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HK1092453A1 - Aromatic oxyphenyl and aromatic sylfanylphenyl derivatives - Google Patents

Aromatic oxyphenyl and aromatic sylfanylphenyl derivatives Download PDF

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Publication number
HK1092453A1
HK1092453A1 HK06112870.4A HK06112870A HK1092453A1 HK 1092453 A1 HK1092453 A1 HK 1092453A1 HK 06112870 A HK06112870 A HK 06112870A HK 1092453 A1 HK1092453 A1 HK 1092453A1
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Hong Kong
Prior art keywords
phenoxy
phenylsulfanyl
ethyl
acetic acid
amino
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HK06112870.4A
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Chinese (zh)
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HK1092453B (en
Inventor
Garrick Paul Smith
Gitte Mikkelsen
Kim Andersen
Daniel Rodriguez Greve
Jørgen ESKILDSEN
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H. Lundbeck A/S
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Priority claimed from PCT/DK2004/000290 external-priority patent/WO2004096761A1/en
Publication of HK1092453A1 publication Critical patent/HK1092453A1/en
Publication of HK1092453B publication Critical patent/HK1092453B/en

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Description

Aromatic hydroxyphenyl and aromatic thiophenyl derivatives
The present invention relates to novel glycine transporter inhibitor compounds which are useful in the treatment of CNS disorders such as schizophrenia.
Background
Glutamate is the major excitatory amino acid in the mammalian Central Nervous System (CNS), and it acts through two classes of ionotropic and metabotropic receptors, respectively. Ionotropic glutamate receptors are divided into three subtypes, based on the affinity of the agonist for the receptor, N-methyl-D-aspartate (NMDA), (R, S) -2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl) propanoic acid (AMPA) and kainic acid (or kainate) receptors.
The NMDA receptor contains a site for binding to regulatory compounds such as glycine and polyamines. Glycine binding to its receptor triggers NMDA receptor activation. Activation of such NMDA receptors may be useful in the treatment of schizophrenia and other diseases associated with NMDA receptor dysfunction. Activation can be achieved by glycine transporter inhibitors.
Molecular cloning confirmed the presence of two glycine transporters: GlyT-1 and GlyT-2, wherein GlyT-1 can be further subdivided into GlyT-1a, GlyT-1b and GlyT-lc.
NMDA receptors can be blocked by compounds such as phencyclidine which cause psychotic states similar to schizophrenia. Likewise, NMDA antagonists such as ketamine cause negative symptoms and cognitive symptoms similar to schizophrenia. This suggests that NMDA receptor dysfunction is involved in the pathophysiology of schizophrenia.
NMDA receptors have been implicated in a variety of diseases such as Pain (Yaksh Pain 1989, 37, 111-.
Glycine transporter antagonists or inhibitors are believed to be very effective in treating schizophrenia (Javitt WO 97/20533).
Glycine transport antagonists or inhibitors are useful in the treatment of both positive and negative symptoms of schizophrenia and other psychoses, and in improving cognition in the following conditions in which cognitive processes are diminished: namely Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which brain is damaged by internal or external influences, such as head trauma or stroke. Also convulsive disorders such as epilepsy, spasticity or myoclonus may benefit from glycine transporter antagonists. Javitt et al, am.J.Psychiatry 1994, 151, 1234-. Treatment with large doses of glycine is reported to improve schizophrenia symptoms. There is a need for compounds that are more effective in the treatment of NMDA-related diseases.
Summary of The Invention
The present invention relates to compounds of formula I which are potent glycine transport inhibitors. In one aspect, the invention relates to compounds of formula I
Wherein the substituents are as defined below.
Furthermore, the present invention provides a compound of formula I as described above for use as a medicament.
Furthermore, the present invention provides a pharmaceutical composition comprising a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, such as a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent.
The present invention also provides the use of a compound of formula I as described above, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for the treatment of a disease selected from schizophrenia, including both positive and negative symptoms, and other psychoses, and for improving cognition in the following conditions in which cognitive processes are diminished: namely Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which brain is damaged by internal or external influences, such as head trauma or stroke, and convulsive diseases, such as epilepsy, spasticity or myoclonus.
The invention also provides the use of a compound of formula I as described above, or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a medicament for the treatment of post-traumatic stress disorder.
The present invention also provides a method of treating diseases and improving cognition in living animals, including humans, for treating diseases selected from schizophrenia, including both positive and negative symptoms, and other psychoses, and for improving cognition in the following conditions in which cognitive processes are diminished: namely alzheimer's disease, multi-infarct dementia, AIDS dementia, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis or diseases in which brain damage is caused by internal or external influences, such as head trauma or stroke, and convulsive diseases, such as epilepsy, spasticity or myoclonus, which comprises administering a therapeutically effective amount of a compound of formula I as described above or a pharmaceutically acceptable acid addition salt thereof.
The present invention also provides a method for the treatment of post-traumatic stress disorder in a living animal, including a human, which comprises administering a therapeutically effective amount of a compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof.
Definition of
The term "halogen" denotes fluorine, chlorine, bromine or iodine.
Expression "C1-6-alk (en/yn) yl "represents C1-6Alkyl radical, C2-6-alkenyl or C2-6-alkynyl. Expression "C3-8-Cycloalk (en) yl "represents C3-8-cycloalkyl-or cycloalkenyl.
The term "C1-6Alkyl "refers to branched or unbranched alkyl groups having 1-6 carbon atoms, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, and 2-methyl-1-propyl.
The term "C2-6Alkenyl "refers to such groups having 2 to 6 carbon atoms including a double bond, including but not limited to ethenyl, propenyl, and butenyl.
The term "C2-6Alkynyl refers to such groups having 2 to 6 carbon atoms, including a triple bondIncluding but not limited to ethynyl, propynyl, and butynyl.
The term "C3-8Cycloalkyl "refers to a monocyclic or bicyclic carbocyclic ring having 3 to 8C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term "C3-8Cycloalkenyl "refers to a monocyclic or bicyclic carbocyclic ring having 3 to 8C-atoms and comprising one double bond.
The term "C3-8-cycloalkyl (en) yl-C1-6C in alk (en/yn) yl3-8Cycloalkyl (en) yl and C1-6-alk (en/yn) yl is as defined above.
The term "C1-6-alk (en/yn) yloxy "," C1-6Alk (en/yn) ylthio (sulfonyl) "," hydroxy-C1-6-alk (en/yn) yl "," halo-C1-6-alk (en/yn) yl "," halo-C1-6-alk (en/yn) yloxy "," C1-6-alk (en/yn) ylsulfonyl "or the like refers to wherein C1-6-alk (en/yn) yl is as defined above for such groups, and "halo" represents halogen.
The term "C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl "means wherein C1-6-alk (en/yn) ylthio and C1-6-alk (en/yn) yl is as defined above for such groups.
The term "C" as used herein1-6The-alk (en/yn) yloxycarbonyl group "denotes the formula C1-6An alk (en/yn) yl-O-CO-group, in which C1-6-alk (en/yn) yl is as defined above.
The term "acyl" as used herein refers to acyl, C1-6-alk (en/yn) ylcarbonyl, arylcarbonyl, aryl-C1-6-alk (en/yn) ylcarbonyl, C3-8Cycloalkyl (en) carbonyl or C3-8-cycloalkyl (en) yl-C1-6-alk (en/yn) yl-carbonyl, wherein aryl is defined as follows.
The term "forms a saturated 3-7 membered heterocyclic ring together with nitrogen" as used herein "By saturated ring systems having 2 to 6 carbon atoms and one nitrogen, e.g. 1-pyrrolidinyl, 1-piperidinyl or 1-azaWherein all radicals may be further substituted by C1-6-alkyl substitution.
The term "together with the nitrogen form a 3-7 membered heterocyclic ring optionally containing one further heteroatom selected from O, S or N" as used herein refers to a saturated or unsaturated ring system having 2 to 6 carbon atoms and one nitrogen, or 2 to 5 carbon atoms and two nitrogens, one nitrogen and one oxygen or one nitrogen and one sulfur, e.g. 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-azanyl1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or 1-pyrazolyl, wherein all radicals may be further substituted by C1-6-alkyl substitution.
The term "aryl" refers to carbocyclic aromatic systems such as phenyl and naphthyl.
The term "monocyclic heteroaryl" refers to a 5 to 6 membered aromatic system containing 1 to 5 carbon atoms and one or more heteroatoms selected from O, S or N, for example a 5 membered monocyclic ring such as oxathiazole, dioxazole, dithiazole, oxadiazole, thiadiazole, triazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, pyrazole, pyrrole, furan or thiophene, for example 3H-1, 2, 3-oxathiazole, 1, 3, 2-dioxazole, 3H-1, 2, 3-dithiazole, 1, 3, 2-dithiazole, 1, 2, 3-oxadiazole, 1, 2, 3-thiadiazole, 1H-1, 2, 3-triazole, isoxazole, oxazole, isothiazole, thiazole, 1H-imidazole, 1H-pyrazole, 1H-pyrrole, furan or thiophene, or a 6-membered monocyclic ring such as oxathiazine, dioxazine, dithiazine, oxadiazine, thiadiazine, triazine, oxazine, thiazine, pyrazine, pyridazine, pyrimidine, oxathiadiene, dioxin, dithiine, pyridine, pyran or thiacyclohexadiene, such as 1, 2, 3-oxathiazine, 1, 2, 4-oxathiazine, 1, 2, 5-oxathiazine, 1, 4, 2-oxathiazine, 1, 4, 3-oxathiazine, 1, 2, 3-dioxazine, 1, 2, 4-dioxazine, 4H-1, 3, 2-dioxazine, 1, 4, 2-dioxazine, 2H-1, 5, 2-dioxazine, 1, 2, 3-dioxazine, 1, 2, 4-dithiazine, 4H-1, 3, 2-dithiazine, 1, 4, 2-dithiazine, 2H-1, 5, 2-dithiazine, 2H-1, 2, 3-oxadiazine, 2H-1, 2, 4-oxadiazine, 2H-1, 2, 5-oxadiazine, 2H-1, 2, 6-oxadiazine, 2H-1, 3, 4-oxadiazine, 2H-1, 2, 3-thiadiazine, 2H-1, 2, 4-thiadiazine, 2H-1, 2, 5-thiadiazine, 2H-1, 2, 6-thiadiazine, 2H-1, 3, 4-thiadiazine, 1, 23-triazine, 1, 2, 4-triazine, 2H-1, 2-oxazine, 2H-1, 3-oxazine, 2H-1, 4-oxazine, 2H-1, 2-thiazine, 2H-1, 3-thiazine, 2H-1, 4-thiazine, pyrazine, pyridazine, 1, 3-pyrimidine, 4H-1, 3-oxathiadiene, 1, 4-oxathiadiene, 4H-1, 3-dioxin, 1, 4-dioxin, 4H-1, 3-dithiine, 1, 4-dithiine, pyridine, 2H-pyran or 2H-thiadiene.
The term "alkali metal" refers to lithium, sodium, potassium and cesium.
Description of the invention
The present invention relates to compounds of formula I which are inhibitors of glycine transporter activity and are therefore useful in the treatment of diseases associated with NMDA dysfunction, such as schizophrenia.
In one aspect, the invention relates to a compound of formula I or a salt, such as a pharmaceutically acceptable salt, thereof
Wherein
X is O, S or CR11R12Wherein R is11And R12Independently selected from H or C1-6An alkyl group;
y is O or S;
R1、R2、R3and R4Independently selected from hydrogen; halogen; a cyano group; a nitro group; c1-6-an alk (en/yn) yl group; c1-6-an alk (en/yn) yloxy group; c1-6-an alk (en/yn) ylthio group; a hydroxyl group; hydroxy-C1-6-an alk (en/yn) yl group; halo-C1-6-an alk (en/yn) yl group; halo-C1-6-an alk (en/yn) yloxy group; c3-8-a cycloalk (en) yl group; c3-8-cycloalkyl (en) yl-C1-6-an alk (en/yn) yl group; an acyl group; c1-6-an alk (en/yn) yloxycarbonyl group; c1-6-an alk (en/yn) ylsulfonyl group; aryl optionally substituted with: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl or C1-6-an alk (en/yn) ylsulfonyl group; a monocyclic heteroaryl optionally substituted with: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl or C1-6-an alk (en/yn) ylsulfonyl group; or-NR13R14Wherein R is13And R14Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl or aryl, or R13And R14Together with the nitrogen, form a 3-7 membered heterocyclic ring optionally containing 1 additional heteroatom selected from O, S or N;
R5is a taskAn aryl or monocyclic heteroaryl group selected for substitution by: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl, C1-6-alk (en/yn) ylsulfonyl, or-NR15R16Wherein R is15And R16Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl or aryl, or R15And R16Together with the nitrogen, form a 3-7 membered heterocyclic ring optionally containing 1 additional heteroatom selected from O, S or N;
R6selected from H, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio or C3-8A cycloalk (en) yl group, with the proviso that if R is6Is selected from C1-6-alk (en/yn) yloxy or C1-6An alk (en/yn) ylthio group, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6An alkyl group;
R7and R8Independently selected from H, C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group;
R9and R9' independently selected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group; or
R6And R8Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R7Selected from H, C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group, and R9And R9'Du' aloneSelected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group; or
R7And R8Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R6Selected from H, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio or C3-8A cycloalk (en) yl group, with the proviso that if R is6Is selected from C1-6-alk (en/yn) yloxy or C1-6An alk (en/yn) ylthio group, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R9And R9Independently selected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group; or
R8And R9Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R6Selected from H, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio or C3-8A cycloalk (en) yl group, with the proviso that if R is6Is selected from C1-6-alk (en/yn) yloxy or C1-6An alk (en/yn) ylthio group, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R7Selected from H, C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group, and R9' selected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group;
R10is H, C1-6Alk (en/yn) yl, aryl-C1-6-an alk (en/yn) yl group, wherein the aryl group is optionally substituted with: halogen, CF3、OCF3、CN、NO2Or C1-6-an alk (en/yn) yl group; or an alkali metal such as sodium, potassium or lithium.
In one embodiment of formula I, X is O. In another embodiment of formula I, X is S. In yet another embodiment, X is CR11R12Wherein R is11And R12Is independently selected from C1-6Alkyl groups such as methyl. In yet another embodiment, X is CHR11Wherein R is11Is selected from C1-6Alkyl groups such as methyl. In yet another embodiment, X is CH2。
In yet another embodiment of formula I, Y is O. In yet another embodiment, Y is S.
In yet another embodiment of formula I, X is O and Y is S.
In still another embodiment of formula I, R1Is hydrogen. In yet another embodiment, R1Is selected from C1-6Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl or tert-butyl radical. In yet another embodiment, R1Selected from halogens, such as Cl, F, Br or I, such as Cl. In still another embodiment of formula I, R1is-NR13R14Wherein R is13And R14Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6An alk (en/yn) yl group or an aryl group. In still another embodiment of formula I, R1is-NR13R14Wherein R is13And R14Together with nitrogen to form an optionally substituted C1-6-alkyl substituted 3-7 membered heterocycle: 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-azaA group, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or 1-pyrazolyl. In still another embodiment of formula I, R1Is phenyl optionally substituted with: halogen, cyano, nitro, C1-6-alk (en/yn) yl、C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3- 8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl or C1-6-alk (en/yn) ylsulfonyl, e.g. substituted by one or two, usually one, selected from C1-6-alkyl or C1-6Phenyl substituted with an alkoxy group such as a methoxy group.
In still another embodiment of formula I, R2Is hydrogen. In yet another embodiment, R2Is selected from C1-6Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl or tert-butyl radical. In yet another embodiment, R2Selected from halogens, such as Cl, F, Br or I, such as Cl. In still another embodiment of formula I, R2Is cyano. In still another embodiment of formula I, R2is-NR13R14Wherein R is13And R14Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6An alk (en/yn) yl group or an aryl group. In still another embodiment of formula I, R2is-NR13R14Wherein R is13And R14Together with nitrogen to form an optionally substituted C1-6-alkyl substituted 3-7 membered heterocycle: 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-azaA group, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or 1-pyrazolyl. In still another embodiment of formula I, R2Is selected from 1-morpholinyl or 1-piperidinyl. In still another embodiment of formula I, R2Is phenyl. In still another embodiment of formula I, R2Is phenyl substituted with the following groups: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6Alkyl (alk; (en;))Alkynyl) oxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl or C1-6-alk (en/yn) ylsulfonyl, e.g. substituted by one or two, usually one, selected from C1-6-alkyl or C1-6Alkoxy, e.g. methoxy, or from cyano or C1-6Phenyl substituted with a substituent of alkylsulfonyl such as methylsulfonyl. In still another embodiment of formula I, R2Is a monocyclic heteroaryl group, such as pyrimidinyl.
In still another embodiment of formula I, R3Is hydrogen. In yet another embodiment, R3Is selected from C1-6Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl or tert-butyl radical. In yet another embodiment, R3Selected from halogens, such as Cl, F, Br or I, such as Cl. In still another embodiment of formula I, R3is-NR13R14Wherein R is13And R14Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6An alk (en/yn) yl group or an aryl group. In still another embodiment of formula I, R3is-NR13R14Wherein R is13And R14Together with nitrogen to form an optionally substituted C1-6-alkyl substituted 3-7 membered heterocycle: 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-azaA group, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or 1-pyrazolyl. In still another embodiment of formula I, R3Is phenyl. In still another embodiment of formula I, R3Is phenyl substituted with the following groups: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl or C1-6-alk (en/yn) ylsulfonyl, e.g. substituted by one or two, usually one, selected from C1-6-alkyl or C1-6Phenyl substituted by an alkoxy group, such as methoxy, or a substituent selected from cyano. In still another embodiment of formula I, R3Is a monocyclic heteroaryl group, such as thienyl.
In still another embodiment of formula I, R4Is hydrogen. In yet another embodiment, R4Is selected from C1-6Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl or tert-butyl radical. In yet another embodiment, R4Selected from halogens, such as Cl, F, Br or I. In still another embodiment of formula I, R4is-NR13R14Wherein R is13And R14Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6An alk (en/yn) yl group or an aryl group. In still another embodiment of formula I, R4is-NR13R14Wherein R is13And R14Together with nitrogen to form an optionally substituted C1-6-alkyl substituted 3-7 membered heterocycle: 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-azaA group, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or 1-pyrazolyl. In still another embodiment of formula I, R4Is phenyl optionally substituted with: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, haloradical-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3- 8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl or C1-6-alk (en/yn) ylsulfonyl, e.g. substituted by one or two, usually one, selected from C1-6-alkyl or C1-6Phenyl substituted with an alkoxy group such as a methoxy group.
In still another embodiment of formula I, R5Is phenyl. In yet another embodiment, R5Is phenyl substituted with the following groups: halogen, C1-6Alkyl radical, C1-6-alkoxy, C1-6Alkylthio, halo-C1-6-an alkyl group. The phenyl ring may contain 1, 2, 3, 4 or 5 substituents, typically 1 or 2 substituents independently selected from the group consisting of above, for example Cl, F, methyl, tert-butyl, methoxy, methylthio or CF3. Without limiting the invention in any way, to illustrate this, the following substructure of formula I is an embodiment of the invention:
wherein R is1、R2、R3、R4、R6、R7、R8、R9、R9’、R10X and Y are as defined above for formula I, including the embodiments described above and below, and R17、R18、R19、R20And R21Independently selected from H, halogen, C1-6Alkyl radical, C1-6-alkoxy, C1-6Alkylthio, halo-C1-6-an alkyl group. In one embodiment, R17Is H. In one embodiment, R18Is selected from H; halogen, such as Cl or F; halo-C1-6Alkyl radicals, e.g. CF3(ii) a Or C1-6Alkyl groups, such as methyl. In one embodiment, R19Is selected from H; halogen, e.g.Cl or F; halo-C1-6Alkyl radicals, e.g. CF3；C1-6-alkyl, such as methyl or tert-butyl; c1-6Alkylthio radicals, e.g. SCH3(ii) a Or C1-6Alkoxy, such as methoxy. In one embodiment, R20Is selected from H; halogen, such as Cl or F; halo-C1-6Alkyl radicals, e.g. CF3(ii) a Or C1-6Alkyl groups, such as methyl. In one embodiment, R21Is H. In general, R17And R21Are all H, R18、R19And R20One or two of which are H, and the remaining substituents are as defined above. In yet another embodiment, R17、R19And R21Are all H, and R18And R20One of which is halogen such as F and the other is hydrogen.
In still another embodiment of formula I, R5Is naphthyl such as 1-naphthyl or 2-naphthyl. In yet another embodiment, R5Naphthyl substituted with the following groups: halogen, C1-6Alkyl radical, C1-6-alkoxy, C1-6Alkylthio, halo-C1-6-an alkyl group. Naphthyl may contain 1, 2, 3, 4 or 5 substituents, typically 1 or 2 substituents independently selected from the group consisting of the above, such as Cl, F, methyl, t-butyl, methoxy, methylthio or CF3. In still another embodiment of formula I, R5Is a monocyclic heteroaryl optionally substituted with: halogen, cyano, nitro, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio, hydroxy-C1-6Alk (en/yn) yl, halo-C1-6Alk (en/yn) yl, halo-C1-6-alk (en/yn) yloxy, C3-8Cycloalkyl (en) yl, C3-8-cycloalkyl (en) yl-C1-6Alk (en/yn) yl, acyl, C1-6-alk (en/yn) yloxycarbonyl, C1-6-alk (en/yn) ylsulfonyl or-NR15R16Wherein R is15And R16Independently selected from hydrogen, C1-6-alk (en/yn) yl, C3-8Cycloalkyl (en) yl, C3-8-cycloalkane (ene)) radical-C1-6Alk (en/yn) yl or aryl, or R15And R16Together with the nitrogen, form a 3-7 membered heterocyclic ring optionally containing 1 additional heteroatom selected from O, S or N. Typically such monocyclic heteroaryl groups are selected from oxathiazole, dioxazole, dithiazole, oxadiazole, thiadiazole, triazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, pyrazole, pyrrole, furan, thiophene, oxathiazine, dioxazine, dithiazine, oxadiazine, thiadiazine, triazine, oxazine, thiazine, pyrazine, pyridazine, pyrimidine, oxathiadiene, dioxin, dithiacyclohexadiene, pyridine, pyran or thins.
In still another embodiment of formula I, R6Is H. In yet another embodiment, R6Is C1-6Alkyl groups, such as methyl. In still another embodiment of formula I, R6Is C1-6Alk (en/yn) yloxy, e.g. C1-6Alkoxy, such as methoxy, with the proviso that X is CR11R12Wherein R is11And R12Independently selected from H or C1-6An alkyl group. In still another embodiment of formula I, R6Is C1-6Alk (en/yn) ylthio radicals, e.g. C1-6Alkylthio, such as methylthio, with the proviso that X is CR11R12Wherein R is11And R12Independently selected from H or C1-6An alkyl group.
In still another embodiment of formula I, R7Is H. In yet another embodiment, R7Is C1-6Alkyl, such as methyl, ethyl or isopropyl. In yet another embodiment, R7Is C3-8Cycloalk (en) yl, e.g. C3-8Cycloalkyl radicals such as cyclopropyl, cyclopentyl or cyclohexyl.
In still another embodiment of formula I, R8Is H. In yet another embodiment, R8Is C1-6Alkyl, such as methyl, ethyl or isopropyl. In yet another embodiment, R8Is C3-8Cycloalk (en) yl, e.g. C3-8Cycloalkyl radicals such as cyclopropyl, cyclopentyl or cyclohexyl.
In still another embodiment of formula I, R9Is H. In yet another embodiment, R9Is C1-6Alkyl, such as methyl, ethyl or isopropyl. In yet another embodiment, R9Is hydroxy-C1-6Alk (en/yn) yl radicals, e.g. hydroxy-C1-6Alkyl groups such as hydroxymethyl. In yet another embodiment, R9Is C1-6Alk (en/yn) ylthio-C1-6Alk (en/yn) yl radicals, e.g. C1-6alkylthio-C1-6Alkyl groups such as methylthioethyl.
In still another embodiment of formula I, R9' is H. In yet another embodiment, R9' is C1-6Alkyl, such as methyl, ethyl or isopropyl. In yet another embodiment, R9' is hydroxy-C1-6Alk (en/yn) yl radicals, e.g. hydroxy-C1-6Alkyl groups such as hydroxymethyl. In yet another embodiment, R9' is C1-6Alk (en/yn) ylthio-C1-6Alk (en/yn) yl radicals, e.g. C1-6alkylthio-C1-6Alkyl groups such as methylthioethyl.
In general R9And R9One of' is hydrogen, but both of them may be independently selected from C1-6-alkyl, such as methyl, ethyl or isopropyl; hydroxy-C1-6Alk (en/yn) yl radicals, e.g. hydroxy-C1-6-an alkyl group; or C1-6Alk (en/yn) ylthio-C1-6Alk (en/yn) yl radicals, e.g. C1-6alkylthio-C1-6-an alkyl group.
In still another embodiment of formula I, R10Is H.
In still another embodiment of formula I, R6And R8Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R7Selected from H, C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group, and R9And R9' independently selected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group. Without limiting the invention in any way, to illustrate this, the following substructure of formula I is a separate embodiment of the invention:
wherein R is1、R2、R3、R4、R5、R7、R9、R9’、R10X and Y are as defined above for formula I, including the embodiments described.
In still another embodiment of formula I, R7And R8Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R6Selected from H, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio or C3-8A cycloalk (en) yl group, with the proviso that if R is6Is selected from C1-6-alk (en/yn) yloxy or C1-6An alk (en/yn) ylthio group, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R9And R9' independently selected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group. Without limiting the invention in any way, to illustrate this, the following substructure of formula I is an embodiment of the invention:
wherein R is1、R2、R3、R4、R5、R6、R9、R9’、R10X and Y are as defined above for formula I, including the embodiments described.
In still another embodiment of formula I, R8And R9Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R6Selected from H, C1-6-alk (en/yn) yl, C1-6-alk (en/yn) yloxy, C1-6-alk (en/yn) ylthio or C3-8A cycloalk (en) yl group, with the proviso that if R is6Is selected from C1-6-alk (en/yn) yloxy or C1-6An alk (en/yn) ylthio group, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R7Selected from H, C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group, and R9' selected from H, C1-6-alk (en/yn) yl, hydroxy-C1-6-alk (en/yn) yl, C1-6Alk (en/yn) ylthio-C1-6-alk (en/yn) yl or C3-8-a cycloalk (en) yl group. Without limiting the invention in any way, to illustrate this, the following substructure of formula I is an embodiment of the invention:
wherein R is1、R2、R3、R4、R5、R6、R7、R9’、R10X and Y are as defined above for formula I, including the embodiments, and the asterisks indicate the symbol "R" together with9'the carbon atom to which' is attached is a chiral center. In one embodiment of the formula Ie,*refers to the racemic mixture of the R-and S-isomers. In yet another embodiment of formula Ie,*refers to the R-isomer. In yet another embodiment of formula Ie,*refers to the S-isomer.
In yet another embodiment of formula I, the compound is any one of the following compounds or a pharmaceutically acceptable salt thereof:
1) (S) -1- {2- [2- (4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
2) (S) -1- {2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
3) (S) -1- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
4) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
5) (S) - {2- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
6) (S) -1- {2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
7) (S) -1- {2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
8) (S) -1- {2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
9) (S) -1- {2- [2- (3-chloro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
10) (S) -1- {2- [2- (4-chloro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
11) (S) -1- {2- [2- (4-methoxy-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
12) (S) -1- {2- [2- (3, 4-difluoro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
13)1- {2(R/S) - [2- (4-chloro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
14)1- {2(R/S) - [2- (3, 4-difluoro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
15) (S) -1- {2- [2- (3-fluoro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
16)1- {2(R/S) - [2- (3-fluoro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
17)1- {2(R/S) - [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
18)1- {2(R/S) - [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
19) ({2- [2- (4-tert-butyl-phenylthio) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
20)2- {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
21) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
22) ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
23) {2- [2- (4-tert-butyl-phenylthio) -phenoxymethyl ] -piperidin-1-yl } -acetic acid,
24) ({2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
25) {4- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -piperidin-1-yl } -acetic acid,
26) (N-2-propyl- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
27) ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
28) (N-ethyl- {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
29)2- {3- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
30) (S) - {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid,
31) ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
32) (N-2-propyl- {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
33) {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid,
34) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
35) ({2- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -ethyl- } N-methyl-amino) -acetic acid,
36) {4- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -piperidin-1-yl } -acetic acid,
37)2- {3- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
38) ({2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -N-2-propyl-amino) -acetic acid
39) ({2- [2- (4-tert-butyl-phenylthio) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
40) {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxymethyl ] -piperidin-1-yl } -acetic acid,
41) ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
42) (N-methyl- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
43)2- {3(R) - [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
44)2- {3(R) - [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
45)2- [3(R) - (2- (4-methylphenyl) -sulfanyl-phenoxy) -pyrrolidin-1-yl ] -propionic acid,
46) {3(R) - [2- (4-tert-butyl-phenylthio) -phenoxy ] -pyrrolidin-1-yl } -acetic acid,
47)2- {3(R) - [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
48)2- {3(R) - [2- (4-chloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
49) ({1- [2- (3-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-ethyl-amino) -acetic acid,
50) ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy) -butan-2-yl } -N-ethyl-amino) -acetic acid,
51) ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-ethyl-amino) -acetic acid,
52) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-ethyl-amino) -acetic acid,
53) ({1- [1- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid,
54) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -4-methyl-but-2-yl) } -N-ethyl-amino) -acetic acid,
55) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] propan-2-yl } -N-ethyl-amino) -acetic acid,
56) (S) - {1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -prop-2-yl } -N-methyl-amino) -acetic acid,
57) (S) - ({1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -prop-2-yl) -N-ethyl-amino) -acetic acid,
58) ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid,
59) ({1- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid,
60) ({1- [2- (3-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-methyl-amino) -acetic acid,
61) ({1- [2- (4-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-ethyl-amino) -acetic acid,
62) (N-ethyl- {1- [2- (3-fluoro-phenylsulfanyl) -phenoxymethyl ] -propyl } -amino) -acetic acid,
63) (R) - ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -1-methyl-ethyl } -N-ethyl-amino) -acetic acid,
64) (S) - (2{2- [2- (4-chloro-phenoxy) -phenoxy ] -propyl-N-methyl-amino) -acetic acid,
65) (R) - (2{2- [2- (3-chloro-phenylthio) -phenoxy ] - } -propyl-N-methyl-amino) -acetic acid,
66) ({2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -N-methyl-amino) -acetic acid,
67) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-ethyl-amino) -acetic acid,
68) ({1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-methyl-amino) -acetic acid,
69) ({ 3-methyl-1- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-ethyl-amino) -acetic acid,
70) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-methyl-amino) -acetic acid,
71) (S) - (1{2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -propan-2-yl } N-methyl-amino) -acetic acid,
72) (S) - (2- {2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -N-methyl-amino) -acetic acid,
73) ({1- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-ethyl-amino) -acetic acid,
74) (S) - ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-methyl-amino) -acetic acid,
75) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl) -N-methyl-amino) -acetic acid,
76) ({1- [2- (4-tert-butyl-phenylthio) -phenoxy ] -3-methyl-propan-2-yl } -N-ethyl-amino) -acetic acid,
77) ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-ethyl-amino) -acetic acid,
78) ({2- [2- (4-methoxy-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-cyclohexyl-amino) -acetic acid,
79) { [2- (2- (4-methylsulfanyl-phenoxy) -propan-1-yl- ] -N-cyclohexyl-amino } -acetic acid,
80) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-cyclohexyl-amino) -acetic acid,
81) (S) -1- {3- [2- (3-fluoro-phenylsulfanyl) -phenyl ] -propyl } -pyrrolidine-2-carboxylic acid,
82) (S) -2- ({2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -methyl-amino) -propionic acid,
83) ({2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -methyl-amino) -acetic acid,
84) (S) -1- {2- [ 4-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
85) (S) -1- {2- [ 3-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } pyrrolidine-2-carboxylic acid,
86) (S) -1- {2- [ 5-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } pyrrolidine-2-carboxylic acid,
87) (S) -1- {2- [ 4-cyano-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
88) (S) -1- [2- (5-chloro-2-phenylsulfanyl-phenoxy) -ethyl ] pyrrolidine-2-carboxylic acid,
89) (S) -1- {2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
90) (S) - {2- [ 4' -methoxy-3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
91) (S) - {2- [ 4' -cyano-3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
92) (S) -1- {2- [ 4' -cyano-4- (3-fluoro-phenylsulfanyl) -biphenyl-3-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
93) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -5-thiophen-3-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
94) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-pyrimidin-5-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
95) (S) -1- {2- [3- (3-fluoro-phenylsulfanyl) -3-methanesulfonyl-biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2 (S) -carboxylic acid,
96) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-morpholin-4-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
97) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-piperidin-1-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid.
Each of these compounds is considered a specific embodiment and may be a separate claim.
The invention also includes salts, typically pharmaceutically acceptable salts, of the compounds of the invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salt acid addition salts including inorganic and organic acid salts.
Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, dimethylenesalicylic (bismaleinic), ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic, theophylline acetic, and 8-halotheophyllines such as 8-bromotheophylline and the like. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in j.pharm.sci.1977, 66, 2, which is incorporated herein by reference.
Examples of metal salts include lithium, sodium, potassium, magnesium salts, and the like.
Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.
In addition, the compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.
The compounds of the present invention may have one or more asymmetric centers and any optically active isomer (i.e., enantiomer or diastereomer) such as isolated, purified or partially purified optical isomers and any mixture thereof including racemic mixtures are intended to be included within the scope of the present invention.
The racemic form can be resolved into the optical antipodes by known methods, for example by separation of the diastereomeric salts thereof with an optically active acid and subsequent liberation of the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based on chromatography on optically active substrates. Racemic compounds of the present invention can also be resolved into their optically active enantiomers by, for example, fractional crystallization of the d-or 1- (tartrate, mandelate or camphorsulfonate) salts. The compounds of the present invention may also be resolved by formation of diastereomeric derivatives.
Other methods of resolving optically active isomers known to those skilled in the art may be used. Such methods include those discussed by j.jaques, a.collet and s.wilen in "enertiomers, racemes, and solutions", John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
Furthermore, when double bonds or fully or partially saturated ring systems are present in the molecule, geometric isomers may be formed. Any geometric isomer, such as an isolated, purified or partially purified geometric isomer or mixtures thereof, is intended to be included within the scope of the present invention. Likewise, molecules with restricted rotational bonds may form geometric isomers. These geometric isomers are also intended to be included in the scope of the present invention.
Furthermore, some compounds of the invention may exist in different tautomeric forms, and thus any tautomeric form which a compound is capable of forming is intended to be included within the scope of the invention.
The invention also encompasses prodrugs of the compounds of the invention which, upon administration, undergo chemical conversion by metabolic processes to become pharmacologically active substances. In general, such prodrugs are functional derivatives of the compounds of formula (I) which can be readily converted in vivo to the desired compounds of formula (I). The general selection and preparation of suitable prodrug derivatives is described, for example, in "Design of Prodrugs", ed.h. bundgaard, Elsevier, 1985.
The invention also includes active metabolites of the compounds of the invention.
As mentioned above, the compounds of formula I are inhibitors of the activity of the glycine transporter and are therefore useful in the treatment of schizophrenia and other psychoses, including the prevention of schizophrenia, both positive and negative, and in improving cognition in the following conditions in which cognitive processes are diminished: namely Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which brain is damaged by internal or external influences, such as head trauma or stroke, and convulsive diseases, such as epilepsy, spasticity or myoclonus.
Thus in a further aspect the invention relates to a compound of formula I for use as a medicament.
The invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent. The composition may comprise any one of the embodiments of formula I described above.
In one embodiment of the pharmaceutical composition, the compound of formula I is present in an amount of about 0.001 to about 100mg/kg body weight per day.
The invention also relates to the use of compounds of formula I for the preparation of medicaments for the treatment of diseases in which glycine transport inhibitors are useful. The medicament may comprise any one of the embodiments of formula I described above.
The invention also relates, inter alia, to the use of a compound of formula I for the preparation of a medicament for the treatment of schizophrenia. Such schizophrenia includes both positive and negative symptoms of schizophrenia and other psychoses.
In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of alzheimer's disease. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of multi-infarct dementia. In a further embodiment, the present invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of AIDS. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of dementia. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of Huntington's disease. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of parkinson's disease. In a further embodiment, the present invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of amyotrophic lateral sclerosis. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of a disease in which the brain is damaged by internal or external influences. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of head trauma. In a further embodiment, the present invention relates to the use of a compound of formula 1 for the manufacture of a medicament for the treatment of stroke. In a further embodiment, the invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of convulsive disorders, and in a further embodiment the invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of epilepsy. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of spasticity. In a further embodiment, the invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment of myoclonus. In a further embodiment, the present invention relates to the use of a compound of formula I as described above, or a pharmaceutically acceptable acid addition salt thereof, for the manufacture of a medicament for the treatment of post-traumatic stress disorder. Such medicaments may comprise any one of the embodiments of formula I described above.
Yet another aspect of the invention relates to a method for treating a disease selected from the group consisting of schizophrenia with positive and negative symptoms, including both positive and negative symptoms, and other psychoses, in a living animal, including a human, and for improving cognition in the following conditions in which cognitive processes are diminished: namely alzheimer's disease, multi-infarct dementia, AIDS dementia, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis or diseases in which brain damage is caused by internal or external influences, such as head trauma or stroke, and convulsive diseases, such as epilepsy, spasticity or myoclonus, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.
A further aspect of the present invention relates to a method for the treatment of post-traumatic stress disorder in a living animal, including a human, which comprises administering a therapeutically effective amount of a compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof.
In a further aspect, the invention relates to a process for the preparation of a compound of formula I, which process comprises reacting an alcohol of formula II
Coupling with phenols of the formula III
Wherein R is1、R2、R3、R4、R5、R6、R7、R8、R9、R9’、R10X and Y are as defined above for formula I.
The reaction is typically carried out at room temperature in a suitable solvent such as tetrahydrofuran or diethyl ether containing a coupling agent such as triphenylphosphine and diethyl azodicarboxylate or 1, 1' - (azodicarbonyl) bipiperidine.
In another aspect, the invention relates to a process for preparing a compound of formula I, which process comprises reacting an amine of formula IV
Alkylation with an alkylating agent of formula V
Wherein R is1、R2、R3、R4、R5、R6、R7、R8、R9、R9’、R10X and Y are as defined above for formula I, and L is a suitable leaving group such as halogen, mesylate or tosylate.
The reaction is typically carried out at elevated temperatures of 40-80 ℃ in a suitable solvent such as ethanol, N-dimethylformamide or acetonitrile containing an inorganic base such as potassium carbonate or cesium carbonate or an organic base such as N-ethyldiisopropylamine.
Or by making Z be iodide, R1-R10Intermediates of formula VI as described above and Y is sulfur
Coupling with an intermediate of formula VII to prepare a compound of formula I.
The cross-coupling reaction is generally carried out as described by Schopper (Tetrahedron, 2001, 57, 3069-5-S-H thiol coupling.
Wherein R is10Compounds of formula I which are hydrogen may be prepared by hydrolysis of the corresponding compound of formula I wherein R10As insoluble polymers or as C1-6Alkyl, aryl or aryl-C1-6-esters of alkyl COOR10To prepare the compound. The reaction can be carried out under basic conditions, for example in an alcoholic solvent with aqueous sodium hydroxide, or under acidic conditions, in which the tert-butyl ester is hydrolysed or dissociated from the insoluble polymer. This method is also an aspect of the present invention.
Pharmaceutical composition
The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier or excipient in single or multiple doses. According to the present invention, the pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients according to conventional techniques, for example as described in Remington: those disclosed in The Science and Practice of Pharmacy, 19 th edition, Gennaro, Ed, Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specially formulated for administration by any suitable route, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes, with oral routes being preferred. It will be appreciated that the preferred route will depend upon the general condition and age of the patient being treated, the nature of the condition being treated and the active ingredient selected.
Oral pharmaceutical compositions include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. If appropriate, they may be formulated with a coating, e.g., an enteric coating, or they may be formulated according to methods well known in the art to provide controlled, e.g., sustained or extended release of the active ingredient.
Oral liquid dosage forms include solutions, emulsions, suspensions, syrups, and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Long acting injectable formulations are also contemplated within the scope of the invention.
Other suitable forms of administration include suppositories, sprays, creams, ointments, gels, inhalants, dermal patches, implants and the like.
Typical oral dosages administered in one or more doses, such as 1 to 3 doses, are from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50mg/kg body weight per day, and more preferably from about 005 to about 10mg/kg body weight per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the condition being treated, and any complications of treatment, as well as other factors which will be apparent to persons skilled in the art.
Formulations in unit dosage form may conveniently be provided by methods known to those skilled in the art. Typical unit dosage forms for oral administration one or more times daily, e.g., 1 to 3 times, may contain from 0.01 to about 1000mg, preferably from about 0.05 to about 500mg, and more preferably from about 0.5mg to about 200 mg.
For parenteral routes such as intravenous, intrathecal, intramuscular and similar routes of administration, typically the dosage is usually about half of the dosage employed orally.
The compounds of the invention are generally used as the free substances or as pharmaceutically acceptable salts thereof. One example is a base addition salt of a compound having the utility of the free acid. When the compound of formula (I) contains a free acid, such salts are prepared in a conventional manner by treating a solution or suspension of the free acid of formula (I) with a stoichiometric amount of a pharmaceutically acceptable base. The foregoing are representative examples.
For parenteral administration, sterile aqueous solutions of the novel compounds of formula (I), aqueous propylene glycol solutions, aqueous vitamin E solutions or solutions of sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent should first be made isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous medium used is readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula (I) with a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods well known in the art of pharmacy.
Discrete units of the formulations of the invention suitable for oral administration, for example capsules or tablets, may be provided, each granule (tablet) containing a predetermined amount of the active ingredient and suitable excipients may be included. Furthermore, the available oral formulations may be powders or granules, aqueous or non-aqueous liquid solutions or suspensions, or oil-in-water or water-in-oil liquid emulsions.
If the solid carrier is for oral administration, the formulation may be in the form of a tablet, a hard gelatin capsule filled in powder or pellet form, or may be in the form of a dragee or lozenge.
The amount of solid support varies widely, but is generally from about 25mg to about 1 g.
If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.
Process for preparing compounds of formula I
The compounds of the present invention can be prepared by the following general methods. Coupling of alcohols of the formula II with phenols of the formula III
Substituent R1-R10As defined above, X is oxygen and Y is oxygen or sulfur. Such as Mitsunobu (Synthesis)s, 1981, 1), the reaction is generally carried out at room temperature in a suitable solvent, for example tetrahydrofuran or diethyl ether, containing a combination of a coupling agent, for example triarylphosphine and diethyl diazodicarboxylate or 1, 1' - (azodicarbonyl) bipiperidine.
Alternatively, the compounds of the present invention may be prepared by alkylating an amine of formula IV with an alkylating agent of formula V.
Substituent R1-R10X and Y are as defined above. L is a suitable leaving group such as halogen, mesylate or tosylate. The reaction is typically carried out at elevated temperatures of 40-80 ℃ in a suitable solvent, e.g. ethanol, N-dimethylformamide or acetonitrile, containing an inorganic base, e.g. potassium carbonate or cesium carbonate, or an organic base, e.g. N-ethyldiisopropylamine.
Alternatively, the compounds of the invention may be prepared by reacting compounds wherein Z is iodide, R1-R10The intermediate of formula VI as described above and Y is sulfur.
The cross-coupling reaction is generally carried out as described by Schopper (Tetrahedron, 2001, 57, 3069-5-S-H.
Wherein R is10Compounds of formula I which are hydrogen may be prepared by hydrolysis of the corresponding compound of formula I wherein R10Is an insoluble polymer or C1-6Alkyl, aryl or aryl-C1-6-esters of alkyl COOR10And (4) preparation. The reaction can be carried out under basic conditions, for example in an alcoholic solvent with aqueous sodium hydroxide, or in the hydrolysis of tert-butyl esters or withThe insoluble polymer is dissociated under an acidic condition.
The compound of formula II can be prepared as shown in scheme 1.
Scheme 1
Wherein R can be alkylated with an alkylating agent of formula IX10、R9’、R9And R8Alkylation of an amino acid derivative of formula VIII as defined above. Or, R may be in10、R9’、R9An acetic acid derivative of the formula X as defined above and L is halogen, mesylate or tosylate and wherein R is5、R6And R7The reaction of the amine of formula XI is as defined above. The reaction is typically carried out at elevated temperatures of 40-150 ℃ in a suitable solvent, e.g. ethanol, N-dimethylformamide, DMSO or acetonitrile, containing an inorganic base, e.g. potassium carbonate or cesium carbonate, or an organic base such as N-ethyldiisopropylamine. P may be hydrogen or a suitable protecting group for an alcohol known to those skilled in the art. This group may be, for example, tert-butyldimethylsilyl or tetrahydropyranyl. The textbook Protective Groups in organic Synthesis, T.W.Greene and p.G.M.Wuts, Wiley Interscience, (1991) ISBN 0571623016 describes methods for alcohol protection and deprotection.
Intermediates of formula III were prepared from 2-cyclohexanone as described by Samoshin et al (Tet. Lett.1994, 35, 7413-one 7414). Alternatively, the appropriately substituted 2-halo-anisole may be metallated with an alkali metal such as magnesium (Gilman, Recl. Trav. Chim. Pays-Bas 1935, 588) or lithium (Hader et al, J. Organomet. chem.1989, 364, 1-16) and then reacted with a diaryl disulfide. On the other hand, in the case where the halogen is iodide, coupling of thiophenol with 2-halo-anisole using palladium/phosphine catalysis can be carried out according to the general procedure described by Schopper (tetrahedron 2001, 57, 3069-.
Intermediates of formula IV are generally commercially available or their synthesis methods are well described in the literature.
Compounds of formula V wherein X is O may be prepared by reacting an intermediate of formula III with ethylene carbonate to give an O-hydroxyethyl derivative which may then be converted to a compound of formula V. Where L is Cl, a solution of carbon tetrachloride and triphenylphosphine in methylene chloride may be used in the reaction. In the case of tosylate and mesylate, the reaction can use tosyl chloride or mesyl chloride, respectively, in a solvent such as dichloromethane or tetrahydrofuran. These methods are standard methods for the person skilled in the art. Compounds of formula V wherein X is carbon can be prepared by alkylation of an appropriately substituted 2-iodo-benzyl halide with diethyl malonate to give 2-iodo-phenylpropionic acid according to the general procedure described in l.f. fieser, e.berlinier, jam.chem. soc.1952, 74, 536. In the case where X is sulfur, coupling with the appropriate thiophenol, according to the method of Bartl et al, Collection Czechloroslovak chem. Commun, 1981, 46, 141, gives 2- (arylthio) phenylpropionic acid, which can be reduced to 2- (arylthio) phenylpropanol by standard methods such as borane-tetrahydrofuran complex or lithium aluminum hydride. The alcohol may be activated for nucleophilic displacement as described above.
The compound of formula VI may be prepared by reacting an intermediate of formula II with an intermediate of formula XII. Substituent R1-R10As defined above, X is oxygen, sulfur or CR11R12Wherein R is11And R12As defined above, and Z is iodide. The reaction is typically carried out at room temperature in a suitable solvent such as tetrahydrofuran or diethyl ether containing a coupling agent such as triphenylphosphine and diethyl azodicarboxylate or 1, 1' - (azodicarbonyl) bipiperidine.
Intermediates of formula XII, wherein Z is iodide, are commercially available or are readily obtained by demethylation of the corresponding 2-iodo-anisole with, for example, boron tribromide in toluene or similar methods well known to those skilled in the art. Alternatively, treatment of the corresponding anisole with t-butyllithium and quenching with iodine followed by demethylation as described by Iwao (J.org.chem 1990, 55, 3622-3627) also affords intermediates of formula XII. The third method is the conversion of the appropriate 2-methoxyaniline derivative to iodide by the Sandmeyer reaction, followed by demethylation, as described by Still (J.org.chem.1987, 52, 748-753) to give the intermediate of formula XII. These methods are well described in the literature.
Can also be prepared by modifying R in the formula1-R4May be bromide or iodide and R10Examples of the preparation of formula I are prepared from compounds of formula I as defined above but which are not hydrogen. In this process, the intermediate can be reacted with, for example, an aryl or heteroaryl boronic acid or ester using Suzuki conditions to give the appropriately substituted aryl or heteroaryl derivative. Or in the case of formula I, palladium catalyzed reaction with an amine gives examples in which the bromide or iodide is replaced by an amine.
Examples
General procedure
Analytical LC-MS data were acquired on a PE Sciex API 150EX instrument equipped with an ion spray (IonSpray) source and Shimadzu LC-8A/SLC-10A LC system. Column: 30X 4.6mm Waters symmetry C18 column with particle size of 3.5 μm; solvent system: a ═ water/trifluoroacetic acid (100: 0.05) and B ═ water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); the method comprises the following steps: elute with a linear gradient from 90% a to 100% B for 4min at a flow rate of 2 mL/min. Purity was determined by UV (254nm) and ELSD trace integration. Retention Time (RT) is expressed in minutes. Preparative LC-MS-purification was performed on the same instrument. Column: 50X 20mm YMC ODS-A, particle size 5 μm; the method comprises the following steps: the elution was carried out with a linear gradient from 80% A to 100% B of 7m1n at a flow rate of 22.7 mL/min. Component collection was performed by split MS detection.
Recording at 500.13MHz on a Bruker Avance DRX500 instrument1H NMR spectrum; or in Bruker AC 250 instrumentOn the instrument, record at 250.13MHz1H NMR spectrum. Deuterated dichloromethane (99.8% D), chloroform (99.8% D) or dimethylsulfoxide (99.8% D) was used as a solvent. TMS was used as an internal reference standard. The chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s is singlet, d is doublet, t is triplet, q is quartet, qui is quintet, h is heptat, dd is doublet, dt is doublet, dq is doublet quartet, tt is triplet, m is multiplet, b is broad singlet.
The following materials were used for ion exchange chromatography: varian Mega Bond ElutSCX-column (1g), Chrompack cat # 220776. Just before use, the SCX-column was pretreated with 10% acetic acid/methanol solution (3 mL). For the radiation decomplexing, a UV light source (300W) from Philipps was used.
Purchase of Polymer-bound PPh from Senn Chemicals3(0.93mmol/g, 100-200 mesh).
Preparation of intermediates of formula XI
1-Cyclohexanylamino-propan-2-ol
Cyclohexanone (0.98g, 10mmol) was mixed with 1-amino-propan-2-ol (0.75g, 10mmol) and MeOH (20mL), acetic acid (12mg, 0.5mmol), cyanoborohydride resin (7g, 14mmol, 2mmol/g, prepared as described in A.R. Sande et al, Tetrahedron Letters 1984, 3501) were added. The reaction mixture was heated under reflux for 16 h. The resin was filtered off and the filtrate evaporated in vacuo. The crude product was used without further purification.
2- (tert-butyl-dimethyl-silanyloxy) -propylamine
Tert-butyl-chloro-dimethyl-silane (2.6g 17mmol) was dissolved in DCM (20 mL). 1-amino-propan-2-ol (1.2g, 16mmol), triethylamine (2.2mL, 16mmol) and a catalytic amount of DMAP were added. The reaction mixture was stirred for 16 h. Water (10mL) was added and the phases separated. The aqueous phase was extracted with EtOAc (2X 100 mL). The combined organic phases were dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The product was isolated as an oil. Obtaining: 2.4g, 80%.
The following intermediates were prepared in a similar manner:
1)2- (tert-butyl-dimethyl-silanyloxy) -1-methyl-ethylamine
2)1- (tert-butyl-dimethyl-silanyloxymethyl) -propylamine
3)1- (tert-butyl-dimethyl-silanyloxymethyl) -2-methyl-propylamine
4)1- (S) -2- (tert-butyl-dimethyl-silanyloxy) -methyl-ethylamine
5)1- (R) -2- (tert-butyl-dimethyl-silanyloxy) -methyl-ethylamine
Preparation of intermediates of formula II
(2-hydroxymethyl-piperidin-1-yl) -acetic acid tert-butyl ester
Tert-butyl bromo-acetate (0.39g, 2mmol) was dissolved in DMF (1 mL). Piperidin-2-yl-methanol (0.25g, 2.2mmol) in DMF (1mL) and diisopropylethylamine (0.38mL, 2.2mmol) were added. The reaction mixture was stirred at 50 ℃ for 16 h. The solvent was removed in vacuo. EtOAc (20mL) and water (7mL) were added. The two phases were separated. The aqueous phase was extracted twice with EtOAc (20 mL). The combined EtOAc phases were dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The product was isolated as an oil. Obtaining: 0.37g, 80%.
The following intermediates were prepared in a similar manner:
1) [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
2) [ ethyl- (2-hydroxy-ethyl) -amino ] -acetic acid tert-butyl ester
3) [ (2-hydroxy-ethyl) -isopropyl-amino ] -acetic acid tert-butyl ester
4) (4-hydroxy-piperidin-1-yl) -acetic acid tert-butyl ester
5) (3-hydroxy-pyrrolidin-1-yl) -acetic acid tert-butyl ester
6) (R) - (3-hydroxy-pyrrolidin-1-yl) -acetic acid tert-butyl ester
7)2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
8) (S) - (3-hydroxy-pyrrolidin-1-yl) -acetic acid tert-butyl ester
9) (S) -2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
10) [ cyclohexyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
[2- (tert-butyl-dimethyl-silanyloxy) -propylamino ] -acetic acid tert-butyl ester
2- (tert-butyl-dimethyl-silanyloxy) -propylamine (6.0g, 31.6mmol) was dissolved in DMF (60 mL). Diisopropylethylamine (5.5mL, 31.6mmol) and bromo-tert-butyl acetate (3.6g, 18.6mmol) were added. The reaction mixture was stirred at 50 ℃ for 16 h. The mixture is evaporated on silica gel and purified by column chromatography, starting with a gradient of ethyl acetate/heptane 20: 80 up to ethyl acetate/heptane 80: 20. The product was isolated as an oil. Obtaining: 4.0g, 71%.
The following intermediates were prepared in a similar manner:
1) [2- (tert-butyl-dimethyl-silanyloxy) -1-methyl-ethylamino ] -acetic acid tert-butyl ester
2) [1- (tert-butyl-dimethyl-silanyloxymethyl) -propylamino ] -acetic acid tert-butyl ester
3) [1- (tert-butyl-dimethyl-silanyloxymethyl) -2-methyl-propylamino ] -acetic acid tert-butyl ester
4) (S) - [2- (tert-butyl-dimethyl-silanyloxy) -1-methyl-ethylamino ] -acetic acid
5) (R) - [2- (tert-butyl-dimethyl-silanyloxy) -1-methyl-ethylamino ] -acetic acid tert-butyl ester
[ ethyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
Reacting [2- (tert-butyl-dimethyl-silanyloxy) -propylamino]Tert-butyl acetate (1.2g, 4mmol) and diisopropylethylamine (9.7mL, 56mmol) were dissolved in DMF (20 mL). Iodo-ethane (2.6mL, 32mmol) was added. The reaction was stirred at 50 ℃ for 16 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (100mL) and the solution was washed with water (20 mL). The organic phase is dried over magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue was dissolved in acetonitrile (30mL) and Et was added3N3 HF (1.3mL, 8 mmol). The reaction was stirred for 16 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (100) mL) and washed with saturated sodium bicarbonate solution (25mL) and saturated sodium chloride solution (25 mL). The organic phase is dried over magnesium sulfate and the solution is filtered slowly through 5g of silica gel. The filtrate was evaporated in vacuo. Obtaining: 0.17g, 20%.
The following intermediates were prepared in a similar manner:
1) [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
2) [ ethyl- (1-hydroxymethyl-propyl) -amino ] -acetic acid tert-butyl ester
3) [ ethyl- (1-hydroxymethyl-2-methyl-propyl) -amino ] -acetic acid tert-butyl ester
4) (S) - [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
5) (R) - [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
Preparation of intermediates of formula II
[ (1-hydroxymethyl-2-methyl-propyl) -methyl-amino ] -acetic acid tert-butyl ester
Reacting { [1- (tert-butyl-dimethyl-silanyloxymethyl) -2-methyl-propyl]-amino } -acetic acid tert-butyl ester (1.9g, 6.1mmol) and diisopropylethylamine (4.2mL, 24mmol) were dissolved in DMF (15 mL). A solution of MeI (0.45mL, 7.3mmol) in DMF (100mL) was added slowly over 15 min. Reaction stirring 21/2h. The solvent was removed in vacuo. The residue product was dissolved in EtOAc (100mL) and the solution was washed with water (20 mL). The organic phase is treated with sulfuric acidMagnesium dried, filtered and the filtrate evaporated in vacuo. The residue was dissolved in acetonitrile (45mL) and Et was added3N3 HF (2mL, 12.3 mmol). The reaction was stirred for 16 h. The solvent was removed in vacuo. The crude product was dissolved in EtOAc (100mL) and washed with saturated sodium bicarbonate solution (25mL) and saturated sodium chloride solution (25 mL). The organic phase is dried over magnesium sulfate and the solution is filtered slowly through 5g of silica gel. The filtrate was evaporated in vacuo. Obtaining: 1.1g, 78%.
The following intermediates were prepared in a similar manner:
1) [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
2) [ (1-hydroxymethyl-propyl) -methyl-amino ] -acetic acid tert-butyl ester
3) (S) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
4) (R) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
5) [ (2-hydroxy-propyl) -methyl-amino ] -acetic acid tert-butyl ester
Preparation of intermediates of formula II from intermediates of formula VIII and intermediates of formula IX
(S) - (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
L-pyrrolidine-2-carboxylic acid tert-butyl ester (0.41g, 2.4mmol) was dissolved in DMF (2mL) containing diisopropylethylamine (1.25mL, 7.2 mmol). A solution of 2-bromo-ethanol (0.34mL, 48mmol) in DMF (1mL) was added. The reaction mixture was stirred at 70 ℃ for 16 h. The solvent was removed in vacuo. EtOAc (20mL) and saturated sodium bicarbonate solution (10mL) were added. The aqueous phase was extracted twice with EtOAc (20 mL). The combined EtOAc phases were dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The product was isolated as an oil. Obtaining: 0.37g and 72 percent.
The following intermediates were prepared in a similar manner:
(S) -1- (2-hydroxy-propyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
Preparation of intermediates of formula III
2- (4-chloro-phenoxy) -phenol
This compound was synthesized as described in G.W.Yeager, D.N.Schissel, Synthesis1995, 28-30.
The following intermediates were prepared in a similar manner:
2- (3, 4-difluoro-phenoxy) -phenol
2- (3-fluoro-phenoxy) -phenol
2- (3-chloro-phenoxy) -phenol
2- (4-methoxy-phenoxy) -phenol
3-chloro-2-iodoanisole
A solution of 3-chlorophenylmethyl ether (1753g, 123mmol) in THF (60mL) was cooled to-95 ℃. A solution of sec-BuLi in cyclohexane (1.3M, 9.5mL, 12.4mmol) was added dropwise, maintaining the internal temperature below-90 ℃. After 1h, I is added dropwise2(3.15g, 12.4mmol) in THF (5 mL). The temperature of the mixture was allowed to reach room temperature overnight. Ether (100mL) was added. 1M Na for organic layer2SO3Water-containing liquid H2O, brine, over Na2SO4And (5) drying. The crude product was adsorbed onto silica gel. Purification by flash silica chromatography eluting with heptane/EtOAc 98: 2 afforded the product as colorless crystals to give: 2.19g, 66%.
4-bromo-2-iodo-anisole
4-bromo-anisole (4.417g, 23.6mmol) was dissolved in acetonitrile (200mL) and placed under a non-light argon atmosphere. Iodobenzene diacetate (9.18g, 28.5mmol) was added followed by iodine (3.6g, 14.2 mmol). The mixture was stirred at ambient temperature for 16 hours. The mixture was then poured over 1M Na2S2O3(200mL) and stirred until the solution was colorless. The solution was extracted with ether (3X 100 mL). The combined organic extracts were then washed with brine, over Na2SO4Dried, filtered and evaporated to dryness. The crude product is filtered through a plug of silica gel using heptane/ethyl acetate (3: 1) (200 mL). The filtrate was concentrated and the residue was distilled off using a Kugelrohr apparatus, collecting the compound at 75 ℃ and 0.01 mbar. This gave 4.092g, 55%.
5-bromo-2-iodo-anisole
4-bromo-2-methoxy-aniline (20g, 99mmol) was dissolved in water (695mL) and concentrated sulfuric acid (113 mL). The solution was cooled to 0 ℃ and a solution of sodium nitrite (7.5g, 109mmol) in water (32mL) was added and stirred at 5-10 ℃ for 1 h. A solution of potassium iodide (21.4g, 129mmol) in water (100mL) was added slowly while the mixture was stirred vigorously. After the addition, the mixture was allowed to warm to room temperature. Ethyl acetate was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 ×). Then 1M NaOH and 1M Na are used2S2O31M HCl, 1M saturated NaHCO3And the combined organic phases were washed with brine. Drying (MgSO)4) The separated organic phase was filtered and concentrated in vacuo. The product was purified by flash chromatography on silica eluting with heptane/ethyl acetate 1: 1. The product was identified from the relevant fractions after combination and vacuum concentration. Obtaining: 24.12g, 78%
3-chloro-2- (3-fluoro-phenylsulfanyl) -phenol
To a dry round bottom flask were added NaOtBu (398mg, 4.14mmol), CuI (62mg, 0.33mmol), Neocuprinol (66mg, 0.30mmol), 3-fluoro-thiophenol (394mg, 3.07mmol), and 3-chloro-2-iodoanisole (698mg, 2.60 mmol). The flask was evacuated and backfilled 3 times with argon. Anhydrous toluene (10mL) was added and the mixture was stirred at 105 ℃ overnight. The mixture was diluted with toluene (40mL), filtered through a pad of silica gel and evaporated to dryness to give the crude 1-chloro-2- (3-fluoro-phenylsulfanyl) -3-methoxy-benzene in quantitative yield. This material was dissolved in toluene (20mL) and cooled to 0 ℃. Dropwise adding pure BBr3(0.38mL, 402mmol), the mixture was allowed to warm to room temperature overnight. Addition of H2The mixture was quenched with O/ice (80mL) and diethyl ether (100 mL). The organic layer was washed with brine. Through Na2SO4After drying, the crude product was adsorbed onto silica gel. Purification by flash chromatography on silica eluting with heptane/EtOAc, 96: 4, gave the title compound as a yellow oil: 642mg, 97% yield over two steps.
4-chloro-1- (3-fluoro-phenylsulfanyl) -2-methoxybenzene
Adding KO into dry round-bottom flasktBu (1.903g, 17.0mmol), 5-chloro-2-iodoanisole (4.054g, 151mmol), Pd2dba3(144mg, 0.16mmol), DPEPhos (176mg, 0.33mmol) and 3-fluoro-thiophenol (1.903g, 17.0 mmol). The flask was evacuated and backfilled 3 times with argon. Anhydrous toluene (80mL) was added and the mixture was stirred at 95 ℃ for 2 h. The mixture was filtered through a pad of silica gel and subsequently adsorbed onto silica gel. Purification by flash chromatography on silica eluting with heptane/EtOAc, 97: 3, gave the title compound as a yellow oil (3.41g, 85%).
The following compounds were prepared in a similar manner:
1) 4-bromo-2- (3-fluoro-phenylsulfanyl) -1-methoxy-benzene
2) 5-bromo-2- (3-fluoro-phenylsulfanyl) -1-methoxy-benzene
3) 4-phenyl-2- (3-fluoro-phenylsulfanyl) -1-methoxy-benzene
4) 4-cyano-2- (3-fluoro-phenylsulfanyl) -1-methoxy-benzene
5-chloro-2- (3-fluoro-phenylsulfanyl) -phenol
A solution of 4-chloro-1- (3-fluoro-phenylsulfanyl) -2-methoxybenzene (3.12g, 11.6mmol) in dry toluene (60mL) was cooled to 0 ℃. Dropwise adding pure BBr3(1.50mL, 15.9mmol), the mixture was allowed to warm to room temperature overnight. Addition of H2The mixture was quenched with O/ice (50mL) and diethyl ether (50 mL). The aqueous layer was extracted with ether (2X 50 mL). The combined organic layers were washed with brine, over Na2SO4Drying and adsorbing on silica gel. After flash chromatography on silica eluting with heptane/EtOAc, 95: 5, the title compound was obtained as a pale yellow oil (2.26g, 77%).
The following phenols were prepared in a similar manner:
1) 2-chloro-6- (3-fluoro-phenylsulfanyl) -phenol
2) 4-chloro-2- (3-fluoro-phenylsulfanyl) -phenol
3) 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenol
4) 5-bromo-2- (3-fluoro-phenylsulfanyl) -phenol
5) 4-phenyl-2- (3-fluoro-phenylsulfanyl) -phenol
6) 4-cyano-2- (3-fluoro-phenylsulfanyl) -phenol
Preparation of intermediate V for example 2
2- (2-iodo-benzyl) -malonic acid diethyl ester
Sodium (0.19g, 8.2mmol) was dissolved in absolute ethanol (12 mL). The solution was cooled on an ice bath. Diethyl malonate (1.3g, 8.1mmol) was added. A solution of 1-chloromethyl-2-iodo-benzene (2.0g, 7.9mmol) in absolute ethanol (6mL), cooled on an ice bath, was added to a solution of diethyl malonate. The solution precipitating the sodium chloride was left at 0 ℃ for 4 hours and then left at room temperature overnight. The solution was neutralized with HCl (4N). The solvent was removed in vacuo and the residue dissolved in dichloromethane (25 mL). Water (15mL) was added and the phases separated. The aqueous phase was extracted with additional dichloromethane (10 mL). Drying (Na)2SO4) The combined organic phases were filtered and evaporated. Obtaining: 2.86g, 92%.
3- (2-iodo-phenyl) -propionic acid
Concentrated HCl (2.3mL) and water (0.3mL) were added to 2- (2-iodo-benzyl) -malonic acid diethyl ester (14g, 3.6mmol) and the mixture was refluxed overnight. The starting material was still visible on TLC. Additional concentrated HCl (2mL) was added and the mixture refluxed overnight. Water (20mL) and diethyl ether (50mL) were added to the mixture. The two phases were separated. The organic phase was extracted with ammonium hydroxide solution (5N, 30 mL). The basic aqueous phase was slowly added to ice cold concentrated HCl. The white precipitate was filtered, washed with ice-cold water and the solvent removed in vacuo. Obtaining: 0.32g, 32%.
3- [2- (3-fluoro-phenylsulfanyl) -phenyl ] -propionic acid
3- (2-iodo-phenyl) -propionic acid (0.3g, 1.1mmol) was dissolved in water (2.8 mL). 3-fluoro-benzenethiol (0.13g, 0.99mmol), KOH (0.15g, 2.6mmol) and Cu (13mg, 0.2mmol) were added. The mixture was refluxed overnight. The hot solution was filtered and the filtrate was made acidic with concentrated HCl. The mixture was extracted with dichloromethane (2X 25 mL). The combined organic phases were washed with water (15mL) and dried (MgSO)4) Filtering and evaporating. Obtaining: 0.26g, 96%.
3- [2- (3-fluoro-phenylsulfanyl) -phenyl ] -propan-1-ol
Mixing LiAlH4(46mg, 1.22mmol) was suspended in diethyl ether (1.7 mL). Slowly adding 3- [2- (3-fluoro-phenylsulfanyl) -phenyl]A solution of propionic acid (2.6g, 0.94mmol) in diethyl ether (1.7 mL). The reaction was stirred at room temperature for 4 h. Hydrolysis of excess LiAlH with Water4. The mixture was made acidic with HCl (4N). Ether (20mL) was added. The two phases were separated and the organic phase was washed with NaOH (2N) and then with water. Organic phase drying (MgSO)4) Filtering and evaporating. Obtaining: 0.14g, 55%.
1- (3-iodo-propyl) -2- (3-fluoro-phenylsulfanyl) -benzene
Polymer-bound PPh3(0.49g, 0.46mmol) was suspended in dichloromethane (4.5 mL). Imidazole (0.03g, 0.46mmol) and I were added2(0.12g, 0.46mmol) and the mixture was stirred for 5 minutes. Adding 3- [2- (3-fluoro-phenylsulfanyl) -phenyl]-Propan-1-ol (0.096g, 0.37mmol) in dichloromethane (0.5mL) and the mixture was stirred at room temperature for 4 h. The resin was filtered off and washed with dichloromethane (2 mL). The filtrate is taken with Na2S2O3(2X 2mL) and water (2 mL). Organic phase drying (MgSO)4) Filtering and evaporating. Obtaining: 0.096g, 71%.
2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethanol
3- (3-fluoro-phenylsulfanyl) -biphenyl-4-ol (2.65g, 8.94mmol) and potassium carbonate (2.113g, 15.3mmol) were dissolved in DMF (30 mL). Ethylene carbonate (1.601g, 18.2mmol) was added and the reaction was heated at 100 ℃ for 150 minutes. The solution was cooled and then carefully poured into 2M HCl (50mL). The product was extracted with diethyl ether (50 mL). The separated organic phase was washed with water (4X 50mL), 4% MgSO4The aqueous solution, brine, and dried (MgSO)4) The separated organic phase. The title product was isolated after concentration in vacuo. Obtaining: 2.96g, 97%
Preparation of intermediate of formula VI for example 4
(S) -1- [2- (5-chloro-2-iodo-phenoxy) -ethyl ] -pyrrolidine-2-carboxylic acid tert-butyl ester
5-chloro-2-iodophenol (801mg, 3.15mmol) and PPh3(1.15g, 4.41mmol) was dissolved in THF (25 mL). DIAD (091mL, 4.62mmol) was added dropwise and the solution stirred for 20 min. A solution of 1- (2-hydroxy-ethyl) -pyrrolidine-2- (S) -carboxylic acid tert-butyl ester (816mg, 3.79mmol) in THF (4mL) was added via catheter. The mixture was stirred at 0 ℃ for 40min, then at room temperature for 1.5h and finally at 50 ℃ for 3 h. The mixture was diluted with heptane (100mL), washed with water (4X 25mL), and washed with Na2SO4Dried and evaporated onto silica gel. After flash chromatography on silica eluting with heptane/EtOAc, 9: 1, the title compound was obtained as a colorless oil (1.023g, 72%).
The following intermediates were prepared in a similar manner:
(S) -1- [2- (3-iodo-biphenyl-4-yloxy) -ethyl ] -pyrrolidine-2-carboxylic acid tert-butyl ester
Preparation of intermediates of formula XII
3-iodo-biphenyl-4-ol
Biphenyl-4-ol ((5.26g, 30.9mmol), sodium iodide (4.635g, 30.9mmol), sodium hydroxide (1.276g, 31.9mmol) were dissolved in methanol (85mL), cooled to 0 ℃ to this solution 12% (w/v) sodium hypochlorite (20mL) was added dropwise, the temperature was kept below 4 ℃ at which the solution was stirred for 1 hour, then 2M sodium thiosulfite (50mL) was added, the solution pH was adjusted to > pH 7 with 1M HCl the mixture was filtered, the filtrate was washed with water the solid was dried in a vacuum oven then recrystallised from heptane to give the title product as crystals 7.08g, 77%.
Preparation of intermediates of formula I for preparation of examples 5-5f, 6 and 6b
(S) -1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester
Under an inert atmosphere, 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenol (2.898g, 9.69mmol) and triphenylphosphine (3.558g, 13.6mmol) were dissolved in tetrahydrofuran (70mL) and cooled to 0 ℃. To this solution was added DEAD (2.81mL, 14.27mmol) dropwise. After 25 min, a solution of 1- (2-hydroxy-ethyl) -pyrrolidine-2- (S) -carboxylic acid tert-butyl ester (2.504g, 1.163mmol) in THF (15mL) was added via a catheter. The mixture was stirred at room temperature for 16 hours. Heptane (350mL) and THF (100mL) were added. The organic phase was then washed successively with water (4X 50mL), brine and dried (Na)2SO4) Filtered and the filtrate concentrated in the presence of silica gel. The crude product was adsorbed onto silica gel and eluted with a heptane-heptane/ethyl acetate (85: 15) gradient. After concentration of the relevant fractions, the product is isolated. Obtaining: 3.342g, 69%
The following intermediates were prepared in a similar manner:
(S) -1- {2- [ 5-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester
Preparation of the Compounds of the invention
Example 1
1aa (S) -1- {2- [2- (4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
A solution of L-1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester (0.068mmol) in THF (0.5mL) was added to the polymer-bound PPh3(75mg, 0.07 mmol). A solution of 2- (3-fluoro-phenylsulfanyl) -phenol (0.04mmol) in THF (0.5mL) and DEAD (0.068mmol) in THF (0.5mL) was added. The reaction was stirred at room temperature for 16 h. The resin was filtered off and washed with methanol (2X 1mL) and THF (1 mL). The solvent was removed by evaporation in vacuo. HCl in acetic acid (1M, 1.5mL) was added and the mixture was stirred for 16 h. The solvent was removed in vacuo. The crude product was purified by preparative LC-MS。
LC/MS(m/z)362.2(MH+) (ii) a RT ═ 1.97; purity (UV, ELSD): 93 percent and 100 percent; obtaining: 7.5 mg.
The following compounds were prepared in a similar manner:
preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ab (S) -1- {2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)400.1(MH+) (ii) a RT ═ 2.45; purity (UV, ELSD): 96 percent and 100 percent; obtaining: 6.2 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ac (S) -1- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)412.0(MH+) (ii) a RT ═ 2.21; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 5.5 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ad (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)362.2(MH+) (ii) a RT ═ 1.98; purity (UV, ELSD): 95 percent and 100 percent; obtaining: 4.8 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ae (S) - {2- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)378.1(MH+) (ii) a RT ═ 2.12; purity (UV, ELSD): 93 percent and 100 percent; obtaining: 5.1 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1af (S) -1- {2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)3781(MH+) (ii) a RT ═ 2.10; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 3.3 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ag (S) -1- {2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)412.0(MH+) (ii) a RT ═ 2.28; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 5.2 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ah (S) -1- {2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)396.1(MH+) (ii) a RT ═ 2.15; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 4.5 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ai (S) -1- {2- [2- (3-chloro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)3621(MH+) (ii) a RT ═ 2.02; purity (UV, ELSD): 96 percent and 100 percent; obtaining: 12.1 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1aj (S) -1- {2- [2- (4-chloro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)362.2(MH+) (ii) a RT ═ 2.12; purity (UV, ELSD): 95 percent and 99 percent; obtaining: 12.7 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ak (S) -1- {2- [2- (4-methoxy-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)358.0(MH+) (ii) a RT ═ 1.83; purity (UV, ELSD): 100 percent and 99 percent; obtaining: 13.8 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1al (S) -1- {2- [2- (3, 4-difluoro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)364.2(MH+) (ii) a RT ═ 1.95; purity (UV, ELSD): 100 percent and 99 percent; obtaining: 13.8 mg.
Preparation from (S) -1- (2(R/S) -hydroxy-propyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1am 1- {2(R/S) - [2- (4-chloro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid
LC/MS(m/z)376.1(MH+) (ii) a RT ═ 2.12; purity (UV, ELSD): 99 percent and 99 percent; obtaining: 4.1 mg.
Preparation from L-1- (2(R/S) -hydroxy-propyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1an 1- {2(R/S) - [2- (3, 4-difluoro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid
LC/MS(m/z)378.1(MH+) (ii) a RT ═ 2.07; purity (UV, ELSD): 96 percent and 99 percent; obtaining: 3.4 mg.
Preparation from (S) -1- (2-hydroxy-ethyl) -pyrrolidine-2-carboxylic acid tert-butyl ester
1ao (S) -1- {2- [2- (3-fluoro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
LC/MS(m/z)346.2(MH+) (ii) a RT ═ 1.99; purity (ELSD): 95 percent; obtaining: 3.44 mg.
Preparation from L-1- (2(R/S) -hydroxy-propyl) -pyrrolidine-2 (S) -carboxylic acid tert-butyl ester
1ap 1- {2(R/S) - [2- (3-fluoro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid
LC/MS(m/z)360.3(MH+) (ii) a RT ═ 2.02; purity (UV, ELSD): 70 percent and 98 percent; obtaining: 7.2 mg.
Preparation from 1- (2(R/S) -hydroxy-propyl) -pyrrolidine-2 (S) -carboxylic acid tert-butyl ester
1aq 1- {2(R/S) - [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid
LC/MS(m/z)376.1(MH+) (ii) a RT ═ 2.10; purity (UV, ELSD): 99 percent and 98 percent; obtaining: 4.3 mg.
Preparation from 1- (2(R/S) -hydroxy-propyl) -pyrrolidine-2 (S) -carboxylic acid tert-butyl ester
1ar 1- {2(R/S) - [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid
LC/MS(m/z)392.2(MH+) (ii) a RT ═ 2.23; purity (UV, ELSD): 94%, 88.9%; obtaining: 2.1 mg.
Preparation from [ ethyl- (2-hydroxy-ethyl) -amino ] -acetic acid tert-butyl ester
1as ({2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)388.2(MH+) (ii) a RT ═ 2.53; purity (UV, ELSD): 94 percent and 95 percent; obtaining: 5.6mg
Preparation from tert-butyl 2- (3-hydroxy-pyrrolidin-1-yl) -propionate
1at 2- {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)400.0(MH+) (ii) a RT ═ 2.40; purity (UV, ELSD): 94 percent and 100 percent; obtaining: 4.2mg
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1au ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)351.9(MH+) (ii) a RT ═ 2.02; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 9.9mg
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1av ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)370.0(MH+) (ii) a RT ═ 2.07; purity (UV, ELSD): 93 percent and 100 percent; obtaining: 6.7mg
Preparation from (2-hydroxymethyl-piperidin-1-yl) -acetic acid tert-butyl ester
1aw {2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxymethyl ] -piperidin-1-yl } -acetic acid
LC/MS(m/z)414.4(MH+) (ii) a RT 2.52 ═ RT; purity (UV, ELSD): 100 percent and 100 percent; obtaining: 2.6mg
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1ax ({2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)336.2(MH+) (ii) a RT ═ 1.96; purity (UV, ELSD): 96 percent and 95 percent; obtaining: 1.8mg
Preparation from (4-hydroxy-piperidin-1-yl) -acetic acid tert-butyl ester
1ay {4- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -piperidin-1-yl } -acetic acid
LC/MS(m/z)400.0(MH+) (ii) a RT ═ 2.48; purity (UV, ELSD): 89 percent and 100 percent; obtaining: 5.5mg
Preparation from [ (2-hydroxy-ethyl) -isopropyl-amino ] -acetic acid tert-butyl ester
1az (N-2-propyl- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid
LC/MS(m/z)414.2(MH+) (ii) a RT ═ 2.26; purity (UV, ELSD): 95 percent and 100 percent; obtaining: 2.4mg
Preparation from [ ethyl- (2-hydroxy-ethyl) -amino ] -acetic acid tert-butyl ester
1ba ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)400.1(MH+) (ii) a RT ═ 2.27; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 8.3mg
Preparation from [ ethyl- (2-hydroxy-ethyl) -amino ] -acetic acid tert-butyl ester
1bb (N-ethyl- {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid
LC/MS(m/z)378.3(MH+) (ii) a RT ═ 2.13; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 8.5mg
Preparation from tert-butyl 2- (3-hydroxy-pyrrolidin-1-yl) -propionate
1bc 2- {3- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)412.0(MH+) (ii) a RT ═ 2.25; purity (UV, ELSD): 100 percent and 100 percent; obtaining: 7.5mg
Preparation from (R) - (3-hydroxy-pyrrolidin-1-yl) -acetic acid tert-butyl ester
1bd (S) - {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid
LC/MS(m/z)386.0(MH+) (ii) a RT ═ 2.42; purity (UV, ELSD): 90 percent and 95 percent; obtaining: 2.2mg
Preparation from [ ethyl- (2-hydroxy-ethyl) -amino ] -acetic acid tert-butyl ester
1be ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)384.2(MH+) (ii) a RT ═ 2.15; purity (UV, ELSD): 97 percent and 100 percent; obtaining: 8.2mg
Preparation from [ (2-hydroxy-ethyl) -isopropyl-amino ] -acetic acid tert-butyl ester
1bf (N-2-propyl- {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid
LC/MS(m/z)392.2(MH+) (ii) a RT ═ 2.17; purity (UV, ELSD): 97 percent and 99 percent; obtaining: 9.9mg
Preparation from (3-hydroxy-pyrrolidin-1-yl) -acetic acid tert-butyl ester
1bg {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid
LC/MS(m/z)386.0(MH+) (ii) a RT ═ 2.38; purity (UV, ELSD): 96 percent and 100 percent; obtaining: 3.1mg
Preparation from [ ethyl- (2-hydroxy-ethyl) -amino ] -acetic acid tert-butyl ester
1bh ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)366.2(MH+) (ii) a RT ═ 2.10; purity (UV, ELSD): 100 percent and 100 percent; obtaining: 11.5mg
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1bi ({2- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -ethyl- } N-methyl-amino) -acetic acid
LC/MS(m/z)352.2(MH+) (ii) a RT ═ 2.12; purity (UV, ELSD): 78%, 97%; obtaining: 22mg
Preparation from (4-hydroxy-piperidin-1-yl) -acetic acid tert-butyl ester
1bj {4- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -piperidin-1-yl } -acetic acid
LC/MS(m/z)412.1(MH+) (ii) a RT ═ 2.32; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 5.9mg
Preparation from tert-butyl 2- (3-hydroxy-pyrrolidin-1-yl) -propionate
1bk 2- {3- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)412.1(MH+) (ii) a RT ═ 2.17; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 6.1mg
Preparation from [ (2-hydroxy-ethyl) -isopropyl-amino ] -acetic acid tert-butyl ester
1bl ({2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -N-2-propyl-amino) -acetic acid
LC/MS(m/z)402.2(MH+) (ii) a RT ═ 2.57; purity (UV, ELSD): 90 percent and 98 percent; obtaining: 8.3mg
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1bm ({2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)373.8(MH+) (ii) a RT ═ 2.34; purity (UV, ELSD): 91%, 100%; obtaining: 89mg of
Preparation from (2-hydroxymethyl-piperidin-1-yl) -acetic acid tert-butyl ester
1bn {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxymethyl ] -piperidin-1-yl } -acetic acid
LC/MS(m/z)4042(MH+) (ii) a RT ═ 2.21; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 26mg of
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1bo ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)385.8(MH+) (ii) a RT ═ 2.19; purity (UV, ELSD): 95 percent and 100 percent; obtaining: 8.1mg
Preparation from [ (2-hydroxy-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1bp (N-methyl- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid
LC/MS(m/z)386.0(MH+) (ii) a RT ═ 2.13; purity (UV, ELSD): 95 percent and 100 percent; obtaining: 5.3mg
Preparation from (S) -2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
1bq-2- {3(R) - [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)400.1(MH+) (ii) a RT ═ 2.44; purity (UV, ELSD): 97 percent and 100 percent; obtaining: 9.2mg
Preparation from (S) -2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
1br 2- {3(R) - [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)412.1(MH+) (ii) a RT ═ 2.26; purity (UV, ELSD): 100 percent and 98 percent; obtaining: 9.4mg
Preparation from (S) -2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
1bs 2- [3(R) - (2- (4-methylphenyl) -thio-phenoxy) -pyrrolidin-1-yl ] -propionic acid
LC/MS(m/z)358.2(MH+) (ii) a RT ═ 2.06; purity (UV, ELSD): 98 percent and 98 percent; obtaining: 81mg of
Preparation from (S) - (3-hydroxy-pyrrolidin-1-yl) -acetic acid tert-butyl ester
1bt {3(R) - [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid
LC/MS(m/z)386.2(MH+) (ii) a RT ═ 2.38; purity (UV, ELSD): 94 percent and 99 percent; obtaining: 3.0mg
Preparation from (S) -2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
1bu2- {3(R) - [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)412.2(MH+) (ii) a RT ═ 2.20; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 9.5mg
Preparation from (S) -2- (3-hydroxy-pyrrolidin-1-yl) -propionic acid tert-butyl ester
1bv 2- {3(R) - [2- (4-chloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid
LC/MS(m/z)378.1(MH+) (ii) a RT ═ 2.13; purity (UV, ELSD): 91%, 100%; obtaining: 6.3mg
Preparation from [ ethyl- (1-hydroxymethyl-propyl) -amino ] -acetic acid tert-butyl ester
1bw ({1- [2- (3-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)394.2(MH+) (ii) a RT ═ 2.29; purity (UV, ELSD): 97 percent and 99 percent; obtaining: 48mg of
Preparation from [ ethyl- (1-hydroxymethyl-propyl) -amino ] -acetic acid tert-butyl ester
1bx ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy) -but-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)4281(MH+) (ii) a RT ═ 2.46; purity (UV, ELSD): 94 percent and 100 percent; obtaining: 4.6mg
Preparation from [ ethyl- (1-hydroxymethyl-2-methyl-propyl) -amino ] -acetic acid tert-butyl ester
1by ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)442.2(MH+) (ii) a RT ═ 2.56; purity (UV, ELSD): 96 percent and 100 percent; obtaining: 10mg of
Preparation from [ ethyl- (1-hydroxymethyl-propyl) -amino ] -acetic acid tert-butyl ester
1bz ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)412.1(MH+) (ii) a RT ═ 2.32; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 4.7mg
Preparation from [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1ca ({1- [1- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)3801(MH+) (ii) a RT ═ 2.18; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 4.8mg
Preparation from [ ethyl- (1-hydroxymethyl-2-methyl-propyl) -amino ] -acetic acid tert-butyl ester
1cb ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -4-methyl-but-2-yl) } -N-ethyl-amino) -acetic acid
LC/MS(m/z)426.2(MH+) (ii) a RT ═ 2.42; purity (UV, ELSD): 90 percent and 100 percent; obtaining: 0.9mg
Preparation from [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1cc ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] prop-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)398.2(MH+) (ii) a RT ═ 2.12; purity (UV, ELSD): 96 percent and 100 percent; obtaining: 3.1mg
Preparation from (S) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1cd (S) - {1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -prop-2-yl } -N-methyl-amino) -acetic acid
LC/MS(m/z)366.2(MH+) (ii) a RT ═ 2.08; purity (UV, ELSD): 98 percent and 97 percent; obtaining: 4.4mg
Preparation from (S) - [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1ce(s) - ({1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -prop-2-yl) -N-ethyl-amino) -acetic acid
LC/MS(m/z)380.2(MH+) (ii) a RT ═ 2.18; purity (UV, ELSD): 72 percent and 100 percent; obtaining: 1.3mg
Preparation from [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1cf ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)416.2(MH+) (ii) a RT ═ 2.34; purity (UV, ELSD): 100 percent and 100 percent; obtaining: 4.9mg
Preparation from [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1cg ({1- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)380.3(MH+) (ii) a RT ═ 219; purity (UV, ELSD): 94 percent and 100 percent; obtaining: 3.9mg
Preparation with [ (1-hydroxymethyl-propyl) -methyl-amino ] -acetic acid tert-butyl ester
1ch ({1- [2- (3-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)380.2(MH+) (ii) a RT ═ 2.21; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 3.6mg
Preparation from [ ethyl- (1-hydroxymethyl-propyl) -amino ] -acetic acid tert-butyl ester
1ci ({1- [2- (4-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)394.3(MH+) (ii) a RT ═ 2.33; purity (UV, ELSD): 96 percent and 100 percent; obtaining: 45mg of
Preparation from [ ethyl- (1-hydroxymethyl-propyl) -amino ] -acetic acid tert-butyl ester
1cj (N-ethyl- {1- [2- (3-fluoro-phenylsulfanyl) -phenoxymethyl ] -propyl } -amino) -acetic acid
LC/MS(m/z)378.3(MH+) (ii) a RT ═ 2.16; purity (UV, ELSD): 99 percent and 100 percent; obtaining: 5.7mg
Preparation from (R) - [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1ck (R) - ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -1-methyl-ethyl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)416.0(MH+) (ii) a RT ═ 2.35; purity (UV, ELSD): 92%, 100%; obtaining: 1.5mg
Preparation from (S) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1cl (S) - (2{2- [2- (4-chloro-phenoxy) -phenoxy ] -propyl-N-methyl-amino) -acetic acid
LC/MS(m/z)350.1(MH+) (ii) a RT ═ 2.00; purity (UV, ELSD): 96 percent and 97 percent; obtaining: 2.6mg
Preparation from (R) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1cm of (R) - (2{2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] - } -propyl-N-methyl-amino) -acetic acid
LC/MS(m/z)366.1(MH+) (ii) a RT ═ 2.10; purity (UV, ELSD): 98 percent and 98 percent; obtaining: 6.1mg
Preparation from [ (2-hydroxy-propyl) -methyl-amino ] -acetic acid tert-butyl ester
1cn ({2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)350.1(MH+) (ii) a RT ═ 1.97; purity (UV, ELSD): 81 percent and 99 percent; obtaining: 2.2mg
Preparation from [ ethyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
1co ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)380.3(MH+) (ii) a RT ═ 2.19; purity (UV, ELSD): 97 percent and 98 percent; obtaining: 2.9mg
Preparation from [ (1-hydroxymethyl-2-methyl-propyl) -methyl-amino ] -acetic acid tert-butyl ester
1cp ({1- [2- (3-chloro-phenylthio) -phenoxy ] -2]-3-methyl-but-2-yl } -N-methyl-amino) -acetic acid LC/MS (m/z)394.2 (MH)+) (ii) a RT ═ 2.31; purity (UV, ELSD): 93 percent and 100 percent; obtaining: 2.3mg
Preparation from [ ethyl- (1-hydroxymethyl-2-methyl-propyl) -amino ] -acetic acid tert-butyl ester
1cq ({ 3-methyl-1- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)442.3(MH+) (ii) a RT ═ 2.46; purity (UV, ELSD): 98 percent and 100 percent; obtaining: 1.7mg
Preparation with [ (1-hydroxymethyl-propyl) -methyl-amino ] -acetic acid tert-butyl ester
1cr ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-methyl-amino) -acetic acid
LC/MS(m/z)398.1(MH+) (ii) a RT ═ 2.24; purity (UV, ELSD): 96 percent and 98 percent; obtaining: 8.1mg
Preparation from (S) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1cs (S) - (1{2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -propan-2-yl } N-methyl-amino) -acetic acid
LC/MS(m/z)384.1(MH+) (ii) a RT ═ 2.16; purity (UV, ELSD): 97 percent and 100 percent; obtaining: 3.7mg
Preparation from (S) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1ct (S) - (2- {2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -N-methyl-amino) -acetic acid
LC/MS(m/z)350.1(MH+) (ii) a RT ═ 1.97; purity (UV, ELSD): 91%, 97%; obtaining: 5.5mg
Preparation from [ ethyl- (1-hydroxymethyl-2-methyl-propyl) -amino ] -acetic acid tert-butyl ester
1cu ({1- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)430.2(MH+) (ii) a RT ═ 2.73; purity (UV, ELSD): 83 percent and 100 percent; obtaining: 10mg of
Preparation from (S) - [ (2-hydroxy-1-methyl-ethyl) -methyl-amino ] -acetic acid tert-butyl ester
1cv(s) - ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -prop-2-yl } -N-methyl-amino) -acetic acid
LC/MS(m/z)400.0(MH+) (ii) a RT ═ 2.27; purity (UV, ELSD): 100 percent and 98 percent; obtaining: 35mg of
Preparation from [ (1-hydroxymethyl-2-methyl-propyl) -methyl-amino ] -acetic acid tert-butyl ester
1cw ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl) -N-methyl-amino) -acetic acid
LC/MS(m/z)412.0(MH+) (ii) a RT ═ 2.35; purity (UV, ELSD): 87 percent and 97 percent; obtaining: 3.0mg
Preparation from [ ethyl- (2-hydroxy-1-methyl-ethyl) -amino ] -acetic acid tert-butyl ester
1cx ({1- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -3-methyl-prop-2-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)402.2(MH+) (ii) a RT ═ 2.53; purity (UV, ELSD): 90 percent and 99 percent; obtaining: 3.4mg
Preparation from [ ethyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
1cy ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-ethyl-amino) -acetic acid
LC/MS(m/z)398.1(MH+) (ii) a RT ═ 2.24; purity (UV, ELSD): 86 percent and 96 percent; obtaining: 2.3mg
Preparation from [ cyclohexyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
1cz ({2- [2- (4-methoxy-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-cyclohexyl-amino) -acetic acid
LC/MS(m/z)430.3(MH+) (ii) a RT ═ 2.32; purity (UV, ELSD): 83 percent and 80 percent; obtaining: 1.5mg
Preparation from [ cyclohexyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
1da { [2- (2- (4-methylsulfanyl-phenoxy) -propan-1-yl- ] -N-cyclohexyl-amino } -acetic acid
LC/MS(m/z)414.4(MH+) (ii) a RT ═ 2.50; purity (UV, ELSD): 79 percent and 100 percent; obtaining: 1.1mg
Preparation from [ cyclohexyl- (2-hydroxy-propyl) -amino ] -acetic acid tert-butyl ester
1db ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-cyclohexyl-amino) -acetic acid
LC/MS(m/z)434.9(MH+) (ii) a RT ═ 2.50; purity (UV, ELSD): 98%, S4%; obtaining: 21mg of
Example 2
(S) -1- {3- [2- (3-fluoro-phenylsulfanyl) -phenyl ] -propyl } -pyrrolidine-2-carboxylic acid hydrochloride
1- (3-iodo-propyl) -2- (3-fluoro-phenylsulfanyl) -benzene (48mg, 0.13mmol) was dissolved in DMF (0.4 mL). S-pyrrolidine-2-carboxylic acid tert-butyl ester (22mg, 0.13mmol) and diisopropylethylamine (25. mu.L, 0.14mmol) were added. The mixture was stirred at 50 ℃ for 6h, then at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in HCl/AcOH (3.1mL) and stirred overnight. The solvent was removed in vacuo. The crude product was purified by preparative LC-MS. Obtaining: 16.2mg, 34%
LC/MS(m/z)360.3(MH+) (ii) a RT ═ 2.18; purity (UV, ELSD): 89 percent and 100 percent
2b (S) -2- ({2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -methyl-amino) -propionic acid hydrochloride
2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethanol (0.493mg, 1.45mmol) was dissolved in dichloromethane, cooled to-78 ℃ and placed under an inert atmosphere. To the solution was added N-ethyldiisopropylamine (0.63mL, 3.62mmol) followed by dropwise addition of trifluoromethanesulfonic anhydride (0.32mL, 1.90 mmol). The solution was stirred for 40 minutes and then warmed to room temperature. L-N-methyl-alanine tert-butyl ester (435 mg; 2.22mmol) was added and the mixture was stirred for 16 h. Silica gel was added to the mixture and the solvent was removed in vacuo. The product was adsorbed onto silica gel and then purified by flash chromatography eluting with heptane/ethyl acetate (90: 10). After evaporation of the relevant components, the butyl ester intermediate is isolated. Yield 403mg, 58%. This was then dissolved in 1M HCl/AcOH (15mL) and stirred at room temperature for 16 h. The solvent was then removed in vacuo to give the title compound as a white solid. Obtaining: 235mg, 60%
1HNMR(DMSO，500MHz)1.33(d，3H)，2.33(s，1H)，2.64(s，3H)，3.35(m，2H)，4.1(m，1H)，4.4(m，2H)，6.9(m，3H)，7.1-7.2(m，2H)，7.2(m，2H)，7.37(m，3H)，7.55(m，1H)
The following compounds were prepared in a similar manner:
preparation from 2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethanol
2c ({2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -methyl-amino) -acetic acid. Obtaining: 282mg, two-step yield 54%
1H NMR(CHCl3，500MHz)2.45(s，1H)，2.7(s，2H)，3.45(m，2H)，3.98(s，2H)，4.42(m，2H)，6.92(m，3H)，7.15(m，2H)，7.24(m，2H)，7.4(dd，3H)，7.55(dd，1H)
LC/MS(m/z)412.5(MH+) (ii) a RT ═ 2.53; purity (UV, ELSD): 95.1 percent and 99.6 percent
Example 3
3a (S) -1- {2- [ 4-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride
A solution of 4-chloro-2- (3-fluoro-phenylsulfanyl) -phenol (290mg, 1.14mmol), PPh3(398mg, 1.52mmol) in dry THF (6mL) was cooled to 0 deg.C. DEAD (0.25mL, 1.59mmol) was added dropwise and the solution stirred for 20 min. A solution of 1- (2-hydroxy-ethyl) -pyrrolidine-2- (S) -carboxylic acid tert-butyl ester (370mg, 1.72mmol) in THF (4mL) was added via catheter. The mixture was stirred at 0 ℃ for 40min, then at room temperature for 1.5h and finally at 50 ℃ for 3 h. The mixture was diluted with heptane (100mL), washed with water (4X 25mL), and washed with Na2SO4Dried and evaporated onto silica gel. After flash chromatography on silica, heptane/EtOAc, 9: 1, tert-butyl ester intermediate was obtained as a colorless oil (393mg, 76%). To a solution of the ester (380mg, 0.84mmol) in ice HOAc (10mL) was added a solution of HCl in HOAc (1M, 10 mL). The mixture was stirred at room temperature overnight. The solution was evaporated to dryness to give the title compound as a colorless foam to give: 367mg, 100%.
1H NMR(CDCl3，500MHz)2.01(br，2H)，2.19(br，1H)，2.44(br，1H)，3.21(br，1H)，3.57(br，1H)，3.94(br，2H)，4.42(br，2H)，4.67(br，1H)，6.92-7.00(m，3H)，7.03-7.06(m，1H)，7.11(b r，1H)，7.21-7.25(m，1H)，7.28-7.33(m，1H).
LC-MS(m/z)396.0(MH+) (ii) a RT ═ 2.31; purity (UV, ELSD): 97.1 percent and 97.9 percent.
The following compounds were prepared in a similar manner:
preparation from 3-chloro-2- (3-fluoro-phenylsulfanyl) -phenol
3b (S) -1- {2- [ 3-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } pyrrolidine-2-carboxylic acid hydrochloride to give 452mg
1H NMR(CDCl3，500MHz)1.86-1.94(br，2H)，2.18(br，1H)，2.34(br，1H)，3.11(br，1H)，3.50(br，1H)，3.74(br，1H)，3.89(br，1H)，4.39(br，2H)，4.65(br，1H)，6.67(d，1H)，6.76-6.79(m，2H)，6.98-7.00(m，1H)，7.18-7.21(m，2H)，7.33-7.36(m，1H).
LC-MS(m/z)396.1(MH+) (ii) a RT ═ 2.21; purity (UV, ELSD): 95.1 percent and 98.7 percent.
Preparation from 5-chloro-2- (3-fluoro-phenylsulfanyl) -phenol
3c(s) -1- {2- [ 5-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } pyrrolidine-2-carboxylic acid hydrochloride to give: 539mg
1H NMR(CDCl3，500MHz)2.01(br，2H)，2.21(br，1H)，2.41(br，1H)，3.19(br，1H)，3.57(br，1H)，3.90(br，1H)，4.41(br，2H)，4.65(br，2H)，6.92-6.96(m，3H)，7.01-7.06(m，2H)，7.14-7.29(m，2H).
LC-MS(m/z)396.1(MH+) (ii) a RT ═ 2.28; purity (UV, ELSD): 93.7%, 99.9% to yield 539mg
Preparation from 4-cyano-2- (3-fluoro-phenylsulfanyl) -phenol
3d(s) -1- {2- [ 4-cyano-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid to give: 257mg, 100%
1H NMR(CDCl3，500MHz)1.82(m，1H)，1.97(m，2H)，2.35(m，1H)，3.13(dd，1H)，3.3(m，2H)，3.68(d，1H)，4.3(t，1H)，4.5(m，2H)，7.2(m，2H)，7.3(d，1H)，7.45(m，1H)，7.55(s，1H)，7.88(d，1H)
LC-MS(m/z)387(MH+) (ii) a RT ═ 1.98; purity (UV/ELSD) 98.4%, 91.7%
Example 4
4a (S) -1- [2- (5-chloro-2-phenylsulfanyl-phenoxy) -ethyl ] pyrrolidine-2-carboxylic acid hydrochloride
To a dry round bottom flask was added 1- [2- (5-chloro-2-iodo-phenoxy) -ethyl]-pyrrolidine-2- (S) -carboxylic acid tert-butyl ester (301mg, 0.666mmol), toluene (4.5mL), KOtBu (100mg, 0.89mmol), thiophenol (78mg, 0.708 mmol). The mixture was evacuated and backfilled with argon three times. To another dry round bottom flask was added Pd2dba3(9.6mg, 0.010mmol) and DPEPhos (16mg, 0.030mmol), evacuated and backfilled with argon three times. Toluene (1.5mL) was added and the mixture was stirred at room temperature for 10 min. 1.0mL of the catalyst mixture was added to the reaction mixture via syringe and the reaction mixture was heated to 90 ℃ for 3 h. The mixture was diluted with heptane (6mL), filtered and adsorbed onto silica gel. Purification by flash chromatography on silica eluting with heptane/EtOAc 92: 8 gave tert-butyl ester as a yellow oil (209mg, 72%). To a solution of tert-butyl ester (200mg) in ice HOAc (10mL) was added a solution of HCl in HOAc (1M, 10 mL). The mixture was stirred at room temperature overnight. The solution was evaporated to dryness to give the title compound as a colorless foam. Obtaining: 136mg, 54%
1H NMR(500MHz，CDCl3)2.05(br，2H)，2.27(br，1H)，2.45(br，1H)，3.24(br，1H)，3.58(b r，1H)，3.95(br，2H)，4.43(br，2H)，4.66(br，1H)，6.85-7.00(m，2H)，7.13(br，1H)，7.26-7.38(m，5H).
LC-MS(m/z)377.9(MH+) (ii) a RT is 2.20 min; purity (UV, ELSD): 99.9 percent and 96.4 percent; yield 136mg
The following compounds were prepared in a similar manner:
preparation from (S) -1- [2- (3-iodo-biphenyl-4-yloxy) -ethyl ] -pyrrolidine-2-carboxylic acid tert-butyl ester and 3-fluoro-thiophenol
4b (S) -1- {2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride, 63mg, 13%
1H NMR(500MHz，CDCl3)1.82(m，1H)，1.92(m，1H)，2.15(m，1H)，2.3(m，1H)，3.02(m，1H)，3.46(br m，1H)，3.73(m，1H)，3.82(m，1H)，4.1-4.4(br m，2H)，4.65(m，1H)，6.7(dd，2H)，6.85(d，1H)，6.95(m，1H)，7.1(d，1H)，7.2(m，1H)，7.26(dd，1H)，7.32(m，2H)，7.4(m，2H)
LC-MS(m/z)438.5(MH+) (ii) a RT ═ 2.51; purity (UV/ELSD) 94.0%, 99.3%
Example 5
5a (S) - {2- [ 4' -methoxy-3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride
1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -was substituted]-ethyl } -pyrrolidine-2 (S) -carboxylic acid tert-butyl ester (387mg, 0.78mmol), 4-methoxyphenylboronic acid (202mg, 1.33mmol) and K2CO3(296mg, 2.14mmol) was dissolved in dimethoxyethane (6mL) and water (3mL) and the solution was degassed with nitrogen for 10 min. Bis (triphenylphosphine) palladium (II) chloride (29mg, 0.041mmol) was added and the mixture was heated at 85 ℃ for 2 h. The mixture was then cooled to room temperature and diluted with ether. The organic layer was separated, then washed with saturated aqueous sodium bicarbonate (10mL), and then dried (MgSO)4). Silica gel was added to the filtrate and the product was adsorbed onto silica gel during evaporation of the solvent in vacuo. The product was then purified by flash column chromatography on a Flashmaster silica gel eluting with a heptane/ethyl acetate gradient from 92: 8 to 85: 15 heptane/ethyl acetate. TrueThe relevant fractions were concentrated in vacuo to give the butyl ester intermediate. 300mg, 73% was obtained. This was then dissolved in 1MHCl/AcOH (10mL) and the solution was stirred at room temperature for 16 h. The solution was then evaporated to dryness and the product was dried in a vacuum oven. 299mg, 104% was obtained.
1H NMR(500MHz，CDCl3)1.93(br m，1H)，2.05(br m，1H)，2.35-2.45(br m，2H)，3.11(brm，1H)，3.5(brm，1H)，3.8(s，3H)，3.9(brm，2H)，4.3(brm，1H)，4.45(brm，1H)，4.7(brm，1H)，6.87(m，2H)，6.94(m，3H)，7.0(brm，1H)，7.2(brm，1H)，7.39(d，2H)，7.49(m，1H)，7.55(m，1H)
LC-MS(m/z)468.5(MH+) (ii) a RT is 2.51 min; purity (UV, ELSD): 86.9 percent and 98.4 percent
The following compounds were prepared in a similar manner:
preparation from (S) -1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester
5b(s) - {2- [ 4' -cyano-3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride, to give: 274mg
1H NMR(500MHz，DMSO)1.78(m，1H)，1.95(m，2H)，2.28(m，1H)，3.11(dd，1H)，3.5(m，2H)，3.7(d，1H)，4.38(m，1H)，4.5(m，2H)，7.09(m，3H)，7.33(d，1H)，7.4(m，2H)，7.7(s，1H)，7.7-7.8(m，5H)
LC-MS(m/z)463(MH+)；RT＝2.2(UV，ELSD)：93.7％，89.5％
Preparation from (S) -1- {2- [ 5-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester
(s) -1- {2- [ 4' -cyano-4- (3-fluoro-phenylsulfanyl) -biphenyl-3-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride to give: 285mg, two-step yield 56%
1H NMR(500MHz，DMSO)1.8(m，1H)，2.0(m，2H)，2.4(m，1H)，3.2(m，1H)，3.6(m，2H)，3.72(m，1H)，3.75(d，1H)，4.4(t，1H)，4.5(m，2H)，7.12(m，3H)，7.3(d，1H)，7.42(m，2H)，7.5(s，1H)，7.95(s，4H)
LC-MS(m/z)463(MH+)；RT＝2.2(UV，ELSD)：90％，100％
1H NMR(500MHz，DMSO)
Preparation from 1- {2- [ 5-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester
5d(s) -1- {2- [2- (3-fluoro-phenylsulfanyl) -5-thiophen-3-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride to give: 330mg, two-step yield 62%
1HNMR(500MHz，DMSO)1.8(m，1H)，1.95(m，2H)，2.35(m，1H)，3.12(m，1H)，355(m，2H)，3.7(d，1H)，4.35(m，1H)，4.5(m，2H)，6.92(d，1H)，7.0(d，1H)，7.05(dd，1H)，7.35-7.5(m，4H)，7.68(m，2H)，8.06(s，1H)
LC-MS (m/z)444(MH+)；RT＝2.45(UV，ELSD)93％，100％
Preparation from 1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester
5e(s) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-pyrimidin-5-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride to give: 251mg, two-step yield 57%
1H NMR(500MHz，DMSO)1.8(m，1H)，1.9-2.0(m，2H)，2.4(m，1H)，3.1(m，1H)，3.5(m，2H)，3.7(m，1H)，4.4(m，1H)，4.5(d，2H)，7.05(m，3H)，7.35(m，2H)，7.8(s，1H)
LC-MS(m/z)439.971(MH+)；RT＝1.78(UV，ELSD)98％，99％
Preparation from 1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid butyl ester
5f (S) -1- {2- [3- (3-fluoro-phenylsulfanyl) -3-methanesulfonyl-biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride to give 390mg, two-step yield 61%
1H NMR(500MHz，DMSO)1.8(m，1H)，1.9(m，2H)，2.4(m，1H)，3.2(d，1H)，3.25(s，3H)，3.6(m，2H)，3.72(d，1H)，4.35(t，1H)，4.4(m，1H)，7.05(m，3H)，7.38(m，2H)，7.73(dd，1H)，7.82(s，1H)，7.85(d，1H)，7.96(d，1H)，8.12(s，1H)
LC-MS(m/z)515.9410(MH+)；RT＝2.05(UV/ELSD)94％，94％
Example 6
6a (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-morpholin-4-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride
1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -was substituted]-Ethyl } -pyrrolidine-2 (S) -carboxylic acid tert-butyl ester (497mg, 1.0mmol) was dissolved in anhydrous tetrahydrofuran (1 mL). Then, dibenzylidene (dibenzylidene) acetonato palladium (II) (Pd)2dba3) (15mg, 0.016mmol, 2- (di-tert-butylphosphino) diphenylphosphine (21mg, 0.07mmol) and potassium tert-butoxide (159mg, 1.42mmol) were added to a vessel placed under an argon atmosphere. Morpholine (0.11mL, 1.26mmol) was added to the mixture, which was then stirred overnight. The mixture was then diluted with ethyl acetate (25mL), filtered and evaporated to dryness. The residue was dissolved in acetic acid (10mL) and 1M HCl/AcOH (10mL) was added. The solution was stirred at room temperature for 16 hours and then evaporated to dryness. The crude product was then purified by preparative LC-MS. The purified compound was dissolved in acetic acid (30mL) and 1MHCL/AcOH (10mL) was added. The solvent was removed in vacuo and after re-evaporation with dichloromethane, the title compound was isolated as a colorless foam. Obtaining: 162mg, two-step yield 34%.
1HNMR(500MHz，DMSO)1.8(m，1H)，1.9-2.0(m，2H)，2.4(m，1H)，3.1(m，1H)，3.2(brs，4H)，3.5(m，2H)，3.7(d，1H)，3.83(m，4H)，4.4(m，3H)，6.97(d，1H)，7.0(d，1H)，7.08(dd，1H)，7.2(d，1H)，7.33(m，3H)
LC-MS(m/z)447.5(MH+)；RT＝1.76(UV/ELSD)＝99.8％，96.4％
6b (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-piperidin-1-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid hydrochloride
Reacting (S) -1- {2- [ 4-bromo-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -n]-Ethyl } -pyrrolidine-2-carboxylic acid tert-butyl ester (990mg, 1.99mmol) was dissolved in toluene (4 mL). To this solution was added tris (dibenzylideneacetone) palladium (II) (Pd) under an inert atmosphere2dba3) Sodium tert-butoxide (270mg, 281mmol) and 2- (dicyclohexylphosphino) biphenyl (15mg, 0.043 mmol). Piperidine (0.24mL, 2.43mmol) was added to the mixture and the mixture was heated to 80 ℃ for 16 hours. The mixture was cooled to room temperature. The mixture was then diluted with ether (35mL), filtered and evaporated to dryness. The residue was then dissolved in ethyl acetate/ether, silica gel was added and the solvent was removed in vacuo. The product adsorbed on silica gel is then placed on a silica column and then eluted with heptane/(heptane: ethyl acetate: triethylamine) 70/30 to 50/50. The butyl ester intermediate was isolated from the relevant fractions (244mg, 0.487mmol) and then dissolved in acetic acid (10 mL). To the solution was added 1MHCl/AcOH (10mL) and the solution was stirred for 16 h. The title compound was isolated after evaporation to dryness.
Obtaining: 301mg, two-step yield 32%
LC-MS(m/z)445.0908(MH+)；RT＝1.44(UV/ELSD)＝88％，98％
Pharmacological test
The compounds of the invention were tested using a well-established and reliable assay for glycine uptake:
[3H]glycine uptake
Cells transfected with human GlyT-1b were seeded in 96-well plates. Prior to the experiment, cells were treated with HBS (10mM Hepes-trs (pH 7, 4), 2, 5mM KCl, 1mM CaCl2、2，5mM MgSO4) Washed twice and preincubated with test compound for 6 minutes. Then, 10nM was added3H-Glycine was added to each well and incubation continued for 15 minutes. Cells were washed twice with HBS. Scintillation fluid was added and plates were counted on a trilux (wallac) scintillation counter.
The results of the tests show that the IC of the compounds prepared according to the invention in the above-mentioned assay50The inhibition was less than 10000 nM.
The compounds of the invention were also tested using well-established and reliable microdialysis experiments.
Method
Male Sprague-Dawley rats weighing 275-350g initially were used. Animals were kept in a 12-hr light/dark cycle under normal room temperature (21 + -2 deg.C) and humidity (55 + -5%) control conditions, and were allowed free access to and drinking tap water.
Rats were anesthetized with fentanyl (hypnorm)/Duomekang (2ml/kg), and intracerebral catheters (CMA/12) were implanted stereotactically into the brain, with the dialysis probe tip positioned on the anterior side of the hippocampus (coordinates: 5.6mm posterior to bregma, 5.0mm lateral, 7.0mm anterior to dura). After surgery, rats were allowed to recover for at least 2 days. On the day of the experiment, a microdialysis probe (CMA/12, 0.5mm diameter, 3mm long) was inserted into the catheter. The probe is connected with the micro-injection pump through the double-channel rotating body. Shortly before insertion of the probe into the brain, perfusion of filtered ringer's solution (145mM NaCl, 3mM KCl, 1mM MgCl) into the microdialysis probe was initiated2，1.2mM CaCl2) The whole experiment was continued at a constant flow rate of 1. mu.l/min. After 165min of stabilization, the experiment was started. During the entire experiment, a 20 or 40min sampling protocol was used. Due to the lag time of the perfusate from the microdialysis site to the probe outlet, the respective time point is corrected.
After the experiment, the rats were sacrificed by decapitation. Brains were removed, frozen, sectioned (20 μm) and probe positions verified.
Analysis of Glycine in dialysate
The pre-column was derivatized on-line with o-phatalaldehyde and the dialysate was analyzed for glycine concentration by HPLC with fluorescence detection. The system consisted of a Hypersil AA-ODS column (5 μm, 21X 200mm, Agilent) and an Agilent 1100 fluorescence detector (excitation wavelength, 266-. The mobile phase is composed of A: 20mM sodium acetate, 0018% triethylamine, 0.3% tetrahydrofuran, pH 7.2; b: 20mM sodium acetate, 40% acetonitrile and 40% methanol, pH 7.2. The column oven temperature was set at 40 ℃ and the flow rate was 0.45 ml/min. After correction with a series of standard glycine solutions (0.1-10 μ M), data were collected and analyzed with ChemStation software (Agilent).
Data reporting
The average of 3 consecutive glycine samples taken just prior to compound administration served as the basal level for each experiment, and the data were converted to a percentage of basal levels (the average basal value before injection was normalized to 100%).

Claims (24)

1. A compound of formula I or a salt thereof
Wherein
X is O, S or CR11R12Wherein R is11And R12Independently selected from H or C1-6An alkyl group;
y is O or S;
R1、R2、R3and R4Independently selected from hydrogen; halogen; a cyano group; a nitro group; c1-6-an alkyl group; c2-6-an alkenyl group; c2-6-an alkynyl group; c1-6-an alkyloxy group; c2-6-alkenyloxy; c2-6-alkynyloxy; c1-6-an alkylthio group; c2-6-an alkenylthio group; c2-6-alkynylthio; a hydroxyl group; hydroxy-C1-6-an alkyl group; hydroxy-C2-6-an alkenyl group; hydroxy-C2-6-an alkynyl group; halo-C1-6-an alkyl group; halo-C2-6-an alkenyl group; halo-C2-6-an alkynyl group; halo-C1-6-an alkyloxy group; halo-C2-6-alkenyloxy; halo-C2-6-alkynyloxy; c3-8-a cycloalkyl group; c3-8-a cycloalkenyl group; c3-8-cycloalkyl-C1-6-an alkyl group; c3-8-cycloalkenyl-C1-6-an alkyl group; c3-8-cycloalkyl-C2-6-an alkenyl group; c3-8-cycloalkenyl-C2-6-an alkenyl group; c3-8-cycloalkyl-C2-6-an alkynyl group; c3-8-cycloalkenyl-C2-6-an alkynyl group; an acyl group; c1-6-an alkyloxycarbonyl group; c2-6-alkenyloxycarbonyl; c2-6-alkynyloxycarbonyl; c1-6-an alkylsulfonyl group; c2-6-an alkenylsulfonyl group; c2-6-an alkynylsulfonyl group; aryl optionally substituted with: halogen, cyano, nitro, C1-6Alkyl radical, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyloxy, C2-6-alkenyloxy, C2-6-alkynyloxy, C1-6-alkylthio radical, C2-6-alkenylthio radical, C2-6Alkynylthio, hydroxy-C1-6-alkyl, hydroxy-C2-6-alkenyl, hydroxy-C2-6-alkynyl, halo-C1-6Alkyl, halo-C2-6-alkenyl, halo-C2-6-alkynyl, halo-C1-6-alkyloxy, halo-C2-6-alkenyloxy, halo-C2-6-alkynyloxy, C3-8-cycloalkyl, C3-8-cycloalkenyl radical, C3-8-cycloalkyl-C1-6Alkyl radical, C3-8-cycloalkenyl-C1-6-an alkyl group,C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkenyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C3-8-cycloalkenyl-C2-6-alkynyl, acyl, C1-6-alkyloxycarbonyl group, C2-6-alkenyloxycarbonyl radical, C2-6-alkynyloxycarbonyl, C1-6-alkylsulfonyl, C2-6-alkenylsulfonyl or C2-6-an alkynylsulfonyl group; a monocyclic heteroaryl optionally substituted with: halogen, cyano, nitro, C1-6-an alkyl group; c2-6-an alkenyl group; c2-6-alkynyl, C1-6-an alkyloxy group; c2-6-alkenyloxy; c2-6-alkynyloxy, C1-6-alkylthio radical, C2-6-alkenylthio radical, C2-6Alkynylthio, hydroxy-C1-6-alkyl, hydroxy-C2-6-alkenyl, hydroxy-C2-6-alkynyl, halo-C1- 6Alkyl, halo-C2-6-alkenyl, halo-C2-6-alkynyl, halo-C1-6-alkyloxy, halo-C2-6-alkenyloxy, halo-C2-6-alkynyloxy, C3-8-cycloalkyl, C3-8-cycloalkenyl radical, C3-8-cycloalkyl-C1-6Alkyl radical, C3-8-cycloalkenyl-C1-6Alkyl radical, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkenyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C3-8-cycloalkenyl-C2-6-alkynyl, acyl, C1-6-alkyloxycarbonyl group, C2-6-alkenyloxycarbonyl radical, C2-6-alkynyloxycarbonyl, C1-6-alkylsulfonyl, C2-6-alkenylsulfonyl or C2-6-an alkynylsulfonyl group; or-NR13R14Wherein R is13And R14Independently selected from hydrogen, C1-6-an alkyl group; c2-6-an alkenyl group; c2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkenyl radical, C3-8-cycloalkyl-C1-6Alkyl radical, C3-8-cycloalkenyl-C1-6Alkyl radical, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkenyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C3-8-cycloalkenyl-C2-6-alkynyl or aryl, or R13And R14Together with the nitrogen, form a 3-7 membered heterocyclic ring optionally containing 1 additional heteroatom selected from O, S or N;
R5is aryl optionally substituted with: halogen, cyano, C1-6Alkyl radical, C1-6-alkyloxy, C1-6Alkylthio, halo-C1-6-an alkyl group;
R6selected from H, C1-6Alkyl radical, C1-6-alkyloxy, C1-6-alkylthio, with the proviso that if R is6Is selected from C1-6-alkyloxy or C1-6Alkylthio, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6An alkyl group;
R7and R8Independently selected from H or C1-6-an alkyl group;
R9and R9' is independently selected from H or C1-6-an alkyl group; or
R6And R8Together with the nitrogen forming a saturated 3-7 membered heterocyclic ring, R7Is selected from H or C1-6-alkyl, and R9And R9' is independently selected from H or C1-6-an alkyl group; or
R7And R8Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R6Selected from H, C1-6Alkyl radical, C1-6-alkyloxy, C1-6-alkylthio, with the proviso that if R is6Is selected from C1-6-alkyloxy or C1-6Alkylthio, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R9And R9' is independently selected from H or C1-6-an alkyl group; or
R8And R9Together with the nitrogen form a saturated 3-7 membered heterocyclic ring, and R6Selected from H, C1-6Alkyl radical, C1-6-alkyloxy, C1-6-alkylthio, with the proviso that if R is6Is selected from C1-6-alkyloxy or C1-6Alkylthio, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R9' is selected from H or C1-6-an alkyl group;
R10is H, C1-6-an alkyl group; or an alkali metal.
2. The compound of claim 1, wherein X is selected from O or CH2。
3. The compound of any one of claims 1-2, wherein Y is O.
4. The compound of any one of claims 1-2, wherein Y is S.
5. A compound according to any one of the preceding claims wherein R is1Selected from hydrogen, C1-6Alkyl, halogen, phenyl or substituted by one or two selected from C1-6-alkyl or C1-6Phenyl substituted with a substituent of alkoxy.
6. A compound according to any one of the preceding claims wherein R is2Selected from hydrogen; a cyano group; c1- 6-an alkyl group; halogen; a phenyl group; phenyl substituted with one or two substituents selected from: cyano radicals, C1-6Alkyl radical, C1-6-alkoxy or C1-6-an alkylsulfonyl group; -NR13R14Wherein R is13And R14Together with the nitrogen, form a 3-7 membered heterocyclic ring optionally containing 1 additional heteroatom selected from O, S or N; or a monocyclic heteroaryl group.
7. The compound of claim 6, wherein R13And R14Together with the nitrogen, form a morpholinyl or piperidinyl group.
8. The compound of claim 6, wherein the monocyclic heteroaryl is pyrimidinyl.
9. A compound according to any one of the preceding claims wherein R is3Selected from hydrogen; c1-6-an alkyl group; halogen; a phenyl group; phenyl substituted with one or two substituents selected from: cyano radicals, C1-6-alkyl or C1-6-an alkoxy group; or a monocyclic heteroaryl group.
10. The compound of claim 9, wherein the monocyclic heteroaryl is thienyl.
11. A compound according to any one of the preceding claims wherein R is4Selected from hydrogen, C1-6Alkyl, halogen, phenyl or substituted by one or two selected from C1-6-alkyl or C1-6Phenyl substituted with a substituent of alkoxy.
12. A compound according to any one of the preceding claims wherein R is5Is phenyl optionally substituted with: halogen, C1-6Alkyl radical, C1-6-alkoxy, C1-6Alkylthio, halo-C1- 6-an alkyl group.
13. A compound according to any one of the preceding claims wherein R is6Is selected from H or C1-6-an alkyl group.
14. A compound according to any one of the preceding claims wherein R is7Is selected from H or C1-6-an alkyl group.
15. A compound according to any one of the preceding claims wherein R is8Is selected from H or C1-6-an alkyl group.
16. A compound according to any one of the preceding claims wherein R is10Is H.
17. The compound of any one of claims 1-12 or 16, wherein R6And R8Together with nitrogen to form an optionally substituted C1-6-alkyl-substituted 1-pyrrolidinyl, 1-piperidinyl or 1-azaRadical, R7Is selected from H or C1-6-alkyl, and R9And R9' independently selected from H, C1-6-an alkyl group.
18. The compound of any one of claims 1-12 or 16, wherein R7And R8Together with nitrogen to form an optionally substituted C1-6-alkyl-substituted 1-pyrrolidinyl, 1-piperidinyl or 1-azaAnd R is6Selected from H, C1-6Alkyl radical, C1-6-alkyloxy, C1-6-alkylthio, with the proviso that if R is6Is selected from C1-6-alkyloxy or C1-6Alkylthio, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl, and R9And R9' independently selected from H, C1-6-an alkyl group.
19. The compound of any one of claims 1-12 or 16, wherein R8And R9Together with nitrogen to form an optionally substituted C1-6-alkyl-substituted 1-pyrrolidinyl, 1-piperidinyl or 1-azaAnd R is6Selected from H, C1-6Alkyl radical, C1-6-alkyloxy, C1-6-alkylthio, with the proviso that if R is6Is selected from C1-6-alkyloxy or C1-6Alkylthio, then X is CR11R12Wherein R is11And R12Independently selected from H or C1-6Alkyl radical, R7Selected from H, C1-6-alkyl, and R9' selected from H, C1-6-an alkyl group.
20. The compound of claim 1 selected from
1) (S) -1- {2- [2- (4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
2) (S) -1- {2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
3) (S) -1- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
4) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
5) (S) - {2- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
6) (S) -1- {2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
7) (S) -1- {2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
8) (S) -1- {2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
9) (S) -1- {2- [2- (3-chloro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
10) (S) -1- {2- [2- (4-chloro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
11) (S) -1- {2- [2- (4-methoxy-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
12) (S) -1- {2- [2- (3, 4-difluoro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
13)1- {2(R/S) - [2- (4-chloro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
14)1- {2(R/S) - [2- (3, 4-difluoro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
15) (S) -1- {2- [2- (3-fluoro-phenoxy) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
16)1- {2(R/S) - [2- (3-fluoro-phenoxy) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
17)1- {2(R/S) - [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
18)1- {2(R/S) - [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propyl } -pyrrolidine-2 (S) -carboxylic acid,
19) ({2- [2- (4-tert-butyl-phenylthio) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
20)2- {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
21) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
22) ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
23) {2- [2- (4-tert-butyl-phenylthio) -phenoxymethyl ] -piperidin-1-yl } -acetic acid,
24) ({2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
25) {4- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -piperidin-1-yl } -acetic acid,
26) (N-2-propyl- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
27) ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
28) (N-ethyl- {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
29)2- {3- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
30) (S) - {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid,
31) ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
32) (N-2-propyl- {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
33) {3- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -acetic acid,
34) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-ethyl-amino) -acetic acid,
35) ({2- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -ethyl- } N-methyl-amino) -acetic acid,
36) {4- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -piperidin-1-yl } -acetic acid,
37)2- {3- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
38) ({2- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -ethyl } -N-2-propyl-amino) -acetic acid
39) ({2- [2- (4-tert-butyl-phenylthio) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
40) {2- [2- (4-methylsulfanyl-phenylsulfanyl) -phenoxymethyl ] -piperidin-1-yl } -acetic acid,
41) ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -ethyl } -N-methyl-amino) -acetic acid,
42) (N-methyl- {2- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -ethyl } -amino) -acetic acid,
43)2- {3(R) - [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
44)2- {3(R) - [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
45)2- [3(R) - (2- (4-methylphenyl) -sulfanyl-phenoxy) -pyrrolidin-1-yl ] -propionic acid,
46) {3(R) - [2- (4-tert-butyl-phenylthio) -phenoxy ] -pyrrolidin-1-yl } -acetic acid,
47)2- {3(R) - [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
48)2- {3(R) - [2- (4-chloro-phenylsulfanyl) -phenoxy ] -pyrrolidin-1-yl } -propionic acid,
49) ({1- [2- (3-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-ethyl-amino) -acetic acid,
50) ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy) -butan-2-yl } -N-ethyl-amino) -acetic acid,
51) ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-ethyl-amino) -acetic acid,
52) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-ethyl-amino) -acetic acid,
53) ({1- [1- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid,
54) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -4-methyl-but-2-yl) } -N-ethyl-amino) -acetic acid,
55) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] propan-2-yl } -N-ethyl-amino) -acetic acid,
56) (S) - {1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -prop-2-yl } -N-methyl-amino) -acetic acid,
57) (S) - ({1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -prop-2-yl) -N-ethyl-amino) -acetic acid,
58) ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid,
59) ({1- [2- (4-chloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-ethyl-amino) -acetic acid,
60) ({1- [2- (3-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-methyl-amino) -acetic acid,
61) ({1- [2- (4-chloro-phenylsulfanyl) -phenoxymethyl ] -propyl } -N-ethyl-amino) -acetic acid,
62) (N-ethyl- {1- [2- (3-fluoro-phenylsulfanyl) -phenoxymethyl ] -propyl } -amino) -acetic acid,
63) (R) - ({2- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -1-methyl-ethyl } -N-ethyl-amino) -acetic acid,
64) (S) - (2{2- [2- (4-chloro-phenoxy) -phenoxy ] -propyl-N-methyl-amino) -acetic acid,
65) (R) - (2{2- [2- (3-chloro-phenylthio) -phenoxy ] - } -propyl-N-methyl-amino) -acetic acid,
66) ({2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -N-methyl-amino) -acetic acid,
67) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-ethyl-amino) -acetic acid,
68) ({1- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-methyl-amino) -acetic acid,
69) ({ 3-methyl-1- [2- (4-trifluoromethyl-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-ethyl-amino) -acetic acid,
70) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -but-2-yl } -N-methyl-amino) -acetic acid,
71) (S) - (1{2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -propan-2-yl } N-methyl-amino) -acetic acid,
72) (S) - (2- {2- [2- (3-fluoro-phenylsulfanyl) -phenoxy ] -propyl } -N-methyl-amino) -acetic acid,
73) ({1- [2- (4-tert-butyl-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl } -N-ethyl-amino) -acetic acid,
74) (S) - ({1- [2- (3, 4-dichloro-phenylsulfanyl) -phenoxy ] -propan-2-yl } -N-methyl-amino) -acetic acid,
75) ({1- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -3-methyl-but-2-yl) -N-methyl-amino) -acetic acid,
76) ({1- [2- (4-tert-butyl-phenylthio) -phenoxy ] -3-methyl-propan-2-yl } -N-ethyl-amino) -acetic acid,
77) ({2- [2- (3-chloro-4-fluoro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-ethyl-amino) -acetic acid,
78) ({2- [2- (4-methoxy-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-cyclohexyl-amino) -acetic acid,
79) { [2- (2- (4-methylsulfanyl-phenoxy) -propan-1-yl- ] -N-cyclohexyl-amino } -acetic acid,
80) ({2- [2- (3-chloro-phenylsulfanyl) -phenoxy ] -propan-1-yl } -N-cyclohexyl-amino) -acetic acid,
81) (S) -1- {3- [2- (3-fluoro-phenylsulfanyl) -phenyl ] -propyl } -pyrrolidine-2-carboxylic acid,
82) (S) -2- ({2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -methyl-amino) -propionic acid,
83) ({2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -methyl-amino) -acetic acid,
84) (S) -1- {2- [ 4-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
85) (S) -1- {2- [ 3-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } pyrrolidine-2-carboxylic acid,
86) (S) -1- {2- [ 5-chloro-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } pyrrolidine-2-carboxylic acid,
87) (S) -1- {2- [ 4-cyano-2- (3-fluoro-phenylsulfanyl) -phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid
88) (S) -1- [2- (5-chloro-2-phenylsulfanyl-phenoxy) -ethyl ] pyrrolidine-2-carboxylic acid,
89) (S) -1- {2- [3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
90) (S) - {2- [ 4' -methoxy-3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
91) (S) - {2- [ 4' -cyano-3- (3-fluoro-phenylsulfanyl) -biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
92) (S) -1- {2- [ 4' -cyano-4- (3-fluoro-phenylsulfanyl) -biphenyl-3-yloxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
93) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -5-thiophen-3-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
94) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-pyrimidin-5-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
95) (S) -1- {2- [3- (3-fluoro-phenylsulfanyl) -3-methanesulfonyl-biphenyl-4-yloxy ] -ethyl } -pyrrolidine-2 (S) -carboxylic acid,
96) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-morpholin-4-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
97) (S) -1- {2- [2- (3-fluoro-phenylsulfanyl) -4-piperidin-1-yl-phenoxy ] -ethyl } -pyrrolidine-2-carboxylic acid,
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier or diluent.
22. Use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of post-traumatic stress disorder or a disease selected from schizophrenia and other psychoses, including both positive and negative symptoms schizophrenia, and for improving cognition in the following conditions in which cognitive processes are diminished: namely Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which brain is damaged by internal or external influences, and convulsive diseases.
23. The use of claim 22, wherein the disease caused by brain injury due to internal or external influences is head trauma or stroke.
24. The use of claim 22, wherein the convulsive disorder is epilepsy, spasticity, or myoclonus.
HK06112870.4A 2003-04-30 2004-04-27 Aromatic oxyphenyl and aromatic sylfanylphenyl derivatives HK1092453B (en)

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DKPA200300649 2003-04-30
DKPA200300649 2003-04-30
PCT/DK2004/000290 WO2004096761A1 (en) 2003-04-30 2004-04-27 Aromatic oxyphenyl and aromatic sulfanylphenyl derivatives

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HK1092453B HK1092453B (en) 2009-08-28

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