AU2002237654A1 - Piperazine derivatives, their preparation and their use for treating central nervous system (CNS) disorders - Google Patents
Piperazine derivatives, their preparation and their use for treating central nervous system (CNS) disordersInfo
- Publication number
- AU2002237654A1 AU2002237654A1 AU2002237654A AU2002237654A AU2002237654A1 AU 2002237654 A1 AU2002237654 A1 AU 2002237654A1 AU 2002237654 A AU2002237654 A AU 2002237654A AU 2002237654 A AU2002237654 A AU 2002237654A AU 2002237654 A1 AU2002237654 A1 AU 2002237654A1
- Authority
- AU
- Australia
- Prior art keywords
- compound
- patient
- pharmaceutically acceptable
- need
- effective amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Description
SEROTONERGIC AGENTS
FIELD OF THE INVENTION This invention relates to novel piperazine derivatives, to their use and to pharmaceutical compositions containing them. The novel compounds are useful as 5- HT^ A binding agents, particularly as 5-HT-JA receptor antagonists.
BACKGROUND U.S. Patent No. 6,127,357 discloses compounds of the general formula (I):
(I) and pharmaceutically acceptable acid addition salts thereof wherein: A is alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups,
Z is oxygen or sulfur, R is H or lower alkyl,
R1 is a mono or bicyclic aryl or heteroaryl radical,
R2 is a mono or bicyclic heteroaryl radical, and R3 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyI, a group of formula -NR4R5 [where
R4 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R^ is hydrogen, lower alkyl, -CO(lower)alkyl, aryl, -Coaryl, aryl(lower)alkyl, cycloalkyl, or cycloalkyl-(lower)alkyl or
R4 and R^ together with the nitrogen atom to which they are both attached represent a saturated hytrocyclic ring which may contain a further heteroatom], or a group of formula OR^ [where R^ is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].
WO 97/03982 discloses compounds of the general formula (II):
(ID including enantiomers and the pharmaceutically acceptable acid addition salts thereof.
The compounds of formula (II) fall within the disclosure of U.S. Patent No. 6,127,357 but are not specifically disclosed therein. Compounds of Formula II were taught to have potent 5-HT-(A antagonist activity in vivo when administered by the oral route.
DETAILED DESCRIPTION OF THE INVENTION
Novel compounds of the invention have the structural formula (111):
(III)
wherein R- is cyano, nitro, trifiuoromethyl or halogen, or pharmaceutically acceptable acid addition salts thereof.
Halogen, as used herein, refers to chlorine, fluorine, bromine and iodine.
The compounds of Formula III contain an asymmetric carbon atom. Accordingly, they may exist in different stereoisomeric forms or mixtures thereof
including racemates. In some preferred embodiments the R stereoisomer (Formula Ilia) is preferred.
Formula Ilia
In accordance with some embodiments of the invention, the (R) stereoisomer is in enantiomeric excess of the (S) stereoisomer. Preferably the compound is made up of a significantly greater proportion of its (R) stereoisomer than the (S) stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of its (R) stereoisomer and about 10% by weight or less of its (S) stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of its (R) stereoisomer and about 1 % by weight or less of the (S) stereoisomer, e.g. substantially free from (S)-stereoisomer, most preferably substantially pure or pure (R) stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. See, for example, Jacques, et al., Enantiomers. Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
The most preferred compounds of the invention are (R)-4-Cyano-N-{2-[4-(2,3- dihydro-benzo[1 ,4]dioxin-5-yl)-piperazin-1 -yl]propyl}-N-pyridin-2-yl-benzamide; and pharmaceutically acceptable acid addition salts thereof.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as, for example, benzoic, phosphoric, sulfuric, hydrochloric,
hydrobromic, citric, maleic, malic, mandelic, mucic, nitric, fumaric, succinic, tartaric, acetic, lactic, pamoic, pantothenic, benzenesulfonic, or methanesulfonic acid. In some embodiments of the invention the preferred acid addition salt is hydrochloric acid.
The compounds of the present invention can be prepared by known methods from known starting materials which are available by conventional methods. For example the compounds may be prepared by the general methods disclosed in EP-A-
0512755 and WO 97/03982. Accordingly this invention provides a process for preparing a compound of formula (III) which comprises one of the following:
a) acylating a compound of formula (IV):
using an acylating agent containing the moiety
wherein Ri is as defined herein;
or b) alkylating an amide or thioamide of formula (VI)
(where R-i is defined above) with an alkylating agent (e.g halide or tosylate) providing the group of formula (VII)
(VII) or c) alkylating a compound of formula (VIII
(VIII) with a compound of formula (IX)
(IX) (where R-j is as defined above and X is a leaving group) or d) heteroarylating a compound of formula (X)
(X)
(where R-i is as defined above) with a compound providing the 2-pyridyl group;
or e) reacting a piperazine compound of formula
(where R-, is as defined above) with a fluoro compound of formula
or f) converting a basic compound of formula (III) as defined herein to a pharmaceutically acceptable acid addition salt thereof or vice versa;
or g) resolving a racemic compound of formula (III) to give an enantiomeric excess of the R form over the S form, or vice versa.
Such disclosed methods include acylating an amine of formula (IV) with a known benzoyl chloride (V) or an alternative acylating derivative thereof. Examples of acylating derivatives include the acid anhydride, imidazolides (e.g. obtained form carbonyldiimidazole), or activated esters.
wherein R-i is cyano, halogen, trifiuoromethyl or nitro.
Novel compounds of the present invention are potent 5-HT-JA binding agents which selectively bind to the 5-HT-IA receptor. Furthermore, the novel compounds of the invention are 5-HT-IA receptor antagonists when tested by standard pharmacological procedures.
In addition, the novel compounds of formula (III) are unique from previously disclosed 5HT1A receptor antagonists in that they possess a superior duration of action as a 5-HT-] A receptor antagonist when administered in vivo.
EXAMPLES
The present invention is illustrated by reference to the following example. Those skilled in the art of organic synthesis may be aware of still other synthetic routes to the invention compound. The reagents and intermediates used herein are either commercially available or prepared according to standard literature procedures.
EXAMPLE 1
(R)-4-Cyano-N-{2-[4-(2,3-Dihydro-Benzo[1,4]dioxin-5-yl)-Piperazin-1-yl]-
Propyl}-N-Pyridin-2-yl-Benzamide A solution of {(R)-2-[4-(2,3-dihydrobenzo[1 ,4]dioxin-5-yl)piperazin-1-yl]propyl}-pyridin- 2-ylamine (0.846 g, 2.38 mmol) in dichloromethane (20 mL) was treated at 0°C with the dropwise addition of a dichloromethane solution of 4-cyanobenzoyl chloride (1.1 equivalents, 2.63 mmol in 5 mL). After stirring for 16 hours the mixture was poured onto hexane (100 mL) to precipitate the titled compound as its mono- hydrochloride salt (white solid, 1.2 g, 97% yield), which was recrystallized from dichloromethane/- hexane.
MS (+) 484 (M + H)+. m.p. 239-240 °C [α] 25/D = + 56 (c = 0.6, MeOH) Elemental Analysis for:
• 1.0 HCI Calculated: C, 64.67; H, 5.81 ; N, 13.47: Found: C, 64.69; H, 5.93; N, 13.52:
In order to demonstrate the superior duration of action of the compounds of formula (III), Example 1 was compared to representative compounds of U.S. Patent No. 6,127,357 and WO 97/03892.
Representative compounds of U.S. Patent No. 6,127,357 possess a cyclohexylamide moiety and a 2-methoxyphenylpiperazine grouping. The most potent example of this general structure (and the most potent compound taught in U.S. Patent No. 6,127,357) is compound A, described as "example 3" in U.S. 6,127,357. The only other class of compounds in U.S. 6,127,357 for which data are given is that which possess a cyclohexylamide moiety and a benzodioxinylpiperazine grouping ("Example 17" in U.S. 6,127,357). A small subset of this class of compounds is specifically claimed in WO97/03892, with the preferred compound being compound B ("example A1" in WO97/03892). Therefore, these two preferred examples from EP-A-0512755 and WO 97/03892 have been chosen as representatives for comparison to the compounds of formula (III).
Compound A Compound B ("Example 3" from U.S. 6,127357) ("Example A1" from WO 97/03892)
EXAMPLE 2 BINDING PROFILE
Compounds were tested for binding to cloned human 5-HT-IA receptors stably transfected into CHO cells using [3H]8-OH-DPAT as the 5-HT<IA radioligand (according to general procedure described in J. Dunlop et al., J. Pharmacol. Tox. Methods, 40, 47-55 (1998)). As shown in Table 1 , compounds of the present invention display high affinity for the 5HT1 A receptor.
EXAMPLE 3
IN VITRO FUNCTIONAL ACTIVITY
A clonal cell line stably transfected with the human 5-HT-IA receptor was utilized to determine the intrinsic activity of compounds (according to the general procedure described in J. Dunlop et al., J Pharmacol. Tox. Methods, 40, 47-55 (1998)). Data are provided in Table 1. As shown in Table 1 , compounds of the present invention antagonized the ability of 10 nM 8-OH-DPAT to inhibit forskolin- stimulated cAMP production in a concentration-related fashion.
Table 1
EXAMPLE 4
IN VIVO FUNCTIONAL ACTIVITY The ability of the compounds to function in vivo as 5-HT^A antagonists was assessed in rats using a Fixed Responding Model (D. Blackman, in "Operant Conditioning: An Experimental Analysis of Behavior", J. Butcher, ed., Methuen and Co., Ltd., London). In this model rats are trained to respond (lever pressing) under a fixed-ratio 30 schedule of food presentation in order to receive a food pellet reinforcer. Administration of the 5-HT<|A agonist 8-OH-DPAT reduces the control response rate (assessed by administration of vehicle placebo). The 5-HT-IA antagonist activity of a test compound is determined by measuring its ability to antagonize this agonist- induced decrease in response rate. A full antagonist effect is considered one in which the test compound completely reverses the agonist-induced response rate, returning it to control levels. The data given in Table 2 demonstrate that a 1 mg/kg dose of the compound of Example 1 completely reverses the decrease in response rate induced
by administration of a 0.3 mg/kg dose of 8-OH-DPAT. Thus, compounds of the present invention function as 5-HT-| A antagonists in vivo.
EXAMPLE 5
DURATION OF ACTION IN VIVO
The duration of action in the Fixed Responding Model was assessed by pre- treating animals with test compound and then challenging with a 0.3 mg/kg dose of the 5-HT-IA agonist 8-OH-DPAT at various time intervals after the administration of test compound. All drug and vehicle administrations were made by the subcutaneous route. Doses of the test compounds selected for comparison were those which caused a ten-fold shift in the 8-OH-DPAT dose-response curve when administered 30 minutes prior to agonist. The doses selected for the duration of action comparison are listed in Table 3.
Data are presented for pre-treatment of the animals with test compound at 0.5 hours, 2 hours, and 4 hours prior to administration of a 0.3 mg/kg dose of 8-OH- DPAT. Results are normalized to control values, with 100% being the control response rate observed when vehicle is administered rather than the agonist 8-OH- DPAT.
Table 4
As can be seen from Table 4, all three test compounds (Compound A, B and Example 1) completely antagonize the agonist-induced decrease in responding 30 minutes after their administration, returning the response rate to control levels. However, when agonist is given 2 hours following test drug administration (Column 3), the 5-HT-jA antagonist effects of compounds A and B no longer return the response rate to control levels while Example 1 still displays complete 5-HTIA antagonist effects. By four hours post-administration (Column 4), the 5-HT-IA antagonist effects of Compounds A and B are completely lost, while Example 1 continues to provide complete antagonism of the agonist-induced decrease in response rate. Thus, the duration of action of Example 1 is longer than 4 hours, while those of Compounds A and B are somewhere between 30 minutes and 2 hours.
The increased duration of action of the novel compounds of the present invention, compared to that of the classes of compounds disclosed in U.S. Patent No. 6,127,357 and WO 97/03892 is particularly advantageous in that a smaller number of doses of the compound can be administered to produce a similar therapeutic effect.
Compounds of the present invention may be used to treat a subject suffering from CNS disorders such as schizophrenia, (and other psychotic disorders such as paranoia and mano-depressive illness), Parkinson's disease and other motor
disorders, anxiety (e.g. generalized anxiety disorders, panic attacks, and obsessive compulsive disorders), depression (such as by the potentiation of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors), Tourette's syndrome, migraine, autism, attention deficit disorders and hyperactivity disorders. Compounds of the present invention may also be useful for the treatment of sleep disorders, social phobias, pain, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke, eating disorders such as for example obesity, anorexia and bulimia, sexual dysfunction, and the treatment of alcohol, drug and nicotine withdrawal.
Compounds of the present invention are also useful for the treatment of cognitive dysfunction. Thus, compounds of the present invention may be useful for the treatment of cognitive dysfunction associated with mild cognitive impairment (MCI)) Alzheimer's disease and other dementias including Lewy Body, vascular, and post stroke dementias. Cognitive dysfunction associated with surgical procedures, traumatic brain injury or stroke may also be treated in accordance with the present invention. Further, compounds of the present invention may be useful for the treatment of diseases in which cognitive dysfunction is a co-morbidity such as, for example, Parkinson's disease, autism and attention deficit disorders.
"Provided", as used herein with respect to providing a compound or substance covered by this invention, means either directly administering such a compound or substance, or administering a prodrug, derivative, or analog which will form an effective amount of the compound or substance within the body. Prodrugs can be prepared such as described in Design of Prodrugs. Bundgaard, H. ed., (Elsevier, New York 1985); Prodrugs as Novel Drug Delivery Systems, Higuchi, T and Stella, V. eds, (American Chemical Society, Washington, D.C. 1975); Design of Biopharmaceutical Properties through Prodrugs and Analogs, Roche, E. ed., (American Pharmaceutical Association Academy of Pharmaceutical Sciences, Washington, D.C., 1977); and Metabolic Considerations in Prodrug Design, Balant, L.P. and Doelker, E. in Burger's Medicinal Chemistry amd Drug Discovery, Fifth Edition, Wolff, M., ed, Volume 1 , pages 949-982, (John Wiley &. Sons, Inc. 1995).
The compounds of the present invention may be administered orally or parentally, 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, tablet-disintegrating agents or encapsulating materials. 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 may 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 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 in liquid or solid composition form. Preferably, the pharmaceutical compositions containing the present compounds are in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dosages containing appropriate quantities of the active ingredients. The unit dosage forms can be packaged compositions, for example, packaged powders, vials,
ampoules, prefilled syringes or sachets containing liquids. Alternatively, 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 may be varied or adjusted by the physician and generally ranges from 0.5 mg to 750 mg, according to the specific condition(s) being treated and the size, age and response pattern of the patient.
The present invention may be embodied in other specific forms without departing from the spirit and essential attributes thereof and accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indicating the scope of the invention.
Claims (28)
- CLAIMS:A compound according to formula (III):(III) wherein R-i is cyano, nitro, trifiuoromethyl or halogen, or pharmaceutically acceptable acid addition salts thereof.
- 2. A compound of Claim 1 wherein R^ is cyano.
- 3. A compound which is 4-Cyano-N-{2-[4-(2,3-dihydro-benzo[1 ,4]dioxin-5- yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide, or its pharmaceutically acceptable acid addition salts.
- 4. A compound which is (R)-4-Cyano-N-{2-[4-(2,3-dihydro-benzo[1 ,4]- dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride.
- 5. A compound according to any one of Claims 1 to 4 in which the R- isomer is in enantiomeric excess of the S-isomer.
- 6. A compound according to any one of Claims 1 to 5 which is made up of about 90% or more by weight R-isomer and about 10% or less by weight S isomer.
- 7 A compound according to any one of Claims 1 to 5 which is made up of about 99% by weight R-isomer and about 1 % by weight S isomer.
- 8. A compound which is (R)-4-Cyano-N-{2-[4-(2,3-dihydro-benzo[1 ,4]- dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide, or its pharmaceutically acceptable acid addition salt, substantially free of its (S) stereoisomer.
- 9. A compound as claimed in any one of Claims 1 to 8 which is in the form of a salt with hydrochloric acid.
- 10. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9, and a pharmaceutically acceptable carrier or excipient.
- 11. A pharmaceutical composition comprising (R)-4-Cyano-N-{2-[4-(2,3- dihydro-benzo[1 ,4]dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide, or its pharmaceutically acceptable acid addition salt, substantially free of its (S) stereoisomer, and a pharmaceutically acceptable carrier or excipient.
- 12. A method of treating a patient suffering from a CNS disorder comprising providing to said patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 13. A method for treating anxiety or depression in a patient in need thereof, comprising providing to the patient in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 14. A method for treating schizophrenia in a patient in need thereof, comprising providing to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 15. A method for treating memory deficits or cognitive dysfunction in a patient in need thereof, comprising providing to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 16. A method for treating alcohol, nicotine and drug withdrawal in a patient in need thereof, comprising providing to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 17. A method for treating Parkinson's disease and motor disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 18. A method for treating migraine in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 19. A method for treating eating disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 20. A method for treating sexual dysfunction in a patient in need thereof, comprising administering to the patient an effective amount a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 21. A method for treating urinary incontinence in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 22. A method for treating stroke in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 23. A method for treating endocrine disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 24. A method for treating sleep disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 25 A method for treating attention deficit disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 26. A method for treating Tourette's syndrome, autism, social phobias, hyperactivity disorders or thermoregulatory disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound or pharmaceutically acceptable salt thereof as claimed in any one of Claims 1 to 9.
- 27. A compound as claimed in any one of claims 1 to 9 for use as a pharmaceutical.
- 28. A process for preparing a compound as claimed in claim 1 which comprises one of the following:a) acylating a compound of formula (IV):using an acylating agent containing the moietywherein Ri is as defined in claim 1 ; or b) alkylating an amide or thioamide of formula (VI)(VI)(where Ri is defined above) with an alkylating agent (e.g halide or tosylate) providing the group of formula (VII)(VII) or c) alkylating a compound of formula (VIII(VIII)with a compound of formula (IX)(IX)(where Ri is as defined above and X is a leaving group) or d) heteroarylating a compound of formula (X)(X)(where Ri is as defined above) with a compound providing the 2-pyridyl group; or e) reacting a piperazine compound of formula(where Ri is as defined above) with a fluoro compound of formulaor f) converting a basic compound of formula (III) as defined in Claim 1 to a pharmaceutically acceptable acid addition salt thereof or vice versa;or g) resolving a racemic compound of formula (III) to give an enantiomeric excess of the R form over the S form, or vice versa.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25330100P | 2000-11-28 | 2000-11-28 | |
US60/253,301 | 2000-11-28 | ||
US29781401P | 2001-06-13 | 2001-06-13 | |
US60/297,814 | 2001-06-13 | ||
PCT/US2001/043160 WO2002044142A2 (en) | 2000-11-28 | 2001-11-27 | Piperazine derivatives, their preparation and their use for treating central nervous system (cns) disorders |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2002237654A1 true AU2002237654A1 (en) | 2002-08-15 |
AU2002237654B2 AU2002237654B2 (en) | 2005-07-28 |
Family
ID=26943115
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU3765402A Pending AU3765402A (en) | 2000-11-28 | 2001-11-27 | Serotonergic agents |
AU2002237654A Ceased AU2002237654B2 (en) | 2000-11-28 | 2001-11-27 | Piperazine derivatives, their preparation and their use for treating central nervous system (CNS) disorders |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU3765402A Pending AU3765402A (en) | 2000-11-28 | 2001-11-27 | Serotonergic agents |
Country Status (25)
Country | Link |
---|---|
US (3) | US6469007B2 (en) |
EP (1) | EP1339406B1 (en) |
JP (1) | JP4198989B2 (en) |
KR (1) | KR100835552B1 (en) |
CN (1) | CN100352437C (en) |
AR (1) | AR035603A1 (en) |
AT (1) | ATE269078T1 (en) |
AU (2) | AU3765402A (en) |
BR (1) | BR0115609A (en) |
CA (1) | CA2428039C (en) |
DE (1) | DE60103927T2 (en) |
DK (1) | DK1339406T3 (en) |
EA (1) | EA005925B1 (en) |
ES (1) | ES2222401T3 (en) |
HK (1) | HK1057864A1 (en) |
HU (1) | HUP0400551A2 (en) |
IL (1) | IL156098A0 (en) |
MX (1) | MXPA03004677A (en) |
NO (1) | NO325501B1 (en) |
NZ (1) | NZ526150A (en) |
PL (1) | PL363219A1 (en) |
PT (1) | PT1339406E (en) |
TR (1) | TR200401546T4 (en) |
TW (1) | TWI224102B (en) |
WO (1) | WO2002044142A2 (en) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6432826B1 (en) * | 1999-11-29 | 2002-08-13 | Applied Materials, Inc. | Planarized Cu cleaning for reduced defects |
US20060223824A1 (en) * | 2000-11-28 | 2006-10-05 | Wyeth | Serotonergic agents |
US20060287335A1 (en) | 2000-11-28 | 2006-12-21 | Wyeth | Serotonergic agents for treating sexual dysfunction |
US7504395B2 (en) * | 2001-07-20 | 2009-03-17 | Psychogenics, Inc. | Treatment for attention-deficit hyperactivity disorder |
US7091349B2 (en) | 2002-03-12 | 2006-08-15 | Wyeth | Process for synthesizing N-aryl piperazines with chiral N′-1-[benzoyl(2-pyridyl)amino]-2-propane substitution |
IL163828A0 (en) | 2002-03-12 | 2005-12-18 | Wyeth Corp | Process for making chiral 1,4-disubstituted piperazines |
CA2477892C (en) | 2002-03-12 | 2010-11-23 | Gregg Brian Feigelson | Process for synthesizing chiral n-aryl piperazines |
US7361773B2 (en) | 2002-03-12 | 2008-04-22 | Wyeth | Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines |
GB0219961D0 (en) * | 2002-08-28 | 2002-10-02 | Pfizer Ltd | Oxytocin inhibitors |
WO2004082686A2 (en) * | 2003-03-13 | 2004-09-30 | Dynogen Pharmaceuticals, Inc. | Use of compounds with combined 5-ht1a and ssri activities to treat sexual dysfunction |
PA8626301A1 (en) * | 2004-03-19 | 2006-12-07 | Wyeth Wyeth | PROCESS TO PREPARE DERIVATIVES OF N-ARIL-PIPERAZINA |
US20050215561A1 (en) * | 2004-03-19 | 2005-09-29 | Krishnendu Ghosh | Pharmaceutical dosage forms and compositions |
US20070099931A1 (en) * | 2004-03-19 | 2007-05-03 | Wyeth | Pharmaceutical dosage forms and compositions |
KR100646337B1 (en) * | 2004-06-30 | 2006-11-23 | 주식회사 롯데기공 | Method for sensing a water leakage of a boiler |
US7572771B1 (en) * | 2004-10-15 | 2009-08-11 | The United States Of America As Represented By The Departments Of Health And Human Services | Multi-domain amphipathic helical peptides and methods of their use |
JP2008531694A (en) * | 2005-03-01 | 2008-08-14 | ワイス | Crystalline and amorphous 4-cyano-N-{(2R) -2- [4- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -piperazin-1-yl] -propyl } -N-pyridin-2-yl-benzamide hydrochloride |
TW200800959A (en) * | 2005-06-10 | 2008-01-01 | Wyeth Corp | Piperazine-piperidine antagonists and agonists of the 5-HT1a receptor |
MX2007015772A (en) * | 2005-06-17 | 2008-02-22 | Wyeth Corp | Tricyclic compounds useful as serotonin inhibitors and 5-ht1a agonists and antagonists. |
EP1993527A4 (en) * | 2006-01-26 | 2009-08-05 | Univ Rochester | Inhibiting amyloid-beta peptide/rage interaction at the blood-brain barrier |
TW200811144A (en) * | 2006-06-09 | 2008-03-01 | Wyeth Corp | Crystalline forms of 6-methoxy-8-[4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline |
TW200808741A (en) * | 2006-06-09 | 2008-02-16 | Wyeth Corp | 6-methoxy-8-[4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline hydrochloric acid salts |
TW200808740A (en) * | 2006-06-09 | 2008-02-16 | Wyeth Corp | Succinate salts of 6-methoxy-8-[4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline and crystalline forms thereof |
CL2007003410A1 (en) * | 2006-11-28 | 2008-04-11 | Wyeth Corp | COMPOUNDS DERIVED FROM 5-FLUORO-8- {4- [4- (6-METOXIQUINOLIN-8-IL) PIPERAZIN-1-IL] PIPERIDIN-1-IL} QUINOLINE; PREPARATION PROCEDURE; INTERMEDIARY COMPOUNDS; PREPARATION PROCEDURE; PHARMACEUTICAL COMPOSITION; AND USE IN THE TREATMENT OF TRAST |
CL2008000119A1 (en) * | 2007-01-16 | 2008-05-16 | Wyeth Corp | COMPOUNDS DERIVED FROM PIRAZOL, ANTAGONISTS OF THE NICOTINIC ACETILCOLINE RECEIVER; PHARMACEUTICAL COMPOSITION; AND USE IN THE TREATMENT OF DISEASES SUCH AS SENILE DEMENTIA, ALZHEIMER AND SCHIZOPHRENIA. |
US8936787B2 (en) * | 2008-04-15 | 2015-01-20 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Peptides promoting lipid efflux |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX9201991A (en) | 1991-05-02 | 1992-11-01 | Jonh Wyeth & Brother Limited | DERIVATIVES OF PIPERAZINE AND PROCEDURE FOR ITS PREPARATION. |
GB9514901D0 (en) | 1995-07-20 | 1995-09-20 | American Home Prod | Piperazine derivatives |
-
2001
- 2001-11-13 US US10/010,575 patent/US6469007B2/en not_active Expired - Fee Related
- 2001-11-27 AU AU3765402A patent/AU3765402A/en active Pending
- 2001-11-27 TW TW090129285A patent/TWI224102B/en not_active IP Right Cessation
- 2001-11-27 ES ES01986458T patent/ES2222401T3/en not_active Expired - Lifetime
- 2001-11-27 CN CNB018196853A patent/CN100352437C/en not_active Expired - Fee Related
- 2001-11-27 EA EA200300619A patent/EA005925B1/en not_active IP Right Cessation
- 2001-11-27 PL PL01363219A patent/PL363219A1/en not_active Application Discontinuation
- 2001-11-27 DK DK01986458T patent/DK1339406T3/en active
- 2001-11-27 DE DE60103927T patent/DE60103927T2/en not_active Expired - Lifetime
- 2001-11-27 PT PT01986458T patent/PT1339406E/en unknown
- 2001-11-27 AR ARP010105502A patent/AR035603A1/en not_active Application Discontinuation
- 2001-11-27 AU AU2002237654A patent/AU2002237654B2/en not_active Ceased
- 2001-11-27 EP EP01986458A patent/EP1339406B1/en not_active Expired - Lifetime
- 2001-11-27 TR TR2004/01546T patent/TR200401546T4/en unknown
- 2001-11-27 JP JP2002546512A patent/JP4198989B2/en not_active Expired - Fee Related
- 2001-11-27 BR BR0115609-8A patent/BR0115609A/en not_active Application Discontinuation
- 2001-11-27 NZ NZ526150A patent/NZ526150A/en unknown
- 2001-11-27 AT AT01986458T patent/ATE269078T1/en not_active IP Right Cessation
- 2001-11-27 KR KR1020037007064A patent/KR100835552B1/en not_active IP Right Cessation
- 2001-11-27 HU HU0400551A patent/HUP0400551A2/en unknown
- 2001-11-27 CA CA2428039A patent/CA2428039C/en not_active Expired - Fee Related
- 2001-11-27 IL IL15609801A patent/IL156098A0/en unknown
- 2001-11-27 WO PCT/US2001/043160 patent/WO2002044142A2/en active IP Right Grant
- 2001-11-27 MX MXPA03004677A patent/MXPA03004677A/en active IP Right Grant
-
2002
- 2002-08-14 US US10/218,251 patent/US6586436B2/en not_active Expired - Fee Related
-
2003
- 2003-05-20 US US10/441,536 patent/US7026320B2/en not_active Expired - Fee Related
- 2003-05-27 NO NO20032390A patent/NO325501B1/en not_active IP Right Cessation
-
2004
- 2004-02-04 HK HK04100730A patent/HK1057864A1/en not_active IP Right Cessation
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1339406B1 (en) | Piperazine derivatives, their preparation and their use for treating central nervous system (cns) disorders | |
AU2002237654A1 (en) | Piperazine derivatives, their preparation and their use for treating central nervous system (CNS) disorders | |
US7189713B2 (en) | Piperidine derivatives | |
BG64387B1 (en) | Halogensubstituted tetracyclic derivatives of tetrahydrofuran | |
IL124095A (en) | Indolealkyl derivatives of benzodioxanmethylamine | |
PL176051B1 (en) | Application of dimethylbezofuranes and dimethylbenzopyranes as antagonists of 5-ht 3 | |
US7816362B2 (en) | Serotonergic agents | |
JP2008509925A (en) | Novel serotonin receptor ligands and their use | |
WO2000049017A1 (en) | 1-((indoly azacycloalkyl) alkyl)-2,1, 3-benzothiadiazole 2,2-dioxides exhibiting 5-ht2a receptor activity | |
ZA200304994B (en) | Piperazine derivatives, their preparation and their use for treating central nervous systems (CNS) disorders. | |
JP2001512491A (en) | 1- (isoquinolin-1-yl) -4- (1-phenylmethyl) piperazine; a dopamine receptor subtype-specific ligand | |
MXPA05002740A (en) | Antidepressant cycloalkylamine derivatives of 2,3-dihydro-1,4-benzodioxan. | |
EP2438050B1 (en) | Novel derivatives of aryl-{4-halogeno-4-[aminomethyl]-piperidin-1-yl}-methanone, their method of preparation and their use as medicinal products | |
JP2002519350A (en) | 6- (4-arylalkylpiperazin-1-yl) benzodioxane and 6- (4-arylalkylpiperazin-1-yl) chroman derivatives: dopamine receptor subtype specific ligands | |
JP2015180608A (en) | Morphinan derivatives | |
JPWO2006121104A1 (en) | Crystals of indole derivatives having a piperidine ring and their production | |
ITMI961861A1 (en) | SPIRO-CONDENSED TETRACYCLIC DERIVATIVES | |
WO2010040808A1 (en) | Novel quinolinylamide derivatives useful as modulators of dopamine and serotonin receptors |