HK1183480A - Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators - 842 - Google Patents

Description

Oxadiazole derivative ligands and their use as metabotropic glutamate receptor potentiators 842

The application is a divisional application of Chinese invention patent application (application date: 2008/6/5; application number: 200880019154.8; invention name: oxadiazole derivative ligand and its use as metabotropic glutamate receptor synergist 842).

Technical Field

The present invention relates to novel compounds which act as potentiators of glutamate receptors, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Background

Metabotropic glutamate receptors (mGluR) constitute a family of GTP-binding protein (G-protein) coupled receptors that are activated by glutamate and play an important role in synaptic activity in the central nervous system, including neuroplasticity, neurodegeneration, and neurodegeneration.

Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; phosphoric acidAn increase in inositol (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenylate cyclase; an increase or decrease in cyclic adenosine monophosphate (cAMP) formation; activation of guanylate cyclase; an increase in cyclic guanosine monophosphate (cGMP) formation; phospholipase A₂Activation of (2); an increase in arachidonic acid release; and increases or decreases in voltage-and ligand-gated ion channel activity. (Schoepp et al, 1993, Trends Pharmacol. Sci.,14:13; Schoepp,1994, neurohem. int.,24:439; Pin et al, 1995, Neuropharmacology 34:1; Bordi et al, 1995, Neuropharmacology 34: 1)&Ugolini,1999,Prog.Neurobiol.59:55)。

Eight mGluR subtypes have been identified, and are divided into three groups based on basic sequence similarity, signal transduction linkages, and pharmacological profile. Group I mglurs include mGluR1 and mGluR5, which activate phospholipase C and generate intracellular calcium signals. Group II mGluRs (mGluR2 and mGluR3) and group III mGluRs (mGluR4, mGluR6, mGluR7 and mGluR8) mediate the inhibition of adenylyl cyclase activity and cyclic adenosine levels. For a review see Pin et al, 1999, eur.j. pharmacol, 375: 277-.

The activity of mGluR family receptors is implicated in a variety of normal processes in the mammalian CNS and is an important target for compounds useful in the treatment of a variety of neurological and psychiatric disorders. Activation of mGluRs requires induction of hippocampal long-term potentiation and cerebellar long-term inhibition (Bashir et al, 1993, Nature,363:347; Bortolotto et al, 1994, Nature,368:740; Aiba et al, 1994, Cell,79:365; Aiba et al, 1994, Cell,79: 377). The role of mGluRs activation in nociception and analgesia has also been demonstrated (Meller et al, 1993, Neuroreport,4:879; Bordi & Ugolini,1999, Brain Res.,871: 223). In addition, activation of mGluRs has been implicated in a variety of other normal processes, including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control, and control of vestibulo-ocular reflex (Nakanishi,1994, Neuron,13:1031; Pin et al, 1995, Neuropharmacology, supra; Knipfel et al, 1995, J.Med.chem.,38: 1417).

Recent advances in the elucidation of the neurophysiological roles of mGluRs have identified these receptors as promising drug targets for the treatment of acute and chronic neurological, psychiatric and pain disorders. Because of the physiological and pathophysiological significance of mGluRs, there is a need for new drugs and compounds that can modulate mGluR function.

Disclosure of Invention

We have identified a class of compounds that modulate mGluR function. In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof:

formula I

Wherein

R¹Is halogen or halogeno C_1-3An alkoxy group;

q isAnd

R²is hydrogen or C_1-3An alkyl group.

The invention also provides a process for preparing compounds of formula I.

The present invention also provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier or excipient; in another aspect, the invention provides methods for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction (glutamate dysfunction) in an animal in need of such treatment. The method comprises the step of administering to the animal a therapeutically effective amount of a compound of formula I or a pharmaceutical composition comprising said amount of a compound of formula I.

The invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of any of the conditions discussed herein.

In addition, the present invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

Detailed Description

The compounds described herein exhibit activity as modulators of metabotropic glutamate receptors, and more particularly, as potentiators of the mGluR2 receptor. The compounds of the invention are expected to be useful in therapy as medicaments, in particular in the treatment of neurological and psychiatric disorders associated with glutamate dysfunction.

Definition of

In this specification, unless otherwise indicated, the Nomenclature used in this specification generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, sections a, B, C, D, E, F, and H, PergamonPress, Oxford,1979, which are incorporated by reference for all purposes to name and rule the chemical structures illustrated. Optionally, the name of the compound can be generated using a chemical naming program (ACD/ChemSketch, Version 5.09/September 2001, Advanced chemistry development, Inc., Toronto, Canada).

The term "C" as used herein_1-3Alkyl "means a straight, branched or cyclic hydrocarbon group containing one to 3 carbon atoms and includes methyl, ethyl, propyl, isopropyl, cyclopropyl, and the like.

The term "halo C" as used herein_1-3Alkoxy "refers to a straight or branched chain alkoxy group having 1 to 3 carbon atoms and having at least one halogen substituent, including fluoromethoxy, trifluoromethoxy, fluoroethoxy, trifluoropropoxy, fluoroisopropoxy, and the like.

The term "halogen" as used herein refers to a halogen, including fluorine, chlorine, bromine, iodine, in radioactive or non-radioactive forms.

The symbol "Δ" when used refers to heating or the application of heat.

The term "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts that are compatible for administration to a patient.

"pharmaceutically acceptable acid addition salts" are any non-toxic organic or inorganic acid addition salts of the compounds represented by formula I. Exemplary inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acids, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids. Examples of such acids are, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Where valency permits, mono-or di-acid salts may be formed, which may exist as hydrates, solvates or substantially anhydrous forms. In general, acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than the free base forms of these compounds. Other non-pharmaceutically acceptable salts (e.g. oxalates) may be used, for example, for isolating compounds of formula I for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

"solvate" refers to a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I having an appropriate solvent molecule incorporated in the crystal lattice. Suitable solvents are physiologically tolerable doses for administration in the form of solvates. Examples of suitable solvents are ethanol, water, and the like. When water is the solvent, the molecule is referred to as a hydrate.

The term "stereoisomer" is a collection of all isomers of a single molecule that differ only in the spatial orientation of the atoms. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).

The terms "treat" or "treating" refer to alleviating a symptom, temporarily or permanently eliminating the cause of the symptom, or preventing or slowing the manifestation of the symptoms of a given disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that is effective to treat a specified disease or condition.

The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other substance with which the active ingredient is combined in order to form a pharmaceutical composition (i.e., a dosage form capable of being administered to a patient). One example of such a carrier is a pharmaceutical oil commonly used for parenteral administration.

Specifically, the present invention relates to the following aspects:

1. a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof:

formula I

Wherein

R¹Is halogen or halogeno C_1-3An alkoxy group;

q isAnd

R²is hydrogen or C_1-3An alkyl group.

2. Item 1 ofA compound or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein R¹Is chlorine or trifluoromethoxy.

3. The compound of item 2 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein R¹Is trifluoromethoxy.

4. The compound of item 1 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein Q is

5. The compound of item 4 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein Q isAnd R is²Is H.

6. The compound of item 1 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein R¹Is chloro or trifluoromethoxy and Q is

7. The compound of item 6 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein R¹Is trifluoromethoxy and Q is

8. The compound of item 1 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein R¹Is chloro or trifluoromethoxy and Q isWherein R is²Is H.

9. The compound of item 1 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof, wherein R¹Is chloro or trifluoromethoxy and Q is

10. A compound of item 1 selected from:

7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl) -2- (4-trifluoromethoxybenzyl) -2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -5- [3- (2, 5-diazabicyclo [2.2.1] hept-2-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -7-methyl-2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -7-methyl-5- [3- (3-methyl-piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl) -2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -7-methyl-5- [3- (2-methyl-piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -2, 3-dihydroisoindol-1-one; or

2- (4-chloro-benzyl) -7-methyl-5- [3- (2-methyl-piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -2, 3-dihydroisoindol-1-one.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier or excipient.

12. A compound according to any one of claims 1 to 10 for use as a medicament.

13. Use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction.

14. The use of item 13, wherein the neurological and psychiatric disorders are selected from the group consisting of brain defects secondary to cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, dementia, AIDS-induced dementia, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders, idiopathic and drug-induced parkinson's disease, muscle spasms including tremors, epilepsy, convulsions and disorders associated with muscle spasms, brain defects secondary to long-term status epilepticus, migraine headache, urinary incontinence, psychoactive substance tolerance, psychoactive substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), Mood disorders, depression, mania, bipolar disorder, circadian rhythm disorders, jet lag syndrome, shift work syndrome, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain and post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder and behavioral disorders.

15. A method for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a compound according to any one of claims 1-10.

16. A method for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising administering to said animal a therapeutically effective amount of the pharmaceutical composition of item 11.

17. The method of item 15 or 16, wherein the neurological and psychiatric disorders are selected from the group consisting of brain defects secondary to cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, dementia, AIDS-induced dementia, alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive disorders, idiopathic and drug-induced parkinson's disease, muscle spasms including tremor, epilepsy, convulsions and disorders associated with muscle spasticity, brain defects secondary to long-term status epilepticus, migraine headache, urinary incontinence, psychoactive substance tolerance, psychoactive substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), Mood disorders, depression, mania, bipolar disorder, circadian rhythm disorders, jet lag syndrome, shift work syndrome, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain and post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder and behavioral disorders.

18. The method of item 17, wherein the neurological and psychiatric disorders are selected from alzheimer's disease, brain deficits secondary to long-term status epilepticus, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), mood disorders, depression, mania, and bipolar disorders.

Compound (I)

The compounds described herein correspond to formula I or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof:

formula I

Wherein

R¹Is halogen or halogeno C_1-3An alkoxy group;

q isAnd

R²is hydrogen or C_1-3An alkyl group.

In one embodiment, R¹Is chlorine or trifluoromethoxy.

In another embodiment, R¹Is trifluoromethoxy.

In still other embodiments, Q is

In still other embodiments, Q isWherein R is²Is H.

In other embodiments, R¹Is chloro or trifluoromethoxy and Q is

In still other embodiments, R¹Is trifluoromethoxy and Q is

In still other embodiments, R¹Is chloro or trifluoromethoxy and Q isWherein R is²Is H.

In another embodiment, R¹Is chloro or trifluoromethoxy and Q is

Pharmaceutically acceptable salts, hydrates, solvates, optical isomers or combinations thereof mentioned in the above embodiments are also included in the scope of the present invention.

It will be understood by those skilled in the art that when a compound of the invention contains one or more chiral centers, then the compound of the invention may exist as enantiomers or diastereomers, as well as separated into enantiomers or diastereomers, or as a racemic mixture. The present invention includes any possible enantiomer, diastereomer, racemate or mixture thereof, of a compound of formula I. Optically active forms of the compounds of the invention may be prepared by: for example chiral chromatographic separation of the racemates, synthesis from optically active starting materials or asymmetric synthesis according to the procedures described later.

It will also be understood by those skilled in the art that certain compounds of the present invention may also exist in solvated, for example hydrated, as well as unsolvated forms. It is also to be understood that the present invention encompasses all such solvated forms of the compounds of formula I.

Salts of the compounds of formula I are also within the scope of the invention. Pharmaceutically acceptable salts of the compounds of the present invention are generally obtained using standard procedures well known in the art.

In one embodiment of the invention, the compounds of formula I may be converted into pharmaceutically acceptable salts or solvates thereof, in particular acid addition salts, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or p-toluenesulfonate salts.

Preparation method

The compounds of formula I can be prepared according to various synthetic methods set forth herein. The choice of specific structural features and/or substituents may therefore influence the choice between different methods.

In accordance with these general guidelines, the methods described herein can be used to prepare an exemplary subset of the compounds of the invention. The definitions of the variables in the described schemes and methods are the same as for formula I, unless otherwise indicated.

Thus, those skilled in the art will appreciate that variations and additions employing one or more of the described methods will be useful in the synthesis of other compounds conforming to formula I.

The invention is further illustrated by means of the following examples, which describe several embodiments of the invention. The synthetic schemes and synthetic procedures provided for examples 1,2 and 4 are for illustration and should not be construed as limiting the invention. It should be apparent to those skilled in the art that other exemplary methods can be readily prepared according to methods similar to those described herein.

The synthesis scheme is as follows:

reagents and conditions used in typical procedures: (a) SOCl₂Delta, 2-chloro-N-hydroxyacetamidine, K₂CO₃MeCN, then DMF, Delta, (c) QH, K₂CO₃、MeCN、Δ。

(a) In a typical procedure, 100mmol of 7-methyl-1-oxo-2- (substituted-benzyl) -2, 3-dihydro-1H-isoindole-5-carboxylic acid are dissolved in excess sulfinyl chloride and then heated at reflux for 30 minutes. The reaction was cooled to room temperature and then concentrated to give 7-methyl-1-oxo-2- (substituted-benzyl) -2, 3-dihydro-1H-isoindole-5-carbonyl chloride.

(b) To a solution of 7-methyl-1-oxo-2- (substituted-benzyl) -2, 3-dihydro-1H-isoindole-5-carbonyl chloride (100mmol) in MeCN (50mL) was added 2-chloro-N-hydroxyethylamidine (110mmol) and K₂CO₃(200 mmol). The reaction mixture was stirred overnight, then diluted with water and extracted with EtOAc. The organic phase was washed with brine and dried (Na)₂SO₄) Filtration and concentration. The residue was dissolved in DMF (50mL) and then heated at reflux for 3.5 h. The cooled solution was diluted with water and extracted with EtOAc. The organic phase was washed with brine and dried (Na)₂SO₄) Filtering and concentrating. Purification by silica gel column chromatography (10-35% EtOAc/hexanes) afforded 2-substituted-benzyl-5- (3-chloromethyl- [1,2, 4)]Oxadiazol-5-yl) -7-methyl-2, 3-dihydroisoindol-1-one.

(c) To 2- (substituted-benzyl) -5- (3-chloromethyl- [1,2, 4)]To a solution of oxadiazol-5-yl) -7-methyl-2, 3-dihydroisoindol-1-one (100mmol) in MeCN was added K₂CO₃(200-300mmol) and the appropriate amine (QH,150-200 mmol). Heating the mixture, and subjecting to silica gel column chromatography (1-5%2 MNH)₃MeOH/CH of₂Cl₂Solution) to obtain the required isoindolone.

Example 1:7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2,4]]Oxadiazol-5-yl) -2- (4-trifluoromethoxybenzyl) -2, 3-dihydroisoindol-1-one

To 5- (3-chloromethyl- [1,2, 4)]To a solution of oxadiazol-5-yl) -7-methyl-2- (4-trifluoromethoxybenzyl) -2, 3-dihydroisoindol-1-one (3.25g,7.43mmol) in MeCN (50mL) was added piperazine-1-carboxylic acid tert-butyl ester (2.77g,14.9mmol) and K₂CO₃(2.57g,18.6 mmol). The mixture was warmed to 40 ℃ for 24 hours, then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc and the organic phase was washed with brine and dried (Na)₂SO₄) Filtering and concentrating. The residue was triturated with hexanes and filtered. Purification by silica gel column chromatography (40-80% EtOAc/hexanes) and purification with 1% MeOH/Et₂After trituration of O, the Boc-protected intermediate (4.78g) was obtained as a colorless solid.

The Boc-protected intermediate was dissolved in CH₂Cl₂(15mL), 1:1TFA/CH was added₂Cl₂(40 mL). After 45 min, the reaction mixture was concentrated with NaHCO₃The aqueous solution is basified to a pH of about 9-10. Product is with CH₂Cl₂And (4) extracting. The organic phase was washed with brine and dried (Na)₂SO₄) Filtering and concentrating. Chromatography on silica gel column (1-5%2M NH)₃MeOH/CH of₂Cl₂Solution) to obtain 7-methyl-5- (5- (piperazin-1-ylmethyl) - [1,2,4]]Oxadiazol-3-yl) -2- (4-trifluoromethoxybenzyl) -2, 3-dihydroisoindol-1-one (3.79g) as a colorless foam.¹H NMR(300MHz,CDCl₃)δ8.05(s,1H),8.00(s,1H),7.36(d,2H),7.20(d,2H),4.81(s,2H),4.33(s,2H),3.77(s,2H),2.94-3.05(m,4H),2.84(s,3H),2.61(br s,4H)。

Example 2:2- (4-chloro-benzyl) -5- [3- (2, 5-diazabicyclo [ 2.2.1)]Hept-2-ylmethyl) - [1,2,4]Oxadiazol-5-yl]-7-methyl-2, 3-dihydroisoindol-1-one

To 2- (4-chloro-benzyl) -5- (3-chloromethyl- [1,2, 4)]To a solution of oxadiazol-5-yl) -7-methyl-2, 3-dihydroisoindol-1-one (40mg,0.103mmol) in MeCN (4mL) was added K₂CO₃(0.309mmol) and (1s,4s) -2, 5-diazabicyclo [2.2.1]Tert-butyl hepta-2-carboxylate (31mg,0.154 mmol). The mixture was heated at 60 ℃ overnight. The reaction mixture was cooled, diluted with water, and then extracted with EtOAc. The organic phase was washed with brine and dried (Na)₂SO₄) Filtering and concentrating. Silica gel column chromatography (1%2M NH)₃MeOH/CH of₂Cl₂Solution) to obtain 2- (4-chlorobenzyl) -5- [3- (2, 5-diazabicyclo [ 2.2.1)]Hept-2-ylmethyl) - [1,2,4]Oxadiazol-5-yl]-7-methyl-2, 3-dihydroisoindol-1-one as a brown solid (27 mg).¹H NMR(300MHz,CDCl₃)δ8.04(s,1H),7.99(s,1H),7.37(d,2H),7.26(d,2H),4.77(s,2H),4.30(s,2H),3.94(dd,2H),3.58(d,2H),3.26(d,1H),3.11(d,1H),2.89(d,1H),2.84(s,3H),2.63(d,1H),1.88(d,1H),1.66(d,1H)。

Example 4:2- (4-chloro-benzyl) -7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2, 4-]Oxadiazol-5-yl) -2, 3-dihydroisoindol-1-ones

To 2- (4-chloro-benzyl) -5- (3-chloromethyl- [1,2, 4)]To a solution of oxadiazol-5-yl) -7-methyl-2, 3-dihydroisoindol-1-one (40mg,0.103mmol) in MeCN (4mL) was added K₂CO₃(3.0 equiv.) and piperazine-1-carboxylic acid tert-butyl ester (29mg,0.154 mmol.) the mixture was heated at 70 ℃ for 1 week. The reaction mixture was cooled, diluted with water, and then extracted with EtOAc. The organic phase was washed with brine and dried (Na)₂SO₄) Filtering and concentrating. Purification by silica gel column chromatography (10-50% EtOAc/hexanes) afforded the Boc-protected intermediate as an oil. The residue was dissolved in 1:1TFA/CH₂Cl₂After 30min, the reaction mixture was concentrated and concentrated with NaHCO₃The aqueous solution is basified to a pH of about 9-10. Product is with CH₂Cl₂And (4) extracting. The organic phase was washed with brine and dried (Na)₂SO₄) Filtering and concentrating. The residue was dissolved in EtOAc and extracted with 1M HCl. Basification of the aqueous phase with 6M NaOH and CH₂Cl₂And (4) extracting. The organic phase is passed through Na₂SO₄After drying, and filtration and concentration, 2- (4-chlorobenzyl) -7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2,4] is obtained]Oxadiazol-5-yl) -2, 3-dihydroisoindol-1-one as a colorless oil (29 mg).¹H NMR(300MHz,CDCl₃)δ8.05(s,1H),7.99(s,1H),7.34(d,2H),7.26(d,2H),4.77(s,2H),4.31(s,2H),3.77(s,2H),2.97(br s,4H),2.84(s,3H),2.62(br s,4H)。

The compounds shown in the following table illustrate the invention:

pharmaceutical composition

In general, the compounds described herein can be formulated into conventional pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents. The solid support may also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided compound of the invention, i.e. the active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

To prepare suppository compositions, low melting beeswax (e.g., a mixture of fatty acid glycerides and cocoa butter) is first melted and the active ingredient dispersed therein, for example, by stirring. The molten homogeneous mixture is then poured into a suitably sized mould and allowed to cool to solidify.

Suitable vectors include, but are not limited to: magnesium carbonate, magnesium stearate, talc, lactose, sucrose, pectin, dextrin, starch, gum tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.

The term "composition" is also intended to encompass the formulation of an active ingredient with an encapsulating material as a carrier to provide a capsule, wherein the active ingredient (with or without other carriers) is surrounded by a carrier so associated. Similarly, cachets are also included.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or aqueous propylene glycol solutions of the active compounds may be liquid formulations suitable for parenteral administration. Liquid compositions may also be formulated in solution form with an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding suitable coloring, flavoring, stabilizing and thickening agents as needed. Aqueous suspensions for oral use can be prepared by dispersing the finely divided active ingredient in water together with a viscous substance such as natural synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose and other suspending agents known in the pharmaceutical formulation art. Exemplary compositions intended for oral administration may contain one or more coloring, sweetening, flavoring and/or preservative agents.

Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05% w (weight percent) to about 99% w of a compound of the present invention, more specifically, from about 0.10% w to 50% w of a compound of the present invention, all weight percents being based on the total weight of the composition.

One of ordinary skill in the art can determine a therapeutically effective amount to practice the invention using known criteria including age, weight, and response of the individual patient, and can be interpreted within the context of the disease being treated or prevented.

Medical application

The compounds described herein exhibit activity as modulators of metabotropic glutamate receptors. More specifically, activity as potentiators of mGluR2 receptors is exhibited. The compounds of the invention are expected to be useful in therapy as medicaments, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in animals, in particular humans.

More specifically, the neurological and psychiatric disorders include, but are not limited to, disorders such as brain defects secondary to heart bypass surgery and transplantation (cardiac defect to cardiac bypass and transplantation), stroke, cerebral ischemia, spinal cord trauma (spinal cord trauma), head trauma (head trauma), perinatal hypoxia (perimenopausal), cardiac arrest, hypoglycemic nerve injury (hypoglycemic nerve damage), dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis (amylotrophic sclerosis), ocular injury (ocular damage), retinopathy (retinophathy), cognitive disorders, idiopathic and drug-induced Parkinson's disease (seizure and seizure related disorders), spasticity, and seizure related disorders of the brain including seizure and related muscle states, Cerebral deficits secondary to prolonged status epilepticus, migraine (including migraine pain), urinary incontinence, psychoactive substance tolerance, psychoactive substance withdrawal (including substances such as opioids, nicotine, tobacco products, alcohol, benzodiazepines, and the like), secondary to prolonged status epilepticusClasses, cocaine, sedatives, hypnotics, etc.), psychosis (psychosis), schizophrenia (schizophrenia), anxiety disorders (including generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD)), mood disorders (including depression, mania, bipolar disorder), circadian rhythm disorders (including jet lag and shift work syndrome), trigeminal neuralgia, hearing loss (hearing loss), tinnitus, macular degeneration of the eye (including acute and chronic pain states, severe pain states, vomiting, cerebral edema, pain (including acute and chronic pain states, severe pain states, and post-traumatic stress disorder (pain)), psychogenic disorders (including depression, mania, bipolar disorder), circadian rhythm disorders (including jet lag), and rotational work syndrome (shift work), trigeminal neuralgia, hearing loss (hearing loss), tinnitus, macular degeneration of the eye, and the like,Intractable pain (intraneuropathic pain), neuropathic pain (neuropathic pain), inflammatory pain (inflammatory pain) and post-traumatic pain (post-traumatic pain)), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder and behavioral disorders.

Accordingly, the present invention provides the use of a compound of formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for the treatment of any of the conditions described above.

Furthermore, the present invention provides a method of treating a subject suffering from any of the disorders described above by administering to a patient in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. The present invention also provides a compound of formula I as defined above or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

Unless otherwise stated to the contrary, in the context of the present specification, the term "treatment" also includes "prevention". The terms "therapeutic" and "therapeutically" should also be understood accordingly. In the context of the present invention, the term "treating" also includes administering an effective amount of a compound of the present invention to alleviate a pre-existing acute or chronic disease condition or recurring disorder. The definition also includes prophylactic treatment for preventing recurrence of the condition and persistent treatment for chronic diseases.

In the treatment of a warm-blooded animal such as man, the compounds of the present invention may be administered by a variety of routes in the form of conventional pharmaceutical compositions, including oral, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, epidural, intrathecal, transdermal, intrapleural and infusion into the joints. In a preferred embodiment of the invention, the route of administration is oral, intravenous or intramuscular.

The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician in determining individual regimens and dosage levels for a particular patient.

As noted above, the compounds described herein may be provided or delivered in a form suitable for oral use, for example, in the form of tablets, lozenges, hard and soft capsules, aqueous solutions, oily solutions, emulsions and suspensions. Alternatively, the compounds may be formulated for topical administration, for example as a cream, ointment, gel, spray, aqueous solution, oily solution, emulsion or suspension. The compounds described herein may also be provided in a form suitable for nasal administration, for example as a nasal spray, nasal drops or dry powder. The compounds may be administered to the vagina or rectum in the form of suppositories. The compounds described herein may also be administered parenterally, for example by intravenous, intravesicular (intravesicular), subcutaneous or intramuscular injection or infusion. The compounds are also administered by insufflation (e.g., as a finely divided powder). The compounds may also be administered transdermally or sublingually.

In addition to their use in therapeutic drugs, the compounds of formula I or salts thereof are useful as pharmacological tools in the development and standardization of in vitro or in vivo test systems for assessing the effect of inhibitors of mGluR-related activity in laboratory animals as part of the study of new therapeutic drugs. Such animals include, for example, cats, dogs, rabbits, monkeys, rats, and mice.

General procedure

The starting materials are commercially available or previously described in the literature.

¹H and¹³c NMR spectra were recorded on Bruker 300, Bruker DPX400 or Varian +400 spectrometers for¹H NMR was operated at 300, 400 and 400MHz, respectively, using TMS or residual solvent signal as reference unless otherwise stated deuterated chloroform as solvent. All reported chemical shifts are expressed in ppm on the delta scale (delta-scale) and the fine splits of the signal are as shown in the recordings (s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet).

Analytical in-line liquid chromatography separation (Analytical in line liquid chromatography) and subsequent mass spectrometric detection was recorded on a Waters LCMS consisting of Alliance 2795(LC) and ZQ single quadrupole mass spectrometer. The mass spectrometer is equipped with an electrospray ion source operating in positive and/or negative ion mode. The ion spray voltage was ± 3kV and the mass spectrometer was scanned from m/z100 to 700 at 0.8s scan time. A linear gradient of 5% to 100% acetonitrile/10 mM ammonium acetate (aq) or 5% to 100% acetonitrile/0.1% TFA (aq) was applied to the column (X-Terra MS, Waters, C8,2.1X50mM,3.5 mM).

Preparative reverse phase chromatography was run on a Gilson self-preparative HPLC with a diode array detector and using XTerra MS C8,19x300mm,7mm as a column.

Purification by Chromatotron was performed on rotating silica gel/gypsum (Merck, 60PF-254 with calcium sulfate) coated glass slides with TC Research 7924T Chromatotron, coating of 1,2 or 4 mm.

The purification of the product was also carried out using a Chem Elut extraction column (Varian, cat # 1219-.

Microwave heating was carried out in a Smith synthesizer single mode microwave cavity (Personal Chemistry AB, Uppsala, Sweden) generating continuous radiation at 2450 MHz.

The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art, for example, as described in Aramori et al, 1992, Neuron,8:757, Tanabe et al, 1992, Neuron,8:169, Miller et al, 1995, J.Neuroscience,15:6103, Balazs, et al, 1997, J.Neurochemistry,1997,69: 151. The methodologies described in these documents are incorporated by reference in the present application. Suitably, intracellular calcium [ Ca ] may be measured by means of expression of mGluR2 in a cell²⁺]_iMobilization assay methods to study the compounds of the invention.

hERG activity was determined using the method described in Bridgland-Taylor, M.H., et al, J.Pharm.Tox.methods 54(2006) 189-199.

Solubility (Solubility) was determined as follows: after equilibration at 25 ℃ for 24 hours, assay was performed in phosphate buffer at pH7.4 and quantitative analysis was performed using HPLC-UV and LC-MSMS.

[³⁵S]The GTP γ S binding assay is used for the functional assay of mGluR2 receptor activation. Use of a membrane prepared from a CHO cell stably expressing a human mGluR2 receptor, using [ [ solution ] ]³⁵S]A GTP γ S binding assay to measure the allosteric activator activity of compounds at the human mGluR2 receptor. The assay is based on the following principle: the agonist binds to a G-protein coupled receptor, thereby stimulating the exchange of GDP-GTP at the G-protein. Because of³⁵S]GTP γ S is a non-hydrolyzable GTP analog, and thus it can be used to provide an indicator of GDP-GTP exchange and the resulting receptor activation. The GTP γ S binding assay thus provides a quantitative measure of receptor activation.

Membranes were prepared from CHO cells stably transfected with human mGluR 2. The membrane (30. mu.g of protein) was incubated with the test compound (3nM to 300. mu.M) at room temperature for 15 minutes, followed by addition of 1. mu.M of glutamic acid, followed by incubation with GDP at a concentration of 30. mu.M and 0.1nM [2 ]³⁵S]500 μ L assay buffer (20mM HEPES,100mM NaCl,10mM MgCl) of-GTP γ S (1250Ci/mmol)₂) Incubated at 30 ℃ for 30 minutes. Reactions were performed in 2mL polypropylene 96-well plates (in triplicate). The reaction was stopped by vacuum filtration using a Packard 96-well harvester and a Unifilter-96, GF/B filtration microplate (filter microplates). The filter plates were washed with 4X 1.5mL of ice-cold wash buffer (10mM sodium phosphate buffer, pH 7.4). The filter plates were dried and then 35 μ L of scintillation fluid (Microscint 20) was added to each well. The amount of radioactive binding is determined by counting the plates on a Packard TopCount. Data were analyzed using GraphPad Prism and EC was calculated using non-linear regression₅₀And E_maxValues (relative to the maximum of glutamate effect).

As shown in the following table, the compounds described herein generally exhibit: the advantageous solubility of the water-soluble polymer in water,activation of hERG ions generally has low capacity and high activity in the assays described herein for mGluR2 modulator activity, with the following EC₅₀The value:

watch (A)

Example numbering	GTPgS EC50μM	Water soluble (Aq. solublity) μ M	hERG μM
				1	0.231	44.9	11.0
2	0.206	336.5	33.0
				3	0.154	396.1	12.0
4	0.378	>500	25.0
				5	0.352	383.9	12.6
6	0.317	>500	18.7

Claims (14)

1. A compound of formula I or a pharmaceutically acceptable salt, hydrate, optical isomer, or combination thereof:

formula I

Wherein

R¹Is halogen or halogeno C_1-3An alkoxy group;

q isAnd

R²is hydrogen or C_1-3An alkyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein R¹Is chlorine or trifluoromethoxy.

3. The compound of claim 2, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein R¹Is trifluoromethoxy.

4. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein Q is

5. The compound of claim 4, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein Q isAnd R is²Is H.

6. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein R¹Is chloro or trifluoromethoxy and Q is

7. The compound of claim 6, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein R¹Is trifluoromethoxy and Q is

8. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein R¹Is chloro or trifluoromethoxy and Q isWherein R is²Is H.

9. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, or optical isomer thereof, wherein R¹Is chloro or trifluoromethoxy and Q is

10. The compound of claim 1 selected from the group consisting of:

7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl) -2- (4-trifluoromethoxybenzyl) -2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -5- [3- (2, 5-diazabicyclo [2.2.1] hept-2-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -7-methyl-2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -7-methyl-5- [3- (3-methyl-piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -7-methyl-5- (3- (piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl) -2, 3-dihydroisoindol-1-one;

2- (4-chloro-benzyl) -7-methyl-5- [3- (2-methyl-piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -2, 3-dihydroisoindol-1-one; or

2- (4-chloro-benzyl) -7-methyl-5- [3- (2-methyl-piperazin-1-ylmethyl) - [1,2,4] oxadiazol-5-yl ] -2, 3-dihydroisoindol-1-one.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

12. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier or excipient.

13. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of schizophrenia.

14. Use of a compound of claim 10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of schizophrenia.