JP2003513063A - Diaryl-enines - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention provides compounds of Formula I: In the formula, Ar ₁ and Ar ₂ are groups each independently selected from the following aryl groups which may be independently substituted with up to 5 substituents, and the substituents include the following groups Alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl , Cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl, heterocycloalkyl-substituted alkoxy, heterocycloalkyl Carboxymethyl - substituted alkoxy, thioaryl, aralkylthio, thioaryl - alkyl, aralkylthio alkyl, _{halo, NO 2, CF 3, CN} , OH, alkylenedioxy, SO ₂ NRR ', NRR' and CO ₂ R (wherein R and R ′ is independently selected from the group consisting of H and alkyl) and the second aryl group optionally substituted as described above; R ₁ is selected from the group consisting of H and alkyl R ₂ is selected from the group consisting of H, alkyl and benzyl; R ₃ is CO ₂ R, CONRR ′, CONH (OH), COSR, SO ₂ NRR ′, PO (OR) (OR ′) And R and R 'are independently selected from the group consisting of H and alkyl; and salts of the above compounds, It is selected from the group consisting of solvates or hydrates.

Description

Detailed Description of the Invention

The present invention relates to a class of substituted amines, pharmaceutical compositions and methods of treating neurological and neuropsychiatric disorders. Synaptic transmission is a significant sequence of differentiated structures in both presynaptic and postsynaptic neurons and the surrounding glial cells.
erable array of specialized structures) (Kanner and Schuldiner, CRC Critical Reviews in Biochemistry , 22 , 10)
32 (1987)). Transporters isolate neurotransmitters from synapses, thereby
In addition to the persistence of neurotransmitters within the synapse, it regulates the concentration of neurotransmitters therein, both of which affect the size of synaptic transmission. Furthermore, by preventing the transmitter from spreading to adjacent synapses, the transporter maintains the fitness of synaptic transmission. Finally, by sequestering the released transmitter into the presynaptic terminal, the transporter allows reuse of the transmitter. Neurotransmitter transport depends on extracellular sodium and the voltage difference across the membrane, and in conditions of strong neural firing, such as during a stroke, transporters are calcium-independent, non-exocyclic. It can release neurotransmitters in a tick-like manner and function in reverse (Attwell et al., Neuron , 11 ,
401-407 (1993)). The pharmacological modulation of neurotransmitter transporters thus provides a means of altering synaptic activity, which provides a useful therapeutic modality for the treatment of neurological and psychiatric disorders. The amino acid glycine is an important neurotransmitter in the mammalian central nervous system and functions at both inhibitory and excitatory synapses. By nervous system is meant both the central and peripheral parts of the nervous system. These different functions of glycine are mediated by two different types of receptors, each associated with different types of glycine transporters. The inhibitory effect of glycine is mediated by the glycine receptor, which is sensitive to the spastic alkaloid strychnine, and is therefore called "strychnine sensitive". Such receptors contain an intrinsic chloride channel that opens when glycine binds to the receptor, and increasing chloride conductance results in a higher threshold for action potential firing. Strykinin-sensitive glycine receptors are found primarily in the spinal cord and brainstem, thus
Drugs that promote activation of such receptors will enhance inhibitory neurotransmission within these areas.

Glycine also functions in excitatory transmission by modulating the action of glutamate, a major excitatory neurotransmitter in the central nervous system [Johnso
n and Ascher, Nature , 325 , 529-531 (1987); Fletcher et al., Glycine Transmission , (Otterson and Storm-Mathisen, editor, 1990), pp. 193-219]. Specifically, glycine is N-methyl-D-aspartate (NMDA).
It is an absolute co-agonist at a class of glutamate receptors called receptors.
Activating the NMDA receptor will increase sodium and calcium conductance, depolarize neurons and increase the likelihood of firing action potentials. NMDA receptors in the hippocampal region of the brain play an important role in a model of synaptic plasticity known as long-term potentiation (LTP), which is essential in some learning and memory. Is something (
Hebb, DO (1949) The Organization of Behavior, Wiley, NY; Bliss and Coll
ingridge (1993) Nature 361: 31-39; Morris et al. (1986) Nature 319: 774-77.
6). Enhanced expression of selected NMDA receptor subunits in transgenic mice results in increased NMDA receptor-mediated current, enhanced LTP and better performance in some tests of learning and memory. (Ta
ng et al. (1999) Nature 401: 63). Conversely, suppression of expression of selected NMDA receptor subunits in transgenic mice resulted in pharmacologically induced schizophrenia including increased mobility, increased hyperactivity and lack of social / sexual interaction. It produces behavioral patterns similar to those of animal models (
Mohn et al. (1999) Cell 98: 427-436). These abnormal behaviors can be ameliorated with the antipsychotics haloperidol and clozapine.

NMDA receptors are widely distributed throughout the brain, particularly in the cerebral cortex and hippocampal body. From molecular cloning, GlyT-1 and GlyT- are found in the mammalian brain.
It is known that there are two types of glycine transporters called 2. GlyT
-1 is mainly found in the forebrain and its distribution corresponds to that of the glutamate pathway and the NMDA receptor (Smith et al., Neuron , 8 , 927-935 (1992)).
From the molecular cloning, it was further confirmed that GlyT-1a, GlyT-1b and GlyT-
The presence of three variants, called 1c was found (Kim like, Molecular Pharmacolo gy, 45, 608-617 (1994)). Two of these variants (1a and 1b) were each found to exhibit a unique distribution in brain and surrounding tissues (Bo
rowsky et al., Neuron, 10, 1993: 851-863; Adams et al., J. Neuroscience
1995: 2524-2532). The third variant 1c was found only in human tissues (Kim et al.
., Molecular Pharmacology, 45, 1994: 608-617). These variants are generated by differential splicing and exon usage and differ in their N-terminal regions. In contrast, GlyT-2 is found primarily in the brainstem and spinal cord, and its distribution closely corresponds to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry , 268). , 22802-22808 (1993); Jursky and Nelson, J. Neurochemistry , 64 , 1026-10.
33 (1995)). Another distinctive feature of the GlyT-2 mediated glycine transporter is that it is not repressed by sarcosine, as is the case with the GlyT-1 mediated glycine transporter. These data show that by controlling the synaptic level of glycine, GlyT-1 and GlyT-2 have N levels, respectively.
Consistent with the notion of affecting the activity of MDA and strychnine-sensitive glycine receptors. Therefore, compounds that inhibit or activate the glycine transporter would be expected to alter the function of the receptor and benefit treatment in a variety of medical conditions. For example, compounds that inhibit the GlyT-1 mediated glycine transporter increase glycine concentration at the NMDA receptor. Although these receptors are located at various positions,
It is especially present in the forebrain. This increase in concentration increases the activity of the NMDA receptor,
It alleviates schizophrenia and strengthens cognitive function. Alternatively, the compound that directly interacts with the glycine receptor component of this NMDA receptor is Gly.
It may have a similar or identical effect to the increase or decrease in extracellular glycine utilization caused by inhibiting or enhancing T-1 activity, respectively.
For example, Pitkanen et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels et al.
, Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neuros.
See ci., 16, 1561-1569 (1996). The present invention provides compounds that affect glycine transport. The present invention is also effective for treating pathologies in which glycine transport regulators, especially glycine inoculation inhibitors, are needed.

[0004] According to the gist one aspect of the present invention of the invention compounds of formula I are provided.

[Chemical 2] In the formula, Ar ₁ and Ar ₂ each independently represent an optionally substituted aryl group, and the substituents each independently represent alkyl, alkenyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy. , Alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-
Substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl, heterocycloalkyl-substituted alkoxy, heterocycloalkyloxy-substituted alkoxy, aralkylthio, thioaryl - alkyl, aralkylthio alkyl, _{halo, NO 2, CF 3, CN} , OH, alkylenedioxy,
SO ₂ NRR ′, NRR ′, CO ₂ R (wherein R and R ′ are independently selected from the group consisting of H and alkyl) and a second aryl group; May have a substituent; R ₁ is selected from the group consisting of H and alkyl; R ₂ is selected from the group consisting of H, alkyl and benzyl; R ₃ is CO ₂ R, CONRR
', CONH (OH), COSR, SO ₂ NRR', PO (OR) (OR ') and tetrazolyl, and R and R'are selected from the group consisting of H and alkyl. And those salts, solvates or hydrates thereof. The compounds of formula I, or precursors of such compounds (eg pro-drugs), suppress glycine transport (or reuptake) via the GlyT-1 transporter, so that other CNS-related cognitive disorders, dementia (Alzheimer's). It has been found to be useful in the treatment of schizophrenia as well as attention disorders and depression. According to another aspect of the invention, there is provided a pharmaceutical composition comprising an amount of a compound of formula I effective to inhibit glycine transport and a pharmaceutically acceptable carrier. In another aspect of the present invention, there is provided a composition containing a compound of the present invention in an amount pharmaceutically used for treating a disease state in which a glycine transport inhibitor is indicated. G
Preferred are compositions containing compounds useful in the treatment of conditions such as schizophrenia or cognitive disorders in which inhibition of lyT-1 mediated glycine transport is required.

DEFINITIONS The term aryl as used herein is phenyl, pyridyl, furyl,
It means a monocyclic aromatic group such as thienyl or a benzo-fused aromatic group such as naphthyl, indanyl, quinolinyl and fluorenyl. The term alkyl, as used herein, refers to straight and branched chain alkyl groups having 1-6 carbon atoms and includes methyl, ethyl and the like. The term cycloalkyl, as used herein, means a cyclic carbocycle having 3-8 carbon atoms and includes cyclopropyl, cyclohexyl and the like. Similarly, the term "cycloalkoxy" refers to carbocycles which are attached to other groups via oxygen, and include cyclohexyloxy and the like. The term heteroalkyl as used herein refers to a 3-8 membered ring containing up to two heteroatoms selected from the group consisting of N, S and O, such as piperidinyl, piperazinyl, thiopyranyl and the like. As a specific example. It is a cyclic heterocycloalkyloxy group such as piperidinyloxy bonded to another group via oxygen. As used herein, aralkyl, aryloxyalkyl, aralkyloxy and aryloxyalkoxy refer to an alkyl or alkoxy group substituted with an aryl or aryloxy group, benzyl, phenethyl, benzyloxy, 2-phenoxyethyl. Etc. are mentioned as a specific example. Similarly, cycloalkyl-substituted alkyl, cycloalkyl-substituted alkoxy, heterocycloalkyl-substituted alkyl and heterocycloalkyl-substituted alkoxy are 2
-Cyclohexyl-ethyl and the like. Further, as the substituents of the alkyl or alkoxy group substituted by another group via a bridging oxygen, there are cycloalkyloxy-substituted alkyl, cycloalkyloxy-substituted alkoxy, heterocycloalkyloxy-substituted alkyl and Heterocycloalkyloxy-substituted alkoxys are mentioned.

As used herein, the terms alkylene (eg, —CH ₂ —CH ₂ —), alkenylene (eg, —CH═CH—) and alkynylene (eg, —CH≡CH—) are methylene, ethylene, It means straight-chain and branched divalent radicals having 1 to 6 carbon atoms, such as vinylene, propenylene and ethynylene. The term alkoxy as used herein refers to straight and branched chain alkoxy groups having 1-6 carbon atoms and includes methoxy, ethoxy and the like. Thioalkyl term used herein means straight and branched chain alkyl groups having 1 to 6 carbon atoms, thiomethyl (CH ₃ -S-), thiopropyl and the like can be given as specific examples . The term thioaryl is bridged to another group via a sulfur atom. Similarly, a thioarylalkyl group is a thioaryl group that is bridged to another group via an alkylene group. Similarly, an aralkylthio group is an aralkyl group such as benzyl, which is bridged to another group via a sulfur atom. Furthermore, an arylalkylthioalkyl group is an arylalkyl group that is bridged to another group via a thioalkyl group. The term alkanoyl as used herein refers to straight and branched chain groups having 1 to 6 carbon atoms, particular examples being acetyl, propionyl and the like. The term halo as used herein means halogen, fluorine, chlorine,
Specific examples include bromine. Haloalkyl the term, such as -CF _3,
Refers to an alkyl group substituted with one or more independently selected halo atoms. Haloalkoxy term similarly refers to an alkoxy group such, substituted with independently 1 to halo atoms selected or more as -OCF _3. The term alkylenedioxy refers to the formula —O— (CH ₂ ) —O _n —, where the terminal oxygen is usually fused to an atom on the aryl group to form a bicyclic system, methylene. Specific examples include dioxy and ethylenedioxy. The term heteroatom as used herein refers to an atom other than carbon, N, S
And O are mentioned as specific examples.

Detailed Description and Preferred Embodiments The geometry of the double bond of the compounds in Formula I is described. That is Ar ₂
The group and the carbon atom to which the R ₁ group is attached are cis to each other. Compounds of formula I include those where Ar ₁ and Ar ₂ are independently optionally substituted aryl groups. Substitution sites on the rings of Ar ₁ and Ar ₂ will in practice be limited to carbon atoms on the ring that are not attached to the core of the molecule. For example, the benzene ring can be substituted with up to 5 substituents, pyridine and pyran can have up to 4 substituents; pyrrole, furan and thiophene can have up to 3 substituents; imidazole Can have two substituents and the triazole can have only one substituent. In one aspect of the invention Ar ₁ is any monocyclic aromatic group such as benzene, pyridine, pyran, thiophene, furan, pyrrole, imidazole and triazole. Ar ₁ may have 1, 2 or 3 substituents on its aromatic ring, and the substituents are alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl. , Thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl, cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocyclo alkyloxy - substituted alkyl, heterocycloalkyl - substituted alkoxy, heterocycloalkyloxy - substituted alkoxy, thioaryl, aralkylthio, thioaryl - alkyl, halo, NO _2, CF ₃ , CN, OH, methylenedioxy, ethylenedioxy, SO ₂ NRR ′, NRR ′ and CO ₂ R (wherein R and R ′ are independently selected from the group consisting of H and alkyl) or the above. Can be selected from the group of aryl groups which may be substituted such as

In a preferred embodiment of the invention Ar ₁ is selected from benzene, pyridine, pyran, thiophene, furan and pyrrole, which are halo, NO ₂ ,
CF ₃ , CN, OH, alkyl, alkoxy, aryl, aralkyl and R "(
X) _n may be substituted with 1, 2 or 3 substituents selected from
Is 0 or 1; X is CH ₂ or a heteroatom; and R ″ is H, alkyl or alkyl, halo, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ′, NRR ′ and CO ₂ R (wherein R is and R 'as the aspects identified from optionally be an optionally substituted aryl. in up to three substituents selected from those that are independently selected from the group consisting of H and alkyl) is, Ar ₁ May be substituted with 1 or 2 substituents selected from alkyl, thioalkyl, alkoxy, halo, haloalkyl, haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, and substituted or unsubstituted aralkyl. a phenyl group. as a concrete embodiment, Ar ₁ is optionally substituted naphthalene, quinoline, indole, Ant Sen, fluorenyl, a benzo-fused aromatic group such as alkylenedioxy phenyl, substituents include halo, NO _2, CF _3, CN,
OH, alkyl, alkoxy, aryl, aralkyl and R "(X) _n (where n is 0 or 1; X is CH ₂ or a heteroatom; and R" is H, alkyl or alkyl, halo, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ', NRR' and C
It may be selected from aryl optionally substituted with up to 3 substituents selected from O ₂ R (wherein R and R ′ are independently selected from the group consisting of H and alkyl). In a particular embodiment, Ar ₁ is naphthyl, quinolyl, indanyl or alkylenedioxyphenyl, which may be substituted with 1 or 2 substituents selected from alkyl, alkoxy, thioalkyl and aryl.

In a particular embodiment, Ar ₁ is selected from unsubstituted naphthalene and methylenedioxyphenyl. Another aspect of the present invention is an optionally substituted aryl, which aryl is a monocyclic aromatic group such as benzene, pyridine, pyran, furan, thiophene, pyrrolidine, or naphthalene, quinoline, indole, anthracene, Benzo-fused aromatic groups such as fluorenyl and alkylenedioxyphenyl. It can have 1, 2 or 3 substituents, which can be independently selected as substituents from halo, haloalkyl, alkyl, haloalkoxy and alkoxy. In a particular embodiment, A is a monocyclic aromatic ring having up to 3 substituents independently selected from halo, haloalkyl, alkyl, haloalkoxy and alkoxy. In a more particular embodiment, A is selected from mono- or di-substituted phenyl substituted with a substituent selected from halo, haloalkyl, alkyl, haloalkoxy and alkoxy. In a specific embodiment, Ar ₂ is a phenyl group which is unsubstituted or has one substituent selected from halo and alkoxy. In a more specific embodiment, Ar ₂ is a phenyl group that is unsubstituted or has one substituent selected from chlorine and fluorine.

[0010]   In another embodiment of the present invention, R₃Is -CO₂R, -CONRR ', -CO
NH (OH), -COSR, -SO₂NRR ', -PO (OR) (OR') and tet
Selected from the group consisting of razolyl, wherein R and R'are H and
To be independently selected from the group consisting of ruquils   In another embodiment of the present invention, R₃Is COOR. Preferred of the present invention
In an embodiment, R₃Is COOH.   The compound of formula I is R₁Is selected from the group consisting of H and alkyl
Including compound. Preferably R₁Is H.   The compound of formula I is R₂Is selected from the group consisting of H, alkyl and benzyl
Are included in the compound. Preferably R₂Is alkyl, more preferred
As R₂Is methyl.   In a preferred embodiment, the compound of formula I is R₁Is H, R₂Is methyl, R₃Is COO
Of H. In this specification, Ar₁And Ar₂Is a substituted or non-substituted
Nyl is preferred. Preferably Ar₁Is phenyl or 4- (substituted
) -Phenyl. If substituted, Ar₁Is 4- (alkyl) -phenyl
It is preferable that the alkyl group is a linear alkyl group.
Specific examples include 4-isopropyl-phenyl, 4-ethyl-phenyl and 4-
n-propyl-phenyl and the like. Ar combined with the above or independently ₂ Is preferably chloro or fluoro substituted phenyl.   In another preferred embodiment, R₁Is H, R₂Is methyl, R₃Is COOH, Ar₂ Is unsubstituted phenyl and Ar₁Is 4-alkyl-phenyl and this alkyl is C_1-4 It is a straight chain.   Another preferred embodiment is R₁Is H, R₂Is methyl, R₃Is COOH, Ar₂Is 2
-Chloro-phenyl with Ar₁Is 4-alkyl-phenyl,
Kill substituents are selected from ethyl and propyl.   Another preferred embodiment of the present invention is R₁Is H, R₂Is methyl, R₃Is COOH, A
r₁Is naphthyl, especially 2-naphthyl, Ar₂Is phenyl.   Another preferred embodiment of the present invention is R₁Is H, R₂Is methyl, R₃Is COOH
, Ar₁Is 3,4-methylenedioxyphenyl and Ar₂Is 3-fluoro-phenyl
It belongs to Le.   A further preferred embodiment of the present invention is R₁Is H, R₂Is methyl, R₃Is COOH, A
r₂Is phenyl and Ar₁Is an optionally substituted aryl-substituted phenyl.   A more preferred embodiment of the present invention is R₁Is H, R₂Is methyl, R₃Is COOH, A
r₂Is phenyl and Ar₁Was substituted with an optionally substituted 5-membered heteroaryl
It is phenyl.   The most preferred embodiment of the present invention is R₁Is H, R₂Is methyl, R₃Is COOH, A
r₂Is phenyl and Ar₁Is 4- (3-furyl) -phenyl.

Specific examples of compounds of formula I include: N- (5- (4-fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N -(5- (2-Fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (2,4-difluorophenyl) -3-phenyl-2-pentene -4
-In-1-yl) -sarcosine N- (5- (3-nitrophenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (5- (4-nitrophenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (3-phenyl-5- (2-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-chlorophenyl) -3- Phenyl-2-penten-4-yne-
1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (3,5-bis (trifluoromethyl) phenyl) -3-phenyl-
2-Penten-4-yn-1-yl) -sarcosine N- (3,5-diphenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-diphenyl) -3- Phenyl-2-pentene-4-yn-1-
Yl) -Sarcosine N- (5- (4-trifluoromethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-benzylphenyl) -3- Phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-ethylphenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (5- (4- ^n- propylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4- ⁿ -butylphenyl)- 3-Phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4- ^n- pentylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N -(5- (4-phenoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine

N- (5- (1-naphthyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-methylphenyl) -3-phenyl-2- Penten-4-in-
1-yl) -sarcosine N- (5- (4-methylphenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (5- (3-isopropylphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (2-naphthyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (3,4-dimethylphenyl) -3-Phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (2-isopropylphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4- Pyrrolylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-trifluoromethoxyphenyl) -3-phenyl-2-penten-4-yn-1 -Yl) -sarcosine N- (5- (3,4-dimethoxyphenyl) -3-phenyl-2-pentene-4
-In-1-yl) -sarcosine N- (3-phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-methylphenyl) ) -3-Phenyl-2-pentene-4-yne-
1-yl) -sarcosine N- (3-phenyl-5- (3-thiophene) -2-penten-4-yn-1-
Yl) -Sarcosine N- (3-phenyl-5- (4-tbutylphenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4- (3-furyl) -phenyl) ) -3-Phenyl-2-pentene-
4-yn-1-yl) -sarcosine N- (5- (4- (3-thiophene) -phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-Isopropylphenyl) -3- (4-trifluoromethyl) phenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (4- Fluorophenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (2-fluorophenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (4-t-butylphenyl) -3- (2-fluorophenyl) -2-
Penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (4-chlorophenyl) -2-
Penten-4-yn-1-yl) -sarcosine N- (5- (4-t-butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (2-chlorophenyl) -2-
Penten-4-yn-1-yl) -sarcosine N- (5- (4-t-butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (3-fluorophenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (3-thienyl) -2-penten-4-yn-1-yl) -sarcosine N- ( 5- (4-isopropylphenyl) -3- (4-methoxyphenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (3,4-methylenedioxyphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1-yl) -Sarcosine N- (5- (4-ethylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-propylphenyl) -3- (2-Chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine

The compounds of formula I can be considered as amino acids or their derivatives. Compounds containing "carboxylate equivalents" such as hydroxamic acid, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, amide or tetrazole in place of the carboxylate group are also considered embodiments of this invention. In another embodiment of the invention, the compound of formula I is labeled in a manner similar to a radionuclide label (eg by incorporation of ³ H or ¹⁴ C into its structure, or labeling by binding to ¹²⁵ I). Offered in shape. In a preferred embodiment of the invention, such compounds are apt to bind to GlyT-1 and can be prepared by conventional techniques in the art.
It can be used to identify yT-1 receptor ligands. This discrimination is performed by incubating the receptor or tissue in the presence of the ligand candidate and then incubating the resulting preparation with an equimolar amount of the radiolabeled compound of the invention. As described above, the GlyT-1 receptor ligand occupies a large amount of the GlyT-1 site and inhibits the binding of the radiolabeled compound of the present invention. The candidate GlyT-1 receptor ligand can also be identified by first incubating with a radiolabel of the compound of the present invention and then incubating the resulting preparation in the presence of the candidate ligand. Higher performing GlyT-1 receptor ligands will replace the radiolabeled compounds of the invention at equimolar concentrations. The acid addition salts of the compounds of formula I are preferably formed from pharmaceutically acceptable acids, eg inorganic acids such as hydrochloric acid, sulfric acid or phosphoric acid and succinic acid, maleic acid, acetic acid or fumaric acid. Salts formed by organic acids such as Other non-pharmaceutically acceptable salts, such as, for example, oxalates, can also be used, for example in the laboratory for the isolation of compounds of formula I and their subsequent conversion into pharmaceutically acceptable salts. Also, base addition salts (such as sodium, potassium and ammonium salts), solvates of the compounds of the present invention, and hydrates are within the scope of the present invention. Base salts are preferred, and sodium and potassium salts are especially preferred. Conversion of the resulting compound salt to the desired compound can be accomplished by standard techniques well known to those skilled in the art. The compounds of the present invention can be prepared in an analogous manner to techniques established in the art. For example, compounds of formula I are readily prepared by the method shown in Scheme 1 below. Intermediate C is Trost (Trost, BM; Sorum, MT; Chan, C .; Ha
rms, AE; Ruther, GJ Am. Chem. Soc. 1997, 119, 698-708; Trost, B. M
Hachiya, I .; McInosh, MC Tetrahedron Lett. 1998, 39, 6445-6448) in the presence of palladium acetate and tris (2,6-dimethoxyphenyl) phosphine. Was prepared by coupling trimethylsilylacetylene B with trimethylsilylacetylene B. Reduction of this ester to an alcohol followed by treatment with N-bromosuccinimide produces bromide D. Treatment of D with a sarcosine ester (such as t-butyl sarcosine) in the presence of base produces the intermediate sarcosine derivative E. Removal of trimethylsilyl groups (eg treatment with potassium carbonate in methanol) followed by Sonogashira coupling (Sonogashira, K .; Yohda, Y. and Hagihara, N .; T
etrahedron Lett., 1975, 4467) by introducing a second aryl group to give the diaryl derivative G, then removing the protecting group, for example by treatment with formic acid, to give the final product H. This route is a good way to simultaneously synthesize a series of related compounds where Ar ₂ is constant and Ar ₁ is a number of different aryl groups. If the common intermediate F is prepared in bulk and treated with an appropriate aryl iodide under Sonogashira conditions, the desired product can be obtained.

[Formula 1]

Alternatively, such compounds can be prepared by the route shown in Scheme 2 below. This route is suitable for the simultaneous synthesis of a series of related compounds in which Ar ₁ is constant and Ar ₂ is many different aryl groups. In this case, the common intermediate L is readily obtained from the aryl iodide M by making the common intermediate L in bulk and then treating with the propiol ester N in the presence of the appropriate arylpropiol ester O (Cul and Pd (PPh ₃ ) _4. The product H can be obtained after treatment and deprotection under the above conditions.

[Formula 2] The following synthetic method (Scheme 3) is useful for preparing compounds in which Ar ₁ is aryl-substituted phenyl (Ar ₃ -phenyl). Intermediate F can be prepared according to Scheme 1 and then coupled to bromoiodobenzene by Sonogashira coupling to give Ss. The aryl bromide of S type is then boric acid (boron
ic acid) (Ar ₃ -boric acid) is reacted under Suzuki coupling conditions to obtain an intermediate G ′ (G ′ corresponds to G in Scheme 1, and Ar ₁ therein is Ar ₃ -phenyl. ). G'is then deprotected as in Scheme 1 to give H '.

[Formula 3] Compounds that inhibit GlyT-1 mediated glycine transport are those that increase glycine levels at the NMDA receptor, and these receptors are present in various locations, especially in the forebrain. This increase in concentration increases the activity of the NMDA receptor,
It reduces schizophrenia and enhances cognitive function. Also, compounds that directly interact with the glycine receptor component of the NMDA receptor are the same or similar to those that increase or decrease the availability of extracellular glycine, which results from inhibiting or enhancing GlyT-1 activity, respectively. Can have the effect. For example Pitkane
n et al., Eur. J. Pharmacol., 253, 125-129 (1994); Thiels et al., Neurosc
ience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16,
See 1561-1569 (1996).

The compounds of the invention may be administered, for example, orally, sublingually, rectally, nasally, intravaginally, topically (patches or other transdermal delivery devices), by the pulmonary route by using aerosols, and for example by muscle. It can be administered by parenteral administration such as intra-, subcutaneous, intra-peritoneal, intra-arterial, intravenous or intrathecal. It can be administered using an intermittent or continuous delivery pump. The compounds of the invention may be administered alone or in admixture with pharmaceutically acceptable carriers or excipients according to standard pharmaceutical means. For oral administration, the compounds of the invention can be used in the form of tablets, capsules, lozenges, chewing gums, troches, powders, syrups, elixirs, aqueous solutions and suspensions and the like. In the case of tablets, carriers used include lactose, sodium citrate and phosphates. Various disintegrants such as starch and lubricants such as magnesium stearate and talc are commonly used in tablets. Diluents useful for oral administration in capsule form are lactose and high molecular weight polyethylene glycols. If desired, certain sweeteners and / or flavoring agents are added. For parenteral administration, the sterilized solution of the present invention is usually prepared, the pH of this solution is adjusted to an appropriate value, and used as a buffer solution. For intravenous use, the total concentration of medium should be adjusted to render the preparation isotonic. For eye drops, the ointment or dripable liquid is delivered by delivery systems for the eye known in the art such as applicators and eye droppers. Such a composition comprises a viscous coagulant such as hyaluronic acid, chondroitin sulphate, hydroxypropylmethylcellulose or polyvinyl alcohol, a preservative such as sorbic acid, EDTA or benzylchromium chloride, and conventional amounts of diluents and / or A carrier can be included. For pulmonary administration, diluents and / or carriers are chosen so that an aerosol can be formed.

Suppository forms of the compounds of the present invention are useful for vaginal, urethral and rectal administration. Such suppositories generally consist of a mixture of compounds that are solid at room temperature but melt at body temperature. The substances commonly used to create such carriers include theobuloma oil,
There are glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, etc. For further studies on suppository dosage forms, see Remington's Pharmaceutical Sciences, 16th Ed., Mack Pub.
See lishing, Easton, PA, 1980, pp.1530-1533. Similar gels or creams may be used for vaginal, urethral and rectal administration. Many dosing carriers will be apparent to those of skill in the art, including, but not limited to, delayed release formulations, liposomal formulations and polymeric matrices. Pharmaceutically acceptable acid addition salts used in the present invention include, for example, hydrochloric acid, hydrobromic acid,
Mineral acids such as phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, tartaric acid, acetic acid, citric acid,
Those derived from organic acids such as malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, p-toluenesulfonic acid and arylsulfonic acid are included. Specific examples of pharmaceutically acceptable basic addition salts used in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organic amine salts such as triethylamine salt. . Many suitable salts are known to those of skill in the art. A doctor or other health care professional can select an appropriate dose and prescription according to the weight, age and physical condition of the subject. Dosages are generally chosen to maintain serum levels of the compounds of the invention between about 0.01 μg / cc and about 1000 μg / cc, preferably between about 0.1 μg / cc and about 100 μg / cc. To be done. For parenteral administration, in an alternative measure, preferably about 0.001 mg / kg to about 10 mg / kg (or about 0.01 mg / kg)
kg to about 10 mg / kg), more preferably about 0.01 mg / kg to about 1 m
g / kg (about 1 mg / kg to about 10 mg / kg) is administered. For oral administration, another preferred dosage measure is from about 0.001 mg / kg to about 10 mg / kg.
mg / kg (about 0.1 mg / kg to about 10 mg / kg), more preferably about 0.
． 01 mg / kg to about 1 mg / kg (about 0.1 mg / kg to about 1 mg / kg
). For suppository-type administration, another measure of the preferred dose is about 0.1.
mg / kg to about 10 mg / kg, more preferably about 0.1 mg / kg to about 1
mg / kg. In use for assaying activity to inhibit glycine transport, eukaryotic cells, preferably QT-6 cells derived from quail fibroblasts, were transfected to obtain three known variants of human GlyT-1, namely GlyT. -1a, GlyT-1b
Alternatively, one of GlyT-1c or human GlyT-2 was expressed. The sequences of these GlyT-1 transporters are Kim et al., Molec Pharm. 45: 608-617, 199.
4, the sequence encoding the N-terminus of GlyT-1a is only deduced from the corresponding rat-derived sequence. The sequence encoding this N-terminal protein is now found to correspond to that inferred by Kim et al. The sequence of human GlyT-2 is described in Albert et al., US patent application Ser. No. 08 / 700,013, filed August 20, 1996, which application is hereby incorporated by reference. There is. Suitable expression vectors include pRc / CMV (Invitrogen), Zap expression vector (Stratagene Cloning
Systems, LaJolla, CA; hereinafter referred to as "Stratagene"), pBk / CMV or pBk-RSV vector (Stratagene), Bluescript II SK +/- Phagemid
Vector (Stratagene), LacSwitch (Stratagene), pMAM and pMAM
neo (Clontech) etc. are mentioned. A suitable expression vector is a suitable host cell, preferably a non-mammalian host cell, which may be a eukaryotic cell, a fungal cell or a prokaryotic cell, and can promote the expression of GlyT DNA contained therein. Such preferred host cells include amphibian, avian, fungal, insect and reptile cells.

[0017] EXAMPLES Example 1: 1-methoxycarbonyl-2-phenyl-4-trimethylsilyl -1
-Buten-4-yne (C) palladium acetate (28 mg, 0.125 mmol) in anhydrous toluene (5
mL) solution with tris (2,6-dimethoxyphenyl) phosphine (55 mg, 0
． 125 mmol) was added. After 15 minutes, methylphenyl propylate (1.
A solution of 00 g, 6.24 mmol) in anhydrous toluene (5 mL) was added. After a further 5 minutes, trimethylsilylacetylene (0.88 mL, 0.61 g, 6.24 mmo
l) was added. After 16 hours the reaction mixture was concentrated. Column chromatography (1
Enine C (1.39 g) as a yellow oil with 0% ethyl acetate / hexane)
, 86%). _{^{C: 1 HNMR (CDC1 3,}} 300 MHz) 0.21 (s, 9H), 3.62 (s, 3H),
6.34 (s, 1H), 7.33-7.44 (m, 5H).

Example 2 1-Hydroxy-3-phenyl-5-trimethylsilyls-2-penten-4-yne Ester C (1.30 g, 5.03 mmol) in anhydrous toluene (20 mL) was added to dry ice / acetone. Cooled in bath. A 1.0 M solution of diisobutylaluminum hydride in toluene (12.6 mL, 12.6 mmol) was added.
The cooling bath was removed after 5 minutes. After an additional 15 minutes, the reaction mixture was recooled in an ice bath. The reaction was stopped by adding Celite and sodium sulfate decahydrate. The slurry was diluted with ethyl acetate and filtered through Celite. The filter cake was washed 3 times with ethyl acetate. The filtrate was washed with water and brine, dried (sodium sulfate), filtered and concentrated to give the alcohol intermediate as a yellow oil (0.821g, 71%). : ¹ HNMR (CDC1 ₃ , 300 MHz
) 0.20 (s, 9H), 1.40 (t, 1H), 4.31 (dd, 2H), 6.37 (t, 1H), 7.33-7.37 (m, 5H).

Example 3: 1-Bromo-3-phenyl-5-trimethylsilyl-2-pentene-
4-yne (D) The above alcohol (0.82 g, 3.56 mmol) in anhydrous dichloromethane (2
0 mL) solution was cooled in a dry ice / acetonitrile bath. Triphenylphosphine (1.40 g, 5.34 mmol) and N-bromosuccinimide (
0.95 g, 5.34 mmol) was added. 30 minutes later. The reaction was quenched with saturated sodium bicarbonate. The reaction mixture was partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer was washed with brine, dried (sodium sulfate), filtered, and concentrated to give crude allyl bromide D, which was used directly in the next step.

Example 4: N- (3-phenyl-5- (trimethylsilyl) -2-pentene-4
-In-1-yl) sarcosine, ^t- butyl ester (E) In a solution of the above bromide in anhydrous acetonitrile (15 mL), t-butyl sarcosine hydrochloride (0.71 g, 3.90 mmol), potassium carbonate (4.91 g, 35).
． 5 mmol) and phosphorus iodide (2.95 g, 17.8 mmol) were added. After 16 hours, the reaction mixture was filtered through Celite. The filter cake was washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated. Column chromatography (25% ethyl acetate / hexane) gave product E as a dark yellow oil (0.74 g, 58% over 2 steps). E: ¹ HNMR (CDC1 ₃ , 300 MHz)
0.19 (s, 9H), 1.41 (s, 9H), 2.32 (s, 3H), 3.10 (s, 2H), 3.31 (d, 2H), 6.33 (t, 1H),
7.26-7.38 (m, 5H).

Example 5: N- (3-phenyl-2-penten-4-yn-1-yl) sarcosine, ^t- butyl ester (F) Methanol (10 mL) of the above compound (0.74 g, 2.06 mmol). Potassium carbonate (1.42 g, 10.3 mmol) was added to the solution. After 20 minutes, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried (sodium sulfate), filtered and then concentrated to give terminal acetylene F (0.58 g, 99%) as an off-white solid. F: ¹
_{HNMR (CDC1 3, 300 MHz)} 1.41 (s, 9H), 2.33 (s, 3H), 2.96 (s, 1H), 3.10 (s, 2H)
, 3.33 (d, 2H), 6.37 (t, 1H), 7.26-7.39 (m, 5H).

Example 6-1: N- (5- (4-fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) Terminal acetylene F ( 4-Fluoroiodobenzene (26 μL, 51 mg, 0.2) in a solution of 50 mg, 0.175 mmol) in triethylamine (2 mL).
28 mmol), tetrakis (triphenylphosphine) palladium (0) (2
0 mg, 0.0175 mmol) and copper (I) iodide (10 mg, 0.052
5 mmol) was added. After 16 hours dilute the reaction mixture with dichloromethane,
Filtered. The filtrate was concentrated. Column chromatography (25% ethyl acetate / hexane) gave acetylene G (51 mg, 77%) as a yellow oil. G
_{^{: 1 HNMR (CDC1 3, 300}} MHz) 1.42 (s, 9H), 2.35 (s, 3H), 3.13 (s, 2H), 3.36 (d, 2
H), 6.37 (t, 1H), 7.00 (dd, 2H), 7.26-7.44 (m, 7H). In a similar manner, intermediate F and 1.3 of the corresponding aryl iodide under the conditions described above.
The following compounds were prepared from equivalent amounts. 6-2: N- (5- (2-fluorophenyl) -3-phenyl-2-pentene-
4-in-1-yl) -sarcosine, ^t- butyl ester (G) Prepared in a similar manner from 2-fluoroiodobenzene to give 45 mg (68%) of a yellow oil. ¹ HNMR (CDC1 ₃ , 300 MHz) 1.42 (s, 9H), 2.36 (s, 3H), 3.14 (s, 2H)
, 3.39 (d, 2H), 6.43 (t, 1H), 7.06 (dd, 2H), 7.24-7.44 (m, 7H). 6-3: N- (5- (2,4-difluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 2,4-difluoroiodobenzene Prepared in a similar manner from to give 49 mg (70%) of a yellow oil. _{^{1 HNMR (CDC1 3, 300 MHz}} ) 1.42 (s, 9H), 2.36 (s, 3H), 3.13 (s, 2
H), 3.38 (d, 2H), 6.42 (t, 1H), 6.83 (dd, 2H), 7.26-7.44 (m, 6H). 6-4: N- (5- (3-nitrophenyl) -3-phenyl-2-pentene-4
Prepared similarly from -in-1-yl) -sarcosine, ^t- butyl ester (G) 3-nitroiodobenzene to give 73 mg (102%) of a yellow oil. _{^{1 HNMR (CDC1 3, 300 MHz}} ) 1.42 (s, 9H), 2.36 (s, 3H), 3.13 (s, 2H), 3.
38 (d, 2H), 6.45 (t, 1H), 7.26-7.40 (m, 5H), 7.48 (dd, 1H), 7.72 (d, 1H), 8.13 (d, 1
H), 8.27 (s, 1H). 6-5: N- (5- (4-nitrophenyl) -3-phenyl-2-pentene-4
Prepared similarly from -in-1-yl) -sarcosine, ^t- butyl ester (G) 4-nitroiodobenzene to give 31 mg (44%) of a yellow oil. _{^{1 HNMR (CDC1 3, 300 MHz}} ) 1.42 (s, 9H), 2.36 (s, 3H), 3.14 (s, 2H), 3.38
(d, 2H), 6.47 (t, 1H), 7.34-7.43 (m, 5H), 7.57 (d, 2H), 8.17 (d, 2H). 6-6: N- (3-phenyl-5- (2-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) From 2-thiomethyliodobenzene Prepared to give 19 mg (26%) of a yellow oil. _{^{1 HNMR (CDC1 3) 1.42 (}} s, 9H), 2.36 (s, 3H), 2.46 (s, 2H), 3.14 (s, 2
H), 3.39 (d, 2H), 6.45 (t, 1H), 7.06 (dd, 1H), 7.14 (d, 1H), 7.24-7.40 (m, 6H), 7.46
(d, 1H). 6-7: N- (5- (4-chlorophenyl) -3-phenyl-2-pentene-4
Prepared similarly from -in-1-yl) -sarcosine, ^t- butyl ester (G) 4-chloroiodobenzene to give 52 mg (75%) of a yellow oil. _{^{1 HNMR (CDC1 3, 300 MHz}} ) 1.42 (s, 9H), 2.35 (s, 3H), 3.13 (s, 2H), 3.36
(d, 2H), 6.38 (t, 1H), 7.26-7.39 (m, 9H). 6-8: Prepared similarly from N- (5- (4-isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-isopropyliodobenzene. Gave 38 mg (53%) of a yellow oil. ¹ HNMR (CDC1 ₃ , 300 MHz) 1.23 (d, 6H), 1.42 (s, 9H), 2.36 (s, 3H)
, 2.89 (hept, 1H), 3.13 (s, 2H), 3.36 (d, 2H), 6.36 (t, 1H), 7.16 (d, 2H), 7.26-7.
42 (m, 7H). 6-9: N- (5- (3,5-bis (trifluoromethyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 3, Similarly prepared from 5-bis (trifluoromethyl) iodobenzene, 40
Obtained mg (46%) of a yellow oil. ¹ HNMR (CDC1 ₃ , 300 MHz) 1.23 (d, 6H), 1.42
(s, 9H), 2.36 (s, 3H), 3.14 (s, 2H), 3.38 (d, 2H), 6.47 (t, 1H), 7.26-7.44 (m, 5H)
, 7.77 (s, 1H), 7.86 (s, 2H). 6-10: N- (3,5-diphenyl-2-penten-4-yn-1-yl)-
Similarly prepared from sarcosine, ^t- butyl ester (G) iodobenzene, yielded 46 mg (33%) of a yellow oil. ¹ H
NMR (CDC1 ₃ , 300 MHz) 1.42 (s, 9H), 2.36 (s, 3H), 3.13 (s, 2H), 3.36 (d, 2H), 6
.38 (t, 1H), 7.26-7.46 (m, 10H). 6-11: From N- (3-phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-thiomethyliodobenzene Prepared to give 30.0 mg (70%) of a yellow oil. 6-12: N- (3-phenyl-5- (4-methylphenyl) -2-pentene-
Prepared similarly from 4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-methyliodobenzene to give 33.0 mg (85%) of a yellow oil. 6-13: N- (5- (3-thiophene) -3-phenyl-2-pentene-4-
Prepared similarly from in-1-yl) -sarcosine, ^t- butyl ester (G) 3-iodothiophene to give 30.0 mg (78%) of a yellow oil. 6-14: N- (3-phenyl-5- (4-tbutylphenyl) -2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-t-butyl iodobenzene Prepared to give 38.0 mg (86%) of a yellow oil. 6-15: similarly prepared from N- (5- (4-methoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-methoxyiodobenzene. To give 31.0 mg (73%) of a yellow oil. 6-16: similarly prepared from N- (5- (2-isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 2-isopropyliodobenzene. 27.0 mg (64%)
To give a yellow oil. 6-17: N- (5- (4-diphenyl) -3-phenyl-2-pentene-4-
Prepared similarly from in-1-yl) -sarcosine, ^t- butyl ester (G) 4-biphenyliodobenzene to give 260 mg (85%) of a yellow oil. 6-18: N- (5- (4-trifluoromethylphenyl) -3-phenyl-2
-Penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-trifluoromethyl iodobenzene similarly prepared 240 mg (80
%) Yellow oil was obtained. 6-19: Prepared similarly from N- (5- (4-benzylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-benzyliodobenzene. To give 240 mg (80%) of a yellow oil. 6-20: N- (5- (4-ethylphenyl) -3-phenyl-2-pentene-
4-In-1-yl) -sarcosine, ^t- butyl ester (G) Prepared similarly from 4-ethyliodobenzene to give 240 mg (88%) of a yellow oil. _{^{6-20: 1 HNMR (CDC1 3,}} 300 MHz) 1.22 (t, 3H), 1.43 (s, 9H), 2.36 (s, 3
H), 2.63 (q, 2H), 3.13 (s, 2H), 3.36 (d, 2H), 6.37 (t, 1H), 7.13 (d, 2H), 7.26-7.4
3 (m, 7H). 6-21: From N- (5- (4-npropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-npropyliodobenzene Prepared to give 240 mg (85%) of a yellow oil. _{^{6-21: 1 HNMR (CDC1 3,}} 300 MHz) 0.93 (t, 3H), 1.43 (s, 9H), 1.57
(sextet, 2H), 2.36 (s, 3H), 2.57 (t, 2H), 3.14 (s, 2H), 3.37 (d, 2H), 6.37 (t, 1H)
, 7.12 (d, 2H), 7.24-7.43 (m, 7H). 6-22: N- (5- (4-nbutylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-n-butyliodobenzene Prepared to give 260 mg (89%) of a yellow oil. 6-23: N- (5- (4-n-pentylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-n-pentyliodobenzene as well Prepared to give 240 mg (79%) of a yellow oil. 6-24: similarly prepared from N- (5- (4-phenoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-phenoxyiodobenzene. To give 34.7 mg (56%) of a yellow film. 6-25: similarly prepared from N- (5- (1-naphthyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 1-iodonafphthalene. Obtained 35.8 mg (63.5%) of product. _{^{6-25: 1 HNMR (CDC1 3,}} 300 MHz) 1.43 (s, 9H), 2.40 (s, 3H), 3.17 (s
, 2H), 3.42 (d, 2H), 6.53 (t, 1H), 7.33-7.57 (m, 8H), 7.67 (d, 1H), 7.75-7.85 (m, 2
H), 8.30 (d, 1H). 6-26: N- (5- (4-methylphenyl) -3-phenyl-2-pentene-
Prepared similarly from 4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-methyliodobenzene to give 34.7 mg (88%) of a pale yellow oil. 6-27: N- (5- (3-isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) Similarly prepared from 3-isopropyliodobenzene. And then 17.6 mg (42%)
The product was obtained. _{^{6-27: 1 HNMR (CDC1 3,}} 300 MHz) 1.23 (d, 6H), 1.42 (s, 9H),
2.36 (s, 3H), 2.87 (septtet, 2H), 3.13 (s, 2H), 3.36 (d, 2H), 6.38 (t, 1H), 7.15-7
.42 (m, 8H), 7.70-7.71 (m, 1H). 6-28: similarly prepared from N- (5- (2-naphthyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 2-iodonafphthalene. Obtained 30.0 mg (69%) of colorless oil. 6-29: N- (5- (3,4-dimethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 3,4-dimethyliodobenzene Similarly prepared from 40.0 mg (98%)
A yellow film was obtained. 6-30: similarly prepared from N- (5- (2-isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 2-isopropyliodobenzene. 27.0 mg (64%)
Off-white oil was obtained. 6-31: N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-
2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) Prepared similarly from 3,4-methylenedioxyiodobenzene to give 40.0 mg (
94%) of a yellow oil was obtained. 6-32: N- (5- (4-pyrrolylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 4-pyrrolyl iodobenzene as well Prepared to give 41.0 mg (92%) of a pale yellow oil. 6-33: N- (5- (4-trifluoromethoxyphenyl) -3-phenyl-
2-Penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 28.5 mg (prepared similarly from 4-trifluoromethoxyiodobenzene
61%) of product was obtained. _{^{6-33: 1 HNMR (CDC1 3,}} 300 MHz) 1.42 (s, 9H), 2.35
(s, 3H), 3.13 (s, 2H), 3.36 (d, 2H), 6.39 (t, 1H), 7.15 (d, 2H), 7.26-7.39 (d, 2H)
, 7.46 (d, 2H). 6-34: N- (5- (3,4-dimethoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) 3,4-dimethoxyiodobenzene Prepared in the same manner from 35.0 mg (80%
) Colorless oil was obtained. In a similar manner, the following compound is formed from intermediate F and 1.3 equivalents of the corresponding aryl iodide treated under the above conditions. 6-35: N- (5- (2-quinoline) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine, ^t- butyl ester (G) Prepared similarly from 2-iodoquinoline It 6-36: N- (5-indaryl) -3-phenyl-2-pentene-4-yn-
1-yl) -sarcosine, ^t- butyl ester (G) Prepared similarly from iodoindaryl.

[0023] Example 7-1: N- (5- (4-fluorophenyl) -3-phenyl-2-pen
Ten-4-in-1-yl) -sarcosine (H)   96% formic acid solution of t-butyl ester 6-1 (51 mg, 0.135 mmol)
The liquid was heated to 40 ° C. for 16 hours. The reaction mixture was cooled and concentrated. Dichroic residue
Take in dichloromethane and pass through a 2 g solid phase extraction tube, dichlo romethane, then vinegar
Elute with ethyl acid then methanol. Concentrate the methanol fraction to a colorless foam
To give amino acid 7-1 (39 mg, 90%):¹HNMR (CDC1₃, 300 MHz)
2.72 (s, 3H), 3.49 (s, 2H), 3.92 (d, 2H), 6.38 (t, 1H), 6.98 (dd, 2H), 7.26-7.42 (m
, 7H). HRMS calculated 324.1400, found 324.1386.   The following compounds were similarly prepared from the corresponding intermediates treated under the above conditions:
It was 7-2: N- (5- (2-fluorophenyl) -3-phenyl-2-pentene-
4-in-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-2 to give 31 mg (81%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.68 (s, 3H), 3.47 (s, 2H), 3.90 (s, 2H), 6.43 (s, 1H)
, 7.05 (dd, 2H), 7.23-7.42 (m, 7H). HRMS calculated value 324.1400, measured value 324.1408. 7-3: N- (5- (2,4-difluorophenyl) -3-phenyl-2-pen
Ten-4-in-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-3 to give 34 mg (82%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.70 (s, 3H), 3.48 (s, 2H), 3.91 (s, 2H), 6.42 (s, 1H)
, 6.78 (dd, 2H), 7.26-7.38 (m, 6H). HRMS calculated value 342.1306, measured value 342.1333. 7-4: N- (5- (3-nitrophenyl) -3-phenyl-2-pentene-4
-In-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-4 to give 42 mg (68%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.72 (s, 3H), 3.50 (s, 2H), 3.94 (s, 2H), 6.50 (s, 1H)
, 7.26-7.48 (m, 6H), 7.70 (d, 1H), 8.12 (d, 1H), 8.22 (s, 1H). HRMS calculated 351.134
5, measured value 351.1353. 7-5: N- (5- (4-nitrophenyl) -3-phenyl-2-pentene-4
-In-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-5 to give 21 mg (80%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.66 (s, 3H), 3.43 (s, 2H), 3.85 (d, 2H), 6.51 (s, 1H)
, 7.26-7.53 (m, 5H), 7.54 (d, 2H), 8.14 (d, 2H). 7-6: N- (3-phenyl-5- (2-thiomethylphenyl) -2-pentene
-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-6 to give 14 mg (87%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.42 (s, 3H), 2.66 (s, 3H), 3.48 (s, 2H), 3.88 (s, 2H)
, 6.40 (s, 1H), 7.12-7.68 (m, 9H). 7-7: N- (5- (4-chlorophenyl) -3-phenyl-2-pentene-4
-In-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-7 to give 40 mg (90%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.68 (s, 3H), 3.48 (s, 2H), 3.87 (s, 2H), 6.39 (s, 1H)
, 7.24-7.37 (m, 9H). HRMS calculated value 340.1104, found value 340.1097. 7-8: N- (5- (4-isopropylphenyl) -3-phenyl-2-pente
N-4-yn-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-8 to give 32 mg (99%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 1.21 (d, 6H), 2.65 (s, 3H), 2.86 (hept, 1H), 3.43 (s, 2
H), 3.86 (d, 2H), 6.36 (t, 1H), 7.14 (d, 2H), 7.26-7.36 (m, 7H). HRMS calculated value 348.1
964, actual value 348.1998. 7-9: N- (5- (3,5-bis (trifluoromethyl) phenyl) -3-ph
Phenyl-2-penten-4-yn-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-9 to give 26 mg (76%) of colorless foam:¹
HNMR (CDC1₃, 300 MHz) 2.67 (s, 3H), 3.46 (s, 2H), 3.87 (d, 2H), 6.52 (t, 1H)
, 7.26-7.40 (m, 5H), 7.77 (s, 1H), 7.83 (s, 2H). HRMS calculated value 442.1242, measured value 442
.1173. 7-10: N- (3,5-diphenyl-2-penten-4-yn-1-yl)-
Sarcosine (H)   Prepared in a similar manner from Intermediate 6-10 to give 18 mg (46%) of colorless foam: ¹ HNMR (CDC1₃, 300 MHz) 2.69 (s, 3H), 3.48 (s, 2H), 3.89 (d, 2H), 6.40 (t, 1H)
, 7.26-7.44 (m, 10H). HRMS calculated 306.1494, found 306.1432. 7-11: N- (5- (4-diphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine (H)   220.0 mg (97%) of a yellow solid was similarly prepared from Intermediate 6-17.
Obtained. 7-12: N- (5- (4-trifluoromethylphenyl) -3-phenyl-2
-Penten-4-yn-1-yl) -sarcosine (H)   200.0 mg (96%) of yellow fill prepared similarly from Intermediate 6-18
I got it. 7-13: N- (5- (4-benzylphenyl) -3-phenyl-2-pentene
-4-yn-1-yl) -sarcosine (H)   Similarly prepared from Intermediate 6-19, 190.0 mg (87%) of a pale yellow solid.
Got 7-14: N- (5- (4-ethylphenyl) -3-phenyl-2-pentene-
4-in-1-yl) -sarcosine (H)   176.1 mg (86%) of grey-green solid similarly prepared from Intermediate 6-20.
Got 7-15: N- (5- (4-ⁿPropylphenyl) -3-phenyl-2-pente
N-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-21 to give 190.9 mg (93%) of a white-orange solid.
Got the body 7-16: N- (5- (4-ⁿButylphenyl) -3-phenyl-2-pentene
-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-22 to give 206.0 mg (91%) of a yellow solid.
Obtained. 7-17: N- (5- (4-ⁿPentylphenyl) -3-phenyl-2-pente
N-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-23 to give 204.4 mg (98%) of a yellow solid.
Obtained. 7-18: N- (5- (4-phenoxyphenyl) -3-phenyl-2-pente
N-4-yn-1-yl) -sarcosine (H)   Similarly prepared from Intermediate 6-24 33.0 mg (100%) of a pale yellow solid.
Got 7-19: N- (5- (1-naphthyl) -3-phenyl-2-penten-4-i
N-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-25 to give 25.4 mg (82%) of a yellow oil.
. 7-20: N- (5- (4-methylphenyl) -3-phenyl-2-pentene-
4-in-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-26 to give 12.6 mg (55%) of a yellow solid.
It was 7-21: N- (5- (3-isopropylphenyl) -3-phenyl-2-pen
Ten-4-in-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-27 to give 12.6 mg (83%) of a tan oil.
It was 7-22: N- (5- (2-naphthyl) -3-phenyl-2-penten-4-i
N-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-28 to give 25.1 mg (97%) of a yellow solid.
It was 7-23: N- (5- (3,4-dimethylphenyl) -3-phenyl-2-pen
Ten-4-in-1-yl) -sarcosine (H)   Similarly prepared from Intermediate 6-29 was 33.2 mg (97%) of a pale yellow solid.
Obtained. 7-24: N- (5- (2-isopropylphenyl) -3-phenyl-2-pen
Ten-4-in-1-yl) -sarcosine (H)   Similarly prepared from Intermediate 6-30 was 15.2 mg (66%) of flaky yellow solid.
Got the body 7-25: N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-
2-Penten-4-yn-1-yl) -sarcosine (H)   Similarly prepared from Intermediate 6-31 was 9.5 mg (31%) of an off-white solid.
Obtained. 7-26: N- (5- (4-pyrrolylphenyl) -3-phenyl-2-pentene
-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-32 to give 24.1 mg (68%) of a yellow solid.
It was 7-27: N- (5- (4-trifluoromethoxyphenyl) -3-phenyl-
2-Penten-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-33 to give 23.0 mg (92%) of a yellow solid.
It was 7-28: N- (5- (3,4-dimethoxyphenyl) -3-phenyl-2-pe
Nten-4-yn-1-yl) -sarcosine (H)   Prepared in a similar manner from Intermediate 6-34 to give 25.7 mg (86%) of a yellow solid.
It was   Similarly, the following compound was prepared from the corresponding intermediate treated under the above conditions.
Is built. 7-29: N- (5- (2-quinoline) -3-phenyl-2-penten-4-i
N-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-35. 7-30: N- (5- (indaryl) -3-phenyl-2-penten-4-yne
-1-yl) -sarcosine (H)   Prepared similarly from Intermediate 6-36.

Example 8-1: N- (3-phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine (H) ^t butyl ester 6-11G ( vi) (30.0 mg, 0.0736 mmol) of 9
The 6% formic acid solution was heated at 50 ° C. for 3 hours. The reaction mixture was cooled then concentrated. The residue was taken up in dichloromethane and passed through a 2 g solid phase extraction tube, eluting with dichloromethane followed by ethyl acetate then methanol. The methanol fraction was concentrated to give amino acid 8-1 (14.9 mg, 58%) as a pale yellow solid. The following compounds were similarly prepared from the corresponding intermediates treated under the above conditions. 8-2: N- (5- (4-methylphenyl) -3-phenyl-2-pentene-4
-In-1-yl) -sarcosine (H) Prepared in a similar manner from Intermediate 6-12 to give 30.0 mg (91%) of a pale yellow solid. 8-3: N- (3-phenyl-5- (3-thiophene) -2-penten-4-yn-1-yl) -sarcosine (H) Prepared in a similar manner from Intermediate 6-13 22.0 mg. A brown solid foam of (87%) was obtained. 8-4: N- (3-phenyl-5- (4-tbutylphenyl) -2-pentene-
4-yn-1-yl) -sarcosine (H) Prepared in a similar manner from Intermediate 6-14 to give 22.9 mg (66%) of a pale yellow solid.

Example 9: N- (5- (4-bromophenyl) -3-phenyl-2-pentene-
4-yn-1-yl) -sarcosine ^t- butyl ester (S) Terminal Acetylene F (3.25 g, 11.4 mmol) Et3N (75).
mL) solution with 4-bromoiodobenzene (4.19 g, 14.8 mmol), P
d (PPh ₃ ) ₄ (1.32 g, 1.14 mmol) and CuI (0.65 g, 3
． 42 mmol) was added. The mixture was stirred overnight then concentrated. Column chromatography (10% EtOAc / hexane) gave bromide S (3.84 g, 76%) as a yellow oil.

Example 10-1: N- (5- (4- (3furyl) phenyl) -3-phenyl-2
-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (G ') Bromide S (3.84 g, 8.72 mmol) in DME (25 mL) was added to 3-furanboronic acid (1). .47 g, 13.1 mmol),
Pd (PPh ₃ ) ₄ (1.01 g, 0.872 mmol) and 2M Na ₂ Co ₃ (
25 mL) was added. The mixture was boiled at reflux for 1 hour, cooled, then partitioned between EtOAc and water. The organic layer washed with brine, dried (MgSO _4), filtered, and concentrated. Column chromatography (10 to 12.5% EtOAc / hexane)
Gave ester G ′ (2.62 g, 78%) as a yellow oil. The following compounds were similarly prepared from the corresponding boric acid treated under the above conditions. 10-2: N- (5- (4- (3-thiophene) phenyl) -3-phenyl-2
-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (G ') 3-thiophene Boric acid was similarly prepared to give 21.0 mg (46%) of a colorless film. The following compounds were similarly prepared from the corresponding boric acid treated under the above conditions. 10-3: N- (5- (4- (4methyl-3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine ^t -butyl ester (
G ') S and similarly prepared from 4-methyl-3-thiophene boric acid. 10-4: N- (5- (4- (4methyl-3-furyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine ^t- butyl ester (G ′
) Prepared similarly from S and 4-methyl-3-furanboric acid. 10-5: N- (5- (4- (cyclohexane) phenyl) -3-phenyl-2
Prepared similarly from -penten-4-yn-1-yl) -sarcosine ^t- butyl ester (G ') S and cyclohexyl boric acid. 10-6: N- (5- (4- (cyclopentyl) phenyl) -3-phenyl-2
Prepared from -penten-4-yn-1-yl) -sarcosine ^t- butyl ester (G ') S and cyclohexpentyl boric acid in a similar manner.

Example 11-1: N- (5- (4- (3furyl) phenyl) -3-phenyl-2
-Penten-4-yn-1-yl) -sarcosine (H ') ester G' (2.62 g, 6.13 mmol) was dissolved in 96% formic acid (26 mL). The solution was warmed to 40 ° C. overnight and then concentrated. To give a pale yellow solid by column chromatography _{(0-8% MeOH / CH 2 Cl} 2). MeO
Addition of H gave pure H '(0.78 g, 34%) as a white solid. 11
11-1 was suspended in methanol to make -1 the corresponding sodium salt and then added to 1 equivalent of 6M sodium hydroxide. The solution was then concentrated and the residue triturated with isopropanol to give a white solid. The following compounds were similarly prepared from the corresponding intermediates treated under the above conditions. 11-2: N- (5- (4-3thiophene) phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine (H ′) similarly prepared from Intermediate 10-2. Yielded 11.7 mg (59%) of an off-white solid. 11-3: N- (5- (4-methyl-3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine (H ′) 10-3 in a similar manner Is prepared. 11-4: N- (5- (4- (4-methyl-3-furyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine (H ′) 10-4 Prepared similarly. 11-5: N- (5- (4- (cyclohexyl) phenyl) -3-phenyl-2
Prepared in a similar manner from -penten-4-yn-1-yl) -sarcosine (H ') 10-5. 11-6: N- (5- (4- (cyclopentyl) phenyl) -3-phenyl-2
Prepared in a similar manner from -penten-4-yn-1-yl) -sarcosine (H ') 10-6.

Example 12-1: 4- (trifluoromethyl) phenylpropiolate ethyl (
A) Ethyl propiolate (0.124 mL, in a triethylamine (2.5 mL) solution of 4-iodobenzotrifluoride (256 mg, 0.941 mmol).
120mg, 1.22mmol), Pd (PPh 3) 4 (109mg, 0.0941
mmol) and Cul (54 mg, 0.282 mmol). After 24 hours the reaction mixture was concentrated. Column chromatography (10% EtOAc / hexane) gave 12-1 (149 mg, 65%) as a colorless oil. The following compounds were similarly prepared from the corresponding aryl iodide treated under the above conditions and 1.3 equivalents of ethyl propiolate. 12-2: 4-Fluorophenylpropiolate ethyl (A) Prepared similarly from 4-fluoroiodobenzene to give 33 mg (4%) of a colorless solid. 12-3: 2-Fluorophenylpropiolate ethyl (A) Prepared similarly from 2-fluoroiodobenzene to give 3.46 g (93%) of a colorless oil. 12-4: 4-Chlorophenylpropiolate ethyl (A) Prepared similarly from 4-chloroiodobenzene to give 4.60 g (100%) of a colorless solid. 12-5: 2-Chlorophenylpropiolate ethyl (A) 7.64 g (100%) of a yellow solid was similarly obtained from 2-chloroiodobenzene. 12-6: 3-thienylpropiolate ethyl (A) 90 mg (53%) of a yellow solid was similarly obtained from 3-thienyliodobenzene. 12-7: 4-Methoxyphenylpropiolate ethyl (A) 117 mg (13%) of colorless oil was similarly obtained from 4-methoxyiodobenzene.

Example 13-1: 1-Ethoxycarbonyl-2- (4- (trifluoromethyl)
Phenyl) -4-trimethylsilyl-1-buten-4-yne (C) Pd (OAc) ₂ (2.6 mg, 0.0115 mmol) in PhMe (2 mL).
Tris (2,6-dimethoxyphenyl) phosphine (5.1 mg, 0.0
115 mmol) was added. After 15 minutes, 12-1 (117 mg, 0.573 mm
ol) in PhMe (3 mL) was added. After 5 minutes, (trimethylsilyl) acetylene (0.081 mL, 56 mg, 0.573 mmol) was added. 21
After time the reaction mixture was concentrated. Column chromatography (10% EtOAc /
Hexane) provided 13-1 (144 mg, 83%) as a yellow oil. The following compounds were similarly obtained from the corresponding propiolate intermediates treated under the above conditions. 13-2: 1-Ethoxycarbonyl-2- (4-fluorophenyl) -4-trimethylsilyl-1-buten-4-yne (C) Prepared similarly from Intermediate 12-2, 29 mg (58%) of yellow. I got oil. 13-3: 1-Ethoxycarbonyl-2- (2-fluorophenyl) -4-trimethylsilyl-1-buten-4-yne (C) 4.19 g (80%) prepared analogously from Intermediate 12-3. To give a yellow oil. 13-4: 1-Ethoxycarbonyl-2- (4-chlorophenyl) -4-trimethylsilyl-1-buten-4-yne (C) Prepared similarly from Intermediate 12-4 to give 4.04 g (60%) of A brown oil was obtained. 13-5: 1-Ethoxycarbonyl-2- (2-chlorophenyl) -4-trimethylsilyl-1-buten-4-yne (C) Prepared in a similar manner from Intermediate 12-5 to give 10.4 g (60%) of A brown oil was obtained. 13-6: 1-Ethoxycarbonyl-2- (3-fluorophenyl) -4-trimethylsilyl-1-buten-4-yne (C) Similarly prepared from the commercially available intermediate 3-fluorophenylpropiolate-ethyl. 73 g (85%) of a yellow oil was obtained. 13-7: 1-Ethoxycarbonyl-2- (3-thienyl) -4-trimethylsilyl-1-buten-4-yne (C) 123 mg (90%) of a yellow oil prepared similarly from Intermediate 12-6. Got 13-8: 1-Ethoxycarbonyl-2- (4-methoxyphenyl) -4-trimethylsilyl-1-buten-4-yne (C) Prepared similarly from Intermediate 12-7 to 144 mg (83%) of yellow. I got oil.

Example 14-1: 1-Hydroxy-3- (4- (trifluoromethyl) phenyl) -5-trimethylsilyl-2-penten-4-yne 13-1 (144 mg, 0.476 mmol) in anhydrous PhMe. (2 mL) The solution was cooled with a dry ice / acetone bath. DIBAL-H PhMe (1.2m
L, 1.19 mmol) in 1.0 M solution was added dropwise. The cooling bath was removed after 5 minutes. After an additional 15 minutes, the reaction mixture was cooled in an ice bath, Celite and Na ₂ S.
The reaction was stopped by adding O ₄ .10H ₂ O. The reaction mixture was filtered through Celite. The filtrate was concentrated. Column chromatography (20% EtOAc / hexane) gave 14-1 (144 mg, 83%) as a yellow oil. The following compounds were similarly prepared from the corresponding ester intermediates under the above conditions. 14-2: 1-Hydroxy-3- (4-fluorophenyl) -5-trimethylsilyl-2-penten-4-yne Intermediate 19-2 was similarly prepared to give 19 mg (80%) of a colorless oil. . 14-3: 1-Hydroxy-3- (2-fluorophenyl) -5-trimethylsilyl-2-pentene-4-yne Intermediate 2-3 was similarly prepared to give 2.65 g (74%) of a yellow oil. Obtained. 14-4: 1-Hydroxy-3- (4-chlorophenyl) -5-trimethylsilyl-2-penten-4-yne Intermediate 13-4 was similarly prepared to give 2.16 g (62%) of a yellow oil. It was 14-5: 1-Hydroxy-3- (2-chlorophenyl) -5-trimethylsilyl-2-penten-4-yne Intermediate 4-5 was similarly prepared to give 4.86 g (54%) of a yellow oil. It was 14-6: 1-Hydroxy-3- (3-fluorophenyl) -5-trimethylsilyl-2-penten-4-yne Intermediate similarly prepared from intermediate 13-6 0.47 g (74%) of pale yellow I got oil. 14-7: 1-Hydroxy-3- (3-thienyl) -5-trimethylsilyl-2
Prepared similarly from -penten-4-yne intermediate 13-7 to give 56 mg (77%) of a yellow oil. 14-8: 1-Hydroxy-3- (4-methoxyphenyl) -5-trimethylsilyl-2-penten-4-yne Intermediate similarly prepared from 13-8 to give 114 mg (92%) of a yellow oil. .

Example 15-1: N- (3- (4- (trifluoromethyl) phenyl) -5- (
Trimethylsilyl) -2-penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) 14-1 (115 mg, 0.385 mmol) in anhydrous CH ₂ Cl ₂ (4 mL) and dry ice / acetonitrile bath. Cooled in. PPh ₃ (152 mg, 0
． 578 mmol) and NBS (103 mg, 0.578 mmol) were added. After 40 minutes, saturated sodium bicarbonate was added. The reaction mixture was partitioned between CH ₂ Cl ₂ and saturated sodium bicarbonate. The organic layer is washed with brine, dried (Na ₂ SO ₄ ), filtered and then concentrated to give crude intermediate D [1-bromo-3- (4- (trifluoromethyl) phenyl) -5-trimethylsilyl-2-pentene. -4-in] was obtained and used directly in the next step. Crude bromide D (139 mg, 0.385 mmol) in anhydrous MeCN (4 mL)
The solution was charged with t-butyl sarcosine hydrochloride (77 mg, 0.424 mmol), K ₂ C.
O ₃ (532 mg, 3.85 mmol) and KI (320 mg, 1.92 mm)
ol) was added. After 24 hours, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated. Column chromatography (15% EtOAc / hexane) gave 15-1 (62 mg, 38% over 2 steps) as a colorless oil. The following compounds were similarly obtained from the corresponding crude bromide treated under the above conditions. 15-2: N- (3- (4-fluorophenyl) -5- (trimethylsilyl)-
2-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Prepared similarly from Intermediate 14-2 to give 18 mg (63% over 2 steps) of colorless oil. 15-3: N- (3- (2-fluorophenyl) -5- (trimethylsilyl)-
2-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Prepared similarly from Intermediate 14-3 to give 3.24 g (81% over 2 steps) of colorless oil. 15-4: N- (3- (4-chlorophenyl) -5- (trimethylsilyl) -2
-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Prepared similarly from Intermediate 14-4 to give 1.55 g (49% over 2 steps) of a colorless oil. 15-5: N- (3- (2-chlorophenyl) -5- (trimethylsilyl) -2
-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Prepared similarly from Intermediate 14-5 to give 5.39 g (75% over 2 steps) of a pale yellow oil. 15-6: N- (3- (3-fluorophenyl) -5- (trimethylsilyl)-
2-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Prepared similarly from Intermediate 14-6 to give 0.63 g (89% over 2 steps) of a pale yellow oil. 15-7: N- (3- (3-thienyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Similarly prepared from Intermediate 14-7. To give 61 mg (71%) of a pale yellow oil. 15-8: N- (3- (4-methoxyphenyl) -5- (trimethylsilyl)-
2-Penten-4-yn-1-yl) -sarcosine ^t- butyl ester (E) Prepared similarly from Intermediate 14-8 to give 14 mg (10%) of a pale yellow oil.

Example 16-1: N- (3- (4-trifluoromethyl) phenyl) -2-penten-4-yn-1-yl) -sarcosine ^t- butyl ester (F) 15-1 (62 mg, 0.146 mmol) in MeOH (2 mL) solution with K ₂
CO ₃ (101mg, 0.730mmol) was added. After 15 minutes, the reaction mixture was poured into water and extracted with EtOAc. The organic layer washed with brine, dried (MgSO ₄₎
Filtration, then concentration gave 16-1 (36 mg, 71%) as a yellow oil. The following compounds were similarly obtained from the corresponding trimethylsilyl intermediate treated under the above conditions. 16-2: N- (3- (4-fluorophenyl) -2-penten-4-yn-1
-Yl) -Sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-2 to give 13 mg (93%) of a yellow oil. 16-3: N- (3- (2-fluorophenyl) -2-penten-4-yn-1
-Yl) -Sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-3 to give 2.22 g (85%) of colorless oil. 16-4: N- (3- (4-chlorophenyl) -2-pentene-4-yn-1-
Il) -sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-4 to give 0.80 g (76%) of a yellow oil. 16-5: N- (3- (2-chlorophenyl) -2-pentene-4-yn-1-
Il) -Sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-5 to give 3.72 g (85%) of a yellow oil. 16-6: N- (3- (3-fluorophenyl) -2-penten-4-yn-1
-Yl) -Sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-6 to give 0.42 g (83%) of a pale yellow solid. 16-7: N- (3- (3-thienyl) -2-penten-4-yn-1-yl)
-Sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-7 to give 46 mg (96%) of a yellow solid. 16-8: N- (3- (4-methoxyphenyl) -2-penten-4-yn-1
-Yl) -Sarcosine ^t- butyl ester (F) Prepared similarly from Intermediate 15-8 to give 15 mg (136%) of a yellow oil.

Example 17-1: N- (5- (4-isopropylphenyl) -3- (4- (trifluoro) phenyl) -2-penten-4-yn-1-yl) -sarcosine ^t -butyl ester (G) 4-iodoisopropylbenzene (32 mg, 0.129 mmol) and Pd in a solution of 16-1 (35 mg, 0.099 mmol) in triethylamine (2 mL).
(PPh ₃ ) ₄ (11 mg, 0.0099 mmol) and CuI (5.5 mg, 0
． 029 mmol) was added. After 18 hours, the reaction mixture was concentrated. By column chromatography (10% EtOAc / hexane) 17-1 (40 mg, 86
%) As a colorless oil. The following compounds were similarly prepared from the corresponding alkyne intermediate and 1.3 equivalents of the appropriate aryl iodide according to the above conditions. 17-2: Prepared similarly from N- (5- (4-isopropylphenyl) -3- (4-fluorophenyl) -2-penten-4-yn-1 intermediate 16-2 and 4-isopropyliodobenzene. 14m
g (76%) of colorless oil was obtained. 17-3: Prepared similarly from N- (5- (4-isopropylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-1 intermediate 16-3 and 4-isopropyliodobenzene. 440
Obtained mg (79%) of a yellow oil. 17-4: From N- (5- (4-t-butylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-1 intermediate 16-3 and 4-t-butyliodobenzene. 500m prepared in the same way
g (87%) of a yellow oil was obtained. 17-5: Prepared similarly from N- (5- (4-isopropylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1 intermediate 16-4 and 4-isopropyliodobenzene. 0.5
g (88%) of a light yellow oil was obtained. 17-6: From N- (5- (4-t-butylphenyl) -3- (4-chlorophenyl) -2-pentene-4-yn-1 intermediate 16-4 and 4-t-butyliodobenzene. 514m
g (83%) of a pale yellow oil was obtained. 17-7: Prepared similarly from N- (5- (4-isopropylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1 intermediate 16-5 and 4-isopropyliodobenzene. 0.5
3 g (97%) of a yellow oil was obtained. 17-8: N- (5- (4-t-butylphenyl) -3- (2-chlorophenyl) -2-pentene-4-yn-1 Intermediate 16-5 and 4-t-butyliodobenzene Prepared to 0.52
g (92%) of a yellow oil was obtained. 17-9: Prepared similarly from N- (5- (4-isopropylphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1 intermediate 16-6 and 4-isopropyliodobenzene. 0.1
Obtained 6 g (103%) of a yellow oil. 17-10: N- (5- (4-isopropylphenyl) -3- (3-thienyl)
2-Penten-4-yn-1 Intermediate 16-7 and 54 m prepared similarly from 4-Isopropyliodobenzene
g (86%) of a yellow oil was obtained. 17-11: Prepared similarly from N- (5- (4-isopropylphenyl) -3- (4-methoxyphenyl) -2-penten-4-yn-1 intermediate 16-8 and 4-isopropyliodobenzene. 21m
g (129%) of colorless oil was obtained. 17-12: N- (5- (3,4-methylenedioxyphenyl) -3- (3-fluorophenyl) -2-pentene-4-yn-1 intermediate 16-6 and 3,4-methylenedi Prepared similarly from oxyiodobenzene to give 74.1 g (106%) of colorless oil: 17-13: N- (5- (4-ethylphenyl) -3- (2-chlorophenyl).
2-Penten-4-yn-1 Intermediate 16-5 and 44.0 mg similarly prepared from 4-ethyliodobenzene.
A (110%) colorless oil was obtained. 17-14: Prepared similarly from N- (5- (4-propylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1 intermediate 16-5 and 4-propyliodobenzene. 39.5m
g (96%) of a pale yellow oil was obtained.

Example 18-1: N- (5- (4-isopropylphenyl) -3- (4- (trifluoromethyl) phenyl) -2-penten-4-yn-1-yl) -sarcosine (H ) 17-1 (40 mg, 0.0849 mmol) in formic acid (2 mL) at 40 ° C.
It was warmed to 18 hours. The reaction mixture was concentrated. Column chromatography (0-1
00% MeOH / CH ₂ Cl ₂ ) gave 18-1 (36 mg, 99%) as a yellow oil. The following compounds were similarly prepared from the corresponding t-butyl ester intermediates under the above conditions. 18-2: N- (5- (4-isopropylphenyl) -3- (4-fluorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Intermediate 17-2 as well. Prepared to give 13 mg (107%) of a colorless oil. 18-3: N- (5- (4-isopropylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Intermediate 17-3 as well. Prepared to give 379 mg (99%) of a pale yellow oil. 18-4: N- (5- (4-t-butylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) From intermediate 17-4 Prepared similarly to give 434 mg (100%) of a yellow oil. 18-5: N- (5- (4-isopropylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) similarly prepared from Intermediate 17-5. Gave 436 mg (96%) of a beige solid. 18-6: N- (5- (4-t-butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Intermediate 17-6 as well. Prepared to give 408 mg (88%) of a beige solid. 18-7: N- (5- (4-Isopropylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Similarly prepared from Intermediate 17-7. Gave 438 mg (95%) of off-white foam. 18-8: N- (5- (4-t-butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Intermediate 17-8 as well. Prepared to give 448 mg (97%) of colorless foam. 18-9: N- (5- (4-isopropylphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Intermediate 17-9 as well. Prepared to give 0.12 g (93%) of a colorless oil. 18-10: N- (5- (4-isopropylphenyl) -3- (3-thienyl)
2-Penten-4-yn-1-yl) -sarcosine (H) Prepared similarly from Intermediate 17-10 to give 34 mg (72%) of a yellow solid. 18-11: N- (5- (4-isopropylphenyl) -3- (4-methoxyphenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Intermediate 17-11 as well. Prepared to give 14 mg (76%) of a colorless oil. 18-12: N- (5- (3,4-methylenedioxyphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) intermediate 17- Prepared similarly from 12 to give 64.1 mg (88%) of an orange-brown oil. 18-13: N- (5- (4-ethylphenyl) -3- (2-chlorophenyl)
2-Penten-4-yn-1-yl) -sarcosine (H) Prepared similarly from Intermediate 17-13 to give 30.1 mg (79%) of colorless oil. 18-14: N- (5- (4-Propylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine (H) Similarly prepared from Intermediate 17-14. To give 13.9 mg (40%) of a pale yellow oil.

Example 20 Assay of Transport via GlyT-1 This example shows a method for measuring glycine uptake by transfected (transfected) cultured cells. Cells stably transfected with GlyT-1C (Kim, et al., M
olecular Pharmacology, 45, 1994: 608-617) in HEPES buffered saline (see
It was washed twice with HBS). The cells were then incubated at 37 ° C. for 10 minutes, then 50 nM [ ³ H] glycine (17.5 Ci / mmol) and (a) potentially non-competitive, (b) 10 mM radioactive non-activated glycine or (c).
) A solvent containing any one of the drug candidates (a) to (c) at a certain concentration was added.
Data for calculating the concentration that results in 50% efficacy (ie IC ₅₀ s, which is the concentration that inhibits glycine uptake by 50%) using several ranges of concentrations of the drug candidate. Was created. The cells were subsequently incubated for a further 10 minutes at 37 ° C. after which the cells were aspirated and washed 3 times with ice cold HBS. The cells were collected, scintillant was added to the cells, the cells were shaken for 30 minutes, and the radioactivity in the cells was counted using a scintillation counter.
Data with and without contact with drug candidates in the same cells were compared depending on the assay being performed. The compounds of the present invention were active as GlyT-1 inhibitors.

Example 21 NMDA Receptor Binding Assay This example illustrates a binding assay to determine the interaction of a compound with a glycine site on the NMDA receptor. Direct binding of [ ³ H] glycine to the NMDA-glycine site was demonstrated by Grimwood et al.
al., Molecular Pharmacology, 41, 923-930 (1992); Yoneda et al., J. Neuroc.
hem, 62, 102-112 (1994). The binding test was performed using 150 μg of membrane protein and 50 in a volume of 0.5 ml.
Performed in eppendorf tubes containing nM [ ³ H] glycine. Non-specific binding was measured with 1 mM glycine. Drugs were dissolved in assay buffer (50 mM Tris-acetate, pH 7.4) or DMSO (0.1% final concentration). Membranes were incubated for 30 minutes on ice and bound radioligand was separated from non-radioactive ligand by filtration over Whatman GF / B glass fiber filters or centrifugation (18,000 xg, 20 minutes). The filters or pellets were quickly washed 3 times with ice-cold 5 mM Tris-acetate buffer. Filters were dried, placed in scintillation tubes and counted. The pellet was dissolved and neutralized in a deoxycholate / NaOH (0.1N) solution overnight, and the radioactivity was measured by scintillation counting. A second binding test for NMDA-glycine sites used [ ³ H] dichlorokynurenate (DCKA) and membranes were prepared as described above. Yoneda et
See al., J. Neurochem., 60, 634-645 (1993). Binding to [ ³ H] glycine was assayed as described above except that [ ³ H] (DCKA) was used to label the glycine site. The final concentration of [ ³ H] (DCKA) was 10 nM and the assay was performed on ice for 10 minutes. The third binding test for NMDA-glycine sites was [ ³ H] MK-8.
By indirect evaluation of the affinity of the ligand for the site by measuring the binding of 01 (dizocilpine). Palmer and Burns, J. Neurochem., 62, 187-1
96 (1994). Membranes for the test were performed as described above.
This binding assay allowed the antagonist and agonist to be detected separately. In this third test, the antagonist was detected and confirmed as follows: 1
00 μg of membrane was added in wells of a 96-well plate with glutamate (10 μM) and glycine (200 nM) and various concentrations of ligand tested. This assay was performed using 5 nM [ ³ H] MK-801 (23.9 Ci / mm).
ol). This [ ³ H] MK-801 binds to the ion channel bound to the NMDA receptor. The final volume of the assay was 200 μl. The assay was performed at room temperature for 1 hour. Bound radioactivity was separated from free by filtration using a TOMTEC collector. Antagonist activity was shown by a decrease in radioactivity bound to the NMDA receptor with increasing concentrations of the ligand tested. The third test was conducted as described above except that the glycine concentration was 200 nM, and the agonist was detected and confirmed. Agonist activity was demonstrated by an increase in radioactivity associated with the NMDA receptor with increasing concentrations of the ligand tested.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/47 A61K 31/47 4C086 31/695 31/695 4C206 A61P 25/18 A61P 25/18 4H006 25 / 28 25/28 C07C 323/32 C07C 323/32 C07D 207/335 C07D 207/335 215/12 215/12 307/52 307/52 317/58 317/58 333/20 333/20 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG) , CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW) ) EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE , KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Frey, Jennifer Canada, Ontario L 6 Doubles 4 tees 3, Brampton, Havelock Dora Bu 7-170 (72) Inventor Isaac, Metbin Canada, Ontario M 9 Buoy 5 E 3, Etobicoke, Markbrook Lane 10, Apartment 1507 F Term (Reference) 4C022 CA07 4C023 CA04 CA07 4C031 BA02 4C037 HA23 4C069 AC07 BB08 BB34 4C086 AA01 AA02 AA03 BA12 BB02 BC05 BC28 DA44 MA01 MA04 NA14 ZA15 ZA16 ZA18 4C206 AA01 AA02 AA03 FA51 KA01 MA01 MA04 NA14 ZA15 ZA16 ZA18 4H006 AA01 AA03 AB21 BJ50 BM10 BM30 BM73 BP72

Claims (39)

[Claims] 1. A compound of formula I: In the formula, Ar ₁ and Ar ₂ are groups each independently selected from the following aryl groups that may be independently substituted with up to 5 substituents, and the substituents are the following groups. Is selected from the group; alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, alkanoyl, thioalkyl, aralkyl, aralkyloxy, aryloxyalkyl, aryloxyalkoxy, cycloalkyl-substituted alkyl , Cycloalkyloxy-substituted alkyl, cycloalkyl-substituted alkoxy, cycloalkyloxy-substituted alkoxy, heterocycloalkyl-substituted alkyl, heterocycloalkyloxy-substituted alkyl, heterocycloalkyl-substituted alkoxy, heterocycloalkyl Carboxymethyl - substituted alkoxy, thioaryl, aralkylthio, thioaryl - alkyl, aralkylthio alkyl, _{halo, NO 2, CF 3, CN} , OH, alkylenedioxy, SO ₂
NRR ′, NRR ′, CO ₂ R, where R and R ′ are independently selected from the group consisting of H and alkyl, and a second aryl group optionally substituted as described above; R ₁ is selected from the group consisting of H and alkyl; R ₂ is selected from the group consisting of H, alkyl and benzyl; R ₃ is CO ₂ R, CONRR ′, CONH (OH), COSR , SO ₂ NRR ', P
O (OR) (OR ') and tetrazolyl, R and R'are selected from the group consisting of H and alkyl; and salts, solvates or hydrates of the above compounds It is selected from the group consisting of things. 2. Ar ₁ is halo, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ', NR.
R ′, CO ₂ R (wherein R and R ′ are independently selected from the group consisting of H and alkyl) and R ″ (X) _n (where n is 0 or 1; Is CH ₂ or a heteroatom; R ″ is H, alkyl or alkyl, halo, NO ₂ ,
CF ₃ , CN, OH, SO ₂ NRR ', NRR' and CO ₂ R (wherein R and R '
Are independently selected from the group consisting of H and alkyl), an aryl group optionally substituted with up to 3 substituents independently selected from, and up to 3 substituents independently selected from The compound according to claim 1, which is an aryl group which may be substituted with a group. 3. The compound according to claim 2, wherein Ar ₁ is phenyl. 4. The compound according to claim 2, wherein Ar ₁ is substituted phenyl. 5. The compound according to claim 4, wherein Ar ₁ is phenyl substituted with optionally substituted 5-membered aryl. 6. The compound according to claim 5, wherein the 5-membered aryl group has introduced at least one hetero atom. 7. The compound according to claim 6, wherein the 5-membered aryl group of Ar ₁ is a 3-furyl group. 8. The compound according to claim 7, wherein Ar ₁ is 4- (3-furyl) phenyl. 9. The compound according to claim 7, wherein Ar ₁ is 4- (3-thienyl) phenyl. 10. The compound according to claim 7, wherein Ar ₁ is 4- (1-pyrrolyl) phenyl. 11. The compound according to claim 4, wherein Ar ₁ is lower alkyl-substituted phenyl. 12. The compound according to claim 11, wherein Ar ₁ is 4- (alkyl) phenyl. 13. The compound according to claim 12, wherein the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl and n-butyl. 14. The compound according to claim 1, wherein Ar ₁ is alkylenedioxyphenyl. 15. The compound according to claim 14, wherein Ar ₁ is methylenedioxyphenyl. 16. The compound according to claim 15, wherein Ar ₁ is 3,4-methylenedioxyphenyl. 17. The compound according to claim 1, wherein Ar ₁ is a benzo-fused aromatic group. 18. The compound according to claim 17, wherein Ar ₁ is carbocyclic. 19. The compound according to claim 18, wherein Ar ₁ is naphthyl. 20. The compound according to claim 19, wherein Ar ₁ is 2-naphthyl. 21. Any of claims 1-20 wherein Ar ₂ is an aryl group optionally having up to 3 substituents independently selected from halo, haloalkyl, alkyl, haloalkoxy and alkoxy. The compound according to claim 7. 22. The compound of claim 21, wherein Ar ₂ is unsubstituted aryl. 23. The compound of claim 22, wherein Ar ₂ is phenyl. 24. The compound according to claim 21, wherein Ar ₂ is substituted phenyl. 25. The compound according to claim 24, wherein Ar ₂ is halo-substituted phenyl. 26. The method of claim 25 Ar ₂ is chloro or fluoro substituted phenyl
The described compound. 27. The compound according to any one of claims 1 to 26, wherein R ₁ is H. 28. The compound according to any one of claims 1-27, wherein R ₂ is H. 29. The compound according to claim 28, wherein R ₃ is methyl. 30. The compound according to any one of claims 1-28, wherein R ₃ is COOR. 31. The compound according to claim 30, wherein R ₃ is COOH. 32. A compound according to claim 1 selected from the following: N- (5- (4-fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (2-Fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (2,4-difluorophenyl) -3-phenyl-2-pentene- Four
-In-1-yl) -sarcosine N- (5- (3-nitrophenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (5- (4-nitrophenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (3-phenyl-5- (2-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-chlorophenyl) -3- Phenyl-2-penten-4-yne-
1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (3,5-bis (trifluoromethyl) phenyl) -3-phenyl-
2-Penten-4-yn-1-yl) -sarcosine N- (3,5-diphenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-diphenyl) -3- Phenyl-2-pentene-4-yn-1-
Yl) -Sarcosine N- (5- (4-trifluoromethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-benzylphenyl) -3- Phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-ethylphenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (5- (4- ^n- propylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4- ⁿ -butylphenyl)- 3-Phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4- ^n- pentylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N -(5- (4-phenoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (1-naphthyl) -3-phenyl-2-pentene-4- In-1-yl) -sarcosine N- (5- (4-methylphenyl) -3-phenyl-2-penten-4-yn-
1-yl) -sarcosine N- (5- (3-isopropylphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (2-naphthyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (3,4-dimethylphenyl) -3-Phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (2-isopropylphenyl) -3-phenyl-2-pentene-4-
In-1-yl) -sarcosine N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4- Pyrrolylphenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-trifluoromethoxyphenyl) -3-phenyl-2-penten-4-yn-1 -Yl) -sarcosine N- (5- (3,4-dimethoxyphenyl) -3-phenyl-2-pentene-4
-In-1-yl) -sarcosine N- (3-phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-methylphenyl) ) -3-Phenyl-2-pentene-4-yne-
1-yl) -sarcosine N- (3-phenyl-5- (3-thiophene) -2-penten-4-yn-1-
Yl) -Sarcosine N- (3-phenyl-5- (4-tbutylphenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4- (3-furyl) -phenyl) ) -3-Phenyl-2-pentene-
4-yn-1-yl) -sarcosine N- (5- (4- (3-thiophene) -phenyl) -3-phenyl-2-penten-4-yn-1-yl) -sarcosine N- (5- (4-Isopropylphenyl) -3- (4-trifluoromethyl) phenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (4- Fluorophenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (2-fluorophenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (4-t-butylphenyl) -3- (2-fluorophenyl) -2-
Penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (4-chlorophenyl) -2-
Penten-4-yn-1-yl) -sarcosine N- (5- (4-t-butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (2-chlorophenyl) -2-
Penten-4-yn-1-yl) -sarcosine N- (5- (4-t-butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (3-fluorophenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (4-isopropylphenyl) -3- (3-thienyl) -2-penten-4-yn-1-yl) -sarcosine N- ( 5- (4-isopropylphenyl) -3- (4-methoxyphenyl) -2
-Penten-4-yn-1-yl) -sarcosine N- (5- (3,4-methylenedioxyphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1-yl) -Sarcosine N- (5- (4-ethylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine and N- (5- (4-propylphenyl) -3. -(2-Chlorophenyl) -2-penten-4-yn-1-yl) -sarcosine. 33. N- (5- (4- (3-furyl) -phenyl) -3-phenyl-
2-Penten-4-yn-1-yl) -sarcosine compound. 34. A composition containing the compound according to any one of claims 1-33 and a carrier. 35. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any of claims 1-33 and a pharmaceutically acceptable carrier. 36. A method of treatment, comprising the step of administering a pharmaceutical composition as defined in claim 35 to a patient having a medical condition in which a glycine transport inhibitor is indicated. 37. The therapeutic method according to claim 36, wherein the medical condition is schizophrenia. 38. The method of treatment according to claim 36, wherein the medical condition is cognitive impairment. 39. The treatment method according to claim 36, wherein the medical condition is Alzheimer's disease.