EP1053235A1 - Oxazole derivatives as serotonin-1a receptor agonists - Google Patents
Oxazole derivatives as serotonin-1a receptor agonistsInfo
- Publication number
- EP1053235A1 EP1053235A1 EP99905632A EP99905632A EP1053235A1 EP 1053235 A1 EP1053235 A1 EP 1053235A1 EP 99905632 A EP99905632 A EP 99905632A EP 99905632 A EP99905632 A EP 99905632A EP 1053235 A1 EP1053235 A1 EP 1053235A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- alkyl
- compound
- aryl
- arylalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- This invention provides oxazole derivatives which are useful for the treatment of conditions related to or are affected by the 5-hydroxytryptamine-lA (5-HT1A) receptor subtype.
- the compounds are particularly useful for the treatment of psychosis (e.g. schizophrenia), anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual dysfunction and memory deficits associated with Alzheimer's disease.
- R- l is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, benzyloxy, trifluoromethyl, chloro, bromo, or fluoro; a dashed line indicates an optional bond;
- X is NR 4 , or no atom;
- R-2 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety is 3-8 carbon atoms and the alkyl moiety is 1-6 carbon atoms, aryl of 5-12 carbon atoms, or arylalkyl of 6-12 carbon atoms;
- R3 is aryl of 5-12 carbon atoms, arylalkyl of 6-12 carbon atoms, or heteroaryl of 5-12 ring atoms;
- R4 is hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in the treatment of psychosis (e.g. schizophrenia), anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual - 2 - dysfunction and memory deficits associated with Alzheimer's disease and other dementias.
- psychosis e.g. schizophrenia
- anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual - 2 - dysfunction and memory deficits associated with Alzheimer's disease and other dementias.
- alkyl includes both straight chain and branched alkyl moieties.
- the aryl, heteroaryl or aryl portion of arylalkyl may be optionally substituted.
- Two substituents on the aromatic ring may be connected together to form another ring system.
- An example of such a bicyclic system is an optionally substituted radical of the formula o
- the aryl or the aryl portion of the arylalkyl substituent has 6 to 10 carbon atoms and is most preferably a phenyl or 1 ,4-benzodioxan-5-yl group.
- the aryl or aryl portion may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, chloro, fluoro, bromo, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms.
- heteroaryl ring contains 1-3 heteroatoms the same or different selected from oxygen, nitrogen, and sulfur and spefically preferred heteroaryl substituents are pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, or indolyl.
- the heteroaryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, chloro, fluoro, bromo, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms.
- the pharmaceutically acceptable salts are those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids.
- preferred members include those in which R 2 is alkyl, cycloalkyl, or cycloalkylalkyl; and those in which R 3 is aryl, and more preferably phenyl.
- This invention also provides processes for preparing the compounds of formula (1) which comprise one of the following: a) reacting a compound of formula (8)
- the amidoalkyl chloride of formula (3) may be prepared from the corresponding amine (5) using standard acylating conditions known to those skilled in the art of organic synthesis. 5 -
- the alkyl chloride (5) is readily available, and may be prepared from the corresponding protected amino acid (6) using, for example, the Arndt-Eistert reaction.
- reaction of the acid chloride of (6) with diazomethane and treatment of the resulting ⁇ - diazoketone (7) with HC1 affords the required product.
- the chloroalkyloxazole (4) may be prepared from the ketoamide (3) by the action of a dehydrating agent such as POCI3.
- a dehydrating agent such as POCI3.
- the subsequent alkylation of (2) with the chloride (4) may be conducted in a suitable solvent (e.g. acetone), optionally utilizing a base (e.g. potassium carbonate or triethylamine) as an acid scavenger.
- a suitable solvent e.g. acetone
- a base e.g. potassium carbonate or triethylamine
- the compounds of this invention are 5-HT1A agonists. Affinity for the serotonin 5-HTIA receptor was established in a standard pharmacological test procedure which measures the compound's ability to displace [ 3 H] 8-OH-DPAT binding in CHO cells stably transfected with human 5HT1 A receptor. Stably transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are scraped off the plate, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4°C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -80 C.
- the cells are thawed on ice and resuspended in buffer.
- the binding assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF B filter presoaked for 30 minutes in 0.5% PEL Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1, and 0.01 mM, and Ki values are determined for the active compounds.
- a representative compound of this invention was evaluated in the standard pharmacological test procedure described above, and had a Ki of 4.4 nM, which demonstrates a high affinity for the 5-HT1A receptor. Based on the results of obtained in the standard pharmacological test procedure, the compounds of this invention are useful in the treatment of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems in addition to the treatment of Alzheimer's disease, Parkinson's disease, obesity and migraine.
- the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
- Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium - 7 - carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
- cellulose derivatives preferably sodium carboxymethyl cellulose solution
- alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
- oils e.g. fractionated coconut oil and arachis oil
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
- the variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient.
- projected daily dosages of the compounds of this invention are 0.1-2000 mg/kg for oral administration, preferrably 0.5-500 mg/kg; and 0.1-100 mg/kg for parenteral administration, preferrably 0.5-50 mg/kg. - 8 -
- the tide compound was prepared using N-pivalyl-L-phenylalanylchloromethyl ketone (4 mmole) in the procedure described in example 2.
- the product was obtained as a light yellow oil (2.24 mmole, 56% yield) after SiO 2 "flash" Chromatography.
- the compound was prepared in 83% yield by substituting cyclohexylacetyl chloride (3 mmole) into the procedure outlined in example 1 above. This provided the titled compound as a light yellow oil (2.5 mmole) which was used without further purification.
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1751798A | 1998-02-03 | 1998-02-03 | |
US17517 | 1998-02-03 | ||
PCT/US1999/002210 WO1999038864A1 (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1a receptor agonists |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1053235A1 true EP1053235A1 (en) | 2000-11-22 |
Family
ID=21783033
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99905632A Withdrawn EP1053235A1 (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1a receptor agonists |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1053235A1 (ja) |
JP (1) | JP2002501920A (ja) |
CN (1) | CN1289333A (ja) |
AU (1) | AU2575399A (ja) |
CA (1) | CA2317515A1 (ja) |
WO (1) | WO1999038864A1 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6242448B1 (en) * | 1998-12-17 | 2001-06-05 | American Home Products Corporation | Trisubstituted-oxazole derivatives as serotonin ligands |
US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
AR032641A1 (es) * | 2001-01-29 | 2003-11-19 | Otsuka Pharma Co Ltd | Agonista de subtipo de receptor 5-ht 1a. |
US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
AR033485A1 (es) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
AU2006206653A1 (en) * | 2005-01-19 | 2006-07-27 | Merck & Co., Inc. | Aminomethyl beta-secretase inhibitors for the treatment of Alzheimer's disease |
GB0516313D0 (en) * | 2005-08-08 | 2005-09-14 | Argenta Discovery Ltd | Azole derivatives and their uses |
CA2931219A1 (en) * | 2013-12-20 | 2015-06-25 | Laboratorios Del Dr. Esteve, S.A. | Piperidine compounds having multimodal activity against pain |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02167280A (ja) * | 1988-08-15 | 1990-06-27 | Glaxo Group Ltd | ラクタム誘導体 |
US5162322A (en) * | 1991-03-06 | 1992-11-10 | A. H. Robbins Company, Incorporated | Method of treating anxiety with 5-[(4-aryl or heteroaryl-1-piperazinyl]alkyl)-2-oxazolidinones |
-
1999
- 1999-02-02 CA CA002317515A patent/CA2317515A1/en not_active Abandoned
- 1999-02-02 WO PCT/US1999/002210 patent/WO1999038864A1/en not_active Application Discontinuation
- 1999-02-02 CN CN99802651A patent/CN1289333A/zh active Pending
- 1999-02-02 JP JP2000529332A patent/JP2002501920A/ja active Pending
- 1999-02-02 EP EP99905632A patent/EP1053235A1/en not_active Withdrawn
- 1999-02-02 AU AU25753/99A patent/AU2575399A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9938864A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1999038864A1 (en) | 1999-08-05 |
AU2575399A (en) | 1999-08-16 |
JP2002501920A (ja) | 2002-01-22 |
CA2317515A1 (en) | 1999-08-05 |
CN1289333A (zh) | 2001-03-28 |
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