CA2317515A1 - Oxazole derivatives as serotonin-1a receptor agonists - Google Patents
Oxazole derivatives as serotonin-1a receptor agonists Download PDFInfo
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- CA2317515A1 CA2317515A1 CA002317515A CA2317515A CA2317515A1 CA 2317515 A1 CA2317515 A1 CA 2317515A1 CA 002317515 A CA002317515 A CA 002317515A CA 2317515 A CA2317515 A CA 2317515A CA 2317515 A1 CA2317515 A1 CA 2317515A1
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- 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
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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 DERIVATIV .S ~S
SEROTONIN-lA RECEPTOR AGONI TS
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 R1 w r N
'. O ~ N
i 'X R2 (1) wherein:
RI 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 cycloallcyl 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 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 n \ /
(ie phenyl substituted by ethylenedioxy).
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-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, malefic, 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.
SEROTONIN-lA RECEPTOR AGONI TS
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 R1 w r N
'. O ~ N
i 'X R2 (1) wherein:
RI 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 cycloallcyl 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 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 n \ /
(ie phenyl substituted by ethylenedioxy).
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-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, malefic, 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) Rt N NH
' ' ~ C C~R2 'X
(8) wherein X, R1, R2, R3 and the dotted line are as defined above with a dehydrating agent, or b) reacting a compound of formula (2) NH
r' ' 'X
(2) wherein X and the dotted line are as defined above with a compound of formula (4) CI~
O .-N
a) reacting a compound of formula (8) Rt N NH
' ' ~ C C~R2 'X
(8) wherein X, R1, R2, R3 and the dotted line are as defined above with a dehydrating agent, or b) reacting a compound of formula (2) NH
r' ' 'X
(2) wherein X and the dotted line are as defined above with a compound of formula (4) CI~
O .-N
(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.
R~ ~ ~
N' 1~
I~~ '' O ,N
'~X R2 (1) A B
R1 NH R3 Ri Rs NH Z
' Z NH ~ ~ ' ' I ~ O \CN
I i . ~ ~ i . ' ~X O O~ R2 ~'X R2 (Z) (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.
NH R~ NH
~' ~ f~~ ~ '\~ M + iP
N
i i OH ~ O
(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.
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.
R~ ~ ~
N' 1~
I~~ '' O ,N
'~X R2 (1) A B
R1 NH R3 Ri Rs NH Z
' Z NH ~ ~ ' ' I ~ O \CN
I i . ~ ~ i . ' ~X O O~ R2 ~'X R2 (Z) (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.
NH R~ NH
~' ~ f~~ ~ '\~ M + iP
N
i i OH ~ O
(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.
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 a-diazoketone (7) with HCl affords the required product.
HO NH-Prot ~ N3 NH-Prot ~ CI NH-Prot O O O
) 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 POC13.
NH R3 R\1 N
'~\ ~~ Z NH ~ I \\
O
O
i , : O ~ i , : R
~x O R2 .x 2 (2) (3) (g) In path B, the chloroalkyloxazole (4) may be prepared from the ketoamide (3) by the action of a dehydrating agent such as POC13. 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.
Rs R3 CI NH CI~
O O~ R O ~N
(3) (4) WO 99/38$64 PCT/US99/02210 The compounds of this invention are 5-HT1A agonists. Affinity for the serotonin 5-HTIp 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 SHT1A 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
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 a-diazoketone (7) with HCl affords the required product.
HO NH-Prot ~ N3 NH-Prot ~ CI NH-Prot O O O
) 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 POC13.
NH R3 R\1 N
'~\ ~~ Z NH ~ I \\
O
O
i , : O ~ i , : R
~x O R2 .x 2 (2) (3) (g) In path B, the chloroalkyloxazole (4) may be prepared from the ketoamide (3) by the action of a dehydrating agent such as POC13. 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.
Rs R3 CI NH CI~
O O~ R O ~N
(3) (4) WO 99/38$64 PCT/US99/02210 The compounds of this invention are 5-HT1A agonists. Affinity for the serotonin 5-HTIp 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 SHT1A 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 ~L. Non-specific binding is determined in the presence of 10 mM SHT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is tem~inated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEI.
Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0. l, 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 amity for the S-HT 1 A 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 can~iers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium 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 Garner 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.
_g_ The following non-limiting examples illustrate the preparation of representative compounds of this invention.
Example 1 N-Cyclohexanoyl-L-Phenylalanylchloromethvlketone A cooled (-10°C) mixture containing L-phenylalanylchloromethylketone (3.2 mmole) in CH2CI2 (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 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: C ~ ~H22C1N02 Calculated: C, 66.33; H, 7.20; N, 4.55 15 F un : C, 66.12; H, 7.12; N, 4.34 Example 2 4-Benzvl-5-chloromethvl-2-cvclohexyloxazole 20 Under a nitrogen atmosphere, a benzene solution (26 ml) of the chloromethyllcetone (2.6 mmole) from example 1 was treated with dimethyiformamide (2 ml) and phosphorous oxychloride (26 mmole). The mixture was heated to reflux for 1 S
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: Cl~H2pC1N0 alc a C, 70.46; H, 6.96; N, 4.83 Found C, 70.35; H, 7.12; N, 5.02 Example 3 ~T-Pivalo~rl-L-Phenylalanxlchloromethylketone 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: C 1 gH2~CIN02 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-chlorometl~l-2-tertbu~yloxazole The title 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 Si02 "flash" Chromatography.
Elemental Ana~rsis for: C15H18C1N0 ula C, 68.30; H, 6.88; N, 5.31 Found: C, 68.52; H, 7.02; N, 5.42 Example 5 ~I-Benzoyl-L-Phenylalan~ylchlorometh ketone 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 Anal3rsis for: C 1~H 16CIN02 cul C, 67.66; H, 5.34; N, 4.64 un : C. 67.55; H, 5.30; N, 4.54 Example 6 4-Benzyl-5-chloromethyl-2-phenvloxazole 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 Si02 "flash" Chromatography.
Elemental Analysis for: C~~H14C1N0 alc ate : C, 71.96; H, 4.97; N, 4.94 Found: C, 72.25; H, 5.15; N, 5.23 Example 7 ht-Cyclohexaneacetyl-L-Phen~lalanvlchloromethxlketone 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 Anal~rsis for: C18H24C1N02 Calcul t~: C, 67.17; H, 7.52; N, 4.35 Found: C, 67.35; H, 7.50; N, 4.51 Example 8 4-Benzvl-5-chlorometh~l-2-~clohe ~lmethyloxazole The title compound was prepared using N-cyclohexaneacetyl-Irphenylalanyl-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 Si02 "flash"
Chromatography.
Elemental Anai_ysis for: C1gH22C1N0 Calculated: C, 71.16; H, 7.30; N, 4.61 Found C, 71.23; H, 7.45; N, 4.65 Example 9 1~-(4-Bend-2-cyclohexvl-oxazol-5-ylmethyll 4-(2-methoxy-nhen~pineridine 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 CH2C12 (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 by "flash" chromatography over silica gel ( 1 % MeOH/CHC13) 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 titled compound as a white crystalline solid.
mp 170-171 °C
Elemental Analysis for: C29H36N202 1.OC4H404 cul C, 70.69; H, 7.19; N, 5.00 pun : C, 70.41; H, 7.18; N, 4.96 Example 10 2-l4-Benzvl-2-cyclohe~l-oxazol-S~imethyl) 2 3.4 9-tetrahydro-1H-~vridoj3.4-blindole A suspension of 1,2,3,4-tetrahydro-9H-pyrido(3,4-B)indole (O.I72 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 mI), 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/CHCI3) 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 titled compound as an off white crystalline solid.
mp 200-201 °C
Elemental An~rsis for: C2gH31N30 O.SC4H404 al la C, 74.51; H, 6.88; N, 8.69 Found: C, 74.28; H, 6.91; N, 8.59 Example 11 1-l4-Benzyl-2-tert-butt']-oxazol-5 xlmethyll-4-(2-methox~r-phenyl)-Ri_peridine 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 CH2C12 (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 (0.4 g) purified by "flash"
chromatography over silica gel ( 1 % MeOH/CHC13) to afford a colorless oil (0.32 g , 76% yield). An ethanolic solution of the product was treated with 1 equivalent of etheral HCl to afford the titled compound as a white crystalline solid.
Elemental Anah sir s for: C2~Hg4N202 1.OHC1 al a d: C, 71.27; H, 7.75; N, 6.16 Found: C, 71.45; H, 7.98; N, 6.36 Example 12 2 (4 Benzy~-2-cyclohexylmethyl-oxazol-5-ylmethvl)-2,,3 4 9-tetrahydro-1H-,~vridoJ~3,4-blindole A suspension of 1,2,3,4-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 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 (0.299 g, 68% yield). An ethanolic solution of the product was treated with etheral HCl to afford the titled compound as an off white crystalline sofid.
elemental Analysis for: C29H33N30 1.OHC1 Calculated: C, 73.17; H, 7.20; N, 8.83 Found: C, 73.28; H, 7.41; N, 8.89
Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0. l, 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 amity for the S-HT 1 A 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 can~iers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium 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 Garner 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.
_g_ The following non-limiting examples illustrate the preparation of representative compounds of this invention.
Example 1 N-Cyclohexanoyl-L-Phenylalanylchloromethvlketone A cooled (-10°C) mixture containing L-phenylalanylchloromethylketone (3.2 mmole) in CH2CI2 (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 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: C ~ ~H22C1N02 Calculated: C, 66.33; H, 7.20; N, 4.55 15 F un : C, 66.12; H, 7.12; N, 4.34 Example 2 4-Benzvl-5-chloromethvl-2-cvclohexyloxazole 20 Under a nitrogen atmosphere, a benzene solution (26 ml) of the chloromethyllcetone (2.6 mmole) from example 1 was treated with dimethyiformamide (2 ml) and phosphorous oxychloride (26 mmole). The mixture was heated to reflux for 1 S
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: Cl~H2pC1N0 alc a C, 70.46; H, 6.96; N, 4.83 Found C, 70.35; H, 7.12; N, 5.02 Example 3 ~T-Pivalo~rl-L-Phenylalanxlchloromethylketone 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: C 1 gH2~CIN02 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-chlorometl~l-2-tertbu~yloxazole The title 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 Si02 "flash" Chromatography.
Elemental Ana~rsis for: C15H18C1N0 ula C, 68.30; H, 6.88; N, 5.31 Found: C, 68.52; H, 7.02; N, 5.42 Example 5 ~I-Benzoyl-L-Phenylalan~ylchlorometh ketone 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 Anal3rsis for: C 1~H 16CIN02 cul C, 67.66; H, 5.34; N, 4.64 un : C. 67.55; H, 5.30; N, 4.54 Example 6 4-Benzyl-5-chloromethyl-2-phenvloxazole 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 Si02 "flash" Chromatography.
Elemental Analysis for: C~~H14C1N0 alc ate : C, 71.96; H, 4.97; N, 4.94 Found: C, 72.25; H, 5.15; N, 5.23 Example 7 ht-Cyclohexaneacetyl-L-Phen~lalanvlchloromethxlketone 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 Anal~rsis for: C18H24C1N02 Calcul t~: C, 67.17; H, 7.52; N, 4.35 Found: C, 67.35; H, 7.50; N, 4.51 Example 8 4-Benzvl-5-chlorometh~l-2-~clohe ~lmethyloxazole The title compound was prepared using N-cyclohexaneacetyl-Irphenylalanyl-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 Si02 "flash"
Chromatography.
Elemental Anai_ysis for: C1gH22C1N0 Calculated: C, 71.16; H, 7.30; N, 4.61 Found C, 71.23; H, 7.45; N, 4.65 Example 9 1~-(4-Bend-2-cyclohexvl-oxazol-5-ylmethyll 4-(2-methoxy-nhen~pineridine 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 CH2C12 (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 by "flash" chromatography over silica gel ( 1 % MeOH/CHC13) 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 titled compound as a white crystalline solid.
mp 170-171 °C
Elemental Analysis for: C29H36N202 1.OC4H404 cul C, 70.69; H, 7.19; N, 5.00 pun : C, 70.41; H, 7.18; N, 4.96 Example 10 2-l4-Benzvl-2-cyclohe~l-oxazol-S~imethyl) 2 3.4 9-tetrahydro-1H-~vridoj3.4-blindole A suspension of 1,2,3,4-tetrahydro-9H-pyrido(3,4-B)indole (O.I72 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 mI), 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/CHCI3) 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 titled compound as an off white crystalline solid.
mp 200-201 °C
Elemental An~rsis for: C2gH31N30 O.SC4H404 al la C, 74.51; H, 6.88; N, 8.69 Found: C, 74.28; H, 6.91; N, 8.59 Example 11 1-l4-Benzyl-2-tert-butt']-oxazol-5 xlmethyll-4-(2-methox~r-phenyl)-Ri_peridine 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 CH2C12 (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 (0.4 g) purified by "flash"
chromatography over silica gel ( 1 % MeOH/CHC13) to afford a colorless oil (0.32 g , 76% yield). An ethanolic solution of the product was treated with 1 equivalent of etheral HCl to afford the titled compound as a white crystalline solid.
Elemental Anah sir s for: C2~Hg4N202 1.OHC1 al a d: C, 71.27; H, 7.75; N, 6.16 Found: C, 71.45; H, 7.98; N, 6.36 Example 12 2 (4 Benzy~-2-cyclohexylmethyl-oxazol-5-ylmethvl)-2,,3 4 9-tetrahydro-1H-,~vridoJ~3,4-blindole A suspension of 1,2,3,4-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 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 (0.299 g, 68% yield). An ethanolic solution of the product was treated with etheral HCl to afford the titled compound as an off white crystalline sofid.
elemental Analysis for: C29H33N30 1.OHC1 Calculated: C, 73.17; H, 7.20; N, 8.83 Found: C, 73.28; H, 7.41; N, 8.89
Claims (19)
1. A compound of Formula 1 having the structure 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 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.
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 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 1-(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 1-(4-benzyl-2-cyclohexyloxazol-5-ylmethyl)-4-(2-methoxy-phenyl)-piperidine fumarate.
6. The compound according to claim 1, which is 2-(4-benzyl-2-cyclohexyl-oxazol-5-ylmethyl)-2,3,4,9-tetrahydro-1H-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-1H-pyrido[3,4-b]indole fumarate.
8. The compound according to claim 1, which is 1-(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 1-(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-1H-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-1H-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 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 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.
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 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.
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 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 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.
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 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.
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 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 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.
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 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 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 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.
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 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-1A (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, 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) wherein X, R1, 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) wherein X and the dotted line are as defined in claim 1 with a compound of formula (4) wherein R2 and R3 are as defined in claim 1 to give a compound of formula (1).
a) reacting a compound of formula (8) wherein X, R1, 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) wherein X and the dotted line are as defined in claim 1 with a compound of formula (4) wherein R2 and R3 are as defined in claim 1 to give a compound of formula (1).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1751798A | 1998-02-03 | 1998-02-03 | |
| US09/017,517 | 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 |
|---|---|
| CA2317515A1 true CA2317515A1 (en) | 1999-08-05 |
Family
ID=21783033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002317515A Abandoned CA2317515A1 (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) |
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 (en) * | 2001-01-29 | 2003-11-19 | Otsuka Pharma Co Ltd | RECEIVER SUBTIPE AGONIST 5-HT 1A. |
| 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 |
| AR033485A1 (en) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME |
| US7820674B2 (en) * | 2005-01-19 | 2010-10-26 | Merck, Sharp & Dohme Corp. | 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 |
| CN105829297B (en) * | 2013-12-20 | 2019-08-09 | 埃斯蒂文制药股份有限公司 | The active piperidine compounds of multiplex mode with anti-pain |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02167280A (en) * | 1988-08-15 | 1990-06-27 | Glaxo Group Ltd | Lactam derivative |
| 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 AU AU25753/99A patent/AU2575399A/en not_active Abandoned
- 1999-02-02 EP EP99905632A patent/EP1053235A1/en not_active Withdrawn
- 1999-02-02 WO PCT/US1999/002210 patent/WO1999038864A1/en not_active Application Discontinuation
- 1999-02-02 JP JP2000529332A patent/JP2002501920A/en active Pending
- 1999-02-02 CN CN99802651A patent/CN1289333A/en active Pending
- 1999-02-02 CA CA002317515A patent/CA2317515A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP1053235A1 (en) | 2000-11-22 |
| WO1999038864A1 (en) | 1999-08-05 |
| AU2575399A (en) | 1999-08-16 |
| JP2002501920A (en) | 2002-01-22 |
| CN1289333A (en) | 2001-03-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |