of normal or branched structure that contain from 1 to 6 carbon atoms, for example, methylene, ethylene, vinylene, propenylene and ethynylene.

The term "alkyl(group)" as used in this description means alkyl radicals of normal or branched structure, which contain from 1 to 6 carbon atoms, and includes methoxy group, ethoxy group, and the like.

The term "thioalkyl" as used herein refers to alkyl radicals of normal or /5 branched structure containing from 1 to 6 carbon atoms, and includes (CH3-5), thiopropyl, and the like.

The term "thiosaryl" refers to an aryl attached to another group via a sulfur atom. Similarly, a tisarylalkyl is a thioaryl connected to another group via a bridging alkylene group. Next, an aralkyl group is called an aralkyl, such as benzyl, connected to another group through a sulfur atom. Further, an arylalkylthioalkyl is an arylalkyl attached to another group via a bridging thioalkyl.

The term "alkanoyl" as used herein means radicals of normal or branched structure containing from 1 to b carbon atoms and includes acetyl, propionyl and the like.

The term "halide" as used herein means a halogen atom and includes fluorine, chlorine, bromine, and the like. The term "haloalkyl" refers to an alkyl group substituted with one or more independently selected halides, such as -C3. Similarly, the term "halo alkoxy(group)" refers to an alkoxy group optionally substituted with one or more independently selected halides, such as -OCE.

The term "alkylenedioxy(group)" refers to a group of the formula -O-(CH 2)4-O- in which the terminal oxygen atoms are, as a rule, connected to aryl atoms to form a bicyclic system, and includes a methylenedioxy group, ethylenedioxy group, etc.

The term "heteroatom" as used in this specification means atoms other than carbon atoms and includes (zu, z, M, 5, and 0.

Geometry of Formula I compounds! relative to the double bond corresponds to the shown formula. That is, the Ag group and the carbon atom to which the K group is attached are in a mutual cis position. uh-

Compounds of Formula I include compounds in which Ag. and Ago are independently selected optionally substituted aryl groups. me)

The location of substituents in Ag cycles. and Ago in practice is limited by carbon atoms, through which the cycle is not attached to the skeleton of the molecule. For example, a benzene ring can carry up to 5 substituents; pyridine and pyran rings can have up to 4 substituents, pyrrole, furan and thiophene can have up to 3 substituents; imidazole - 2 substituents, and triazole can carry only one substituent.

In embodiments of the invention, Ag is optionally a monocyclic aromatic group, such as benzene, pyridine, pyran, thiophene, furan, pyrrole, imidazole, and triazole. The group Ag and can have in the aromatic ring 1,2... c or C substituents that can be selected from such groups as alkyl, alkoxy group, cycloalkyl, cycloalkyloxy group, heterocycloalkyl, heterocycloalkyloxy group, alkanoyl, thioalkyl, aralkyl, ;" aralkyloxy group, aryloxyalkyl group, aryloxyalkyloxy group, alkyl substituted by cycloalkyl, alkyl substituted by cycloalkyloxy group, alkoxy group substituted by cycloalkyl group, alkoxy group substituted by cycloalkyloxy group,

BAlkyl substituted by heterocycloalkyl, alkyl substituted by heterocycloalkyloxy group, alkoxy group substituted by -I heterocycloalkyl, alkoxy group substituted by heterocycloalkyloxy group, thioaryl, aralkylthio group, thioarylalkyl, halide, MO», SEz, CM, OH, methylenedioxy group, ethylenedioxy group, ZO2MKK, MKK, SOZH (where K and o K are independently selected from the group consisting of H and alkyl) or an aryl group, optionally -I substituted as indicated above.

In useful embodiments of the invention, Ar is selected from the group consisting of benzene, pyridine, pyran, thiophene, furan, and pyrrole, optionally substituted with 1, 2, or C substituents selected from

Ge) group, which includes halide, MO 5, CEz, CM, OH, alkyl, alkoxy group, aryl, aralkyl and K"X), dep is 0 or 1, X is СНо or a heteroatom, and K" is H, alkyl or aryl, optionally substituted with up to three substituents selected from the group consisting of alkyl, halide, MO", CEz, CM, OH, 50O2MAK, MKK and CO (where K and K' are independently two ONE of each other selected from the group , which includes H and alkyl).

In specific variants of implementation of the invention Ag. - phenyl, optionally substituted by 1, 2 or C substituents, (F) selected from the group consisting of halide, MO», CEz, CM, OH and K»(X)v, dep is 0 or 1, X is CH» . , MKK, SOZH (where K and K' are independently selected from the group that includes H and alkyl).

According to more specific variants of the invention, Ag. - phenyl optionally substituted by 1 or 2 substituents selected from the group consisting of alkyl, thioalkyl, alkoxy, halide, haloalkyl, haloalkyloxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, and substituted or unsubstituted aralkyl. 65 According to certain variants of implementation of the invention Ag. - monosubstituted phenyl, in which the substituent is in position 4 and is selected from the group consisting of methyl, ethyl, p-propyl, isopropyl, p-butyl, C3-furyl and C3-thienyl.

According to other embodiments of the invention, Ag 1 is an optionally substituted condensed benzoaromatic system, such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl, etc., where the substituents can be selected from the group consisting of halide, MO 5, CEz, SM . the group that includes alkyl, halide, MO", СЕз5, СМ, ОН, 50О2МКК, МАК and СОжЖ (where K and K' are independently selected from the group that includes H and alkyl).

In specific embodiments of the invention, Ag 4 may be naphthyl, quinolinyl, indanyl, or alkylenedioxyphenyl, optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, 10-alkyl, thioalkyl, and aryl.

According to one separate embodiment of the invention, Ag. selected from the group consisting of unsubstituted naphthalene and methylenedioxyphenyl.

In other embodiments of the invention, Ago is optionally substituted aryl, where aryl is a monocyclic aromatic group such as benzene, pyridine, pyran, furan, thiophene, pyrrolidine, etc., or a fused benzoaromatic system such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl etc. This group may bear 1, 2, or C substituents, which may be independently selected from the group consisting of halo, haloalkyl, alkyl, haloalkyl, and alkoxy.

In a specific embodiment, Ago is a monocyclic aromatic group that carries up to three substituents independently selected from the group consisting of halo, haloalkyl, alkyl, haloalkyl, and 20-alkyl. According to more specific embodiments, Ago is mono- or disubstituted phenyl, wherein the substituents are selected from the group consisting of halo, haloalkyl, alkyl, haloalkyl, and alkoxy.

In specific embodiments, Ago is phenyl, unsubstituted or substituted with one substituent, namely, a halide or an alkoxy group.

According to more specific embodiments of the invention, Ago is unsubstituted phenyl or substituted phenyl, where the substituent is chlorine or fluorine.

According to other variants of implementation of the invention, KZ is selected from the group that includes -СО Kk, -СОМКК, (8) -СОМН(ОН), -СО5К, -502МКК, -"РО(ОКХОК) and tetrazolyl, where K and K ' are independently selected from the group consisting of H and alkyl.

In specific versions, Kz - SOOK. In preferred embodiments of the invention, Kz is COOH. Gee! zo Compounds of Formula I include those in which K is selected from the group consisting of H and alkyl. Preference among Ku values is given to N. "

To the compounds of Formula | include those in which K is selected from the group consisting of H, alkyl and benzyl. M

Compounds where K" is alkyl are suitable; greater preference is given to compounds where K» is methyl.

In preferred embodiments of the invention, compounds of Formula I! there are compounds where K 4 - H, K» - i)

Zv Metyl, Kz - SOON. In this context, it is desirable that Ag. and Ago were substituted or unsubstituted phenyls. In the preferred variants, Ag. - phenyl or phenyl substituted in position 4. In the case of such substitution, it is desirable that Ag. was 4-alkylphenyl, and groups where this alkyl has a normal structure are particularly preferred, including 4-ethylphenyl and 4-n-propylphenyl. 4-isopropylphenyl is also preferred. In combination with such Ag. or regardless of it, preference among Ago values is given to chloro- or "fluorine-substituted phenyl. with c In another preferred variant, K. is H, K»o is methyl, Kz is COOH, Ag» is unsubstituted phenyl and Ag4 /- 4-alkyl-substituted phenyl, where the alkyl is a C..4 chain of normal structure. with In yet another preferred embodiment, K 4 is H, K»o is methyl, Kz is COOH, Ag» is 2-chlorophenyl and Ag. /- 4-alkylphenyl, where the alkyl substituent is ethyl or propyl.

In yet another preferred embodiment of the invention, K 4 is H, K" is methyl, Kz is COOH, Ag is naphthyl, in particular, 2-naphthyl, and Ag is phenyl.

In another preferred embodiment of the invention, K 4 - H, Ko - methyl, Kz - COOH, Ag. - about 3,4-methylenedioxyphenyl and Ago - 3-fluorophenyl. -I According to another preferred embodiment of the invention, K. is H, K" is methyl, Kz is COOH, 500 Ag is phenyl and Ag is phenyl substituted with an optionally substituted aryl. pi In the preferred embodiment of the invention, K 4 - H, K" - methyl, Kz - COOH, Ag" -

Ge) phenyl and Ag. - phenyl substituted with an optionally substituted 5-lene heteroaryl.

In the most preferred embodiment of the invention, K 4 - H, K»o - methyl, Kz - COOH, Ago /- phenyl and Ag. - 4--3-furyl)phenyl.

Specific compounds of Formula I include: (1). mch-(5-(4-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

F) (2). M-(5-(2-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine ka (3). M-(5-(2,4-difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (4). M-(5-(3-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine in (5). M-(5-(4-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (6). M-(3-phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl-sarcosine (7). M-(5-(4-chlorophenyl)-3-phenyl-2-pentene -4-yn-1-yl)-sarcosine (8). M-(5-(4-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (9). M -(5-(3,5-bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine 65 (10). M-(3,5-diphenyl-2- penten-4-yn-1-yl)y-sarcosine (11). m-(5-(4-biphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

(12). M-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (13). M-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (143. M-(5-(4-ethylphenyl)-3-phenyl-2-pentene -4-yn-1-yl-sarcosine (153. M-(5-(4-p-propylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (16). M- (5-(4-p-butylphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine (17). M-(5-(4-l-pentylphenyl)-3-phenyl-2 -penten-4-yn-1-yl)y-sarcosine (18).M-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine (19). M-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine 70 (20). M-(5-(4-methylphenyl)-3-phenyl-2 -penten-4-yn-1-yl)-sarcosine (21). M-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (223. M -(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (23). M-(5-(3,4-dimethylphenyl)-3-phenyl-2 -penten-4-yn-1-yl)y-sarcosine (24). M-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (25) M-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine (26). M-(5-(4-pyrrolylphenyl)-3-phenyl- 2-penten-4-yn-1-yl-sarcosine (27). M-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (28) M-(5-(3,4-dime toxyphenyl)-3-phenyl-2-pentene-4-yn-1-yl-sarcosine (29). M-(3-phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl-sarcosine (30). M-(5-(4-methylphenyl)-3-phenyl-2-pentene -4-yn-1-yl)-sarcosine (31). M-(3-phenyl-5-(3-thiophene)-2-penten-4-yn-1-yl-sarcosine (32). M-( 3-phenyl-5-(4-tert-butylphenyl)-2-penten-4-yn-1-yl)-sarcosine (33). M-(5-(4-(3-furyl)-phenyl)-3 -phenyl-2-penten-4-yn-1-yl-sarcosine (34). M-(5-(4-(3-thiophene)-phenyl)-3-phenyl-2-penten-4-yn-1 -yl-sarcosine (35). M-(5-(4-isopropylphenyl)-3-(4-trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine (36). M- (5-(4-isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine and) (37). M-(5-(4-isopropylphenyl)-3- (2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine (38). M-(5-(4-tert-butylphenyl)-3-(2-fluorophenyl)-2-penten-4 -yn-1-yl)-sarcosine (39). ). M-(5-(4-tert-butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl-sarcosine (41). M-(5-(4-isopropylphenyl) -3-(2-chlorophenyl)-2-penten-4-yn-1-yl-sarcosine - (42). Mch-(5-(4-tert-butylphenyl)-3-(2-chlorophenyl)-2- pentene-4-in- 1-yl-sarcosine M (43). M-(5-(4-isopropylphenyl)-3-(33-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine (44). M-(5-(4-isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)-sarcosine me) (45). Mch-(5-(4-isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)y-sarcosine (46). M-(5-(3,4-methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)y-sarcosine (47). M-(5-(4-ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl-sarcosine (48). M-(5-(4-propylphenyl)-3-( 2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine

Compounds Formula | can be considered as amino acids or their derivatives. Compounds that instead of carboxylic "

Groups containing "carboxyl equivalents", such as hydroxamic acids, phosphonic acids, phosphinic acids, with sulfonic acids, sulfinic acids, amides or tetrazoles, are also considered as embodiments of the present invention. ;" According to another embodiment of the invention, a compound of Formula I is proposed! in a labeled form, such as in a radioactively labeled form (that is, labeled by introducing ZN or "C" into its structure, or by

Binding to 125 |), In a preferred embodiment of the invention, such compounds that preferentially bind to SIUT-1 can be used to identify SIUT-1 receptor ligands by methods known in the art. This can be done by incubating the receptor or tissue in the presence of the intended ligand followed by incubating the resulting drug with an equimolar amount of the radiolabeled compound according to the invention. In this way, the ligands of the SIUT-1 receptor are found to largely occupy the 50th position of SIUT-1 and prevent the binding of the radiolabeled compound according to the invention. According to an alternative variant, the putative ligands of the SIUT-1 receptor can be identified by first incubating iChe) a radioactively labeled compound according to the invention, and then incubating the resulting preparation in the presence of the putative ligand. A more effective ligand of the SIuUT-1 receptor at an equimolar concentration will displace the radiolabeled compound according to the invention.

Acid salts of the compounds of Formula I are preferably prepared on the basis of pharmaceutically acceptable acids, and include, for example, salts of inorganic acids, for example, hydrochloric, sulfuric or phosphoric acids, as well as organic acids, for example, succinic, maleic, acetic or fumaric acids to acid Other pharmaceutically unacceptable salts, such as oxalates, can be used, for example, to isolate compounds of Formula | for laboratory use or for further conversion into salts of pharmaceutically acceptable acids. This invention also encompasses base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of the compounds of the invention. Base addition salts are preferred, and sodium and potassium salts are particularly preferred.

Conversion of this salt of the compound into the desired salt is achieved using standard methods well known to those skilled in the art. 65 The compounds of the present invention can be prepared in a manner analogous to methods known in the art.

For example, compounds of Formula I! is readily obtained by the method shown in Scheme 1 below. Intermediate product C was obtained by the method of I.V.M. Trost. Tgovy, M.T. Zogyt, S. Spap, A.E. Nagtv, b. KyiPeg, 9. At.

Spent boss. 1997, 119, 698-708; V.M. Tgovi, I. Naspiua, M.S. Msipiosiy, Teigapedgop Gen. 1998, 39, 6445-6448) by coupling an arylpropiol ester such as A with trimethylsilylacetylene B in the presence of palladium acetate and tris(2,6-dimethoxyphenyl)phosphine. By reducing the ester to alcohol and processing

M-bromosuccinimide gave bromide 0. Reaction of O with a sarcosine ester (such as tert-butylsarcosine) in the presence of a base gave the intermediate derivative E of sarcosine. After cleavage of the trimethylsilyl group (for example, by treatment with potassium carbonate in methanol) and the subsequent introduction of a second aryl group by the Sonogashira IR coupling method. Zopodazpiga, U. Mopaa, M. Nadinaga, Teiigapeagop I! Hey. 1975, 4467| 7/0 Viaryl compound b was obtained, from which the final product H was obtained by removing the protecting group, for example, with formic acid.

This method is favorable for the parallel synthesis of a number of similar compounds in which the Ag group is the same, and the Ag group is represented by various aryls. The co-derivative E can be prepared in large quantities and then simply treated with the appropriate iodide aryls under Sonogashira synthesis conditions to afford the desired 7/5 products. n Me

AND! and Y g. | sa tn 2 shk 7 s o

And in | .

I and eh GT owls ve

Ag straight to Shi. at

Tk, E m.

Yes, that's it

A: with ; I "

Reagents: (i) palladium acetate, phosphine ligand; (II) (a) diisobutylaluminum hydride, (5) M-bromosuccinimide, Her" triphenylphosphine; (ii) tert-butylsarcosine, CoCO», KI; (m) CoCO", methanol; (M) Ag--I, SiI, RYAI(RRPNz)4, triethylamine; so (mi) formic acid, 502C

Scheme 1 -

Alternatively, such compounds can also be prepared by the method shown in Scheme 2 below.

This method complements the above in that it provides the possibility of parallel syntheses of similar compounds in which the Ag group. is the same, and the Ago group is represented by various aryls. In this case, the common "derivative Y can be prepared in significant quantities, and then simply treated with the corresponding arylpropiol esters O (which are easily prepared from the aryl iodide M by treatment with the ester of propiolic acid M in the presence of Si and RA(PP3)4) U under the above-mentioned conditions, obtaining after cleavage of the h protecting group the desired products N. are" ; tm5 and

АЖ ЖЕНЛМ5О ---- m pitnu p 1 ! K! "zhk ha -I (95) and in - Ari - BOYU ---- Af-zhE ozh i i o iz 50 3e)

F) name) 60 b5 h on so, mm Sh ry tt j Yes 1 h z a i R

X, 70: ayk and ra

FI shi shi m, - 5 A, t , i s n

Reagents: (i) Si, RYAA(PPAZ)4, triethylamine; (ii) KSO", methanol; (ii) palladium acetate, phosphine ligand, toluene; (im) diisobutylaluminum hydride, toluene, -782C; (M) M-bromosuccinimide, triphenylphosphine; (mi) tert-butylsarcosine,

KSO", KI, acetonitrile; (my) formic acid, 509

Scheme 2

To obtain compounds where Ag. is an aryl-substituted phenyl (Ag--phenyl), the method of synthesis shown in Fig

Scheme 3. Intermediate E can be prepared according to Scheme 1 and then coupled with bromoiodobenzene by the Sonogashira method to give compound 5. The aryl bromide of compound C can then be reacted with boric acid (Az-boric acid) under Suzuki coupling conditions with by obtaining the intermediate product C. su (C is the equivalent of OS according to Scheme 1, where Ag. is Agz-phenyl). Then from C" you can split off the protection group according to Scheme 1 and get H'. o teki ped

Mo som Mo sovy tn sodva

I i z tr ra ia lt ra F

N her Ag chI

E z o e - so 35. - and "cheques ron - with Y

AND,

I» " z n -I Reagents: (ii) 4-bromoiodobenzene, Si!, РЯ(РРАз)4, triethylamine, room temperature, overnight; (II)

Agz-boric acid, Pa(PPRI»3), 2M sodium carbonate, ethylene glycol dimethyl ether, 1109, h.; (her) me formic acid, 402С, during the night. Compounds that inhibit the transport of glycine mediated by C1IUT-1 increase the concentration of glycine in MMOA receptors, which are located, in particular, in the forebrain. This increase in concentration increases the activity of MMOA receptors, thereby alleviating the schizophrenic state and improving cognitive function. On the other hand, compounds that directly interact with the glycine receptor component of the MMOA receptor may produce the same or similar effect, respectively facilitating or hindering the availability of extracellular glycine caused by inhibition or enhancement of SIUT-1 activity. See, for example, Pitkänen et al.

Meipgossiepse, 46, 501-509 (19923); and Kretschmer and Schmidt (Kgeivespteg apa siti! 9. Meiygovsi., 16, 1561-1569 imo) (1996).

The compounds of the present invention can be administered, for example, orally, sublingually, rectally, or intranasally, vaginally, topically (including using patches or other means for transdermal administration), through the lungs using an aerosol, or parenterally, in including, intramuscular, subcutaneous, intraperitoneal, intraarterial, intravenous or intramembranous methods. Compounds can be administered intermittently or continuously using a pump. The compounds of the invention are administered alone or in combination with a pharmaceutically acceptable carrier or diluent in accordance with standard pharmaceutical procedures and regulations. In the case of oral administration, the compound according to the invention is used in the form of tablets, capsules, pastilles, chewing gum,

cakes, powders, syrups, elixirs, aqueous solutions and suspensions, etc. When preparing tablets, carriers are used, which include lactose, sodium citrate, and salts of phosphoric acid. As a rule, various disintegrants, such as starch, and lubricating agents, such as magnesium stearate and talc, are introduced into the composition of tablets. For oral use in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. Certain sweeteners and/or flavorings can be added if desired.

For parenteral use, sterile solutions of the compounds according to the invention are usually prepared, while the pH values of the solutions are appropriately set using buffers. For intravenous administration, the total concentration of dissolved substances should be controlled taking into account the achievement of isotonicity of the drugs. 7/0 Ointments or drops can be used for administration to the eyes using injection systems known in practice, for example, applicators or eye droppers. Such compositions may contain mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, ethylenediaminetetraacetic acid or benzylchromic chloride, and customary amounts of diluents and/or carriers. For pulmonary administration, diluents and/or carriers are selected appropriately to ensure the formation of aerosols.

Compositions based on the compounds of the invention in the form of suppositories are useful for vaginal, urethral and rectal administration. Such suppositories are usually made using a mixture of substances that is solid at room temperature but melts at body temperature. Substances commonly used for the preparation of such bases include cocoa butter, glycerinated gelatin, hydrogenated 2O vegetable oils, mixtures of polyethylene glycols of various molecular weights, and esters of polyethylene glycols with fatty acids. In more detail, dosed medicines in the form of suppositories are discussed in the monograph

Remington's "Pharmacy" Zsiepse, 16 Sho Ba. Musk Rybi., Eaviop, RA, 1980, 1530-1533). Gels or creams can also be used for vaginal, urethral, and rectal administration. with

Numerous possible options for dosage forms, including sustained-release forms, liposomal forms, and polymeric matrices, will be apparent to one skilled in the art. i9)

Examples of pharmaceutically acceptable salts of acids for use in the present invention are salts of mineral acids, for example, hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and salts of organic acids, for example, tartaric, acetic, citric, malic, lactic, He»! fumaric, benzoic, glycolic, gluconic, succinic, para-toluenesulfonic and arylsulfonic acids. Examples of pharmaceutically acceptable salts of bases for use in this invention are C salts of non-toxic metals, for example, sodium or potassium, ammonium salts, and salts of organic amines, for example, r-triethylamine. Numerous salts suitable for this purpose are known to those skilled in the art.

A therapist or other specialist in the field of medicine is able to choose the appropriate dose and treatment regimen, taking into account the body weight, age and physical condition of the patient. The dosage should generally be selected to provide a concentration of the compounds of the invention in blood plasma in the range of from about 0.01 µg/cm C to about 100 Ωg/cm, with concentrations of about 0.1 µg/cm Ω to about 10 Ωg being preferred. /smu.

For parenteral administration, an alternative preferred dose of the compound is from about 0.001mg/kg to about 1Omg/kg (alternatively from about 0.01mg/kg to about 1Omg/kg), with doses from about 0, 01 mg/kg to about mg/kg (from about 0.1 mg/kg to about mg/kg). For oral administration, an alternative preferred dose of the compound is from about 0.001 mg/kg to about 1 . .01 mg/kg to about mg/kg (from about 0.1 mg/kg to about 1 mg/kg) When administered in suppository form, an alternative preferred dose of the compound is in the range of about 0.1 mg/kg to about 1 mg/kg /kg, doses from about 0.1 mg/kg to about mg/kg are more preferred. o For use in glycine transport inhibitory activity tests, eukaryotic cells, preferably OT-6 cells isolated from partridge fibroblasts, were transfected to express one of -and three known varieties (human SIUT-1, namely: SIUT-Ta, SIUT-15 or SIUT-1c, or human SIUT-2. iz 50 The sequences in these SIUT-1 transporters are described in the work of Kim et al. (Kit ei ai., Moyes. RNagt. 45:608-617, 1994), with the exception that followed The sequence that encodes the external M-terminus of SIuUT-1 was postulated i3e) to be identical to the corresponding sequence determined for rats. This sequence, which codes for the M-terminus of the protein, has now been confirmed to be the one suggested by Kim et al. The sequence for human SIUT-2 is described by Albert et al. (Airey et al.) in US Patent Application Serial No. 08/700,013, dated August 20, 1996, which is incorporated herein by reference in its entirety. The relevant expression vectors include, along with

Gee! by others, rKks/SMM (firm Ipmiygodep), gar Ehrgezz Mesiog (firm 5igaiadepe Siotpd Zuzietv, I adoPa, SA, hereinafter "Bigaiadepe"), vectors rVK/SMM or rvk-K5M (Zigaiadepe), Visezsgiri PI ZK h-/- Rpadetiy Mesiogz (5igadepe), de Gaszm/ysp (Zigaidepe), RMAM and rMAM peo (Siopiesp firm). An expression vector suitable for this purpose is capable of facilitating the expression of the DNA included in C1IUT-1 in a suitable host cell, preferably in a non-mammalian host cell 60 , which may be eukaryotic, fungal or prokaryotic. Preferred host cells include amphibian, avian, fungal, insect and reptilian cells.

Example 1: 1-methoxycarbonyl-2-phenyl-4-trimethylsilyl-1-buten-4-yne (C)

To a solution of palladium acetate (28 mg, 0.125 mmol) in anhydrous toluene (bml) was added tris(2,6-dimethoxyphenyl)phosphine (55 mg, 0.125 mmol). After 15 minutes a solution of methyl phenyl propiolate 65 (1.00 g, 6.24 mmol) in anhydrous toluene (ml) was added. After another 5 minutes. trimethylsilylacetylene (0.88ml, 0.61g, 6.24mmol) was added. After 16 hours. the reaction mixture was concentrated. After column chromatography (eluent 1090 ethyl acetate in hexane), enyne C (1.39 g, 8695) was obtained as a yellow oil. "H NMR: (SOCI3, 300 MHz) 0.21 (85, 9H), 3.62 (8, 3H), 6.34 (v, 1H), 7.33-7 44 (t, 5H).

Example 2: 1-hydroxy-3-phenyl-5-trimethylsilyl-2-buten-4-yne

A solution of ester C (1.30g, 5.03mmol) in anhydrous toluene (20ml) was cooled in a bath with a mixture of dry ice and acetone. A 1.0M solution of diisobutylaluminum hydride in toluene (12.bml, 12.bmmol) was added.

After 5 minutes the cooling bath was removed. Another 15 minutes later. the reaction mixture was cooled again in an ice bath.

The reaction was stopped by adding celite and 10-aqueous sodium sulfate. The suspension was diluted with ethyl acetate and filtered through celite. The precipitate on the filter was washed three times with ethyl acetate. The filtrate was washed with water and 70% brine, dried over sodium sulfate, filtered and concentrated to give the intermediate alcohol (0.821g, 7195) as a yellow oil. "H NMR: (SOCI3, ZOOMHz) 0.20 (in, 9H), 1.40 (i, 1H), 4.31 (av, 2H), 6.37 (i, 1H), 7.33-7 ,37 (t, 5H).

Example 3: 1-bromo-3-phenyl-5-trimethylsilyl-2-buten-4-yne (0)

A solution of the above-mentioned alcohol (0.82 g, 3.5 mmol) in anhydrous methylene chloride (20 ml) was cooled to 75 °C in a bath with a mixture of dry ice and acetonitrile. Triphenylphosphine (1.40 g, 5.34 mmol) was added and

M-bromosuccinimide (0.95 g, 5.34 mmol). Through ЗОхв. the reaction was stopped by adding a saturated solution of sodium bicarbonate. The reaction mixture was distributed between a saturated solution of sodium bicarbonate and methylene chloride. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated, obtaining crude allyl bromide 0, which was used in the next stage without additional purification.

Example 4: M-(3-phenyl-5-(trimethylsilyl)-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (E)

Tert-butylsarcosine hydrochloride (0.71g, 3.900mmol), potassium carbonate (4.91g, 35.5mmol) and potassium iodide (2.95g, 17.8mmol) were added to a solution of the above bromide in anhydrous acetonitrile (1bml).

After 16 hours. the reaction mixture was filtered through celite. The precipitate on the filter was washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over with sodium sulfate, filtered and concentrated. After column chromatography (eluent 2595 ethyl acetate (5) in hexane), product E (0.74 g, two-stage yield 58965) was obtained as a light yellow oil. "N

NMR: (SOSIZ, ZOOMHC) 0.19 (v, 9H), 1.41 (v, 9H), 2.32 (v, ЗН), 3.10 (v, 2H), 3.31 (a, 2H ), 6.33 (i 1H), 7.26-7.38 (t, 5H).

Example 5: M-(3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P) (e)

Potassium carbonate (1.42 g, 10.0 mmol) was added to a solution of the above compound (0.74 g, 2.0 mmol) in methanol (1 mL). After 20 Okhv. the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. her

Acetylene derivative E (0.58g, 9996) was obtained as a slightly colored solid. "N NMR: (SOSIv, p

ZOOMHz) 1.41 (v, 9H), 2.33 (v, ЗН), 2.96 (v, 1H), 3.10 (v, 2H), 3.33 (a, 2H), 6.37 (i, 1H), 7.26-7.39 (t, 5H).

From Example 6-1: M-(5-(4-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl complex ester (5) i-

To a solution of acetylene derivative E (50mg, 0.175mmol) in triethylamine (2ml) was added 4-fluoroiodobenzene (2bml, 51mg, 0.228mmol), tetrakis(triphenylphosphine)-palladium (0) (20mg, 0.0175mmol) and copper iodide (I ) (1Omg, 0.0525mmol). After 1 week the reaction mixture was diluted with methylene chloride and filtered. The filtrate was concentrated. After column chromatography (eluent 25905 ethyl acetate in hexane), acetylene derivative C (51 mg, yield 7790) was obtained as a yellow oil. "IN NMR: (SOSIz, ZOOMHC) 1.42 (v, 9H), 2.35 (v, ZN), no) c 3.13 (v, 2H), 3.36 (9, 2H), 6, 37 (i, 1H), 7.00 (aa, 2H), 7.26-7 44 (t, 7H). z" In a similar way from the intermediate product E and the corresponding aryl iodides, taken in the amount of 1.3 equivalents, in the above the following compounds were obtained under the conditions: 6-2: M-(5-(2-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5) - 15 Obtained in a similar way from 2-fluoroiodobenzene, yield 45 mg (68965) in the form of a yellow oil. "H NMR: (SOCI3, ZOOMHC) 1.42 (in, 9H), 2.36 (in, ЗН), 3.14 (in , 2H), 3.39 (d, 2H), 6.43 (i, 1H), 7.06 (ad, 2H), 7.24-7 44 (t, 7H). (95) 6-3: M-(5-(2,4-difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) - Obtained by a similar method from 2,4-difluoroiodobenzene , yield 49 mg (7095) in the form of a yellow oil. (a, 2H), 642 (i tn), 6.83 (aa, 2H), t. 7.26-7 44 (t, 6H).

Ge) 6-4: M-(5-(3-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 3-nitroiodobenzene, yield 7Zmg (10295) in the form of a yellow oil. "H NMR: (SOCI3, ZOOMHC) 1.42 (v, 9H), 2.36 (v, ЗН), 3.13 (v, 2H), 3.38 (y, 2H), 645 (f 1), 7 ,26-7.40 (t, 5H), vv 748 (da, 1H), 7.72 (d, 1H), 8.13 (a, 1H), 8.27 (8, 1H). : M-(5-(4-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) o Obtained by a similar method from 4-nitroiodobenzene, yield 31mg (4495) in the form of a yellow oil. "H NMR: ime) (SOSIZ, ZOOMHC) 1.42 (8, 9Н), 2.36 (85, ЗН), 3.14 (в, 2Н), 3.38 (а, 2H), 6.47 (i, 1H), 7.34-743 (t, 5H), 7.57 (a, 2h), 8.17 (a, 2H). in 6-6: M-(3-phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 2-thiomethyliodobenzene, yield 19 mg (2695) in the form of a yellow oil. TN NMR: (SOCI3) 1.42 (in, 9H), 2.36 (in, ЗН), 2.46 (in, НН), 3.14 (in, 2Н), 3.39 (y, 2Н) , 6.45 (i tn), 7.06 (aa, mn), 7.14 (a, 1n), 7.24-7.40 (t, 6H), 7.46 (4, 1H). 6-7: M-(5-(4-chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (0) b5 Obtained by a similar method from 4-chloroiodobenzene, yield 52 mg (7595) in the form of a yellow oil. "H NMR: (SOCI3, ZOOMHC) 1.42 (in, 9H), 2.35 (8, ЗН), 3.13 (in, 2Н), 3.36 ( y, 2H), 6.38 (y, 1H), 7.26-7.39 (t, 9H).

6-8: M-(5-(4-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 4-isopropyliodobenzene, yield ZZmg (5395) in the form of a yellow oil. "N

NMR: (SOSIS, ZOOMHC) 1.23 (0, 6H), 1.42 (in, 9H), 2.36 (85, ЗН), 2.89 (heptet, 1Н), 3.13 (in, 2Н ), 3.36 (a, 2H), 6.36 (I, 1H), 7.16 (a, 2H), 7.26-7.42 (t, 7H). 6-9: M-(5-(3,5-bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (6)

Obtained in a similar way from 3,5-bis(trifluoromethyl)-iodobenzene, yield 40 mg (46905) in the form of a yellow oil. "H NMR: (SOSIZ, ZOOMHC) 1.42 (v, 9H), 2.36 (v, ZN), 3.14 (v, 2), 3.38 (8, 2H), 647 (B MN) , 70..7.26-7 44 (t, 5H), 7.77 (c, 1H), 7.86 (c, 2H). 6-10: M-(3,5-diphenyl-2-pentene -4-yn-1-yl)-sarcosine, tert-butyl ester (0)

Obtained in a similar way from iodobenzene, yield 4 mg (3395) in the form of a yellow oil. TN YAM: (SOSI),

ZOOMHz) 1.42 (8, 9H), 2.36 (v, ЗН), 3.13 (v, 2H), 3.36 (a, 2H), 6.38 (i, 1H), 7.26 -7.46 (t, 1OH). 6-11: M-(3-phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 4-thiomethyliodobenzene, yield 30.Omg (7095) in the form of a yellow oil. 6-12: M-(3-phenyl-5-(4-methylphenyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5)

Obtained by a similar method from 4-methyliodobenzene, yield 33.Omg (8595) in the form of a yellow oil. 6-13: M-(5-(3-thiophene)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from C3-iodothiophene, yielding ZO,Omg (7890) in the form of a brown oil. 6-14: M-(3-phenyl-5-(4-tert-butylphenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained by a similar method from 4-tert-butyliodobenzene, yield 38.Omg (86905) in the form of a yellow oil. 6-15: M-(5-(4-methoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5)

Obtained in a similar manner from 4-methoxyiodobenzene, yield 31.Omg (7395) in the form of a yellow oil. 6-16: M-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (C) c

Obtained by a similar method from 2-isopropyliodobenzene, yield 27.Omg (64905) in the form of an amber-colored oil. 6-17: M-(5-(4-biphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 4-biphenyliodobenzene, yield 2bOmg (8595) in the form of a yellow oil. 6-18: M-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) (e)

Obtained in a similar way from 4-trifluoromethyliodobenzene, yield 24Omg (80905) in the form of a yellow oil. "t 6-19: M-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5)

Obtained by a similar method from 4-benzyliodobenzene, yield 24Omg (8095) in the form of a light yellow oil. - 6-20: M-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) so

Obtained in a similar way from 4-ethyliodobenzene, yield of product 24Omg (8896). "H-NMR: (SOCI3, 30 MHz) 32 1.22 (5 З3Н), 1.43 (в, 9Н), 2.36 (в, ЗН), 2.63 (d, 2Н), 313 (в, 2H), 3.36 (a, 2H), 6.37 (5 1), 7.13 (a, - 2H), 7.26-7.43 (t, 7H). 6-21: M-( 5-(4-p-propylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (0)

Obtained in a similar way from 4-p-propyliodobenzene, product yield 24Omg (8595). "N-NMR: (SOSIv, "

ZOOMHz) 0.93 (Her, ZN), 1.3 (v, 9H), 1.57 (sextet, 2H), 2.36 (v, ZN), 2.57 (y 2H), 3.14 ( c, 2H), 3.37 (a, C t0 2H), 6.37 (i, 1H), 7.12 (9, 2H), 7.24-7 43 (t, 7H). c 6-22: M-(5-(4-p-butylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) c» Obtained by a similar method from 4-p-butyliodobenzene, yield 26bOmg (89905) as a yellow oil. 6-23: M-(5-(4-p-pentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 4-p-pentyliodobenzene, yield 24Omg (7995) in the form of a yellow oil. 6-24: M-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) and Obtained by a similar method from 4-phenoxyiodobenzene , yield 34.7 mg (5695) in the form of a yellow film. oz 6-25: M-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (0) - Obtained by a similar method from 1-iodonaphthalene , product yield 35.8 mg (63.595). "H-NMR: (SOCI3, 30 MHz) 1.43 (8, 9H), 2.40 (85, ЗН), 3.17 (в, 2Н), 3.42 (0, 2H), 6.53 (f 1), 7.33-7.57 (t, 8H), 7.67 (a, MH), t. 50 7.75-7.85 (t, 2H ), 8.30 (a, 1Hn). p 6-26: M-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5)

Obtained by a similar method from 4-methyliodobenzene, yield 34.7 mg (88905) in the form of a light yellow oil. 6-27: M-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (C)

Obtained in a similar way from 3-isopropyliodobenzene, product yield 17.bmg (42965). "N-NMR: (SOSIs),

ZOOMHz) 1.23 (y, 6H), 1.42 (v, 9H), 2.36 (v, 3H), 2.87 (septet, 71H), 3.13 (v, 2H), 3.36 (a, 2H), 6.38 (i, (F. 1H), 7.15-7.42 (t, 8H), 7.70-7.71 (t, 1H).

GI 6-28: M-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (0)

Obtained in a similar way from 2-iodonaphthalene, yield 30.Omg (69905) in the form of a colorless oil. in 6-29: M-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (0)

Obtained in a similar way from 3,4-dimethyliodobenzene, yield. 40.Omg (9895) in the form of a yellow film. 6-30: M-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (C)

Obtained in a similar manner from 2-isopropyliodobenzene, yield 27.Omg (64905) as an amber oil. 65 6-31: M-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5)

Obtained by a similar method from 3,4-methylenedioxy-iodobenzene, yield 40.Omg (9495) in the form of a yellow oil. 6-32: M-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5)

Obtained in a similar manner from 4-pyrrolyliodobenzene, yield 41.Omg (9295) in the form of a light yellow oil. 6-33: M-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 4-trifluoromethoxy-iodobenzene, product yield 28.5 mg (6196). "H-NMR: (SOCI3, ZOOMHC) 1.2 (8, 9H), 2.35 (b, ЗН), 3.13 (b, 2H), 3.36 (a, 2), 6.39 ( 5 1), 7.15 (49, 2H), 7.26-7.39 (4, 2H), 7.46 (a, 2H). 6-34: M-(5-(3,4-dimethoxyphenyl) )-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) 70 Obtained by a similar method from 3,4-dimethoxyiodobenzene, yield 35.00 mg (8095) in the form of a colorless oils

In a similar way, from the intermediate product E and the corresponding aryl iodides taken in the amount of 1.3 equivalents, the following compounds were obtained under the above conditions: 6-35: M-(5-(2-quinoline)-3-phenyl-2-pentene- 4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from 2-iodohinoline. 6-36: M-(5-(indanyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from iodindan.

Example 7-1: M-(5-(4-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

A solution of tert-butyl ester 6-1 (51 mg, 0.135 mmol) in 9695 formic acid was heated at 409C for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved in methylene chloride and passed through an extraction tube with 2 g of the solid phase, eluting sequentially first with methylene chloride, then with ethyl acetate, and finally with methanol. The methanol fraction was concentrated and amino acid 7-1 (ZOmg, 90965) was obtained in the form of a colorless foam. "H NMR: (SOSIZ, ZOOMHC) 2.72 (v, ZN), 3.49 (v, 2H), 3.92 (y, 2H), 6.38 (y, 1H), 6.98 (aa , 2H), 7.26-7.42 (t, 7H). Mass spectrum of high resolution SEM (MOSVR): calculated 324.1400, obtained 324.1386. o

In a similar way, the following compounds were obtained from the corresponding intermediates under the above conditions: 7-2: M-(5-(2-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H )

Obtained in a similar manner from intermediate 6-2, yield Zimg (8195) as a colorless foam. "N Me)

NMR: (SOS3, ZOOMHz) 2.68 (v, ЗН), 3.47 (v, 2Н), 3.90 (v, 2Н), 6.43 (v, 1Н), 7.05 (aa, 2Н ), 7.23-7.42 (t, « 7Н). MSVR calculated 324.1400, received 324.1408. 7-3: M-(5-(2,4-difluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H) -

Obtained in a similar manner from intermediate 6-3, Zamg (8295) yielded as a colorless foam. "N co

NMR: (SOS3, ZOOMHC) 2.70 (in, ZN), 3.48 (in, 2H), 3.91 (in, 2H), 6.42 (in, 1H), 6.78 (aa, 2H ), 7.26-7.38 (t, vH). MSVR calculated 342.1306, received 342.1333. - 7-4: M-(5-(Z-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-4, yield 42 mg (6895) as a colorless foam. "N

NMR: (SOSI, ZOOMHz) 2.72 (8, ЗН), 3.50 (в, 2Н), 3.94 (0, 2Н), 6.50 (и, 1Н), 7.26-7.48 (t, 6H), 7.70 (a, « 1H), 8.12 (j, 1H), 8.22 (c, 18). MSVR calculated 351.1345, received 351.1353. 7 70 7-5: M-(5-(4-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H) c Obtained by a similar method from intermediate 6-5, yield 21 mg (8095) in the form of colorless foam. "H:z" NMR: (SOSIZ, ZOOMHC) 2.66 (85, ЗН), 3.43 (v, 2Н), 3.85 (40, 2Н), 6.51 (85, 71Н), 7, 26-7.53 (t, 5H), 7.54 (a, 2H), 8.14 (a, 2Hn). 15 7-6: M-(3-phenyl-5-(2-thiomethylphenyl)-2 -penten-4-yn-1-yl)y-sarcosine (H)-I Obtained by a similar method from intermediate 6-6, yield 14 mg (8795) in the form of a colorless foam. "H

NMR: (SOSI», ZOOMHC) 2.42 (v, ZN), 2.66 (v, ZN), 3.48 (v, 2H), 3.88 (8, 2H), 6.40 (v, 1H), 7.12-7.68 (t, 9H). and 7-7: М-А(5-(4-chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)-I Obtained in a similar way from the intermediate product 6-7, output 4Omg (9095) in the form of colorless foam. "H iz 50 NMR: (SOSIz, ZOOMHz) 2.68 (8, ЗН), 3.48 (в, 2Н), 3.87 (в, 2Н), 6.39 (в, 1Н), 7.24 -7.37 (t, 9H). MOVR calculated 340.1104, obtained 340.1097.

Ge) 7-8: M-(5-(4-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar way from intermediate 6-8, yield 32 mg (9996) in the form of a colorless foam. "N

NMR: (SOCI3, ZOOMHz) 1.21 (a, 6H), 2.65 (5, 3H), 2.86 (heptet, 1H), 3.43 (b, 2H), 3.86 (a, 2H ), 6.36 (i, 1H), 7.14 (a, 2H), 7.26-7.36 (t, 7H), MSVR calculated 348.1964, obtained 348.1998. o 7-9: M-(5-(3,5-bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-9, yield 26 mg (7695) as a colorless foam. "H name) NMR: (SOSI, ZOOMHC) 2.67 (8, ЗН), 3.46 (в, 2Н), 3.87 (y, 2), 6.52 (B 1), 7.26- 7.40 (t, 5H), 7.77 (v, 1H), 7.83 (5, 2H). MSVR calculated 442.1242, obtained 442.1173. because 7-10: M-(3,5- diphenyl-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 6-10, yield 18 mg (4695) as a colorless foam. "N

NMR: (SOSIZ, ZOOMHz) 2.69 (v, ZN), 3.48 (v, 2H), 3.89 (y, 2), 6.40 (B 1H), 7.26-7.44 ( t, 10H). MOSVR calculated 306.1494, received 306.1432. 7-11: M-(5-(4-biphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H) was obtained in a similar way from intermediate 6-17, yield 220, Omega (9790) is a yellow solid.

7-12: M-(5-(4-trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-18, yield 200.Omg (9695) in the form of a yellow film. 7-18: M-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-19, yield 190.Omg (8790) as a light yellow solid. 7-14: M-(5-(4-ethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-20, yield 176.1 mg (87905) as a 7/0 gray-green solid. 7-15: M-(5-(4-p-propylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-21, yield 190.Omg (93905) as an orange-white solid. 7-16: M-(5-(4-p-butylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-22, yield 206.Omg (9190) as a yellow solid. 7-17: M-(5-(4-p-pentylphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 6-23, yield 204 4 mg (9890) as a yellow solid. 7-18: M-(5-(4-phenoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 6-24, yield 33.Omg (100905) as a light yellow solid. 7-19: M-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-25, yield 25.4 mg (8295) as a yellow oil. p 7-20: M-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar way from intermediate 6-26, yield 12.bmg (5595) in the form of a yellow solid i) color. 7-21: M-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-27, yield 12.bmg (8395) in the form of a thick brown oil. 7-22: M-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H) -

Obtained in a similar manner from intermediate 6-28, yield 25.1 mg (97905) as a pale yellow solid. 7-23: M-(5-(3,4-dimethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (H) me)

Obtained in a similar manner from intermediate 6-29, yield 33.2 mg (97905) as light yellow solid M. 7-24: M-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-30, yield 15.2 mg (6695) as a yellow flaky solid. « 7-25: M-(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H) with c Obtained by a similar method from intermediate product 6-31 , output 9.5 mg (31905) in the form of a slightly colored . solid matter. and?" 7-26: M-(5-(4-pyrrolylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-32, yield 24.1 mg (6895) as a solid

Yellow color. -I 7-27: M-(5-(4-fluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 6-33, yield 23.Omg (92905) as a yellow solid. -I 7-28: M-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 6-34, yield 25.7 mg (86905) as a yellow solid.

Ge) In a similar way, the following compounds were obtained from the corresponding intermediate products under the above conditions: 7-29: M-(5-(2-quinoline)-3-phenyl-2-penten-4-yn-1-yl-sarcosine

Obtained in a similar way from intermediate 6-35. 7-30: M-(5-(indanyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine

F) Obtained in a similar way from intermediate product 6-36. Example 8-1: H-(3-phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

A solution of tert-butyl ester 6-11 C(mi) (30.00 mg, 0.073 mmol) in 96-95% formic acid was heated at 5092 during The reaction mixture was cooled and concentrated. The residue was dissolved in methylene chloride and passed through an extraction tube with 2 g of the solid phase, eluting sequentially first with methylene chloride, then with ethyl acetate, and finally with methanol. The methanol fraction was concentrated and amino acid 8-1 (14.9 mg, 5890) was obtained as a light yellow solid.

In a similar way, the following compounds bb5 were obtained from the corresponding intermediates under the above conditions: 8-2: M-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (N)

Obtained in a similar manner from intermediate 6-12, yield ZO,Omg (9195) as a light yellow solid. 8-3: M-(3-phenyl-5-(3-thiophene)-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 6-13, yield 22.0 mg (8795) as a solid brown foam. 8-4: M-(3-phenyl-5-(4-tert-butylphenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 6-14, yield 22.9 mg (6695) as a light yellow solid. 70 Example 9: M-(5-(4-bromophenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

To a solution of acetylene derivative E (3.25 g, 11.4 mmol) in triethylamine (/5 ml) was added 4-bromoiodobenzene (4.19 g, 14 mmol), tetrakis(triphenyl-phosphine)-palladium (1.32 g, 1.14 mmol ) and copper iodide (I) (0.65 g, 3.42 mmol).

The mixture was stirred overnight and concentrated. After column chromatography (eluent 10905 ethyl acetate in hexane), bromide 5 (3.84 g, 7695) was obtained as a yellow oil.

Example 10-1: M-(5-(4--3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5)

3-furanboric acid (1.47g, 13.1mmol), tetrakis(triphenylphosphine)-palladium (1.01g, O0.872mmol) were added to a solution of bromide C (3.84g, 8.72mmol) in ethylene glycol dimethyl ether (25ml) and 2M sodium carbonate solution (25ml). The mixture was heated under reflux for 1 h, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. After column chromatography (eluent 10-12.596 ethyl acetate in hexane), ester C (2.62 g, 7895) was obtained as a yellow oil.

In a similar way, the following compounds were obtained from the appropriate intermediate product under the above conditions: c 10-2:. M-(5-(4-(3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (0)

Obtained by a similar method from 3-thiophenboric acid, yield 21.Omg (4695) in the form of a colorless film. and)

In a similar way, the following compounds were obtained from the corresponding boric acid derivatives under the above conditions: 10-3: M-(5-(4--4-metal-3-thiophene)phenyl)-3-phenyl-2-pentene-4- in-1-yl)-sarcosine, tert-butyl complex ether Ge! zo Obtained in a similar way from 3 and 4-methyl-3-thiophenboric acid. 10-4: M-(5-(4--4-methyl-3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester -

Obtained in a similar way from C and 4-methyl-3-furanboric acid. M 10-5: M-(5-(4-(cyclohexyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester

Obtained in a similar way from C and cyclohexylboric acid. me) 10-6: M-(5-(4-(cyclopentyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester

Obtained in a similar way from 5 and cyclopentylboronic acid.

Example 11-1: M-(5-(4-(3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (NO)

Ester c" (2.62 g, 6.13 mmol) was dissolved in 9695 formic acid (2 bml). The solution was heated at 409C overnight, and then concentrated. After column chromatography (eluent 0-895 methanol in "methylene chloride) a pale yellow solid product was obtained. After trituration with methanol - c, pure H' (0.78 g, 3490) was obtained as a white solid. Compound 11-11 was converted into the corresponding sodium salt by suspending 11-1 in methanol and adding 1 EM equivalent of sodium hydroxide solution."» Then the solution was concentrated and the residue was triturated with isopropanol, obtaining a solid white substance.

In a similar way, the following compounds were obtained from the appropriate intermediate product under the above conditions: -I 11-21. 4-(5-(4-(3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (NO)

Obtained in a similar manner from intermediate 10-2, yield 11.7 mg (59965) in the form of slightly

Mn of colored solid. - And 11-81. 4-(5-(4-(4-methyl-3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)y-sarcosine

Obtained in a similar way from intermediate 10-3. in 11-41. M-(5-(4--4-methyl-3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine (Che) Obtained by a similar method from intermediate product 10-4 . 11-65: M-(5-(4-(cyclohexyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Obtained in a similar manner from intermediate 10-5. 11-6:. M-(5-(4-(cyclopentyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)-sarcosine

Obtained in a similar way from intermediate 10-6. o Example 12-1: Ethyl 4-(trifluoromethyl)phenylpropiolate (A) co To a solution of 4-iodobenzotrifluoride (256 mg, 0.941 mmol) in triethylamine (2.5 mL) was added ethyl propiolate (0.124 mL, 12 Ω, 1.22 mmol), tetrakis -(triphenylphosphine)palladium (109 mg, 0.0941 mmol) and copper (I) iodide (54 mg, 0.282 mmol). After 24 hours the reaction mixture was concentrated. After column chromatography (eluent 1090 ethyl acetate in hexane), compound 12-1 (149 mg, 6595) was obtained as a colorless oil.

The following compounds were obtained by a similar method from the corresponding aryl iodides and 1.3 equivalents of ethyl propiolate under the above conditions: 12-2: Ethyl 4-fluorophenylpropiolate (A) 65 Obtained by a similar method from 4-fluoroiodobenzene, the yield of ZZmg (495) in the form of a colorless solid substances

12-3: Ethyl 2-fluorophenyl propiolate (A)

Obtained in a similar way from 2-fluoroiodobenzene, yield 3.46 bg (93905) in the form of a colorless oil. 12-4: Ethyl-4-chlorophenylpropiolate (A)

Obtained in a similar way from 4-chloroiodobenzene, yield 4.60 g (10090) in the form of a colorless solid. 12-5: Ethyl 2-chlorophenyl propiolate (A)

Obtained in a similar way from 2-chloroiodobenzene, yield 7.64 g (10095) in the form of a yellow liquid. 12-6: Ethyl 3-thienyl propiolate (A) 76 Obtained in a similar manner from 3-thienyl iodobenzene, yield ZOmg (5395) as a yellow solid. 12-7: Ethyl 4-methoxyphenyl propiolate (A)

Obtained by a similar method from 4-methoxyiodobenzene, yield 117 mg (13905) in the form of a colorless oil.

Example 13-1: 1-ethoxycarbonyl-2-(4-trifluoromethyl)phenyl)-4-trimethyl-silyl-1-buten-4-yne (C)

To a solution of palladium acetate (2.bmg, 0.0115mmol) in toluene (2ml) was added tris(2,6-dimethoxyphenyl)phosphine (5.1mg, 0.0115mmol). After 15 minutes a solution of compound 12-1 (117mg, 0.573mmol) in toluene (3ml) was added. Through the former (trimethylsilyl)acetylene (0.08µl, 5mg, 0.573mmol) was added. After 21 h, the reaction mixture was concentrated. After column chromatography (eluent 1095 ethyl acetate in hexane), compound 13-1 (144 mg, 8395) was obtained as a yellow oil.

In a similar way, the following compounds were obtained from the corresponding propiolate intermediates under the above conditions: 13-2: 1-ethoxycarbonyl-2-(4-fluorophenyl)-4-trimethylsilyl-1-buten-4-yne (C)

Obtained in a similar manner from intermediate 12-2, yield 29 mg (58905) as a yellow oil. 13-3: 1-ethoxycarbonyl-2-(2-fluorophenyl)-4-trimethylsilyl-1-buten-4-yne (C) ch

Obtained in a similar manner from intermediate 12-3, yield 4.19 g (8095) as a yellow oil. 13-4: 1-ethoxycarbonyl-2-(4-chlorophenyl)-4-trimethylsilyl-1-buten-4-yne (C) and)

Obtained in a similar manner from intermediate 12-4, yield 4.04 g (6095) as a brown oil. 13-5: 1-ethoxycarbonyl-2-(2-chlorophenyl)-4-trimethylsilyl-1-buten-4-yne (C)

Obtained in a similar manner from intermediate 12-5, yield 10.4 g (9395) as a brown oil. b zo 13-6: 1-ethoxycarbonyl-2-(3-fluorophenyl)-4-trimethylsilyl-1-buten-4-yne (C)

Obtained in a similar way from the commercially available intermediate ethyl-3-fluorophenylpropiolate, yield 0.7g (8595) in the form of a yellow oil. h- 13-7: 1-ethoxycarbonyl-2-(3-thienyl)-4-trimethylsilyl-1-buten-4-yne (C)

Obtained in a similar manner from intermediate 12-6, yield 12Zmg (9095) as a yellow oil. o 13-8: 1-ethoxycarbonyl-2-(4-methoxyphenyl)-4-trimethylsilyl-1-buten-4-yne (C) i-

Obtained in a similar manner from intermediate 12-7, yield 144 mg (8395) as a yellow oil.

Example 14-1: 1-hydroxy-3-(4-fluoromethyl)phenyl-5-trimethylsilyl-2-penten-4-yne

A solution of compound 13-1 (144mg, 0.47bmmol) in anhydrous toluene (2ml) was cooled in a bath with a mixture of dry ice and acetone. A 1.0 M solution of diisobutylaluminum hydride in toluene (1.2 ml, 119 mmol) was added drop by drop. After 5 minutes the cooling bath was removed. Another 15 minutes later. the reaction mixture was cooled again in an ice bath and celite and Ma»5O,-10H2O were added to stop the reaction. The reaction mixture was filtered through celite. The filtrate was concentrated. After column chromatography (eluent 2095 ethyl acetate in hexane), compound 14-1 (114 mg, 9290) was obtained as a yellow oil.

In a similar way, the compounds listed below were obtained from the corresponding intermediate products - complex esters under the above conditions: - and 14-2:. 1-hydroxy-3-(4-fluorophenyl)-5-trimethylsilyl-2-penten-4-yne

Obtained in a similar manner from intermediate 13-2, yield 19 mg (80905) as a colorless oil. at 14-3:. 1-Hydroxy-3-(2-fluorophenyl)-5-trimethylsilyl-2-penten-4-yne -I Obtained by a similar method from intermediate 13-3, yield 2.65 g (7495) in the form of a yellow oil. 14-4:. 1-Hydroxy-3-(4-chlorophenyl)-5-trimethylsilyl-2-penten-4-ynth Obtained by a similar method from intermediate 13-4, yield 2.16 g (6295) in the form of a yellow oil.

Ge) 14-5:. 1-hydroxy-3-(2-chlorophenyl)-5-trimethylsilyl-2-penten-4-yne

Obtained in a similar manner from intermediate 13-5, yield 4.86 g (5495) as a yellow oil. 14-6:. 1-hydroxy-3-(3-fluorophenyl)-5-trimethylsilyl-2-penten-4-yne

Obtained in a similar manner from intermediate 13-6, yield 0.47 g (7495) as a light yellow oil. iF) 14-7: 1-hydroxy-3-(3-thienyl)-5-trimethylsilyl-2-penten-4-ynco Obtained by a similar method from intermediate 13-7, yield 5 mg (7790) in the form of a yellow oil. 14-8:. 1-Hydroxy-3-(4-methoxyphenyl)-5-trimethylsilyl-2-penten-4-yne Obtained in a similar manner from intermediate 13-8, yield 114 mg (9295) as a yellow oil.

Example 15-1: M-(3-(4--trifluoromethyl)phenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (E)

A solution of compound 14-1 (115 mg, O0.385 mmol) in anhydrous methylene chloride (4 ml) was cooled in a bath with a mixture of dry ice and acetonitrile. Triphenylphosphine (152mg, 0.578mmol) and M-bromosuccinimide 65 (1oZmg, 0.57vmmol) were added. After 40 minutes saturated sodium bicarbonate solution was added. The reaction mixture was distributed between a saturated solution of sodium bicarbonate and methylene chloride. The organic phase was washed with brine,

dried over sodium sulfate, filtered and concentrated. The obtained crude intermediate Y (1-bromo-3-(4-trifluoromethyl)phenyl)-5-(trimethylsilyl)-2-penten-4-yne) was used in the next stage without additional purification.

Tert-butylsarcosine hydrochloride (77mg, 0.424mmol), potassium carbonate (532mg, 3.85mmol) and potassium iodide (32Omg, 1.92mmol) were added to a solution of crude bromide 0 (139mg, 0.385mmol) in anhydrous acetonitrile (4ml). After 24 hours the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. After column chromatography (eluent 1595 ethyl acetate in hexane), compound 16-1 was obtained (b2 mg, yield in two 7/o stages 3890) in the form of a colorless oil.

In a similar way, the following compounds were obtained from the corresponding ester intermediates under the above conditions: 15-2: M-(3-(4-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1- yl)-sarcosine, tert-butyl ester (E)

Obtained in a similar manner from intermediate 14-2, yield 18 mg (6395 over two stages) in the form of /5 colorless oil. 15-3:. M-(3-(2-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (E)

Obtained in a similar manner from intermediate 14-3, yield 3.24 g (8195 over two stages) as a yellow oil. 15-4:. M-(3-(4-chlorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (E)

Obtained in a similar manner from intermediate 14-4, yield 1.55 g (4995) in the form of a yellow oil. 15-5:. M-(3-(2-chlorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (E)

Obtained in a similar manner from intermediate 14-5, yield 5.39g (7595) as a light yellow oil. 15-6:. M-(3-(3-fluorophenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (E)

Obtained in a similar way from intermediate 14-6, yield 0.6Zg (8995) in the form of a yellow oil. 15-7: M-(3-(3-thienyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (E) and)

Obtained in a similar manner from intermediate 14-7, yield b1mg (71905) as a yellow oil. 15-8: M-(3-(4-methoxyphenyl)-5-(trimethylsilyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (E)

Obtained in a similar manner from intermediate 14-8, yield 14 mg (10905) as a yellow oil. b zo Example 16-1: M-(3-(4--trifluoromethyl)phenyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (P)

To a solution of compound 15-1 (62 mg, 0.14 mmol) in methanol (2 ml) was added potassium carbonate (101 mg, 0.73 mmol). -

After 15 minutes the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with M brine, dried over magnesium sulfate, filtered and concentrated. Compound 16-1 (Zbmg, 7190) was obtained as a yellow oil. at

In a similar way, the following compounds were obtained from the corresponding intermediate products - trimethylsilyl derivatives under the above conditions: 16-2: M-(3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P)

Obtained in a similar manner from intermediate 15-2, yield 1 Zmg (93905) as a yellow oil. 16-3: M-(3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P) «

Obtained in a similar manner from intermediate 15-3, yield 2.22 g (85905) as a colorless oil. shsh c 16-4:M--(3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P) . Obtained in a similar manner from intermediate 15-4, yield 0.80 g (7695) in the form of a yellow oil. and?" 16-5:M-(3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P)

Obtained in a similar way from intermediate product 15-5, yield 3.72 g (8595) in the form of a yellow oil. 16-6: M-(3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P)-I Obtained in a similar way from intermediate 15-6, yield 0.42g (8390) as a light yellow solid. about 16-7: M-(3-(3-thienyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (E)-I Obtained in a similar way from intermediate 15-7, yield 4bmg (96905) as a solid

Yellow color. ve 16-8: M-(3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (P)

Ge) Obtained in a similar manner from intermediate 15-8, yield 15 mg (13695) as a yellow oil.

Example 17-1: IM-(5-(4-isopropylphenyl)-3-(4-(trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

To a solution of compound 16-1 (Zb5mg, 0.099mmol) in triethylamine (2ml) was added 4-iodoisopropylbenzene (Z32mgH, 0.129mmol), tetrakis-(triphenylphosphine)-palladium (11mg, 0.0099mmol) and copper iodide (I) (5 .5 mg, 0.029 mmol).

F) After 18 hours. the reaction mixture was concentrated. After column chromatography (eluent 1095 ethyl acetate in hexane) compound 17-1 (40mg, 86905) was obtained as a colorless oil.

The following compounds were obtained by a similar method using 1.3 equivalents of the corresponding aryl iodide and the corresponding intermediate boron product - alkyne under the above conditions: 17-2: M-(5-(4-isopropylphenyl)-3-(4-fluorophenyl)-2 -penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar manner from intermediate 16-2 and 4-isopropyliodobenzene, yield 14 mg (7695) as a colorless oil. 17-3: M-(5-(4-isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5) 65 Obtained by a similar method from intermediate 16-3 and 4-isopropyliodobenzene, yield 44Omg (79905) as a yellow oil.

17-4:. M-(5-(4-tert-butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester

Obtained in a similar way from intermediate 16-3 and 4-tert-butyliodobenzene, yield 50mg (87905). IN

Appearance of yellow oil. 17-5: M-(5-(4-isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (6)

Obtained in a similar way from the intermediate product 16-4 and 4-isopropyliodobenzene, yield O.50g (8895). in the form of light yellow oil. 17-6:. M-(5-(4-tert-butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester 70 (8)

Obtained in a similar manner from intermediate 16-4 and 4-tert-butyliodobenzene, yield 514 mg (8395) as a light yellow oil. 17-7: M-(5-(4-isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (6)

Obtained in a similar manner from intermediate 16-5 and 4-isopropyliodobenzene, yield 0.53g (9795) in /5 Appearance of a yellow oil. 17-8:.. M-(5-(4-tert-butylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)y-sarcosine, tert-butyl ester (5 )

Obtained in a similar way from the intermediate product 16-5 and 4-tert-butyliodobenzene, yield 0.52 g (92905) in the form of a yellow oil. 17-9: M-(5-(4-isopropylphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from the intermediate product 16-6 and 4-isopropyliodobenzene, yield 0.16 g (10390) in the form of a yellow oil. 17-10: M-(5-(4-isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from the intermediate product 16-7 and 4-isopropyliodobenzene, yield 54 mg (8695) in c g Appearance of a yellow oil. 17-11: M-(5-(4-isopropylphenyl)-3-"4-methoxyphenyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (C)

Obtained in a similar manner from intermediate 16-8 and 4-isopropyliodobenzene, yield 21 mg (12995) as a yellow oil. b zo 17-12: IM-(5-(3,4-methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5) -

Obtained in a similar manner from intermediate 16-6 and 3,4-methylenedioxyiodobenzene, yield 74.1 mg M (10695) as a brown oil. 17-18: Mch-(5-(4-ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl-sarcosine, tert-butyl ester (5) me)

Obtained in a similar way from the intermediate product 16-5 and 4-ethyliodobenzene, yield 44.00 mg (11095). in M form of light yellow oil. 17-14: M-(5-(4-propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine, tert-butyl ester (5)

Obtained in a similar way from the intermediate product 16-5 and 4-propyliodobenzene, yield 39.5 mg (96905). in the form of light yellow oil. "

Example 18-1: M-(5-(4-isopropylphenyl)-3-(4--trifluoromethyl)phenyl)-2-penten-4-yn-1-yl)-sarcosine (H) with c Solution of compound 17- 1 (40 mg, 0.0849 mmol) in formic acid (2 ml) was heated at 402 for 18 hours. and The reaction mixture was concentrated. After column chromatography (0-10095 methanol in methylene chloride), compound 18-1 (Zbmg, 9990) was obtained as a yellow oil.

In a similar way, the following compounds were obtained from the corresponding intermediate products - tert-butyl esters under the above conditions: - and 18-2:. M-(5-(4-isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained by a similar method from intermediate 17-2, yield 1 Zmg (10795) in the form of a colorless oil. - And 18-3:. M-(5-(4-isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained by a similar method from intermediate 17-3, yield 37Omg (99965) in the form of a light yellow oil.

Ge) 18-4:. M-(5-(4-tert-butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-4, yield 434 mg (100965) as a yellow oil. 18-5:. M-(5-(4-isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-5, yield 43bmg (96905) as a beige solid. iF) 18-6:. M-(5-(4-tert-butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H) co Obtained by a similar method from intermediate 17-6, yield 408mg (88905) as a beige solid. at 18-7:. M-(5-(4-isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-7, yield 438 mg (9595) as a slightly colored foam. 18-8:. M-(5-(4-tert-butylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-8, yield 448 mg (97965) as a colorless foam. 65 18-9:. M-(5-(4-isopropylphenyl)-3-(33-fluorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-9, yield 0.12 g (93905) as a colorless oil.

18-10: M-(5-(4-isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 17-10, yield 34 mg (7290) as a yellow solid. 18-11: M-(5-(4-isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-11, yield 14 mg (7695) as a colorless oil. 18-12: H-(5-(3,4-methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 17-12, yield 64.1 mg (88905) as 7/o0 orange-brown oil. 18-13: M-(5-(4-ethylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)-sarcosine (H)

Obtained in a similar manner from intermediate 17-13, yield ZO, mg (7995) as a colorless oil. 18-14. M-(5-(4-propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)y-sarcosine (H)

Obtained in a similar manner from intermediate 17-14, yield 13.9 mg (40905) as a light yellow oil.

Example 19: Test of transport through SIUT-1

This example illustrates a method for measuring glycine uptake by a culture of transfected cells.

Cells stably transfected with SIUT-1 c (see Kim et al. - Kit et al., Myelasiag RNpagtasiodo, 45, 1994, 608-617) were washed twice with a saline solution supplemented with 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid ( HERE5) as a buffer (HB). Then the cells were incubated at 372C for 10 minutes, after which 5O0nNM | ZNI-glycine (17.5Ci/mmol) and a reagent according to one of three options: (a) no potential competitor, (b) 10 mM non-radioactive glycine, or (c) a certain concentration of the suspected drug. In order to obtain data for calculating the concentration that gives the 5096th effect of si (ie, ISvo, or the concentration of the drug that inhibits the absorption of glycine by 5095), a certain range of concentrations of the putative drugs was used. Then the cells were incubated for another 10 minutes. at 372C, after which the culture was separated by suction and washed three times with HB5, cooled with ice. The cells were separated, a scintillator was added to them, and they were shaken for 30 minutes. and measured the radioactivity of the cells using a scintillation counter. The data were compared for the same cells that were and were not in contact with the suspected drug, depending on the conditions of the tests. "

Compounds of the present invention have been found to act as SIUT-1 inhibitors.

Example 20: MMOA receptor binding test -

This example illustrates a binding test to measure the interaction of the compounds of the invention with the glycine paratope of the MMOA receptor. 3 Direct binding | ZNI-glycine with the glycine paratope of the MMOA receptor was performed according to the method of Grimwood and others (Sgitmood ei ai., Moiesciag Rnagtasoiodo, 41, 923-930 (1992)) and Yoneda and others (Uopeda ei! ai.,..

Meshygospet., 62, 102-112 (1994).

Binding tests were performed in Eppendorf tubes containing 150 μg of membrane protein and

BONM (|ZNI-glycine in a volume of 0.5 ml. Non-specific binding was determined using 1 mM glycine. Medicinal compounds were dissolved in a buffer solution (X0 mM Tris-acetate, pH 7) or in dimethyl sulfoxide (final concentration of 0.195). Membranes were incubated on ice for 30 minutes, and bound radiolabeled ligand was separated from free radiolabeled ligand by filtration through a glass fiber filter MUpaytap SRG/V or centrifugation (18,000x, 20 min). Filters or centrifuged sediment were quickly washed three times with chilled ice with 5MM Tris-acetate buffer. Filters were dried, placed in scintillation tubes, and scintillation counted. The precipitates were dissolved in sodium hydroxide deoxycholate (0.1M) overnight, - neutralized, and radioactivity was measured by scintillation counting. o Second binding test for glycine paratope MMOA was performed using

I-NI-dichlorokynurenic acid (OSKA) and membranes prepared as described above. See Yoneda and others to them (Uopeda ei ai., U. Meiyhospet., 60, 634-645 (1993)). Binding tests were performed as described above for t" 50 I" NiI-glycine, with the exception that for labeling the glycine paratope | ZNIOSKA was used. Final

Ge; the concentration (-NI-OSKA was 10 nm, and the tests were performed for 10 minutes on ice.

A third test for binding of the glycine paratope of MMOA was performed using an indirect assessment of the affinity of the ligands to the paratope by measuring the binding | ZNI-MK-801 (dizocilpine). See Palmer dv | Berne (Raiteg apa Vytv, .). Meshygospet., 62, 187-196 (1994)). Membranes were prepared for the test as described above.

The technique provided separate detection of antagonists and agonists. (F, To identify antagonists, the third binding test was performed in the following way: 100 μg of membranes were added to the wells of a 9b-well Petri dish together with glutamate (1 μM) and glycine (200 μM) and different concentrations of the tested ligands. The test began with the addition of 5 nM | ZNI-MK-801 (23.9Ki/mmol), because it binds to ion channels associated with MMOA receptors.The final volume of the sample was 200μl.

The tests were performed within an hour. at room temperature. The bound radioactive compound was separated from the free residue by filtration using a TOMTES device. The activity of the antagonists was determined from the data on the decrease of the radioactivity bound to the MMOA receptor when the concentration of the tested ligand was increased. 65 To identify agonists, the third binding test was performed as described above, with the exception that the concentration of glycine was 200 nM. The activity of the antagonists was determined from the data on the increase in radioactivity,

bound to the MMOA receptor, with an increase in the concentration of the tested ligand.

Claims (39)

The formula of the invention 1. Compound of formula I: where B. what 70 sho zi KZ At B where: Ag and Ago are independently selected aryl groups, optionally substituted with up to five substituents, independently selected from the group that includes alkyl , алкоксигрупа, циклоалкіл, циклоалкілоксигрупа, гетероциклоалкіл, гетероциклоалкілоксигрупа, алканоїл, тіоалкіл, аралкіл, аралкілоксигрупа, арилоксіалкіл, арилоксіалкоксигрупа, алкіл, заміщений циклоалкілом, алкіл, заміщений циклоалкілоксигрупою, алкоксигрупа, заміщена циклоалкілом, алкоксигрупа, заміщена циклоалкілоксигрупою, 2о апкіл, заміщений гетероциклоалкілом, алкіл , substituted by a heterocycloalkyloxy group, alkoxy group, substituted by a heterocycloalkyl group, alkoxy group substituted by a heterocycloalkyloxy group, thioaryl, aralkylthio group, thioarylalkyl, aralkylthioalkyl, halide, MO», CEz, CM, OH, alkylenedioxy group, ХО2МКК, МКК, СОХ (where K and are independently selected from groups that include H and alkyl) and a second aryl group which may be substituted as indicated in ische, ta, Ag. - a substituent of the formula K"(X)-, X - CH", MK, 5 or O and KK" - aryl, optionally substituted with up to three substituents selected from the group that includes alkyl, halide, MO", CEz, CM, OH, 5O2MKE, MAK and SOR, where K and K' are independently selected as indicated above; i) Ku is selected from the group consisting of H and alkyl; E" is selected from the group consisting of H, alkyl and benzyl; Kz is selected from the group consisting of CO ok, SOMAC, SOMN(OH), SOBK, ZOM, PO(KHOK) and dozo tetrazolyl, where K and K' are independently selected from the group consisting of H and alkyl ; and a salt, solvate, or hydrate of such compound. " 2. The compound according to claim 1, where Ag is aryl, optionally substituted with up to three substituents, selected by M independently of each other from the group that includes halide, MO», СЕз, СМ, ОН, 5О2МКА, МКК, СОж (where К and are independently selected from the group consisting of H and alkyl) and a substituent of the formula K"X), where n is 0 or 1; and X is СНо or ME, 5.0; M K" is H, alkyl or aryl optionally substituted with up to three substituents selected from the group consisting of alkyl, halide, MO5, CE3, CM, OH, 5O2MKK, MKK, and CO, wherein K and K are independently selected from the group consisting of include H and alkyl. Z. Compound according to claim 2, where Ag. - phenyl. " 4. Compound according to claim 2, where Ag. - substituted phenyl. shsh c 5. The compound according to claim 4, where Ag is phenyl substituted with an optionally substituted five-membered aryl group. . 6. The compound according to claim 5, where the specified five-membered aryl group contains at least one heteroatom. and 7. The compound according to claim 6, where the specified five-membered aryl group is Z-furyl. 8. The compound according to claim 7, where Ag is 4-(3-furyl)phenyl. 9. Compound according to claim 7, where Ag. - 4-(3-thienyl)uphenyl. -and 10. Compound according to claim 7, where Ag. - 4-(3-pyrrolyl)phenyl. 11. Compound according to claim 4, where Ag. - phenyl substituted by lower alkyl. at 12. Compound according to claim 11, where Ag. - 4-(alkyl)phenyl. -and 13. The compound of claim 12, wherein said alkyl is selected from the group consisting of methyl, ethyl, p-propyl, boron isopropyl and p-butyl. ve 14. Compound according to claim 1, where Ag. - alkylenedioxyphenyl. Gee) 15. Compound according to claim 14, where Ag. - methylenedioxyphenyl. 16. Compound according to claim 15, where Ag. - 3,4-methylenedioxyphenyl. 17. Compound according to claim 1, where Ag. - condensed benzoaromatic system. 18. The compound according to claim 17, where Ag is a carbocyclic system. 19. Compound according to claim 18, where Ag. - naphthyl F) 20. Compound according to claim 19, where Ag. - 2-naphthyl. ka 21. A compound according to any one of claims 1-20, where Ago is aryl, optionally substituted with up to three substituents independently selected from the group consisting of halo, haloalkyl, alkyl, halohaloalkyl, and alkoxy. 22. The compound according to claim 21, where Ago is an unsubstituted aryl. 23. The compound according to claim 22, where Ag" is phenyl. 24. The compound according to claim 21, where Ago is substituted phenyl. 25. The compound according to claim 24, where Ag" is phenyl substituted with a halide. 65 26. The compound according to claim 25, where Ago is phenyl substituted with chlorine or fluorine. 27. Compound according to any of claims 1-26, where K. - N. 28. Compound according to any of claims 1-27, where K" - N. 29. The compound according to any of claims 1-27, where K" is methyl. 30. Compound according to any of claims 1-29, where Kz is SOOV. 31. The compound according to item ZO, where Kz is SOON. 32. The compound according to claim 1, selected from the following: (1). M-(5-(4-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (2). M-(5-(2-fluorophenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (3) M(5-(2,4-difluorophenyl)-3-phenyl-2- penten-4-yn-1-yl)sarcosine, 70 (4). Mch-(5-(3-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosin, (5). M-(5-(4-nitrophenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (6). M-(3-phenyl-5-(2-thiomethylphenyl)-2-penten-4-yn-1-yl)usarcosine, (7). Mm-(5-(4-chlorophenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (8). M-(5-(4-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)sarcosine, (9). M-(5-(3,5-bis(trifluoromethyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (10). M-(3,5-diphenyl-2-penten-4-yn-1-yl)usarcosine, (11). M-(5-(4-biphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (12). M-(5-(4--trifluoromethylphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (13). M-(5-(4-benzylphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (143. m-(5-(4-ethylphenyl)-3-phenyl-2-pentene -4-yn-1-yl)usarcosine, (153. M-(5-(4-p-propylphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarscosine, (16). M -(5-(4-p-butylphenyl)-3-phenyl-2-penten-4-yn-1-yl)sarcosine, (17). M-(5-(4-p-pentylphenyl)-3-phenyl -2-penten-4-yn-1-yl sarcosine, (18). M-(5-(1-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (20). M-(5-(4-methylphenyl)-3-phenyl-2 -penten-4-yn-1-yl)usarcosine, i) (21). M-(5-(3-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarscosine, (223 M-(5-(2-naphthyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (23). M-(5-(3,4-dimethylphenyl)-3-phenyl -2-penten-4-yn-1-yl)sarcosine, Hezo (24). M-(5-(2-isopropylphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine , (25). M(5-(3,4-methylenedioxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, - (26). M-(5-(4-pyrrolylphenyl) -3-phenyl-2-penten-4-yn-1-yl)usarcosin, M (27). M-(5-(4-trifluoromethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl )usarcosin, (28). M-(5-(3,4-dimethoxyphenyl)-3-phenyl-2-penten-4-yn-1-yl)sarcosine, me) (29). M-(3-phenyl-5-(4-thiomethylphenyl)-2-penten-4-yn-1-yl)usarcosine, i- (30). M-(5-(4-methylphenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, (31). M-(3-phenyl-5-(3-thiophene)-2-penten-4-yn-1-yl)usarcosine, (32). M-(3-phenyl-5-(4-tert-butylphenyl)-2-penten-4-yn-1-yl)sarcosine, (33). M-(5-(4-(3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)usarcosine, « (34). M-(5-(4-(3-thiophene)phenyl)-3-phenyl-2-penten-4-yn-1-yl)sarcosine, from c (35). M-(5-(4-isopropylphenyl)-3-«4--rifluoromethyl)phenyl)-2-penten-4-yn-1-yl)usarcosine, . (36). M-(5-(4-isopropylphenyl)-3-(4-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, and? (37). M-(5-(4-isopropylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, (38). M-(5-(4-tert-butylphenyl)-3-(2-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, (39). M-(5-(4-isopropylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)sarcosine, -I (40). h-(5-(4-tert-butylphenyl)-3-(4-chlorophenyl)-2-penten-4-yn-1-yl)usarcosine, (41). M-(5-(4-isopropylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)sarcosine, about (42). h-(5-(4-tertbutylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)usarcosine, -I (43). M-(5-(4-isopropylphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)sarcosine, (44). M-(5-(4-isopropylphenyl)-3-(3-thienyl)-2-penten-4-yn-1-yl)usarcosine, ve (45). Mch-(5-(4-isopropylphenyl)-3-(4-methoxyphenyl)-2-penten-4-yn-1-yl)usarcosine, Ge) (46). M-(5-(3,4-methylenedioxyphenyl)-3-(3-fluorophenyl)-2-penten-4-yn-1-yl)usarcosine, (47) M-(5-(4-ethylphenyl)-3 -(2-chlorophenyl)-2-penten-4-yn-1-yl)usarcosine and (48). M-(5-(4-propylphenyl)-3-(2-chlorophenyl)-2-penten-4-yn-1-yl)usarcosine. 33. Compound M-(5-(4-(3-furyl)phenyl)-3-phenyl-2-penten-4-yn-1-yl)sarcosine. 34. A composition comprising a compound specified in any of claims 1-33 and a carrier. F) 35. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any one of claims 1-33 and a pharmaceutically acceptable carrier. 36. A method of treating a patient who is in a painful condition, in which an inhibitor of glycine transport is indicated, in which the pharmaceutical composition according to claim 35 is administered to the patient's body. 37. The method according to claim 36, which differs in that the disease state is schizophrenia. 38. The method according to claim 36, which differs in that the disease state is a disorder of cognitive function. 39. The method according to claim 36, which differs in that the disease state is Alzheimer's disease. 65 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 9, 15.09.2005. State Department of Intellectual Property of the Ministry of Education and