WO1996025387B1 - Alkylcarboxy amino acids-modulators of the kainate receptor - Google Patents
Alkylcarboxy amino acids-modulators of the kainate receptorInfo
- Publication number
- WO1996025387B1 WO1996025387B1 PCT/US1996/002227 US9602227W WO9625387B1 WO 1996025387 B1 WO1996025387 B1 WO 1996025387B1 US 9602227 W US9602227 W US 9602227W WO 9625387 B1 WO9625387 B1 WO 9625387B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compounds
- formula
- pharmaceutically acceptable
- independently
- Prior art date
Links
- 102000000079 Kainic Acid Receptors Human genes 0.000 title abstract 2
- 108010069902 Kainic Acid Receptors Proteins 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract 16
- 239000011780 sodium chloride Substances 0.000 claims abstract 6
- 150000003839 salts Chemical class 0.000 claims abstract 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract 4
- -1 class of alkyl carboxy amino acid Chemical class 0.000 claims abstract 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract 3
- 150000002367 halogens Chemical class 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 2
- VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- 230000000051 modifying Effects 0.000 claims 1
- 239000003921 oil Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N Kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 abstract 2
- 230000004913 activation Effects 0.000 abstract 2
- 229950006874 kainic acid Drugs 0.000 abstract 2
- 102000005962 receptors Human genes 0.000 abstract 2
- 108020003175 receptors Proteins 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 239000000774 AMPA receptor agonist Substances 0.000 abstract 1
- 108091005504 Cation channels Proteins 0.000 abstract 1
- 206010057668 Cognitive disease Diseases 0.000 abstract 1
- 229960002989 Glutamic Acid Drugs 0.000 abstract 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract 1
- 235000001014 amino acid Nutrition 0.000 abstract 1
- 230000003042 antagnostic Effects 0.000 abstract 1
- 239000005557 antagonist Substances 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 230000002708 enhancing Effects 0.000 abstract 1
- 235000013922 glutamic acid Nutrition 0.000 abstract 1
- 239000004220 glutamic acid Substances 0.000 abstract 1
- 230000001057 ionotropic Effects 0.000 abstract 1
- 239000002909 kainic acid receptor agonist Substances 0.000 abstract 1
- 230000003924 mental process Effects 0.000 abstract 1
- 230000000626 neurodegenerative Effects 0.000 abstract 1
- 230000000926 neurological Effects 0.000 abstract 1
- 230000003557 neuropsychological Effects 0.000 abstract 1
Abstract
Compounds of a class of alkyl carboxy amino acid analogs of glutamic acid according to formula I act as specific regulators of kainic acid EAA receptor cation channel, wherein R1 is 1) CH¿3?, or 2) halogen; R?2 and R3¿ are independently 1) H, 2) C1-C6-alkyl, 3) C3-C4-alkenyl, 4) C3-C5-cycloalkyl, 5) C1-C6-alkyl-CO-, 6) C1-C6-alkyl-OCO-, 7) C1-C6-alkyl-NHCO-, 8) CHO-, or 9) C3-C6-alkynyl; R?2 and R3¿ taken together can be -CH¿2?(CH2)pCH2-; p is 0, 1, 2 or 3; and pharmaceutically acceptable salts of these compounds, but not including compounds of Formula I wherein R?2 and R3¿ are H and R1 is CH¿3 or R?1 is F. These compounds are useful for treating neurological, neuropsychological, neuropsychiatric, neurodegenerative, neuropsychopharmacological and functional disorders associated with excessive or insufficient activation of the kainic acid subtype of the ionotropic EAA receptors; treating cognitive disorders associated with deactivation, suboptimal activation or over-activation of the kainic acid receptor; alleviating pain and improving and enhancing memory, learning, and associated mental processes. A method for designing novel AMPA or kainic acid receptor agonists or antagonists is also disclosed.
Claims
1. Alkyl carboxy amino acid compounds having the following formula:
wherein: R1 is
1) CH3, or
2) halogen;
R2 and R3 are independently
1) H,
2) Cl - C6-alkyl,
3) C3 - C4-alkenyl,
4) C3 - C5-cycloalkyl,
5) Cl - C6-alkyl-CO-,
6) Cl - C6-alkyl-OCO-,
7) Cl - C6-alkyl-NHCO-,
8) CHO-, or
9) C3 - C6-alkynyl;
R2 and R3 taken together can be -CH2(CH2)PCH2- ; p is 0, 1, 2 or 3; and pharmaceutically acceptable salts of these compounds, but not including compounds of Formula I where R: and R3 are H and R1 is CH3 or R1 is F or Cl; or where one of R2 or R3 is CHO and the other of R2 or R3 is H and R1 is F. 4 6
2. The compounds of claim 1 of Formula I wherein: R1 is CH3;
R2 and R3 are independently
1) H,
2) Cl - C3-alkyl,
3) C3 - C4-alkenyl,
4) C3-cycloalkyl,
5) HCO-, or
6) CH3-(CH2)n-CO-;
R2 and R3 taken together can be -CH2(CH2)pCH2-; n is 0 or 1; p is 0, 1, 2 or 3; and pharmaceutically acceptable salts of these compounds; but not including compounds of Formula I where R2 and R3 are H and R1 is CH3 or R1 is F.
3. The compounds of claim 2 of Formula I wherein: R2 and R3 are independently
1) H,
2) Cl - C3-alkyl,
3) HCO-, or
4) CH3-CO-; and pharmaceutically acceptable salts of these compounds; but not including compounds of Formula I where R2 and R3 are H and R1 is CH3 or R1 is F.
4. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier for administration to a patient in need thereof.
5. The composition of claim 4 wherein the carrier is selected from the group consisting of water, oil, saline, an aqueous sugar solution, and a glycol. 47
6. A pharmaceutical composition comprising a compound selectively modulating ion flow through the Kainate ("KA") receptor in combination with a pharmaceutically acceptable carrier for administration to a patient in need thereof; wherein the compound is an alkyl carboxy amino acid compound having the following formula:
wherein: R1 is
1) CH3, or
2) halogen;
R2 and R3 are independently
1) H,
2) Cl - C6-alkyl,
3) C3 - C4-alkenyl, . 4) C3 - C5-cycloalkyl,
5) Cl - C6-alkyl-CO-,
6) Cl - C6-alkyl-OCO-,
7) Cl - C6-alkyl-NHCO-,
8) CHO-, or
9) C3 - C6-alkynyl;
R2 and R3 taken together can be -CH2(CH2)_CHr ; p is 0, 1 , 2 or 3; and pharmaceutically acceptable salts of these compounds.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96908476A EP0809624B1 (en) | 1995-02-15 | 1996-02-13 | Alkylcarboxy amino acids-modulators of the kainate receptor |
DE69614835T DE69614835T2 (en) | 1995-02-15 | 1996-02-13 | ALKYLCARBOXY-AMINO ACID MODULATORS FOR THE CAINATE RECEPTOR |
JP8525195A JPH11501619A (en) | 1995-02-15 | 1996-02-13 | Modulators of alkyl carboxy amino acid-kainate receptors |
AT96908476T ATE204852T1 (en) | 1995-02-15 | 1996-02-13 | ALKYLCARBOXY-AMINO ACID MODULATORS FOR THE KAINATE RECEPTOR |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US38991695A | 1995-02-15 | 1995-02-15 | |
US389,916 | 1995-02-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1996025387A1 WO1996025387A1 (en) | 1996-08-22 |
WO1996025387B1 true WO1996025387B1 (en) | 1996-10-17 |
Family
ID=23540296
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/002227 WO1996025387A1 (en) | 1995-02-15 | 1996-02-13 | Alkylcarboxy amino acids-modulators of the kainate receptor |
Country Status (7)
Country | Link |
---|---|
US (1) | US5731348A (en) |
EP (1) | EP0809624B1 (en) |
JP (1) | JPH11501619A (en) |
AT (1) | ATE204852T1 (en) |
CA (1) | CA2216648A1 (en) |
DE (1) | DE69614835T2 (en) |
WO (1) | WO1996025387A1 (en) |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE204852T1 (en) * | 1995-02-15 | 2001-09-15 | Bearsden Bio Inc | ALKYLCARBOXY-AMINO ACID MODULATORS FOR THE KAINATE RECEPTOR |
GB2346883B (en) * | 1996-09-02 | 2001-02-14 | Lilly Industries Ltd | GluR5 receptor binding assay |
JP2002513405A (en) * | 1997-02-28 | 2002-05-08 | ベアーズデン バイオ,インコーポレイテッド | Method for determining protein-ligand interaction by computer modeling |
EP0980358A4 (en) * | 1997-04-07 | 2001-02-07 | Lilly Co Eli | Pharmacological agents |
US6245521B1 (en) | 1999-03-03 | 2001-06-12 | Eli Lilly And Company | Assay for evaluating the affinity of compounds to the glutamate GluR5 receptor |
MXPA01010217A (en) | 1999-04-08 | 2005-09-08 | Johnson & Johnson | Anticonvulsant derivatives useful in treating chronic neurodegenerative disorders. |
CA2421507A1 (en) * | 2000-09-01 | 2002-03-07 | Karina Aprico | Screen for glutamate reuptake inhibitors, stimulators, and modulators |
CA2427819A1 (en) * | 2000-10-30 | 2002-05-23 | Xue-Feng Pei | Method for modulation, stimulation, and inhibition of glutamate reuptake |
WO2002055479A2 (en) * | 2000-10-30 | 2002-07-18 | Annovis, Inc. | Esters of alkylcarboxy amino acids as prodrugs of modulators of the kainate receptor |
MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
AR049646A1 (en) * | 2004-06-16 | 2006-08-23 | Janssen Pharmaceutica Nv | USEFUL SULFAMATE AND SULFAMIDE DERIVATIVES FOR THE TREATMENT OF EPILEPSY AND RELATED DISORDERS |
MY142329A (en) * | 2004-08-24 | 2010-11-15 | Janssen Pharmaceutica Nv | Novel benzo-fused heteroaryl sulfamide derivatives useful as anticonvulsant agents. |
US8283478B2 (en) * | 2005-05-20 | 2012-10-09 | Janssen Pharmaceutica Nv | Process for preparation of sulfamide derivatives |
US20070155824A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives for disease modification / epileptogenesis |
US8716231B2 (en) * | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
US20070155823A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives as neuroprotective agents |
US8492431B2 (en) * | 2005-12-19 | 2013-07-23 | Janssen Pharmaceutica, N.V. | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity |
US20070155827A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of depression |
US8497298B2 (en) * | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US8691867B2 (en) * | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US8937096B2 (en) * | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
US20070191451A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-heteroaryl sulfamide derivatives as neuroprotective agents |
US20070191460A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of Benzo-Heteroaryl Sulfamide Derivatives for the Treatment of Disease Modification / Epileptogenesis |
US20070191474A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of migraine |
JP2009537635A (en) * | 2006-05-19 | 2009-10-29 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Co-therapy for treatment of hemorrhoids |
US20090247616A1 (en) * | 2008-03-26 | 2009-10-01 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of anxiety |
US20090247617A1 (en) * | 2008-03-26 | 2009-10-01 | Abdel-Magid Ahmed F | Process for the preparation of benzo-fused heteroaryl sulfamates |
US8809385B2 (en) | 2008-06-23 | 2014-08-19 | Janssen Pharmaceutica Nv | Crystalline form of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide |
US8815939B2 (en) * | 2008-07-22 | 2014-08-26 | Janssen Pharmaceutica Nv | Substituted sulfamide derivatives |
WO2012090201A2 (en) | 2010-12-26 | 2012-07-05 | Carmel-Haifa University Economic Corp. | Methods of improving cognitive function |
CN115650881A (en) | 2022-09-06 | 2023-01-31 | 浙江医药股份有限公司新昌制药厂 | Process method for synthesizing quinolone compound intermediate by using microreactor |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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GB1057652A (en) * | 1963-01-16 | 1967-02-08 | Merck & Co Inc | Amino derivatives of amino acids |
DK146787A (en) * | 1987-03-23 | 1988-09-24 | Ferrosan | HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND USE |
US4904681A (en) * | 1987-12-01 | 1990-02-27 | G. D. Searle & Co. | D-cycloserine and its prodrugs as cognitive enhancers |
US5061721A (en) * | 1989-03-15 | 1991-10-29 | G. D. Searle & Co. | Composition containing d-cycloserine and d-alanine for memory and learning enhancement or treatment of a cognitive or psychotic disorder |
US5086702A (en) * | 1990-04-12 | 1992-02-11 | Atlas Powder Company | Modular blasting system |
US5364876A (en) * | 1992-12-02 | 1994-11-15 | Guilford Pharmaceuticals Inc. | Omega-[2-(alkyl)phenyl]-2-aminoalkanoic acids as antagonists of excitatory amino acid receptors |
AU6836394A (en) * | 1993-06-01 | 1994-12-20 | Cortex Pharmaceuticals, Inc. | Use of metabotropic receptor agonists in progressive neurodegenerative deseases |
ATE204852T1 (en) * | 1995-02-15 | 2001-09-15 | Bearsden Bio Inc | ALKYLCARBOXY-AMINO ACID MODULATORS FOR THE KAINATE RECEPTOR |
-
1996
- 1996-02-13 AT AT96908476T patent/ATE204852T1/en not_active IP Right Cessation
- 1996-02-13 WO PCT/US1996/002227 patent/WO1996025387A1/en active IP Right Grant
- 1996-02-13 US US08/600,330 patent/US5731348A/en not_active Expired - Fee Related
- 1996-02-13 EP EP96908476A patent/EP0809624B1/en not_active Expired - Lifetime
- 1996-02-13 CA CA002216648A patent/CA2216648A1/en not_active Abandoned
- 1996-02-13 JP JP8525195A patent/JPH11501619A/en active Pending
- 1996-02-13 DE DE69614835T patent/DE69614835T2/en not_active Expired - Fee Related
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