WO1999038864A1 - Oxazole derivatives as serotonin-1a receptor agonists - Google Patents
Oxazole derivatives as serotonin-1a receptor agonists Download PDFInfo
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- WO1999038864A1 WO1999038864A1 PCT/US1999/002210 US9902210W WO9938864A1 WO 1999038864 A1 WO1999038864 A1 WO 1999038864A1 US 9902210 W US9902210 W US 9902210W WO 9938864 A1 WO9938864 A1 WO 9938864A1
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- 0 *1c2ccccc2C2C1CNCC2 Chemical compound *1c2ccccc2C2C1CNCC2 0.000 description 2
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
This invention provides compounds of Formula (1), wherein R1 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 NR4, or no atom; R2 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety is 3-8 cabon 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 dysfunction and memory deficits associated with Alzheimer's disease and other dementias.
Description
OXAZOLE DERIVATIVES AS SEROTONIN- 1 A RECEPTOR AGONISTS
FIELD OF THE INVENTION
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.
DESCRIPTION OF THE INVENTION
In accordance with this invention, there are compounds of Formula (1), having the structure
(1)
wherein:
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 NR4, 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.
The term 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
(ie phenyl substituted by ethylenediox oy).
It is preferred that 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. It is preferred that the 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.
Of the compounds of this invention, preferred members include those in which R2 is alkyl, cycloalkyl, or cycloalkylalkyl; and those in which R3 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)
(8) wherein X, Ri, R2, R3 and the dotted line are as defined above with a dehydrating agent, or b) reacting a compound of formula (2)
(2) wherein X and the dotted line are as defined above with a compound of formula (4)
R3
Cl
R2
(4) wherein R2 and R3 are as defined above.
Compounds of the present invention may be conveniently prepared using conventional methods, utilizing for example the disconnections A and B shown in scheme 1 below.
4 -
R3 R3
Z H
O---*
°
R2
(2) (3) (2) (4)
Scheme 1
Aryl piperidines (2, X = no atom) and aryl-tetrahydropyridines (2, X = no atom) can be either commercially available, or alternatively can be readily prepared by those skilled in the art of organic synthesis, for example by the reaction of a suitably N-protected-4- piperidone with an aryl-lithium or aryl-magnesium compound as shown in scheme 2.
Ri
(2)
Scheme 2
In path A, 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 -
R3 R3
Cl
NH2 Cl
NH
O O
O R2
(5) (3)
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. For example, reaction of the acid chloride of (6) with diazomethane and treatment of the resulting α- diazoketone (7) with HC1 affords the required product.
R3 R3
N3 NH-Prot ' Cl NH-Prot
O O
(6) (7) (5)
Reaction of (2) with an alkyl chloride (3) affords the ketoamide (8). This product can be cyclized to the desired oxazole (1) by the action of a dehydrating agent such as the chlorinating agent POCl3.
R3
R1 a^" NH
NH
°cA R2
O
R2 ^ -X
(2) (3) (8)
In path B, the chloroalkyloxazole (4) may be prepared from the ketoamide (3) by the action of 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.
R3 R3
Cl
o 0
•R2 R2
(3) (4)
- 6 -
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 [3H] 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. On the day of assay, 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 μL. 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, the compound of Example 9, 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. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, 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) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration 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.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, 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. In therapeutic treatment, 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 following non-limiting examples illustrate the preparation of representative compounds of this invention.
Example 1 N-Cvclohexanoyl-L-Phenylalanylchloromethylketone
A cooled (-10 C) mixture containing L-phenylalanylchloromethylketone (3.2 mmole) in CH2C-2 (30 ml) and potassium carbonate (10 mmole) in water (10 ml) was treated with cyclohexanecarbonylchloride (3.2 mmole). The resulting mixture was stirred for two hours at ambient temperature. The organic layer was separated, washed with water (3 x 20 ml) and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave the titled compound as a cream colored solid (2.6 mmole, 81%). Elemental Analysis for: C17H22CINO2
Calculated: C, 66.33; H, 7.20; N, 4.55 Found: C, 66.12; H, 7.12; N, 4.34
Example 2 4-Benzyl-5-chloromethyI-2-cyclohexyloxazole
Under a nitrogen atmosphere, a benzene solution (26 ml) of the chloromethylketone (2.6 mmole) from example 1 was treated with dimethylformamide (2 ml) and phosphorous oxy chloride (26 mmole). The mixture was heated to reflux for 15 minutes while water was collected in a Dean-Stark apparatus. After cooling to room temperature, the reaction mixture was poured onto ice (25 g), the solution made basic with sodium bicarbonate and the product was extracted with ethyl acetate (2 x 30 ml). The combined organics were washed with water (2 x 30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the crude product. This was purified by silica-gel flash chromatography, eluting with dichloromethane, to afford the titled product as a light yellow oil (1.03 mmole, 40 %). Elemental Analysis for: C17H20CINO
Calculated: C, 70.46; H, 6.96; N, 4.83 Found: C, 70.35; H, 7.12; N, 5.02
- 9 -
Example 3 N-Pivaloyl-L-Phenylalanylchloromethylketone
The titled compound was isolated in 80% yield when pivaloyl chloride (5 mmole) was used in the procedure outlined in example 1 above. Elemental Analysis for: C15H20CINO2
Calculated: C, 63.94; H, 7.15; N, 4.97 Found: C, 64.23; H, 7.27; N, 5.12
Example 4
4-Benzyl-5-chloromethyl-2-tertbutyloxazole
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 SiO2 "flash" Chromatography.
Elemental Analysis for: C15H18C1NO Calculated: C, 68.30; H, 6.88; N, 5.31 Found: C, 68.52; H, 7.02; N, 5.42
Example 5
N-Benzoyl-L-Phenylalanylchloromethylketone
The titled compound was prepared in 88% yield by substituting benzoyl chloride (5 mmole) into the procedure outlined in example 1 above. The product (4.4 mmole) was obtained as a yellow oil, and was used without further purification. Elemental Analysis for: C17H16CINO2
Calculated: C, 67.66; H, 5.34; N, 4.64 Found: C 67.55; H, 5.30; N, 4.54
Example 6
4-Benzyl-5-chloromethyl-2-phenyloxazole
The title compound was prepared using N-benzoyl-L-phenylalanylchloromethylketone (4.4 mmole) in the procedure described in example 2. The product was obtained as a light yellow oil ( 1.4 mmole, 32% yield) after SiO2 "flash" Chromatography.
- 10 - Elemental Analysis for: Cι7H14ClNO Calculated: C, 71.96; H, 4.97; N, 4.94 Found: C, 72.25; H, 5.15; N, 5.23
Example 7 N-Cvclohexaneacetyl-L-Phenylalanylchloromethylketone
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.
Elemental Analysis for: C18H24C1NO2
Calculated: C, 67.17; H, 7.52; N, 4.35 Found: C, 67.35; H, 7.50; N, 4.51
Example 8 4-Benzyl-5-chloromethyl-2-cyclohexylmethyloxazole
The title compound was prepared using N-cyclohexaneacetyl-L-phenylalanyl- chloromethyl ketone (2.5 mmole) in the procedure described in example 2. The product was obtained as a light yellow oil (1.2 mmole, 48% yield) after SiO2 "flash"
Chromatography .
Elemental Analysis for: CigE CINO Calculated: C, 71.16; H, 7.30; N, 4.61 Found: C, 71.23; H, 7.45; N, 4.65
Example 9 l-(4-BenzyI-2-cvclohexyl-oxazol-5-ylmethyl)- 4-(2-methoxy-phenyl)-piperidine
A suspension of 4-(2-methoxy-phenyl)-piperidine (0.19 g, 1.0 mmole), potassium carbonate (0.345 g, 2.5 mmole), potassium iodide (0.066 g, 0.4 mmole) and 4-benzyl- 5-chloromethyl-2-cyclohexyloxazole (0.244 g, 0.85 mmole) from example 2, in acetone (15 ml), was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo, water (50 ml) added and the product extracted into CH2CI2 (3 x 50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the product (0.415 g) purified
- 11 - by "flash" chromatography over silica gel (1% MeOH/CHCl3) to afford a colorless oil (0.376 g, 99% yield). An ethanolic solution of the product was treated with 1 equivalent of fumaric acid in ethanol (2 ml) to afford the tided compound as a white crystalline solid. mp 170-171°C
Elemental Analysis for: C29H36N2O2 I.OC4H4O4
Calculated: C, 70.69; H, 7.19; N, 5.00 Found: C, 70.41; H, 7.18; N, 4.96
Example 10
2-(4-Benzyl-2-cvclohexyl-oxazol-5-ylmethyl)- 2.3.4.9-tetrahvdro-lH-pyridor3.4-b1indole
A suspension of l,2,3,4-tetrahydro-9H-pyrido(3,4-B)indole (0.172 g, 1.0 mmole), potassium carbonate (0.345 g, 2.5 mmole), potassium iodide (0.066 g, 0.4 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexyloxazole (0.289 g, 1.0 mmole) from example 2, in acetone (13 ml), was stirred at ambient temperature for two hours. The solvent was removed in vacuo, water (50 ml) added and the product extracted into CH2C12 (2 x 20 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the product (0.401 g) purified by "flash" chromatography over silica gel (2% MeOH/CHC13) to afford a colorless oil (0.256 g, 60% yield). An ethanolic solution of the product was treated with 0.5 equivalents of fumaric acid in ethanol (2 ml) to afford the tided compound as an off white crystalline solid, mp 200-201°C Elemental Analysis for: C28H3lN3O 0.5C4H4O4
Calculated: C, 74.51; H, 6.88; N, 8.69 Found: C, 74.28; H, 6.91; N, 8.59
Example 11 l-(4-Benzyl-2-tert-butyI-oxazol-5-ylmethvP-
4-(2-methoxy-phenyl -piperidine
A suspension of 4-(2-methoxy-phenyl)-piperidine (0.19 g, 1.0 mmole), potassium carbonate (0.345 g, 2.5 mmole), potassium iodide (0.066 g, 0.4 mmole) and 4-benzyl- 5-chloromethyl-2-tertbutyloxazole (0.263 g, 1.0 mmole) from example 4, in acetone (15 ml), was stirred at ambient temperature for 12 hours. The solvent was removed in vacuo, water (50 ml) added and the product extracted into CH2CI2 (3 x 50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium
- 12 - sulfate, filtered and concentrated in vacuo and the product (0.4 g) purified by "flash" chromatography over silica gel (1% MeOH/CHC^) to afford a colorless oil (0.32 g,
76% yield). An ethanolic solution of the product was treated with 1 equivalent of etheral HC1 to afford the titled compound as a white crystalline solid. Elemental Analysis for: C27H34N2O2 1.0HC1
Calculated: C, 71.27; H, 7.75; N, 6.16 Found: C, 71.45; H, 7.98; N, 6.36
Example 12 2-(4-Benzyl-2-cvcIohexylmethyl-oxazol-5-ylmethyl)-
2.3.4.9-tetrahvdro-lH-pyridor3.4-blindole
A suspension of l,2,3,4-tetrahydro-9H-pyrido(3,4-B)indole (0.172 g, 1.0 mmole), potassium carbonate (0.345 g, 2.5 mmole), potassium iodide (0.066 g, 0.4 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexylmethyloxazole (0.303 g, 1.0 mmole) from example 8, in acetone (15 ml), was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo, water (50 ml) added and e product extracted into CH2CI2 (2 x 20 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the product (0.401 g) purified by "flash" chromatography over silica gel (2% MeOH/CHC^) to afford a colorless oil (0.299 g, 68% yield). An ethanolic solution of the product was treated with etheral HC1 to afford the titled compound as an off white crystalline solid. Elemental Analysis for: C29H33N3O 1.0HC1 Calculated: C, 73.17; H, 7.20; N, 8.83 Found: C, 73.28; H, 7.41; N, 8.89
Claims
1. A compound of Formula 1 having the structure
wherein:
Rj 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 NR4, or no atom;
R2 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.
2. The compound of claim 1 , wherein R3 is aryl of 5- 12 carbon atoms.
3. The compound of claim 1 or claim 2, wherein R2 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or cycloalkylalkyl wherein the cycloalkyl moiety is 3-8 carbon atoms and the alkyl moiety is 1-6 carbon atoms.
4. The compound according to claim 1, which is l-(4-benzyl-2-cyclohexyloxazol- 5-ylmethyl)-4-(2-methoxy-phenyl)-piperidine or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1, which is l-(4-benzyl-2-cyclohexyloxazol- 5-ylmethyl)-4-(2-methoxy-phenyl)-piperidine fumarate. - 14 -
6. The compound according to claim 1, which is 2-(4-benzyl-2-cyclohexyl- oxazol-5-ylmethyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, which is 2-(4-benzyl-2-cyclohexyl-oxazol- 5-ylmethyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole fumarate.
8. The compound according to claim 1, which is l-(4-benzyl-2-tert-butyl-oxazol- 5-ylmethyl)-4-(2-methoxy-phenyl)-piperidine or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, which is l-(4-benzyl-2-tert-butyl-oxazol- 5-ylmethyl)-4-(2-methoxy-phenyl)-piperidine hydrochloride.
10. The compound according to claim 1, which is 2-(4-benzyl-2-cyclohexylmethyl- oxazol-5-ylmethyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , which is 2-(4-benzyl-2-cyclohexylmethyl- oxazol-5-ylmethyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole hydrochloride.
12. A method of treating anxiety in a mammal in need thereof which comprises administering to said mammal a compound of Formula 1 having the structure
R3
R2 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; - 15 -
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.
13. A method of treating depression in a mammal in need thereof which comprises administering to said mammal a compound of Formula 1 having the structure
R3
R] 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 , or no atom; R2 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; R is hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof.
14. A method of treating Alzheimer's disease, cognitive disorders, dementias, sleep disorders, drug, alcohol addiction, or panic disorders in a mammal in need thereof which comprises administering to said mammal a compound of Formula 1 having the structure ΓÇö 3
A ,N 
R2
(1) wherein: Rj 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; - 16 - X is NR4, or no atom;
R2 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.
15. A pharmaceutical composition which comprises a compound of Formula 1 having the structure r- R3
N
R2 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, and a pharmaceutical carrier.
16. A compound as claimed in any one of Claims 1 to 11 for use as a medicament.
17. Use of a compound as claimed in any one of Claims 1 to 11 in the preparation of a medicament for the treatment of a disease condition related to or affected by the
5-hydroxytryptamine-lA (5-HT1A) receptor subtype.
18. Use of a compound as claimed in any one of Claims 1 to 11 in the preparation of a medicament for the treatment of anxiety, depression, Alzheimer's disease, - 17 - cognitive disorders, dementias, sleep disorders, drug addiction, alcohol addiction, or panic disorders.
19. A process for preparing a compound of formula 1 as claimed in claim 1 which comprises one of the following: a) reacting a compound of formula (8)
I ΓÇö R3
-x
(8) wherein X, Rl, R2. R3 and the dotted line are as defined in claim 1 with a dehydrating agent to give a compound of formula (1), or b) reacting a compound of formula (2)
(2) wherein X and the dotted line are as defined in claim 1 with a compound of formula (4) rΓÇö - 3
01 X"
R2
(4) wherein R2 and R3 are as defined in claim 1 to give a compound of formula (1).
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99905632A EP1053235A1 (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1a receptor agonists |
| CA002317515A CA2317515A1 (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1a receptor agonists |
| AU25753/99A AU2575399A (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1a receptor agonists |
| JP2000529332A JP2002501920A (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1A receptor agonists |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1751798A | 1998-02-03 | 1998-02-03 | |
| US09/017,517 | 1998-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999038864A1 true WO1999038864A1 (en) | 1999-08-05 |
Family
ID=21783033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1999/002210 WO1999038864A1 (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1a receptor agonists |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1053235A1 (en) |
| JP (1) | JP2002501920A (en) |
| CN (1) | CN1289333A (en) |
| AU (1) | AU2575399A (en) |
| CA (1) | CA2317515A1 (en) |
| WO (1) | WO1999038864A1 (en) |
Cited By (7)
| 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 |
| WO2002060423A2 (en) * | 2001-01-29 | 2002-08-08 | Otsuka Pharmaceutical Co., Ltd. | Substituted carbostyril derivatives as 5-ht1a receptor subtype agonists |
| US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
| EP1855679A2 (en) * | 2005-01-19 | 2007-11-21 | Merck & Co., Inc. | Aminomethyl beta-secretase inhibitors for the treatment of alzheimer's disease |
| US7910589B2 (en) | 2001-09-25 | 2011-03-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
| US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0356098A2 (en) * | 1988-08-15 | 1990-02-28 | Glaxo Group Limited | Lactam derivatives |
| 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 EP EP99905632A patent/EP1053235A1/en not_active Withdrawn
- 1999-02-02 CN CN99802651A patent/CN1289333A/en active Pending
- 1999-02-02 AU AU25753/99A patent/AU2575399A/en not_active Abandoned
- 1999-02-02 WO PCT/US1999/002210 patent/WO1999038864A1/en not_active Application Discontinuation
- 1999-02-02 JP JP2000529332A patent/JP2002501920A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0356098A2 (en) * | 1988-08-15 | 1990-02-28 | Glaxo Group Limited | Lactam derivatives |
| 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 |
Cited By (32)
| 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 |
| EP1621198A3 (en) * | 2001-01-29 | 2006-04-12 | Otsuka Pharmaceutical Co., Ltd. | Substituted carbostyril derivatives as 5-HT 1A receptor subtype agonists |
| US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
| US9089567B2 (en) | 2001-01-29 | 2015-07-28 | Otsuka Pharmaceutical Co., Ltd. | Method of treating cognitive impairments and schizophrenias |
| US8680105B2 (en) | 2001-01-29 | 2014-03-25 | Otsuka Pharmaceutical Co., Ltd. | Method of treating down's syndrome |
| US8030312B2 (en) | 2001-01-29 | 2011-10-04 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1A receptor subtype agonist |
| EP1712225A1 (en) * | 2001-01-29 | 2006-10-18 | Otsuka Pharmaceutical Co., Ltd. | Substituted carbostyril derivatives as 5-HT 1A receptor subtype agonists |
| US9387207B2 (en) | 2001-01-29 | 2016-07-12 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1A receptor subtype agonist |
| US8642600B2 (en) | 2001-01-29 | 2014-02-04 | Otsuka Pharmaceutical Co., Ltd. | Method of treating autism |
| EP1621198A2 (en) * | 2001-01-29 | 2006-02-01 | Otsuka Pharmaceutical Co., Ltd. | Substituted carbostyril derivatives as 5-HT 1A receptor subtype agonists |
| WO2002060423A3 (en) * | 2001-01-29 | 2003-04-10 | Otsuka Pharma Co Ltd | Substituted carbostyril derivatives as 5-ht1a receptor subtype agonists |
| WO2002060423A2 (en) * | 2001-01-29 | 2002-08-08 | Otsuka Pharmaceutical Co., Ltd. | Substituted carbostyril derivatives as 5-ht1a receptor subtype agonists |
| US9006248B2 (en) | 2001-01-29 | 2015-04-14 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1A receptor subtype agonist |
| US8426423B2 (en) | 2001-01-29 | 2013-04-23 | Otsuka Pharmaceutical Co., Ltd. | Method of treating Attention Deficit Hyper-Activity Disorder |
| US8722680B2 (en) | 2001-01-29 | 2014-05-13 | Otsuka Pharmaceutical Co., Ltd. | Method of treating neurodegenerative diseases |
| US8604041B2 (en) | 2001-01-29 | 2013-12-10 | Otsuka Pharmaceutical Co., Ltd. | Method of treating panic disorder |
| US8623874B2 (en) | 2001-01-29 | 2014-01-07 | Otsuka Pharmaceutical Co., Ltd. | Method of treating neurodegenerative diseases |
| US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
| US7910589B2 (en) | 2001-09-25 | 2011-03-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8901130B2 (en) | 2001-09-25 | 2014-12-02 | Ostuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation |
| US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8703773B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8580796B2 (en) | 2001-09-25 | 2013-11-12 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US10150735B2 (en) | 2001-09-25 | 2018-12-11 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8901303B2 (en) | 2001-09-25 | 2014-12-02 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8642760B2 (en) | 2001-09-25 | 2014-02-04 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8993761B2 (en) | 2001-09-25 | 2015-03-31 | Otsuka Pharamceutical Co. Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8399469B2 (en) | 2001-09-25 | 2013-03-19 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US8017615B2 (en) | 2001-09-25 | 2011-09-13 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| US9359302B2 (en) | 2001-09-25 | 2016-06-07 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| EP1855679A2 (en) * | 2005-01-19 | 2007-11-21 | Merck & Co., Inc. | Aminomethyl beta-secretase inhibitors for the treatment of alzheimer's disease |
| EP1855679A4 (en) * | 2005-01-19 | 2014-07-23 | Merck Sharp & Dohme | Aminomethyl beta-secretase inhibitors for the treatment of alzheimer's disease |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1053235A1 (en) | 2000-11-22 |
| CN1289333A (en) | 2001-03-28 |
| CA2317515A1 (en) | 1999-08-05 |
| AU2575399A (en) | 1999-08-16 |
| JP2002501920A (en) | 2002-01-22 |
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