SK6202002A3 - Diaryl-enynes - Google Patents

Abstract

Provided, among other things, is a compound of Formula (I), wherein, Ar1 and Ar2 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, cycloalkyl-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, CF3, 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 may 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 the group consisting of CO2R, CONRR', CONH(OH), COSR, SO2NRR', PO(OR)(OR') and tetrazolyl, wherein R and R' are independently selected from the group consisting of H and alkyl; and a salt, solvate or hydrate thereof.

Description

A compound

Technical field

The present invention relates to a class of diarylenes, pharmaceutical compositions containing them, and methods of treating neurological and neuropsychiatric diseases using these compounds.

BACKGROUND OF THE INVENTION

Synaptic transmission of communications, which structures surrounding Reviwes sequestered concentrations of it, further, maintain the fidelity released by the transporter new is a complex form of intracellular involves a very large set of specialized both post-synaptic (Kanner and Schuldiner,

22, 1987: 1032).

from synapses to synapses and affects propagation to synaptic to presynaptic use of carriers.

as in glial

Biochemistry, a neurotransmitter neurotransmitter which together prevent pre-cells in size by adjacent transmission.

terminal and

CRC Critical

The transporters thus regulate the duration of the transmission. and a

also her synaptic synapses,

Finally, sequestration allows for termination

Neurotransmitter transport is dependent on extracellular sodium and the difference in tension along the membrane; under conditions of intense neuronal outburst, such as during a seizure, transporters may act in reverse, releasing the non-transporter in a calcium-independent nonexocytotic manner (Attwell et al., Neuron, 11, 1993: 401-407). Thus, pharmacological modulation of the transporter transporters provides a means for modifying synaptic activity, thus allowing useful therapy for the treatment of neurological and psychiatric disorders.

The amino acid glycine is a major neurotransmitter in the mammalian central nervous system, acting in both inhibitory and exiting synapses. Both the central and peripheral parts of the nervous system are considered to be the nervous system. These overt glycine functions are mediated by two types of receptors, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors which are sensitive to the convulsive alkaloid strychnine and are thus reported to be sensitive to strychnine. Such receptors contain an internal chloride channel that is open upon binding of glycine to the receptor; by increasing the chloride conductivity, the ignition potential threshold is raised. Strychnine-sensitive glycine receptors are mainly found in the spinal cord and brainstem, and pharmacological agents that enhance activation of such receptors will increase inhibitory neurotransmission in these regions.

Glycine also causes modulation of the effects of glutamate, a major excitatory neurotransmitter in the central nervous system in excitatory transmission (Johnson and Ascher, Nature, 325, 1987: 529-531; Fischer et al., Glycine Transmission, Otterson and Strom-Mathisen, eds. 1990: Specifically, glycine is a linked co-agonist in the glutamate receptor class, called the N-methyl-D-aspartate (NMDA) receptor, and activation of NMDA receptors increases sodium and calcium conductivity, which depolarizes the neuron and thereby increases the likelihood of action potential flare.

NMDA receptors in the brain hippocampus region play an important role in a model of synaptic plasticity, known as long-term potentiation (LTP), which is integral to certain types of learning and memory ability (Hebb, DO (1949) The Organization of Behavior; Wiley, NY; Bliss and Collingridge (1993) Nature 361: 31-39; Morris et al (1986) Nature 319: 774-776). Increased expression of selected NMDA receptor subunits in transgenic mice results in an increase in NMDA receptor-mediated currents, an increase in LTP, and a better result in assays for learning and memory (Tan et al. (1999) Nature 401: 63).

Conversely, decreased expression of selected NMDA receptor subunits in transgenic mice leads to behavior similar to pharmacologically induced schizophrenia models, including increased mobility, increased stereotypes, and deficits in social and sexual relationships (Mohn et al.

(1999) Cell 98: 427-436). These abnormal behaviors can be improved by using antipsychotics and haloperidol and clozapine.

NMDA receptors are largely distributed by the brain, particularly high density in the cerebral cortex and hippocampal formation.

Molecular cloning revealed the existence of two classes of glycine transporters in the mammalian brain, called GlyT-1 and GlyT-2. GlyT-1 is found throughout the brain and spinal cord and has been found to be consistent with that of glutametergic pathways and NMDA receptors (Smith et al., Neuron, 8, 1992: 927-935). Molecular cloning further revealed the existence of three variants of GlyT-1, termed GlyT-1α, GlyT1b and GlyT-1c. Two of these variants (1a and 1b) have been found in rodents, each showing a unique distribution in the brain and peripheral tissues (Borowsky et al., Neuron, 10, 1993: 851-863; Adams et al., J. Neuroscience , 15, 1995: 2524-2532). The third variant, 1c, was detected only in human tissues (Kim et al., Molecular Pharmacology, 45, 1994: 608 617). These variants result from differential splicing and exon utilization and differ in their N-terminal regions. In contrast, GlyT-2 has been found mainly in the brainstem and spinal cord, and its distribution corresponds to the exact distribution of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jurský and Nelson, J. Neurochemistry, 64, 1995: 1026-1033). Another distinct feature of GlyT-2-mediated glycine transport is that it is not inhibited by sarcosine, as is the case with GlyT-1-mediated transport. These data are consistent with the view that the regulation of synaptic levels of GlyT-1 and GlyT-2 glycine selectively affects the activity of NMDA receptors and strychnine-sensitive glycine receptors.

Compounds that inhibit or activate glycine transport are expected to alter receptor function and thus be therapeutically useful in a variety of disease states.

For example, compounds that inhibit glycine transport mediated by GlyT-1 will increase glycine concentrations to

NMDA receptors that are located in the forebrain, among other locations. This increase in concentration will increase the activity of NMDA receptors, thereby reducing schizophrenia and increasing cognitive function. Alternatively, compounds that interact directly with the glycine receptor component of the NMDA receptor may have the same or similar effects as increasing or decreasing the availability of extracellular glycine due to inhibition or increase in GlyT-1 activity. See. for example, Pitkänen et al., Eur. J. Pharmacol., 253: 125-129 (1994); Thiels et al., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561-1569 (1996).

The present invention provides compounds that affect glycine transport. The invention further provides a composition for the treatment of medical conditions for which a glycine transport modulator and in particular glycine absorption inhibitors are indicated.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides compounds of Formula I:

where:

Ar ¹ and Ar are independently selected from aryl groups optionally substituted with up to five substituents independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, alkanoyl, thioalkyl, arylalkyl, arylalkyloxyalkyl, aryloxyalkyloxy, aryloxyalkyloxy, aryloxyalkyloxy, aryloxyalkyloxy, , alkyl substituted cycloalkoxy, alkoxy, substituted cycloalkyl, alkoxy, substituted cycloalkoxy, alkyl substituted by heterocycloalkyl, alkyl substituted heterocyclic cycloalkoxy, alkoxy, substituted heterocycloalkyl, substituted alkoxy heterocycloaliphaticoxy, thioaryl, arylalkylthio, tioarylalkyl, arylalkyltioalkyl, halogen, N0 _2, CF _3, CN, OH, alkylenedioxy, SO ₂ NRR ', NRR', CO ₂ R (wherein R and R 'are selected from the group consisting of H and alkyl) and a second aryl group which may be substituted as above;

R ¹ is selected from the group consisting of H and alkyl;

R ² is selected from the group consisting of H and alkyl, and benzyl;

R ³ is selected from the group consisting of CO ₂ R, CONRR ', CONH (OH), COSR, SO ₂ NRR', PO (OR) (OR ') and tetrazolyl, wherein R and R' are independently selected from the group consisting of: which is H and alkyl;

and a salt, solvate or hydrate thereof.

Compounds of Formula I have been found to inhibit glycine transport (or re-sorption) of the Glyl-1 transporter or are precursors (e.g., prodrugs) of such compounds and are thus useful in the treatment of schizophrenia as well as other related CNS diseases such as cognitive dysfunction, dementia ( including dementias related to Alzheimer's disease), diseases with deficits for concentration and depression.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I in an amount effective to inhibit glycine transport and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides compositions comprising the compounds of the present invention in an amount for pharmaceutical use for the treatment of conditions for which a glycine transport inhibitor is indicated. Preferred are compositions comprising compounds useful for the treatment of medical conditions for which inhibition of glycine transport mediated by GlyT-1 is necessary, such as treatment of schizophrenia or cognitive dysfunction.

definitions

The term aryl as used herein means a monocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl and the like or a benzofused heterocyclic group such as naphthyl, indanyl, quinolyl, fluorenyl and the like.

The term alkyl as used herein means straight or branched chain alkyl groups containing one to six carbon atoms, and includes methyl, ethyl, and the like.

The term cycloalkyl as used herein means a carbocyclic ring containing three to eight carbon atoms and including cyclopropyl, cyclohexyl and the like. Similarly, the term cycloalkoxy means a carbocyclic ring that is bonded via an oxygen atom to another group and includes cyclohexyloxy and the like.

The term heterocycloalkyl as used herein means a three to eight membered ring containing up to two heteroatoms selected from the group consisting of N, S and O, and includes piperidinyl, piperazinyl, thiopyranyl and the like. Such rings which are linked to another group via oxygen, such as piperidinyloxy and the like, are also contemplated as heterocycloalkoxy groups.

The terms arylalkyl, aryloxyalkyl and aryloxyalkoxy, as used herein, mean alkyl or alkoxy substituted by aryl or aryloxy and include benzyl, phenethyl, and the like. Similarly, the terms alkoxy substituted with heterocycloalkyl and heterocycloalkyl mean similarly. Other substituents are substituted

2-phenoxyethyl and cycloalkyl, substituted substituted benzyloxy, alkyl substituted cycloalkyl, alkyl alkoxy groups such as 2-cyclohexylethyl and wherein the alkyl or alkoxy group via another bridging oxygen group are referred to herein as cycloalkoxy substituted alkyl, alkoxy substituted alkoxy, alkoxy substituted alkoxy, alkoxy substituted alkoxy substituted with heterocycloalkyloxy.

The terms alkylene (e.g. -CH ₂ -CH ₂ -), alkenylene (e.g. -CH = CH-) and alkynylene (e.g. -OC-) as used herein refer to straight or branched bivalent groups containing one to six carbon atoms, such as methylene, ethylene, vinylene, propenylene and ethynylene.

The term alkoxy, as used herein, means straight or branched chain alkoxy groups containing one to six carbon atoms and includes methoxy, ethoxy, and the like.

The term thioalkyl as used herein means straight or branched chain alkyl groups containing one to six carbon atoms and includes thiomethyl (CH ₃ -S-), thiopropyl, and the like.

The term thioaryl means an aryl group that is linked to another group via a sulfur atom. Similarly, a thioarylalkyl group is a thioaryl group linked to another group via an alkylene group. Also, an arylalkylthio group is an arylalkyl group, such as benzyl, which is bonded to another group via a sulfur atom. Further, an arylalkylthioalkyl group is an arylalkyl group that is bonded to another group via a thioalkyl group.

As used herein, the term alkanoyl means straight or branched chain groups containing one to six carbon atoms and includes acetyl, propionyl and the like.

The term halogen as used herein means halogen and includes fluorine, chlorine, bromine and the like. The term haloalkyl means an alkyl group substituted with one or more independently selected halogen atoms, such as -CF ₃ . Similarly, the term haloalkoxy means alkoxy substituted with one or more independently selected halogen atoms, such as -CF ₃ .

The term alkylenedioxy means a group of the formula -O (CH ₂ ) _n -O-, wherein the terminal oxygen atoms are typically fused to atoms on the aryl ring to form a bicyclic ring system and include methylenedioxy, ethylenedioxy, and the like.

The term heteroatom, as used herein, means an atom other than carbon and includes N, S and O.

Detailed description and preferred embodiments

Geometry about double bond of compounds of general formula

I is drawn. That is, Ar ₂ and the carbon atom to which R ^1x is attached are cis to each other.

Compounds of formula I include those wherein Ar ¹ and Ar ² are independent, optionally substituted aryl groups.

The substitution sites on the Ar ¹ and Ar ² rings will in practice be limited to ring carbon atoms that are not bound to the core of the molecule. For example, the benzene ring may be substituted with up to 5 substituents; pyridine and pyran may contain up to 4 substituents, pyrrole, furan and thiophene may contain up to 3 substituents; imidazole 2 substituents and triazole may contain only one substituent.

In an embodiment of the invention, Ar ^{1 is an} optionally monocyclic aromatic group such as benzene, pyridine, pyran, thiophene, furan, pyrrole, imidazole and triazole. Ar ¹ preferably contains 1, 2 or 3 substituents on the aromatic ring and these substituents may be selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, alkyloxy, substituted alkoxy substituted with cycloalkyl, alkoxy, alkoxy, thioxy, wherein R and R 'are the second aryl above.

alkanoyl, thioalkyl, arylalkyl, aryloxyalkyl, aryloxyalkoxy, cycloalkyl, alkoxy alkyl substituted by heterocycloalkoxy, alkoxy arylalkylthio, cf ₃ , cn, oh,

NRR ', CO ₂ R and alkyl) and said arylalkyl cycloalkyl, alkyl substituted cycloalkoxy, substituted cycloalkoxy, alkyl substituted heterocycloalkyl, heterocycloalkyloxy, thioaryl, arylalkylthioalkyl, halogen, ethylenedioxy, optionally selected from the group consisting of

N0 ₂ ,

SO ₂ NRR 'are substituted as

In a preferred embodiment of the invention Ar ¹ is selected from the group consisting of benzene, pyridine, pyran, thiophene, furan and pyrrole, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH , alkyl, alkoxy, aryl, arylalkyl, and R '(X) _n / wherein n is 0 or 1; X is CH ₂ or a heteroatom; and R '' is H, alkyl or aryl, optionally substituted with up to three substituents selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ',

NRR 'and CO ₂ R (wherein R and R' are selected from the group consisting of H and alkyl).

In a preferred embodiment of the invention Ar ¹ is phenyl, optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH and R '(X) _n , wherein n is 0 or 1; X is CH ₂ , O, S or NR; and R '' is H, alkyl or aryl, optionally substituted with up to three substituents independently selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ', NRR' and CO ₂ R (wherein R and R 'are selected from the group consisting of H and alkyl).

In a more preferred embodiment, Ar ¹ is phenyl, optionally substituted with 1 or 2 substituents selected from the group consisting of alkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, and substituted or unsubstituted arylalkyl.

In a specific embodiment, Ar ¹ is monosubstituted phenyl wherein the substituent is in the 4-position and is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, 3-furyl and 3-thienyl.

In another embodiment, Ar ¹ is an optionally substituted benzofused aromatic group such as naphthalene, quinoline, indole, anthracene, fluorenyl, alkylenedioxyphenyl and the like, wherein the substituents may be selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH, alkyl , alkoxy, aryl, arylalkyl, and R '' (X) _{n /} wherein n is 0 or 1; X is CH ₂ or a heteroatom; and R '' is H, alkyl or aryl, optionally substituted with up to three substituents selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ', NRR' and CO ₂ R (where R and R are selected from the group consisting of H and alkyl).

In a preferred embodiment, Ar ¹ may be naphthyl, quinolinyl, indanyl, or alkylenedioxyphenyl, optionally substituted with 1.

or alkyl, 2 substituents selected from alkoxy, thioalkyl and aryl. groups, that they make up IN specific embodiments Ar ¹ is selected from

unsubstituted naphthalene and methylenedioxyphenyl.

In another embodiment of the invention, Ar ² is an optionally substituted aryl wherein the aryl is a monocyclic aromatic group such as benzene, pyridine, pyran, furan, thiophene, pyrrolidine and the like or a benzo-fused aromatic ring system such as naphthalene, quinoline, indole, anthracene, fluorenyl , alkylenedioxyphenyl and the like. 1, 2 or 3 substituents may be present and may be independently selected from the group consisting of halogen, haloalkyl, alkyl, haloalkoxy and alkoxy.

In a preferred embodiment, A is a monocyclic aromatic ring that contains up to three substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, haloalkoxy, and embodiment is A mono substituents are selected alkoxy. More preferably or disubstituted phenyl, wherein from the group halogen, haloalkyl, alkyl, haloalkoxy and alkoxy.

In a specific embodiment, Ar ^{2 is a} phenyl group which is either unsubstituted or contains one substituent selected from halogen and alkoxy.

In a more specific embodiment, Ar ^{2 is} selected from unsubstituted or monosubstituted phenyl wherein the substituent is selected from chlorine and fluorine.

In other embodiments of the invention, R ^{3 is} selected from the group consisting of -CO ₂ R-, -CONRR'-, -CONH (OH), -COSR, -SO ₂ NRR ', -PO (OR) (OR') and tetrazolyl wherein R and R 'are independently selected from H and alkyl.

In a preferred embodiment, R ³ is COOR. In a preferred embodiment of the invention, R ³ is COOH.

Compounds of formula I include those wherein R ^{1 is} selected from the group consisting of H and alkyl. Preferably R ¹ is H.

Compounds of formula I include those wherein R ^{2 is} selected from the group consisting of H, alkyl and benzyl. Preferably R ² is alkyl, preferably R ² is methyl.

In preferred embodiments, compounds of formula

I are those wherein R ¹ is H, R ² is methyl, R ³ is COOH. In this regard, Ar ¹ and Ar ^{2 are} suitably substituted or unsubstituted phenyl. Preferably Ar ^{1 is} either phenyl or 4 (substituted) -phenyl. When substituted Ar ¹ is preferably

4- (alkyl) -phenyl, especially wherein the alkyl group is a straight or branched chain comprising 4-isopropylphenyl, 1-ethylphenyl and 4-n-propylphenyl. Ar ² , whether in combination or independently, is preferably chloro or fluoro substituted phenyl.

In another preferred embodiment, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ² is unsubstituted phenyl, and Ar ¹ is 4-alkyl substituted phenyl, wherein the alkyl is straight chain and contains 1 to 4 carbon atoms.

In another preferred embodiment, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ² is 2-chlorophenyl and Ar ¹ is 4-alkylphenyl, wherein the alkyl substituent is selected from ethyl and propyl.

In another preferred embodiment of the invention, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ¹ is naphthyl, especially 2-naphthyl, and Ar ² is phenyl.

In yet another preferred embodiment of the invention, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ¹ is 3,4-methylenedioxyphenyl and Ar ² is 3-fluorophenyl.

In yet another preferred embodiment of the invention, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ² is phenyl and Ar ¹ is optionally substituted aryl substituted phenyl.

In a more preferred embodiment of the invention, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ² is phenyl and Ar ¹ is phenyl substituted with 5-membered heteroaryl which is optionally substituted.

In a most preferred embodiment of the invention, R ¹ is H, R ² is methyl, R ³ is COOH, Ar ² is phenyl and Ar ¹ is 4- (3-furyl) phenyl.

Specific 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-l-yl) sarcosine,

N- (5- (2,4-difluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine,

N- (5- (3-nitrophenyl) -3-phenyl-2-penten-4-yn-l-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-chloro-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (3,5-Bis (trifluoromethyl) phenyl) -3-phenyl-2-penten-4-yn-yl) sarcosine,

N- (3,5-diphenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-diphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-trifluoromethylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-benzyloxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-ethyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-n-propylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-n-butylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-n-pentylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-phenoxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (1-naphthyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-methylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (3-isopropylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (2-naphthyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (3,4-dimethyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (2-isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine,

N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-pyrrolylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-trifluoromethoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine,

N- (5- (3,4-dimethoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine,

N- (3-phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-methylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (3-phenyl-5- (3-thiophene) -2-penten-4-yn-1-yl) sarcosine,

N- (3-phenyl-5- (4-tert-butylphenyl) -2-penten-4-yn-1-yl) sarcosine,

N- (5- (4- (3-furyl) phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4- (3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (4- (trifluoromethyl) phenyl-2-penten-4yn-l-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (4-fluorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (2-fluorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-tert-butylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (4-chlorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-tert-butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (2-chlorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-tert-butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (3-fluorophenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (3-thienyl) -2-penten-4-yn-l-yl) sarcosine,

N- (5- (4-isopropyl-phenyl) -3- (4-methoxyphenyl) -2-penten-4-yn-yl) sarcosine,

N- (5- (3,4-methylenedioxyphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-lyl) 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.

Compounds of formula I are considered to be amino acids or derivatives thereof. Compounds that contain a carboxylate equivalent in place of a carboxyl group, such as hydroxamic acids, phosphonic acids, phosphinic acids, sulfonic acids, sulfic acids, amides, or tetrazolyl are also contemplated embodiments of the present invention.

In another embodiment of the present invention, the compound of Formula I is provided in a labeled form, such as a radiolabeled form (for example, labeled by incorporating into its structure ³ H or ¹⁴ C or conjugating to ¹²⁵ I). In a preferred embodiment of the present invention, such compounds that bind preferentially to GlyT-1 can be used to identify GlyT-1 receptor ligands by techniques known in the art. This can be accomplished by incubating the receptor or tissue in the presence of a ligand candidate and then incubating the resulting composition with an equimolar amount of a radiolabeled compound of the invention. GlyT-1 receptor ligands are thus shown to substantially occupy the GlyT-1 site and prevent binding of the radiolabeled compound of the invention. Alternatively, GlyT-1 receptor ligand candidates can be identified by first incubating the radiolabeled form of a compound of the invention and then incubating the resulting composition in the presence of the ligand candidate. A more potent GlyT-1 receptor ligand will define a radiolabeled compound of the invention at equimolar concentration.

Acid addition salts of compounds of formula I are most conveniently prepared from pharmaceutically acceptable acids and include, for example, those prepared with inorganic acids, for example hydrochloric, sulfuric or phosphoric acids, and organic acids, for example succinic, maleic, acetic or fumaric. Other salts which are not pharmaceutically acceptable, for example oxalates, can be used, for example, to isolate the compounds of formula I for laboratory use or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included are basic addition salts (e.g., sodium, potassium, and ammonium salts), solvates, and hydrates of the compounds of the invention. Basic salts are preferred, and sodium and potassium salts are particularly preferred.

Conversion of the salt of the compound into the desired salt is accomplished by standard techniques well known to those skilled in the art.

The compounds of the invention can be prepared by analogous procedures described in the prior art. For example, a compound of Formula I is readily prepared as described in Scheme 1 below. Intermediate C was prepared according to the Trost method (Trost, BM; Sorum, MT; Chan, C; Harms, AE; Ruther, GJ Am. Chem. Soc. 1997, 119, 698-708; Trost, BM; Hachiya, I .; McIntosch, MC Tetrahedron Lett. 1998, 39, 6445-6448) by condensation of an arylpropiolic acid ester such as A with trimethylsilylacetylene B in the presence of palladium (II) acetate and tris (2,6-dimethoxy (2,6-dimethoxyphenyl) phosphine. with N-bromosuccinimide gives bromide D. Treatment of D with a sarcosine ester (such as tert-butyl sarcosine) in the presence of a base provides the intermediate sarcosine derivative E. Removal of the trimethylsilyl group (e.g., potassium carbonate in methanol) and subsequent introduction of a second aryl condensation Sonogashira, K .; Yohda, Y and Hagihara, N .; Tetrahedron Lett., 1975, 4467) yields a diaryl compound G which, after removal of the protecting group, e.g. the final product H.

This route is advantageous for the parallel synthesis of a number of related compounds in which the group Ar ^{2 is the} same, but the group Ar ¹ represents a number of different aryl groups. The general intermediate F can be prepared in larger quantities and then the desired products are obtained by simple treatment with the appropriate aryl iodide under Sonogashira conditions.

reaction agents: (I) Pd (OAc) ₂ , a phosphine ligand; (ii) (a) DIBAL-H, (b) the NBS, PPh ₃ ; (iii) t-Bu sarcosine, K ₂ CO ₃ , CI; (Iv) K _: CO ₃ , MeOH; (in) Ar ¹ -! Cul, Pd (PPh ₃ ) ₄ , Et ₃ N; (Vi) acid formic acid, 50 ’C. Scheme 1 alternately the such compounds may also to prepare

as shown in Scheme 2 below. This procedure complements the above procedure in that it allows the parallel synthesis of a number of related compounds wherein Ar ¹ is the same, but the group Ar ^J represents a number of different aryl groups. In this case, general intermediate L can be prepared in large quantities and by simple treatment with the appropriate arylpropiol ester O (readily available from aryl iodide M by treatment with propiolic acid ester N in the presence of CuI and Pd (PPh ₃ )), under the conditions above and after deprotection yields products H.

Reagents: (i) CuI, Pd (PPh ₃ ), Et ₃ N; (ii) K ₃ CO ₃ , MeOH; (iii) Pd (OAc): Phosphine ligand, PhMe; (iv) DIBAL-H, PhMe, -78 C; (v) NBS, PPh ₃ ; (vi) t-Bu sarcosine, K _: CO _{3 /} KI, MeCN;

(vii) formic acid, 50 ° C.

Scheme 2

To prepare compounds wherein Ar ¹ is aryl-substituted phenyl (Ar ³ -phenyl), the following synthesis is carried out (Scheme 3). Intermediate F can be prepared according to Scheme 1, then coupled to bromoiodobenzene by Sonogashira coupling to give compound S. The aryl bromide of compound S can then be reacted with boronic acid (Ar ^3- boronic acid) under Suzuki coupling conditions to yield intermediate G '. (G 'is equivalent to G in Scheme 1, where Ar' is Ar ³ -phenyl). UG 'is then deprotected as in Scheme 1 to give H'.

(i) 4-bromoiodobenzene, Pd (PPh ₃ ) ₄ , Cul, Et ₃ N, rt, overnight; (ii) Ar ³ -boronic acid, Pd (PPh ₃ ) ₄ , 2 M Na ₂ CO ₃ , DME, 110 ° C, 1 hour; (iii) formic acid, 40 ° C, overnight.

Scheme 3

Compounds that inhibit GlyT-1 mediated glycine transport will increase glycine concentrations at the NMDA receptors that are located in the forebrain, among other locations. This increase in concentration will increase the activity of NMDA receptors, thereby reducing schizophrenia and increasing cognitive function. Alternatively, compounds that interact directly with the glycine receptor component of the NMDA receptor may have the same or similar effects as increasing or decreasing the usefulness of extracellular glycine due to inhibition or increase in GlyT-1 activity. See. for example, Pitkänen et al., Eur. J. Pharmacol., 253, 125-129 (1994);

Thiels et al., Neuroscience, 46, 501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561-1569 (1996).

For example, the compounds of the invention are administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of patches or other transdermal means), by pulmonary route using an aerosol or parenterally, e.g. Administration may be by means of a pump for periodic or continuous delivery. The compounds of the invention are administered alone or in combination with a pharmaceutically acceptable carrier or excipient according to standard pharmaceutical practice. For oral administration, the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, powders, syrups, elixirs, aqueous suspensions, and the like. In the case of tablets, the carriers used include lactose, sodium citrate, and phosphoric acid salts. Typically, various disintegrating agents such as starch and lubricating agents such as magnesium stearate and talc are used in the tablets. For oral administration in the form of capsules, diluents such as lactose and high molecular weight polyethylene glycols are preferably used. If desired, sweeteners and flavoring agents are added. For parenteral administration, sterile solutions of the compounds of the invention are usually prepared, the pH of the solutions usually being adjusted and buffered. For intravenous administration, the total concentration of solute will be controlled to obtain an isotonic solution. For ophthalmic administration, they may be used to spread an ointment or drip liquid, using eye spread systems such as known applicators or eye droppers in the art. Such compositions include mucomimetics such as hylauronic acid, chondrointine sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzalkonium chloride and conventional amounts of diluents and / or carriers. For pulmoral administration, the diluents and / or carriers may be selected to allow aerosol formation.

Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administration. Thus, suppositories will usually be made from a mixture of a substance that is solid at room temperature but melts at body temperature. Substances commonly used to form such vehicles include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of different molecular weight polyethylene glycols, and fatty acid esters of polyethylene glycol. For further discussion on suppository dosage forms, see, e.g. Remington's Pharmaceutical Sciences, 16th ed., Mack Publishing, Easton, PA, 1980, p. 1530-1533. Analogous gels or creams can be used for vaginal, urethral and rectal administration.

A variety of delivery vehicles, including, but not limited to, slow release formulations, liposomal formulations, and polymer matrices are apparent to those skilled in the art.

Examples of pharmaceutically acceptable acid addition salts for use in the invention include salts derived from mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid and organic acids such as tartaric acid, acetic acid, acid citric acid, lactic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, p-toluenesulfonic acid and arylsulfonic acid. Examples of pharmaceutically acceptable base addition salts for use herein include salts derived from non-toxic metals such as sodium or potassium, ammonium salts, and organoamine salts such as triethylamine salts. One skilled in the art will recognize many such suitable salts.

A physician or other health care professional may select the appropriate dose and dosage regimen based on the weight, age and physical condition of the object. The dose will usually be selected to maintain a serum level of the compound of the invention of between about 0.01 pg / cm ³ and about 1000 pg / cm ³ , preferably between about 0.1 pg / cm ³ and about 100 pg / cm ³ . For parenteral administration, an alternative rate of preferred amount is from about 0.001 mg / kg to about 10 mg / kg (alternatively from about 0.01 mg / kg to about 10 mg / kg), more preferably from about 0.01 mg / kg to about 1 mg / kg. mg / kg (from about 0.1 mg / kg to about 1 mg / kg). For oral administration, an alternative rate of preferred amount of administration is from about 0.001 mg / kg to about 10 mg / kg (from about 0.1 mg / kg to about 10 mg / kg), more preferably from about 0.01 mg / kg to about 1 mg / kg. mg / kg (from about 0.1 mg / kg to about 1 mg / kg). For suppository administration, an alternative rate of suitable amount of administration is from about 0.1 mg / kg to about 10 mg / kg, more preferably from about 0.1 mg / kg to about 1 mg / kg.

For use in assays of glycine transport inhibition activity, eukaryotic cells, preferably degenerate fibroblast-derived QT-β cells, are transfected to express one of three variants of human GlyT-1, namely GlyT-1α, GlyT-1b or GlyT-1c or human GlyT-2 . The sequences of these GlyT-1 transporters are described by Kim et al., Molec. Pharm. 45: 608-617, 1994, except that the sequence encoding the extreme N-terminus of GlyT-1 was only deduced from the corresponding rat-derived sequence. This N-terminal, protein coding sequence has now been confirmed to correspond to the sequence predicted by Kim et al. The sequence of human GlyT-2 has been described by Albert et al., U.S. patent application Ser. No. 08 / 700,013, filed Aug. 20, 1996, which is incorporated herein by reference. Suitable expression vectors o.i. include pRc / CMV (Invitrogen), Zap Express Vector (Stratagene Cloning System LaJolla, Ca; hereinafter referred to as Stratagene) / pBk / CMV or pBk-RSV vectors (Stratagene), Bluescript II SK ± Phagemid Vectors (Stratagene), LacSwitch (Stratagene) ), pMAM and pMAM neo (Clontech). A suitable expression vector is capable of promoting expression of a GlyT DNA found in a suitable host cell, preferably a non-mammalian host cell, which may be eukaryotic, fungal, or procaroyant. Such preferred host cells include amphibian, avian, fungal, insect and reptilian cells.

DETAILED DESCRIPTION OF THE INVENTION

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 (5 mL) was added tris (2,6-dimethoxyphenyl) phosphine (55 mg, 0.125 mmol). After 15 minutes, a solution of methylphenyl propiolate (1.00 g, 6.24 mmol) in anhydrous toluene (5 mL) was added. After an additional 5 minutes, trimethylsilylacetylene (0.88 mL, 0.61 g, 6.24 mmol) was added. After 16 hours, the reaction mixture is concentrated. Column chromatography (10% ethyl acetate / hexanes) gave enyn C (1.39 g, 86%) as a yellow oil. C: 1 H NMR (CDCl 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-trimethylsilyl-2-penten-4-yne

A solution of ester C (1.30 g, 5.03 mmol) in anhydrous toluene (20 mL) was cooled in a dry ice / acetone bath. Then a 1.0 M solution of diisobutylaluminium hydride in toluene (12.6 ml,

12.6 mmol). After 5 minutes the cooling bath was removed. 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 three times with ethyl acetate. The filtrate was washed with water and brine, dried (sodium sulfate), filtered and concentrated to give the intermediate alcohol (0.821 g, 71%) as a yellow oil. ¹ H NMR (CDCl 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-penten-4-yne (D)

A solution of the above alcohol (0.82 g, 3.56 mmol) in anhydrous dichloromethane (20 mL) was cooled in a dry ice / acetonitrile bath. Then triphenylphosphine (1.40 g, 5.34 mmol) and N-bromosuccinimide (0.95 g, 5.34 mmol) were added. After 30 minutes, the reaction is quenched with saturated sodium bicarbonate. The reaction mixture was partitioned between saturated sodium bicarbonate and dichloromethane. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated to give crude allylic bromide D which is used directly in the next step.

Example 4 N- (3-Phenyl-5- (trimethylsilyl) -2-penten-4-yn-lyl) sarcosine tert-butyl ester (E)

To a solution of the above bromide in anhydrous acetonitrile (15 mL) was added tert-butyl sarcosine hydrochloride (0.71 g,

3.90 mmol), potassium carbonate (4.91 g, 35.5 mmol) and potassium iodide (2.95 g, 17.8 mmol). 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 phase was washed with water and brine, dried (sodium sulfate), filtered and concentrated. Column chromatography (25%

ethyl acetate / hexane) the gives E (0.74 9 / 58% h two degrees) in the form of yellow oil. E: ^j H NMR (CDCl ₃ , 300 MHz) 0.19 (s, 9H), 1.41 (with, 9H), 2.32 (s, 3H) 3 10 (s, 2H) 3, 31 (d, 2H), 6.33 (t, 1 H), 7.26 - 7.38 (m, 5 H).

Example 5 N- (3-Phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (F)

To a solution of the above compound (0.74 g, 2.06 mmol) in methanol (10 mL) was added potassium carbonate (1.42 g, 10.3 mmol). After 20 minutes, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated to give the final acetylene F (0.58 g, 99%) as an off-white solid. F: NMR (CDCl ₃ , 300 MHz) 1.41 (s, 9H), 2.33 (s,

3H), 2.96 (s, 1 H), 3.10 (s, 2 H), 3.33 (d, 2 H), 6.37 (t, 1 H),

7.26-7.39 (m, 5H).

Example 6-1 N- (5- (4-Fluorophenyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine tert-butyl ester (G)

To a solution of the final acetylene F (50 mg, 0.175 mmol) in triethylamine (2 mL) was added 4-fluoroiodobenzene (26 μΐ, 51 mg, 0.228 mmol), tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.0175 mmol). ) and copper (I) iodide (10 mg, 0.0525 mmol). After 16 hours, the reaction mixture was diluted with dichloromethane and filtered. The filtrate is concentrated. Column chromatography (25% ethyl acetate / hexanes) gave acetylene G (51 mg, 77%) as a yellow oil. E: ^{Τ Η} NMR (CDC1 _3, 300 MHz) 1.42 (s, 9 H), 2.35 (s, 3H), 3.13 (s, 2H), 3.36 (d, 2H), 6, 37 (t, 1H); 7.00 (dd, 2H); 7.26-7.44 (m, 7H).

In a similar manner, the following compounds were prepared from intermediate F and 1.3 equivalents of the corresponding aryl iodide under the conditions described above:

6-2: N- (5- (2-Fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 2-fluoro-iodobenzene to give 45 mg (68%) of a yellow oil. NMR (CDC1 _3, 300 MHz) 1.42 (s, 9 H), 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-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 2,4-difluoroiodobenzene to give 49 mg (70%) of a yellow oil. ¹ H NMR (CDCl ₃ , 300 MHz)

1.42 (s, 9H), 2.36 (s, 3H), 3.13 (s, 2H), 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-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 3-nitroiodobenzene to give 73 mg (102%) of a yellow oil. ^T 1 HNMR (CDCl _3, 300 MHz) 1.42 (s, 9 H), 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, 1H),

8.27 (s, 1 H).

6-5: N- (5- (4-Nitrophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-nitroiodobenzene to give 31 mg (44%) of a yellow oil. ^T 1 HNMR (CDCl _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-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 2-thiomethyl-iodobenzene to give 19 mg (26%) of a yellow oil. ¹ H NMR (CDCl ₃ ) 1.42 (s,

9H), 2.36 (s, 3H), 2.46 (s, 3H), 3.14 (s, 2H), 3.39 (d, 2H),

6.45 (t, 1 H), 7.06 (dd, 1 H), 7.14 (d, 1 H), 7.24-7.44 (m, 6H),

7.46 (d, IH).

6-7: N- (5- (4-chlorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-chloroiodobenzene to give 52 mg (75%) of a yellow oil. ¹ H NMR (CDCl 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: N- (5- (4-Isopropylphenyl) -3-phenyl-2-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 4-isopropyl iodobenzene to give 38 mg (53%) of a yellow oil. ¹ H NMR (CDCl 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 2 H, 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 tert-butyl ester (G)

Prepared in a similar manner from 3,5-bis (trifluoromethyl) iodobenzene to give 40 mg (46%) of a yellow oil. NMR (CDC1 _3, 300 MHz) 1.42 (s, 9 H), 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) sarcosine tert-butyl ester (G)

Prepared in a similar manner from iodobenzene to give 46 mg (33%) of a yellow oil. ¹ H NMR (CDCl 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: N- (3-phenyl-5- (4-thiomethylphenyl) -2-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 4-thiomethyl-iodobenzene to give 30.0 mg (70%) of a yellow oil.

6-12: N- (3-Phenyl-5- (4-methylphenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-methyl iodobenzene to give 33 mg (85%) of a yellow oil.

6-13: N- (5- (3-Thiophene) -3-phenyl-2-penten-4-yn-lyl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 3-iodothiophene to give 30 mg (78%) of a brown oil.

6-14: N- (3-Phenyl-5- (4-tert-butylphenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from tert-butyl iodobenzene to give 38.0 mg (86%) of a yellow oil.

6-15: N- (5- (4-Methoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-methoxy-iodobenzene to give 31.0 mg (73%) of a yellow oil.

6-16: N- (5- (2-Isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 2-isopropyl iodobenzene to give 27.0 mg (64%) of an amber oil.

6-17: N- (5- (4-Diphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from biphenyl iodobenzene to give 260 mg (85%) of a yellow oil.

6-18: N- (5- (4-Trifluoromethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-trifluoromethyl iodobenzene to give 240 mg (80%) of a yellow oil.

6-19: N- (5- (4-Benzylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-benzyl iodobenzene to give 240 mg (80%) of a yellow oil.

6-20: N- (5- (4-ethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-ethyl-iodobenzene to give 240 mg (88%) of the product. 6-20: ^T 1 HNMR (CDCl _3, 300 MHz) 1.22 (t, 3H), 1.43 (s, 9 H), 2.36 (s, 3H), 2.63 (q, 2H); 3.13 (s, 2H), 3.36 (d, 2H), 6.37 (t, 1H), 7.13 (d, 2H), 7.26-7.43 (m, 7H).

6-21: N- (5- (4-n-propylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-n-propyl iodobenzene and

is obtained 240 mg (85 %) product. 6-21: ⁴ H NMR (CDCl 300 MHz) 0.93 (t, 3H), 1.43 (with, 9H), 1.57 (Sextet, 2H) , 2.36 (with, 3H), 2.57 (t, 2H), 3, 14 (with, 2H), 3.37 (d, 2H) 6.37 (t, 1H), 7, 12 (d, 2H) 7.24 - 7, 43 (M, 7H).

6-22: N- (5- (4-n-Butylphenyl) -3-phenyl-2-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 4-n-butyl iodobenzene to give 260 mg (89%) of a yellow oil.

6-23: N- (5- (4-n-Pentylphenyl) -3-phenyl-2-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 4-n-pentyl iodobenzene to give 240 mg (79%) of a yellow oil.

6-24: N- (5- (4-Phenoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-phenoxyiodobenzene to give 34.7 mg (56%) of a yellow film.

6-25: N- (5- (1-naphthyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 1-iodonaphthalene to give 35.8 mg (63.5%) of product. 6-25: ⁴ H NMR (CDCl 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, 2H),

8.30 (d, IH).

6-26: N- (5- (4-Methylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-methyl-iodobenzene 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 tert-butyl ester (G)

Prepared in a similar manner from 3-isopropyl iodobenzene to give 17.6 mg (42%) of product. 6-27: ⁴ H NMR (CDCl ₃ , 300 MHz)

1.23 (d, 6H), 1.42 (s, 9H), 2.36 (s, 3H), 2.87 (septet, 1H),

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: N- (5- (2-naphthyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 2-iodonaphthalene to give 30.0 mg (69%) of a colorless oil.

6-29: N- (5- (3,4-Dimethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 3,4-dimethyl iodobenzene to give 46 mg (98%) of a yellow film.

6-30: N- (5- (2-Isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 2-isopropyl iodobenzene to give 27.0 mg (64%) of an amber oil.

6-31: N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 3,4-methylenedioxyiodobenzene to give 40 mg (94%) of a yellow oil.

6-32: N- (5- (4-Pyrrolylphenyl) -3-phenyl-2-pentene-) tert-butyl ester

4-yn-1-yl) sarcosine (G)

Prepared in a similar manner from 4-pyrrolyl iodobenzene to give 41.0 mg (92%) of a yellow oil.

6-33: N- (5- (4-Trifluoromethoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 4-trifluoromethoxy-iodobenzene to give 28.5 mg (61%) of the product. 633: NMR (CDC1 _3, 300 MHz) 1.42 (s, 9 H), 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 tert-butyl ester (G)

Prepared in a similar manner from 3,4-dimethoxy iodobenzene to give 35.0 mg (80%) of a colorless oil.

In a similar manner, the following compounds were prepared from intermediate F and 1.3 equivalents of the corresponding aryl iodide treated under the conditions above:

6-35: N- (5- (2-quinolin) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from 2-iodoquinoline.

6-36: N- (5- (Indalyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine tert-butyl ester (G)

It is prepared in a similar manner from iodoindane.

Example 7-1

N- (5- (4-Fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

A solution of 6-1 tert-butyl ester (51 mg, 0.135 mmol) in 96% formic acid was heated at 40 ° C for 16 h. The reaction mixture was cooled and concentrated. The residue is taken up in dichloromethane and passed through an extraction tube with 2 g of solid phase, eluting with dichloromethane, then ethyl acetate and then methanol. The methanol fraction was concentrated to give amino acid 7-1 (39 mg, 90%) as a colorless foam.

NMR (CDC1 _3, 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 calcd 324.1400, found 324.1386.

In a similar manner, the following compounds were prepared from the corresponding intermediate treated according to the conditions outlined above:

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

Prepared in a similar manner from intermediate 6-2 to give 31 mg (81%) of a colorless foam. ³ H NMR (CDCl 3, 300 MHz) 2.68 (s, 3H), 3.47 (s, 2H), 3.90 (s, 2H), 6.43 (s, 1H), 7.05 (dd) 2 H, 7.23-7.42 (m, 7H). HRMS calcd 324.1400, found 324.1408.

7-3: N- (5- (2,4-Difluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-3 to give 34 mg (82%) of a colorless foam. ¹ H NMR (CDCl ₃ , 300 MHz) 2.70 (s, 3H), 3.48 (s, 2H), 3.91 (s, 2H), 6.42 (s, 1H), 6.78 (s) dd,

2H), 7.26-7.38 (m, 6H). HRMS calcd 342.1306, found

342, 1333.

7-4: N- (5- (3-Nitrophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine

(H) It is prepared in a similar way from intermediate 6-4 a obtained the 42 mg (68%) of a colorless foam. ^X H NMR (CDCl 3, 300 MHz) 2.72 (with, 3H), 3.50 (s, 2H), 3.94 (d, 2H), 6.50 (t, IH); 7.26 - 7.48 (M, 6H), 7.70 (d, 1H), 8.12 (d, 1H); 1H), 8.22 (s, 1H). HRMS

calcd 351.1345, found 351.1353.

7-5: N- (5- (4-Nitrophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-5 to give 21 mg (80%) of a colorless foam. ^X 1 HNMR (CDCl _3, 300 MHz) 2.66 (s, 3H), 3.43 (s, 2H), 3.85 (d, 2H), 6.51 (s, 1 H), 7.26 - 7.53 (m, 5H), 7.54 (d, 2H), 8.14 (d, 2H).

7-6: N- (3-Phenyl-5- (2-thiomethylphenyl) -2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-6 to give 14 mg (87%) of a colorless foam. ^T 1 HNMR (CDCl _3, 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-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-7 to give 40 mg (90%) of a colorless foam. ^and 1 HNMR (CDCl _3, 300 MHz) 2.68 (s, 3H), 3.48 (s, 2H), 3.87 (s, 2H), 6.39 (s, 1 H), 7.24 - 7.37 (m, 9H). HRMS calcd 340.1104, found 340.1097.

7-8: N- (5- (4-Isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-8 to give 32 mg (99%) of a colorless foam. ^T 1 HNMR (CDCl _3, 300 MHz) 1.21 (d, 6H), 2.65 (s, 3H), 2.86 (hept, 1H), 3.43 (s, 2H), 3.86 ( d.

2Η), 6.36 (t, 1H), 7.26-7.36 (m, 7H). HRMS calculated

348.1964, found 348.1998.

7-9: N- (5- (3,5-Bis (trifluoromethyl) phenyl) -3-phenyl-2-penten-4-yne-

1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-9 to give 26 mg (76%) of a colorless foam. ^X 1 HNMR (CDCl _3, 300 MHz) 2.67 (s, 3H), 3.46 (s, 2H), 3.87 (d, 2H), 6.52 (t, 1 H), 7.26 - 7.40 (m, 5H), 7.77 (s, 1H), 7.83 (s, 2H). HRMS calcd 442.1242, found 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 a colorless foam. ¹ H NMR (CDCl ₃ , 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 calcd 306.1494, found 306.1432.

7-11: N- (5- (4-Diphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-17 to afford 220.0 mg (97%) of a yellow solid.

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

Prepared in a similar manner from intermediate 6-18 to afford 200 mg (96%) of a yellow film.

7-13: N- (5- (4-Benzylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-19 to give 190.0 mg (87%) of a light yellow solid.

7-14: N- (5- (4-Ethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-20 to give 176.1 mg (86%) of a greenish solid.

7-15: N- (5- (4-n-Propylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-21 to afford 190.9 mg (93%) of an orange-white solid.

7-16: N- (5- (4-n-Butylphenyl) -3-phenyl-2-penten-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.

7-17: N- (5- (4-n-Pentylphenyl) -3-phenyl-2-penten-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.

7-18: N- (5- (4-Phenoxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-24 to give 33.0 mg (100%) of a light yellow solid.

7-19: N- (5- (1-Naphthyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-25 to afford 25.4 mg (82%) of a yellow oil.

7-20: N- (5- (4-Methylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-26 to give 12.6 mg (55%) of a yellow solid.

7-21: N- (5- (3-Isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-27 to give 12.6 mg (83%) of a green-brown oil.

7-22: N- (5- (2-Naphthyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-28 to give 25.1 mg (97%) of a yellow solid.

7-23: N- (5- (3,4-Dimethylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-29 to give 33.2 mg (97%) of a pale yellow solid.

7-24: N- (5- (2-Isopropylphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-30 to give 15.2 mg (66%) of a flaky yellow solid.

7-25: N- (5- (3,4-Methylenedioxyphenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 6-31 to give 9.5 mg (31%) of an off-white solid.

7-26: N- (5- (4-Pyrolylphenyl) -3-phenyl-2-penten-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.

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.

7-28: N- (5- (3,4-Dimethoxyphenyl) -3-phenyl-2-penten-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.

In a similar manner, the following compounds were prepared from the corresponding intermediate processed under the conditions described above:

7-29: N- (5- (2-Quinoline) -3-phenyl-2-penten-4-yn-1-yl) sarcosine

Prepared in a similar manner from 6-35.

7-30: N- (5- (Indanyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine

Prepared in a similar manner from 6-36.

Example 8-1

N- (3-Phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-1-yl) sarcosine (H)

A solution of 6-11 G (vi) tert-butyl ester (30.0 mg, 0.0736 mmol) in 96% formic acid was heated at 50 ° C for 3 hours. The reaction mixture was cooled and concentrated. The residue is taken up in dichloromethane and passed through an extraction tube containing 2 g of solid phase, then eluted with dichloromethane, then ethyl acetate and then methanol. The methanol fraction was concentrated to give amino acid 8-1 (14.9 mg, 58%) as a pale yellow solid.

In a similar manner, the following compounds were prepared from the corresponding intermediate under the conditions described above:

8-2: N- (5- (4-Methylphenyl) -3-phenyl-2-penten-4-yn-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 to give 22.0 mg (87%) of a brown solid foam.

8-4: N- (3-Phenyl-5- (4-tert-butylphenyl) -2-penten-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-penten-4-yn-lyl) sarcosine (S) tert-butyl ester

To a solution of the final acetylene F (3.25 mg, 11.4 mmol) in Et ₃ N (75 mL) was added 4-bromo-iodobenzene (4.19 g, 14.8 mmol), Pd (PPh ₃ ) ₄ (1, 1, 2). 32 g, 1.14 mmol) and CuI (0.65 g, 3.42 mmol). The mixture was stirred overnight and concentrated. Column chromatography (10% EtOAc / hexanes) afforded bromide S (3.84 g, 76%) as a yellow oil a.

Example 10-1 N- (5- (4- (3-Furyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (G ') tert-butyl ester

To a solution of bromide S (3.84 g, 8.72 mmol) in DME (25 mL) was added 3-furaneboronic 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). The mixture was heated at reflux for 1 hour, cooled and partitioned between EtOAc and water. The organic phase was washed with brine, dried _(MgSO4), filtered and concentrated. Column chromatography (10 to 12.5% EtOAc / hexanes) afforded ester G '(2.62 g, 78%) as a yellow oil.

In a similar manner, the following compounds were prepared from the corresponding boronic acid under the conditions outlined above:

10-2: N- (5- (4- (3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (G ') tert-butyl ester

Prepared in a similar manner from 3-thiopheneboronic acid to give 21.0 mg (46%) of a colorless film.

In a similar manner, the following compounds were prepared from the corresponding boronic acid under the conditions outlined above:

10-3: N- (5- (4- (4-Methyl-3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester

Prepared in a similar manner from S and 4-methyl-3-thiopheneboronic acid.

10-4: N- (5- (4- (4-Methyl-3-furyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester

Prepared in a similar manner from S and 4-methylfuraneboronic acid.

10-5: N- (5- (4- (cyclohexyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester

Prepared in a similar manner from S and cyclohexylboronic acid.

10-6: N- (5- (4- (cyclopentyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine tert-butyl ester

Prepared in a similar manner from S and cyclopentylboronic acid.

Example 11

N- (5- (4- (3-Furyl) 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 heated at 40 ° C overnight and then concentrated. Column chromatography (0-8% MeOH / CH ₂ Cl ₂ ) gave a yellow solid. Trituration with MeOH gave pure compound H '(0.78%, 34%) as a white solid. Conversion of 11-1 to the corresponding sodium salt is accomplished by suspending 11-1 in methanol and adding 1 equivalent of 6M sodium hydroxide. The solution was then concentrated and the residue triturated with isopropanol to give a white solid.

In a similar manner, the following compounds are obtained from the corresponding intermediate processed under the conditions described above:

11-2: N- (5- (4- (3-Thiophene) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine (H ')

Prepared in a similar manner from intermediate 10-2 to give 11.7 mg (59%) of an off-white solid.

11-3: N- (5- (4- (4-Methyl-3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine

Prepared in a similar manner from 10-3.

11-4: N- (5- (4- (4-Methyl-3-furyl) phenyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine

Prepared in a similar manner from 10-4.

11-5: N- (5- (4- (Cyclofexyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine

Prepare in a similar manner from 10-5.

11-6: N- (5- (4- (Cyclopentyl) phenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine

Prepared in a similar manner from 10-6.

Example 12-1

Ethyl 4- (trifluoromethyl) phenylpropiolate (A)

To a solution of 4-iodobenzotrifluoride (256 mg, 0.941 mmol) in triethylamine (2.5 mL) was added ethyl propiolate (0.124 mL, 120 mg, 1.2 mmol), Pd (PPh ₃ ) ₄ (109 mg, 0.0941 mmol). ) and CuI (54 mg, 0.282 mmol). After 24 hours, the reaction mixture is concentrated. Column chromatography (10% EtOAc / hexanes) afforded 12-1 (143 mg, 65

%) as a colorless oil.

In a similar manner, the following compounds were prepared from the corresponding aryl iodide and 1.3 equivalents of ethyl propiolate treated under the conditions described above:

12-2: Ethyl 4-fluorophenyl propiolate (A)

Prepared in a similar manner from 4-fluoro-iodobenzene to give 33 mg (4%) of a colorless solid.

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

Prepared in a similar manner from 2-fluoro-iodobenzene to give 3.46 g (93%) of a colorless solid.

12-4: Ethyl 4-chlorophenyl propiolate (A)

Prepared in a similar manner from 4-chloroiodobenzene to give 4.60 g (100%) of a colorless solid.

12-5: Ethyl 2-chlorophenyl propiolate (A)

Prepared in a similar manner from 2-chloroiodobenzene to give 7.64 g (100%) of a yellow liquid.

12-6: Ethyl 3-thienylpropiolate (A)

Prepared in a similar manner from 3-thienyl iodobenzene to give 90 mg (53%) of a yellow solid.

12-7: Ethyl 4-methoxyphenyl propiolate (A)

Prepared in a similar manner from 4-methoxy-iodobenzene to give 117 mg (13%) of a colorless oil.

Example 13-1 1-Ethoxycarbonyl-2- (4- (trifluoromethyl) phenyl) -4-trimethylsilyl-1-buten-4-yne (C)

To a solution of Pd (OAc) ₂ (2.6 mg, 0.0115 mmol) in PhMe (2 mL) was added tris (2,6-dimethoxyphenyl) phosphine (5.1 mg, 0.0115 mmol). After 15 minutes, a solution of 12-1 (117 mg, 0.573 mmol) in PhMe (3 mL) was added. After 5 minutes, (trimethylsilyl) acetylene (0.081 mL, 56 mg, 0.573 mmol) was added. After 21 hours, the reaction mixture is concentrated. Column chromatography (10% EtOAc / hexanes) afforded 13-1 (144 mg, 83%) as a yellow oil.

In a similar manner, the following compounds were prepared from the corresponding propiolate intermediate treated under the conditions described above:

13-2: 1-Ethoxycarbonyl-2- (4-fluorophenyl) -4-trimethylsilyl-1-butene-

4-yn

Prepared in a similar manner from intermediate 12-2 to give 29 mg (58%) of a yellow oil.

13-3: 1-Ethoxycarbonyl-2- (2-fluorophenyl) -4-trimethylsilyl-1-butene-

4-yn

Prepared in a similar manner from intermediate 12-3 to give 4.19 g (80%) of a yellow oil.

13-4: 1-Ethoxycarbonyl-2- (4-chlorophenyl) -4-trimethylsilyl-1-butene-

4-yn

Prepared in a similar manner from intermediate 12-4 to give 4.04 g (60%) of a brown oil.

13-5: 1-Ethoxycarbonyl-2- (2-chlorophenyl) -4-trimethylsilyl-1-butene-

4-yn

Prepared in a similar manner from intermediate 12-5 to give 10.4 g (93%) of a brown oil.

13-6: 1-Ethoxycarbonyl-2- (3-fluorophenyl) -4-trimethylsilyl-1-butene-

4-yn

Prepared in a similar manner from the commercially available ethyl 3-fluorophenyl propionate intermediate to give 0.73 g (85%) of a yellow oil.

13-7: 1-Ethoxycarbonyl-2- (3-thienyl) -4-trimethylsilyl-1-buten-4-yne (C)

Prepared in a similar manner from intermediate 12-6 to give 123 mg (90%) of a yellow oil.

13-8: 1-Ethoxycarbonyl-2- (4-methoxyphenyl) -4-trimethylsilyl-1-buten-4-yne (C)

Prepared in a similar manner from intermediate 12-7 to give 144 mg (83%) of a yellow oil.

Example 14-1 1-Hydroxy-3- (4- (trifluoromethyl) phenyl) -5-trimethylsilyl-2-penten-4-yne

A solution of 13-1 (144 mg, 0.476 mmol) in anhydrous PhMe (2 mL) was cooled in a dry ice / acetone bath. A 1.0 M solution of DIBAL-H in PhMe (1.2 mL, 1.12 mmol) was then added dropwise. After cooling for 5 minutes, the bath is removed. After a further 15 minutes, the reaction mixture was cooled in an ice bath and celite and Na ₂ SO ₄ .10H ₂ O were added to quench the reaction. The reaction mixture was filtered through celite. The filtrate is concentrated. Column chromatography (20%)

EtOAc / hexanes) afforded 14-1 (114 mg, 92%) as a yellow oil.

In a similar manner, the following compounds were prepared from the corresponding ester intermediates under the conditions described above:

14-2: 1-Hydroxy-3- (4-fluorophenyl) -5-trimethylsilyl-2-penten-4-yne

Prepared in a similar manner from intermediate 13-2 to give 19 mg (80%) of a colorless oil.

14-3: 1-Hydroxy-3- (2-fluorophenyl) -5-trimethylsilyl-2-penten-4-yne

Prepared in a similar manner from intermediate 13-3 to give 2.65 g (74%) of a yellow oil.

14-4: 1-Hydroxy-3- (4-chlorophenyl) -5-trimethylsilyl-2-penten-4-yne

Prepared in a similar manner from intermediate 13-4 to give 2.16 g (62%) of a yellow oil.

14-5: 1-Hydroxy-3- (2-chlorophenyl) -5-trimethylsilyl-2-penten-4-yne

Prepared in a similar manner from intermediate 13-5 to give 4.86 g (54%) of a yellow oil.

14-6: 1-Hydroxy-3- (3-fluorophenyl) -5-trimethylsilyl-2-penten-4-yne

Prepared in a similar manner from intermediate 13-6 to give 0.47 g (74%) of a pale yellow oil.

14-7: 1-Hydroxy-3- (3-thienyl) -5-trimethylsilyl-2-penten-4-yne

Prepared in a similar manner from 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

Prepared in a similar manner from intermediate 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 tert-butyl ester (E)

A solution of 44-1 (115 mg, 0 385 mmol) in dry CH ₂ C1 ₂ (4 mL) was cooled in a dry ice-acetonitrile. PPh ₃ (152 mg, 0.578 mmol) and NBS (103 mg, 0.578 mmol) were then added. After 40 minutes, saturated NaHCO ₃ solution was added. The reaction mixture was partitioned between CH ₂ C1 ₂ and saturated NaHCO _third The organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give crude intermediate D (1-bromo-3- (4 (trifluoromethyl) phenyl) -5-trimethylsilyl-2-pentene-5- yn, which is used directly in the next step.

To a solution of crude bromide D (139 g, 0.385 mmol) in anhydrous MeCN (4 mL) was added tert-butyl sarcosine hydrochloride (77 mg, 0.424 mmol), K ₂ CO ₃ (532 mg, 3.85 mmol), and KI (320 mg, 1.92 mmol). After 24 h, the reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. Column chromatography (15% EtOAc / hexanes) afforded 15-1 (62 mg, 38% over two steps) as a colorless oil.

In a similar manner, the following compounds were prepared from the corresponding crude bromide and conditions described above:

15-2: N- (3- (4-Fluorophenyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-2 to give 18 mg (63% over two steps) of a colorless oil.

15-3: N- (3- (2-Fluorophenyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-3 to give 3.24 g (81% over two steps) of a yellow oil.

15-4: N- (3- (4-chlorophenyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-4 to give 1.55 g (49%) of a yellow oil.

15-5: N- (3- (2-chlorophenyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-5 to give 5.39 g (75%) of a yellow oil.

15-6: N- (3- (3-Fluorophenyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-6 to give 0.63 g (89%) of a yellow oil.

15-7: N- (3- (3-Thienyl) -5- (trimethylsilyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-7 to give 61 mg (71%) of a yellow oil.

15-8: N- (3- (4-methoxyphenyl) -5- (trimethylsilyl) 2-penten-4-yn-1-yl) sarcosine tert-butyl ester (E)

Prepared in a similar manner from intermediate 14-8 to give 14 mg (10%) of a yellow oil.

Example 16-1 N- (3- (4- (Trifluoromethyl) phenyl) -2-penten-4-yn-lyl) sarcosine tert-butyl ester (F)

To a solution of 15-1 (62 mg, 0.146 mol in MeOH (2 mL)) was added

K ₂ CO ₃ (101 mg, 0.730 mmol). After 15 h, the reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried _(MgSO4), filtered and concentrated to give

16-1 (36 mg, 71%) as a yellow oil.

In a similar manner, the following compounds were prepared from the corresponding trimethylsilyl derivatives and under the conditions outlined above:

16-2: N- (3- (4-Fluorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (F)

Prepared in a similar manner from intermediate 15-2 to give 13 mg (93%) of a yellow oil.

16-3: N- (3- (2-Fluorophenyl) -2-penten-4-yn-lyl) sarcosine tert-butyl ester (F)

Prepared in a similar manner from intermediate 15-3 to give 2.22 g (85%) of a colorless oil.

16-4: N- (3- (4-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (F)

Prepared in a similar manner from intermediate 15-4 to give 0.80 g (76%) of a yellow oil.

16-5: N- (3- (2-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (F)

Prepared in a similar manner 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 tert-butyl ester (F)

Prepared in a similar manner 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 tert-butyl ester (F)

Prepared in a similar manner from intermediate 15-7 to give 48 mg (96%) of a yellow solid.

16-8: N- (3- (4-methoxyphenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (F)

Prepared in a similar manner from intermediate 15-8 to give 15 mg (136%) of a yellow oil.

Example 17-1 N- (5- (4-Isopropylphenyl) -3- (4- (trifluoromethyl) phenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

To a solution of 16-1 (35 mg, 0.099 mmol) in triethylamine (2 mL) was added 4-iodoisopropylbenzene (32 mg, 0.129 mmol), Pd (PPh ₃ ) ₄ (11 mg, 0.0099 mmol) and CuI (5 mL). (5 mg, 0.29 mmol). After 18 hours, concentrate the reaction mixture. Column chromatography (10%

EtOAc / hexanes) afforded 17-1 (40 mg, 86%) as a colorless oil.

In a similar manner, the following compounds were prepared from 1.3 equivalents of the appropriate aryl iodide and the corresponding alkyne intermediate according to the conditions described above:

17-2: N- (5- (4-Isopropylphenyl) -3- (4-fluorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-2 and 4-isopropyl iodobenzene to give 14 mg (76%) of a colorless oil.

17-3: N- (5- (4-Isopropylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-3 and 4-isopropyl iodobenzene to give 440 mg (79%) of a yellow oil.

17-4: N- (5- (4-tert-Butylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-3 and 4-tert-butyl iodobenzene to give 500 mg (87%) of a yellow oil.

17-5: N- (5- (4-Isopropylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-4 and 4-isopropyl iodobenzene to give 0.50 g (88%) of a pale yellow oil.

17-6: N- (5- (4-tert-Butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediates 16-4 and 4terc. butyl iodobenzene to give 514 mg (83%) of a pale yellow oil and.

17-7: N- (5- (4-Isopropylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-5 and 4-isopropyl iodobenzene to give 0.53 g (97%) of a yellow oil.

17-8: N- (5- (4-tert-Butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-5 and 4-tert-butyl iodobenzene to give 0.52 g (92%) of a yellow oil.

17-9: N- (5- (4-Isopropylphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-6 and 4-isopropyl iodobenzene to give 0.16 g (103%) of a yellow oil.

17-10: N- (5- (4-Isopropylphenyl) -3- (3-thienyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-7 and 4-isopropyl-iodobenzene to give 54 mg (86%) of a yellow oil.

17-11: N- (5- (4-Isopropylphenyl) -3- (4-methoxyphenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-8 and 4-isopropyl iodobenzene to give 21 mg (129%) of a colorless oil.

17-12: N- (5- (3,4-methylenedioxyphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-6 and 3,4-methylenedioxy iodobenzene to give 71.4 mg (106%) of a brown oil.

17-13: N- (5- (4-ethylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-5 and 4-ethyl iodobenzene to give 44.0 mg (110%) of a pale yellow oil.

17-14: N- (5- (4-propylphenyl) -3- (2-chlorophenyl) 2-penten-4-yn-1-yl) sarcosine tert-butyl ester (G)

Prepared in a similar manner from intermediate 16-5 and 4-propyl iodobenzene to give 39.5 mg (96%) of a pale yellow oil.

Example 18-1

N- (5- (4-Isopropylphenyl) -3- (4- (trifluoromethyl) phenyl-2-penten-4-yn-1-yl) sarcosine (H)

A solution of 17-1 (40 mg, 0.0849 mmol) in formic acid (2 mL) was heated at 40 ° C for 18 hours. The reaction mixture was concentrated. Column chromatography (0-100% MeOH / CH ₂ Cl ₂ O to give 18-1 (36 mg, 99%) as a yellow oil.

In a similar manner, the following compounds were prepared from the corresponding tert-butyl ester intermediate under the conditions outlined above:

18-2: N- (5- (4-isopropylphenyl) -3- (4-fluorophenyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner from intermediate 17-2 to give 13 mg (107%) of a colorless oil.

18-3: N- (5- (4-Isopropylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner from intermediate 17-3 to give 379 mg (99%) of a pale yellow oil.

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

Prepared in a similar manner from intermediate 17-4 to give 434 mg (100%) of a yellow oil.

18-5: N- (5- (4-Isopropylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner from intermediate 17-5 to afford 436 mg (96%) of an ocher solid.

18-6: N- (5- (4-tert-Butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 17-6 to afford 408 mg (88%) of an ocher solid.

18-7: N- (5- (4-Isopropylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner from intermediate 17-7 to give 438 mg (95%) of an off-white foam.

18-8: N- (5- (4-tert-Butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 17-8 to give 448 mg (97%) of a colorless foam.

18-9: N- (5- (4-Isopropylphenyl) -3- (3-fluorophenyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner from intermediate 17-9 to give 0.12 g (93%) of a colorless oil.

18-10: N- (5- (4-isopropylphenyl) -3- (3-ienyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner 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)

Prepared in a similar manner from intermediate 17-11 to give 14 mg (76%) of a colorless oil.

18-12: N- (5- (3,4-Methylenedioxyphenyl) -3- (3-fluorophenyl) -2-pentene-

4-Yn-1-yl) sarcosine (H)

Prepared in a similar manner from intermediate 17-12 to afford 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 in a similar manner from intermediate 17-13 to give 30.1 mg (79%) of a colorless oil.

18-14: N- (5- (4-Propylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-lyl) sarcosine (H)

Prepared in a similar manner from intermediate 17-14 to give 13.9 mg (40%) of a pale yellow oil.

Example 20

GlyT-1 transport assay

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

Cells stably transfected with GlyT-1C (see Kim et al., Molecular Pharmacology 45, 1994: 608-617) were washed twice with HEPES buffered saline (HBS). These cells were then incubated for 10 minutes at 37 ° C and then a solution containing 50 nM [ ³ H] glycine (17.5 Ci / mmol) and either (a) no potential competitor, (b) 10 mM non-radioactive glycine or ( c) the concentration of the candidate drug. The range of concentrations of the candidate drug was such that the concentration calculation data that generated 50% of the effect was generated (e.g. IC ₅₀ , which is the drug concentration inhibiting adsorptionuglycine by 50%). These cells were then incubated for an additional 10 minutes at 37 ° C and then the cells were aspirated and washed three times with ice-cold HBS. Cells were harvested, scintillant added, cells were shaken for 30 minutes and radioactivity was determined using a scintillation counter. Data were compared to the same cells that were contacted or not contacted with the candidate agent, depending on the assay performed.

The compounds of the invention were active as GlyT1 inhibitors.

Example 21

Binding to NMDA receptors

This example illustrates binding assays to measure the interaction of compounds with a glycine site at the NMDA receptor.

Direct binding of [Ή] glycine to the NMDA-glycine site was performed according to the method described by Grimwood et al., Molecular Pharmacology, 41, 923-930 (1992); Yoneda et al., J. Neurochem., 62, 102-112 (1994).

The binding assay is performed in eppendorf tubes containing 150 µg membrane protein and 50 nM [ ³ H] glycine in a volume of 0.5 ml. Non-specific binding was determined with 1 mM glycine. Drug is dissolved in assay buffer (50 mM Tris-acetate, pH 7.4) or DMSO (0.1% final concentration). The membranes are incubated on ice for 30 minutes and bound radioligand is separated from free radioligand by filtration on Whatman GF / B glass filters or by centrifugation (18,000 xg, 20 minutes). The filters or pellets are washed three times quickly with ice-cold 5 mM Trisacetate buffer. The filters are dried and placed in scintillation tubes and counted. The pellets were dissolved in a solution of a mixture of deoxycholate and NaOH (0.1 N) overnight, neutralized and radioactivity determined by scintillation counting.

The second NMDA-glycine binding site binding assay uses [3H] dichlorocyanenenic acid (DCKA) and membranes prepared as described above. See. Yoneda et al., J.

Neurochem., 60, 634-645 (1993). The binding assay is performed as described above for [ ³ H] glycine above, except that [ ³ H] DCKA is used to mark 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 assay used for the NMDA-glycine site used indirectly to examine the affinity of ligands for the site by measuring [3 H] MK-801 (dizocilpine). See. Palmer and Burns, J. Neurochem. 62, 187-196 (1994). Preparation of membranes for the assay was the same as above. The binding assay allowed separate detection of antagonists and agonists.

A third binding assay was performed to identify antagonists as follows: 100 µg of membranes were plated into wells of a 96-well plate along with glutamate (10 µM) and glycine (200 nM) and various concentrations of the ligand to be tested.

The assay was initiated by the addition of 5 nM [ ³ H] MK-801 (23.9 Ci / mmol), which binds to the ion channel associated with

NMDA receptors.

The final assay volume was 200 µl. hour at room temperature, separated from free filtration with

The assay was performed 1 Binding radioactivity using a TOMTEC collector.

Antagonist activity was indicated by a decrease in NMDA receptor-associated radioactivity with an increase in test ligand concentration.

A third binding assay was performed to identify agonists by performing the assay as described above, except that the glycine concentration was 200 nM. Agonist activity was indicated by a decrease in NMDA receptor-associated radioactivity with an increase in test ligand concentration.

Claims (35)

PATENT CLAIMS 1. A diarylene derivative of the general formula I: where: Ar ¹ and Ar ² are independently selected from aryl groups, optionally substituted with up to five substituents independently selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, alkanoyl, thioalkyl, arylalkyl, arylalkyloxy, aryloxyalkyloxy, aryloxyalkyloxy, aryloxyalkyloxy, cycloalkyl, alkyl substituted cycloalkoxy, alkoxy, substituted cycloalkyl, alkoxy, substituted cycloalkoxy, alkyl substituted by heterocycloalkyl, alkyl substituted with heterocycloalkyl-, alkoxy, substituted heterocycloalkyl, substituted alkoxy heterocycloaliphaticoxy, thioaryl, arylalkylthio, tioarylalkyl, arylalkyltioalkyl, halogen, N0 _2, CF _3, CN, OH, alkylenedioxy, SO ₂ NRR ', NRR', CO ₂ R (wherein R and R 'are selected from the group consisting of H and alkyl) and a second aryl group which may be substituted as above; R ¹ is a selected from groups, which is H and alkyl; R is a selected from groups, which consists of H, alkyl and benzyl; R ³ is a selected from groups, which is CO _; R, CONRR ', CONH (OH) COSR. SO> NRR 1 r PO (OR) (OR ') and tetrazolyl, wherein R and R 'are independently selected from the group consisting of H and alkyl; and a salt, solvate or hydrate thereof. A compound according to claim 1, wherein Ar ¹ is an aryl group optionally substituted with up to three substituents independently selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ', NRR' and CO ₂ R (wherein R and R 'are selected from the group consisting of H and alkyl) and a substituent of formula R''(X) _n -, wherein n is 0 or 1; X is CH ₂ or a heteroatom; R '' is H, alkyl or aryl, optionally substituted with up to three substituents selected from the group consisting of halogen, NO ₂ , CF ₃ , CN, OH, SO ₂ NRR ', NRR' and CO ₂ R (wherein R and R ' are selected from the group consisting of H and alkyl). The diaryleneyn of claim 2, wherein Ar ¹ is phenyl. The diaryleneyn of claim 2, wherein Ar ¹ is substituted phenyl. The diaryleneyn of claim 4, wherein Ar ¹ is phenyl substituted with an optionally substituted 5-membered aryl group. The diaryleneyn of claim 5, wherein said 5-membered aryl group comprises at least one heteroatom. The diaryleneyn of claim 6, wherein Ar ¹ as a 5-membered aryl group is a 3-furyl group. The diaryleneyn of claim 7, wherein Ar ¹ is 4- (3-furyl) phenyl. The diarylene of claim 7, wherein Ar ¹ is 4- (3-thienyl) phenyl. The diaryleneyn of claim 7, wherein Ar ¹ is 4- (1-pyrrolyl) phenyl. The diaryleneyn of claim 4, wherein Ar ¹ is lower alkyl substituted phenyl. The diaryleneyn of claim 11, wherein Ar ¹ is 4- (alkyl) phenyl. The diaryleneyn of claim 12, wherein said alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl. The diaryleneyn of claim 1, wherein Ar ¹ is alkylenedioxyphenyl. The diaryleneyn of claim 14, wherein Ar ¹ is methylenedioxyphenyl. 16. The compound according to claim 15, wherein ^Ar1 is 3,4-methylenedioxyphenyl. The diaryleneyn of claim 1, wherein Ar ^{1 is an} aromatic group. is benzocondensed 18th A compound by claim 17 where Ar ¹ is carbocyclic. 19th A compound by claim 18 where Ar ¹ is naphthyl. 20th A compound by claim 19 where Ar ¹ is naphthyl. 21st A compound by any from claims 1 to 20, wherein Ar ² aryl, optionally independently selected, are alkyl, haloalkoxy, and alkoxy substituents. substituted with up to three of halo, haloalkyl, 22. A compound according to claim 21, aryl. where Ar ² is unsubstituted 23rd A compound according to claim 22, wherein Ar ² is phenyl. 24th The diaryleneyn of claim 21, wherein Ar ² is substituted phenyl. Diaryleneyn according to claim 25th substituted phenyl. 24, wherein Ar ² is halogen A diarylene according to claim 25, with chlorine or fluorine. where Ar ² is phenyl substituted 27th Diaryleneyn according to any one of claims 1 to 11 26, where R ¹ is H. 28th Diaryleneyn according to any one of claims 1 to 11 27, where R ² is H. 29th A compound according to claim 28, wherein R ³ is methyl. A compound COOR. 30th according to any one of claims 1 to 15 28, where R ³ is The diaryleneyn of claim 30, wherein R ³ is COOH. 32. The diarylene of claim 1 selected from the group consisting of: N- (5- (4-fluorophenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (2-fluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine, N- (5- (2,4-difluorophenyl) -3-phenyl-2-penten-4-yn-1-yl) sarcosine, N- (5- (3-nitrophenyl) -3-phenyl-2-penten-4-yn-l-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-l-yl) sarcosine, N- (5- (4-chloro-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (3,5-Bis (trifluoromethyl) phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (3,5-diphenyl-2-penten-4-yn-1-yl) sarcosine, N- (5- (4-diphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-trifluoromethylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-benzyloxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-ethyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-n-propylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-n-butylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-n-pentylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-phenoxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (1-naphthyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-methylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (3-isopropylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (2-naphthyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (3,4-dimethyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (2-isopropyl-phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (3,4-methylenedioxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-pyrrolylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-trifluoromethoxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (3,4-dimethoxyphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (3-phenyl-5- (4-thiomethylphenyl) -2-penten-4-yn-1-yl) sarcosine, N- (5- (4-methylphenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (3-phenyl-5- (3-thiophene) -2-penten-4-yn-l-yl) sarcosine, N- (3-phenyl-5- (4-tert-butylphenyl) -2-penten-4-yn-l-yl) sarcosine, N- (5- (4- (3-furyl) phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4- (3-thiophene) phenyl) -3-phenyl-2-penten-4-yn-l-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3- (4- (trifluoromethyl) phenyl-2-penten-4yn-l-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3- (4-fluorophenyl) -2-penten-4-yn-l-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3- (2-fluorophenyl) -2-penten-4-yn-l-yl) sarcosine, N- (5- (4-tert-butylphenyl) -3- (2-fluorophenyl) -2-penten-4-yn-l-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3- (4-chlorophenyl) -2-penten-4-yn-l-yl) sarcosine, N- (5- (4-tert-butylphenyl) -3- (4-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3- (2-chlorophenyl) -2-penten-4-yn-l-yl) sarcosine, N- (5- (4-tert-butylphenyl) -3- (2-chlorophenyl) -2-penten-4-yn-1-yl) sarcosine, N- (5- (4-isopropyl-phenyl) -3- (3-fluorophenyl) -2-penten-4-yn-l-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-lyl) 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. The compound N- (5- (4- (3-furyl) phenyl) -3-phenyl-2-penten-4-yn-lyl) sarcosine. A composition comprising a compound according to any one of claims 1 to 33 and a carrier. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 33 and a pharmaceutically acceptable carrier. 36. A method of treating a patient with a condition in need of treatment for which a glycine transport inhibitor is indicated, comprising the step of administering to the patient a pharmaceutical composition as defined in claim 35. The step of claim 36, wherein the condition requiring treatment is schizophrenia. The step of claim 36, wherein the condition requiring treatment is cognitive dysfunction. The step of claim 36, wherein the condition requiring treatment is Alzheimer's disease.